ESSENTIALS

ELSEVIER

JOHN E. BENNETT RAPHAEL DOLIN

MARTIN J. BLASER

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Mandell, Douglas, and Bennett’s

Infectious Disease ESSENTIALS

Mandell, Douglas, and Bennett’s

Infectious Disease ESSENTIALS

JOHN E. BENNETT, MD, MACPAdjunct Professor of Medicine

Uniformed Services University of the Health SciencesF. Edward Hebert School of Medicine

Bethesda, Maryland

RAPHAEL DOLIN, MDMaxwell Finland Professor of Medicine (Microbiology and Molecular Genetics)

Harvard Medical School;Attending Physician

Beth Israel Deaconess Medical Center;Brigham and Women’s Hospital

Boston, Massachusetts

MARTIN J. BLASER, MDMuriel G. and George W. Singer Professor of Translational Medicine

Professor of MicrobiologyDirector, Human Microbiome Program

Departments of Medicine and MicrobiologyNew York University School of Medicine

Langone Medical CenterNew York, New York

1600 John F. Kennedy Blvd.Ste 1800Philadelphia, PA 19103-2899

MANDELL, DOUGLAS, AND BENNETT’S INFECTIOUS DISEASE ESSENTIALS ISBN: 978-0-323-43101-9

Copyright © 2017 by Elsevier Inc. All rights reserved.

Chapters listed below are in public domain; therefore the copyright line for these chapters is: 2017 Published by Elsevier Inc.46: Foodborne Disease by Rajal K. Mody and Patricia M. Griffin77: Human Herpesvirus Types 6 and 7 (Exanthem Subitum) by Jeffrey I. Cohen79: Herpes B Virus by Jeffrey I. Cohen162: Yersinia Species (Including Plague) by Paul S. Mead204: Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes by Louis V. Kirchhoff205: Agents of African Trypanosomiasis (Sleeping Sickness) by Louis V. Kirchhoff217: Visceral Larva Migrans and Other Uncommon Helminth Infections by Theodore E. Nash224: Infections Caused by Percutaneous Intravascular Devices by Susan E. Beekmann and David K. Henderson228: Transfusion- and Transplantation-Transmitted Infections by Matthew J. Kuehnert and Sridhar V. Basavaraju

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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

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Library of Congress Cataloging-in-Publication DataNames: Bennett, John E. (John Eugene), 1933- , editor. | Dolin, Raphael, editor. | Blaser, Martin J., editor.Title: Mandell, Douglas, and Bennett’s infectious disease essentials / [edited by] John E. Bennett, Raphael Dolin,

Martin J. Blaser.Other titles: Infectious disease essentialsDescription: Philadelphia, PA : Elsevier, [2017]Identifiers: LCCN 2015048664 | ISBN 9780323431019 (paperback : alk. paper)Subjects: | MESH: Communicable Diseases | HandbooksClassification: LCC RA643 | NLM WC 39 | DDC 616.9–dc23 LC record available at http://lccn.loc.gov/2015048664

Senior Content Strategist: Suzanne ToppySenior Content Development Manager: Taylor BallPublishing Services Manager: Catherine JacksonBook Production Specialist: Kristine FeehertyDesign Direction: Renee Duenow

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

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Contributors

Fredrick M. Abrahamian, DOProfessor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Director of Education, Department of Emergency Medicine, Olive View–UCLA Medical Center, Sylmar, CaliforniaBites

Ban Mishu Allos, MDAssociate Professor, Departments of Medicine and Preventive Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeCampylobacter jejuni and Related Species

Michael A. Apicella, MDProfessor and Head, Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, IowaNeisseria meningitidis; Neisseria gonorrhoeae (Gonorrhea)

Kevin L. Ard, MD, MPHInstructor in Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, MassachusettsPulmonary Manifestations of Human Immunodeficiency Virus Infection

Cesar A. Arias, MD, MSc, PhDAssociate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas; Director, Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, ColombiaEnterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species

Michael H. Augenbraun, MDProfessor of Medicine, Chief, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New YorkGenital Skin and Mucous Membrane Lesions; Urethritis; Vulvovaginitis and Cervicitis

Francisco Averhoff, MD, MPHDivision of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus

Dimitri T. Azar, MD, MBADean and B.A. Field Chair of Ophthalmologic Research, Distinguished Professor of Ophthalmology, Pharmacology, and Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IllinoisMicrobial Conjunctivitis; Microbial Keratitis

Larry M. Baddour, MDProfessor of Medicine, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis

Carol J. Baker, MDProfessor of Pediatrics, Molecular Virology, and Microbiology, Department of Pediatrics, Infectious Diseases Section, Baylor College of Medicine; Attending Physician, Texas Children’s Hospital, Houston, TexasStreptococcus agalactiae (Group B Streptococcus)

Ronald C. Ballard, MSB, PhDAssociate Director for Laboratory Science, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GeorgiaKlebsiella granulomatis (Donovanosis, Granuloma Inguinale)

Scott D. Barnes, MDChief, Warfighter Refractive Eye Surgery Clinic, Womack Army Medical Center, Fort Bragg, North CarolinaMicrobial Conjunctivitis; Microbial Keratitis

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Dan H. Barouch, MD, PhDProfessor of Medicine, Harvard Medical School; Director, Center for Virology and Vaccine Research, Staff Physician, Beth Israel Deaconess Medical Center; Associate Physician, Brigham and Women’s Hospital, Boston, MassachusettsAdenoviruses

Alan D. Barrett, PhDDirector, Sealy Center for Vaccine Development, Professor, Departments of Pathology and Microbiology & Immunology, University of Texas Medical Branch, Galveston, TexasFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Miriam Baron Barshak, MDAssistant Professor of Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Massachusetts General Hospital, Boston, MassachusettsPancreatic Infection

Sridhar V. Basavaraju, MDCenters for Disease Control and Prevention, Atlanta, GeorgiaTransfusion- and Transplantation-Transmitted Infections

Byron E. Batteiger, MDProfessor of Medicine, Microbiology, and Immunology, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, IndianaChlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)

Stephen G. Baum, MDProfessor of Medicine, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, New YorkMumps Virus

Arnold S. Bayer, MDProfessor of Medicine, Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Associate Chief, Adult Infectious Diseases, Department of Internal Medicine, Harbor-UCLA Medical Center; Senior Investigator, St. John’s Cardiovascular Research Center, Los Angeles Biomedical Research Institute, Torrance, CaliforniaEndocarditis and Intravascular Infections

J. David Beckham, MDAssistant Professor, Departments of Medicine, Neurology, and Microbiology, Division of Infectious Diseases, Director, Infectious Disease Fellowship Training Program, Medical Director, Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, ColoradoEncephalitis

Susan E. Beekmann, RN, MPHUniversity of Iowa Carver College of Medicine, Iowa City, IowaInfections Caused by Percutaneous Intravascular Devices

Beth P. Bell, MD, MPHDirector, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus

John E. Bennett, MD, MACPAdjunct Professor of Medicine, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, MarylandChronic Meningitis

Dennis A. Bente, DVM, PhDAssistant Professor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TexasCalifornia Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirus Hemorrhagic Fevers

Elie F. Berbari, MDProfessor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis

Adarsh Bhimraj, MDHead, Section of Neurologic Infectious Diseases, Associate Program Director, Internal Medicine Residency Program, Cleveland Clinic, Cleveland, OhioCerebrospinal Fluid Shunt and Drain Infections

Alan L. Bisno, MDProfessor Emeritus, Department of Medicine, University of Miami Miller School of Medicine; Staff Physician, Miami Veterans Affairs Medical Center, Miami, FloridaNonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis

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Brian G. Blackburn, MDClinical Associate Professor, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford Hospital and Clinics, Stanford, CaliforniaFree-Living Amebae

Lucas S. Blanton, MDAssistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TexasRickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus)

Martin J. Blaser, MDMuriel G. and George W. Singer Professor of Translational Medicine, Professor of Microbiology, Director, Human Microbiome Program, Departments of Medicine and Microbiology, New York University School of Medicine, Langone Medical Center, New York, New YorkCampylobacter jejuni and Related Species; Helicobacter pylori and Other Gastric Helicobacter Species

Thomas P. Bleck, MDProfessor of Neurological Sciences, Neurosurgery, Medicine, and Anesthesiology, Rush Medical College; Associate Chief Medical Officer (Critical Care), Associate Vice President, Director, Laboratory of Electroencephalography and Evoked Potentials, Rush University Medical Center, Chicago, IllinoisRabies (Rhabdoviruses); Tetanus (Clostridium tetani); Botulism (Clostridium botulinum)

David A. Bobak, MDAssociate Professor of Medicine, Associate Chair for Clinical Affairs, Division of Infectious Diseases and HIV Medicine, Case Western Reserve University School of Medicine; Director, Traveler’s Healthcare Center, Chair, Health System Medication Safety and Therapeutics Committee, Staff Physician, Transplant Infectious Diseases Clinic, University Hospitals Case Medical Center, Cleveland, OhioNausea, Vomiting, and Noninflammatory Diarrhea

William Bonnez, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New YorkPapillomaviruses

John C. Boothroyd, MDProfessor of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CaliforniaToxoplasma gondii

Patrick J. Bosque, MDAssociate Professor, Department of Neurology, University of Colorado Denver School of Medicine; Neurologist, Department of Medicine, Denver Health Medical Center, Denver, ColoradoPrions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)

John Bower, MDAssociate Professor of Pediatrics, Northeast Ohio Medical University, Rootstown, OhioCroup in Children (Acute Laryngotracheobronchitis); Bronchiolitis

Robert W. Bradsher, Jr., MDEbert Professor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, ArkansasBlastomycosis

Kevin E. Brown, MD, MRCPConsultant Medical Virologist, Virus Reference Department, Public Health England, Microbiology Services, London, United KingdomHuman Parvoviruses, Including Parvovirus B19V and Human Bocaparvoviruses

Patricia D. Brown, MDProfessor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine; Corporate Vice President of Quality and Patient Safety, Detroit Medical Center, Detroit, MichiganInfections in Injection Drug Users

Barbara A. Brown-Elliott, MS, MT(ASCP)SMResearch Assistant Professor, Microbiology, Supervisor, Mycobacteria/Nocardia Laboratory, University of Texas Health Science Center, Tyler, TexasInfections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

Roberta L. Bruhn, MS, PhDStaff Scientist, Department of Epidemiology, Blood Systems Research Institute, San Francisco, CaliforniaHuman T-Lymphotropic Virus (HTLV)

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Amy E. Bryant, PhDResearch Career Scientist, Infectious Diseases Section, Veterans Affairs Medical Center, Boise, IdahoStreptococcus pyogenes

Eileen M. Burd, PhDAssociate Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine; Director, Clinical Microbiology, Emory University Hospital, Atlanta, GeorgiaOther Gram-Negative and Gram-Variable Bacilli

Jane C. Burns, MDProfessor of Pediatrics, University of California San Diego School of Medicine, La Jolla, CaliforniaKawasaki Disease

Larry M. Bush, MDAffiliated Associate Professor of Medicine, University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida; Affiliated Professor of Medicine, Charles E. Schmidt School of Medicine, Florida Atlantic University, Boca Raton, FloridaPeritonitis and Intraperitoneal Abscesses

Luz Elena Cano, PhDHead of Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas; Titular Professor, Microbiology School, Universidad de Antioquia, Medellín, ColombiaParacoccidioidomycosis

Charles C. J. Carpenter, MDProfessor of Medicine, Warren Alpert Medical School of Brown University; Attending Physician, Division of Infectious Diseases, Miriam Hospital, Providence, Rhode IslandOther Pathogenic Vibrios

Mary T. Caserta, MDProfessor of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New YorkPharyngitis; Acute Laryngitis

Elio Castagnola, MDInfectious Diseases Unit, Istituto Giannina Gaslini, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients

Richard E. Chaisson, MDProfessor of Medicine, Epidemiology, and International Health, Johns Hopkins University School of Medicine, Baltimore, MarylandGeneral Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)

Sharon C-A. Chen, MBBS, PhDClinical Associate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species

Anthony W. Chow, MDProfessor Emeritus, Department of Internal Medicine, Division of Infectious Diseases, University of British Columbia; Honorary Consultant, Department of Internal Medicine, Division of Infectious Diseases, Vancouver Hospital, Vancouver, British Columbia, CanadaInfections of the Oral Cavity, Neck, and Head

Jeffrey I. Cohen, MDChief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandIntroduction to Herpesviridae; Human Herpesvirus Types 6 and 7 (Exanthem Subitum); Herpes B Virus

Myron S. Cohen, MDYergin-Bates Eminent Professor of Medicine, Microbiology, and Epidemiology, Director, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash

Lawrence Corey, MDProfessor of Medicine and Laboratory Medicine, University of Washington School of Medicine; President and Director, Fred Hutchinson Cancer Research Center, Seattle, WashingtonHerpes Simplex Virus

Timothy L. Cover, MDProfessor of Medicine, Professor of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TennesseeHelicobacter pylori and Other Gastric Helicobacter Species

Kent B. Crossley, MD, MHAProfessor, Department of Medicine, University of Minnesota Medical School; Chief of Staff, Minneapolis Veterans Administration Healthcare System, Minneapolis, MinnesotaInfections in the Elderly

Clyde S. Crumpacker II, MDProfessor of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MassachusettsCytomegalovirus (CMV)

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Bart J. Currie, MBBS, DTM&HProfessor in Medicine, Department of Infectious Diseases, Royal Darwin Hospital; Global and Tropical Health Division, Menzies School of Health Research, Darwin, AustraliaBurkholderia pseudomallei and Burkholderia mallei: Melioidosis and Glanders

Erika D’Agata, MD, MPHAssociate Professor of Medicine, Brown University; Department of Medicine, Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode IslandPseudomonas aeruginosa and Other Pseudomonas Species

Inger K. Damon, MD, PhDAdjunct Clinical Faculty, Department of Medicine, Emory University School of Medicine; Director, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GeorgiaOrthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses

Rabih O. Darouiche, MDVA Distinguished Service Professor, Departments of Medicine, Surgery, and Physical Medicine and Rehabilitation, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TexasInfections in Patients with Spinal Cord Injury

Roberta L. DeBiasi, MDActing Chief, Division of Pediatric Infectious Diseases, Children’s National Medical Center; Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine; Principal Investigator, Center for Clinical and Translational Science, Children’s Research Institute, Washington, DCOrthoreoviruses and Orbiviruses; Coltiviruses and Seadornaviruses

George S. Deepe, Jr., MDProfessor, Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OhioHistoplasma capsulatum (Histoplasmosis)

Andrew S. Delemos, MDTransplant Hepatologist, Carolinas Healthcare System, Charlotte, North CarolinaViral Hepatitis

Gregory P. DeMuri, MDAssociate Professor, University of Wisconsin School of Medicine and Public Health; Attending Physician, American Family Children’s Hospital, Madison, WisconsinSinusitis

Robin Dewar, PhDPrincipal Scientist, Leidos Biomedical Research—Frederick, National Cancer Institute—Frederick, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection

James H. Diaz, MD, MPHTM, DrPHProfessor of Public Health and Preventive Medicine, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LouisianaIntroduction to Ectoparasitic Diseases; Lice (Pediculosis); Scabies; Myiasis and Tungiasis; Mites, Including Chiggers; Ticks, Including Tick Paralysis

Jules L. Dienstag, MDDean for Medical Education, Carl W. Walter Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, MassachusettsViral Hepatitis

Raphael Dolin, MDMaxwell Finland Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Attending Physician, Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital, Boston, MassachusettsZoonotic Paramyxoviruses: Nipah, Hendra, and Menangle; Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses

Michael S. Donnenberg, MDProfessor of Medicine, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MarylandEnterobacteriaceae

Gerald R. Donowitz, MDProfessor of Medicine and Infectious Diseases/International Health, Department of Medicine, University of Virginia, Charlottesville, VirginiaAcute Pneumonia

Philip R. Dormitzer, MD, PhDHead of U.S. Research, Global Head of Virology, Vice President, Novartis Vaccines, Cambridge, MassachusettsRotaviruses

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James M. Drake, MB BCh, MScProfessor of Surgery, University of Toronto Faculty of Medicine; Neurosurgeon-in-Chief and Harold Hoffman Shopper’s Drug Mart Chair in Pediatric Neurosurgery, Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, CanadaCerebrospinal Fluid Shunt and Drain Infections

J. Stephen Dumler, MDProfessor, Departments of Pathology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MarylandRickettsia typhi (Murine Typhus)

Herbert L. DuPont, MDProfessor and Director, Center for Infectious Diseases, University of Texas School of Public Health; Chief, Internal Medicine Service, Baylor St. Luke’s Medical Center; Professor and Vice Chairman, Department of Medicine, Baylor College of Medicine, Houston, TexasBacillary Dysentery: Shigella and Enteroinvasive Escherichia coli

David T. Durack, MB, DPhilConsulting Professor of Medicine, Duke University School of Medicine, Durham, North CarolinaProphylaxis of Infective Endocarditis

Marlene L. Durand, MDAssociate Professor of Medicine, Harvard Medical School; Physician, Infectious Disease Unit, Massachusetts General Hospital; Director, Infectious Disease Service, Massachusetts Eye and Ear Infirmary, Boston, MassachusettsEndophthalmitis; Infectious Causes of Uveitis; Periocular Infections

Paul H. Edelstein, MDProfessor of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine; Director of Clinical Microbiology, Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PennsylvaniaLegionnaires’ Disease and Pontiac Fever

Morven S. Edwards, MDProfessor of Pediatrics, Baylor College of Medicine; Attending Physician, Department of Pediatrics, Infectious Diseases Section, Texas Children’s Hospital, Houston, TexasStreptococcus agalactiae (Group B Streptococcus)

Richard T. Ellison III, MDProfessor, Departments of Medicine and Microbiology & Physiological Systems, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MassachusettsAcute Pneumonia

Timothy P. Endy, MD, MPHProfessor of Medicine, Division Chief of Infectious Diseases, Upstate Medical University, State University of New York, Syracuse, New YorkFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

N. Cary Engleberg, MDProfessor, Departments of Infectious Diseases and Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MichiganChronic Fatigue Syndrome

Hakan Erdem, MDDepartment of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul, TurkeyBrucellosis (Brucella Species)

Joel D. Ernst, MDProfessor, Departments of Medicine, Pathology, and Microbiology, New York University School of Medicine, New York, New YorkMycobacterium leprae (Leprosy)

Rick M. Fairhurst, MD, PhDChief, Malaria Pathogenesis and Human Immunity Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MarylandMalaria (Plasmodium Species)

Jessica K. Fairley, MDAssistant Professor of Medicine, Emory University School of Medicine, The Emory Clinic, Atlanta, GeorgiaTapeworms (Cestodes)

Ann R. Falsey, MDProfessor of Medicine, Infectious Diseases Unit, University of Rochester School of Medicine, Rochester, New YorkHuman Metapneumovirus

Thomas Fekete, MDProfessor of Medicine and Chief, Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PennsylvaniaBacillus Species and Related Genera Other Than Bacillus anthracis

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Paul D. Fey, PhDProfessor, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NebraskaStaphylococcus epidermidis and Other Coagulase-Negative Staphylococci

Steven M. Fine, MD, PhDAssociate Professor of Medicine, Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New YorkVesicular Stomatitis Virus and Related Vesiculoviruses

Daniel W. Fitzgerald, MDAssociate Professor of Medicine, Microbiology, and Immunology, Weill Cornell Medical College, New York, New YorkMycobacterium tuberculosis

Anthony R. Flores, MD, MPH, PhDAssistant Professor, Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, TexasPharyngitis

Derek Forster, MDSection on Infectious Diseases, Wake Forest School of Medicine, Winston-Salem, North CarolinaInfectious Arthritis of Native Joints

Vance G. Fowler, Jr., MD, MHSProfessor of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, North CarolinaEndocarditis and Intravascular Infections

David O. Freedman, MDProfessor of Medicine and Epidemiology, Gorgas Center for Geographic Medicine, Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine; Director, University of Alabama at Birmingham Travelers Health Clinic, University of Alabama at Birmingham Health System, Birmingham, AlabamaProtection of Travelers; Infections in Returning Travelers

Arthur M. Friedlander, MDAdjunct Professor of Medicine, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Senior Scientist, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MarylandBacillus anthracis (Anthrax)

John N. Galgiani, MDProfessor of Internal Medicine, Director, Valley Fever Center for Excellence, University of Arizona College of Medicine; Chief Medical Officer, Valley Fever Solutions, Tucson, ArizonaCoccidioidomycosis (Coccidioides Species)

Robert C. Gallo, MDDirector, Institute of Human Virology, Professor, Department of Medicine, University of Maryland School of Medicine, Baltimore, MarylandHuman Immunodeficiency Viruses

Tejal N. Gandhi, MDClinical Assistant Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, MichiganBartonella, Including Cat-Scratch Disease

Wendy S. Garrett, MD, PhDAssistant Professor, Immunology & Infectious Diseases and Genetic & Complex Diseases, Department of Medicine, Harvard School of Public Health; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MassachusettsGas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)

Charlotte A. Gaydos, DrPH, MPH, MSProfessor of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine; Emergency Medicine Department and Epidemiology, Population, Family and Reproductive Health, Bloomberg Johns Hopkins School of Public Health; Director, International Sexually Transmitted Diseases Research Laboratory, Baltimore, MarylandChlamydia pneumoniae

Thomas W. Geisbert, PhDProfessor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TexasMarburg and Ebola Hemorrhagic Fevers (Filoviruses)

Jeffrey A. Gelfand, MDClinical Professor of Medicine, Harvard Medical School; Attending Physician, Infectious Diseases Division, Massachusetts General Hospital, Boston, MassachusettsBabesia Species

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Dale N. Gerding, MDProfessor of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Research Physician, Department of Medicine, Edward Hines, Jr., Veterans Affairs Hospital, Hines, IllinoisClostridium difficile Infection

Anne A. Gershon, MDProfessor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New YorkRubella Virus (German Measles); Measles Virus (Rubeola)

Janet R. Gilsdorf, MDRobert P. Kelch Research Professor of Pediatrics and Communicable Diseases, University of Michigan Medical School and C.S. Mott Children’s Hospital, Ann Arbor, MichiganInfections in Asplenic Patients

Ellie J. C. Goldstein, MDClinical Professor of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California; Director, R.M. Alden Research Laboratory, Santa Monica, CaliforniaBites

Fred M. Gordin, MDProfessor of Medicine, George Washington University School of Medicine; Chief, Infectious Diseases, Veterans Affairs Medical Center, Washington, DCMycobacterium avium Complex

Paul S. Graman, MDProfessor of Medicine, University of Rochester School of Medicine and Dentistry; Attending Physician and Clinical Director, Infectious Diseases Division, Strong Memorial Hospital, Rochester, New YorkEsophagitis

Patricia M. Griffin, MDChief, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaFoodborne Disease

Richard L. Guerrant, MDProfessor of Medicine, Infectious Diseases, and International Health, University of Virginia School of Medicine, Charlottesville, VirginiaNausea, Vomiting, and Noninflammatory Diarrhea; Bacterial Inflammatory Enteritides

H. Cem Gul, MDDepartment of Infectious Diseases and Microbiology, Gulhane Military Medical Academy, Ankara, TurkeyBrucellosis (Brucella Species)

David A. Haake, MDProfessor, Departments of Medicine, Urology, and Microbiology, Immunology, & Molecular Genetics, The David Geffen School of Medicine at UCLA; Staff Physician, Department of Medicine, Division of Infectious Diseases, The Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CaliforniaLeptospira Species (Leptospirosis)

David W. Haas, MDProfessor of Medicine, Pharmacology, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TennesseeMycobacterium tuberculosis

Charles Haines, MD, PhDDivision of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandGastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection

Caroline Breese Hall, MD†

Professor of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New YorkRespiratory Syncytial Virus (RSV)

Joelle Hallak, BS, MSResearch Assistant, Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, IllinoisMicrobial Keratitis

Scott A. Halperin, MDProfessor, Departments of Pediatrics and Microbiology & Immunology, Director, Canadian Center for Vaccinology, Dalhousie University; Head, Pediatric Infectious Diseases, IWK Health Centre, Halifax, Nova Scotia, CanadaBordetella pertussis

Margaret R. Hammerschlag, MDProfessor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New YorkChlamydia pneumoniae

†Deceased.

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Rashidul Haque, MDScientist and Head of Parasitology Laboratory, Laboratory Sciences Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, BangladeshEntamoeba Species, Including Amebic Colitis and Liver Abscess

Jason B. Harris, MD, MPHAssistant Professor of Pediatrics, Harvard Medical School; Division of Infectious Diseases, MassGeneral Hospital for Children, Boston, MassachusettsEnteric Fever and Other Causes of Fever and Abdominal Symptoms

Claudia Hawkins, MD, MPHAssistant Professor, Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IllinoisHepatitis B Virus and Hepatitis Delta Virus

Roderick J. Hay, DMProfessor of Cutaneous Infection, Department of Dermatology (KCH Campus), Kings College London, London, United KingdomDermatophytosis (Ringworm) and Other Superficial Mycoses

David K. Henderson, MDDeputy Director for Clinical Care, Clinical Center, National Institutes of Health, Bethesda, MarylandInfections Caused by Percutaneous Intravascular Devices; Human Immunodeficiency Virus in Health Care Settings; Nosocomial Herpesvirus Infections

David R. Hill, MD, DTM&HProfessor, Department of Medical Sciences, Director, Global Public Health, Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, ConnecticutGiardia lamblia

Martin S. Hirsch, MDProfessor of Medicine, Harvard Medical School; Professor of Infectious Diseases and Immunology, Harvard School of Public Health; Senior Physician, Infectious Diseases Service, Massachusetts General Hospital, Boston, MassachusettsAntiretroviral Therapy for Human Immunodeficiency Virus Infection

Aimee Hodowanec, MDAssistant Professor, Department of Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, IllinoisTetanus (Clostridium tetani); Botulism (Clostridium botulinum)

Robert S. Holzman, MDProfessor Emeritus of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New YorkMycoplasma pneumoniae and Atypical Pneumonia

Edward W. Hook III, MDProfessor and Director, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaEndemic Treponematoses

Thomas M. Hooton, MDProfessor of Clinical Medicine, Department of Medicine, Clinical Director, Division of Infectious Diseases, University of Miami Miller School of Medicine; Chief of Medicine, Miami Veterans Affairs Healthcare System, Miami, FloridaNosocomial Urinary Tract Infections

Harold W. Horowitz, MDProfessor of Medicine, Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine; Chief of Service Infectious Diseases, Bellevue Hospital Center, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease

C. Robert Horsburgh, Jr., MD, MUSProfessor of Epidemiology, Biostatistics, and Medicine, Boston University Schools of Public Health and Medicine, Boston, MassachusettsMycobacterium avium Complex

James M. Horton, MDChief, Division of Infectious Diseases, Department of Internal Medicine, Carolinas Medical Center, Charlotte, North CarolinaRelapsing Fever Caused by Borrelia Species

Duane R. Hospenthal, MD, PhDAdjunct Professor of Medicine, Department of Medicine, Infectious Disease Division, University of Texas Health Science Center at San Antonio, San Antonio, TexasAgents of Chromoblastomycosis; Agents of Mycetoma; Uncommon Fungi and Related Species

Nicole M. Iovine, MD, PhDAssistant Professor of Medicine, Director, Antimicrobial Stewardship Program, Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida School of Medicine, Gainesville, FloridaCampylobacter jejuni and Related Species

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Jonathan R. Iredell, MBBS, PhDAssociate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Director, Department of Infectious Diseases, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species

Michael G. Ison, MD, MSAssociate Professor, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IllinoisParainfluenza Viruses

J. Michael Janda, PhD, D(ABMM)Laboratory Director, Public Health Laboratory, Department of Public Health, County of Los Angeles, Downey, CaliforniaCapnocytophaga

Edward N. Janoff, MDProfessor of Medicine, Microbiology, and Immunology, Departments of Medicine and Infectious Diseases, University of Colorado Denver, Aurora, Colorado; Director, Mucosal and Vaccine Research Center, Denver Veterans Affairs Medical Center, Denver, ColoradoStreptococcus pneumoniae

Eric C. Johannsen, MDAssistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Physician, Division of Infectious Diseases, University of Wisconsin Hospitals and Clinics, Madison, WisconsinEpstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases)

Donald Kaye, MDProfessor of Medicine, Drexel University College of Medicine, Philadelphia, PennsylvaniaUrinary Tract Infections

Kenneth M. Kaye, MDAssociate Professor, Department of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MassachusettsEpstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases); Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)

James W. Kazura, MDProfessor of International Health, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OhioTissue Nematodes (Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis)

Jay S. Keystone, MD, MSc (CTM)Professor of Medicine, University of Toronto; Senior Staff Physician, Tropical Disease Unit, Toronto General Hospital, Toronto, CanadaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

Yury Khudyakov, PhDDivision of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus

Rose Kim, MDAssociate Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New JerseyOther Coryneform Bacteria and Rhodococci

Charles H. King, MDProfessor of International Health, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OhioTapeworms (Cestodes)

Louis V. Kirchhoff, MD, MPHProfessor of Internal Medicine, University of Iowa; Staff Physician, Medical Service, Department of Veterans Affairs Medical Center, Iowa City, Iowa; Professor of Medicine, State University of New York Upstate Medical University, Syracuse, New YorkTrypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes; Agents of African Trypanosomiasis (Sleeping Sickness)

Jerome O. Klein, MDProfessor, Department of Pediatrics, Boston University School of Medicine; Former Director, Division of Pediatric Infectious Diseases, Boston Medical Center, Boston, MassachusettsOtitis Externa, Otitis Media, and Mastoiditis

Michael Klompas, MD, MPHAssociate Professor of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute; Associate Hospital Epidemiologist, Brigham and Women’s Hospital, Boston, MassachusettsNosocomial Pneumonia

Bettina M. Knoll, MD, PhDAssistant Professor of Medicine, Warren Alpert Medical School of Brown University; Physician, Miriam Hospital and Rhode Island Hospital, Providence, Rhode IslandProsthetic Valve Endocarditis

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Kirk U. Knowlton, MDProfessor of Medicine, Chief of Cardiology, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis

Jane E. Koehler, MA, MDProfessor of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CaliforniaBartonella, Including Cat-Scratch Disease

Stephan A. Kohlhoff, MDAssistant Professor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Co-Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New YorkChlamydia pneumoniae

Dimitrios P. Kontoyiannis, MDFrances King Black Endowed Professor, Department of Infectious Diseases, Deputy Head, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TexasAgents of Mucormycosis and Entomophthoramycosis

Igor J. Koralnik, MDProfessor of Neurology, Harvard Medical School; Chief, Division of Neuro-Virology, Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, Boston, MassachusettsJC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)

Anita A. Koshy, MDAssistant Professor, Departments of Neurology and Immunobiology, University of Arizona, Tucson, ArizonaFree-Living Amebae

Joseph A. Kovacs, MDSenior Investigator, Head, AIDS Section, Critical Care Medicine Department, National Institute of Health Clinical Center, Bethesda, MarylandToxoplasma gondii

Phyllis Kozarsky, MDProfessor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Medical Director, TravelWell, Emory University Hospital, Atlanta, GeorgiaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

John Krieger, MDProfessor, Department of Urology, University of Washington; Chief, Urology Section, Veterans Affairs Puget Sound Health Care System, Seattle, WashingtonProstatitis, Epididymitis, and Orchitis

Matthew J. Kuehnert, MDDirector, Office of Blood, Organ, and Other Tissue Safety, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GeorgiaTransfusion- and Transplantation-Transmitted Infections

Nalin M. Kumar, DPhilProfessor, Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, IllinoisMicrobial Conjunctivitis

Paul N. Levett, PhD, DScAssistant Clinical Director, Saskatchewan Disease Control Laboratory, Regina, Saskatchewan, CanadaLeptospira Species (Leptospirosis)

Donald P. Levine, MDProfessor of Medicine, Associate Vice Chair for Continuing Medical Education and Community Affairs, Department of Medicine, Wayne State University, Detroit, MichiganInfections in Injection Drug Users

Matthew E. Levison, MDProfessor of Public Health, Drexel University School of Public Health; Adjunct Professor of Medicine, Drexel University College of Medicine, Philadelphia, PennsylvaniaPeritonitis and Intraperitoneal Abscesses

Russell E. Lewis, PharmDAssociate Professor, Department of Medical Sciences and Surgery, University of Bologna Infectious Diseases Unit, S. Orsola Malpighi Hospital, Bologna, ItalyAgents of Mucormycosis and Entomophthoramycosis

Aldo A. M. Lima, MD, PhDProfessor, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Ceará, BrazilBacterial Inflammatory Enteritides

Ajit P. Limaye, MDProfessor, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WashingtonInfections in Solid-Organ Transplant Recipients

W. Ian Lipkin, MDDirector, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New YorkZoonoses

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Nathan Litman, MDProfessor of Pediatrics, Albert Einstein College of Medicine; Vice Chair, Clinical Affairs, Department of Pediatrics, Chief, Division of Pediatric Infectious Diseases, Children’s Hospital at Montefiore, Bronx, New YorkMumps Virus

Bennett Lorber, MD, DSc (Hon)Thomas M. Durant Professor of Medicine, Professor of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PennsylvaniaBacterial Lung Abscess; Listeria monocytogenes

Rob Roy MacGregor, MDProfessor, Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaCorynebacterium diphtheriae (Diphtheria)

Philip A. Mackowiak, MD, MBAProfessor and Vice Chairman, Department of Medicine, University of Maryland School of Medicine; Chief, Medical Care Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, MarylandFever of Unknown Origin

Lawrence C. Madoff, MDProfessor of Medicine, University of Massachusetts Medical School; Director, Division of Epidemiology and Immunization, Massachusetts Department of Public Health; Division of Infectious Disease and Immunology, University of Massachusetts Memorial Medical Center, Worcester, MassachusettsInfections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis); Splenic Abscess

Alan J. Magill, MDDirector, Malaria, Bill and Melinda Gates Foundation, Seattle, WashingtonLeishmania Species: Visceral (Kala-Azar), Cutaneous, and Mucosal Leishmaniasis

James H. Maguire, MD, MPHProfessor of Medicine, Harvard Medical School; Senior Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, MassachusettsIntestinal Nematodes (Roundworms); Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes)

Frank Maldarelli, MD, PhDHead, Clinical Retrovirology Section, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection

Lewis Markoff, MDChief, Laboratory of Vector-Borne Virus Diseases, Office of Vaccines, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MarylandAlphaviruses

Jeanne M. Marrazzo, MD, MPHAssociate Professor of Medicine, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WashingtonNeisseria gonorrhoeae (Gonorrhea)

Thomas J. Marrie, MDDean, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, CanadaCoxiella burnetii (Q Fever)

Thomas Marth, MDProfessor of Internal Medicine, Chief, Division of Internal Medicine, Krankenhaus Maria Hilf, Daun, GermanyWhipple’s Disease

David H. Martin, MDHarry E. Dascomb, M.D., Professor of Medicine, Department of Internal Medicine, Professor of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LouisianaGenital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma Species

Gregory J. Martin, MDChief, Infectious Diseases—Tropical Medicine, Office of Medical Services, U.S. Department of State, Washington, DC; Associate Professor of Medicine and Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, MarylandBacillus anthracis (Anthrax)

Francisco M. Marty, MDAssociate Professor of Medicine, Department of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, MassachusettsCystic Fibrosis

Henry Masur, MDChief, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MarylandManagement of Opportunistic Infections Associated with Human Immunodeficiency Virus Infection

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John T. McBride, MDProfessor of Pediatrics, Northeast Ohio Medical University, Rootstown, Ohio; Vice Chair, Department of Pediatrics, Akron Children’s Hospital, Akron, OhioCroup in Children (Acute Laryngotracheobronchitis); Bronchiolitis

William M. McCormack, MDDistinguished Teaching Professor of Medicine and of Obstetrics and Gynecology, Emeritus, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New YorkUrethritis; Vulvovaginitis and Cervicitis

Catherine C. McGowan, MDAssociate Professor, Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeProstatitis, Epididymitis, and Orchitis

Kenneth McIntosh, MDProfessor of Pediatrics, Harvard Medical School; Senior Physician, Department of Medicine, Children’s Hospital, Boston, MassachusettsCoronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)

Paul S. Mead, MD, MPHChief, Epidemiology and Surveillance Activity, Bacterial Disease Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Fort Collins, ColoradoYersinia Species (Including Plague)

Malgorzata Mikulska, MDDivision of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients

Robert F. Miller, MBBSReader in Clinical Infection, Honorary Professor, London School of Hygiene and Tropical Medicine; Honorary Consultant Physician, Camden Provider Services, Central and North West London NHS Foundation Trust, and at University College London Hospitals, University College London, London, United KingdomPneumocystis Species

Samuel I. Miller, MDProfessor of Medicine, Microbiology, Genome Sciences, and Immunology, Department of Immunology, University of Washington School of Medicine, Seattle, WashingtonSalmonella Species

David H. Mitchell, MBBSClinical Senior Lecturer, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species

John F. Modlin, MDProfessor of Pediatrics and Medicine, Chair, Department of Pediatrics, Senior Advising Dean, Geisel School of Medicine at Dartmouth; Interim Director, Children’s Hospital at Dartmouth, Lebanon, New HampshirePoliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses

Rajal K. Mody, MD, MPHLead, National Surveillance Team, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaFoodborne Disease

José G. Montoya, MDProfessor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CaliforniaToxoplasma gondii

Philippe Moreillon, MD, PhDProfessor and Vice Rector for Research, Department of Fundamental Microbiology, University of Lausanne, Lausanne, SwitzerlandStaphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)

J. Glenn Morris, Jr., MD, MPH&TMDirector, Emerging Pathogens Institute, University of Florida; Professor of Medicine, Division of Infectious Diseases, University of Florida College of Medicine, Gainesville, FloridaHuman Illness Associated with Harmful Algal Blooms

Robert S. Munford, MDSenior Clinician, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSepsis, Severe Sepsis, and Septic Shock

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Edward L. Murphy, MD, MPHProfessor, Departments of Laboratory Medicine and Epidemiology/Biostatistics, University of California School of Medicine; Senior Investigator, Blood Systems Research Institute, San Francisco, CaliforniaHuman T-Lymphotropic Virus (HTLV)

Timothy F. Murphy, MDSUNY Distinguished Professor, Clinical and Translational Research Center, University at Buffalo, State University of New York, Buffalo, New YorkMoraxella catarrhalis, Kingella, and Other Gram-Negative Cocci; Haemophilus Species, including H. influenzae and H. ducreyi (Chancroid)

Barbara E. Murray, MDJ. Ralph Meadows Professor and Director, Division of Infectious Diseases, Department of Internal Medicine and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, TexasEnterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species

Clinton K. Murray, MDChief, Infectious Disease, Brooke Army Medical Center, Fort Sam Houston, Houston, Texas; Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Clinical Professor of Medicine and Infectious Diseases, University of Texas Health Sciences Center, San Antonio, TexasBurns

Daniel M. Musher, MDProfessor of Medicine and of Molecular Virology and Microbiology, Distinguished Service Professor, Baylor College of Medicine; Infectious Disease Section, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TexasStreptococcus pneumoniae

Anna Narezkina, MDFellow, Division of Cardiology, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis

Theodore E. Nash, MDHead, Gastrointestinal Parasites Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandGiardia lamblia; Visceral Larva Migrans and Other Uncommon Helminth Infections

Jennifer L. Nayak, MDAssistant Professor, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New YorkEpiglottitis

Marguerite A. Neill, MDAssociate Professor of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Attending Physician, Division of Infectious Diseases, Memorial Hospital of Rhode Island, Pawtucket, Rhode IslandOther Pathogenic Vibrios

Christopher A. Ohl, MDProfessor of Medicine, Section on Infectious Diseases, Wake Forest School of Medicine; Medical Director, Center for Antimicrobial Utilization, Stewardship, and Epidemiology, Wake Forest Baptist Medical Center, Winston-Salem, North CarolinaInfectious Arthritis of Native Joints

Pablo C. Okhuysen, MDProfessor, Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TexasSporothrix schenckii

Andrew B. Onderdonk, PhDProfessor of Pathology, Harvard Medical School; Microbiology Laboratory, Brigham and Women’s Hospital, Boston, MassachusettsGas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)

Douglas R. Osmon, MDProfessor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis

Michael N. Oxman, MDProfessor of Medicine and Pathology, University of California San Diego School of Medicine, La Jolla, California; Staff Physician, Infectious Diseases, Veterans Affairs San Diego Healthcare System, San Diego, CaliforniaMyocarditis and Pericarditis

Slobodan Paessler, DVM, PhDProfessor, Department of Pathology, Director, Preclinical Studies Core, Director, Animal Biosafety Level 3, Galveston National Laboratory, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

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Raj Palraj, MBBSInstructor of Medicine, Mayo Clinic College of Medicine; Senior Associate Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis

Peter G. Pappas, MDProfessor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaChronic Pneumonia

Mark S. Pasternack, MDChief, Pediatric Infectious Disease Unit, Massachusetts General Hospital, Boston, MassachusettsCellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis

Thomas F. Patterson, MDProfessor, Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TexasAspergillus Species

Deborah Pavan-Langston, MDProfessor, Department of Ophthalmology, Harvard Medical School; Attending Physician, Massachusetts Eye and Ear Infirmary, Boston, MassachusettsMicrobial Conjunctivitis; Microbial Keratitis

David A. Pegues, MDProfessor of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania; Medical Director, Healthcare Epidemiology, Infection Prevention and Control; Antimicrobial Management Program, Hospital of the University of Pennsylvania, Philadelphia, PennsylvaniaSalmonella Species

Robert L. Penn, MDProfessor of Medicine, Infectious Diseases Section, Louisiana State University School of Medicine in Shreveport; Physician, Infectious Diseases Section, Overton Brooks Veterans Affairs Medical Center, Shreveport, LouisianaFrancisella tularensis (Tularemia)

John R. Perfect, MDJames B. Duke Professor of Medicine, Chief, Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North CarolinaCryptococcosis (Cryptococcus neoformans and Cryptococcus gattii)

Stanley Perlman, MD, PhDProfessor, Department of Microbiology and Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IowaCoronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)

Brett W. Petersen, MD, MPHMedical Officer, Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GeorgiaOrthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses

Phillip K. Peterson, MDProfessor of Medicine, Director, International Medical Education and Research, University of Minnesota Medical School, Minneapolis, MinnesotaInfections in the Elderly

William A. Petri, Jr., MD, PhDWade Hampton Frost Professor of Epidemiology, University of Virginia; Chief, Division of Infectious Disease and International Health, University of Virginia Health System, Charlottesville, VirginiaEntamoeba Species, Including Amebic Colitis and Liver Abscess

Cathy A. Petti, MDCEO, HealthSpring Global, Inc., Bradenton, FloridaStreptococcus anginosus Group

Michael Phillips, MDAssociate Professor (Clinical), Associate Director for Clinical Affairs, Division of Infectious Disease and Immunology, New York University School of Medicine; Hospital Epidemiologist and Director of Infection Prevention and Control, NYU Langone Medical Center, New York, New YorkAcinetobacter Species

Yok-Ai Que, MD, PhDInstructor and Researcher, University of Lausanne School of Medicine; Attending Physician, Department of Critical Care Medicine, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, SwitzerlandStaphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)

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Justin D. Radolf, MDProfessor, Departments of Medicine, Pediatrics, Immunology, Genetics & Developmental Biology, and Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut; Senior Scientific Advisor, Connecticut Children’s Medical Center, Hartford, ConnecticutSyphilis (Treponema pallidum)

Didier Raoult, MD, PhDProfessor and President, Aix Marseille Université; Director, Clinical Microbiology Laboratory for the University Hospitals; Founder, WHO Collaborative Center; President, Universite de la Mediteranee in Marseille, Marseille, FranceRickettsia akari (Rickettsialpox); Coxiella burnetii (Q Fever); Orientia tsutsugamushi (Scrub Typhus)

Stuart C. Ray, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis C

Annette C. Reboli, MDFounding Vice Dean, Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New JerseyOther Coryneform Bacteria and Rhodococci; Erysipelothrix rhusiopathiae

Marvin S. Reitz, Jr., PhDProfessor, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MarylandHuman Immunodeficiency Viruses

Cybèle A. Renault, MD, DTM&HClinical Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California; Attending Physician, Veterans Affairs Palo Alto Health Care, Palo Alto, CaliforniaMycobacterium leprae (Leprosy)

Angela Restrepo, MSc, PhDSenior Researcher, Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas, Medellín, Antioquia, ColombiaParacoccidioidomycosis

John H. Rex, MDAdjunct Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Center for the Study of Emerging and Reemerging Pathogens, University of Texas Medical School, Houston, Texas; Head of Infection, Global Medicines Development, AstraZeneca Pharmaceuticals, Waltham, MassachusettsSporothrix schenckii

Elizabeth G. Rhee, MDDirector, Clinical Research, Department of Clinical Pharmacology, Merck Research Laboratories, Kenilworth, New JerseyAdenoviruses

José R. Romero, MDHorace C. Cabe Professor of Infectious Diseases, Department of Pediatrics, University of Arkansas for Medical Sciences; Director, Pediatric Infectious Diseases Section, Department of Pediatrics, Arkansas Children’s Hospital; Director, Clinical Trials Research, Arkansas Children’s Hospital Research Institute, Little Rock, ArkansasPoliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses

Alan L. Rothman, MDResearch Professor, Institute for Immunology and Informatics and Department of Cell and Molecular Biology, University of Rhode Island, Providence, Rhode IslandFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Craig R. Roy, PhDProfessor, Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, ConnecticutLegionnaires’ Disease and Pontiac Fever

Mark E. Rupp, MDProfessor and Chief, Infectious Diseases, University of Nebraska Medical Center; Medical Director, Infection Control and Epidemiology, The Nebraska Medical Center, Omaha, NebraskaMediastinitis; Staphylococcus epidermidis and Other Coagulase-Negative Staphylococci

Charles E. Rupprecht, VMD, PhDResearch Coordinator at Global Alliance for Rabies Control, Atlanta, Georgia; Professor, Ross University School of Veterinary Medicine, Basseterre St. Kitts, West IndiesRabies (Rhabdoviruses)

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Thomas A. Russo, MD, CMProfessor of Medicine and Microbiology, Division of Infectious Diseases, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Staff Physician, Veterans Affairs Western New York Health Care System, Buffalo, New YorkAgents of Actinomycosis

William A. Rutala, MS, PhD, MPHProfessor of Medicine, Director, Statewide Program for Infection Control and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Director, Hospital Epidemiology, Occupational Health and Safety, University of North Carolina Health Care, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash

Edward T. Ryan, MDProfessor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Tropical Medicine, Massachusetts General Hospital, Boston, MassachusettsEnteric Fever and Other Causes of Fever and Abdominal Symptoms; Vibrio cholerae

Amar Safdar, MD, MBBSAssociate Professor of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine; Director, Transplant Infectious Diseases, Department of Medicine, NYU Langone Medical Center, New York, New YorkStenotrophomonas maltophilia and Burkholderia cepacia

Juan C. Salazar, MD, MPHProfessor and Chairman, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, Connecticut; Physician-in-Chief, Head of Division of Pediatric Infectious Diseases and Immunology, Connecticut Children’s Medical Center, Hartford, ConnecticutSyphilis (Treponema pallidum)

Maria C. Savoia, MDDean for Medical Education, Professor of Medicine, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis

Paul E. Sax, MDProfessor of Medicine, Harvard Medical School; Clinical Director, Division of Infectious Diseases and Human Immunodeficiency Virus Program, Brigham and Women’s Hospital, Boston, MassachusettsPulmonary Manifestations of Human Immunodeficiency Virus Infection

W. Michael Scheld, MDGerald L. Mandell–Bayer Professor of Infectious Diseases, Professor of Medicine, University of Virginia School of Medicine; Clinical Professor of Neurosurgery, Director, Pfizer Initiative in International Health, University of Virginia Health System, Charlottesville, VirginiaEndocarditis and Intravascular Infections; Acute Meningitis

Joshua T. Schiffer, MD, MScAssistant Professor, Department of Medicine, University of Washington; Assistant Member, Vaccine and Infectious Diseases Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WashingtonHerpes Simplex Virus

David Schlossberg, MDProfessor, Department of Medicine, Temple University School of Medicine; Medical Director, Tuberculosis Control Program, Philadelphia Department of Public Health, Philadelphia, PennsylvaniaPsittacosis (Due to Chlamydia psittaci)

Thomas Schneider, MD, PhDProfessor of Infectious Diseases, Charité University Hospital, Benjamin Franklin Campus, Berlin, GermanyWhipple’s Disease

Jane R. Schwebke, MDProfessor of Medicine, Medicine/Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaTrichomonas vaginalis

Leopoldo N. Segal, MDAssistant Professor, Department of Medicine, New York University School of Medicine, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease

Parham Sendi, MDConsultant and Lecturer, Basel University Medical Clinic, Liestal, Switzerland; Department of Infectious Diseases, University Hospital and Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandOrthopedic Implant–Associated Infections

Kent A. Sepkowitz, MDDeputy Physician-in-Chief, Quality and Safety, Memorial Sloan Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College, New York, New YorkHealth Care–Acquired Hepatitis

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Edward J. Septimus, MDClinical Professor, Department of Internal Medicine, Texas A&M Health Science Center, Houston, Texas; Medical Director, Infection Prevention and Epidemiology, Clinical Services Group, HCA, Inc., Nashville, TennesseePleural Effusion and Empyema

Alexey Seregin, PhDResearch Scientist, Department of Pathology, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

Stanford T. Shulman, MDVirginia H. Rogers Professor of Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine; Chief, Division of Infectious Diseases, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IllinoisNonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis

George K. Siberry, MD, MPHMedical Officer, Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MarylandPediatric Human Immunodeficiency Virus Infection

Omar K. Siddiqi, MDClinical Instructor, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Honorary Lecturer, Department Medicine, University of Zambia School of Medicine, Lusaka, ZambiaNeurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

Costi D. Sifri, MDAssociate Professor of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine; Attending Physician, Department of Medicine, University of Virginia Health System, Charlottesville, VirginiaInfections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis)

Michael S. Simberkoff, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New YorkMycoplasma pneumoniae and Atypical Pneumonia

Francesco R. Simonetti, MDGuest Researcher, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection

Kamaljit Singh, MD, D(ABMM)Associate Professor, Departments of Medicine and Pathology, Rush University Medical Center, Chicago, IllinoisRabies (Rhabdoviruses)

Nina Singh, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Pittsburgh and VA Pittsburgh Healthcare System, Pittsburgh, PennsylvaniaInfections in Solid-Organ Transplant Recipients

Upinder Singh, MDAssociate Professor of Medicine, Departments of Infectious Diseases and Microbiology & Immunology, Stanford School of Medicine, Stanford, CaliforniaFree-Living Amebae

Scott W. Sinner, MDHyperbaric Medical Director, Mercy-Clermont Hospital, Batavia, OhioViridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms

Leonard N. Slater, MDProfessor of Infectious Diseases, Department of Internal Medicine, College of Medicine, University of Oklahoma, Oklahoma City, OklahomaBartonella, Including Cat-Scratch Disease

A. George Smulian, MB BCh, MScAssociate Professor, University of Cincinnati College of Medicine; Chief, Infectious Disease Section, Veterans Affairs Cincinnati Medical Center, Cincinnati, OhioPneumocystis Species

Jack D. Sobel, MDProfessor of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, MichiganUrinary Tract Infections

M. Rizwan Sohail, MDAssociate Professor of Medicine, Divisions of Infectious Diseases and Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MinnesotaInfections of Nonvalvular Cardiovascular Devices

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David E. Soper, MDProfessor and Vice Chairman, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South CarolinaInfections of the Female Pelvis

Tania C. Sorrell, AM, MD, MBBSProfessor and Director, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia; Director, Centre for Infectious Diseases and Microbiology and Service Director, Infectious Diseases and Sexual Health, Westmead, New South Wales, AustraliaNocardia Species

James M. Steckelberg, MDProfessor of Medicine, Consultant, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis

Allen C. Steere, MDProfessor of Medicine, Harvard Medical School, Harvard University; Director, Translational Research in Rheumatology, Massachusetts General Hospital, Boston, MassachusettsLyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferi

James P. Steinberg, MDProfessor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Chief Medical Officer, Emory University Hospital Midtown, Atlanta, GeorgiaOther Gram-Negative and Gram-Variable Bacilli

David S. Stephens, MDStephen W. Schwarzmann Distinguished Professor of Medicine, Chair, Department of Medicine, Emory University School of Medicine; Vice President for Research, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, GeorgiaNeisseria meningitidis

Timothy R. Sterling, MDProfessor of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeGeneral Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases); Mycobacterium tuberculosis

Dennis L. Stevens, MD, PhDAssociate Chief of Staff, Research and Development Service, Veterans Affairs Medical Center, Boise, Idaho; Professor of Medicine, Department of Medicine, University of Washington, Seattle, WashingtonStreptococcus pyogenes

Charles W. Stratton IV, MDAssociate Professor of Pathology and Medicine, Vanderbilt University School of Medicine; Director, Clinical Microbiology Laboratory, Vanderbilt University Medical Center, Nashville, TennesseeStreptococcus anginosus Group

Anthony F. Suffredini, MDSenior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MarylandSepsis, Severe Sepsis, and Septic Shock

Kathryn N. Suh, MD, MScAssociate Professor of Medicine, University of Ottawa; Division of Infectious Diseases, The Ottawa Hospital, Ottawa, CanadaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

Mark S. Sulkowski, MDProfessor of Medicine, Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, MarylandGastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection

Morton N. Swartz, MD†

Associate Firm Chief, Infectious Diseases Unit, Massachusetts General Hospital, Boston, MassachusettsCellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis

Thomas R. Talbot, MD, MPHAssociate Professor of Medicine and Health Policy, Vanderbilt University School of Medicine; Chief Hospital Epidemiologist, Vanderbilt University Medical Center, Nashville, TennesseeSurgical Site Infections and Antimicrobial Prophylaxis

C. Sabrina Tan, MDAssistant Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MassachusettsJC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)

Ming Tan, MDProfessor of Medicine, Microbiology and Molecular Genetics, University of California at Irvine School of Medicine, Irvine, CaliforniaChlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)

†Deceased.

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Chloe Lynne Thio, MDAssociate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis B Virus and Hepatitis Delta Virus

David L. Thomas, MD, MPHProfessor of Medicine, Director, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis C

Stephen J. Thomas, MDDirector, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MarylandFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Anna R. Thorner, MDAssistant Clinical Professor of Medicine, Department of Medicine, Harvard Medical School; Associate Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, MassachusettsZoonotic Paramyxoviruses: Nipah, Hendra, and Menangle

Angela María Tobón, MDDirector, Chronic Infectious Diseases Unit, Department of Internal Medicine, Corporación para Investigaciones Biológicas, Medellín, ColombiaParacoccidioidomycosis

Edmund C. Tramont, MDAssociate Director, Special Projects, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSyphilis (Treponema pallidum)

John J. Treanor, MDChief, Division of Infectious Diseases, Department of Medicine, University of Rochester Medical Center, Rochester, New YorkInfluenza (Including Avian Influenza and Swine Influenza); Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses

Athe M. N. Tsibris, MD, MSAssistant Professor in Medicine, Division of Infectious Diseases, Harvard Medical School; Brigham and Women’s Hospital, Boston, MassachusettsAntiretroviral Therapy for Human Immunodeficiency Virus Infection

Allan R. Tunkel, MD, PhD, MACPProfessor of Medicine, Associate Dean for Medical Education, Warren Alpert Medical School of Brown University, Providence, Rhode IslandAcute Meningitis; Brain Abscess; Subdural Empyema, Epidural Abscess, and Suppurative Intracranial Thrombophlebitis; Cerebrospinal Fluid Shunt and Drain Infections; Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms

Ronald B. Turner, MDProfessor of Pediatrics, University of Virginia School of Medicine, Charlottesville, VirginiaThe Common Cold; Rhinovirus

Kenneth L. Tyler, MDReuler-Lewin Family Professor of Neurology and Professor of Medicine and Microbiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Chief, Neurology Service, Denver Veterans Affairs Medical Center, Denver, ColoradoEncephalitis; Orthoreoviruses and Orbiviruses; Coltiviruses and Seadornaviruses; Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)

Ahmet Uluer, DO, MSAssistant Professor of Pediatrics, Department of Medicine, Harvard Medical School; Boston Children’s Hospital, Boston, MassachusettsCystic Fibrosis

Diederik van de Beek, MD, PhDProfessor, Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsAcute Meningitis

Edouard G. Vannier, PharmD, PhDAssistant Professor of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine, Boston, MassachusettsBabesia Species

Trevor C. Van Schooneveld, MDAssistant Professor of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NebraskaMediastinitis

Claudio Viscoli, MDDivision of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients

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Ellen R. Wald, MDAlfred Dorrance Daniels Professor on Diseases of Children, University of Wisconsin School of Medicine and Public Health; Pediatrician-in-Chief, American Family Children’s Hospital, Madison, WisconsinSinusitis

Matthew K. Waldor, MD, PhDEdward H. Kass Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MassachusettsVibrio cholerae

David H. Walker, MDProfessor, Department of Pathology, University of Texas Medical Branch; Executive Director, Center for Biodefense and Emerging Infectious Diseases, Galveston, TexasRickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus); Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae

Richard J. Wallace, Jr., MDChairman, Department of Microbiology, University of Texas Health Northeast, Tyler, TexasInfections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

Edward E. Walsh, MDProfessor of Medicine, Department of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New YorkAcute Bronchitis; Respiratory Syncytial Virus (RSV)

Stephen R. Walsh, MDAssistant Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, MassachusettsHepatitis E Virus

Peter D. Walzer, MD, MScEmeritus Professor of Medicine, University of Cincinnati; Retired Associate Chief of Staff for Research, Cincinnati VA Medical Center, Cincinnati, OhioPneumocystis Species

Christine A. Wanke, MDProfessor, Department of Medicine, Associate Chair, Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MassachusettsTropical Sprue: Enteropathy

Cirle A. Warren, MDAssistant Professor, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VirginiaBacterial Inflammatory Enteritides

Ronald G. Washburn, MDAssociate Chief of Staff for Research and Development, Medical Research, Chief of Infectious Diseases, Medical Service, Shreveport Veterans Affairs Medical Center; Professor of Medicine, Infectious Diseases Section, Louisiana State University Health Sciences Center, Shreveport, LouisianaRat-Bite Fever: Streptobacillus moniliformis and Spirillum minus

Valerie Waters, MD, MScAssociate Professor, Department of Pediatric Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, CanadaBordetella pertussis

David J. Weber, MD, MPHProfessor of Medicine, Pediatrics, and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Associate Chief of Staff and Medical Director, Hospital Epidemiology and Occupational Health, University of North Carolina Health Care, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash

Michael D. Weiden, MDAssociate Professor, Departments of Medicine and Environmental Medicine, New York University School of Medicine, Langone Medical Center, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease

Geoffrey A. Weinberg, MDProfessor of Pediatrics, Department of Pediatrics, University of Rochester School of Medicine and Dentistry; Director, Pediatric HIV Program, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, New YorkEpiglottitis; Pediatric Human Immunodeficiency Virus Infection

Daniel J. Weisdorf, MDProfessor of Medicine, Division of Hematology, Oncology, and Transplantation, Director, Adult Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, MinnesotaInfections in Recipients of Hematopoietic Stem Cell Transplants

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Louis M. Weiss, MD, MPHProfessor, Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New YorkMicrosporidiosis

David F. Welch, PhDClinical Consultant, Medical Microbiology Consulting, LLC, Dallas, TexasBartonella, Including Cat-Scratch Disease

Thomas E. Wellems, MD, PhDChief, Laboratory of Malaria and Vector Research, Chief, Malaria Genetics Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MarylandMalaria (Plasmodium Species)

A. Clinton White, Jr., MDPaul R. Stalnaker Distinguished Professor, Director, Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TexasCryptosporidiosis (Cryptosporidium Species)

Richard J. Whitley, MDDistinguished Professor of Pediatrics, Loeb Eminent Scholar Chair in Pediatrics, Professor of Microbiology, Medicine, and Neurosurgery, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AlabamaChickenpox and Herpes Zoster (Varicella-Zoster Virus)

Walter R. Wilson, MDProfessor of Medicine and Assistant Professor of Microbiology, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis

William F. Wright, DO, MPHAssistant Professor of Medicine and Microbiology, Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DCFever of Unknown Origin

Jo-Anne H. Young, MDProfessor of Medicine, Division of Infectious Disease and International Medicine, Medical Director of the Program in Adult Transplant Infectious Disease University of Minnesota, Minneapolis, Minnesota; Editor-in-Chief, Clinical Microbiology Reviews, American Society of Microbiology, Washington, DCInfections in Recipients of Hematopoietic Stem Cell Transplants

Vincent B. Young, MD, PhDAssociate Professor, Department of Internal Medicine, Division of Infectious Diseases, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MichiganClostridium difficile Infection

Nadezhda Yun, MDAssistant Professor, Department of Pathology, Assistant Director, Preclinical Studies Core, Galveston National Laboratory, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

Werner Zimmerli, MDProfessor, Basel University Medical Clinic, Liestal, SwitzerlandOrthopedic Implant–Associated Infections

John J. Zurlo, MDProfessor of Medicine, Department of Medicine/Infectious Diseases, Penn State Hershey Medical Center, Hershey, PennsylvaniaPasteurella Species

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Preface

This handbook is an introduction to Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, also known as PPID, which is the detailed, authoritative reference book for the field. The handbook consists of “short view summaries” that introduce 241 of the 324 chapters in the 8th edition of PPID and that appear at the beginning of each chapter in a template format. The summaries are accompanied by tables and figures that illustrate the material contained therein. In addition, this handbook reflects the annual updates that appear in the electronic version of PPID.

The field of infectious disease is undergo-ing an extraordinary expansion of knowl-edge, with dramatic advances in diagnosis, therapy, and prevention of infectious dis-eases, as well as recognition of novel patho-gens and diseases. The handbook is intended to provide information on these topics in an easy-to-use form, and to facilitate access to further information as needed. In this regard,

the handbook is organized on the same basis as the parent textbook, PPID. Information is presented according to major infectious clinical syndromes, and individual pathogens are addressed in more detail subsequently. Examples of topics in which important new developments have occurred include hepati-tis B and C, Ebola, influenza, Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), tuberculosis, human immu-nodeficiency virus, and Middle East respira-tory syndrome (MERS).

We hope this handbook will be a conve-nient, useful, and current source of informa-tion for those interested in infectious diseases, and that it will serve as an introduction to the more detailed and comprehensive material that can be found in the parent text, PPID.

John E. Bennett, MD, MACPRaphael Dolin, MD

Martin J. Blaser, MD

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Contents

I MAJORCLINICALSYNDROMES

A FEVER 1 FeverofUnknownOrigin  2

William F. Wright and Philip A. Mackowiak

2 TheAcutelyIllPatientwithFeverandRash  3David J. Weber, Myron S. Cohen, and William A. Rutala

B UPPERRESPIRATORYTRACTINFECTIONS 3 TheCommonCold  5

Ronald B. Turner

4 Pharyngitis  6Anthony R. Flores and Mary T. Caserta

5 AcuteLaryngitis  10Mary T. Caserta

6 CroupinChildren(AcuteLaryngotracheobronchitis)  11John Bower and John T. McBride

7 OtitisExterna,OtitisMedia,andMastoiditis  12Jerome O. Klein

8 Sinusitis  14Gregory P. DeMuri and Ellen R. Wald

9 Epiglottitis  15Jennifer L. Nayak and Geoffrey A. Weinberg

10 InfectionsoftheOralCavity,Neck,andHead  17Anthony W. Chow

C PLEUROPULMONARYANDBRONCHIALINFECTIONS 11 AcuteBronchitis  22

Edward E. Walsh

12 AcuteExacerbationsofChronicObstructivePulmonaryDisease  23Leopoldo N. Segal, Michael D. Weiden, and Harold W. Horowitz

13 Bronchiolitis  24John Bower and John T. McBride

14 AcutePneumonia  25Richard T. Ellison III and Gerald R. Donowitz

15 PleuralEffusionandEmpyema  28Edward J. Septimus

16 BacterialLungAbscess  30Bennett Lorber

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17 ChronicPneumonia  31Peter G. Pappas

18 CysticFibrosis  33Ahmet Uluer and Francisco M. Marty

D URINARYTRACTINFECTIONS 19 UrinaryTractInfections  37

Jack D. Sobel and Donald Kaye

E SEPSIS 20 Sepsis,SevereSepsis,andSepticShock  40

Robert S. Munford and Anthony F. Suffredini

F INTRA-ABDOMINALINFECTIONS 21 PeritonitisandIntraperitonealAbscesses  42

Matthew E. Levison and Larry M. Bush

22 InfectionsoftheLiverandBiliarySystem(LiverAbscess,Cholangitis,Cholecystitis)  48Costi D. Sifri and Lawrence C. Madoff

23 PancreaticInfection  49Miriam Baron Barshak

24 SplenicAbscess  54Lawrence C. Madoff

25 Appendicitis  55Costi D. Sifri and Lawrence C. Madoff

26 DiverticulitisandTyphlitis  56Costi D. Sifri and Lawrence C. Madoff

G CARDIOVASCULARINFECTIONS 27 EndocarditisandIntravascularInfections  58

Vance G. Fowler, Jr., W. Michael Scheld, and Arnold S. Bayer

28 ProstheticValveEndocarditis  63Raj Palraj, Bettina M. Knoll, Larry M. Baddour, and Walter R. Wilson

29 InfectionsofNonvalvularCardiovascularDevices  65M. Rizwan Sohail, Walter R. Wilson, and Larry M. Baddour

30 ProphylaxisofInfectiveEndocarditis  67David T. Durack

31 MyocarditisandPericarditis  69Kirk U. Knowlton, Anna Narezkina, Maria C. Savoia, and Michael N. Oxman

32 Mediastinitis  72Trevor C. Van Schooneveld and Mark E. Rupp

H CENTRALNERVOUSSYSTEMINFECTIONS 33 AcuteMeningitis  75

Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld

34 ChronicMeningitis  78John E. Bennett

35 Encephalitis  80J. David Beckham and Kenneth L. Tyler

36 BrainAbscess  84Allan R. Tunkel

37 SubduralEmpyema,EpiduralAbscess,andSuppurativeIntracranialThrombophlebitis  86Allan R. Tunkel

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38 CerebrospinalFluidShuntandDrainInfections  88Adarsh Bhimraj, James M. Drake, and Allan R. Tunkel

I SKINANDSOFTTISSUEINFECTIONS 39 Cellulitis,NecrotizingFasciitis,andSubcutaneousTissueInfections  90

Mark S. Pasternack and Morton N. Swartz

40 MyositisandMyonecrosis  92Mark S. Pasternack and Morton N. Swartz

41 LymphadenitisandLymphangitis  94Mark S. Pasternack and Morton N. Swartz

J GASTROINTESTINALINFECTIONSANDFOODPOISONING 42 Esophagitis  98

Paul S. Graman

43 Nausea,Vomiting,andNoninflammatoryDiarrhea  100David A. Bobak and Richard L. Guerrant

44 BacterialInflammatoryEnteritides  102Aldo A. M. Lima, Cirle A. Warren, and Richard L. Guerrant

45 EntericFeverandOtherCausesofFeverandAbdominalSymptoms  104Jason B. Harris and Edward T. Ryan

46 FoodborneDisease  105Rajal K. Mody and Patricia M. Griffin

47 TropicalSprue:Enteropathy  107Christine A. Wanke

K BONEANDJOINTINFECTIONS 48 InfectiousArthritisofNativeJoints  108

Christopher A. Ohl and Derek Forster

49 Osteomyelitis  111Elie F. Berbari, James M. Steckelberg, and Douglas R. Osmon

50 OrthopedicImplant–AssociatedInfections  113Werner Zimmerli and Parham Sendi

L DISEASESOFTHEREPRODUCTIVEORGANSANDSEXUALLYTRANSMITTEDDISEASES

51 GenitalSkinandMucousMembraneLesions  116Michael H. Augenbraun

52 Urethritis  117Michael H. Augenbraun and William M. McCormack

53 VulvovaginitisandCervicitis  118William M. McCormack and Michael H. Augenbraun

54 InfectionsoftheFemalePelvis  119David E. Soper

55 Prostatitis,Epididymitis,andOrchitis  120Catherine C. McGowan and John Krieger

M EYEINFECTIONS 56 MicrobialConjunctivitis  122

Scott D. Barnes, Nalin M. Kumar, Deborah Pavan-Langston, and Dimitri T. Azar

57 MicrobialKeratitis  124Scott D. Barnes, Joelle Hallak, Deborah Pavan-Langston, and Dimitri T. Azar

58 Endophthalmitis  125Marlene L. Durand

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59 InfectiousCausesofUveitis  127Marlene L. Durand

60 PeriocularInfections  129Marlene L. Durand

N HEPATITIS 61 ViralHepatitis  130

Jules L. Dienstag and Andrew S. Delemos

O ACQUIREDIMMUNODEFICIENCYSYNDROME 62 DiagnosisofHumanImmunodeficiencyVirusInfection  138

Francesco R. Simonetti, Robin Dewar, and Frank Maldarelli

63 GeneralClinicalManifestationsofHumanImmunodeficiencyVirusInfection(IncludingAcuteRetroviralSyndromeandOral,Cutaneous,Renal,Ocular,Metabolic,andCardiacDiseases)  140Timothy R. Sterling and Richard E. Chaisson

64 PulmonaryManifestationsofHumanImmunodeficiencyVirusInfection  142Paul E. Sax and Kevin L. Ard

65 Gastrointestinal,Hepatobiliary,andPancreaticManifestationsofHumanImmunodeficiencyVirusInfection  144Charles Haines and Mark S. Sulkowski

66 NeurologicDiseasesCausedbyHumanImmunodeficiencyVirusType1andOpportunisticInfections  146Omar K. Siddiqi and Igor J. Koralnik

67 PediatricHumanImmunodeficiencyVirusInfection  147Geoffrey A. Weinberg and George K. Siberry

68 AntiretroviralTherapyforHumanImmunodeficiencyVirusInfection  149Athe M. N. Tsibris and Martin S. Hirsch

69 ManagementofOpportunisticInfectionsAssociatedwithHumanImmunodeficiencyVirusInfection  155Henry Masur

P MISCELLANEOUSSYNDROMES 70 ChronicFatigueSyndrome  172

N. Cary Engleberg

II INFECTIOUSDISEASESANDTHEIRETIOLOGICAGENTS

A VIRALDISEASES 71 Orthopoxviruses:Vaccinia(SmallpoxVaccine),Variola(Smallpox),Monkeypox,

andCowpox  176Brett W. Petersen and Inger K. Damon

72 OtherPoxvirusesThatInfectHumans:Parapoxviruses(IncludingOrfVirus),MolluscumContagiosum,andYatapoxviruses  178Brett W. Petersen and Inger K. Damon

73 HerpesSimplexVirus  179Joshua T. Schiffer and Lawrence Corey

74 ChickenpoxandHerpesZoster(Varicella-ZosterVirus)  183Richard J. Whitley

75 Cytomegalovirus(CMV)  185Clyde S. Crumpacker II

76 Epstein-BarrVirus(InfectiousMononucleosis,Epstein-BarrVirus–AssociatedMalignantDiseases,andOtherDiseases)  186Eric C. Johannsen and Kenneth M. Kaye

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77 HumanHerpesvirusTypes6and7(ExanthemSubitum)  188Jeffrey I. Cohen

78 Kaposi’sSarcoma–AssociatedHerpesvirus(HumanHerpesvirus8)  189Kenneth M. Kaye

79 HerpesBVirus  190Jeffrey I. Cohen

80 Adenoviruses  192Elizabeth G. Rhee and Dan H. Barouch

81 Papillomaviruses  194William Bonnez

82 JC,BK,andOtherPolyomaviruses:ProgressiveMultifocalLeukoencephalopathy(PML)  196C. Sabrina Tan and Igor J. Koralnik

83 HepatitisBVirusandHepatitisDeltaVirus  198Chloe Lynne Thio and Claudia Hawkins

84 HumanParvoviruses,IncludingParvovirusB19VandHumanBocaparvoviruses  202Kevin E. Brown

85 OrthoreovirusesandOrbiviruses  203Roberta L. DeBiasi and Kenneth L. Tyler

86 ColtivirusesandSeadornaviruses  204Roberta L. DeBiasi and Kenneth L. Tyler

87 Rotaviruses  205Philip R. Dormitzer

88 Alphaviruses  207Lewis Markoff

89 RubellaVirus(GermanMeasles)  209Anne A. Gershon

90 Flaviviruses(Dengue,YellowFever,JapaneseEncephalitis,WestNileEncephalitis,St.LouisEncephalitis,Tick-BorneEncephalitis,KyasanurForestDisease,AlkhurmaHemorrhagicFever,Zika)  210Stephen J. Thomas, Timothy P. Endy, Alan L. Rothman, and Alan D. Barrett

91 HepatitisC  212Stuart C. Ray and David L. Thomas

92 Coronaviruses,IncludingSevereAcuteRespiratorySyndrome(SARS)andMiddleEastRespiratorySyndrome(MERS)  215Kenneth McIntosh and Stanley Perlman

93 ParainfluenzaViruses  216Michael G. Ison

94 MumpsVirus  217Nathan Litman and Stephen G. Baum

95 RespiratorySyncytialVirus(RSV)  218Edward E. Walsh and Caroline Breese Hall

96 HumanMetapneumovirus  219Ann R. Falsey

97 MeaslesVirus(Rubeola)  220Anne A. Gershon

98 ZoonoticParamyxoviruses:Nipah,Hendra,andMenangle  222Anna R. Thorner and Raphael Dolin

99 VesicularStomatitisVirusandRelatedVesiculoviruses  224Steven M. Fine

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100 Rabies(Rhabdoviruses)  225Kamaljit Singh, Charles E. Rupprecht, and Thomas P. Bleck

101 MarburgandEbolaHemorrhagicFevers(MarburgandEbolaViralDiseases)(Filoviruses)  227Thomas W. Geisbert

102 Influenza(IncludingAvianInfluenzaandSwineInfluenza)  228John J. Treanor

103 CaliforniaEncephalitis,HantavirusPulmonarySyndrome,andBunyavirusHemorrhagicFevers  231Dennis A. Bente

104 LymphocyticChoriomeningitis,LassaFever,andtheSouthAmericanHemorrhagicFevers(Arenaviruses)  232Alexey Seregin, Nadezhda Yun, and Slobodan Paessler

105 HumanT-LymphotropicVirus(HTLV)  234Edward L. Murphy and Roberta L. Bruhn

106 HumanImmunodeficiencyViruses  236Marvin S. Reitz, Jr., and Robert C. Gallo

107 Poliovirus  237José R. Romero and John F. Modlin

108 Coxsackieviruses,Echoviruses,andNumberedEnteroviruses(EV-D68)  238José R. Romero and John F. Modlin

109 HumanParechoviruses  239José R. Romero and John F. Modlin

110 HepatitisAVirus  240Francisco Averhoff, Yury Khudyakov, and Beth P. Bell

111 Rhinovirus  243Ronald B. Turner

112 NorovirusesandSapoviruses(Caliciviruses)  244Raphael Dolin and John J. Treanor

113 AstrovirusesandPicobirnaviruses  246Raphael Dolin and John J. Treanor

114 HepatitisEVirus  247Stephen R. Walsh

B PRIONDISEASES115 PrionsandPrionDiseasesoftheCentralNervousSystem(Transmissible

NeurodegenerativeDiseases)  248Patrick J. Bosque and Kenneth L. Tyler

C CHLAMYDIALDISEASES

116 Chlamydia trachomatis(Trachoma,GenitalInfections,PerinatalInfections,andLymphogranulomaVenereum)  249Byron E. Batteiger and Ming Tan

117 Psittacosis(DuetoChlamydia psittaci)  253David Schlossberg

118 Chlamydia pneumoniae  254Margaret R. Hammerschlag, Stephan A. Kohlhoff, and Charlotte A. Gaydos

D MYCOPLASMADISEASES119 Mycoplasma pneumoniaeandAtypicalPneumonia  255

Robert S. Holzman and Michael S. Simberkoff

120 GenitalMycoplasmas:Mycoplasma genitalium, Mycoplasma hominis,andUreaplasmaSpecies  256David H. Martin

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E RICKETTSIOSES,EHRLICHIOSES,ANDANAPLASMOSIS121 Rickettsia rickettsiiandOtherSpottedFeverGroupRickettsiae(RockyMountain

SpottedFeverandOtherSpottedFevers)  257David H. Walker and Lucas S. Blanton

122 Rickettsia akari(Rickettsialpox)  259Didier Raoult

123 Coxiella burnetii(QFever)  260Thomas J. Marrie and Didier Raoult

124 Rickettsia prowazekii(EpidemicorLouse-BorneTyphus)  262Lucas S. Blanton and David H. Walker

125 Rickettsia typhi(MurineTyphus)  264Lucas S. Blanton, J. Stephen Dumler, and David H. Walker

126 Orientia tsutsugamushi(ScrubTyphus)  265Didier Raoult

127 Ehrlichia chaffeensis(HumanMonocytotropicEhrlichiosis),Anaplasma phagocytophilum(HumanGranulocytotropicAnaplasmosis),andOtherAnaplasmataceae  266J. Stephen Dumler and David H. Walker

F BACTERIALDISEASES128 Staphylococcus aureus(IncludingStaphylococcalToxicShockSyndrome)  268

Yok-Ai Que and Philippe Moreillon

129 Staphylococcus epidermidisandOtherCoagulase-NegativeStaphylococci  275Mark E. Rupp and Paul D. Fey

130 Streptococcus pyogenes  277Amy E. Bryant and Dennis L. Stevens

131 NonsuppurativePoststreptococcalSequelae:RheumaticFeverandGlomerulonephritis  279Stanford T. Shulman and Alan L. Bisno

132 Streptococcus pneumoniae  281Edward N. Janoff and Daniel M. Musher

133 EnterococcusSpecies,Streptococcus gallolyticusGroup,andLeuconostocSpecies  283Cesar A. Arias and Barbara E. Murray

134 Streptococcus agalactiae(GroupBStreptococcus)  285Morven S. Edwards and Carol J. Baker

135 ViridansStreptococci,NutritionallyVariantStreptococci,GroupsCandGStreptococci,andOtherRelatedOrganisms  287Scott W. Sinner and Allan R. Tunkel

136 Streptococcus anginosusGroup  289Cathy A. Petti and Charles W. Stratton IV

137 Corynebacterium diphtheriae(Diphtheria)  290Rob Roy MacGregor

138 OtherCoryneformBacteriaandRhodococci  292Rose Kim and Annette C. Reboli

139 Listeria monocytogenes  293Bennett Lorber

140 Bacillus anthracis(Anthrax)  296Gregory J. Martin and Arthur M. Friedlander

141 BacillusSpeciesandRelatedGeneraOtherThanBacillus anthracis  298Thomas Fekete

142 Erysipelothrix rhusiopathiae  299Annette C. Reboli

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143 Whipple’sDisease  300Thomas Marth and Thomas Schneider

144 Neisseria meningitidis  301David S. Stephens and Michael A. Apicella

145 Neisseria gonorrhoeae(Gonorrhea)  305Jeanne M. Marrazzo and Michael A. Apicella

146 Moraxella catarrhalis, Kingella,andOtherGram-NegativeCocci  307Timothy F. Murphy

147 Vibrio cholerae  308Matthew K. Waldor and Edward T. Ryan

148 OtherPathogenicVibrios  312Marguerite A. Neill and Charles C. J. Carpenter

149 Campylobacter jejuniandRelatedSpecies  314Ban Mishu Allos, Nicole M. Iovine, and Martin J. Blaser

150 Helicobacter pyloriandOtherGastricHelicobacterSpecies  315Timothy L. Cover and Martin J. Blaser

151 Enterobacteriaceae  316Michael S. Donnenberg

152 Pseudomonas aeruginosaandOtherPseudomonasSpecies  317Erika D’Agata

153 Stenotrophomonas maltophiliaandBurkholderia cepacia  318Amar Safdar

154 Burkholderia pseudomalleiandBurkholderia mallei: MelioidosisandGlanders  320Bart J. Currie

155 AcinetobacterSpecies  323Michael Phillips

156 SalmonellaSpecies  324David A. Pegues and Samuel I. Miller

157 BacillaryDysentery:ShigellaandEnteroinvasiveEscherichia coli  325Herbert L. DuPont

158 HaemophilusSpecies,IncludingH. influenzaeandH. ducreyi(Chancroid)  326Timothy F. Murphy

159 Brucellosis(BrucellaSpecies)  328H. Cem Gul and Hakan Erdem

160 Francisella tularensis(Tularemia)  330Robert L. Penn

161 PasteurellaSpecies  335John J. Zurlo

162 YersiniaSpecies(IncludingPlague)  337Paul S. Mead

163 Bordetella pertussis  339Valerie Waters and Scott A. Halperin

164 Rat-BiteFever:Streptobacillus moniliformisandSpirillum minus  341Ronald G. Washburn

165 Legionnaires’DiseaseandPontiacFever  342Paul H. Edelstein and Craig R. Roy

166 Capnocytophaga  344J. Michael Janda

167 Bartonella,IncludingCat-ScratchDisease  346Tejal N. Gandhi, Leonard N. Slater, David F. Welch, and Jane E. Koehler

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168 Klebsiella granulomatis(Donovanosis,GranulomaInguinale)  348Ronald C. Ballard

169 OtherGram-NegativeandGram-VariableBacilli  349James P. Steinberg and Eileen M. Burd

170 Syphilis(Treponema pallidum)  351Justin D. Radolf, Edmund C. Tramont, and Juan C. Salazar

171 EndemicTreponematoses  353Edward W. Hook III

172 LeptospiraSpecies(Leptospirosis)  354David A. Haake and Paul N. Levett

173 RelapsingFeverCausedbyBorreliaSpecies  356James M. Horton

174 LymeDisease(LymeBorreliosis)DuetoBorrelia burgdorferi  357Allen C. Steere

175 Clostridium difficileInfection  358Dale N. Gerding and Vincent B. Young

176 Tetanus(Clostridium tetani)  360Aimee Hodowanec and Thomas P. Bleck

177 Botulism(Clostridium botulinum)  361Aimee Hodowanec and Thomas P. Bleck

178 GasGangreneandOtherClostridium-AssociatedDiseases  362Andrew B. Onderdonk and Wendy S. Garrett

179 Bacteroides, Prevotella, Porphyromonas,andFusobacteriumSpecies(andOtherMedicallyImportantAnaerobicGram-NegativeBacilli)  364Wendy S. Garrett and Andrew B. Onderdonk

180 Mycobacterium tuberculosis  365Daniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas

181 Mycobacterium leprae(Leprosy)  371Cybèle A. Renault and Joel D. Ernst

182 Mycobacterium aviumComplex  373Fred M. Gordin and C. Robert Horsburgh, Jr.

183 InfectionsCausedbyNontuberculousMycobacteriaOtherThanMycobacterium AviumComplex  375Barbara A. Brown-Elliott and Richard J. Wallace, Jr.

184 NocardiaSpecies  378Tania C. Sorrell, David H. Mitchell, Jonathan R. Iredell, and Sharon C-A. Chen

185 AgentsofActinomycosis  380Thomas A. Russo

G MYCOSES186 AspergillusSpecies  381

Thomas F. Patterson

187 AgentsofMucormycosisandEntomophthoramycosis  385Dimitrios P. Kontoyiannis and Russell E. Lewis

188 Sporothrix schenckii  386John H. Rex and Pablo C. Okhuysen

189 AgentsofChromoblastomycosis  387Duane R. Hospenthal

190 AgentsofMycetoma  388Duane R. Hospenthal

191 Cryptococcosis(Cryptococcus neoformansandCryptococcus gattii)  390John R. Perfect

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192 Histoplasma capsulatum(Histoplasmosis)  393George S. Deepe, Jr.

193 Blastomycosis  396Robert W. Bradsher, Jr.

194 Coccidioidomycosis(CoccidioidesSpecies)  398John N. Galgiani

195 Dermatophytosis(Ringworm)andOtherSuperficialMycoses  400Roderick J. Hay

196 Paracoccidioidomycosis  402Angela Restrepo, Angela María Tobón, and Luz Elena Cano

197 UncommonFungiandRelatedSpecies  404Duane R. Hospenthal

198 PneumocystisSpecies  410Peter D. Walzer, A. George Smulian, and Robert F. Miller

199 Microsporidiosis  412Louis M. Weiss

H PROTOZOALDISEASES200 EntamoebaSpecies,IncludingAmebicColitisandLiverAbscess  413

William A. Petri, Jr., and Rashidul Haque

201 Free-LivingAmebae  415Anita A. Koshy, Brian G. Blackburn, and Upinder Singh

202 Malaria(PlasmodiumSpecies)  417Rick M. Fairhurst and Thomas E. Wellems

203 LeishmaniaSpecies:Visceral(Kala-Azar),Cutaneous,andMucosalLeishmaniasis  419Alan J. Magill

204 TrypanosomaSpecies(AmericanTrypanosomiasis,Chagas’Disease):BiologyofTrypanosomes  420Louis V. Kirchhoff

205 AgentsofAfricanTrypanosomiasis(SleepingSickness)  422Louis V. Kirchhoff

206 Toxoplasma gondii  424José G. Montoya, John C. Boothroyd, and Joseph A. Kovacs

207 Giardia lamblia  426David R. Hill and Theodore E. Nash

208 Trichomonas vaginalis  428Jane R. Schwebke

209 BabesiaSpecies  429Jeffrey A. Gelfand and Edouard G. Vannier

210 Cryptosporidiosis(CryptosporidiumSpecies)  431A. Clinton White, Jr.

211 Cyclospora cayetanensis, Cystoisospora (Isospora) belli, SarcocystisSpecies,Balantidium coli,andBlastocystisSpecies  432Kathryn N. Suh, Phyllis Kozarsky, and Jay S. Keystone

I DISEASESDUETOTOXICALGAE212 HumanIllnessAssociatedwithHarmfulAlgalBlooms  435

J. Glenn Morris, Jr.

J DISEASESDUETOHELMINTHS213 IntestinalNematodes(Roundworms)  437

James H. Maguire

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214 TissueNematodes(Trichinellosis,Dracunculiasis,Filariasis,Loiasis,andOnchocerciasis)  439James W. Kazura

215 Trematodes(SchistosomesandLiver,Intestinal,andLungFlukes)  440James H. Maguire

216 Tapeworms(Cestodes)  443Charles H. King and Jessica K. Fairley

217 VisceralLarvaMigransandOtherUncommonHelminthInfections  445Theodore E. Nash

K ECTOPARASITICDISEASES218 Lice(Pediculosis)  446

James H. Diaz

219 Scabies  448James H. Diaz

220 MyiasisandTungiasis  450James H. Diaz

221 Mites,IncludingChiggers  452James H. Diaz

222 Ticks,IncludingTickParalysis  453James H. Diaz

L DISEASESOFUNKNOWNETIOLOGY223 KawasakiDisease  454

Jane C. Burns

III SPECIALPROBLEMS

A NOSOCOMIALINFECTIONS224 InfectionsCausedbyPercutaneousIntravascularDevices  456

Susan E. Beekmann and David K. Henderson

225 NosocomialPneumonia  458Michael Klompas

226 NosocomialUrinaryTractInfections  460Thomas M. Hooton

227 HealthCare–AcquiredHepatitis  462Kent A. Sepkowitz

228 Transfusion-andTransplantation-TransmittedInfections  463Matthew J. Kuehnert and Sridhar V. Basavaraju

B INFECTIONSINSPECIALHOSTS229 ProphylaxisandEmpiricalTherapyofInfectioninCancerPatients  464

Elio Castagnola, Małgorzata Mikulska, and Claudio Viscoli

230 InfectionsinRecipientsofHematopoieticStemCellTransplants  470Jo-Anne H. Young and Daniel J. Weisdorf

231 InfectionsinSolid-OrganTransplantRecipients  474Nina Singh and Ajit P. Limaye

232 InfectionsinPatientswithSpinalCordInjury  475Rabih O. Darouiche

233 InfectionsintheElderly  476Kent B. Crossley and Phillip K. Peterson

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234 InfectionsinAsplenicPatients  477Janet R. Gilsdorf

235 InfectionsinInjectionDrugUsers  479Donald P. Levine and Patricia D. Brown

236 SurgicalSiteInfectionsandAntimicrobialProphylaxis  482Thomas R. Talbot

C SURGICAL-ANDTRAUMA-RELATEDINFECTIONS237 Burns  486

Clinton K. Murray

238 Bites  487Ellie J. C. Goldstein and Fredrick M. Abrahamian

D ZOONOSES239 Zoonoses  490

W. Ian Lipkin

E PROTECTIONOFTRAVELERS240 ProtectionofTravelers  491

David O. Freedman

241 InfectionsinReturningTravelers  493David O. Freedman

PART I

Major Clinical Syndromes

2

A  Fever

1  Fever of Unknown OriginWilliam F. Wright and Philip A. Mackowiak

DEFINITION• Occurrenceofseveraloccasionsoffeverhigherthan38.3°C(101°F)withadurationgreater

thanat least3weeksdespite1weekofhospitalevaluationisstillrecognizedastheclassicdefinitionforfeverofunknownorigin(FUO).

• Theadventof improveddiagnostic testingmodalitiescoupledwithan increasingnumberof immunocompromised patients led to a revised definition in which cases of FUO arecurrently codified into four distinct subclasses: classic FUO, health care–associated FUO,immune-deficientFUO,andhumanimmunodeficiencyvirus(HIV)-relatedFUO.

ETIOLOGY AND EPIDEMIOLOGY• Infections, neoplasms, connective tissue diseases, miscellaneous causes, and undiagnosed

feversremainthemostcommoncausesofclassicFUO.• The frequencywithwhich infectionsandneoplasmshavebeen identifiedas thecausesof

classic FUO has decreased steadily, whereas the proportion of miscellaneous causes andundiagnosedconditionshasriseninrecentyears.

DIAGNOSIS• Acomprehensivemedicalhistorywithverificationoffeverandadetailedphysicalexamina-

tionareessentialindirectingformallaboratorytesting.

THERAPY• Empirical therapeutic trials of antimicrobial agents continue to have a limited role in the

managementofpatientswithFUO.• Owingtotherelativelyhighprevalenceofseriousbacterialinfectionsresponsibleforfevers

inpatientswithneutropenia,suchpatientsshouldreceivebroad-spectrumantipseudomonaltherapyimmediatelyaftersamplesforappropriatecultureshavebeenobtained.

PROGNOSIS• AlthoughtheprognosisofanFUOisdeterminedby itsetiologyandunderlyingdiseases,

mostpatientswithprolongedundiagnosedFUOgenerallyhaveafavorableoutcome.

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2 The Acutely Ill Patient with Fever and RashDavid J. Weber, Myron S. Cohen, and William A. Rutala

DEFINITION• Skinlesionsarefrequentlypresentinacutelyillpatientswithseriousinfectiousdiseasesand

mayprovideimportantcluesthataidinearlydiagnosisandtreatment.

EPIDEMIOLOGY• Acutelyillpatientswithapotentialinfectiousdiseaseandskinlesions(orrash)shouldhave

ahistoryobtainedthatelicits the following:recentdrug ingestion; traveloutside the localarea;potentialoccupationalexposures;recentimmunizations;riskfactorsforsexuallytrans-mittedinfections,includinghumanimmunodeficiencyvirusinfection;factorsaffectinghostresistanceor immunocompromisingconditions;priorallergies toantibiotics;recentexpo-surestofebrileorillpersons;exposuretoruralhabits,insects,arthropods,andwildanimals;andexposuretopetsoranimals.

• Patientswithskinlesionsorrashesconsistentwithacommunicableinfectiousdisease(e.g.,invasive meningococcal infection) should be immediately placed on appropriate isolationprecautions(i.e.,contact,droplet,orairborne).

• Infectiousdiseasephysiciansshouldbe familiarwith theskin lesions(orrash) thatmightaccompanyapatientwithdisease that couldbe the resultof the intentionaluseof abio-weapon(e.g.,anthrax,smallpox,plague,viralhemorrhagicfevers).

MICROBIOLOGY• Serious bacterial infections with skin lesions include Staphylococcus aureus (toxic shock

syndrome,scaldedskinsyndrome),Streptococcus pyogenes(toxicshocksyndrome),Salmo­nella entericaserotypeTyphi,Neisseria meningitidis,andRickettsia rickettsii.

• Potentiallyseriousviral infectionswithskin lesions includemeasles, rubella,Epstein-Barrinfection,cytomegalovirus,humanherpesvirus6,andviralhemorrhagicfevers(e.g.,Ebola,Marburg,Lassa).

• Life-threatening drug reactions may result from antibiotic therapy for disorders such asStevens-Johnsonsyndrome/toxicepidermolysisnecrosisandfromdrugreactionwitheosin-ophiliaandsystemicsymptoms(DRESS).

DIAGNOSIS• Keyaspectsofskinlesionsthataidinaproperdiagnosisinclude(1)primarytype(s)ofskin

lesions,(2)distributionofthelesions,(3)patternofprogressionoftherash,and(4)timingofonsetoftherashrelativetotheonsetoffeverandothersystemicsigns.

• The appearance of skin lesions may be very useful in the diagnosis of specific infectiousdiseases. Maculopapular rashes are usually seen in viral illnesses, drug eruptions, andimmune complex–mediated diseases. Nodular lesions are suggestive of mycobacteria orfungalinfections.Diffuseerythemasuggestsscarletfever,toxicshocksyndrome,Kawasakidisease, or Stevens-Johnson syndrome/toxic epidermal necrolysis. Bullous lesions suggeststreptococcal erysipelas with necrotizing fasciitis, ecthyma gangrenosum, and Vibrio

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infections.Petechialeruptionssuggestgram-negativesepsis,invasiveNeisseria meningitidisinfection,andrickettsialinfections.

• Considerationshouldbegiventobiopsyofskinlesions, ifpresent, inacutelyill immuno-compromisedpatientsforappropriatestains(e.g.,Gramstain,fungalstain)andculturesandforpathologicstudy.

THERAPY• Empiricaltherapyshouldoftenbeinitiatedinacutelyillpatientswithskinlesionsbasedon

theclinicaldiagnosis.• Mostacutelyillpatientswithskinlesionswillrequiresystemictherapy.

PREVENTION• Standard vaccines should be provided to children and adults because many vaccine-

preventablediseasesproducerashes(e.g.,measles,rubella,varicella).• Underlyingnoninfectiousdiseasesthatleadtodisruptionofskinshouldbetreatedbecause

thedamagedskinservesasriskfactorforinfection.

5

B  Upper Respiratory Tract Infections

3  The Common ColdRonald B. Turner

DEFINITION• Thecommoncoldisanupperrespiratoryillnessthatincludesrhinorrheaandnasalobstruc-

tionasprominentsymptoms.

EPIDEMIOLOGY• Commoncoldillnessesoccur5to7timesperyearinchildrenand2to3timesperyearin

adults.• Illnesses occur most commonly between the early fall and late spring in temperate

climates.• Transmissionoftheviralpathogenscausingthecommoncoldmayoccurviadirectcontact,

large-particleaerosol,orsmall-particleaerosol.

MICROBIOLOGY• Therhinovirusesareresponsibleforthemajorityofcommoncoldillnesses.• Coronavirus,respiratorysyncytialvirus,andmetapneumovirusmayalsobeassociatedwith

thecommoncoldsyndrome.• Otherrespiratoryvirusesmaycausecommoncoldsymptomsbutarefrequentlyassociated

withlowerrespiratorysymptomsinadditiontotheupperrespiratoryillness.• Coinfectionwithmorethanonepathogeniscommonintheseillnesses.

DIAGNOSIS• Thediagnosisofthecommoncoldisaclinicaldiagnosis.• Theresponsiblepathogen(s)canbedeterminedbypolymerasechainreactionassay,butthis

israrelyusefulinthemanagementofthepatient.

THERAPY• Therearenospecificantiviralagentsthatareusefulfortreatmentofthecommoncold.• Managementdependsonsymptomatictherapywithtreatmentdirectedatthemostbother-

somesymptoms.

PREVENTION• Therearenoproveninterventionsforpreventionofthecommoncold.

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4  PharyngitisAnthony R. Flores and Mary T. Caserta

DEFINITION• Pharyngitisisdefinedasthetriadofsorethroat,fever,andpharyngealinflammation.• Generallyaprimarydisease,pharyngitismaybeassociatedwithsystemicdisorders.

EPIDEMIOLOGY• Pharyngitis isoneof themostcommondisorders inadultsandchildren,withmore than

10millionambulatoryvisitsperyear.• The highest burden of disease is found in children and young adults, with 50% of cases

identifiedbetweentheagesof5to24years.• In temperate climates, most cases occur in winter months, corresponding with peaks in

respiratoryviruses.

MICROBIOLOGY• Virusesarethesinglemostcommoncauseofpharyngitis,withadenovirusbeingthemost

commonlyidentified(seeTable4-1).• Group A Streptococcus (GAS) is the bacterial cause for which ample evidence exists for

antibiotictherapytopreventpostinfectioussequelae.• Fusobacterium necrophorum has been recently recognized as a cause of pharyngitis with

potentialseverecomplications(i.e.,Lemierresyndrome),especiallyinyoungadults.

DIAGNOSIS• Essential to diagnosis is the identification of treatable causes (e.g., GAS) to prevent

complications.• SignsandsymptomsofGASpharyngitisincludeacuteonsetofsorethroatwithtonsillaror

pharyngealexudates,tenderanteriorcervicallymphadenopathy,andfever(seeTable4-2).• Signs and symptoms consistent with viral etiologies include conjunctivitis, coryza, oral

ulcers,cough,anddiarrhea.• TestingforGASpharyngitisshouldnotbepursuedinthosewithsignsandsymptomsindica-

tiveofaviraletiology(seeTable4-3).• Rapidantigendetectiontests(RADTs)alonearesufficientforthediagnosisofGASinadults,

butnegativeresultsshouldbebackedupbythroatcultureinchildren.• Specifictechniquesshouldbeusedtoidentifyothercauseswhereappropriate.

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THERAPY• Treatment of pharyngitis is focused on prevention of postinfectious sequelae (e.g., acute

rheumaticfever)fromGAS.• Penicillin and its derivatives remain the primary treatment for GAS pharyngitis (see

Table4-4).• Antimicrobial therapy should not be used to prevent GAS pharyngitis except in special

circumstances.• Given thepotential severityofcomplications frompharyngitis causedbyF. necrophorum,

signs of bacteremia or neck swelling warrant expansion of antibiotic therapy and furtherevaluation.

TABLE 4-1  Microbial Causes of Acute Pharyngitis

PATHOGEN ASSOCIATED DISORDER(S)

BacteriaStreptococcus, group A Pharyngitis, tonsillitis, scarlet fever

Streptococcus, groups C and G Pharyngitis, tonsillitis

Mixed anaerobes Vincent’s angina

Fusobacterium necrophorum Pharyngitis, tonsillitis, Lemierre syndrome

Neisseria gonorrhoeae Pharyngitis, tonsillitis

Corynebacterium diphtheria Diphtheria

Arcanobacterium haemolyticum Pharyngitis, scarlatiniform rash

Yersinia pestis Plague

Francisella tularensis Tularemia, oropharyngeal form

Treponema pallidum Secondary syphilis

VirusesRhinovirus Common cold

Coronavirus Common cold

Adenovirus Pharyngoconjunctival fever

Herpes simplex type 1 and 2 Pharyngitis, gingivostomatitis

Parainfluenza Cold, croup

Enteroviruses Herpangina, hand-foot-mouth disease

Epstein-Barr virus Infectious mononucleosis

Cytomegalovirus CMV mononucleosis

Human immunodeficiency virus Primary HIV infection

Influenza A and B Influenza

Respiratory syncytial virus Cold, bronchiolitis, pneumonia

Human metapneumovirus Cold, bronchiolitis, pneumonia

MycoplasmaMycoplasma pneumoniae Pneumonia, bronchitis, pharyngitis

ChlamydiaChlamydia psittaci Acute respiratory disease, pneumonia

Chlamydia pneumoniae Pneumonia, pharyngitis

CMV, cytomegalovirus; HIV, human immunodeficiency virus.Modified from Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007;21:449-469, vii;

with permission.

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TABLE 4-2  Clinical and Epidemiologic Findings Associated with Group A Streptococcus Pharyngitis

Suggestive of Group A StreptococcusSudden onsetSore throatFeverHeadacheNausea, vomiting, and abdominal painInflammation of pharynx and tonsilsPatchy discrete exudatesTender, enlarged anterior cervical nodesPatient aged 5-15 yrPresentation in winter or early springHistory of exposure

Suggestive of Viral EtiologyConjunctivitisCoryzaCoughDiarrheaDiscrete ulcerative lesions

Suggestive of Complications of PharyngitisDysphagiaStridorDroolingDysphoniaMarked neck swellingRespiratory distressPharyngeal pseudomembraneHemodynamic instabilityHIV behavioral riskTravel to or exposure to individuals from a region endemic for diphtheriaLack of diphtheria immunization

HIV, human immunodeficiency virus.Modified from Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and manage-

ment of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55:e86-e102; and Kociolek LK, Shulman ST. In the clinic. Pharyngitis. Ann Intern Med. 2012;157:ITC3-1-ITC3-16; with permission.

TABLE 4-3  Modified Centor Score and Culture Management Approach for Pharyngitis

CRITERIA POINTSTemperature >38° C 1

Absence of cough 1

Swollen, tender anterior cervical nodes 1

Tonsillar swelling or exudate 1

Age3-14 yr 1

15-44 yr 0

45 yr or older −1

SCORERISK OF STREPTOCOCCAL INFECTION

SUGGESTED MANAGEMENT

≤0 1%-2.5% No further testing or antibiotic

1 5%-10%

2 11%-17% Culture all: antibiotics only for positive culture results3 28%-35%

≥4 51%-53% Treat empirically with antibiotics and/or culture

From McIsaac WJ, Kellner JD, Aufricht P, et al. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA. 2004;291:1587-1595; with permission.

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TABLE 4-4  Antimicrobial Therapy for Group A Streptococcal Pharyngitis

DRUG DOSE DURATION

Oral RegimensPenicillin V Children: 250 mg bid or tid

Adolescents and adults: 250 mg tid or qid or 500 mg bid10 days

Amoxicillin 50 mg/kg once daily (maximum 1000 mg)Alternative: 25 mg/kg bid (maximum 500 mg)

10 days

For Penicillin-Allergic PatientsErythromycin Varies with formulation 10 days

First-generation cephalosporins Varies with agent 10 days

Intramuscular RegimensBenzathine penicillin G 600,000 units for patients <27 kg 1 dose

1.2 million units for patients ≥27 kg 1 dose

Mixtures of benzathine and procaine penicillin G

Varies with formulation 1 dose

Modified from Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007;21:449-469, vii; with permission.

10

5 Acute LaryngitisMary T. Caserta

DEFINITION• Acutelaryngitisisaclinicalsyndromecharacterizedbyahoarsevoicewithdecreasedphona-

tionandvoiceprojection,usuallyoccurringafteranupperrespiratorytractinfectionwithcough.

EPIDEMIOLOGY• Approximately1%ofmedicalcareclaimsareduetodysphonia,with42%ofthoseclassified

asacutelaryngitis.• Two percent of individuals with acute respiratory symptoms are diagnosed with acute

laryngitis.• Acute laryngitis is diagnosed more frequently in women (mean age, 36 years) than men

(meanage,41years).• Morecasesarediagnosedinthecoldermonthsoftheyear.

MICROBIOLOGY• Aviralupperrespiratorytractinfectionisoftenassociated(seeTable5-1).• Bacterialinfectionsoftheupperrespiratorytracthavealsobeenimplicated.• Unusualcausesincludetuberculosis,blastomycosis,histoplasmosis,coccidiomycosis,cryp-

tococcosis,andherpesvirusinfectionsofthelarynx.

DIAGNOSIS• Clinicaldiagnosisisbasedontheappropriatehistoryandchangesofthevoice.• Visualizationofthelarynxrevealsedemaandvascularengorgementofthemucousmem-

braneswithhyperemicanderythematousvocalfolds.

THERAPY• Treatmentisbasedontheunderlyingcauseofthelaryngealpathologicprocess.• Often,symptomatictherapywithvoicerest,analgesics,andhumidificationissufficient.

TABLE 5-1  Frequency of Laryngitis Associated with Common Respiratory Pathogens

PATHOGEN FREQUENCY (%)Rhinovirus 25-29

Influenza 28-35

Parainfluenza 8.5

Adenovirus 22-35

Coronavirus 25

Mycoplasma pneumoniae 3-37

Chlamydia pneumoniae 30

Group A β-hemolytic streptococcus 2.3-19

Human metapneumovirus 3-91

11

6 Croup in Children (Acute Laryngotracheobronchitis)John Bower and John T. McBride

DEFINITION• Croupisanacuteviralinfectionoftheupperairwaypresentingasstridorandabrassycough.• Mostchildrendevelopcrouponlyonce,butafewchildrendeveloprecurrentepisodescalled

spasmodiccroup.

EPIDEMIOLOGY• Croupcanbesporadicbutusuallyoccursinepidemicsinthefallthatintemperateclimates

recentlyhavebeenworseinodd-numberedyears.

ETIOLOGY AND MICROBIOLOGY• Parainfluenzatype1virusinfectionisthemostcommoncauseofviralcroup.• Theotherparainfluenzaviruses,respiratorysyncytialvirus(RSV),adenovirus,andmeasles

areafewoftheotheragentsassociatedwithviralcroup.• Bacterialinfectionsoftheairway,includingepiglottitis(Haemophilus influenzaetypeb)and

tracheitis(Staphylococcus aureus, Streptococcus),representmedicalemergenciesandshouldberapidlydiscriminatedfromviralcroup.

• Diphtheria should be considered in the developing world and in nonimmunizedpopulations.

DIAGNOSIS• Diagnosisisclinical,althoughradiographsoftheupperairwaymaybehelpful.• Children with epiglottitis and bacterial tracheitis are typically toxic and have difficulty

swallowingandusuallylackthebrassycoughandharshstridor.• Recurrent(spasmodic)croupmaybemorecommoninchildrenwithatopyorgastroesopha-

gealreflux.

THERAPY• Homeremediesincludingmistandcoldairhavenotbeenproventobeeffective.• Asingledoseofasystemiccorticosteroiddecreasestheseverityandlengthofcroup.

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7 Otitis Externa, Otitis Media, and MastoiditisJerome O. Klein

DEFINITIONOtitis Externa• Otitisexternaisaninfectionandinflammationoftheexternalauditorycanal.

Otitis Media• Acuteotitismedia(AOM)isanacuteillnessmarkedbythepresenceoffluidinthemiddle

earandinflammationof themucosa liningthemiddleearspace.Fluidmaypersist inthemiddleearforweekstomonthsafterappropriatelytreatedAOMandistermedotitismediawitheffusion.

Mastoiditis• Mastoiditis is infectionandinflammationofthemastoidaircellsandusuallyresultsfrom

episodesofsevereAOM.

EPIDEMIOLOGYOtitis Externa• Acutediffuseotitisexternaorswimmer’searoccursinhothumidweather.• Invasiveormalignantotitis externaoccurs indiabetic, immunocompromised,anddebili-

tatedpatients.• Childrenarepronetoplaceforeignobjectsintheexternalearcanal,whichmaycausemac-

erationandinfectionoftheskinliningtheexternalcanal.

Otitis Media• Otitismediaoccursatallages,butthepeakagegroupischildreninthefirst3yearsoflife.• Childrenatriskforsevereandrecurrentotitismediaaremorefrequentlymale,haveagenetic

predisposition to ear infections, and may be in large-group daycare exposed to frequentrespiratoryvirusesandbacterialpathogens.

Mastoiditis• Theepidemiologyofmastoiditisparallelsthatofotitismedia.

MICROBIOLOGYOtitis Externa• Themicrobialmicrobiotaoftheexternalearcanalresponsibleforotitisexternaissimilarto

thatofskinelsewhere,includingstaphylococcalspeciesandanaerobicbacteria.• Pseudomonas aeruginosaisafrequentcauseofswimmer’searandmalignantotitisexterna.

Otitis Media• Streptococcus pneumoniae and nontypeable Haemophilus influenzae are the most frequent

bacterialpathogensinallagegroups.• Moraxella catarrhalis, group A Streptococcus and Staphylococcus aureus are less frequent

causesofAOM.• RespiratoryvirusesarefrequentcausesofAOMaloneorassociatedwithbacterialpathogens.

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Mastoiditis• ThemicrobiologyofmastoiditisissimilartothatofAOM.• Patients with persistent perforation of the tympanic membrane may have invasion of

the mastoid by organisms present in the external ear canal, including S. aureus andP. aeruginosa.

DIAGNOSISOtitis Externa• Acute localized otitis externa may occur as a pustule or furuncle that is visualized in the

canal.• Swimmer’searisidentifiedbyedema,swelling,anderythemaofthecanalwall.• Malignantotitisexternaisassociatedwithseverepainandtendernessofthetissuesaround

thepinnaandmastoid;pusmaybepresentinthecanal.

Otitis Media• AOMisanacuteillnesswithfluidinthemiddleearandbulgingordecreasedmobilityand

inflammationofthetympanicmembrane.

Mastoiditis• Thesignsofmastoiditisincludeswelling,redness,andtendernessoverthemastoidbone.• The pinna is displaced downward and outward, and a purulent discharge may emerge

throughaperforationofthetympanicmembrane.

THERAPYOtitis Externa• Swimmer’searmaybemanagedwithgentlecleansingandirrigationoftheexternalcanal.• Antibiotic solutions, including fluoroquinolone eardrops, are effective in localized

infections.• Systemic antimicrobial therapy, including activity against P. aeruginosa, is necessary to

manageinvasiveexternalotitis.

Otitis Media• High-doseamoxicillinisthepreferreddrugforpatientswithAOM.• Ifamoxicillinfails,amoxicillin-clavulanateorparenteralceftriaxoneispreferred.• SomechildrenwithAOMimprovewithoutuseofantimicrobialagents.• Placementoftympanostomytubesmaybewarrantedforchildrenwithsevereandrecurrent

episodesofAOM.

Mastoiditis• AntimicrobialtherapyissimilartothatofAOM.• Incisionanddrainagemaybenecessarywhenabscessesforminthemastoidaircells.

PREVENTIONOtitis Externa• Patientsshouldbedissuadedfromplacingforeignobjects,includingcotton-tippedapplica-

tors,intheexternalcanal.

Otitis Media• Chemoprophylaxis may be of value for prevention of episodes of AOM in children with

severeandrecurrentdisease.• PneumococcalconjugatevaccineshavebeeneffectiveinreducingepisodesofAOMdueto

vaccineserotypes.• InfluenzavirusvaccinesreducetheincidenceofAOMduringthewinterrespiratoryseason.

Mastoiditis• PreventionissimilartothatofAOM.

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8  SinusitisGregory P. DeMuri and Ellen R. Wald

DEFINITION• Sinusitisisdefinedasaninflammatorydisorderoftheparanasalsinuses.

EPIDEMIOLOGY• Bacterialinfectionofthesinusesisestimatedtooccurin0.5%to2%ofcasesofviralupper

respiratoryinfection(URI)inadultsand6%to13%ofchildren.

MICROBIOLOGY• Classicstudiesofthebacteriologyofsinusitishaveobtainedaspecimenofsinussecretions

bypunctureofthemaxillaryantrumtoreducetheriskofnasalcontamination.• Streptococcus pneumoniaeisthemostfrequentlyisolatedorganism,followedbynontypeable

Haemophilus influenzaeandMoraxella catarrhalis.• Staphylococcus aureusisnotlikelyasignificantcauseofacutesinusitisbutdoesplayarole

inthecomplicationsofsinusitis.• The frequency of isolation of S. pneumoniae is decreasing recently with an increase in

β-lactamase–producingH. influenzae.

DIAGNOSIS• Imaging studies are not indicated for the routine diagnosis of acute sinusitis but may be

usefulwhencomplicationsaresuspected.• The following three clinical presentations will identify patients with acute bacterial

sinusitis:• Onset with persistent symptoms or signs, lasting at least 10 days without evidence of

clinicalimprovement• Onsetwithseveresymptomsorsignsofhighfever(≥39°C)andpurulentnasaldischarge

lastingfor3to4consecutivedays• Onsetwithworseningsymptomsorsignscharacterizedbythenewdevelopmentoffever,

headache,or increasednasaldischargeaftera typicalviralURI that lasted5 to6dayswithinitialimprovement

THERAPY• Formostadultsandchildren,amoxicillinwithorwithoutclavulanateremainsanexcellent

first-lineagentforthetreatmentofsinusitis.• Second-line agents include fluoroquinolones, cefdinir, cefuroxime, or the combination of

cefiximewitheitherclindamycinorlinezolid.• The duration of therapy should be for 7 days after the patient becomes free of signs and

symptoms.• Adjunctivetherapiessuchasantihistamines,decongestants,nasalsteroids,andnasalwashes

haveprovidedminimalimprovementinacutesinusitis.• Surgicaldrainageisindicatedforthecomplicationsofacutebacterialsinusitis.

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9  EpiglottitisJennifer L. Nayak and Geoffrey A. Weinberg

EPIDEMIOLOGY AND ETIOLOGY• Pediatric epiglottitis: a localized, invasive Haemophilus influenzae type b infection of the

supraglotticarea, including theepiglottis, that canbeassociatedwithbacteremia (60% to98%);routineconjugatevaccinationhaslargelyeliminatedthisformofepiglottitis.

• Adult epiglottitis:ofteninvolvesmoreofthesupraglotticstructures(aryepiglotticfolds,val-lecula,tonguebase)andisnotassociatedwithbacteremia(<15%);whenabacterialpathogenis identified, it is more likely to be Streptococcus pneumoniae, Streptococcus pyogenes, orNeisseria meningitidis.

• BeforeroutineinfantimmunizationwithH. influenzaetypebconjugatevaccines65%to75%ofallpatientswithepiglottitiswerechildren1to4yearsofage;currently,90%to95%areadults.

• Incidenceofadultepiglottitis in theUnitedStatesandEurope isapproximately2/100,000population.

CLINICAL MANIFESTATIONS• Pediatric epiglottitis:anabruptillnessinafebrileyoungchildwithatoxicappearance,dys-

phagia or sore throat, a muffled or hoarse voice, stridor, drooling, and often a distinctiveposture—the“tripodposition,”comprisingapprehension,sittingverystill,preferringtoleanforward with hyperextension of the neck, and protrusion of the chin. Cough is distinctlyuncommon.

• Adult epiglottitis:80%to95%haveodynophagiaandsorethroat;only20%to40%havefever,drooling,orstridor.

DIAGNOSIS• Airwaymanagementshouldbepromptlyevaluatedassoonasthediagnosisisconsidered.

Laboratoryandradiologictestinginachildwithsuspectedepiglottitisshouldbeperformedonlyinasafeenvironment(i.e.,intheoperatingroom,emergencydepartment,orintensivecareunit,withanindividualtrainedinpediatricairwayintubation),becauseofthepropen-sitytodevelopacuteairwayobstruction(althoughairwayobstructionismuchlesscommoninadults).

• Peripheral leukocytosis is common but not universal. Lateral and anteroposterior neckradiographsshowenlargementoftheepiglottis(the“thumbsign,”asopposedtothe“pencil-pointnarrowing”oftheairwayinviralcroup).

• Directorindirectlaryngoscopyandfiberopticnasopharyngealendoscopyarethedefinitivediagnostictests.

DIFFERENTIAL DIAGNOSIS• Stridorwithtoxicityanddroolingbutlackofcoughfavorsepiglottitis;stridor,barkingcough,

and lack of drooling favors viral croup (laryngotracheobronchitis). Other conditions thatmimicinfectiousepiglottitisincludebacterialtracheitis,thermalepiglottitis(scaldburnfrom

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smoke or hot beverages), possibly angioneurotic edema, retropharyngeal or peritonsillarabscesses,uvulitis,anddiphtheria.

THERAPY• Pediatric epiglottitis:Ideally,diagnosisisconfirmedbyvisualizationatthetimetheairwayis

securedbyintubation,atwhichtimelaryngealandbloodculturesandcompletebloodcellcountsmaybeobtained.Emergenttracheotomyorcricothyroidotomyisrarelyrequired.

• Adult epiglottitis: In contrast to children, adults with epiglottitis generally tolerate directvisualizationoftheepiglottisfordiagnosis.Hospitalizationinanintensivecareunitduringtheacutephaseoftheillnessissuggested;however,inmostadults(75%to80%)theinfectionissuccessfullymanagedwithoutendotrachealintubationortracheotomy.

• Empiricaltherapyforepiglottitisincludesintravenouscefotaxime,ceftriaxone,orampicillin-sulbactam to treat streptococci, pneumococci, H. influenzae, and meningococci. Inareaswithahighproportionofdrug-resistantpneumococci, empirical therapy shouldbebroadened.

• TherapydirectedagainstStaphylococcus aureus shouldbeconsideredifbacterial tracheitiscannotbeexcluded.

PREVENTION• ChemoprophylaxisforhouseholdcontactsofchildrenwithH. influenzaetypebepiglottitis

shouldbegivenforthosehouseholdscontainingunderimmunizedornonimmunizedchil-drenyoungerthan4yearsofageorimmunocompromisedchildren.

• Contactsofadultswithepiglottitisareunlikelytorequireanyprophylaxis,exceptintherareinstanceofprovenH. influenzaetypebormeningococcalinfection.

17

10 Infections of the Oral Cavity, Neck, and HeadAnthony W. Chow

DEFINITION• Infections of the oral cavity, neck, and head are diverse in etiology and clinical

presentation.• Although uncommon in the postantibiotic era, deep fascial space infections and vascular

complications are potentially life-threatening. These include Lemierre syndrome andLudwig’sangina.

• A clear understanding of their interrelationships, anatomic routes of spread, and salientclinicalfeaturesiscriticaltodiagnosisandmanagement.

EPIDEMIOLOGY• Infectionsoftheoralcavityaremostcommonlyodontogenicinoriginandincludedental

caries,periodontaldisease,anddeepfascialspaceinfections.• Nonodontogenicinfectionsoftheoralcavityincludethoseoftheoralmucosaandinfections

ofthemajorsalivaryglands.• Miscellaneousinfectionsoftheheadandneckmostcommonlyresultfromhumanoranimal

bites, irradiation, or surgical procedures but may also arise from suppurative adenitis,infectedembryologiccysts,andsuppurativethyroiditis.

MICROBIOLOGY• Themicrobiotaassociatedwithodontogenicinfectionsgenerallyreflecttheindigenousoral

microbiotaandare typicallypolymicrobial involvingbothstrictanaerobesand facultativebacteria.

• Dentalcariesoriginatefrom“cariogenic”bacteriaresidingwithinthesupragingivalplaque,whereas periodontal disease arises from “periodontopathic” bacteria residing within thesubgingivalplaque.

• Importantdifferenceswithinthesecomplexbacterialcompositionssupporttheconceptofthe“specific”plaquehypothesisofdentalcariesandperiodontaldisease.

DIAGNOSIS• Microbiologic investigation requires proper specimen collection, taking care to minimize

contaminationbyresidentcommensalmicrobiota.• Needle aspiration of loculated pus by an extraoral approach is desirable, and specimens

shouldbetransportedimmediatelytothelaboratoryunderanaerobicconditions.• Tissuebiopsyspecimensshouldberoutinelyexaminedforhistopathologicevidenceofacute

orchronicinflammationandinfection.• ImmunofluorescencestainingandrapidmoleculardiagnostictoolssuchasDNAprobesor

polymerase chain reaction are valuable for the detection of fastidious or noncultivablepathogens.

• Computedtomography(CT)withcontrastisthemosteffectivetoolforlocalizingandevalu-atingtheextentofdeepspaceinfectionsoftheoralcavity,head,andneck.

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• Magneticresonanceimaging(MRI)withorwithoutangiographyismoresensitivethanCTforassessingsofttissueandboneinvolvement,aswellasvascularcomplications.

• Technetiumbonescansincombinationwithgallium-orindium-labeledwhitebloodcellsmaybeusefulforthediagnosisofacuteorchronicosteomyelitis.

THERAPY• Surgicaldrainageofloculatedinfectionandremovalofnecrotictissuearethekeystoman-

agementofdeepfascialspaceinfectionsoftheoralcavity,head,andneck.• Antimicrobialtherapyisimportantinhaltingthelocalspreadofinfectionandinpreventing

hematogenousdissemination.• Choiceofantimicrobialregimensisempirical,dependingontheprimarysource(e.g.,odon-

togenicororopharyngealvs.rhinogenicorotogenic),anticipatedcausativemicroorganisms,andimmunityofthehost(seeTables10-1and10-2).

PREVENTION• Oralhygieneanddentaltreatmenttopreventcariesandadvancedperiodontaldisease• Dietarycounselinganduseoftopicalfluoridesandchlorhexidineoralrinsesforpatientsat

highriskfordentalcaries• Behavioralmodificationofriskfactorssuchastobaccosmoking

TABLE 10-1  Antimicrobial Regimens for Various Odontogenic and Nonodontogenic Orofacial Infections

CLINICAL ENTITYCOMMON CAUSATIVE ORGANISMS ANTIMICROBIAL REGIMENS

OdontogenicSupragingival dental plaque and dental caries prevention

Streptococcus mutans, other streptococci, Actinomyces spp.

Fluoride-containing toothpaste or oral rinses (e.g., sodium fluoride 1.1% or stannous fluoride 0.4%) two or three times daily

with or without

Fluoride-containing varnishes (e.g., sodium fluoride 5%) applied three or four times yearly

with or without

Chlorhexidine 0.12% oral rinses

Acute simple gingivitis

Streptococci, Actinomyces spp., oral spirochetes

Penicillin G, 2-4 MU IV q4-6h (or penicillin V, 500 mg q8h) plus metronidazole, 500 mg PO or IV q8h

or

Ampicillin-sulbactam, 1.5-3 g IV q6-8h

or

Amoxicillin-clavulanate, 500 mg PO q8h

or

Clindamycin, 450 mg PO q6-8h or 600 mg IV q6-8h

Acute necrotizing ulcerative gingivitis (ANUG), or Vincent’s angina

Prevotella intermedia, Fusobacterium spp., Tannerella forsythensis, Treponema denticola, other oral spirochetes

Metronidazole, 500 mg PO or IV q8h

or

Amoxicillin-clavulanate, 500 mg PO q8h

or

Ampicillin-sulbactam, 1.5-3 g IV q6h

or

Clindamycin, 450 mg PO q6h or 600 mg IV q6-8h

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CLINICAL ENTITYCOMMON CAUSATIVE ORGANISMS ANTIMICROBIAL REGIMENS

Early-onset, “aggressive,” or “localized juvenile” periodontitis

Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia

Doxycycline, 200 mg PO or IV q12h (only in patients ≥8 yr of age)

or

Metronidazole, 500 mg PO or IV q8h

Adult or “established“ periodontitis

Treponema denticola, other oral spirochetes, black-pigmented Bacteroides spp. (Porphyromonas gingivalis and Prevotella melaninogenica), Tannerella forsythensis

Topical application of minocycline microspheres (Arestin)

or

Topical application of doxycycline hyclate periodontal extended-release liquid (Atridox)

NonodontogenicGangrenous stomatitis (noma)

Fusobacterium nucleatum, Borrelia vincentii, Prevotella melaninogenica, other oral anaerobes

Penicillin G, 2-4 MU IV q4-6h plus metronidazole, 500 mg PO or IV q8h

or

Ampicillin-sulbactam, 1.5-3 g IV q6-8h

or

Amoxicillin-clavulanate, 500 mg PO q8h

or

Clindamycin, 450 mg PO q6-8h or 600 mg IV q6-8h

Severe oral mucositis in immunocompromised hosts

Viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes, facultative gram-negative bacilli

Topical chlorhexidine (0.1%) mouth rinses TID plus one of the following:

Cefotaxime, 2 g IV q6h

or

Ticarcillin-clavulanate, 3.1 g IV q4h

or

Piperacillin-tazobactam, 3.375 g IV q6h

or

Imipenem, 500 mg IV q6h

or

Meropenem, 1 g IV q8h

Sialadenitis and suppurative parotitis

Staphylococcus aureus,* Streptococcus viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes

Nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus either

Metronidazole, 0.5 g IV q6h

or

Clindamycin, 600 mg IV q6h

IV, intravenously; MU, million units; PO, orally; TID, three times a day.*For Staphylococcus aureus infections in which methicillin-resistant S. aureus is suspected, replace nafcillin with

vancomycin, 1 g IV q12h; in immunosuppressed hosts, cefotaxime or ceftriaxone or imipenem, as described in the table, can be added.

TABLE 10-1  Antimicrobial Regimens for Various Odontogenic and Nonodontogenic Orofacial Infections—cont’d

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TABLE 10-2  Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck

INFECTIONUSUAL CAUSATIVE ORGANISMS

ANTIBIOTIC REGIMENS, NORMAL HOST*

Suppurative orofacial odontogenic infections, including Ludwig’s angina

Streptococcus viridans and other streptococci, Peptostreptococcus spp., Bacteroides spp., and other oral anaerobes

Penicillin G, 2-4 MU IV q4-6h plus metronidazole, 0.5 g IV q6h

or

Ampicillin-sulbactam, 2 g IV q4h

or

Clindamycin, 600 mg IV q6h

or

Cefoxitin, 1-2 g IV q6h

Lateral pharyngeal or retropharyngeal space infections

Odontogenic S. viridans and other streptococci, Staphylococcus spp., Peptostreptococcus spp., Bacteroides spp., and other oral anaerobes

Penicillin G, 2-4 MU IV q4-6h plus metronidazole 0.5 g IV q6h

or

Ampicillin-sulbactam 2 g IV q4h

or

Clindamycin 600 mg IV q6h

Rhinogenic Streptococcus pneumoniae, Haemophilus influenzae, viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes

One of the following:(1) Penicillin G, 2-4 MU IV q4-6h, or

levofloxacin, 500 mg IV q24h, or ciprofloxacin, 750 mg IV q12h

plus

Metronidazole, 0.5 g IV q6h, or clindamycin, 600 mg IV q6h

or

(2) Moxifloxacin, 400 mg IV q24h

Otogenic Same as for rhinogenic space infections

Same as for rhinogenic space infections

Suppurative cervical adenitis and infected embryologic cysts

Streptococcus pyogenes, Peptostreptococcus spp., Fusobacterium spp., oral anaerobes

One of the following:(1) Penicillin G, 2-4 MU IV q4h, plus

metronidazole, 500 mg IV q6h

or

(2) Ampicillin-sulbactam, 2 g IV q4h

or

(3) Clindamycin, 600 mg IV q6h

or

(4) Cefoxitin, 1-2 g IV q6h

Suppurative thyroiditis S. aureus, S. pyogenes, S. pneumoniae, Haemophilus influenzae, Streptococcus viridans and other streptococci, oral anaerobes

Nafcillin, 2 g IV q4-6h, or vancomycin, 1 g IV q12h plus either

Metronidazole, 500 mg IV q6h

or

Clindamycin, 600 mg IV q6h

Cervicofacial actinomycosis

Actinomyces israelii, Arachnia propionica, Actinobacillus actinomycetemcomitans

One of the following:(1) Penicillin G, 2-4 MU IV q4-6h

or

(2) Doxycycline, 200 mg PO or IV q12h

or

(3) Clindamycin, 450 mg PO q6h or 600 mg IV q6h

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INFECTIONUSUAL CAUSATIVE ORGANISMS

ANTIBIOTIC REGIMENS, NORMAL HOST*

Human or animal bites S. pyogenes, S. aureus, Eikenella corrodens, oral anaerobes Pasteurella multocida

One of the following:(1) Ampicillin-sulbactam, 2 g IV q4h

or

(2) Amoxicillin-clavulanate, 500 mg PO q8h

or

(3) Moxifloxacin, 400 mg IV or PO q12h

Maxillofacial trauma, postsurgical wound infections

S. aureus, S. pyogenes, Peptostreptococcus spp., other oral anaerobes, Pseudomonas aeruginosa, Enterobacteriaceae spp.

Nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus one of the following:

(1) Ticarcillin-clavulanate, 3.1 g IV q4h

or

(2) Piperacillin-tazobactam, 3.375 g IV q6h

or

(3) Imipenem-cilastatin, 500 mg IV q6h

or

(4) Meropenem, 1 g IV q8h

or

(5) Moxifloxacin, 400 mg IV or PO q24h

or

(6) Tigecycline, 100 mg IV, then 50 mg IV q12h

Suppurative jugular thrombophlebitis (Lemierre syndrome)

Fusobacterium necrophorum; same as for odontogenic space infections

Same as for odontogenic space infections

Suppurative cavernous sinus thrombosis

Same as for odontogenic, rhinogenic, or otogenic space infections

Same as for odontogenic, rhinogenic, or otogenic space infections

Mandibular osteomyelitis Same as for odontogenic space infections

Clindamycin, 600 mg IV q6h

or

Moxifloxacin, 400 mg PO or IV q24h

Extension of osteomyelitis from prevertebral space infection

Staphylococcus aureus,† facultative gram-negative bacilli

Either nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus

Either tobramycin, 1.7 mg/kg IV q8h, or ciprofloxacin, 400 mg IV q12h

IV, intravenously; MU, million units; PO, orally.*For immunocompromised hosts, consider replacing penicillin G with one of the following: cefotaxime, 2 g IV

q4h; ceftriaxone, 1 g IV q12h; or cefepime, 2 g IV q12h. Other regimens to consider are ticarcillin-clavulanate, 3.1 g IV q64h; piperacillin/tazobactam, 3.375 g IV q6h; imipenem, 500 mg IV q6h; meropenem, 1 g IV q8h; moxi-floxacin, 400 mg IV q24h; or tigecycline, 100 mg IV, then 50 mg IV q12h.

†For Staphylococcus aureus infections in which methicillin-resistant S. aureus is suspected, replace nafcillin with vancomycin, 1 g IV q12h; in immunosuppressed hosts, cefotaxime or ceftriaxone or imipenem, as described in the table, can be added.

TABLE 10-2  Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck—cont’d

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11 Acute BronchitisEdward E. Walsh

DEFINITION• Acutebronchitis is a self-limited syndromecharacterizedbyacutecoughwithorwithout

sputumbutwithoutsignsofpneumonia.

EPIDEMIOLOGY• Acutebronchitisoccursyear-roundandiscausedbyalargenumberofrespiratorypathogens

accordingtothetypicalepidemiologyofeachpathogen.

MICROBIOLOGY• Acutebronchitisisprimarilycausedbyviralinfections.Mostcommonarerhinovirus,influ-

enzaviruses,respiratorysyncytialvirus,metapneumovirus,coronaviruses,andadenovirus.Fewer than10%ofcasesarecausedbyMycoplasma pneumoniae, Chlamydia pneumoniae,andBordetellapertussis.

DIAGNOSIS• Diagnosisisprimarilymadebytheclinicalpresentationintheabsenceofsignsandsymp-

tomsofpneumonia.

THERAPY• Therapyissymptomaticbecauseantibioticsareuncommonlyrequiredandunnecessaryin

themajorityofcases.

PREVENTION• Prevention is directed at specific pathogens when possible (e.g., influenza and pertussis

vaccination).

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12 Acute Exacerbations of Chronic Obstructive Pulmonary DiseaseLeopoldo N. Segal, Michael D. Weiden, and Harold W. Horowitz

DEFINITION• Chronic lung disease with irreversible airflow limitation with reduced forced expiratory

volumein1second(FEV1)andFEV1/forcedvitalcapacity(FVC)ratio• Acute exacerbation indicated by acute change from a patient’s baseline with increased

dyspnea, sputum volume, or sputum purulence; number of changes clinically definesseverity

EPIDEMIOLOGY• Prevalence expected to reach 10% of the overall population and 50% of smokers; fourth

leadingcauseofdeathworldwide• Increasedriskforacuteexacerbationinwinter• Riskfactors:cigarettesmoking,environmentalparticulatematter,geneticpredisposition

PATHOGENESIS• Intermittentprogressiveairwayinflammation;remodelingandlossoflungfunction• Ciliary dysfunction; excess mucus production; impaired phagocytosis leading to bacterial

colonization

MICROBIOLOGY• Airways of patients with stable disease are frequently colonized with Streptococcus pneu-

moniae, Haemophilus influenzae, and Moraxella catarrhalis; respiratory syncytial virus ismostfrequentcolonizingvirus.

• Microaspirationinstablediseaseintroducesoralanaerobes(e.g.,PrevotellaandVeillonellaspp.)intolowerairway.

• Duringacute exacerbation,bacteriaorvirusesorbothmaybe isolated,withmoregram-negative rods found with worsening lung function. “Atypical” bacteria are not frequentlyisolated.Acquisitionofnewpathogenisassociatedwithexacerbation.

DIAGNOSIS• Acuteexacerbationisdefinedbyincreasedsputumpurulence,volume,anddyspnea.

THERAPY• Useofbronchodilatorshasincreasedformildexacerbationwithoutantibiotictherapy.• Oralorintravenouslyadministeredcorticosteroidsandearlyempiricalantibiotictherapyare

advisedformoderatetosevereexacerbations.

PREVENTION• Avoidexposuretoparticulatematterandceasesmoking.• Administerinfluenza,pneumococcal,andpertussisvaccines.• Prescribeprophylacticdailyazithromycininpatientswithadvanceddiseasewithahistory

ofexacerbationandnocardiacriskfactors.

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13 BronchiolitisJohn Bower and John T. McBride

DEFINITION• Bronchiolitisissmallairwayinflammation/obstructionmostfrequentlycausedbyinfection

withrespiratorysyncytialvirus(RSV)inthefirstyearsoflife.

EPIDEMIOLOGY• RSVbronchiolitisoccursinwinterepidemicsintemperateclimatesandsporadicallyinthe

tropics.• Bronchiolitis is a leading cause of hospitalization in the first year of life in the developed

world.

MICROBIOLOGY• Manyotherrespiratoryvirusesmaycausebronchiolitis,includinghumanmetapneumovirus,

influenza,parainfluenza,adenovirus,coronavirus,andbocavirus.

DIAGNOSIS• DiagnosisisclinicallybasedonpresenceofRSVinthecommunity,initialepisodeofwheez-

ing,andevidenceofupperrespiratoryinfection.• Othercausesofwheezinginearlychildhoodshouldbeexcluded,suchascongenitalheart

diseasewithfailure,foreign-bodyaspiration,dysphagia,andasthma.• Apneamayoccurearlyinthecourseofviralbronchiolitis,usuallyininfantsyoungerthan

44weeks’postconceptionalage.

THERAPY• Therapyissupportiveandincludeshydration,oxygen,andrespiratorysupportasneeded.• Corticosteroidsandbronchodilatorsarenotgenerallybeneficial.• Hypertonicsalineaerosolsdeliveredthreetimesdailymayhastenrecoverybuthavenotbeen

widelyadopted.• Respiratorysupportbyhigh-flownasalcannulamaypreventordelayintubationinpatients

withapneaorrespiratoryfailure.

PREVENTION• CarefulattentiontohandsanitationisimportantinlimitingspreadofRSVinfectionduring

epidemics.• Monoclonalantibodyprophylaxismaypreventormitigateinfectioninhighriskinfants.

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14 Acute PneumoniaRichard T. Ellison III and Gerald R. Donowitz

EPIDEMIOLOGY AND ETIOLOGY• Pneumoniaisthemostcommoncauseofinfection-relateddeath.• Predominant pathogens of community-acquired pneumonia (CAP) in adults include

Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,andChlamydia pneumoniae.

• Legionellaspecies,Staphylococcus aureus,andentericgram-negativebacilliarelessfrequentcausesthatcanproducemoreseveredisease.

• PredominantpathogensofpatientsrecentlyhospitalizedornursinghomeresidentsincludeS. aureus, aerobic gram-negative rods, including Pseudomonas aeruginosa, and mixedaerobic/anaerobicorganisms.

DIAGNOSIS• Typicalclinicalmanifestationsarecough—thesinequanonofpneumonia—sputumproduc-

tion,dyspnea,chestpain,fever,fatigue,sweats,headache,nausea,myalgia,andoccasionallyabdominalpainanddiarrhea.

• Gramstainandcultureofsputumsamplesremainvaluablediagnosticassays.• Bloodculturesshouldbeobtainedinallpatientswhoareimmunocompromised,havehealth

care–associated (HCAP)orhospital-acquiredpneumonia (HAP),orarehospitalizedwithsevereCAP.

• Chestradiographsshouldbeobtainedonallpatientswithsuspectedpneumonia.• Severalbiomarkers,includingprocalcitoninandC-reactiveprotein,areunderassessmentas

discriminatoryassays todefinepopulationswithahigher likelihoodofbacterial infectionthatcouldbenefitfromantibiotictherapy,buttheclinicalutilityofsuchassayshasnotyetbeenestablished.

THERAPY• Oneofthreeseverityindexscores(PSI,CURB-65,orCRB-65)canbeusedtoassesstheneed

forhospitalizationinimmunocompetentpatientswithCAP,andsimilarindicescanbeusedtodefinetheneedforintensivecareunitadmission.

• Antibiotictherapyforpneumoniashouldbestartedassoonasthediagnosisisconsideredlikely.

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TABLE 14-1  Guide to Empirical Choice of Antimicrobial Agent for Treating Adult Patients with Community-Acquired Pneumonia or Health Care–Acquired Pneumonia

PATIENT CHARACTERISTICS PREFERRED TREATMENT OPTIONS

OutpatientPreviously Healthy

No recent antibiotic therapy Macrolidea or doxycycline (100 mg 2 times/day)

Recent antibiotic therapyb A respiratory fluoroquinolonec alone, an advanced macrolided plus oral β-lactame

Comorbidities (COPD, Diabetes, Renal Failure or Congestive Heart Failure, or Malignancy)

No recent antibiotic therapy An advanced macrolide plus oral β-lactam or a respiratory fluoroquinolone

Recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus a β-lactam

Suspected aspiration with infection Amoxicillin-clavulanate or clindamycin (600 mg IV q8h or 300 mg PO q6h)

Influenza with bacterial superinfection Vancomycin, linezolid, or other coverage for MRSA, including community-acquired MRSAf

InpatientMedical Ward

No recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus an intravenous β-lactamg

Recent antibiotic therapy An advanced macrolide plus an intravenous β-lactam, or a respiratory fluoroquinolone alone (regimen selected will depend on nature of recent antibiotic therapy)

Intensive Care Unit (ICU)

Pseudomonas infection is not a concern A β-lactamg plus either an advanced macrolide or a respiratory fluoroquinolone

Pseudomonas infection is not a concern but patient has a β-lactam allergy

A respiratory fluoroquinolone, with or without clindamycin

Pseudomonas infection is a concernh (cystic fibrosis, impaired host defenses)

Either (1) an antipseudomonal β-lactami plus ciprofloxacin (400 mg IV q8h or 750 mg PO q12h), or (2) an antipseudomonal agent plus an aminoglycosidej plus a respiratory fluoroquinolone or a macrolide

Pseudomonas infection is a concern but the patient has a β-lactam allergy

Aztreonam (2 g IV q8h) plus aminoglycoside plus a respiratory fluoroquinolone

• Advancedmacrolides,respiratoryfluoroquinolones,andβ-lactamagentsare theprincipalantibioticsusedforthetreatmentofCAP.CoverageforS. aureusandmixedanaerobesshouldbeconsideredinselectsituations(seeTable14-1forsuggestedagentsanddosages).

• Antibiotic treatment for HCAP should include coverage for potentially drug-resistantS. aureus and aerobic gram-negative bacilli and in most settings includes coverage forPseudomonas aeruginosa(seeTable14-1forsuggestedagentsanddosages).

• Thedurationofintravenoustreatment,inpatienthospitalization,andtotalintravenousandoralantibiotictherapyforCAPshouldbeguidedbythepatient’sclinicalstability.

PREVENTION• Provideimmunizationasappropriatewithinfluenzaandpneumococcalvaccines.• Encouragecessationoftobaccosmoking.

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PATIENT CHARACTERISTICS PREFERRED TREATMENT OPTIONS

Health Care–Associated Pneumoniak

— Either (1) an antipseudomonal β-lactam plus ciprofloxacin or levofloxacin or (2) an antipseudomonal agent plus an aminoglycoside plus a respiratory fluoroquinolone or a macrolide plus vancomycin or linezolid (for MRSA coverage)

COPD, chronic obstructive pulmonary disease; MRSA, methicillin-resistant S. aureus.Note: All dosages are usual adult doses and may require adjustment in relation to renal or hepatic function, a

patient’s body mass index, or drug-drug interactions.aAzithromycin, clarithromycin, or erythromycin.bThat is, the patient was given a course of antibiotic(s) for treatment of any infection within the past 3 months,

excluding the current episode of infection. Such treatment is a risk factor for drug-resistant Streptococcus pneu-moniae and possibly for infection with gram-negative bacilli. Depending on the class of antibiotics recently given, one or another of the suggested options may be selected. Recent use of a fluoroquinolone should dictate selection of a nonfluoroquinolone regimen and vice versa.

cMoxifloxacin (400 mg once daily), gemifloxacin (320 mg once daily), or levofloxacin (750 mg once daily).dAzithromycin (500 mg once daily), clarithromycin (250-500 mg twice daily), erythromycin (250-500 mg four

times a day).eHigh-dose amoxicillin (1 g three times a day), high-dose amoxicillin-clavulanate (2 g twice daily), cefpodoxime

(200 mg twice daily), or cefuroxime (500 mg twice daily).fVancomycin dosing should target a vancomycin trough level of 15 to 20 µg/mL; linezolid (600 mg twice daily).gCefotaxime (1-2 g IV q4-8h), ceftriaxone (1 g IV daily), ampicillin (1-2 g IV q4-6h), ampicillin-sulbactam (1.5-3 g

IV q6h), or ertapenem (1 g IV daily).hRisk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent

antibiotic therapy, health care–associated exposures or stay in hospital (especially in the ICU). For patients with community-acquired pneumonia in the ICU, coverage for S. pneumoniae and Legionella species must always be considered.

iPiperacillin (3 g IV q4h), piperacillin-tazobactam (3.375 g IV q6h), imipenem (500-1000 mg IV q6h), meropenem (1-2 g IV q8h), ceftazidime (2 g IV q6-8h), or cefepime (1-2 g IV q8h) are excellent β-lactams and are adequate for most S. pneumoniae and H. influenzae infections. They may be preferred when there is concern for relatively unusual pathogens of community-acquired pneumonia, such as P. aeruginosa, Klebsiella species, and other gram-negative bacteria.

jData suggest that older adults receiving aminoglycosides have worse outcomes. Traditionally dosed aminoglyco-sides should achieve peak levels of at least 8 µg/mL for gentamicin or tobramycin and 25-35 µg/mL for amikacin and troughs less than 2 µg/mL for gentamicin and tobramycin and less than 10 µg/mL for amikacin. Once-daily dosing for gentamicin or tobramycin is 7 mg/kg IV with trough target <1 µg/mL, and 20 mg/kg IV for amikacin with trough target <4 µg/mL.

kPneumonia developing in patients who have been hospitalized for 2 or more days within 90 days of developing infection; patients attending hospital or hemodialysis clinics; patients receiving intravenous antibiotic therapy, wound care, or chemotherapy at home within 30 days of developing infection; and residents of long-term care facilities or nursing homes.

Modified from Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72; and American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

TABLE 14-1  Guide to Empirical Choice of Antimicrobial Agent for Treating Adult Patients with Community-Acquired Pneumonia or Health Care–Acquired Pneumonia—cont’d

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15  Pleural Effusion and EmpyemaEdward J. Septimus

DIAGNOSIS• Fluidinthepleuralspacemaybetransudativeorexudative(seeTable15-1).Anexudative

effusionwithpusinthepleuralspaceiscalledanempyema.Computedtomography(CT)isbetter than a chest radiograph for distinguishing pleural fluid from pneumonia and mayallowvisualizationofstrandingorloculationwithinanempyema.

THORACENTESIS• For pleural fluid suspected of empyema, send fluid in capped syringe for pH, inoculate

aerobic and anaerobic blood culture bottles directly at bedside, moisten syringe withpreservative-free heparin because clotting interferes with white blood cell count (WBC),cytology, and Gram stain. Laboratory studies: WBC, differential, protein, glucose, lactatedehydrogenase(LDH),Gramstain,cultureforbacteria,cytology,mycobacteriaandfungi.SendbloodforLDHandproteintodeterminepleuralfluid–to-serumratio.

• Specialstudiesonpleuralfluid:immunochromatographictestforStreptococcus pneumoniaeantigen,polymerasechainreaction(PCR)targeting16SribosomalDNA,modifiedacid-faststainforNocardia,PCR,ornucleicacidamplificationtestoradenosinedeaminaseorcultureofpleuralbiopsyforMycobacterium tuberculosis

• Sourceofempyemaaffectsthemostcommonorganisms:• Community-acquiredpneumonia:S. pneumoniae, Staphylococcus aureus• Community-acquiredempyema:Streptococcus anginosusgroup,Prevotella, Bacteroides• Post-traumaorpostoperativehemothorax:Staphylococcus aureus• Complicationofviralinfluenza:S. pneumoniae, S. aureus, Streptococcus pyogenes• Esophagealrupture:mixedaerobicandanaerobicbacteria,Candida• Hematogenousseedingofserouseffusion:gram-negativebacilli• Spreadacrossdiaphragm:amebiasis,mixedaerobic-anaerobic

TREATMENT• Systemicantibioticsplusadequatedrainageisnecessaryforempyema.Empiricalantibiotic

choices for a presumed bacterial empyema include ampicillin-sulbactam, piperacillin-tazobactam,imipenem,ertapenem,doripenem,meropenem,orcombinationofathird-orfourth-generationcephalosporinandeitherclindamycinormetronidazole.Indicationsfordrainage includecloudyfluid,pH<7.2,glucose<60mg/dL,protein>3g/dL,LDH>1000,orratioofpleuralfluidtoserumforprotein>0.5orLDH>0.6.

• Video-assisted thoracoscopy is being used earlier in empyema treatment, particularly inchildren,andinadultswithempyemanotrespondingtoCT-orultrasound-guidedcathetertubedrainage.Fibrinolytictherapystillhasadvocates,althoughitiscontraindicatedifbron-chopleuralfistulaispresent.

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TABLE 15-1  Features Differentiating Exudative from Transudative Pleural Effusion

FEATURE TRANSUDATE EXUDATEAppearance Serous Cloudy

Leukocyte count <10,000/mm3 >50,000/mm3

pH >7.2 <7.2

Protein <3.0 g/dL >3.0 g/dL

Ratio of pleural fluid protein to serum <0.5 >0.5

Lactate dehydrogenase (LDH) <200 IU/L >200 IU/L

Ratio of pleural fluid LDH to serum <0.6 >0.6

Glucose ≥60 mg/dL <60 mg/dL

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16  Bacterial Lung AbscessBennett Lorber

DEFINITION• Localizednecrosisoflungtissuecausedbymicrobialinfection.Oneormorecavities.

EPIDEMIOLOGY• Primary lung abscess: bad teeth, altered consciousness, aspiration. Secondary: airway

obstructionorimmunosuppression.

MICROBIOLOGY• Polymicrobial. Predominantly mouth anaerobes and streptococci. Klebsiella or Staphylo­

coccus aureusuncommonly.

DIAGNOSIS• Radiographorcomputedtomography(CT):thick-walledcavitywithair-fluidlevel.Putrid

sputuminhalfofcases.

THERAPY• β-Lactam/β-lactamasecombinationorclindamycin.

PREVENTION• Maintainoralhygiene.Elevateheadofbedforthosewithalteredconsciousness.

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17  Chronic PneumoniaPeter G. Pappas

DEFINITION• Persistent or progressive cough, dyspnea, often with chronic sputum production, with or

withoutfever,lastingweeksormonthsratherthandays• Alwaysassociatedwithabnormalchestradiography• Constitutionalsymptoms,includingweightlossandanorexia,aretypical• Definitiondoesnotincludeasymptomaticsolitarypulmonarynodules• Maybeinfectiousornoninfectious

EPIDEMIOLOGY• Age,race/ethnicity,andgenderareimportantconsiderations• Underlyinghealthissuesandcomorbidconditions• Currentandpastresidence,occupation,travel,andrecreationhistorymaybeimportant• Recenthospitalizationorhistoryofimprisonment• Drugandalcoholhistory• Recentprescriptiondrugexposure

MICROBIOLOGY• Bacterial: anaerobes, microaerophilic and viridans streptococci; Staphylococcus aureus;

selected community-acquired and nosocomial gram-negative bacilli; Burkholderia pseudomallei

• Higher-orderbacteria:Mycobacterium tuberculosis, Mycobacterium kansasii,andothernon-tuberculousmycobacteria;Nocardiaspp.;Rhodococcus equi; Actinomycesspp.

• Fungi: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis/posadasii, Paracoccidioides brasiliensis, Cryptococcus neoformans, and Cryptococcus gattii, Aspergillusspp.,Scedosporiumspp.

• Parasites:Dirofilaria, Echinococcus granulosus, Paragonimus westermani,filariasis• Noninfectiouscauses:vasculitides,neoplasia,druginduced,sarcoidosis,pulmonaryalveolar

proteinosis,andahostofotherconditions

DIAGNOSIS• Carefulclinicalassessment,includingdetailedhistory,isessential.• Clinicalfindingsaregenerallynonspecific;rash,osteoarticularfindings,andmucocutaneous

andneurologicfindingsmayprovidehelpfulclues.• Radiographicimaging,includingroutinechestradiographorchestcomputedtomography,

orboth,arecriticaltodiagnosis.• Routine microbiologic studies, including sputum examination by Gram stain, potassium

hydroxide,acid-faststain,andpreparationsforovaandparasites,areimportant.• Cultureforroutinebacteria,fungi,andacid-fastbacilliwhenpossible.• Biopsyandcultureofnonpulmonaryspecimens(e.g.,skin,bone,orbrainbiopsy)inclini-

callyrelevantsettings.PotentiallyimportantserologicstudiesincludethequantiFERONgold

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assayfortuberculosis;Histoplasmaantigen;cryptococcalantigen;andserumandbronchoal-veolarlavagegalactomannan.

• Bronchoalveolar lavage for acid-fast, modified acid-fast, and Gram stain; wet mount orcalcofluor stain; cultures forbacteria,mycobacteria, and fungi; galactomannanassay; andcytopathology.

THERAPY• Specifictherapyisentirelydependentonthemostlikelyetiologies,ofwhichtherearemany

possibilities,usuallyincludingantimicrobials.

PREVENTION• Inthisbroadcategoryofdisease,preventiongenerallyentailstherecognitionandavoidance

ofcircumstances,whichincreasethelikelihoodofdevelopingchronicpneumonia.Inselectedsettings,suchashigh-riskpatientsreceivingchemotherapy,prophylacticantimicrobialsmaybewarranted.

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18  Cystic FibrosisAhmet Uluer and Francisco M. Marty

DEFINITION• Cystic fibrosis (CF) is a genetically inherited autosomal-recessive disease resulting from

mutationstothecysticfibrosistransmembraneconductanceregulatorgene(CFTR,locatedonthe longarmofchromosome7),andalthoughit isamultisystemdisorder,respiratoryandgastrointestinalmanifestationspredominate.

EPIDEMIOLOGY• Staphylococcus aureusandPseudomonas aeruginosa(PA)arethemostcommonCF-associated

pathogens. The prevalence of other bacterial infections varies between countries and CFclinics.

MICROBIOLOGY• Chronicairwayinfectionandinflammation,mostcommonlyassociatedwithPA,arestrongly

associated with morbidity and mortality. Many other pathogens, including methicillin-resistantS. aureus, Burkholderia cepaciacomplexorganisms,andStenotrophomonas malto-philia,arealsoimplicatedinchronicprogressivelungdisease.

DIAGNOSIS• NewbornscreeningisnowavailableintheUnitedStatesandothercountries.• SweatchloridetestingandCFTRgenemutationanalysisarethemainstayfordiagnosingCF,

alongwithimmunoreactivetrypsinogenassociatedwithnewbornscreening.• Acutepulmonaryexacerbationsareusuallylinkedtoprogressionofdisease(seeTable18-1).

Respiratoryvirusesmaytriggerpulmonaryexacerbations.

THERAPY• Maintenance therapy includes mucolytics, airway hydrating agents, chest physiotherapy,

anti-inflammatories,andacombinationoforalandinhaledantibiotics(seeTable18-2).• Acutepulmonaryexacerbationmaybetreatedwithoralandnebulizedantibioticsasneeded,

whereasmoreseriousexacerbationsusuallyrequireintravenousantibiotics,intenseairwayclearanceaccompanyingmucolyticsandairwayhydratingagents,andaggressivenutritionalmanagementwhilemonitoringforcomplications(seeTable18-2)

• Selectionofantibioticsisguidedbycurrentandpreviouspatientrespiratorycultures.Severityofexacerbationwilldeterminewhetheroralorintravenousantibioticswillbeused.

• CFpatientsrequirehigherdosesofmanyhydrophilicantibioticsbecauseofCF-associatedincreasedvolumeofdistributionandclearance.Theseincludeaminoglycosides,penicillins,andcephalosporins.

• InadditiontotheCFTRmodulatorivacaftor—U.S.FoodandDrugAdministration[FDA]approved for those with at least one gating defect mutation (e.g., G551D)—and R117H,Orkambi,acombinationofivacaftorandlumacaftor,hasalsobeenapprovedbytheFDAfortherapyofpatientshomozygousfortheF508delmutation.

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TABLE 18-1  Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013

TREA

TMEN

T

REC

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MEN

DA

TIO

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N

Inhaled tobramycin—moderate to severe disease*

For individuals with CF, 6 yr of age and older, with moderate to severe lung disease and Pseudomonas aeruginosa persistently present in culture of the airways, the CF Foundation strongly recommends the chronic use of inhaled tobramycin to improve lung function, improve quality of life, and reduce exacerbations.

High Substantial A

Dornase alfa—moderate to severe disease*

For individuals with CF, 6 yr of age and older, with moderate to severe lung disease, the CF Foundation strongly recommends the chronic use of dornase alfa to improve lung function, improve quality of life, and reduce exacerbations.

High Substantial A

Ivacaftor† For individuals with CF, 6 yr of age and older, with at least one G551D CFTR mutation, the Pulmonary Clinical Practice Guidelines Committee strongly recommends the chronic use of ivacaftor to improve lung function, improve quality of life, and reduce exacerbations.

High Substantial A

Inhaled aztreonam—moderate to severe disease*

For individuals with CF, 6 yr of age and older, with moderate to severe lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation strongly recommends the chronic use of inhaled aztreonam to improve lung function and quality of life.

High Substantial A

Dornase alfa—mild disease*

For individuals with CF, 6 yr of age and older, with asymptomatic or mild lung disease, the CF Foundation recommends the chronic use of dornase alfa to improve lung function and reduce exacerbations.

High Moderate B

Azithromycin with P. aeruginosa

For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of azithromycin to improve lung function and reduce exacerbations.

High Moderate B

Inhaled tobramycin—mild disease*

For individuals with CF, 6 yr of age and older, with mild lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of inhaled tobramycin to reduce exacerbations.

Moderate Moderate B

Inhaled hypertonic saline

For individuals with CF, 6 yr of age and older, the CF Foundation recommends the chronic use of inhaled hypertonic saline to improve lung function, improve quality of life, and reduce exacerbations.

Moderate Moderate B

Inhaled aztreonam—mild disease†

For individuals with CF, 6 yr of age and older, with mild lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of inhaled aztreonam to improve lung function and quality of life.

Moderate Moderate B

Chronic use of ibuprofen (age < 18 yr)

For individuals with CF, between 6 and 17 yr of age, with an FEV1 ≥60% predicted, the CF Foundation recommends the chronic use of oral ibuprofen, at a peak plasma concentration of 50-100 µg/mL, to slow the loss of lung function.

Moderate Moderate B

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TREA

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BEN

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BEN

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MEN

DA

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Azithromycin without P. aeruginosa

For individuals with CF, 6 yr of age and older, without P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of azithromycin should be considered to reduce exacerbations.

Moderate Small C

Inhaled corticosteroids For individuals with CF, 6 yr of age and older, without asthma or allergic bronchopulmonary aspergillosis, the CF Foundation recommends against the routine use of inhaled corticosteroids to improve lung function or quality of life and reduce pulmonary exacerbations.

High Zero D

Oral corticosteroids For individuals with CF, 6 yr of age and older, without asthma or allergic bronchopulmonary aspergillosis, the CF Foundation recommends against the chronic use of oral corticosteroids to improve lung function, quality of life, or reduce exacerbations.

High Negative D

Other inhaled antibiotics

For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in cultures of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of other inhaled antibiotics (i.e., carbenicillin, ceftazidime, colistin, gentamicin) to improve lung function and quality of life or reduce exacerbations.

Low — I

Oral antipseudomonal antibiotics

For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in the culture of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the routine use of chronic oral antipseudomonal antibiotics to improve lung function and quality of life or reduce exacerbations

Low — I

Leukotriene modifiers For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the routine chronic use of leukotriene modifiers to improve lung function and quality of life or reduce exacerbations.

Low — I

Inhaled or oral N-acetylcysteine, or inhaled glutathione

For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of inhaled or oral N-acetylcysteine or inhaled glutathione to improve lung function and quality of life or reduce exacerbations.

Low — I

Inhaled anticholinergics

For individuals with CF, 6 yr of age or older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of inhaled anticholinergic bronchodilators to improve lung function and quality of life or reduce exacerbations.

Low — I

Chronic use of ibuprofen (age ≥ 18 yr)

For individuals with CF, 18 years of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of oral ibuprofen to slow the loss of lung function or reduce exacerbations.

Low — I

Continued

TABLE 18-1  Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013—cont’d

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TREA

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TY O

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BEN

EFIT

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F N

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BEN

EFIT

REC

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DA

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N

Chronic inhaled β2-adrenergic receptor agonists

For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against chronic use of inhaled β2-adrenergic receptor agonists to improve lung function and quality of life or reduce exacerbations.

Low — I

Oral antistaphylococcal antibiotics, chronic use

For individuals with CF, 6 yr of age and older, with Staphylococcus aureus persistently present in cultures of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of oral antistaphylococcal antibiotics to improve lung function and quality of life or reduce exacerbations.

Low — I

A, substantial; B, moderate; C, small; CF, cystic fibrosis; D, zero negative; FEV1, forced expiratory volume in 1 second; I, the committee concludes that the current evidence is insufficient to assess the balance of benefits, and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance and harms cannot be determined.

*Severity of lung disease is defined by FEV1% predicted as follows: normal, >90% predicted; mildly impaired, 70%-89% predicted; moderately impaired, 50%-69% predicted; and severely impaired, <40% predicted (1).

†CF Foundation personnel did not participate in any activity related to ivacaftor.From Mogayzel PJ, Naureckas ET, Robinson KA. Cystic fibrosis pulmonary guidelines. Am J Respir Crit Care Med.

2013;187:680-689.

TABLE 18-1  Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013—cont’d

PREVENTION• StrictlyadheretoinfectioncontrolmeasurestopreventtransmissionofCF-associatedpatho-

gensamongCFpatients.• EarlyeradicationwillpreventchronicairwayinfectionwithPAandotherpathogensassoci-

atedwithchronicprogressivelungdisease.

TABLE 18-2  Acute Pulmonary Exacerbations in Cystic Fibrosis*Increase in sputum volume or colorNew or increased hemoptysisIncreased coughIncreased dyspneaMalaiseFatigue or lethargyTemperature >38° CAnorexia or weight lossSinus pain or tendernessChange in sinus dischargeChange in physical examination of the chestDecrease in FEV1 by 10% or moreRadiographic changes in support of a pulmonary infection

FEV1, forced expiratory volume in 1 second.*Generally defined as the presence of four of the above.From Cystic Fibrosis Foundation. Treatment of pulmonary exacerbations of cystic fibrosis. In: Clinical Practice

Guidelines for Cystic Fibrosis. Bethesda, MD: Cystic Fibrosis Foundation; 1997.

37

D  Urinary Tract Infections

19 Urinary Tract InfectionsJack D. Sobel and Donald Kaye

PATHOLOGIC CHARACTERISTICS• Withacutepyelonephritisthereissuppurativenecrosisorabscessformation.• Withchronicpyelonephritisthereisunevenscarring.• Withpapillarynecrosisoneormorepyramidsmayslough.

PATHOGENESIS• Mosturinarytractinfections(UTIs)aretheresultofretrogradeascendinginfection,conse-

quenttonumerousbehavioralfactors.• Becauseofefficienthostdefensemechanisms,bacterialpathogenscapableofcausingUTIs

(uropathogens)areselectedbyvirtueofgeneticallydeterminedvirulencefactors.• Virulencefactorsfacilitatemicroorganismpersistenceintheurinarytract.• Virulence factors include adhesins, bacterial capsules, aerobactin, cytotoxic necrotizing

factors,hemolysins,andsiderophorereceptors.• Infunctionalandstructurallycompromisedurinarytracts,thereisreducedrequirementfor

virulencefactorsinordertoproduceinfection.

HOST DEFENSES• Nonimmunemechanisms,especiallyantibacterialactivityofurine,shearingforceofmicturi-

tion,andurineflow,arehighlyeffectiveinreducingUTIfrequency.• Adaptiveimmunity,bothantibody-andcell-mediatedmechanisms,hasalimitedprotective

role.• Innateimmunitybasedonuroepithelialcellsandresponsetoadherentmicrobesreflectsa

complexrecognitionandreactiveproinflammatoryresponseconsistingofmultiplecytokinesandinflammatorycells.

• Protective cytokine response is genetically determined and influences outcome spectrumfromasymptomaticbacteriuriatosuppurativerenaldisease.

• GeneticsusceptibilitytoUTIisstillminimallyrecognizedandunderstood.

EPIDEMIOLOGY AND NATURAL HISTORY• Escherichia coliisthemostcommoninfectingorganism.• ResistantE. coli andotherresistantbacteriaare increased inhealthcare–related infection

comparedwithcommunityinfection.• ResistantbacteriaareincreasedincomplicatedUTI.• Asymptomaticbacteriuriaiscommonandoflittleconsequenceexceptinafewgroups.• UTIsoccurin1%to2%ofinfants,about5%ofgirls,and0.5%orlessofboys.• Renaldamageisrelatedtovesicoureteralreflux,whichoccursin30%to50%ofpreschool

childrenwithinfection;structuralorfunctionalobstructionalsocausesdamage.• UTIsaremuchmorecommoninwomenthanmenandaremostoftenasymptomatic.• Upto60%ofwomenhavesymptomaticUTIsduringtheirlifespan,and10%ofwomenhave

UTIseachyear.• TwotofivepercentofwomenhaverecurrentUTIswithageneticpredisposition.

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• UTIinmenisuncommonbutoftenassociatedwithstructuralorfunctionalabnormality.• Renalinfectionrarelycausesend-stagerenaldiseasewithoutotherunderlyingdisease.

DIAGNOSIS• Urinedipsticksforpyuriaandbacteriuriaareusefulscreeningtests.• AnegativetestforpyuriamakesUTIunlikely.• NegativetestsforbacteriuriaarecommoninUTIbecauseoflowtitersofbacteria.• Twourinecultureswithgreaterthanorequalto105ofthesameuropathogen/mLurineare

requiredfordiagnosisofasymptomaticbacteriuria.• Oneculturewith102/mLormoreofagram-negativebacillaryuropathogenisdiagnosticin

symptomaticUTI.• Onethirdofyoungwomenwithcystitishavefewerthan105bacteria/mLurine.

MANAGEMENT AND TREATMENT (SEE TABLE 19-1)• AllsymptomaticUTIisusuallytreatedforreliefofsymptoms.• Mostasymptomaticinfectionshouldbeneithersoughtnortreatedbecauseoflackofbenefit;

exceptions are pregnancy and those who are to have traumatic urologic procedures.Controversialexceptionsaresomeyoungchildrenandafterrenaltransplantation.

• Nonantimicrobialpreventionmeasuresaredirectedatreinfectionsandreducingriskfactors.Theyincludeavoidanceofspermicidaljelliesandcatheterizationandinvestigationaluseofestrogens,cranberryproducts,andprobiotics.

• Treatment for infants younger than 3 months involves a β-lactam and aminoglycosideintravenously.

• Treatmentforinfantsolderthan3monthsisasmentionedaboveforthoseseriouslyillandoralβ-lactamortrimethoprim-sulfamethoxazole(TMP-SMX)forothers.

• Treatmentforacute,uncomplicatedpyelonephritisinnonpregnantwomenisaurinecultureandthenfluoroquinolone.

• Treatmentforuncomplicatedcystitisinwomenisshort-coursetherapywithnitrofurantoin,TMP-SMX,fosfomycin,pivmecillinam,orfluoroquinolone.

• TreatmentforcomplicatedUTIisurinecultureandthenfluoroquinolone.Cystitisnitrofu-rantoinandfosfomycinareoptions.

• Treatment of relapses is prolonged therapy or chronic suppression. Complicated UTI orprostatitisispossible.

• Reinfectionscanbeself-treatedperepisodeorpreventedusingsingle-doseprophylaxisforintercourseorlong-termprophylaxis.

PREGNANCY• Asymptomaticbacteriuriaofpregnancyrequirestherapyandpost-treatmentsurveillanceto

reducetheriskofmaternalpyelonephritis,hypertension,andpretermdelivery.• UTItreatmentoptionsarereducedgivenlackofavailabilityofquinolones,tetracyclines,and

sulfonamides(atterm)astreatmentoptions.

IMAGING• The ever-improving quality and availability of renal ultrasonography has facilitated the

diagnosisofrenalcomplicationsandunderlyingurologicabnormalities.Excretoryurogra-phy(intravenouspyelography)hasfastdisappeared,replacedbycomputedtomographyscanandmagneticresonanceimagingexaminations.

• The use of imaging studies in infants and preschool children with febrile UTIs remainscontroversialwithreducedrelianceoncystourethrographyandthepreferenceshiftingtoa“top-down”approachselectingchildrenwhowouldmostbenefitfrominvestigation.

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TABLE 19-1  Recommendations for Initial Therapy of Urinary Tract Infection in Adults

PARAMETER ORAL*PARENTERAL (SWITCH TO ORAL WHEN RESPONSE)

Uncomplicated PyelonephritisGNB or no urine Gram stain available

CP 7 days, LV 5 days; if cannot use FQ, TMP-SMX 14 days ± 1 dose CT or AM

FQ 7 days or extended spectrum β-lactam (e.g., CT), 14 days ± AM

GPC in chains Amoxicillin, 14 days Ampicillin, 14 days

GPC in clusters Linezolid or TMP-SMX, 14 days Vancomycin, 14 days

Complicated PyelonephritisNonpregnant women or men

As for uncomplicated pyelonephritis FQ, 7 days plus extended spectrum β-lactam initially ± AM

Pregnant women Extended spectrum β-lactam;TMP-SMX† only if known sensitive both for 14 days

Extended spectrum β-lactam ± AM for 14 days

Uncomplicated CystitisNonpregnant women Nitrofurantoin, 5 days or fosfomycin, 1

dose, or TMP-SMX, 3 days, or pivmecillinam, 3-7 days; FQ in reserve, 3 days

Complicated CystitisWomen or men FQ or nitrofurantoin, 7 days or fosfomycin,

1 dose

Pregnant women Cephalexin, 3-5 days or fosfomycin, 1 dose or nitrofurantoin, 7 days or TMP-SMX,† 3 days if sensitive

GNB, gram-negative bacilli; GPC, gram-positive cocci.Drugs and Doses:

CP, ciprofloxacin orally 500 mg twice/day or 1000 mg once/day.LV, levofloxacin orally 750 mg once/day.TMP-SMX, trimethoprim-sulfamethoxazole orally 160/800 mg twice/day.CT, ceftriaxone parenterally 1 g/day.FQ, fluoroquinolone parenterally—ciprofloxacin 500 mg twice/day or levofloxacin 750 mg once/day.FQ, fluoroquinolone orally—ciprofloxacin 500 mg twice/day or 1000 once/day or levofloxacin 750 mg

once/day.AM, aminoglycoside parenterally (e.g., gentamicin 5 mg/kg/day).Amoxicillin orally 875 mg twice/day.Ampicillin parenterally 2 g every 4 hr.Linezolid orally 600 mg twice/day.Vancomycin parenterally 15 mg/kg twice/day.Nitrofurantoin orally 100 mg twice/day.Fosfomycin orally 3 g once.Pivmecillinam orally 400 mg twice/day.Cephalexin orally 500 mg four times/day.

*Preferred if the patient is reliable, compliant, hemodynamically stable, and able to take oral therapy.†TMP-SMX should be avoided in the third trimester.

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E  Sepsis

20 Sepsis, Severe Sepsis, and Septic ShockRobert S. Munford and Anthony F. Suffredini

DEFINITIONS• Sepsisisthebody’sharmfulsystemicreactiontomicrobialinfection.• Severesepsis isorgandysfunctioncomplicatinginfection; ifhypotensionispresent, itcan

bereversedwithintravenousfluids.• Septicshockissepsis-associatedhypotensionthatrequirespharmacologicreversal.

EPIDEMIOLOGY• Mostcommonlyaffectedpersonsaretheveryyoungandolderadults.• Majoroutcomedeterminantsareageandcomorbidity,especiallyimmunosuppressiveillness.

MICROBIOLOGY• Virtuallyanymicrobecantriggersepsis.• Most cases today occur in previously morbid individuals and are caused by opportunists

fromthepatient’sownmicrobiome.

DIAGNOSIS• Usualsigns:tachycardia,tachypnea,leukocytosisorleukopenia,feverorhypothermia• Frequent, suggestive: thrombocytopenia, lactatemia, delirium, respiratory alkalosis,

hyperbilirubinemia

THERAPY• Promptadministrationofantimicrobialdrugsthatcankillthepatient’soffendingmicrobe

(seeTable20-1)• Intravenousfluidsandpressorsupportasneeded• Source control: eliminating the local site of infection, usually with surgery or removal of

indwellingdevice• Supportivecare

PREVENTION• Hospitalinfectioncontrol• Vaccination

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TABLE 20-1  Empirical Antibiotic Options for Patients with Severe Sepsis or Septic Shock

SUSPECTED SOURCE

LUNG ABDOMENSKIN/SOFT TISSUE

URINARY TRACT

SOURCE UNCERTAIN

Major Community-Acquired Pathogens

Streptococcus pneumoniaeHaemophilus influenzaeLegionellaChlamydia pneumoniae

Escherichia coliBacteroides fragilis

Streptococcus pyogenesStaphylococcus aureusPolymicrobial

E. coliKlebsiella speciesEnterobacter speciesProteus spp.Enterococci

Empirical Antibiotic Therapy

Moxifloxacin or levofloxacin or azithromycin plus cefotaxime or ceftazidime or cefepime or piperacillin-tazobactam

Imipenem or meropenem or doripenem or piperacillin-tazobactam ± aminoglycosideIf biliary source: piperacillin-tazobactam, ampicillin-sulbactam, or ceftriaxone with metronidazole

Vancomycin or daptomycin plus either imipenem or meropenem or piperacillin-tazobactam; ± clindamycin

Ciprofloxacin or levofloxacin (if gram-positive cocci, use ampicillin or vancomycin ± gentamicin)

Vancomycin plus either doripenem or ertapenem or imipenem or meropenem

Major Commensal or Nosocomial Microorganisms

Aerobic gram-negative bacilli

Aerobic gram-negative rodsAnaerobesCandida spp.

Staphylococcus aureus (? MRSA)Aerobic gram-negative rods

Aerobic gram-negative rodsEnterococci

Consider MDRO if in area of high prevalenceConsider echinocandin if neutropenic or indwelling intravascular catheter

Empirical Antibiotic Therapy

Imipenem or meropenem or doripenem or cefepime (if Acinetobacter baumanii or carbapenem-resistant Klebsiella in ICU, add colistin)

Imipenem or meropenem ± aminoglycoside (consider echinocandin)

Vancomycin or daptomycin plus imipenem-cilastatin or meropenem or cefepime, ± clindamycin

Vancomycin plus imipenem or meropenem or cefepime

Cefepime plus vancomycin ± caspofungin

Dosages for intravenous administration (normal renal function):*Imipenem-cilastatin, 0.5-1.0 g q6-8h*Meropenem, 1-2 g q8h*Doripenem, 0.5 g q8hPiperacillin-tazobactam, 3.375 g q4h or 4.5 g q6hVancomycin, load 25-30 mg/kg, then 15-20 q8-12hCefepime, 1-2 g q8hLevofloxacin, 750 mg q24hCiprofloxacin, 400 mg q8-12hMoxifloxacin, 400 mg qdCeftriaxone, 2.0 g q24hCaspofungin, 70 mg, followed by 50 mg q24hColistin: loading dose = 5 mg/kg body weight. For maintenance dosing, see University of California, Los Angeles

Dosing Protocol: www.infectiousdiseases-ucla-affiliated.org/Intranet/FILES/ColistinDosing.pdfICU, intensive care unit; MDRO, multidrug-resistant organisms; MRSA, methicillin-resistant Staphylococcus aureus.For MDRO, resistance usually includes carbapenems.*Carbapenems are less susceptible to extended-spectrum β-lactamases; base choice on local resistance pattern.

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F  Intra-abdominal Infections

21 Peritonitis and Intraperitoneal AbscessesMatthew E. Levison and Larry M. Bush

DEFINITION• Infectionintheabdominalcavityencompassesawidespectrumofentitiesandmayinvolve

anyintra-abdominalorganorspace.• Peritonitisisaninflammatoryresponsewithintheperitonealcavityastheresultofcontami-

nationwithmicroorganisms,chemicals,orboth.• Infectiveperitonitisisclassifiedaseitherdiffuseorlocalized,primary(spontaneous),second-

ary,ortertiaryandisfurthercharacterizedas“uncomplicated”or“complicated.”• Inprimaryperitonitis,thereisnointra-abdominalsource,whereasinsecondary,thereisan

intra-abdominalsourceofinfection.• Uncomplicatedinfectionsarecontainedwithinasingleorganwithoutanatomicdisruption,

whereas complicated infections involve extension beyond the organ, either localized orgeneralizedperitonitis,withspillageofmicroorganismsintothesterileperitonealspace.

• Peritonitisisacommoncomplicationoccurringinpatientsundergoingcontinuousambula-toryperitonealdialysis(CAPD).

• Intraperitonealabscessesarefocalcollectionsofpuscomplicatingeitherprimaryorsecond-aryperitonitis,withlocationsgenerallyrelatedtothesiteofprimarydiseaseandthedirectionofdependentperitonealdrainage.

• Themajorityofintra-abdominalinfections(80%)are“communityacquired”andaregradedfrom“mildtomoderate”to“moresevere”onthebasisofphysiologicscoringsystems(AcutePhysiologyandChronicHealthEvaluationII[APACHEII]),thepatient’scomorbidcondi-tions,underlyingimmunestatus,andaninabilitytoachieveadequatesourcecontrol.

• Healthcare–associatedintra-abdominalinfectionsaremostcommonlyacquiredascompli-cationsofpreviouselectiveoremergencyabdominalsurgeries.

EPIDEMIOLOGY• Primaryperitonitisaccountsforapproximately1%ofallperitonitiscases.• Adultpatientsusuallyhavecirrhosisandascitesandareatgreaterriskifthereisacoexisting

gastrointestinalhemorrhage,previousepisode,orlowasciticproteinconcentration.• Secondaryperitonitisisthemostcommonintra-abdominalinfection(80%to90%),caused

bymicrobialorchemicalcontaminationofthesterileperitonealcavityfrommultiplediseaseprocesses(seeTable21-1).

• Tertiaryperitonitisreferstoapersistentorrecurrentinfectionwithoutasurgicallytreatablefocus,maybeduetodisturbanceinthehost’simmuneresponse,andoftenisassociatedwithlessvirulentandpotentiallyresistantmicroorganisms.

• CAPDperitonitisisthemajorcomplicationofperitonealdialysisandmostoftenisduetotouchcontaminationorcatheter-relatedinfection.

• Itrecursin20%to30%andistheprimaryreasonforaswitchtohemodialysis.• Intraperitonealabscessesoccursecondarilyasaconsequenceofdiseasedorgans,penetrating

trauma,orasurgicalprocedure.

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MICROBIOLOGY• Primaryperitonitisisamonomicrobialinfectionwithmorethan60%ofepisodesincirrhotic

patientscausedbygram-negativeentericbacteria.• In children, hematogenous spread of Streptococcus pneumoniae and other streptococcal

speciesismorefrequent.• Staphylococcus aureusisrarelyisolatedinprimaryperitonitis.• Variantsofprimaryperitonitisincludeascitesthatgrowsasingletypeoforganismbuthas

fewerthan250polymorphonuclearwhitebloodcells(PMNWBCs)/mm3(monomicrobialnon-neutrocyticbacterascites)orhasmorethan250PMNWBCs/mm3withnegativecul-tures(culture-negativeneutrophilicascites).

• Secondaryperitonitisischaracteristicallypolymicrobial(seeTable21-2)anddependsuponthemicrofloraassociatedwiththeprimarydiseaseprocess,whichmaybealteredbypreviousantibiotictherapy,othermedications,andspecifichostfactors.

• Enterococci and Candida spp. can often be isolated, the significance of which iscontroversial.

TABLE 21-1  Causes of Secondary PeritonitisDistal esophagus Boerhaave syndrome

MalignancyTraumaIatrogenic*

Stomach Peptic ulcer perforationMalignancyTraumaIatrogenic*

Duodenum Peptic ulcer perforationTraumaIatrogenic*

Biliary tract CholecystitisStone perforation from gallbladder or common ductMalignancyTraumaIatrogenic*

Pancreas Pancreatitis (e.g., alcohol, drugs, gallstones)TraumaIatrogenic*

Small bowel Ischemic bowelIncarcerated herniaCrohn’s diseaseMalignancyMeckel’s diverticulumTrauma

Large bowel and appendix Ischemic bowelDiverticulitisMalignancyUlcerative colitis and Crohn’s diseaseAppendicitisVolvulusTrauma (mostly penetrating)Iatrogenic*

Uterus, salpinx, and ovaries Pelvic inflammatory disease (e.g., salpingo-oophoritis, tubo-ovarian abscess, ovarian cyst)TraumaMalignancyIatrogenic*

*Dehiscence of surgical anastomosis or inadvertent injury during a procedure (e.g., endoscopy).Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-

abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133-164.

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• CAPD peritonitis is caused by gram-positive organisms (Staphylococcus epidermidis, S. aureus,andStreptococcusspp.)in60%to80%ofcases.

• Gram-negativebacteria(e.g.,Enterobacteriaceae,Pseudomonasspp.,andAcinetobacterspp.)makeup15%to30%ofcases,oftenderivedfromurinarytract,bowel,skin,orcontaminatedwater.

• Fungalandmycobacterialspeciesareoccasionallyinvolved.• PolymicrobialperitonitisinCAPDisassumedtobesecondarytoanintestinalprocess(e.g.,

bowelperforation).• Intraperitoneal abscesses are mostly polymicrobial and involve the same microorganisms

thatcausesecondaryperitonitis.• Pathogensincludeobligateanaerobicspecies(e.g.,Bacteroides fragilis,anaerobiccocci,and

Clostridia)alongwithfacultativegram-negativebacilli(e.g.,Escherichia coliandProteusandKlebsiellaspp.)

DIAGNOSIS• Primary peritonitis is diagnosed by excluding a primary source of intra-abdominal

infection.• AsciticfluidstudiesincludeWBCcountwithdifferential,proteinconcentration,Gramstain,

andculture.• Thedifferencebetweenserumandasciticfluidalbuminconcentrationisgreaterthan1.1g/

dL,whichiscorrelatedwithportalhypertension.• Asciticfluidglucose,amylase,andlactatedehydrogenasemeasurementsmayhelptodistin-

guishprimaryfromsecondaryperitonitis.• Patientssuspectedofhavingsecondaryperitonitisoranintraperitonealabscessonthebasis

of clinical findings or peritoneal fluid examination require radiologic evaluation with acomputedtomographyscanand/orultrasonography.

TABLE 21-2  Organisms Causing Complicated Intra-abdominal Infections

ORGANISM PATIENTS (%)

Facultative and Aerobic Gram-Negative BacilliEscherichia coli 71

Klebsiella spp. 14

Pseudomonas aeruginosa 14

Proteus mirabilis 5

Enterobacter spp. 5

AnaerobicBacterioides fragilis 35

Other Bacterioides spp. 71

Clostridium spp. 29

Prevotella spp. 12

Peptostreptococcus spp. 17

Fusobacterium spp. 9

Eubacterium spp. 17

Gram-Positive Aerobic CocciStreptococcus spp. 38

Enterococcus faecalis 12

Enterococcus faecium 3

Enterococcus spp. 8

Staphylococcus aureus 4

Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infec Dis. 2010;50:133-164.

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• When clinically suspected, CAPD peritonitis is confirmed by finding greater than 100WBCs/mm3(predominantlyPMNcells)inmostlycloudydialysate,togetherwiththeisola-tionofamicroorganism(90%to95%ofcases).

THERAPY• Pendingconfirmatorystudies,empiricalantibiotictherapyforsuspectedprimaryperitonitis

shouldbeinitiated(seeTable21-3)onthebasisofthemostlikelypathogens.• Fivedaysofantibiotictherapyissufficientinmostinstances,andoralantibiotictherapymay

beanoptioninselectedcases.• Thetreatmentofsecondaryperitonitisrequiresantibiotictherapy(seeTables21-4and21-5),

alongwithappropriatemedical support, sourcecontrol,andremovalofadiseasedorgan,

TABLE 21-3  Primary Peritonitis: Indications for Initiation of TherapyTemperature >37.8° C (100° F)Abdominal pain and/or tendernessAn unexplained change in mental statusLaboratory abnormalities suggestive of infection (e.g., renal failure, acidosis, or peripheral leukocytosis)Peritoneal fluid neutrophil count ≥250 cells/mm3

TABLE 21-4  Recommended Agents for Treatment of Complicated Intra-abdominal Infections

TYPE OF THERAPYa

FOR MILD TO MODERATELY SEVERE INFECTIONSb

FOR HIGHLY SEVERE  COMMUNITY-ACQUIRED,  HEALTH CARE–ASSOCIATED,  AND TERTIARY INFECTIONSc

Single Agentβ-lactam/β-lactamase inhibitor combinations

Ticarcillin-clavulanic acid Piperacillin-tazobactamd

Fluoroquinolonee Moxifloxacinf Moxifloxacinf

Carbapenems Ertapenem Imipenem-cilastatind or meropenem or doripenem

Glycylcyclines Tigecyclinef Tigecyclinef

Combination TherapyCephalosporin based Cefazolin, cefuroxime, cefotaxime,

ceftriaxone plus metronidazoleThird- or fourth-generation cephalosporin (ceftazidime or cefepime) plus metronidazoleCeftazidime/avibactam plus metronidazoleg

Ceftolozane/tazobactam plus metronidazole

Fluoroquinolone basede

Ciprofloxacin or levofloxacin, each in combination with metronidazoleg

Ciprofloxacin in combination with metronidazoleh

Monobactam based Aztreonam plus vancomycinf or clindamycin plus metronidazole

aEmpirical antimicrobial regimens should be adjusted according to culture and susceptibility reports to ensure activity against the predominant pathogens isolated in culture.

bApplies mainly to community-acquired intra-abdominal infections.cApplies to health care–associated and tertiary peritonitis cases, as well as some severe community-acquired intra-

abdominal infections. However,  tigecycline  should  NOT  be  used  as  empirical  therapy  for  health  care–associated or tertiary infection due to inactivity of tigecycline against Pseudomonas aeruginosa.

dIn vitro activity may be less, compared to alternative antibiotics.eFluoroquinolone-resistant Escherichia coli has become common in some communities, and fluoroquinolones

should not be used unless hospital surveys indicate at least 90% susceptibility of E. coli to fluoroquinolones.fRisk of mortality may be greater compared with alternative antimicrobials.gClinical cure rates were lower than those achieved with meropenem in a phase III trial, with baseline creatinine

clearance (CrCL) of 30 to 50 mL/min. However, patients treated with ceftazidime/avibactam received a 33% lower daily dose than is currently recommended for patients with this CrCL.

hBecause Bacteroides strains are resistant to these fluoroquinolones, addition of metronidazole is necessary.

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TABLE 21-5  Antibiotic Dosage for Peritonitis during Peritoneal Dialysis

DRUGINTERMITTENT (PER EXCHANGE, ONCE DAILY)

CONTINUOUS (ALL EXCHANGES)

AminoglycosidesGentamicin 0.6 mg/kg LD: 8 mg/L

MD: 4 mg/L

Tobramycin 0.6 mg/kg LD: 8 mg/LMD: 4 mg/L

CephalosporinsCefazolin 15 mg/kg LD: 500 mg/L

MD: 125 mg/L

Cefepime 1 g LD: 500 mg/LMD: 125 mg/L

Ceftazidime 1-1.5 g LD: 500 mg/LMD: 125 mg/L

Cefotaxime 1 g LD: 500 mg/LMD: 125 mg/L

PenicillinsAmpicillin ND MD: 125 mg/L

Oxacillin ND MD: 125 mg/L

Penicillin G ND LD: 50,000 UMD: 25,000 U

Piperacillin ND LD: 500 mg/LMD: 250 mg/L

QuinolonesCiprofloxacin ND LD: 50 mg/L

MD: 25 mg/L

OthersVancomycin 15-30 mg/kg every 5-7 days LD: 1000 mg/L

MD: 25 mg/L

Aztreonam ND LD: 1000 mg/LMD: 250 mg/L

Trimethoprim-sulfamethoxazole ND LD: 320/1600 mg/L POMD: 80/400 mg/L PO daily

CombinationsAmpicillin-sulbactam 2 g every 12 hr LD: 1000 mg/L

MD: 100 mg/L

Imipenem-cilastatin 1 g every 12 hr LD: 500 mg/LMD: 200 mg/L

AntifungalsAmphotericin B NA 1.5 mg/L

Fluconazole ND 200 mg/L IP or PO daily

IP, intraperitoneal; LD, loading dose; MD, maintenance dose; NA, not applicable; ND, no data; PO, orally.Modified from Piraino B, Bailie GR, Bernardini J, et al. Peritoneal dialysis-related infections recommendations: 2005

update. Perit Dial Int. 2005;25:107-131.

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TABLE 21-6  CAPD Peritonitis: Indications for Catheter RemovalPersistent infection at skin exit site or tunnelRelapsing peritonitis with same organism—within 4 wkRefractory peritonitis—failure to respond within 5 daysFungal, mycobacterial, Pseudomonas aeruginosa peritonitisIntraperitoneal abscessCatheter malfunction

CAPD, continuous ambulatory peritoneal dialysis.

necrotic tissue, purulence, blood, feces, and other intraperitoneal foreign material, whenpresent.

• CAPDperitonitis is treatedwithintraperitonealantibiotics(seeTable21-6)usuallyfor10to21days.

• Peritonealdialysiscatheterremovalisnecessaryin10%to20%ofpatients,particularlywithfungalandnontuberculousmycobacterialinfections(seeTable21-6).

• Intraperitoneal abscesses require drainage (percutaneous catheter or surgical), antibiotictherapy(seeTables21-4and21-5),andpossiblysourcecontrol.

PREVENTION• Primaryperitonitisprophylaxisisrecommendedincirrhoticpatientswithasciteswhoare

havingagastrointestinalhemorrhage.• Long-term antibiotic prophylaxis (e.g., norfloxacin or trimethoprim-sulfamethoxazole) is

indicatedinpatientswithoneormoreepisodesofprimaryperitonitis,aswellasincirrhoticpatientswithasciticfluidproteinconcentrationslessthan1.5g/dL.

48

22 Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis)Costi D. Sifri and Lawrence C. Madoff

DEFINITION• Apyogenicliverabscessistheendresultofanumberofpathologicprocessesresultingina

focal,purulentbacterialcollectionintheliver.• Anamebicliverabscessisaninvasivecomplicationofintestinalamebiasisresultinginafocal

collectionofnonpurulentfluidintheliver.• Cholecystitis: Inflammation/bacterial infection of the gallbladder often resulting from

obstructing gallstones. Acalculous cholecystitis is a similar process in the absence ofgallstones.

• Cholangitisisinflammation/infectionofthebileducts.

EPIDEMIOLOGY• Anestimated10to20casesofpyogenicliverabscessoccurper100,000hospitaladmissions,

or11casespermillionpersonsperyear.• Amebicliverabscessesarerarer,about1permillionpersons,butmorecommoninendemic

regions.Theyaffectmenabout10timesmorefrequentlythanwomen.• Tens of millions in the United States have gallstones; 1% to 3% are complicated by acute

cholecystitis.• Approximately120,000cholecystectomiesoccureachyearintheUnitedStates.• Between 2% and 15% of cases occur without gallstones, known as “acalculous

cholecystitis.”• Inendemicregions,parasitessuchasAscarisandClonorchismaycausebiliarydisease.

MICROBIOLOGY• Pyogenicliverabscessesmaybemonomicrobial,especiallywhencausedbybacteremia,or

polymicrobialinvolvingaerobicgram-negativebacilliandanaerobes.• Klebsiella pneumoniae(typicallyK1andK2strains)arenowanimportantcauseofpyogenic

liverabscess,particularlyinpartsofAsia,butincreasinglyelsewhere.• AmebicliverabscessesarecausedbyinvasivestrainsofEntamoeba histolytica.

DIAGNOSIS• Symptomsareoftennonspecific,andahighindexofsuspicionisrequired.• Diagnostic imaging, especially by ultrasonography, radionuclide cholescintigraphy, or

computed tomography, is essential. For pyogenic liver abscesses, it is often coupled withdiagnostic/therapeuticaspiration.

THERAPY• Somepyogenicprocessesrequirepromptrecognitionandurgentimage-guideddrainageor

definitivesurgery.• Antibioticsdirectedatthesuspectedpathogensplayanimportantroleasadjunctstosurgery

or, in limited cases, may be the sole form of therapy (e.g., small pyogenic liver abscesses,amebicliverabscess).

49

23  Pancreatic InfectionMiriam Baron Barshak

DEFINITION• Infectionofpancreatictissue.• Mostcommonlydevelopsasacomplicationofacutepancreatitis(AP),intissuethathasbeen

damagedbyinflammation(seeTable23-1).• Pancreaticabscessisacircumscribedcollectionofpususuallyinornearthepancreas,arising

asaconsequenceofAPorpancreatictrauma.

EPIDEMIOLOGY• Approximately185,000casesofAPperyear intheUnitedStates,20%ofwhichmayhave

significantpancreaticnecrosis.• Upto70%ofpatientswithpancreaticnecrosismaydeveloppancreaticinfection.

MICROBIOLOGY• Gastrointestinalbacterialfloramostcommon(aerobesandanaerobes,gram-positive,and

gram-negative).• Use of preemptive antibiotics may select for more resistant bacterial species and fungal

pathogens.

DIAGNOSIS• Mustbedistinguishedfromsterilepancreaticnecrosis,whichcanbeassociatedwithasepsis-

likesyndrome.• Tissuesamplingisrequiredtoidentifyinfection.

THERAPY• Antimicrobial therapy targeting organisms identified in cultures of the infected site, in

combination with catheter drainage and/or surgical removal of the infected material (seeTable23-2).

• Delayinsurgeryfor infectedpancreaticnecrosismayallowforamorestablepatientwithbetter-demarcatedareasofnecrotictissue.

• Newer surgical approaches include video-assisted retroperitoneal débridement and endo-scopictransgastricnecrosectomy.

PREVENTION• Avoidtoo-earlyenteralfeeding.• Aconsensus favoringuseofearly (preemptive) systemicantibioticsemerged in the1990s

and2000s,usingcarbapenemaloneorquinoloneplusmetronidazoleasfirst-choicetherapy.• Morerecentrandomizedcontrolledstudieshavenotdemonstratedabenefitfromthisprac-

tice,andsomeguidelinesnolongerrecommendpreemptiveantibioticsforpatientswithAP.

50Part

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TABLE 23-1  Definitions Derived from the International Symposium on Acute Pancreatitis, 1992

TERM DEFINITIONAcute pancreatitis Acute inflammatory process of the pancreas with variable involvement of other

regional tissues or remote organ systems

Severe acute pancreatitis Association with organ failure or local complications, or both, such as necrosis, abscess, or pseudocyst

Acute fluid collection Occurs early in the course of AP, located in or near the pancreas, always lacking a wall of granulation or fibrous tissue; bacteria variably present; occurs in 30%-50% of severe AP; most acute fluid collections regress, but some progress to pseudocyst or abscess

Pancreatic necrosis Diffuse or focal area(s) of nonviable pancreatic parenchyma, typically associated with peripancreatic fat necrosis, diagnosed by computed tomography scan with intravenous contrast enhancement

Acute pseudocyst Collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue that arises as a consequence of AP, pancreatic trauma, or chronic pancreatitis; formation requires 4 or more weeks from onset of AP

Pancreatic abscess Circumscribed intraabdominal collection of pus usually in or near the pancreas, containing little or no pancreatic necrosis, arises as a consequence of AP or pancreatic trauma

AP, acute pancreatitis.Note: The use of terms such as phlegmon, infected pseudocyst, hemorrhagic pancreatitis, and persistent acute

pancreatitis is explicitly discouraged.From Bradley EL. A clinically based classification system for acute pancreatitis. Arch Surg. 1993;128:586-590.

51C

hap

ter 23 Pancreatic In

fection

TAB

LE 2

3-2

 Pan

creati

c In

fect

ion

 In

cid

en

ce a

nd

 Mo

rtali

ty R

ate

 in

 Co

ntr

oll

ed

 Tri

als

 wit

h A

nti

bio

tics

 an

d M

eta

-An

aly

ses

AU

THO

RA

NTI

BIO

TIC

NO

. O

F PA

TIEN

TS

PAN

CR

EATI

C

INFE

CTI

ON

R

ATE

(%

) C

ON

TRO

L/C

ASE

MO

RTA

LITY

R

ATE

(%

) C

ON

TRO

L/C

ASE

CO

MM

ENTS

Luite

n et

al

SGD

: en

tera

l col

istin

, no

rflox

acin

, an

d am

phot

eric

in B

, un

til

clin

ical

rec

over

y pl

us IV

ce

fota

xim

e un

til g

ram

-ne

gativ

e ba

cter

ia a

re

elim

inat

ed f

rom

the

ora

l ca

vity

102

seve

re A

P38

/18*

35/2

2N

onbl

inde

d.N

ecro

sis

not

defin

ed.

Mor

talit

y di

ffer

ence

sta

tistic

ally

sig

nific

ant

whe

n di

seas

e se

verit

y di

ffer

ence

s be

twee

n th

e gr

oups

are

tak

en in

to

acco

unt.

Pre

dom

inan

t ef

fect

on

gram

-neg

ativ

e pa

ncre

atic

in

fect

ion

(8%

in S

GD

gro

up v

s. 3

3% in

con

vent

iona

l tre

atm

ent

grou

p).

Trea

tmen

t w

ith in

trav

enou

s ce

furo

xim

e as

wel

l as

ente

ral S

GD

obs

cure

s in

terp

reta

tion

of t

he e

ffec

t of

ent

eral

tr

eatm

ents

alo

ne.

Pede

rzol

i et

al

Imip

enem

, 50

0 m

g IV

tid

, 14

day

s74 ne

crot

izin

g pa

ncre

atiti

s,

mos

tly o

f bi

liary

orig

in

30/1

2*12

/7N

ot p

lace

bo-c

ontr

olle

d.N

onpa

ncre

atic

infe

ctio

ns a

lso

redu

ced

(15%

vs.

49%

, P <

.01)

. N

o ch

ange

in m

ultio

rgan

fai

lure

rat

e, n

eed

for

surg

ery,

or

surv

ival

com

pare

d w

ith n

o ea

rly a

ntib

iotic

tre

atm

ent.

Sain

io e

t al

Cef

urox

ime,

1.5

g IV

tid

, un

til c

linic

al r

ecov

ery

and

norm

aliz

atio

n of

CRP

leve

l

60 seve

re a

cute

alc

ohol

ic

panc

reat

itis

and

necr

osis

of

at le

ast

one

third

of

the

panc

reas

by

cont

rast

-enh

ance

d C

T

40/3

023

/3*

Not

pla

cebo

-con

trol

led.

Red

uctio

n in

tot

al in

fect

ions

, in

fect

ions

pe

r pa

tient

, an

d op

erat

ions

als

o st

atis

tical

ly s

igni

fican

t. R

ate

of

cultu

re-p

rove

n se

psis

not

sta

tistic

ally

sig

nific

ant.

Onl

y ur

inar

y tr

act

infe

ctio

ns w

ere

redu

ced

sign

ifica

ntly

.

Del

cens

erie

et

al

Cef

tazi

dim

e, a

mik

acin

, an

d m

etro

nida

zole

IV,

10 d

ays

23 alco

hol-i

nduc

ed s

ever

e A

P

58/0

*25

/9C

T w

ith t

wo

or m

ore

fluid

col

lect

ions

, ne

cros

is n

ot d

efine

d

Schw

arz

et a

lO

floxa

cin

and

met

roni

dazo

le IV

, 10

day

s26 C

T-co

nfirm

ed

panc

reat

ic n

ecro

sis

53/6

115

/0N

ot p

lace

bo-c

ontr

olle

d. F

NA

per

form

ed o

n da

ys 1

, 3,

5,

7, a

nd

10 in

all

patie

nts;

ant

ibio

tics

give

n to

con

trol

pat

ient

s w

ith

evid

ence

of

infe

ctio

n. B

ette

r cl

inic

al c

ours

e in

inte

rven

tion

grou

p, b

ut n

o ef

fect

on

deve

lopm

ent

of p

ancr

eatic

infe

ctio

ns.

Bass

i et

alPe

floxa

cin

(400

mg

bid)

vs.

im

ipen

em (

500

mg

tid),

14

days

60 seve

re n

ecro

tizin

g pa

ncre

atiti

s

Peflo

xaci

n: 3

3*

Imip

enem

: 10

*Pe

floxa

cin:

24

Imip

enem

: 10

Non

blin

ded.

CT

confi

rmed

at

leas

t 50

% n

ecro

sis.

Cont

inue

d

52Part

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AU

THO

RA

NTI

BIO

TIC

NO

. O

F PA

TIEN

TS

PAN

CR

EATI

C

INFE

CTI

ON

R

ATE

(%

) C

ON

TRO

L/C

ASE

MO

RTA

LITY

R

ATE

(%

) C

ON

TRO

L/C

ASE

CO

MM

ENTS

Isen

man

n et

al

Cip

roflo

xaci

n (4

00 m

g bi

d)

and

met

roni

dazo

le (

500

mg

bid)

IV,

or p

lace

bo,

14 o

r 21

day

s

114

AP

plus

ser

um C

RP

>150

mg/

L an

d/or

ne

cros

is o

n co

ntra

st-

enha

nced

CT

12/9

5/7

Rand

omiz

ed,

doub

le-b

linde

d, p

lace

bo-c

ontr

olle

d; 2

8% o

f C

IP/

MET

gro

up a

nd 4

6% o

f pl

aceb

o gr

oup

requ

ired

open

an

tibio

tic t

reat

men

t; m

ost

plac

ebo

grou

p sw

itche

s m

otiv

ated

by

ext

rapa

ncre

atic

infe

ctio

ns;

over

all m

orta

lity

and

rate

s of

pa

ncre

atic

infe

ctio

n lo

w,

num

ber

of p

atie

nts

with

pan

crea

tic

necr

osis

low

Gol

ub e

t al

Met

a-an

alys

is o

f ei

ght

cont

rolle

d tr

ials

, in

clud

ing

tria

ls f

rom

the

197

0s

Find

ings

: Ea

rly a

ntib

iotic

adm

inis

trat

ion

redu

ced

mor

talit

y fr

om

AP

but

only

for

pat

ient

s w

ith s

ever

e pa

ncre

atiti

s w

ho r

ecei

ved

broa

d-sp

ectr

um a

ntib

iotic

s re

achi

ng t

hera

peut

ic le

vels

in

panc

reat

ic t

issu

e

Shar

ma

et a

lM

eta-

anal

ysis

incl

udin

g on

ly r

ando

miz

ed,

cont

rolle

d, n

onbl

inde

d st

udie

s ev

alua

ting

patie

nts

with

nec

rotiz

ing

panc

reat

itis

who

rec

eive

d ei

ther

no

pree

mpt

ive

antib

iotic

s or

pre

empt

ive

trea

tmen

t w

ith a

ntib

iotic

s re

achi

ng t

hera

peut

ic le

vels

in

nec

rotic

pan

crea

tic t

issu

e

84 rece

ived

ant

ibio

tic

prop

hyla

xis;

76

did

not;

of

not

e, t

he t

otal

of

160

patie

nts

in t

he

pool

ed d

ata

set

is

inad

equa

te f

or

dete

ctio

n of

a 5

0%

redu

ctio

n in

the

rat

e of

in

fect

ions

Find

ings

: N

onsi

gnifi

cant

tre

nd t

owar

d de

crea

sed

loca

l inf

ectio

n in

pat

ient

s gi

ven

early

imip

enem

, ce

furo

xim

e, o

r ofl

oxac

in.

Inci

denc

e of

sep

sis

and

over

all m

orta

lity

sign

ifica

ntly

low

er

(abs

olut

e ris

k re

duct

ions

, 21

.1%

and

12.

3%,

resp

ectiv

ely,

for

a

rela

tive

risk

redu

ctio

n of

72%

) fo

r an

tibio

tic t

reat

men

t. O

n th

is

basi

s, t

he a

utho

rs r

ecom

men

d th

at “

all p

atie

nts

with

acu

te

necr

otiz

ing

panc

reat

itis…

be g

iven

pro

phyl

axis

with

an

antib

iotic

w

ith p

rove

n ef

ficac

y in

nec

rotic

pan

crea

tic t

issu

e.”

Vill

ator

o et

al

Coc

hran

e Re

view

incl

udin

g ra

ndom

ized

con

trol

led

tria

ls

com

parin

g an

tibio

tics

with

pl

aceb

o in

AP

with

C

T-pr

oven

nec

rosi

s

294

(fro

m 5

eva

luab

le

stud

ies)

Find

ings

: Si

gnifi

cant

ly le

ss m

orta

lity

with

the

rapy

(6%

) vs

. co

ntro

ls (

15.3

%).

No

diff

eren

ces

in r

ates

of

infe

cted

pan

crea

tic

necr

osis

, op

erat

ive

trea

tmen

t, n

onpa

ncre

atic

infe

ctio

n, a

nd

fung

al in

fect

ion.

Sub

grou

p an

alys

is o

f β-

lact

am t

reat

men

t:

Sign

ifica

ntly

less

mor

talit

y (6

.3%

vs.

16.

7%)

than

in c

ontr

ols,

w

ithou

t si

gnifi

cant

diff

eren

ces

in r

ates

of

oper

ativ

e tr

eatm

ent

or n

onpa

ncre

atic

infe

ctio

ns.

No

sign

ifica

nt d

iffer

ence

s w

ith

quin

olon

e pl

us im

idaz

ole

trea

tmen

t. β

-Lac

tam

s as

soci

ated

with

si

gnifi

cant

ly d

ecre

ased

mor

talit

y an

d in

fect

ed p

ancr

eatic

ne

cros

is.

Rokk

e et

al

Pros

pect

ive

rand

omiz

ed

cont

rolle

d tr

ial,

imip

enem

(5

00 m

g tid

for

5-7

day

s)

vs.

no a

ntib

iotic

s

73:

36 r

ecei

ved

imip

enem

; 37

rec

eive

d no

an

tibio

tics

43/1

4*11

/8U

nder

pow

ered

stu

dy (

slow

pat

ient

acc

rual

).N

o di

ffer

ence

s in

leng

th o

f ho

spita

l sta

y, n

eed

of in

tens

ive

care

, ne

ed o

f ac

ute

inte

rven

tions

, ne

ed f

or s

urge

ry,

or 3

0-da

y m

orta

lity

rate

s.A

utho

rs c

oncl

ude

that

“th

e st

udy,

alth

ough

und

erpo

wer

ed,

supp

orts

the

use

of

early

pro

phyl

actic

tre

atm

ent

with

imip

enem

in

ord

er t

o re

duce

the

rat

e of

sep

tic c

ompl

icat

ions

in p

atie

nts

with

sev

ere

panc

reat

itis.

”

Del

linge

r et

al

Mul

ticen

ter,

pros

pect

ive,

do

uble

-blin

d, p

lace

bo-

cont

rolle

d ra

ndom

ized

st

udy

set

in 3

2 ce

nter

s w

ithin

Nor

th A

mer

ica

and

Euro

pe

100

clin

ical

ly s

ever

e,

confi

rmed

nec

rotiz

ing

panc

reat

itis:

50 r

ecei

ved

mer

open

em

(1g

IV q

8h);

50 r

ecei

ved

plac

ebo

with

in 5

day

s of

sym

ptom

ons

et,

for

7 to

21

days

12/1

818

/20

No

stat

istic

ally

sig

nific

ant

diff

eren

ce b

etw

een

the

trea

tmen

t gr

oups

for

pan

crea

tic o

r pe

ripan

crea

tic in

fect

ion,

mor

talit

y, o

r re

quire

men

t fo

r su

rgic

al in

terv

entio

n.

Jafr

i et

alM

eta-

anal

ysis

ass

essi

ng t

he

clin

ical

out

com

e of

pat

ient

s w

ith s

ever

e A

P tr

eate

d w

ith

prop

hyla

ctic

ant

ibio

tics

com

pare

d w

ith t

hat

of

patie

nts

not

trea

ted

with

an

tibio

tics

502

(fro

m 8

stu

dies

)Fi

ndin

gs:

No

effe

ct o

f an

tibio

tics

on m

orta

lity,

rat

es o

f in

fect

ed

necr

osis

, or

fre

quen

cy o

f su

rgic

al in

terv

entio

n. A

ppar

ent

bene

fit r

egar

ding

non

panc

reat

ic in

fect

ions

(RR

, 0.

60;

95%

CI,

0.44

-0.8

2),

with

a R

R re

duct

ion

of 4

0% (

95%

CI,

18%

-56%

); ab

solu

te r

isk

redu

ctio

n of

15%

(95

% C

I, 6%

-23%

), an

d nu

mbe

r ne

eded

to

trea

t of

7 (

95%

CI,

4-17

).

Vill

ator

o et

al

Coc

hran

e Re

view

incl

udin

g ra

ndom

ized

con

trol

led

tria

ls

com

parin

g an

tibio

tics

with

pl

aceb

o in

AP

with

C

T-pr

oven

nec

rosi

s

404

(fro

m 7

eva

luab

le

stud

ies)

Find

ings

: N

o be

nefit

of

antib

iotic

s in

pre

vent

ing

infe

ctio

n of

pa

ncre

atic

nec

rosi

s or

mor

talit

y, e

xcep

t w

hen

imip

enem

was

co

nsid

ered

on

its o

wn,

in w

hich

cas

e a

sign

ifica

nt d

ecre

ase

in

panc

reat

ic in

fect

ion

was

fou

nd (

P =

.02;

RR,

0.3

4; 9

5% C

I, 0.

13-0

.84)

with

out

effe

ct o

n m

orta

lity.

“N

one

of t

he s

tudi

es

incl

uded

in t

his

revi

ew w

ere

adeq

uate

ly p

ower

ed.

Furt

her

bett

er d

esig

ned

stud

ies

are

need

ed if

the

use

of

antib

iotic

pr

ophy

laxi

s is

to

be r

ecom

men

ded.

”

AP,

acu

te p

ancr

eatit

is;

CI,

confi

denc

e in

terv

al;

CIP

/MET

, ci

profl

oxac

in/m

etro

nida

zole

; C

RP,

C-r

eact

ive

prot

ein;

CT,

com

pute

d to

mog

raph

y; F

NA

, fin

e-ne

edle

asp

iratio

n; IV

, in

trav

enou

s; R

R,

rela

tive

risk;

SG

D,

sele

ctiv

e gu

t de

cont

amin

atio

n.*P

< .

05.

Mod

ified

fro

m T

ooul

i J,

Broo

ke-S

mith

M,

Bass

i C,

et a

l. G

uide

lines

for

the

man

agem

ent

of a

cute

pan

crea

titis

. J

Gas

troe

nter

ol H

epat

ol.

2002

;17(

supp

l):S1

5-S3

9.

TAB

LE 2

3-2

 Pan

creati

c In

fect

ion

 In

cid

en

ce a

nd

 Mo

rtali

ty R

ate

 in

 Co

ntr

oll

ed

 Tri

als

 wit

h A

nti

bio

tics

 an

d 

Meta

-An

aly

ses—

con

t’d

53C

hap

ter 23 Pancreatic In

fection

AU

THO

RA

NTI

BIO

TIC

NO

. O

F PA

TIEN

TS

PAN

CR

EATI

C

INFE

CTI

ON

R

ATE

(%

) C

ON

TRO

L/C

ASE

MO

RTA

LITY

R

ATE

(%

) C

ON

TRO

L/C

ASE

CO

MM

ENTS

Isen

man

n et

al

Cip

roflo

xaci

n (4

00 m

g bi

d)

and

met

roni

dazo

le (

500

mg

bid)

IV,

or p

lace

bo,

14 o

r 21

day

s

114

AP

plus

ser

um C

RP

>150

mg/

L an

d/or

ne

cros

is o

n co

ntra

st-

enha

nced

CT

12/9

5/7

Rand

omiz

ed,

doub

le-b

linde

d, p

lace

bo-c

ontr

olle

d; 2

8% o

f C

IP/

MET

gro

up a

nd 4

6% o

f pl

aceb

o gr

oup

requ

ired

open

an

tibio

tic t

reat

men

t; m

ost

plac

ebo

grou

p sw

itche

s m

otiv

ated

by

ext

rapa

ncre

atic

infe

ctio

ns;

over

all m

orta

lity

and

rate

s of

pa

ncre

atic

infe

ctio

n lo

w,

num

ber

of p

atie

nts

with

pan

crea

tic

necr

osis

low

Gol

ub e

t al

Met

a-an

alys

is o

f ei

ght

cont

rolle

d tr

ials

, in

clud

ing

tria

ls f

rom

the

197

0s

Find

ings

: Ea

rly a

ntib

iotic

adm

inis

trat

ion

redu

ced

mor

talit

y fr

om

AP

but

only

for

pat

ient

s w

ith s

ever

e pa

ncre

atiti

s w

ho r

ecei

ved

broa

d-sp

ectr

um a

ntib

iotic

s re

achi

ng t

hera

peut

ic le

vels

in

panc

reat

ic t

issu

e

Shar

ma

et a

lM

eta-

anal

ysis

incl

udin

g on

ly r

ando

miz

ed,

cont

rolle

d, n

onbl

inde

d st

udie

s ev

alua

ting

patie

nts

with

nec

rotiz

ing

panc

reat

itis

who

rec

eive

d ei

ther

no

pree

mpt

ive

antib

iotic

s or

pre

empt

ive

trea

tmen

t w

ith a

ntib

iotic

s re

achi

ng t

hera

peut

ic le

vels

in

nec

rotic

pan

crea

tic t

issu

e

84 rece

ived

ant

ibio

tic

prop

hyla

xis;

76

did

not;

of

not

e, t

he t

otal

of

160

patie

nts

in t

he

pool

ed d

ata

set

is

inad

equa

te f

or

dete

ctio

n of

a 5

0%

redu

ctio

n in

the

rat

e of

in

fect

ions

Find

ings

: N

onsi

gnifi

cant

tre

nd t

owar

d de

crea

sed

loca

l inf

ectio

n in

pat

ient

s gi

ven

early

imip

enem

, ce

furo

xim

e, o

r ofl

oxac

in.

Inci

denc

e of

sep

sis

and

over

all m

orta

lity

sign

ifica

ntly

low

er

(abs

olut

e ris

k re

duct

ions

, 21

.1%

and

12.

3%,

resp

ectiv

ely,

for

a

rela

tive

risk

redu

ctio

n of

72%

) fo

r an

tibio

tic t

reat

men

t. O

n th

is

basi

s, t

he a

utho

rs r

ecom

men

d th

at “

all p

atie

nts

with

acu

te

necr

otiz

ing

panc

reat

itis…

be g

iven

pro

phyl

axis

with

an

antib

iotic

w

ith p

rove

n ef

ficac

y in

nec

rotic

pan

crea

tic t

issu

e.”

Vill

ator

o et

al

Coc

hran

e Re

view

incl

udin

g ra

ndom

ized

con

trol

led

tria

ls

com

parin

g an

tibio

tics

with

pl

aceb

o in

AP

with

C

T-pr

oven

nec

rosi

s

294

(fro

m 5

eva

luab

le

stud

ies)

Find

ings

: Si

gnifi

cant

ly le

ss m

orta

lity

with

the

rapy

(6%

) vs

. co

ntro

ls (

15.3

%).

No

diff

eren

ces

in r

ates

of

infe

cted

pan

crea

tic

necr

osis

, op

erat

ive

trea

tmen

t, n

onpa

ncre

atic

infe

ctio

n, a

nd

fung

al in

fect

ion.

Sub

grou

p an

alys

is o

f β-

lact

am t

reat

men

t:

Sign

ifica

ntly

less

mor

talit

y (6

.3%

vs.

16.

7%)

than

in c

ontr

ols,

w

ithou

t si

gnifi

cant

diff

eren

ces

in r

ates

of

oper

ativ

e tr

eatm

ent

or n

onpa

ncre

atic

infe

ctio

ns.

No

sign

ifica

nt d

iffer

ence

s w

ith

quin

olon

e pl

us im

idaz

ole

trea

tmen

t. β

-Lac

tam

s as

soci

ated

with

si

gnifi

cant

ly d

ecre

ased

mor

talit

y an

d in

fect

ed p

ancr

eatic

ne

cros

is.

Rokk

e et

al

Pros

pect

ive

rand

omiz

ed

cont

rolle

d tr

ial,

imip

enem

(5

00 m

g tid

for

5-7

day

s)

vs.

no a

ntib

iotic

s

73:

36 r

ecei

ved

imip

enem

; 37

rec

eive

d no

an

tibio

tics

43/1

4*11

/8U

nder

pow

ered

stu

dy (

slow

pat

ient

acc

rual

).N

o di

ffer

ence

s in

leng

th o

f ho

spita

l sta

y, n

eed

of in

tens

ive

care

, ne

ed o

f ac

ute

inte

rven

tions

, ne

ed f

or s

urge

ry,

or 3

0-da

y m

orta

lity

rate

s.A

utho

rs c

oncl

ude

that

“th

e st

udy,

alth

ough

und

erpo

wer

ed,

supp

orts

the

use

of

early

pro

phyl

actic

tre

atm

ent

with

imip

enem

in

ord

er t

o re

duce

the

rat

e of

sep

tic c

ompl

icat

ions

in p

atie

nts

with

sev

ere

panc

reat

itis.

”

Del

linge

r et

al

Mul

ticen

ter,

pros

pect

ive,

do

uble

-blin

d, p

lace

bo-

cont

rolle

d ra

ndom

ized

st

udy

set

in 3

2 ce

nter

s w

ithin

Nor

th A

mer

ica

and

Euro

pe

100

clin

ical

ly s

ever

e,

confi

rmed

nec

rotiz

ing

panc

reat

itis:

50 r

ecei

ved

mer

open

em

(1g

IV q

8h);

50 r

ecei

ved

plac

ebo

with

in 5

day

s of

sym

ptom

ons

et,

for

7 to

21

days

12/1

818

/20

No

stat

istic

ally

sig

nific

ant

diff

eren

ce b

etw

een

the

trea

tmen

t gr

oups

for

pan

crea

tic o

r pe

ripan

crea

tic in

fect

ion,

mor

talit

y, o

r re

quire

men

t fo

r su

rgic

al in

terv

entio

n.

Jafr

i et

alM

eta-

anal

ysis

ass

essi

ng t

he

clin

ical

out

com

e of

pat

ient

s w

ith s

ever

e A

P tr

eate

d w

ith

prop

hyla

ctic

ant

ibio

tics

com

pare

d w

ith t

hat

of

patie

nts

not

trea

ted

with

an

tibio

tics

502

(fro

m 8

stu

dies

)Fi

ndin

gs:

No

effe

ct o

f an

tibio

tics

on m

orta

lity,

rat

es o

f in

fect

ed

necr

osis

, or

fre

quen

cy o

f su

rgic

al in

terv

entio

n. A

ppar

ent

bene

fit r

egar

ding

non

panc

reat

ic in

fect

ions

(RR

, 0.

60;

95%

CI,

0.44

-0.8

2),

with

a R

R re

duct

ion

of 4

0% (

95%

CI,

18%

-56%

); ab

solu

te r

isk

redu

ctio

n of

15%

(95

% C

I, 6%

-23%

), an

d nu

mbe

r ne

eded

to

trea

t of

7 (

95%

CI,

4-17

).

Vill

ator

o et

al

Coc

hran

e Re

view

incl

udin

g ra

ndom

ized

con

trol

led

tria

ls

com

parin

g an

tibio

tics

with

pl

aceb

o in

AP

with

C

T-pr

oven

nec

rosi

s

404

(fro

m 7

eva

luab

le

stud

ies)

Find

ings

: N

o be

nefit

of

antib

iotic

s in

pre

vent

ing

infe

ctio

n of

pa

ncre

atic

nec

rosi

s or

mor

talit

y, e

xcep

t w

hen

imip

enem

was

co

nsid

ered

on

its o

wn,

in w

hich

cas

e a

sign

ifica

nt d

ecre

ase

in

panc

reat

ic in

fect

ion

was

fou

nd (

P =

.02;

RR,

0.3

4; 9

5% C

I, 0.

13-0

.84)

with

out

effe

ct o

n m

orta

lity.

“N

one

of t

he s

tudi

es

incl

uded

in t

his

revi

ew w

ere

adeq

uate

ly p

ower

ed.

Furt

her

bett

er d

esig

ned

stud

ies

are

need

ed if

the

use

of

antib

iotic

pr

ophy

laxi

s is

to

be r

ecom

men

ded.

”

AP,

acu

te p

ancr

eatit

is;

CI,

confi

denc

e in

terv

al;

CIP

/MET

, ci

profl

oxac

in/m

etro

nida

zole

; C

RP,

C-r

eact

ive

prot

ein;

CT,

com

pute

d to

mog

raph

y; F

NA

, fin

e-ne

edle

asp

iratio

n; IV

, in

trav

enou

s; R

R,

rela

tive

risk;

SG

D,

sele

ctiv

e gu

t de

cont

amin

atio

n.*P

< .

05.

Mod

ified

fro

m T

ooul

i J,

Broo

ke-S

mith

M,

Bass

i C,

et a

l. G

uide

lines

for

the

man

agem

ent

of a

cute

pan

crea

titis

. J

Gas

troe

nter

ol H

epat

ol.

2002

;17(

supp

l):S1

5-S3

9.

54

24  Splenic AbscessLawrence C. Madoff

DEFINITION• Theabscessescompriseoneormorefocalcollectionsinducedbybacteria,mycobacteria,or

fungiinthespleen.• Predisposingconditionsincludeimmunosuppression,trauma,diabetes,hemoglobinopathy,

Felty’ssyndrome,intravenousdruguse,andendocarditis.

EPIDEMIOLOGY• Splenic abscesses are uncommon and have only been reported in small numbers in the

medicalliterature.• Splenicabscessesarepresentin0.2%to0.7%ingeneralautopsyseries.• Splenicabscessesarea frequentfinding inbacterialendocarditisandarepresent inup to

onethirdofpatientsatautopsy.• Thereisabimodalagedistribution,withpeaksinthethirdandsixthdecadesoflife.

MICROBIOLOGY• Streptococci,staphylococci,salmonellae,andEscherichia coliareimportantcausativeagents

and,alsoincreasingly,fungiandmycobacteria.• InspecificgeographicareasofAsia,Klebsiella pneumoniae andBurkholderia pseudomallei

areimportantcausativeagents.• Anaerobesarerare.

CLINICAL FINDINGS AND DIAGNOSIS• Feverispresent,withabdominalpaininleftupperquadrantbutapaucityofspecificsymp-

tomsandfindings.• Ultrasound, computed tomography, and magnetic resonance tomography are used for

diagnosis.

THERAPY• Splenectomy has been the gold standard of treatment, along with antibiotic treatment of

underlyinginfectionelsewhere.• Recentemphasisisontheuseofpercutaneousdrainagewithantibiotictreatmentor,insome

cases,antibiotictreatmentalone,inanattempttoreducemorbidityandpreservethespleen.

55

25 AppendicitisCosti D. Sifri and Lawrence C. Madoff

DEFINITION• Appendicitis is acute inflammation of the vermiform appendix that is often related to

obstructionandmaybecomplicatedbypolymicrobialinfection.• Complicationsincludeperforation,peritonitis,andintra-abdominalabscesses.

EPIDEMIOLOGY• Acuteappendicitisisarelativelycommondisease,oftenpresentinginadolescenceandearly

adulthood.• Lifetimeriskforappendicitisis8.6%inmenand6.7%inwomen.• Over300,000appendectomiesareperformedannuallyintheUnitedStates.

MICROBIOLOGY• Theinflammationisusuallypolymicrobial,frequentlyinvolvingaerobicandanaerobicgram-

negativebacilli.• Alargevarietyofmicrobeshavebeenisolatedfromacuteappendicitisandrelatedabscesses.• InfectionsbyYersiniaspp.,parasites,includingEntamoeba histolytica,andvirusesmaymimic

appendicitis(e.g.,mesentericadenitis)orcauseobstructionleadingtoacuteappendicitis.

DIAGNOSIS• Clinicaldiagnosisisenhancedbytheuseofimaging,especiallycomputedtomographyand

ultrasonography.• Diagnosis ismoredifficult inwomenof childbearingage inwhomgynecologicprocesses

maymimicappendicitis.

THERAPY• Surgicalremovaloftheappendix,oftendonelaparoscopically,iscurative.• Adjunctiveuseofbroad-spectrumantibiotics,suchaspiperacillin-tazobactam,ceftriaxone,

andmetronidazole,mayberequired.

56

26 Diverticulitis and TyphlitisCosti D. Sifri and Lawrence C. Madoff

DEFINITION• Diverticulitisisinflammationandinfectionofthebowelwall,leadingtomicroperforation

ofcolonicdiverticula.• Typhlitis (neutropenic enterocolitis) is characterized by abdominal pain and fever during

periodsofneutropeniaresultingfrommucosalinflammation,degeneration,andmicrobialinvasion.

EPIDEMIOLOGY• Diverticulitisoccursin10%to25%ofallindividualswithdiverticulosis,whichhasapreva-

lenceof30%to40%inWesternsociety.• Diverticulitisleadsto150,000hospitaladmissionsand24,000electiveoperationsannually

intheUnitedStates.• Theincidenceoftyphlitisisunknownbuthasbeenestimatedtobe5%inhospitalizedneu-

tropenicadultswithcancer.• Bacteremiaorfungemiaoccursin14%to44%ofpatientswithtyphlitis.

MICROBIOLOGY• Acutediverticulitisisapolymicrobialinfectioncausedbyendogenousanaerobicandfaculta-

tivebacteria,includingBacteroidesspp.,Peptostreptococcusspp.,Enterobacteriaceae,viridansstreptococci,andenterococci.

• Pseudomonas aeruginosa, Enterobacteriaceae, Bacteroides fragilis, viridans streptococci,enterococci,andCandidaspp.arecommoncausesofbloodstreaminfectionsinpatientswithtyphlitis.

DIAGNOSIS• Radiographic imaging (computed tomography and ultrasonography) is essential for the

evaluationofsuspecteddiverticulitisandtyphlitis.• More than half of patients with clinically suspected diverticulitis are diagnosed with an

alternativeconditionafterdiagnosticimaging.• Radiographicfindingsofdiverticulitisincludepericolicfatstranding,diverticula,bowelwall

thickening,andphlegmonorabscessformation.• Typhlitiscanbedefinedasbowelwallthickeninggreaterthan4mm,usuallyofthececum,

withneutropenia,fever,andabdominalpain.

THERAPY• Acute uncomplicated diverticulitis can be safely treated in select outpatients with a short

courseoforalantibiotics.• However,thenecessityofantibiotictherapyforthetreatmentofuncomplicateddiverticulitis

iscontroversial.• Complicateddiverticulitisorpatientswithcomorbiditiesorotherpredictorsofworseout-

comesshouldbehospitalized.

57C

hap

ter 26 Diverticu

litis and

 Typh

litis

• Percutaneousdrainageoflargeabscesses(>5cmindiameter)canbetemporizinginacutelyillpatients.

• Management of typhlitis includes bowel rest, intravenous fluids, nutritional support, andbroad-spectrum parenteral antibiotics that cover enteric facultative and anaerobic flora,Pseudomonas aeruginosa,andperhapsyeast.

• Surgery may be required for patients with diverticulitis or typhlitis with intraperitonealperforation,uncontrolledsepsis,persistentgastrointestinalbleeding,obstruction,orwhofailtorespondtomedicaltherapy.

PREVENTION• Highdietaryfiberandphysicalactivitymaybeassociatedwithreducedsymptomaticdiver-

ticulardisease.

58

G  Cardiovascular Infections

27 Endocarditis and Intravascular InfectionsVance G. Fowler, Jr., W. Michael Scheld, and Arnold S. Bayer

DEFINITION• Infective endocarditis(IE)isaninfectionoftheendocardialsurfaceoftheheart.

EPIDEMIOLOGY• Itistraditionallyassociatedwithheartvalvesdamagedbyrheumaticheartdisease.• Inthecurrentera,healthcarecontactandinjectiondrugusearetheprimaryriskfactors.

MICROBIOLOGY• Staphylococcus aureusisnowtheleadingcauseofIEinmostoftheindustrializedworld.• Historically,viridansgroupstreptococciwerethemostcommoncauseofendocarditis.• Bartonellaspp.arethemostcommoncauseofculture-negativeIEintheUnitedStates.Other

commoncausesofculture-negativeIEaresummarizedinTable27-1.

DIAGNOSIS• Resultsofbloodculturesremainthecornerstoneofdiagnosisofendocarditis.• Clinicalevaluationaloneisinsufficienttoexcludethepossibilityofendocarditis.• Echocardiography,particularlytransesophagealechocardiography,hasgreatlyimprovedthe

clinician’sabilitytoidentifyendocarditis.• Diagnosticschema,suchasthemodifiedDukeCriteria,areusefulinestablishingthepres-

enceofendocarditis.

THERAPY• Cardiacsurgeryisrequiredinuptohalfofpatientswithendocarditisandimprovespatient

outcome.• Cardiacsurgeryisespeciallyimportantinpatientswithendocarditiswhohaveheartfailure,

paravalvularabscess,recurrentembolicevents,orongoingsepsisorwhoareinfectedwithhighlyresistantorfungalpathogens.

• Althoughthetimingofcardiacsurgery,particularlyafteremboliceventsinvolvingthecentralnervoussystem,remainscontroversial,emergingevidencesupportsthebenefitofearlyvalvereplacementsurgeryforendocarditis.

• Antibiotic therapy involves extended courses of antibiotics. Treatment is highly pathogenspecificandissummarizedinTable27-2.GuidelinesfortreatmentofIEwerepublishedin2005andarecurrentlybeingupdated.

• Additionofadjunctivelow-dose,short-coursegentamicintostandardantibiotictreatmentofS. aureusnativevalveIEhasbeenshowntoconferhighriskfornephrotoxicitywithoutsignificantimprovementinclinicaloutcomesandisnotencouraged.

• Severalobservationalstudiessupporttheuseofhigh-doseceftriaxoneincombinationwithampicillinforthetreatmentofampicillin-susceptible,aminoglycoside-resistantenterococcalendocarditisorforpatientswithunderlyingrenaldisease.

http://internalmedicinebook.com

59C

hap

ter 27 End

ocard

itis and

 Intravascu

lar Infectio

ns

PREVENTION• Prevention of endocarditis involves reduction of bloodstream infections, especially in the

healthcaresetting.• The role of antibiotic prophylaxis for the prevention of endocarditis is controversial.

GuidelineshavebeenpublishedfromtheAmericanHeartAssociation.

TABLE 27-1  Causes of Culture-Negative Endocarditis

ORGANISMEPIDEMIOLOGY AND EXPOSURES DIAGNOSTIC APPROACHES

Aspergillus and other noncandidal fungi

Prosthetic valve Lysis-centrifugation technique; also culture and histopathologic examination of any emboli

Bartonella spp. B. henselae: exposure to cats or cat fleasB. quintana: louse infestation; homelessness, alcohol abuse

Most common cause of culture-negative IE in United States; serologic testing (may cross-react with Chlamydia spp.); PCR assay of valve or emboli is best test; lysis-centrifugation technique may be useful

Brucella spp. Ingestion of unpasteurized milk or dairy products; livestock contact

Blood cultures ultimately become positive in 80% of cases with extended incubation time of 4-6 wk; lysis-centrifugation technique may expedite growth; serologic tests are available

Chlamydia psittaci Bird exposure Serologic tests available but exhibit cross-reactivity with Bartonella; monoclonal antibody direct stains on tissue may be useful; PCR assay now available

Coxiella burnetii(Q fever)

Global distribution; exposure to unpasteurized milk or agricultural areas

Serologic tests (high titers of antibody to both phase 1 and phase 2 antigens); also PCR assay on blood or valve tissue

HACEK spp. Periodontal disease or preceding dental work

Although traditionally a cause of culture-negative IE, HACEK species are now routinely isolated from most liquid broth continuous monitoring blood culture systems without prolonged incubation times

Legionella spp. Contaminated water distribution systems; prosthetic valves

Serology available; periodic subcultures onto buffered charcoal yeast extract medium; lysis-centrifugation technique; PCR assay available

Nutritionally variant streptococci

Slow and indolent course Supplemented culture media or growth as satellite colonies around Staphylococcus aureus streak; antimicrobial susceptibility testing often requires processing specialized microbiology laboratory

Tropheryma whipplei (Whipple’s disease)

Typical signs and symptoms include diarrhea, weight loss, arthralgias, abdominal pain, lymphadenopathy, central nervous system involvement; IE may be present without systemic symptoms

Histologic examination of valve with periodic acid–Schiff stain; valve cultures may be done using fibroblast cell lines; PCR assay on vegetation material

HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.; IE, infective endocarditis; PCR, polymerase chain reaction.

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TABLE 27-2  Summary of Treatment Options for EndocarditisORGANISM/REGIMENa COMMENTS

Staphylococcus aureus

Native Valve

Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 4-6 wkOptional: gentamicin, 1 mg/kg IV q8h × 3-5 daysb

Use of gentamicin in native valve S. aureus IE is associated with significant nephrotoxicity without clear clinical benefit and therefore is not encouraged

Cefazolin, 2 g IV q8h × 4-6 hrOptional: gentamicin, 1 mg/kg IV q8h × 3-5 daysb

Acceptable in setting of penicillin allergy other than immediate hypersensitivity. See above cautions about gentamicin use.

Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 6 wkb

Also acceptable in setting of immediate hypersensitivity or anaphylaxis to penicillin; goal vancomycin trough level 15-20 µg/mL is recommended

Prosthetic Valve

Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk

Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × ≥6 wk plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk

Goal vancomycin trough level 15-20 µg/mL is recommended

Injection Drug Use

Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 2 wk; plus gentamicin, 1 mg/kg IV q8h × 2 wk

Two-week regimen only for use in injection drug users with infection limited to tricuspid valve, no renal insufficiency, and no extrapulmonary infection. Two weeks of monotherapy with antistaphylococcal penicillin has also been successfully used in these patients.

Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk

Use of gentamicin in this setting is not recommended. Goal vancomycin trough level 15-20 µg/mL is recommended.

Daptomycin, 6 mg/kg IV qd × 4-6 wk Daptomycin is U.S. Food and Drug Administration–approved for treatment of right-sided S. aureus IE; for adults, some experts recommend 8-10 mg/kg IV

Coagulase-Negative Staphylococci

Native Valve

Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 4-6 wkOptional: gentamicin, 1 mg/kg IV q8h × 3-5 days

Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 6 wk

Also acceptable in setting of immediate hypersensitivity or anaphylaxis to penicillin. Goal vancomycin trough level 15-20 µg/mL is recommended.

Prosthetic Valve

Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk

Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk

Goal vancomycin trough level 15-20 µg/mL is recommended

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Penicillin-Susceptible Viridans Streptococci (MIC ≤0.1 µg/mL) and Streptococcus bovis (S. gallolyticus)

Penicillin, 2-3 million units IV q4h × 4 wk, or ampicillin, 2 g IV q4h × 4wk

Also effective for other penicillin-susceptible nonviridans streptococci (e.g., group A streptococci)

Ceftriaxone, 2 g IV qd × 4 wk For penicillin allergy; patients with uncomplicated viridans streptococcal IE are candidates for outpatient therapy

Penicillin, 2-3 million units IV q4h × 2 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk

Uncomplicated native valve IE only; not acceptable for nutritionally variant streptococci

Nutritionally variant strain

Penicillin, 2-4 million units IV q4h × 4 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk

For prosthetic valve IE, give 6 wk of penicillin. Nutritionally variant streptococci are often penicillin tolerant.

Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk

For penicillin allergy

Relatively Penicillin-Resistant Viridans Streptococci (MIC 0.12-<0.5 µg/mL)Penicillin, 4 million units IV q4h × 4 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk

Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk

For penicillin allergy or to avoid gentamicin

Enterococcic and Penicillin-Resistant Viridans Streptococci (Penicillin MIC >0.5 µg/mL)Penicillin-susceptible, aminoglycoside-susceptible enterococci

Penicillind 3-5 g IV q4h × 4-6 wk, plus gentamicin, 1 mg/kg IV q8h × 4-6 wk; orAmpicillin, 2 g IV q4h, plus gentamicin, 1 mg/kg IV q8h × 4-6 wk

Increase duration of both drugs to 6 wk for prosthetic valve infection or for enterococcal IE with symptoms >3 mo. For older patients and those with underlying renal disease, can consider shortening the duration of gentamicin to 2 wk.

Penicillin-resistant, vancomycin-susceptible, aminoglycoside-susceptible enterococci

Vancomycin, 15-20 mg/kg IV q8-12h × 6 wk, plus gentamicin, 1 mg/kg q8h × 6 wke

Also for patients with penicillin allergy. This regimen is associated with enhanced risk of nephrotoxicity. Penicillin desensitization should be considered as an alternative to this regimen when possible.

Penicillin-susceptible, aminoglycoside-resistant enterococci

Ampicillin, 2 g IV q4h, plus ceftriaxone, 2 g IV q12h

Useful for patients with significant underlying renal disease

Penicillin-resistant, vancomycin-resistant enterococci

No standard therapy; daptomycin, linezolid, and quinupristin-dalfopristin have been used

Consult infectious diseases specialist

HACEK StrainsCeftriaxone, 2 g IV qd × 4 wk Increase duration to 6 wk for infections

involving prosthetic valves

Ampicillin-sulbactam, 3 g IV q6h × 4 wk (if β-lactamase producing strain)a

Increase duration to 6 wk for infections involving prosthetic valves

Non-HACEK Gram-Negative Bacillif

Enterobacteriaceae Extended-spectrum penicillin (e.g., piperacillin-tazobactam) or cephalosporin plus aminoglycosides for susceptible strains

Treat for a minimum of 6-8 wk. Some species exhibit inducible resistance to third-generation cephalosporins. Valve surgery is often required for patients with left-sided IE caused by gram-negative bacilli, especially for prosthetic valve IE. Consultation with an infectious diseases specialist is recommended.

TABLE 27-2  Summary of Treatment Options for Endocarditis—cont’d

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Pseudomonas aeruginosa

Antipseudomonal penicillin (e.g., piperacillin) plus high-dose tobramycin, 8 mg/kg/day IV or IM in once-daily doses; orHigh-dose ceftazidime, cefepime, or imipenem

Goal tobramycin peak and trough concentrations of 15-20 µg/mL and ≤2 µg/mL, respectively. Treat for a minimum of 6-8 wk. Early valve surgery usually required for left-sided Pseudomonas IE; consultation with a specialist in infectious diseases is recommended.

Fungif

Treatment with a parenteral antifungal agent (usually an amphotericin B–containing product) is usually recommended as initial therapy

Fungal endocarditis is usually an indication for valve replacement surgery. Long-term/lifelong suppressive therapy with oral antifungal agents is often required. Consultation with a specialist in infectious diseases is recommended.

HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.; IE, infective endocarditis; MIC, minimal inhibitory concentration.

aDosages assume normal renal function. For patients with renal insufficiency, adjustments must be made for all antibiotics except nafcillin, rifampin, and ceftriaxone. Gentamicin doses should be adjusted to achieve a peak serum concentration of approximately 3 µg/mL 30 minutes after dosing and a trough gentamicin level of <1 µg/mL.

bPrimarily relevant to left-sided IE.cEnterococci must undergo antimicrobial susceptibility testing. These recommendations are for enterococci sus-

ceptible to penicillin, gentamicin, and vancomycin except as indicated.dAmpicillin, 12 g/day, can be used instead of penicillin.eThe need to add an aminoglycoside has not been demonstrated for penicillin-resistant streptococci.fLimited data exist.Modified from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis,

antimicrobial therapy, and management of complications. Circulation. 2005;111:e394-e433.

TABLE 27-2  Summary of Treatment Options for Endocarditis—cont’d

Non-HACEK Gram-Negative Bacillif—cont’d

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28  Prosthetic Valve EndocarditisRaj Palraj, Bettina M. Knoll, Larry M. Baddour, and Walter R. Wilson

DEFINITION• Prostheticvalveendocarditis(PVE)isapotentiallylife-threateninginfectionthatinvolvesa

valveprosthesisorannuloplastyring.

EPIDEMIOLOGY• Prosthetic valve endocarditis is an uncommon but well-recognized complication of valve

replacementorrepair.• Healthcare–associatedPVEisincreasinginincidence.• Staphylococcus aureusisthemostcommoncauseofPVE.

MICROBIOLOGY• Early-onset(illnessonsetwithin1yearofvalvesurgery)PVEisusuallycausedbymicroor-

ganisms acquired perioperatively, such as S. aureus and coagulase-negative staphylococci(CoNS).Nosocomialgram-negativepathogens,manyofwhicharemultidrugresistant,andfungirarelycauseearly-onsetPVE.

• Late-onsetPVEisusuallycausedbyorganismsrepresentativeof“normalmicrobiota”andincludeviridansgroupstreptococciandenterococci.

• S. aureusandCoNSarealsocommonpathogensoflate-onsetPVEdue,inpart,toanincreaseinfrequencyofhealthcare–associatedexposureinthelateperiod.

DIAGNOSIS• ModifiedDukecriteriahavebeenusedtodefinesuspectcasesofPVE.• Blood cultures are critical in both supporting a PVE diagnosis and directing selection of

antimicrobialtherapy.• Transesophageal echocardiography (TEE) is the preferred imaging modality to support a

diagnosisand to identifycomplications suchas severevalvedysfunctionandperivalvularextensionofinfection,whichmayrequiresurgicalintervention.

THERAPY• Parenteral antimicrobial therapydirectedagainst a specificpathogen foraminimumof6

weeksisrecommended(seeTable28-1).• TEEmayneed toberepeatedduringantimicrobial therapy to identifycomplications that

wouldpromptsurgicalintervention.• Early surgical intervention should be considered in complicated PVE with perivalvular

extension,severeheartfailure,severevalvedysfunction/dehiscence,multipleemboli,unre-sponsiveinfection,andPVEduetomultidrug-resistantorganismsorfungi(seeTable28-2).

PREVENTION• Perioperativeantibioticprophylaxis, strict infectioncontrolmeasures,good surgical tech-

nique,and limiting theuseofcentralvenouscathetersare important inpreventingearly-onsetPVE.

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• Maintenanceofgoodoralhygieneis importanttopreventlate-onsetcommunity-acquiredPVE.

• Althoughtherehasbeennorandomized,placebo-controlledtrialtodefinetheefficacyandsafetyofantibioticprophylaxis, it is recommended foranydentalprocedure that involvesmanipulationofthegingivalorperiapicalregionofteethorperforationoforalmucosa,aswellasforproceduresontherespiratorytract,infectedskin,skinstructures,and/ormuscu-loskeletaltissue.

TABLE 28-1  Therapy for Prosthetic Valve Endocarditis Caused by Staphylococci, Suggested by American Heart Association

REGIMEN DOSAGE AND ROUTE DURATION

Methicillin-Susceptible StaphylococciNafcillin or oxacillin*plus

2 g IV q4h ≥6 wk

Rifampin†

plus300 mg PO or IV q8h ≥6 wk

Gentamicin‡ 3 mg/kg IV/IM q24h in 2 or 3 equally divided doses 2 wk

Methicillin-Resistant StaphylococciVancomycin§

plus15 mg/kg IV q12h ≥6 wk

Rifampin†

plus300 mg PO or IV q8h ≥6 wk

Gentamicin‡ 3 mg/kg per IV/IM in 2 or 3 equally divided doses 2 wk

Dosages recommended are for patients with normal renal function.*Penicillin G, 24 million U/24 hr IV, may be used in place of nafcillin or oxacillin if the strain is penicillin susceptible

(MIC ≤0.1 µg/mL) and does not produce β-lactamase. Cefazolin 2 g IV q8h may be substituted for nafcillin or oxacillin. Cefazolin can be used in non–immediate-type allergic reaction to penicillin. Consider skin testing for patients with history of immediate-type allergy to penicillin. Vancomycin is recommended only in patients unable to tolerate penicillins and cephalosporins.

†It is recommended to initiate rifampin therapy only after susceptibility results are known and ideally after 2 days of effective combination therapy, in an attempt to reduce the risk of emergence of rifampin resistance.

‡Gentamicin should be administered in close proximity to vancomycin, nafcillin, or oxacillin to maximize synergy. Renal function and serum gentamicin concentrations should be closely monitored. Goal trough level is <1 µg/mL and peak level (1 hr postdose) is 3-4 µg/mL.

§Vancomycin dosage should be adjusted to a trough level of 10-15 µg/mL.From Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and man-

agement of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-e434.

TABLE 28-2  Indications for Consideration of Surgical InterventionSevere heart failure; mild-moderate heart failure unresponsive to medical therapyValvular dehiscence, obstruction, or leaflet perforationPerivalvular extension of infection leading to myocardial abscess, fistula, or shuntNew severe conduction defects suggestive of perivalvular extensionMultiple (>1) systemic emboli despite appropriate antimicrobial therapyUncontrolled infection—persistent fever and positive blood cultures for >5 daysFungal, Pseudomonas spp., or other multidrug-resistant organisms

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29 Infections of Nonvalvular Cardiovascular DevicesM. Rizwan Sohail, Walter R. Wilson, and Larry M. Baddour

CARDIOVASCULAR IMPLANTABLE ELECTRONIC DEVICE (CIED) INFECTIONS• TheinfectionrateofCIEDinfectionisrisingdisproportionatetotherateofimplantation.• Mostearly-onset(within6monthsofimplantation)CIEDpocketinfectionsarecausedby

devicecontaminationatthetimeofimplantation,whereashematogenousseedingisafre-quentsourceoflate-onset(after6monthsofimplantation)CIEDleadinfections.

• HematogenousseedingofCIEDleadsisrarewithgram-negativebacteremiafromadistantsource.

• Bloodculturesshouldbeobtainedinallpatientsatinitialpresentation.Ifbloodculturesarepositive,thentransesophagealechocardiographyshouldbedonetoexcludeendocarditis.

• CompleteremovaloftheCIEDsystemisrequiredforeradicationofinfection.• Areplacementdevicecanbeimplantedoncebloodculturesarenegativefor72hoursand

perhapsearlierincasesinwhichadmissionbloodculturesarenegative.A2-weekdelayisrecommendedforpatientswithvalvularendocarditis.

• All patients should receive perioperative antibiotics as primary prevention of CIEDinfection.

LEFT VENTRICULAR ASSIST DEVICE (LVAD) INFECTIONS• In addition to being a bridge to transplantation, LVADs are increasingly being used as

destination therapy for patients with end-stage heart failure who are not transplantcandidates.

• Continuous-flowpumpsareatlowerriskofinfectioncomparedwithdeviceswithpulsatileflowpumps.

• Driveline exit-site infections are the most common type of LVAD-specific infections, fol-lowedbyLVAD-relatedbacteremiaandendocarditis.

• Staphylococcus aureusandcoagulase-negativestaphylococciareresponsibleforthemajorityofLVAD-specificinfections.

• MostLVADinfectionsaretreatedwiththeinfecteddeviceleftinsitubecausedeviceremovalisnotanoptioninmostcases.

• Suppressive antibiotics are continued lifelong or until the infected LVAD is removed andcardiactransplantationisperformed.

• Immobilizingthedrivelineattheskinexitsitetopreventrepeatedskintraumareducestheriskoflocalinfections.

PROSTHETIC VASCULAR GRAFT INFECTIONS (PVGIS)• StaphylococcalspeciesarethepredominantpathogensinPVGIs.• Microbialseedingofagraftatthetimeofimplantationorintheimmediatepostoperative

periodisoperativeingraftinfections.• Computedtomographic(CT)scanningisthebesttoolinthediagnosticevaluationofgraft

infection.CTfindingsofperigraftfluidaccumulation,fatstrandingorgasbubbles,lackof

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fat plane between graft and bowel, and anastomotic aneurysms are all suggestive of graftinfection.

• Surgical management of an infected graft includes complete excision of infected graftmaterial,débridementofallinfectedanddevitalizedtissues,andrevascularizationofdistaltissues.

• If complete excision of an infected graft is not feasible, patients should be prescribedlifelongoralsuppressiveantibioticsafteraninitial4-weekcourseofparenteralantimicrobialtherapy.

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30 Prophylaxis of Infective EndocarditisDavid T. Durack

DEFINITION OF THE ISSUEInfective endocarditis (IE) continues to cause serious morbidity and mortality; therefore, pre-vention of IE is a priority.

EPIDEMIOLOGY• The incidence of IE is increasing in developing countries.• Contributing factors include aging populations, the steadily increasing number of medical

procedures, implants and prostheses, and the rising frequency of health care–associated infections, especially catheter-related bloodstream infections.

MICROBIOLOGY• Staphylococci have superseded viridans streptococci as the predominant pathogens.• Methicillin-sensitive, methicillin-resistant, and coagulase-negative strains of staphylococci

all contribute to the increase in cases of staphylococcal IE.• Increasing resistance to β-lactams, aminoglycosides, and vancomycin among staphylococci,

streptococci, and enterococci presents new challenges for prevention and therapy of IE.

PREVENTION OF INFECTIVE ENDOCARDITIS• Many dental, medical, and diagnostic procedures cause bacteremias, which occasionally

result in IE.• Antibiotics can prevent IE in vivo in experimental animals.• For more than 50 years, administration of antibiotics before procedures known to cause

bacteremias was recommended to prevent IE, but there is no definitive evidence that this practice is effective or cost-effective in humans. Antibiotics can cause unwanted side effects, including profound and persistent alterations of the microbiome.

• Therefore, recent guidelines sharply restrict use of antibiotic prophylaxis for IE, limiting it to patients at highest risk of an adverse outcome of IE: those with prosthetic heart valves; with cyanotic congenital heart disease (CHD); with repaired CHD with implanted prosthetic material, for the first 6 months only; with a history of previous episode(s) of IE; with valvu-lopathy after a heart transplant (see Table 30-1).

• For this small group of high-risk patients, the standard regimen is a single 2-g dose of amoxicillin given orally 30 to 60 minutes before the dental procedure. Alternative regimens are recommended for penicillin-allergic patients and those unable to take oral medication, and dosages are adjusted for children (see Table 30-2).

• There is no evidence that this major change in prevention guidelines has resulted in any increase in the number of cases of IE.

• Continuing surveillance of epidemiologic trends and microbial resistance, together with education of patients at risk for IE and their health care providers, is recommended.

• Prevention and prompt treatment of health care–associated infections is important, to reduce the incidence of bacteremias that can cause IE.

• Because preventive measures may fail, early diagnosis and prompt therapy of IE are impor-tant, to reduce morbidity and mortality.

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TABLE 30-1  Preexisting Cardiac Conditions Associated with Highest Risk of Adverse Outcome from Infective Endocarditis• Prostheticcardiacvalve(s)orprostheticmaterialinsertedforcardiacvalverepair• Previousinfectiveendocarditis• Congenitalheartdisease(CHD)

• UnrepairedcyanoticCHD,includingpalliativeshuntsandconduits• CompletelyrepairedCHDwithprostheticmaterialordevice,whetherplacedbysurgeryorcatheter

intervention,duringthefirst6monthsaftertheprocedure• RepairedCHDwithresidualdefectsatsiteoradjacenttositeofprostheticpatchorprostheticdevice

(whichinhibitendothelialization)• Cardiactransplantrecipientswhodevelopcardiacvalvulopathy

ModifiedfromWilsonW,TaubertKA,GewitzM,etal.Preventionof infectiveendocarditis:guidelines fromtheAmericanHeartAssociation:aguidelinefromtheAmericanHeartAssociationRheumaticFever,Endocarditis,andKawasaki Disease Committee; Council on Cardiovascular Disease in the Young; and the Council on ClinicalCardiology;CouncilonCardiovascularSurgeryandAnesthesia;andtheQualityofCareandOutcomesResearchInterdisciplinaryWorkingGroup.Circulation.2007;116:1736-1754.

TABLE 30-2  Regimens for Antibiotic Prophylaxis of Infective Endocarditis during Dental Procedures*

CLINICAL SITUATION ANTIBIOTIC DOSAGE FOR ADULTS† DOSAGE FOR CHILDREN†,‡

Standardoralregimen—formostpatients

Amoxicillin 2.0gPO 50mg/kgPO

Ifunabletotakeoralmedication

Ampicillinorceftriaxone

2.0gIMorIV1.0gIMorIV

50mg/kgIMorIV50mg/kgIMorIV

Ifallergictopenicillins Clindamycinorazithromycinorclarithromycin

600mgPO500mgPO500mgPO

15mg/kgPO15mg/kgPO15mg/kgPO

Ifallergictopenicillinsandunabletotakeoralmedication

Clindamycin 600mgIMorIV 20mg/kgIMorIV

IM,intramuscular;IV,intravenous;PO,oral.*Onlyforpatientswithhighestriskofadverseoutcomeofinfectiveendocarditis;seeTable30-1.†Singledose,30to60minutesbeforeprocedure.‡Nottoexceedadultdose.ModifiedfromWilsonW,TaubertKA,GewitzM,etal.Preventionofinfectiveendocarditis:guidelinesfromthe

AmericanHeartAssociation:aguidelinefromtheAmericanHeartAssociationRheumaticFever,Endocarditis,andKawasaki Disease Committee; Council on Cardiovascular Disease in the Young; and the Council on ClinicalCardiology;CouncilonCardiovascularSurgeryandAnesthesia;andtheQualityofCareandOutcomesResearchInterdisciplinaryWorkingGroup.Circulation.2007;116:1736-1754.

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31 Myocarditis and PericarditisKirk U. Knowlton, Anna Narezkina, Maria C. Savoia, and Michael N. Oxman

MYOCARDITIS• Inflammationofthemyocardium,whichisclinicallymanifestedbychestpain,arrhythmias,

orcongestiveheartfailure(CHF)

Etiologic Agents• Most commonly associated with viral infections, particularly enteroviruses, adenoviruses,

parvovirusB19,humanherpesvirus6,anddengueviruses(seeTable31-1).• Occasionallycausedbybacteria,asaresultofbacteremia,directextensionfromacontiguous

focus,orabacterialtoxin.• CausedbyTrypanosoma cruzi,thecauseofChagas’disease,whichisprevalentinSouthand

CentralAmerica.

Diagnosis• In the setting of clinical suspicion, elevations of cardiac enzymes, electrocardiographic

changes (nonspecific), echocardiography, and cardiac magnetic resonance imaging arehelpful.

• Evidenceofcoincidentviralinfection,eitherbycultureorserology,iscircumstantial.• Endomyocardial biopsy can provide a definitive diagnosis, but sampling errors limit its

utility.

Treatment• SupportivecareandmanagementofCHFareessential.• Thebenefitofimmunosuppressivetherapyisnotestablished.• Theefficacyofintravenousimmunoglobulintherapyisalsonotestablished.

PERICARDITIS• Inflammationofthepericardiumisclinicallymanifestedbychestpain,pericardialfriction

rub, and pericardial effusion. These may be present individually or in combination.Monitoringforcardiactamponadeisimportant.

Etiologic Agents• Enterovirusesaremostcommon,butothervirusesmaysometimesberesponsible(seeTable

31-2).• Bacteriararelymaycausepurulentpericarditis,usuallyasacomplicationofpneumonia.• Mycobacterium tuberculosiscancausepericarditis,usuallyasacomplicationofpulmonary

tuberculosis.This isamajorprobleminAfrica inassociationwithacquired immunodefi-ciencysyndrome.

Diagnosis• Etiologyisoftenundeterminedinindividualcases.• Pericardiocentesismayyieldanetiologicagentbutisnegativeinthemajorityofpatients.

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• Evidenceofviralinfectionbydetectioninperipheralsamplesorbyserologyprovidesonlycircumstantialevidenceofpossibleetiology.

• Percutaneous pericardial biopsy or pericardiotomy with biopsy and drainage increase thediagnosticyield.

Treatment• For presumed viral or idiopathic pericarditis, analgesic treatment with nonsteroidal anti-

inflammatorydrugs(NSAIDs),togetherwithbedrest,isoftensuccessfulinrelievingsymp-toms.NSAIDsaregenerallycontinuedfor1to2weeks,oruntilsymptomsresolve.

• Colchicine given with NSAIDs has been found to improve rate of recovery and reducerecurrence.

• Purulentpericarditisusuallyrequiresdrainagetogetherwithappropriateantibiotics.• Tuberculouspericarditisrequiresappropriateantituberculoustherapy;concomitantadmin-

istrationofcorticosteroidsreducesdevelopmentofconstrictivepericarditisandtheneedforrepeatedpericardiocentesis.

TABLE 31-1  Infectious Causes of Myocarditis

VirusesCoxsackie B virusesCoxsackie A virusesAdenovirusesEchovirusesParvovirus B19Nonpolio enterovirusesPoliovirusesRabies virusMumps virusRubeola (measles) virusInfluenza A and B virusesRubellaDengue virusesChikungunya virusYellow fever virusArgentine hemorrhagic fever virus (Junin virus)Bolivian hemorrhagic fever virus (Machupo virus)Lymphocytic choriomeningitis virusLassa fever virusVaricella-zoster virusHuman cytomegalovirusEpstein-Barr virusHuman herpesvirus 6Herpes simplex virusVariola virusVaccinia virusHepatitis B virusHepatitis C virusRespiratory syncytial virusHuman immunodeficiency virus

Bacteria and RickettsiaeBrucellaCampylobacterCorynebacterium diphtheriaeClostridium perfringens

Francisella tularensisNeisseria meningitidisSalmonellaShigellaStreptococcus pyogenesStaphylococcus aureusListeria monocytogenesVibrio choleraeMycobacterium tuberculosisLegionella pneumophilaMycoplasma pneumoniaeChlamydia psittaciChlamydia pneumoniaeRickettsia rickettsiiRickettsia prowazekiiRickettsia (Orientia) tsutsugamushiCoxiella burnetiiEhrlichiaBorrelia burgdorferiTropheryma whippeliiUreaplasma spp.

FungiAspergillusCandida speciesBlastomycesCoccidioides immitisCryptococcus neoformansHistoplasma capsulatum

ParasitesTrypanosoma cruziTrypanosoma gambienseTrypanosoma rhodesienseTrichinella spiralisToxoplasma gondiiToxocara canis

Bacteria and Rickettsiae—cont’d

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TABLE 31-2  Infectious Causes of Pericarditis

VirusesCoxsackie A virusesCoxsackie B virusesEchovirusesAdenovirusesMumps virusInfluenza A and B virusesLymphocytic choriomeningitis virusLassa fever virusVaricella-zoster virusHuman cytomegalovirusEpstein-Barr virusHerpes simplex virusVariola (smallpox) virusVaccinia virusHepatitis B virusHuman immunodeficiency virus

Bacteria and RickettsiaStreptococcus pneumoniaeOther streptococcal speciesStaphylococcus aureusNeisseria meningitidisNeisseria gonorrhoeaeHaemophilus influenzaeSalmonellaYersiniaFrancisella tularensisPseudomonas

CampylobacterBrucellaListeria monocytogenesNocardiaActinomycesOther anaerobic bacteriaCorynebacterium diphtheriaeMycobacterium tuberculosisNontuberculous mycobacteriaLegionella pneumophilaMycoplasma pneumoniaeCoxiella burnetiiChlamydiaBorrelia burgdorferi

FungiAspergillusCandida speciesBlastomycesCoccidioides immitisCryptococcus neoformansHistoplasma capsulatum

ParasitesEntamoeba histolyticaToxoplasma gondiiToxocara canisSchistosoma

Bacteria and Rickettsia—cont’d

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32  MediastinitisTrevor C. Van Schooneveld and Mark E. Rupp

DEFINITION• Mediastinitisisaninfectioninvolvingthestructuresofthemediastinum(seeFig.32-1).

EPIDEMIOLOGY• Acutemediastinitisusuallyoccursviaoneofthreeroutes:esophagealperforation,extension

of a head and neck infection (descending necrotizing mediastinitis), and post–cardiacsurgery(seeTable32-1).

• Post–cardiacsurgerymediastinitisoccursin1%to2%ofcardiacsurgerycases,andimpor-tantriskfactorsformediastinitisincludeobesity,diabetes,Staphylococcus aureuscoloniza-tion,useofbilateralinternalthoracicarteries,needforreexploration,andreceiptofmultiplebloodproducts.

• Chronic/fibrosing mediastinitis is usually due to an excessive immune reaction to histo-plasma antigens in mediastinal lymph nodes, which results in fibrosis and narrowing ofmediastinalstructures.

MICROBIOLOGY• Oral flora, including streptococci, gram-negative bacilli, and anaerobes predominate in

mediastinitisduetoesophagealperforationanddescendingheadandneckinfections.• Poststernotomymediastinitisismostfrequentlyduetogram-positivecocci,especiallystaph-

ylococci,whereasgram-negativebacilliandcandidaarelesscommon.

DIAGNOSIS• Esophageal rupture is usually manifested by chest pain, shortness of breath, and

odynophagia.• Signsof the initiatingheadandneck infection (swelling,pain, erythema)predominate in

descendingnecrotizingmediastinitis.• Post–cardiacsurgerymediastinitisfindingsmayrangefromsubtletofulminantbutusually

presentwithin2weeksofsurgery.Fever,wounddrainage,cellulitis,andchestpainareusuallypresent.

• Laboratory findings often include leukocytosis and a rising procalcitonin in postmediansternotomypatients.

• Fibrosing mediastinitis manifestations include cough, dyspnea, chest pain, and exerciseintolerancebutdependonthestructuresbeingoccluded.

• Computedtomographyisthepreferreddiagnosticimagingforallformsofmediastinitis.

THERAPY• Broad-spectrumantimicrobialstargetedtoexpectedpathogensareessential.• Aggressivesurgicalinterventionisessentialinallformsofmediastinitiswithdébridement

ofanyinfectedornecrotictissues.• Early esophageal perforation may occasionally be managed with stenting, but most cases

requireurgentsurgicalrepair.• Post–cardiacsurgerymediastinitisrequiressternalandmediastinaldébridement.

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FIGURE 32-1  Anatomic boundaries and divisions of the mediastinum. 

Superior

Posterior

Middle

Anterior

First rib

TABLE 32-1  Causes of Acute Mediastinitis

Esophageal PerforationIatrogenic

Esophagogastroduodenoscopy, esophageal dilation, esophageal variceal sclerotherapy, nasogastric tube, Sengstaken-Blakemore tube, endotracheal intubation, esophageal surgery including endoscopic resection, paraesophageal surgery, transesophageal echocardiography, anterior stabilization of cervical vertebral bodies, catheter ablation of atrial fibrillation

Swallowed Foreign Bodies

Bones, coins, can pull-tabs, drug-filled condoms, swords, ballpoint pens, button batteries

Trauma

Penetrating—gunshot wound, knife woundBlunt—steering wheel injury, seatbelt injury, cardiopulmonary resuscitation, whiplash injury, barotrauma

Spontaneous or Other

Emesis, cricoid pressure during anesthesia induction, heavy lifting, defecation, parturition, carcinoma, ingestion of caustic or corrosive liquids

Head and Neck InfectionsOdontogenic, Ludwig’s angina, pharyngitis, tonsillitis, parotitis, epiglottitis, Lemierre syndrome

Infection Originating at Another SitePneumonia; pleural space infection or empyema; subphrenic abscess; pancreatitis; cellulitis or soft tissue 

infection of the chest wall; osteomyelitis of sternum, clavicle, ribs, or vertebrae; hematogenous spread from distant foci

Lymph nodes—necrosis and hemorrhage (anthrax) or caseous necrosis (tuberculosis)

Cardiothoracic Surgery (Median Sternotomy)Coronary artery bypass grafting, cardiac valve replacement, repair of congenital heart defect, heart 

transplantation, heart-lung transplantation, cardiac assist devices, extracorporeal membrane oxygenation (ECMO), other types of cardiothoracic surgery

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• Multiple surgical techniques can be utilized for surgical treatment of poststernotomymediastinitis with increasing use of vacuum-assisted closure and soft tissue flaps forreconstruction.

• Therole,ifany,forantifungaltherapyinfibrosingmediastinitisisnotestablished.• In fibrosing mediastinitis, stenoses of vessels and other structures are often successfully

managedbyeithersurgicalbypassorstenting.

PREVENTION• Preventionofpost–cardiacsurgeryisamajorfocusofqualitymeasuresandguidelines.• Keyfactorsassociatedwithdecreasedpost–cardiacsurgeryinfectionratesincludeappropri-

ateantimicrobialprophylaxis(administrationwithin1hourbeforesurgeryandfornolongerthan24to48hoursanduseoftheappropriateagent),controlofpostoperativebloodglucose,anduseofnasalmupirocininpatientscolonizedwithS. aureus.

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33 Acute MeningitisAllan R. Tunkel, Diederik van de Beek, and W. Michael Scheld

DEFINITION• Meningitis, or inflammation of the meninges, is identified by an abnormal number of

white blood cells in cerebrospinal fluid (CSF). Acute meningitis is clinically defined as asyndromecharacterizedbytheonsetofmeningealsymptomsoverthecourseofhourstouptoseveraldays.

EPIDEMIOLOGY• EstimatesfromtheCentersforDiseaseControlandPrevention(CDC)indicatethat10to

15 million symptomatic enteroviral infections occur annually in the United States, whichincludes30,000to75,000casesofmeningitis.

• Inasurveillancestudyamongresidentsineightsurveillanceareasrepresenting17.4millionpersonsfrom1998to2007,theimpactoftheheptavalentpneumococcalconjugatevaccinewasappreciated,inwhichtheincidenceofbacterialmeningitiscausedbyvaccineserotypesdecreasedfrom0.61cases/100,000populationin1998to1999to0.05cases/100,000popula-tionin2006to2007.

• Inpatients16yearsoldorolder,therelativefrequencyofisolationofmeningealpathogensin patients with community-acquired bacterial meningitis is somewhat different than ininfantsandchildren,withmostcasescausedbyStreptococcus pneumoniae, Neisseria menin-gitidis,andListeria monocytogenes.

MICROBIOLOGY• Enteroviruses, currently the leading recognizable cause of aseptic meningitis syndrome,

accountfor85%to95%ofallcasesinwhichapathogenisidentified.• DNA of herpes simplex virus (HSV) has been detected in the CSF of published cases of

Mollaret’smeningitis(nowtermedrecurrent benign lymphocytic meningitis),almostallbeingHSV-2.

• Aprofoundreductionhasbeenseenintheincidenceofinvasiveinfections(includingbacte-rialmeningitis)causedbyHaemophilus influenzaetypebintheUnitedStatesandWesternEurope;thisdecreaseininfectionisattributed,inpart,tothewidespreaduseofconjugatevaccinesagainstH. influenzaetypebthathavebeenlicensedforroutineuseinallchildrenbeginningat2monthsofage.

• From1998to2007,atotalof2262casesofmeningococcaldiseasewerereportedtotheActiveBacterialCoresurveillancesites,withanannualincidenceof0.53cases/100,000population;theincidencedecreasedfrom0.92cases/100,000populationin1998to0.33cases/100,000population in 2007 before the introduction of the quadrivalent meningococcal conjugatevaccine.

• Patientswithpneumococcalmeningitisoftenhavecontiguousordistantfociofpneumococ-cal infection, such as pneumonia, otitis media, mastoiditis, sinusitis, and endocarditis;seriousinfectionmaybeobservedinpatientswithvariousunderlyingconditions(e.g.,sple-nectomyorasplenicstates,multiplemyeloma,hypogammaglobulinemia,alcoholism,mal-nutrition,chronicliverorrenaldisease,malignancy,anddiabetesmellitus).

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• OutbreaksofListeriainfectionhavebeenassociatedwiththeconsumptionofcontaminatedcoleslaw,rawvegetables,milk,andcheese,withsporadiccasestracedtocontaminatedturkeyfranks,alfalfatablets,cantaloupe,dicedcelery,hogheadcheese(ameatjellymadefromhogheadsandfeet),andprocessedmeats,thuspointingtotheintestinaltractastheusualportalofentry.

• GroupBstreptococcusisacommoncauseofmeningitisinneonates,with52%ofallcasesintheUnitedStatesreportedduringthefirstmonthoflife.

• Aerobic gram-negative bacilli (e.g., Klebsiella spp., Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter spp., Salmonella spp.) have become increasinglyimportant as etiologic agents in patients with bacterial meningitis; these agents may beisolatedfromtheCSFofpatientsafterheadtraumaorneurosurgicalproceduresandmayalsobefoundinneonates,olderadults,immunosuppressedpatients,andpatientswithgram-negativesepsis.

DIAGNOSIS• Nucleicacidamplificationtests,suchaspolymerasechainreaction(PCR)assay,arethemost

promisingalternativestoviralcultureforthediagnosisofenteroviralmeningitis.• CSFcultureisthegoldstandardindiagnosisofbacterialmeningitisandispositivein80%

to 90% of patients of community-acquired disease if CSF is obtained before the start ofantimicrobialtherapy.

• Broad-based bacterial PCR can be used to detect the most common microorganisms ofbacterialmeningitis inonlyonetestandhasadequatesensitivityandexcellentspecificity;thesetestscanbedonewithin2hoursinmostindustrializedcountries,buttheyarescarceinresource-poorcountries.

• ThediagnosticaccuracyofCSFlactateisbetterthanthatoftheCSFwhitebloodcellcount,glucose,andproteininthedifferentiationofbacterialfromasepticmeningitis,withsensitivi-tiesof93%and97%andspecificitiesof96%and94%,respectively.

THERAPY• The initial management of a patient with presumed bacterial meningitis includes perfor-

manceofalumbarpuncturetodeterminewhethertheCSFformulaisconsistentwiththatdiagnosis.

• Ifpurulentmeningitisispresent,institutionofantimicrobialtherapyshouldbebasedontheresultsofGramstaining;however,ifnoetiologicagentcanbeidentifiedbythismeansorifperformanceofthelumbarpunctureisdelayed,institutionofempiricalantimicrobialtherapyshouldbebasedonthepatient’sageandunderlyingdiseasestatus.

• Certainpatientswithbacterialmeningitisshouldalsobetreatedwithadjunctivedexametha-sone.InaCochraneDatabaseSystematicreviewof24studiesinvolving4041participants,adjunctivedexamethasonedidnotreduceoverallmortalitybuttherewasatrendtolowermortalityinadults;corticosteroidswereassociatedwithlowerratesofseverehearingloss,anyhearingloss,andneurologicsequelae,althoughthesebenefitswereonlyseeninstudiesfromhigh-incomecountries.

• Penicillincanneverberecommendedasempiricaltherapyinpatientswithsuspectedpneu-mococcalmeningitis;asanempiricalregimen,thecombinationofvancomycinplusathird-generationcephalosporin(eithercefotaximeorceftriaxone)isrecommended.

• Empiricaltreatmentofgram-negativemeningitiscouldbeginwithceftazidime,cefepime,ormeropenem.Iftheorganismis laterfoundtoberesistanttothesecephalosporinsandthecarbapenems,colistin(usuallyformulatedascolistimethatesodium)orpolymyxinBshouldbesubstitutedformeropenemandmayalsoneedtobeadministeredbytheintraventricularorintrathecalroute.

PREVENTION• Chemoprophylaxisisalsonecessaryforclosecontactsofpatientswithinvasivemeningococ-

caldisease;theCDCcurrentlyrecommendstheadministrationofrifampin,ciprofloxacin,or ceftriaxone,whichareall 90% to95%effectiveat eradicatingnasopharyngeal carriage,althoughcasesofciprofloxacin-resistantN. meningitidishavebeenreportedinNorthDakota

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andMinnesota,leadingtheCDCtonolongerrecommendciprofloxacinformeningococcalchemoprophylaxisinselectedcountiesofthesestates.

• Vaccinationtopreventinfectionwithspecificmeningealpathogensisaveryusefulmeasurefordecreasingtheincidenceofbacterialmeningitis.

• ForH. influenzaetypeb,theavailabilityofconjugatevaccineshasdecreasedthenumberofcasesofH. influenzaetypebmeningitismorethan90%.

• Thefirstmeningococcalconjugatevaccine(meningococcalpolysaccharide-diphtheriatoxoidconjugatevaccinecontainingserogroupsA,C,W135,andYpolysaccharides)waslicensedforuseintheUnitedStatesforroutinevaccinationofallpersonsaged11to18yearswithonedose;inupdatedguidelines,aboosterdoseisnowrecommendedatage16yearsandatwo-doseprimaryseriesisadministered2monthsapartforpersonsaged2through54yearswithpersistentcomplementcomponentdeficiencyorfunctionaloranatomicaspleniaandforadolescentswithhumanimmunodeficiencyvirusinfection;otherpersonswhoareatriskformeningococcaldisease(e.g.,microbiologistsortravelerstoanepidemicorhighlyendemiccountry)shouldreceiveasingledose.

• TheAdvisoryCommitteeonImmunizationPracticesnowrecommendsuseofthe13-valentpneumococcal conjugate vaccine to prevent pneumococcal disease in infants and youngchildrenagedyoungerthan6years;thisvaccinehasactivityagainsttheserotypesthatwerepresentintheheptavalentvaccine(4,6B,9V,14,18C,19F,and23F)alongwithsixadditionalserotypes(1,3,5,6A,7F,and19A).

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34  Chronic MeningitisJohn E. Bennett

DEFINITION• Chronicmeningitis,definedhereasatleast4weeksofsymptomswithsignsofinflammation

inthecerebrospinalfluid,mustbedistinguishedfromrecurrentasepticmeningitis,chronicmyeloradiculitis,andchronicencephalitis.

ETIOLOGY• Majorcausesarefungalinfections,tuberculosis,syphilis,andmalignancy(seeTable34-1)

DIAGNOSIS• Majordiagnostictoolsaregadolinium-enhancedmagneticresonanceimagingandcerebro-

spinalfluidstudies(seeTable34-2).Surgicalbiopsyhasalowyield.• Polymerase chain reaction assay has taken on an increasing role, including its use in the

diagnosis of Whipple’s disease, chronic enteroviral meningitis, lymphoma, toxoplasmosis,andtuberculosis.

THERAPY• Empirical therapy for suspected tuberculous meningitis is often done because of disease

severity,butadditionofprednisonemaycausedeteriorationofunsuspectedfungalmenin-gitis.Worseningofinfectionmaynotbedetectedinitiallybecausecorticosteroidscantem-porarily improve hypoglycorrhachia, fever, and cerebral edema on T2-weighted magneticresonanceimages.Thesameissueariseswithcorticosteroidtreatmentofsuspectedsarcoidorautoimmunemeningitis.Itisonlywhensubsequent,potentiallyirreversibledeteriorationoccursdespitecorticosteroidsthataninfectiouscauseisfound.Thebenefitofcorticosteroidsinempiricalregimensisusuallyoutweighedbytheharm.

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TABLE 34-1  Differential Diagnosis of Chronic Meningitis

MycosesCryptococcus (cryptococcosis)Coccidioides (coccidioidomycosis)Histoplasma (histoplasmosis)Candida (candidiasis)Sporothrix (sporotrichosis [rare])Blastomyces (blastomycosis [rare])Other molds (rare): Scedosporium, Aspergillus, Cladophialophora and other dark-walled molds

BacteriaMycobacterium tuberculosis (tuberculosis)Treponema pallidum (syphilis)Borrelia burgdorferi (Lyme disease)Tropheryma whipplei (Whipple’s disease)Actinomyces (actinomycosis [parameningeal, rare])Nocardia (nocardiosis [with brain abscess])Brucella (brucellosis [rare])

ParasitesAcanthamoeba (acanthamebiasis)Taenia solium (cysticercosis)Angiostrongylus cantonensis (angiostrongyliasis)

VirusesEchovirus (meningoencephalitis)

Postneurosurgical CausesInfected cerebrospinal fluid shuntInfected prosthetic material

TumorsDiffuse gliomatosisMetastatic meningeal malignancy, including lymphomatous meningitis

Other CausesSarcoidosisVogt-Koyanagi-Harada syndromeBehçet’s syndromeIgG4-related hypertrophic pachymeningitis

TABLE 34-2  Diagnostic Tests for Chronic Meningitis

Cerebrospinal Fluid TestsGlucose, blood, protein, and cell count and differential (including eosinophils)India ink on centrifuged sedimentFungal culture of 3 to 5 mL of cerebrospinal fluidCytopathology for malignant cells, including polymerase chain reaction assay or flow cytometry for

monoclonal B cellsPeriodic acid–Schiff stain of cytopathologic specimen for Whipple’s diseaseVenereal Disease Research Laboratory test (VDRL) for syphilisCryptococcal antigenHistoplasma antigenAspergillus galactomannan antigenComplement fixation for antibody to Coccidioides speciesMTB Direct (Gen-Probe, San Diego, CA)Polymerase chain reaction assay for tuberculosis, Whipple’s disease, enterovirus infection, toxoplasmosis,

lymphomaCulture for enterovirus, Acanthamoeba

Serum TestsRapid plasma reagin (RPR) test or antitreponemal antibody testAntibody to Coccidioides, Histoplasma, Toxoplasma, BrucellaHistoplasma antigen

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35  EncephalitisJ. David Beckham and Kenneth L. Tyler

DEFINITION• Encephalitis is an inflammatory process involving the brain parenchyma associated with

clinicalorlaboratoryevidenceofneurologicdysfunction.

EPIDEMIOLOGY• Itoccursmostfrequentlyininfantsyoungerthan1yearofageandinelderlypatientsolder

thantheageof65withintermediateincidenceinindividualsbetweentheseageextremes.

MICROBIOLOGY• Upto60%ofencephalitiscasesresultfromanunidentifiedetiologicagent.• Viruses,bacteria,andautoimmuneinflammationcausethemajorityofknownencephalitis

cases.

DIAGNOSIS• Acompatiblefebrilesyndromewithevidenceofcentralnervoussystemimpairmentexists

(seeTable35-1).• Standard cerebral spinal fluid (CSF) analysis and neuroimaging with magnetic resonance

imagingarepreferred.• SpecificCSForserumstudiesfordefinedetiologiesofencephalitis,orboth,arewarranted

(seeTable35-2).

THERAPY• Early, empirical use of high-dose acyclovir is warranted to treat possible herpes simplex

encephalitispendingdiagnosticstudies.• Antiviral therapy is indicated for the treatment of other herpes viruses that cause

encephalitis.• Empirical antiviral therapy is recommended for suspected encephalitis associated with

influenza.• There is currently no therapy of known benefit for patients with encephalitis due to

arboviruses.

PREVENTION• RoutinevaccinationforcommonpathogensandvaccinationforJapaneseencephalitisvirus

inselectedtravelersmaypreventsomecasesofencephalitis.• Procedures to decrease exposure to mosquito bites may decrease the risk for arbovirus-

relatedcasesofencephalitis.

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TABLE 35-1  Comparison of Encephalitis and Encephalopathy

ENCEPHALITIS ENCEPHALOPATHY

Clinical FeaturesFever Common Uncommon

Headache Common Uncommon

Depressed mental status May fluctuate Steady decline in mental status

Focal neurologic signs Common Uncommon

Seizures Common Uncommon

Types of seizures Generalized or focal Generalized

Laboratory ResultsComplete blood count Leukocytosis common Leukocytosis uncommon

Cerebrospinal fluid Pleocytosis common Pleocytosis uncommon

Electroencephalogram Diffuse slowing and occasional focal abnormalities or periodic patterns

Diffuse slowing

Magnetic resonance imaging May have focal abnormalities No focal abnormalities

Modified from Davis LE. Diagnosis and treatment of acute encephalitis. Neurologist. 2000;6:145-159.

TABLE 35-2  Other Important and Emerging Causes of Viral Encephalitis

VIRAL ETIOLOGY EPIDEMIOLOGY

CLINICAL FEATURES DIAGNOSIS TREATMENT

Adenovirus Children and immunocompromised patients

Associated pneumonia PCR or culture of brain biopsy specimen or CSF

Supportive

Chikungunya virus

Epidemic setting; India and Southeast Asia; mosquito vector

Febrile syndrome with rash and arthralgias

CSF and serum IgM and PCR

Supportive

Hendra virus Australia; fruit bat reservoir; humans infected by secretions of bats

Fever, drowsiness, seizures, and coma associated with a flulike prodrome

Contact Special Pathogens Branch at CDC

Supportive

HIV Worldwide epidemic; recent high-risk behavior

Fever, headache-associated acute retroviral syndrome; commonly associated with HIV dementia

HIV serology testing and HIV quantitative PCR of CSF; MRI may reveal T2 or FLAIR hyperintense lesions in periventricular regions and centrum semiovale

Combination antiretroviral therapy

Influenza Fall and winter seasonal predilection; worldwide distribution; rare complication in children

Associated febrile syndrome, myalgias, respiratory prodrome; may be associated with bilateral thalamic necrosis

Viral culture, antigen detection, and PCR in respiratory secretions

Oseltamivir (C-III); poor outcomes

Japanese encephalitis

Mosquito vector, swine and bird reservoirs; most common cause of epidemic viral encephalitis throughout Southeast Asia and Australia

Seizures and parkinsonian features common; acute flaccid paralysis; case-fatality rate of 20%-30%

Serum IgM or acute/convalescent IgG; CSF IgM or antigen; MRI can show T2 and FLAIR hyperintense lesions at basal ganglia, thalami, and midbrain

Supportive; formalin-inactivated mouse brain–derived vaccine available for prevention

Continued

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VIRAL ETIOLOGY EPIDEMIOLOGY

CLINICAL FEATURES DIAGNOSIS TREATMENT

JC virus Cell-mediated immunodeficiencies (AIDS) and immunomodulating therapy (natalizumab, rituximab, efalizumab)

Cognitive dysfunction, limb weakness, gait disturbance, visual loss, focal neurologic findings

CSF PCR (sensitivity 50%-70% for PML); MRI shows ≥1 nonenhancing, confluent subcortical white matter hyperintensity on T2 and FLAIR sequences

Combination antiretroviral therapy in AIDS patients or reversal of immunosuppression

Louping ill virus

Tick-borne disease; found in Ireland, Scotland, and England; associated with livestock

Usually mild febrile illness with associated confusion and stupor in some; deaths are rare

Serum IgM ELISA or a 4-fold increase in IgG antibody in paired acute and convalescent sera

Supportive

LCMV Rodent-borne virus infects humans with exposure to infected urine, feces, saliva, or blood; severe disease in immunocompromised patients

Fever, headache, leukopenia, and thrombocytopenia; encephalitis characterized by personality changes, increased ICP, paraplegia, and cranial nerve and sensory dysfunction

CSF and serum IgM ELISA

Supportive

Me Tri virus Mosquito-borne; Southeast Asia; transmitted among livestock

Fever, rash, seizures, lethargy, and meningismus

CSF PCR and IgM ELISA, serology

Supportive

Monkeypox Prairie dog exposure Vesiculopustular rash on head, extremities, palms, and soles; adenopathy; encephalitis is rare, with confusion, somnolence, and diminished reflexes

Skin biopsy, CSF, and serum IgM, serology; MRI showing T2 and FLAIR hyperintense lesions of the pons, thalamus, and subparietal cortex

Supportive care; consider cidofovir or vaccinia immune globulin (C-III)

Mumps virus Unvaccinated Previous parotitis followed by headaches, vomiting, seizures, altered consciousness, and sensorineural hearing loss

4-fold IgG increase in paired acute and convalescent sera, culture of saliva, CSF culture and PCR

Supportive

Murray Valley encephalitis virus

Mosquito vector; bird reservoir; Australia and New Guinea

Rapid onset in infants with case-fatality rate of 15%-30%

IgG antibody testing with 4-fold increase in paired acute and convalescent sera

Supportive

Nipah virus Exposure to infected pigs; pteropid bat reservoir; exposure to infected bats or bat roosting sites; close contact to infected humans; South Asia

Fever, headache, altered consciousness, dizziness, vomiting, myoclonus, dystonia, areflexia, hypotonia; pneumonitis

4-fold IgG increase in paired acute and convalescent sera; CSF culture; MRI may show T2 focal hyperintensity of subcortical and deep white matter of cerebral hemispheres; contact Special Pathogens Branch at CDC

Supportive; ribavirin (C-III)

TABLE 35-2  Other Important and Emerging Causes of Viral Encephalitis—cont’d

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TABLE 35-2  Other Important and Emerging Causes of Viral Encephalitis—cont’d

VIRAL ETIOLOGY EPIDEMIOLOGY

CLINICAL FEATURES DIAGNOSIS TREATMENT

Powassan virus

Tick vector; rodent reservoir; New England states, Canada, and Asia

Case-fatality rate of 10%-15% and focal neurologic findings in >50% of patients

Serum and CSF IgM; IgG antibody 4-fold increase in acute and convalescent paired sera

Supportive

Rift Valley fever virus

Sub-Saharan Africa, Egypt, Saudi Arabia, Yemen; mosquito vector and livestock reservoir; humans infected via exposure to infected animal secretions

1% of infected humans develop encephalitis with headache, meningismus, and altered consciousness

ELISA antigen detection or culture from serum and PCR; contact Special Pathogens Branch at CDC

Supportive

Rocio virus Cause of epidemic encephalitis in Brazil; mosquito vector

Fever, headache, confusion, motor impairment, and cerebellar syndrome; sequelae include ataxia, dysphagia, incontinence, and memory problems

4-fold IgG increase in acute and convalescent sera

Supportive

Rubella virus Unvaccinated adults Rash followed by headache, dizziness, behavioral changes, and seizures

CSF IgM; 4-fold IgG increase in paired acute and convalescent sera

Supportive

Snowshoe hare virus

Mosquito-borne; North America; children predominantly affected by encephalitis

Fever, headache, confusion, and lethargy; low mortality and rare long-term neurologic sequelae

CSF and serum IgM ELISA or 4-fold increase in IgG acute and convalescent sera

Supportive

Tick-borne encephalitis virus

Tick vector; rodent reservoir; unpasteurized milk; Eastern Russia, central Europe, Far East

Acute encephalitis; acute flaccid paralysis

Serum IgM or 4-fold increase in IgG antibody in paired acute and convalescent sera

Supportive

Toscana virus Sandfly vector; infection during summer months in Mediterranean countries

Fever, headache, meningismus, and meningoencephalitis with coma, lethargy, hydrocephalus, and hepatosplenomegaly

CSF PCR; serum and CSF IgM; 4-fold increase in IgG acute and convalescent sera

Supportive

Vaccinia Most cases are postinfectious; rare event after vaccination

Abrupt encephalopathy with focal neurologic signs 2-30 days postvaccination

CSF PCR or IgM Supportive; corticosteroids if postvaccination (C-III); consider cidofovir or vaccinia immune globulin

AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FLAIR, fluid-attenuated inversion recovery; HIV, human immu-nodeficiency virus; ICP, intracranial pressure; LCMV, lymphocytic choriomeningitis virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.

Modified from Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Disease Society of America. Clin Infect Dis. 2008;47:303-327.

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36  Brain AbscessAllan R. Tunkel

DEFINITION• Brainabscess isa focal, intracerebral infection thatbeginsasa localizedareaofcerebritis

anddevelopsintoacollectionofpussurroundedbyawell-vascularizedcapsule.

EPIDEMIOLOGY• Before the advent of human immunodeficiency virus (HIV) infection, brain abscess

accountedfor1500to2500casestreatedintheUnitedStateseachyear;theincidencewasestimatedat0.3to1.3casesper100,000peopleperyear.

• Inmostpediatricandadultseries,amalepredominanceexists(aratioof2:1to3:1)withamedianageof30to40years,althoughtheagedistributionvariesdependingonthepre-disposingconditionleadingtotheformationofbrainabscess.

• Theincidenceofbrainabscessisalsoaffectedbythegeneralhealthofthepopulation.Inonestudy of 973 patients from one tertiary hospital in South Africa from 1983 to 2002, theincidencedeclinedduringthestudyperiodasaresultof improvements insocioeconomicstandardsandavailabilityofhealthcareservices.

• Theincidenceofotogenicabscesseshasdecreased,whereastheincidenceofpost-traumaticandpostoperativebrainabscesseshasincreased.

MICROBIOLOGY• Streptococci(aerobic,anaerobic,andmicroaerophilic)arethebacteriamostcommonly(70%

ofcases)culturedfrompatientswithbacterialbrainabscess,andtheyarefrequentlyisolatedinmixedinfections(30%to60%ofcases).

• Staphylococcus aureusaccountsfor10%to20%ofisolates,usuallyinpatientswithcranialtrauma or infective endocarditis, and it is often isolated in pure culture; cases caused bycommunity-associatedmethicillin-resistantS. aureusstrainshavebeenreported.

• The attention to proper culture techniques has increased the isolation of anaerobes frombrainabscesseswithBacteroidesandPrevotellaspp.,isolatedin20%to40%ofpatients,ofteninmixedculture.

• Enteric gram-negative bacilli (e.g., Proteus spp., Escherichia coli, Klebsiella spp., andPseudomonasspp.)areisolatedin23%to33%ofpatients,ofteninpatientswithotiticfociof infection, with septicemia, who have had neurosurgical procedures, or who areimmunocompromised.

• Nocardialbrainabscessmayoccurasanisolatedcentralnervoussystem(CNS)lesionoraspartofadisseminatedinfectioninassociationwithpulmonaryorcutaneousdisease.

• Theincidenceoffungalbrainabscesshasincreasedasaresultoftheprevalentadministrationofimmunosuppressiveagents,broad-spectrumantimicrobialtherapy,andcorticosteroids.

DIAGNOSIS• Magneticresonanceimaging(MRI)hasbeenextensivelyevaluatedinthediagnosisofbrain

abscessandisthefirstimagingchoiceintheevaluationofapatientsuspectedtohavethisdisorder.

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• ThecombineduseofprotonMRspectroscopy,diffusion-weighted imaging, anddiffusiontensorimaginghasbeenshowntoimprovethespecificityofdiagnosisoffocalring-enhancinglesions and differentiating brain abscess from other cystic lesions of the brain, includingtumors.

• Amajoradvanceintheuseofcomputedtomography(CT)inpatientswithsuspectedbrainabscessistheabilitytoperformstereotacticCT-guidedaspirationtofacilitatemicrobiologicdiagnosisandtoguideantimicrobialtherapy;atthetimeofaspiration,specimensshouldbesentforGramstain,routineaerobicandanaerobiccultures,andculturesformycobacteriaandfungi.

THERAPY• When abscess material has been obtained for microbiologic and histopathologic studies,

empiricalantimicrobialtherapyshouldbeinitiatedonthebasisofthepatient’spredisposingconditionsandthepresumedpathogenesisofabscessformation(seeTable36-1).

• InHIV-infectedpatientswithCNSmasslesions,theinitialapproachtomanagementisdif-ferentbecauseofthehighlikelihoodofthediagnosisoftoxoplasmicencephalitis.

• Antimicrobial therapy with high-dose intravenous agents has traditionally been adminis-teredfor6to8weeksinpatientswithbacterialbrainabscesses.

• Mostpatientswithbacterialbrainabscessrequiresurgicalmanagementforoptimaltherapy.• The combination of surgical aspiration or removal of all abscesses larger than 2.5cm in

diameter,a6-weekorlongercourseofintravenousantimicrobialtherapy,andresponseonfollow-upneuroimagingshouldresultinacurerateofmorethan90%.

TABLE 36-1  Empirical Antimicrobial Therapy for Bacterial Brain Abscess

PREDISPOSING CONDITION ANTIMICROBIAL REGIMENOtitis media or mastoiditis Metronidazole + third-generation cephalosporin*

Sinusitis (frontoethmoid or sphenoid) Metronidazole + third-generation cephalosporin*†

Dental infection Penicillin + metronidazole

Penetrating trauma or postneurosurgical Vancomycin + third- or fourth-generation cephalosporin*‡

Lung abscess, empyema, bronchiectasis Penicillin + metronidazole + sulfonamide§

Bacterial endocarditis Vancomycin‖

Congenital heart disease Third-generation cephalosporin*

Unknown Vancomycin + metronidazole + third- or fourth-generation cephalosporin*‡

*Cefotaxime or ceftriaxone; the fourth-generation cephalosporin cefepime may also be used.†Add vancomycin when infection caused by methicillin-resistant Staphylococcus aureus is suspected.‡Use ceftazidime or cefepime as the cephalosporin if Pseudomonas aeruginosa is suspected.§Trimethoprim-sulfamethoxazole; include if a Nocardia spp. is suspected.‖Additional agents should be added based upon other likely microbiologic etiologies.

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37 Subdural Empyema, Epidural Abscess, and Suppurative Intracranial ThrombophlebitisAllan R. Tunkel

DEFINITION• Subduralempyemareferstoacollectionofpusbetweentheduraandarachnoid.• Epiduralabscessisalocalizedcollectionofpusbetweentheduramaterandoverlyingskull

orvertebralcolumn.• Suppurative intracranial thrombophlebitis includes dural venous sinus thrombosis and

suppuration.

EPIDEMIOLOGY• Themostcommonconditionspredisposingtocranialsubduralempyemaareotorhinologic

infections, especially of the paranasal sinuses, which are affected in 40% to 80% of cases.Spinalsubduralempyemaoriginateshematogenously.

• About 0.2 to 2/10,000 hospitalized patients have spinal epidural abscess, with most casesusuallysecondarytoextensionfromvertebralosteomyelitis.

• Suppurativeintracranialthrombophlebitismayoccurafterinfectionoftheparanasalsinuses,middleear,mastoid,face,ororopharynx.

MICROBIOLOGY• Anumberofbacterialspecieshavebeenisolatedinpatientswithcranialsubduralempyema,

includingaerobicstreptococci,staphylococci,aerobicgram-negativebacilli,andanaerobicstreptococciandotheranaerobes.

• Staphylococcus aureus isthemostcommonetiologicagentinpatientswithspinalepiduralabscess.

• The likely infecting pathogens in patients with suppurative intracranial thrombophlebitisdependonthepathogenesisofinfection.

DIAGNOSIS• Magneticresonanceimaging(MRI),withgadoliniumenhancement,isthediagnosticpro-

cedureofchoiceinpatientswithsubduralempyemaandepiduralabscess.• The noninvasive diagnostic procedure of choice in patients with suppurative intracranial

thrombophlebitis is MRI and magnetic resonance venography; computed tomographyvenographyisdoneinpatientsunabletoundergoMRI.

THERAPY• Subduralempyemaisamedicalandsurgicalemergency.Thegoalsofsurgeryaretoachieve

adequatedecompressionofthebrainandcompletelyevacuatetheempyema;basedonret-rospectiveoutcomedata,craniotomyisthesurgicalprocedureofchoice.

• Theprinciplesoftherapyforspinalepiduralabscessarepromptlaminectomyandsurgicaldecompressioninpatientswithneurologicdysfunction,drainageoftheabscess,andlong-termantimicrobialtherapy.Antimicrobialtherapyalonecanbeconsideredinpatientswithlocalizedpainandradicularsymptomswithoutlong-tractfindings,butfrequentneurologic

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examinationsandserialMRIstudiesshouldbeperformedtodemonstrateresolutionoftheabscess.

• Empirical antimicrobial therapy for suppurative intracranial thrombophlebitis is usuallyvancomycin,metronidazole,andathird-orfourth-generationcephalosporin;anticoagula-tionshouldalsobeusedinpatientswithsepticcavernoussinusthrombosisunlesstherearecontraindications.

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38 Cerebrospinal Fluid Shunt and Drain InfectionsAdarsh Bhimraj, James M. Drake, and Allan R. Tunkel

DEFINITION• Ventriculoperitoneal(VP)shuntinfectionscanbeeithersuperficial,involvingtheskinand

softtissueadjacenttotheshuntvalveorreservoir,oritcanbeadeeperinfection,involvingthecerebralventricles,proximallyortheperitoneumdistally.

• Cerebrospinalfluid(CSF)draininfectionscanbetunnelinfections,catheterexitsiteinfec-tions,orventriculitis.

EPIDEMIOLOGY• The case incidence of CSF shunt infection (i.e., the occurrence of infection in any given

patient)hasrangedfrom5%to41%,althoughusuallyitis4%to17%.• Theoperative incidence (i.e., theoccurrenceof infectionperprocedure)has ranged from

2.8%to14%,althoughusuallyitislessthan4%.• InpatientswithCSFdrains,theincidenceofventriculitishasrangedfromzeroto22%.

MICROBIOLOGY• StaphylococcalspeciesaccountforthemajorityofisolatesinpatientswithCSFshuntinfec-

tions,withStaphylococcus epidermidismostfrequentlyisolated(47%to64%ofinfections),followedbyStaphylococcus aureus(12%to29%ofinfections).

• The most common isolated gram-negative species are Escherichia coli, Klebsiella, Proteus,andPseudomonas;casesofAcinetobactermeningitishavealsobeenreportedinpatientswithVPshunts.

• Inrecentyears,anincreasingprevalenceofdiphtheroids(includingPropionibacterium acnes)hasbeenfoundinCSFshuntinfections.

DIAGNOSIS• ThediagnosisisestablishedbyeitherdirectcultureoftheCSFobtainedbyshuntaspiration

orbycultureoftheproximalshuntcomponentsiftheshuntisexplanted.• CSFculture fromtheshunt, reservoir,ordrain is themost important test toestablish the

diagnosisofinfection.• Inpatientswithlumbardrainsorexternalizedventriculardrains,definiteinfectionisdefined

asapositiveCSFculture(obtainedfromtheventricularorlumbarcatheter)associatedwithCSFpleocytosis.

THERAPY• TheprinciplesofantimicrobialtherapyforCSFshuntinfectionsaregenerallythesameas

thoseforacutebacterialmeningitis; theagentselectedmustpenetratethecentralnervoussystem,attainadequateCSFconcentrations,andhavebactericidalactivityagainsttheinfect-ingpathogen.

• Empirical therapy with intravenous vancomycin plus either cefepime, ceftazidime, ormeropenemisappropriate.

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• OptimaltherapyofaninfectedCSFshuntisaninitial intravenousantimicrobial,followedbyremovalofallcomponentsoftheinfectedshunt,insertionofafreshventricularcatheter,andaperiodofexternaldrainage.Later,thedrainisremovedandanewshuntisplaced.

• Directinstillationofantimicrobialagentsintothelateralventricleor,inthecaseoflumbarshunts, intothe lumbarthecalsacmaybenecessary inpatientswithshunt infectionsthataredifficulttoeradicatewithintravenousantimicrobialtherapyandshuntremovalorwhenthepatientisunabletoundergoshuntreplacement.

PREVENTION• Thereisevidencetosupporttheuseofperiproceduralprophylacticantimicrobialadminis-

trationforpatientsundergoingCSFshuntinsertionandplacementofexternalventriculardrains.

• Useofantimicrobial-impregnatedCSFshuntsandCSFdrainsappearstobesafeandeffectiveinpreventionofventriculitis,althoughprospective,randomizedcontrolledtrialsareneededtofirmlyconfirmtheirbenefits.

• UseofastandardizedprotocolandreducingvariationbyadherencetoacommonprotocolareeffectiveatreducingCSFshuntinfectionrates.

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I  Skin and Soft Tissue Infections

39 Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue InfectionsMark S. Pasternack and Morton N. Swartz*

DEFINITION• Skin and soft tissue infections are characterized by location, depth of infection, etiologic

agent,andclinicalsettingandmayresultfromeitherprimarycutaneousinoculationor,lesscommonly,hematogenousseeding.

• Impetigoisasuperficialcrustingandattimesbullousinfectionoftheskin;localizedprogres-sionintothedermisleadstoecthyma.

• Folliculitisisalocalizedinfectionofhairfollicles,whichcanextendintosubcutaneoustissue,resultinginfuruncles.These,inturn,maycoalesce,leadingtocarbuncleformation.

• Erysipelasisarapidlyprogressiveinfectionofthesuperficialdermis,withsharperythema-tousborders;cellulitisreflectsdeeperdermalinvolvement.

• Necrotizing skin and soft tissue infections, including necrotizing fasciitis, are rare life-threateninginfections,occurinavarietyofclinicalsettings,andrequirepromptdiagnosisandsurgicalintervention.

EPIDEMIOLOGY• Significant skin and soft tissue infection may occur throughout the age spectrum. Minor

localtraumaastheinitialpathogeniceventisacommonfeatureoftheseprocesses.Althoughinvasive infections may occur in previously healthy individuals, a variety of systemic riskfactorspredisposesindividualstotheseinfections.

MICROBIOLOGY• HemolyticstreptococciandStaphylococcus aureus,includingmethicillin-resistantS. aureus

(MRSA),arethemostcommoncausesofsuperficialcutaneousinfection.• Mixedinfectionoffacultativegram-negativebacilli,anaerobes,andgram-positiveorganisms

mostfrequentlycausenecrotizinginfection,butgroupAstreptococci,clostridia,andVibriospeciescanalsocausenecrotizingfasciitis.

• Abroaddifferentialdiagnosismostbeconsideredinconfrontinginfectionsinimmunocom-promisedpatients.

DIAGNOSIS• Mostcutaneousinfectionsarenotassociatedwithbacteremia,anddiagnosisandempirical

therapyarebasedonphysicalfindingsandclinicalsetting.• Incompromisedhosts,tissuebiopsyformicrobiologicandhistologicstudyiscriticaltoplan

definitivetherapy.

*MortonN.Swartz,a long-timecontributor tochapters inpreviouseditionsofPrinciples and Practice of Infectious Diseases,diedonSeptember9,2013.

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THERAPY• Oraltherapytargetedagainstgram-positivepathogensisappropriateformilddisease,with

closefollow-upandrevisionoftherapyforinadequateresponse.Parenteraltherapytargetedmore broadly against gram-positive organisms, including S. aureus and MRSA, gram-negativepathogens,andanaerobesisrequiredinmanysettingsofsevereinfection,particu-larlyincompromisedhosts.

• Necrotizinginfectionsrequireurgentsurgicaldébridement.• Infectionsassociatedwithtoxicshocksyndromearetreatedwithprotein-synthesisinhibitors

such as clindamycin and with intravenous immune globulin to neutralize streptococcaltoxins.

PREVENTION• Good hygienic practices and attention to early therapy for superficial processes such as

dermatophyteinfectionreducetheriskforcutaneousandsofttissueinfection.• Individualswithrecurrentcellulitismaybenefitfromchronicantibioticsuppression.

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40 Myositis and MyonecrosisMark S. Pasternack and Morton N. Swartz*

DEFINITION• Myositisisaninflammatoryandgenerallynecrotizingprocessprimarilyduetohematoge-

nousseedingofmusclewithsubsequentbacterialinvasion.Directinoculationofmuscleasthe result of penetrating trauma is also an important mechanism of infection (associatedwithclostridialmyonecrosis).Moregeneralizedmuscleinflammationmayalsoaccompanyavarietyofacuteandchronicviralandparasiticdisorders.

EPIDEMIOLOGY• Pyomyositisoccursacrosstheagespectrumintemperateregionsandmayoccurinprevi-

ouslyhealthyaswellasimmunocompromisedindividuals; inwarmclimates, infectionsinchildrenpredominate(i.e., tropicalpyomyositis).Clostridialmyonecrosismostcommonlycomplicatespenetratingtrauma(e.g.,vehicularaccidents,war,naturaldisasters),especiallyinresource-limitedsettings.

MICROBIOLOGY• Staphylococcus aureus is the classic cause of pyomyositis, but similar illnesses have been

associated with a wide variety of bacterial pathogens, particularly in compromised hosts.Clostridium perfringensmyonecrosiscomplicatespenetratingtrauma,butnontraumaticclos-tridial myonecrosis may develop after hematogenous dissemination of more aerotolerantspecies(e.g.,C. septicum, C. sordellii).GroupAstreptococcicanalsocauseseveremyone-croticinfection,whichisatruemedicalemergency.Acutegeneralizedmuscleinflammationoccursafterinfluenzaanddenguevirusinfections,butawidevarietyofviralpathogenshavesporadicallyledtosignificantmuscleinjuryandevensevererhabdomyolysis.

DIAGNOSIS• Considerationof theseuncommonprocesses is thefirststeptowardtheproperdiagnosis,

becausethefocalprogressivepainofpyomyositismimicsavarietyofdisorders.Bloodcul-turesand(percutaneous)drainagebasedonthefindingsofcross-sectionalimagingconfirmthediagnosisandguidetherapy.Pyomyositismayaccompanytoxicshock,andinvestigationofafocalprocessresponsibleforfulminantsystemicillnessisessential.Gasproductioninmuscle and soft tissue in the setting of a rapidly progressive illness occurs in clostridialmyonecrosisandrelatedinfections;thisisasurgicalemergencyandexplorationfordébride-mentofnonviabletissueandappropriateculturesiscritical.

THERAPY• Ideally, after expedited imaging and drainage, empirical broad-spectrum antibacterial

therapy effective against S. aureus (including methicillin-resistant S. aureus) and

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gram-negativebacilliaswellasanaerobesshouldbeadministered.Thefindingsofassociatedtoxic shock mandate the addition of a protein synthesis inhibitor (e.g., clindamycin) andpossiblyintravenousimmunoglobulintherapy.Narrow-spectrumtherapyisappropriateafteridentificationandsensitivity testingof the isolatedpathogen.Patientspresentingwith theclinical findings of gas gangrene (clostridial myonecrosis) require immediate high-dosepenicillinandclindamycinandurgentsurgicalexploration.

PREVENTION• Becausemostepisodesofpyomyositisdevelopaftertransientbacteremia,preventionisnot

practical.Promptdébridementofdevitalizedtissueafterpenetratinginjuryishighlyeffectiveatpreventingclostridialmyonecrosis.

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41  Lymphadenitis and LymphangitisMark S. Pasternack and Morton N. Swartz*

DEFINITION: LYMPHADENITIS• Acute(suppurative)orchronic(oftengranulomatous)inflammationofthelymphnodes

EPIDEMIOLOGY• Suppurativelymphadenitismostcommonamongyoungchildren;granulomatouslymphad-

enitismayoccurinindividualsofallages.

MICROBIOLOGY (SEE TABLE 41-1)

• SuppurativelymphadenitisprimarilyduetoStaphylococcus aureus(methicillinsensitiveandmethicillinresistant)andgroupAstreptococciinnormalhosts;avarietyofpathogensmaycausesuppurativelymphadenitisinimmunocompromisedindividuals.

• Granulomatouslymphadenitisisdueprimarilytonontuberculousmycobacteriainhealthychildren. Mycobacterium tuberculosis is the most important etiology in older patients butmaybeduetoavarietyofpathogensincompromisedhosts.

DIAGNOSIS• Needleaspiration,incisionalbiopsy,orexcisionalbiopsy,dependingonthetempoandsever-

ityoftheillnessandpossibleimmunodeficiency

THERAPY• Drainage of established abscesses and conventional antimicrobial therapy against gram-

positivepathogensforacutesuppurativelymphadenitis• Targetedtherapybasedonmicrobiologic/histopathologicinvestigationforchronicgranulo-

matouslymphadenitis

PREVENTION• Earlytherapyofprimarysuperficialinfectionsandearlytherapyofacuteadenitisepisodes

mayreducetheriskofsuppurationandneedforsurgicaldrainage.

DEFINITION: LYMPHANGITIS• Lymphangitisisaninflammationoflymphaticchannels,usuallyinsubcutaneoustissues.It

iscausedbyanacuteprocessofbacterialoriginorasachronicprocessofmycotic,myco-bacterial,orfilarialetiology(seeTable41-2).

*MortonSwartz,along-termcontributortopreviouseditionsofPrinciples and Practice of Infectious Diseases,diedonSeptember9,2013.

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TABLE 41-1  Forms of Lymphadenitis

DIS

EASE

INFE

CTI

NG

OR

GA

NIS

M

REG

ION

AL

REG

ION

AL

WIT

H

SUPP

UR

ATI

ON

(O

R

CA

SEA

TIO

N)

ING

UIN

AL

BU

BO

FO

RM

ATI

ON

ULC

ERO

GLA

ND

ULA

R

OC

ULO

GLA

ND

ULA

R

GEN

ERA

L

BacterialPyogenic Group A or B streptococci,

Staphylococcus aureus+ +

Scarlet fever Group A streptococci + + +Diphtheria Corynebacterium diphtheriae +Fusospirochetal angina Prevotella melaninogenica,

peptostreptococci, etc.+

Scrofula Mycobacterium tuberculosis + +Mycobacterium scrofulaceum + +Mycobacterium avium-intracellulare

+ +

Miliary tuberculosis M. tuberculosis + +Brucellosis Brucella + +Leptospirosis Leptospira + +Syphilis Treponema pallidum + +Chancroid Haemophilus ducreyi +Plague Yersinia pestis + + +Tularemia Francisella tularensis + + + + +Rat-bite fever Streptobacillus moniliformis +

Spirillum minus + +Anthrax Bacillus anthracis + + +Listeriosis Listeria monocytogenes +Melioidosis Burkholderia pseudomallei + + +Glanders Burkholderia mallei + + +Cat-scratch disease Bartonella henselae + + ± ± +Typhoid fever Salmonella typhi +

MycoticHistoplasmosis Histoplasma capsulatum +

H. capsulatum var. duboisii +Coccidioidomycosis Coccidioides immitis +Paracoccidioidomycosis Paracoccidioides brasiliensis +Cryptococcosis Cryptococcus neoformans + +

RickettsiaeBoutonneuse fever, etc. Rickettsia conorii +Scrub typhus Rickettsia tsutsugamushi +Rickettsialpox Rickettsia akari +

ChlamydialLymphogranuloma venereum

Chlamydia trachomatis + + +

Continued

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 I M

ajo

r C

linic

al S

ynd

rom

es

DIS

EASE

INFE

CTI

NG

OR

GA

NIS

M

REG

ION

AL

REG

ION

AL

WIT

H

SUPP

UR

ATI

ON

(O

R

CA

SEA

TIO

N)

ING

UIN

AL

BU

BO

FO

RM

ATI

ON

ULC

ERO

GLA

ND

ULA

R

OC

ULO

GLA

ND

ULA

R

GEN

ERA

L

ViralMeasles Measles virus +Rubella Rubella virus +Infectious mononucleosis

Epstein-Barr virus +

Cytomegalovirus mononucleosis

Cytomegalovirus +

Dengue fever Dengue virus +West Nile fever West Nile virus +Lassa fever Lassa fever virus +Oropharyngeal herpes infection

Herpes simplex virus type 1 + ± +

Genital herpes infection Herpes simplex virus type 2 +Primary HHV-6 infection

Human herpesvirus 6 +

Primary HHV-7 infection

Human herpesvirus 7 +

Cowpox Cowpox virus + ±Pharyngoconjunctival fever

Adenovirus (types 3 and 7) + +

Epidemic keratoconjunctivitis

Adenovirus (types 8 and 19) +

AIDS, AIDS-related complex

Human immunodeficiency virus +

ProtozoanKala azar Leishmania donovani +African trypanosomiasis Trypanosoma brucei + +Chagas’ disease Trypanosoma cruzi + +Toxoplasmosis Toxoplasma gondii + + +

HelminthicFilariasis Wuchereria bancrofti + +

Brugia malayi + +Loiasis Loa loa +Onchocerciasis Onchocerca volvulus +

AIDS, acquired immunodeficiency syndrome; HHV, human herpesvirus; +, present; ±, rare.

TABLE 41-1  Forms of Lymphadenitis—cont’d

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TABLE 41-2  Causes of Lymphangitis

CLINICAL FORM ETIOLOGIC AGENT

RELATIVE FREQUENCY AS CAUSE OF LYMPHANGITIS

Acute Group A streptococci CommonStaphylococcus aureus OccasionalPasteurella multocida OccasionalStreptobacillus moniliformis (rat-bite fever) RareWuchereria bancrofti; Brugia malayi (filariasis) Rare (only in immigrants from endemic areas)

Chronic Sporothrix schenckii (sporotrichosis) OccasionalMycobacterium marinum (swimming pool granuloma)

Occasional

Mycobacterium kansasii RareNocardia brasiliensis RareW. bancrofti; B. malayi Rare (only in immigrants from endemic areas)Nocardia asteroides Very rareMycobacterium chelonae Very rareS. aureus (botryomycosis) Very rareLeishmania brasiliensis or Leishmania mexicana Very rareFrancisella tularensis Very rare

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J  Gastrointestinal Infections and Food Poisoning

42  EsophagitisPaul S. Graman

DEFINITION• Inflammationoftheesophagus,ofnoninfectiousorinfectiousetiology

EPIDEMIOLOGY• Gastroesophageal reflux disease is the most common cause. Esophageal infections occur

predominantlyinpatientswithimpairedimmunity,particularlythosewithacquiredimmu-nodeficiencysyndromeorreceivingcancerchemotherapy.Immunocompetentpersonsareoccasionallyaffected.

MICROBIOLOGY• Candidaspecies,herpessimplexvirus(HSV),andcytomegalovirusaremostcommon.

DIAGNOSIS• Endoscopyandbiopsyforimmunohistopathologyandculture,polymerasechainreaction

THERAPY (SEE TABLE 42-1)• Candida: fluconazole, itraconazole, amphotericin lipid formulations, voriconazole,

echinocandins• Herpessimplexvirus:acyclovirorvalacyclovir,famciclovir;foscarnetforacyclovir-resistant

HSV• Cytomegalovirus:ganciclovir,valganciclovir,orfoscarnet• Aphthousulceration(inacquiredimmunodeficiencysyndrome):prednisone,thalidomide

PREVENTION• Recipientsofallogeneichematologicstemcelltransplantswhoareneutropeniccommonly

receiveantiviralandantifungalprophylaxis.

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TABLE 42-1  Treatment of Esophagitis

CAUSEUSUAL TREATMENT  (ADULT DOSE) ALTERNATIVE DRUGS

Candida Fluconazole, 100-200 mg/day PO or IV for 14-21 days; maintenance suppressive therapy may be necessary in AIDS (fluconazole, 100-200 mg/day PO)

Itraconazole oral suspension, 100-200 mg bid POVoriconazole, 200 mg bid PO*Amphotericin B, 0.3-0.7 mg/kg/day IV for 7 daysCaspofungin, 50 mg/day IV after 70-mg loading dose*Micafungin, 150 mg/day IVAnidulafungin, 100 mg on day 1, then 50 mg/day IV

Herpes simplex virus

Acyclovir, 5 mg/kg IV q8h for 7-14 days or 400 mg 5 times daily PO for 14-21 daysOr valacyclovir, 1 g PO tid for 14-21 days†; maintenance suppressive therapy may be necessary in AIDS

Famciclovir, 500 mg bid PO for 14-21 days (not for acyclovir-resistant infection)Foscarnet, 90 mg/kg q12h IV for 7-14 days (used for acyclovir-resistant infection)

Cytomegalovirus Ganciclovir, 5 mg/kg IV q12h for 14-21 days; maintenance suppressive therapy usually is necessary in AIDS (ganciclovir, 5 mg/kg/day IV 7 days/wk or 6 mg/kg/day IV 5 days/wk)

Foscarnet, 90 mg/kg q12h IV for 14-21 days; suppression with foscarnet, 90-120 mg/kg/day IVValganciclovir, 900 mg bid PO for treatment, and 900 mg qd for maintenance/suppression†

Aphthous ulceration (in AIDS)

Prednisone, 40 mg/day PO for 14 days, then taper

Thalidomide, 200 mg/day PO†

AIDS, acquired immunodeficiency syndrome.*Amphotericin, echinocandins, and voriconazole are indicated for severe or refractory esophageal candidiasis.†Not approved by the U.S. Food and Drug Administration for this indication.

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43 Nausea, Vomiting, and Noninflammatory DiarrheaDavid A. Bobak and Richard L. Guerrant

DEFINITION• A disease group consisting of acute and chronic forms of gastroenteritis occurs in both

pediatric and adult patients, and these diseases have the unifying characteristic of beingpredominantlynoninflammatoryinnature.

EPIDEMIOLOGY• Noninflammatorygastroenteritidesareamongthemostcommoninfectionsofhumans.As

agroup,theyaresecondinincidenceonlytoviralupperrespiratoryinfections.• Mostcasesofthesediseasesarenottrackedorreportedbutareestimatedtoaffecttensof

millionsofpeopleworldwideeachyear.• Therearebaselineendemicandseasonalratesaswellasepidemicoutbreaksofmostforms

oftheseinfections.• Theratesofinfectionaswellasetiologicagentsvaryaccordingtoage,climate,andgeography.

Inaddition,therearedifferencesintheseparametersobservedforplaceofacquisition(e.g.,community-vs.healthcarefacility–acquiredinfections).

MICROBIOLOGY• Viruses,includingmembersoftherotavirus,norovirus,adenovirus,andastrovirusgenera,

arethecauseofmostcasesofnoninflammatorygastroenteritis.• Amongthebacterialcausesofthissyndrome,certainpathogenicstrainsofEscherichia coli

andsomeserotypesofcholeraandnoncholeraVibrioareparticularlynoteworthy.• Certainprotozoan typesofparasitescancauseapredominantlynoninflammatory typeof

gastroenteritis and include members of the Giardia, Cryptosporidium, Cystoisospora, andCyclosporagenera.

• Althoughmanyoftheetiologicagentsaresimilar,therearealsosomeimportantdifferencesbetweentheendemicandepidemiccausesofnoninflammatorygastroenteritisindeveloping,newly industrialized, and developed countries. Newborn nursery–associated and noso-comial outbreaks of this syndrome have differences from those cases acquired in thecommunity.

• Thenumberofpotential infectiousagents ismuchgreater in immunocompromisedcom-paredwithimmunocompetenthosts.

DIAGNOSIS• Thetypicalclinical syndromeconsistsofvaryingdegreesofnausea,vomiting,andwatery

diarrhea,oftenincombinationwithfever,myalgias,andarthralgias.• Mostcasesofthissyndromeareself-limited,andnospecificetiologyisidentified.• Incertaininstances,suchasepidemic,nosocomial,andfoodbornecases,anetiologicagent

canbeidentifiedbyeithercultureormoleculardiagnosticassay.

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THERAPY• Adequatereplacementoffluidsandelectrolytesremainsthemainstayofallformsofgastro-

enteritis,includingthenoninflammatorygastroenteritidesdiscussedinthischapter.• Inmostcasesofnoninflammatorygastroenteritis,specificantimicrobialtherapyisnotused.

However,inmoresevereorspecificformsofthisinfection,specificantiviral,antibacterial,orantiparasitictreatmentmaybebeneficial.

PREVENTION• Adequate sanitation for the local water supply and food processing and distribution

systems helps to prevent many forms of endemic, community-acquired noninflammatorygastroenteritis.

• Althoughtherehasbeentremendousinterestindevelopingeffectivevaccinationorimmu-nizationschemesformanyoftheseinfectiousagents,onlyvaccinesforrotavirusarecurrentlyavailableforgeneraluse.

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44  Bacterial Inflammatory EnteritidesAldo A. M. Lima, Cirle A. Warren, and Richard L. Guerrant

DEFINITION• Acuteandchronicinflammatoryenteritidesarecausedbyseveralspecificinfectiousagents.

EPIDEMIOLOGY• Acute dysenteric syndromes are influenced by the unusually low inoculum required for

infectionbyorganismssuchasshigellae.• Thebacterial entericpathogensmostassociatedwith illnesses inchildrenyounger than5

years intheUnitedStatesarenontyphoidSalmonella, followedbyCampylobacter, Yersinia enterocolitica,andEscherichia coliO157.

• Venerealexposure,particularlyamongmenwhohavesexwithmen,mayimplicategono-cocci, herpes simplex virus, Chlamydia trachomatis, or Treponema pallidum as a cause ofproctitis, or Campylobacter, Shigella, C. trachomatis (lymphogranuloma venereum sero-types),orClostridium difficileasacauseofcolitis.

• Ahistoryofantibioticintakeand/orrecentadmissiontoahealthcarefacilitywouldstronglysuggestC. difficileinfection.

MICROBIOLOGY• GenomicstudiesofShigellaspecieshaveindicatedthatShigellaandenteroinvasiveE. coliare

derivedfrommultipleoriginsofE. coliandformasinglepathovar.• Thecauseofarecentoutbreakofbloodydiarrheaandseverehemolytic-uremicsyndrome,

unlike prior enterohemorrhagic E. coli strains that had exhibited enteropathogenic E. colitraitsofattachmentandeffacement,wasaShigatoxin–producingenteroaggregativeE. colistrain.

• Campylobacterspp.haveasmallgenome(1.6to2.0Mb)andcancauseintestinalandsys-temicinfections.

• TheprimaryvirulencefactorsthatareknowntocauseclinicaldiseaseinC. difficileinfectionarethetwolargetoxins:C. difficiletoxin(Tcd)A,ortoxinA(308kDa),andTcdB,ortoxinB(270kDa).

• Vibrio parahaemolyticushasbeenrecognizedsince1950inJapanandisacauseofseafoodpoisoning.

• SalmonellaflagellinisregulatedbythefliCgene,whichisthemajorligandfortheToll-likereceptor5,nucleotideoligomerizationdomain–likereceptors,andICEprotease-activatingfactor(Ipaf)protein.

DIAGNOSIS• Anyoftheabovemicroorganismsmaycauseanacutedysenterysyndromewithbloodand

pusinthestool.• Examinationforleukocytesorforfecallactoferrinmaysuggestintestinalinflammation,even

ifbloodisnotpresentinthestoolongrossexamination.

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• Recent approaches using a laboratory-developed TaqMan Array Card for simultaneousdetection of several enteropathogens hold promise, with high accuracy, sensitivity, andspecificityaswellasbeingpotentiallysuitedforsurveillanceorclinicalpurposes.

THERAPY AND PREVENTION• Becausetherearemanyetiologicagents,thetreatmentandpreventionrelyoneachspecific

causeofacuteandchronicinflammatoryenteritides

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45 Enteric Fever and Other Causes of Fever and Abdominal SymptomsJason B. Harris and Edward T. Ryan

DEFINITION• Enteric fever is a nonspecific febrile illness caused by typhoidal Salmonella; the diagnosis

shouldbeconsideredinanypatientwithotherwiseunexplainedprolongedfever.• Thetermtyphoidal feverissometimesusedmorebroadlytorefertoasyndromeofpersistent

high-gradefevers,oftenwithnolocalizingfeatures.

EPIDEMIOLOGY• Tensofmillionsofcasesofentericfeveroccureachyear, largely in impoverishedareasof

AsiaandAfrica.• Entericfeverisfecally/orallytransmitted,withcontaminatedmunicipalwatersuppliesbeing

commonlyinvolvedintransmission.• Multidrug-resistantstrainsofthemajorcausativeagentsofentericfever(Salmonella enterica

serotypeTyphiandParatyphiA)arenowcommonworldwide.

CLINICAL MANIFESTATIONS• Commonlife-threateningcomplicationsofentericfeverincludeintestinalhemorrhage,per-

foration,encephalopathy,andshock.• Untreated,patientswithentericfevermaybefebrilefor3to4weeksorlonger,withmortality

ratesexceeding10%,andprolongedastheniaandfatiguearecommonamongsurvivors.• Chronic biliary carriage of typhoidal Salmonella may occur after resolution of the acute

illness.

DIAGNOSIS• Currentdiagnostictestsforentericfeverareimperfect:bloodculturesare30%to70%sensi-

tive,bonemarrowculturesaremoresensitivebutareimpractical,serologicassayslackbothsensitivityandspecificity,especiallyinentericfeverendemicareas,andnucleicacidampli-ficationassayswithsensitivityarenotavailable.

THERAPY• Given the morbidity of typhoid fever, the risk of complications, and the lack of optimal

diagnostic tests, the initiationofantibiotics fortreating individualswithsuspectedentericfevermaybebasedonapresumptivediagnosis,particularlyinresource-limitedsettings.

• The most commonly used agents for treating individuals with enteric fever are fluoro-quinolones, azithromycin, and cefixime or ceftriaxone. Chloramphenicol, trimethoprim-sulfamethoxazole,andamoxicillinmaybeusedtotreatpatientswithsusceptiblestrains.

• Anoral-attenuatedtyphoidvaccineandinjectablepolysaccharidevaccineareinternationallycommerciallyavailableandprovide50%to75%protectionfor5and2years,respectively.Injectable typhoid conjugate vaccines are in late-stage development. No vaccine effectiveagainstparatyphoidAiscurrentlycommerciallyavailable.

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46  Foodborne DiseaseRajal K. Mody and Patricia M. Griffin

DEFINITION• Foodbornediseasesareillnessesthatareacquiredthroughingestionoffoodcontaminated

withpathogenicmicroorganisms,bacterialandnonbacterialtoxins,orothersubstances.

EPIDEMIOLOGY• Anestimated48millionfoodborneillnessescausedbypathogensortheirtoxinsareacquired

annuallyintheUnitedStates.• Manyagentsthatcausefoodborneinfectioncanalsobeacquiredinotherways,including

ingestionofcontaminateddrinkingorrecreationalwater,throughcontactwithanimalsortheirenvironment,andfromonepersontoanotherdirectlyorthroughfomites.

• Somefoodbornediseasescanleadtolong-termsequelae,suchasimpairedkidneyfunctionafter Shiga toxin–producing Escherichia coli infection, Guillain-Barré syndrome afterCampylobacterinfection,andreactivearthritisandirritablebowelsyndromeafteravarietyofinfections.

• Groups at higher risk of acquiring or experiencing more severe foodborne diseaseincludeinfants,youngchildren,pregnantwomen,olderadults,andimmunocompromisedpersons.

• Afoodbornediseaseoutbreakshouldbeconsideredwhenanacuteillness,especiallywithgastrointestinalorneurologicmanifestations,affectstwoormorepeoplewhosharedameal.However,mostfoodbornediseasesdonotoccurinthecontextofanoutbreak.

MICROBIOLOGY• Many pathogens, including bacteria, viruses, and parasites, can cause foodborne

disease.• Someillnessesarecausedbyingestionofchemicals(e.g.,heavymetals,mushroomtoxins)

orpreformedmicrobialtoxins(e.g.,staphylococcaltoxin,botulinumtoxin).

DIAGNOSIS• Detection of pathogens has mostly relied on isolating bacterial pathogens in culture, by

visualizingparasitesbymicroscopy,andbyenzyme-linkedimmunosorbentassays.• Newermoleculartestsposeopportunitiesandchallengestobothclinicalpracticeandpublic

healthsurveillance.• Manyintoxicationsmustbediagnosedbasedonclinicalsuspicionalone.

THERAPY• Therapyformostfoodbornediseasesissupportive;replacingfluidandelectrolytelossesis

importantindiarrhealillnesses.• Antimicrobialagentsareusedtotreatparasiticinfectionsandselectedbacterialinfections.• Resistancetoantimicrobialagentscomplicatestreatmentandcanincreasethelikelihoodof

clinicallyapparentinfection.

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PREVENTION

• Toreducecontamination, foodproducers identifypointswhere theriskofcontaminationcanbecontrolledanduseproductionsystemsthatdecreasethehazards.

• Outbreak investigation is important to identify foodsafetygaps thatmaybepresentany-whereinthefoodproductionchain,fromthefarmtothetable.

• Individualscanreducetheirriskofillnessbyadheringtosafefoodhandlingpractices.

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47  Tropical Sprue: EnteropathyChristine A. Wanke

DEFINITION• Syndromeofdiarrhea,malabsorptionofatleasttwodistinctnutrients,abnormalduodenal

histopathology,andweightloss.

EPIDEMIOLOGY• Most frequent in Asia and the Caribbean islands, more frequent in adults than children;

occursinlong-termtravelerstoendemicregions.

MICROBIOLOGY• Nosingleagentassociatedwithcausality,smallbowelovergrowthcommon.

DIAGNOSIS• Appropriate clinical syndrome (persistent diarrhea, malabsorption of at least two distinct

nutrients,weightloss)withconsistentsmallbowelseriesorupperendoscopy.Responsetofolateandtetracyclineultimatelyconfirmsdiagnosis.

THERAPY• Removalfromareaofrisk,treatmentwithfolateandtetracycline.

PREVENTION• Goodhygienepractices.

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48 Infectious Arthritis of Native JointsChristopher A. Ohl and Derek Forster

DEFINITION• Infectious arthritis is an infection of one or more joints that can be caused by bacteria,

viruses,fungi,andparasites.

CLINICAL CATEGORIESAcute Bacterial Arthritis• Overall incidence in native joints is 2 to 10/100,000 per year, increased in rheumatoid

arthritis.• Infectioncanbeacquiredfromhematogenousdissemination,directjointinoculation,ora

contiguousfocus.Mostinfectionsaremonarticular;10%to20%arepolyarticular.Thekneeismostofteninvolved.

• Microbiology• Gram-positive organisms, including Staphylococcus aureus and Streptococcus spp.

predominate.• Gram-negativebacilliin5%to20%aremainlyinneonates,theelderly,intravenousdrug

users,andimmunocompromised.• Prevalence rates of gonococcal arthritis have markedly decreased. There are two syn-

dromes of joint involvement: monarticular arthritis and disseminated gonorrhea withfebriletenosynovitisandskinlesions.

Viral Arthritis• It may occur sporadically or in community outbreaks that may be small (e.g., parvovirus

B19)orexplosive(e.g.,chikungunyavirus).• Itiscausedbyinfectionofthejointspaceorbyimmune-mediatedinflammation.• Itisusuallyanacutepolyarticulararthritisthatoccurssimultaneouslywithothersystemic

symptomsofviralinfection.• Causes include parvovirus B19, rubella (which may follow immunization), hepatitis B,

hepatitisC,andalphaviruses,includingchikungunyavirus,RossRivervirus,ando’nyong-nyongvirus.

• Itmayoccasionallycauseprolongedorchronicarthritisafteracuteinfection.

CLINICAL EVALUATION• Bacterial arthritis is an emergency and should be considered in any patient with acute

monoarticularorpolyarticulararthritis.• Themostusefuldemographic risk factorsarepresenceorabsenceof recent joint surgery,

rheumatoidarthritis,advancedage,concomitantskininfection,ordiabetesmellitus.• Themosthelpfullaboratoryparametersarethesynovialfluidleukocytecountanddifferen-

tial,andexaminationforcrystalstoruleoutgoutorpseudogout.• Diagnosticimagingshouldincludeplainfilmradiography.Forprolongedoratypicalsymp-

toms, or for deep joints, computed tomography or magnetic resonance imaging isrecommended.

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• Identificationof the infectingorganismonsynovialfluidGramstainandcultureremainsthedefinitivediagnostictest.Thepolymerasechainreaction(PCR)assaycontinuestoshowpromise.

THERAPYAcute Bacterial Arthritis• Jointdrainagebyrepeataspiration,arthroscopy,orarthrotomyisrequired.• EmpiricalselectionshouldbebasedonsynovialfluidGramstain(seeTable48-1).• Intravenous therapy, in some instanceswithanoral transition, isusuallyprescribed fora

totalof2to4weeks.

Chronic Infectious Arthritis• Itisusuallymonarticular,involvingthelargeperipheraljoints.• Itisrelativelyuncommoncomparedwithacutebacterialarthritisbutisincreasinglyseenin

immunocompromisedorchronicallyillhosts.EtiologyincludesMycobacterium tuberculosisandnontuberculosismycobacteria.Fungal causes includeCandida,dimorphic fungi (e.g.,Blastomyces, Coccidioides, Histoplasma, and Sporothrix), Cryptococcus, and Aspergillus,amongothers.

• TherapyofM. tuberculosisarthritisissimilartopulmonarytuberculosis.• Manyfungalarthritidesaredifficulttotreatandresultinchronicjointdisability.Treatment

variesbyinfectingorganism.Experienceusingtheazoles(includingnewtriazoles)andtheechinocandinsisgrowing,andinmanycases,thesedrugsarereplacingamphotericin.

• ExceptforCryptococcusandperhapsSporothrix,fungalarthritisrequiressurgicaldrainageanddébridement.

TABLE 48-1  Recommended Empirical Therapy for Adult Native Joint Bacterial Arthritis

GRAM STAIN PREFERRED ANTIBIOTICa ALTERNATIVE ANTIBIOTICGram-positive cocci Vancomycin, 15-20 mg/kg (ABW) daily

every 8-12 hrbDaptomycin, 6-8 mg/kg dailyc or linezolid, 600 mg IV or PO every 12 hrc

Gram-negative coccid Ceftriaxone, 1 g every 24 hr Cefotaxime, 1 g every 8 hre

Gram-negative rodsf Ceftazidime, 2 g every 8 hr orCefepime, 2 g every 8 hr orPiperacillin-tazobactam, 4.5 g every 6 hr

Aztreonam, 2 g every 8 hr orFluoroquinoloneg orCarbapenemh,i

Gram-stain negativef VancomycinplusCeftazidime orCefepime

Daptomycinc or linezolidc

plusPiperacillin-tazobactam orAztreonam orFluoroquinoloneg orCarbapenemh,i

ABW, actual body weight; IgE, immunoglobulin E; IV, intravenous; PO, by mouth.aUnless noted otherwise, dosages are IV for persons with normal renal function.bTherapeutic monitoring should target a serum trough of 15-20 mg/L.cFor patients allergic to, or intolerant of, vancomycin.dEquivocal gram-negative morphology should be considered as gram-negative rods.eGram-negative cocci with epidemiology or history suggestive of gonococcal infection should be initially treated

per Centers for Disease Control and Prevention Sexually Transmitted Disease Guidelines. Alternative therapies have not been suggested for patients with a history of a Stevens-Johnson syndrome or severe IgE-mediated allergy to β-lactam antibiotics. Possible empirical options for penicillin-allergic patients, pending culture sensitivities, include azithromycin, ciprofloxacin, tobramycin, gentamicin, and spectinomycin (not available in United States).

fFor patients with risk factors for resistant gram-negative pathogens (significant health care exposure, immunosup-pression, or history of extended-spectrum β-lactamase gram-negative infection or colonization), drug selection should consider regional or local antibiograms.

gCiprofloxacin, 400 mg IV every 8 hr or 750 mg PO every 12 hr or levofloxacin, 750 mg IV or PO every 24 hr.hDoripenem, 500 mg every 8 hr; imipenem, 500 mg every 6 hr; or meropenem, 1 g every 8 hr.iUsually reserved for patients with risk factors for resistant gram-negative pathogens (significant health care

exposure, immunosuppression, or history of extended-spectrum β-lactamase gram-negative infection or colonization).

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SEPTIC BURSITIS• Itpredominantlyinvolvestheprepatellar,olecranon,andtrochantericbursa.• Itcanbecausedbydirectinoculation,contiguousinfection,orlesscommonly,fromahema-

togenoussource.• Morethan80%ofcasesareduetoStaphylococcus aureus.• Diagnosisismadefromtheclinicalpresentationandbyaspiratingthebursaforfluidanalysis,

Gramstain,andculture.• Treatmentincludesantibiotics(usually14to21days)anddailyaspirationofthebursauntil

sterile fluid is obtained. Except for severe cases, oral antistaphylococcal agents that haveactivityagainstcommunity-acquiredmethicillin-resistantS. aureus(CA-MRSA)arerecom-mended pending culture and sensitivity. For moderate-to-severe cases or patients withimmunosuppression,intravenousantibioticsshouldbeselected.

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49 OsteomyelitisElie F. Berbari, James M. Steckelberg, and Douglas R. Osmon

CLASSIFICATION• Osteomyelitiscandevelopastheresultofcontiguousspreadfromadjacentsofttissuesand

joints,hematogenousseeding,ordirect inoculationofmicroorganisms into theboneasaresultoftraumaorsurgery.

• TheCiernyandMaderclassificationisbasedontheaffectedportionofthebone,thephysi-ologicstatusofthehost,andthelocalenvironment.

• The Lew and Waldvogel classification is based on the duration of illness (acute versuschronic), themechanismof infection(hematogenousvs.contiguous),andthepresenceofvascularinsufficiency.

GENERAL PRINCIPLES• Thediagnosisofosteomyelitisissuspectedonclinicalgrounds.Confirmationusuallyentails

acombinationofradiologic,microbiologic,andpathologictests.• Cross-sectionalimagingmodalities,suchascomputedtomographyormagneticresonance

imaging(MRI),areconsideredstandardofcareinthediagnosisofosteomyelitis.• Repeatedswabculturesofthesameorganismfromdrainingwoundsandsinustractsmay

beofdiagnosticbenefit,althoughfailuretorecoverthetruepathogeniscommon,exceptforStaphylococcus aureus.

• Bonebiopsyorneedleaspirationisbestfororganismidentification.• Therapy is typically a combinationof complete surgicaldébridementand4 to6weeksof

antimicrobialtherapy(seeTable49-1).

OSTEOMYELITIS AFTER A CONTAMINATED OPEN FRACTURE• Contaminatedopenfracturescanleadtothedevelopmentofosteomyelitisofthefractured

bone,typicallyatthefracturesitein3%to25%ofcases.• Staphylococciandaerobicgram-negativebacilliarethetwomostcommongroupsofmicro-

organismsinthissetting.• Thehallmarkofosteomyelitisafteropen fracture isnonunionof the fracture siteorpoor

woundhealingafterwoundclosureorsofttissuecoverage.• Managementofopencontaminatedfracturesentailsearlyaggressivewoundirrigationand

débridement, administration of parenteral and local antimicrobials, fracture fixation, andsofttissuecoverageofexposedbone.

VERTEBRAL OSTEOMYELITIS AND SPONDYLODISKITIS• The origin is hematogenous in most native cases; it may also occur postoperatively or

postprocedurally.• S. aureus, coagulase-negative staphylococci,Mycobacterium tuberculosis, andBrucella spp.

arethemostcommonmicroorganismsencounteredinvertebralosteomyelitis.• MRIofthespineishighlyaccurateinthediagnosisofvertebralosteomyelitis.• Image-guidedaspirationandbiopsyishighlyspecificbutlackssensitivity.• Mostcasescanbetreatedwitha6-weekcourseofparenteralantimicrobialtherapywithout

surgery.

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OSTEOMYELITIS IN PATIENTS WITH DIABETES MELLITUS OR VASCULAR INSUFFICIENCY• Patientstypicallyhaveosteomyelitiscontiguoustoanulcerofthelowerextremity.• The sensitivity of exposed bone or a probe-to-bone test was 60%, and the specificity

was91%.• Thiscategoryofosteomyelitisisoftenpolymicrobial.• Therapy requires a combination of broad-spectrum antimicrobial regimen and surgical

débridement.

ACUTE HEMATOGENOUS OSTEOMYELITIS• Acute hematogenous osteomyelitis of long bones occurs mainly in prepubertal children,

elderlypatients,intravenousdrugabusers,andpatientswithindwellingcentralcatheters.• ThemostcommonrecoveredmicroorganismisS. aureus.• Acutehematogenousosteomyelitisoflongbonesinprepubertalchildrenistypicallytreated

witha2-to3-weekcourseofantimicrobialtherapy.

TABLE 49-1  Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

MICROORGANISMS FIRST CHOICE* ALTERNATIVE CHOICE*Staphylococci

  Oxacillin sensitive Nafcillin sodium or oxacillin sodium, 1.5-2 g IV q4h for 4-6 wk, or cefazolin, 1-2 g IV q8h for 4-6 wk

Vancomycin, 15 mg/kg IV q12h for 4-6 wk; some add rifampin, 600 mg PO qd, to nafcillin/oxacillin

  Oxacillin resistant (MRSA)

Vancomycin,† 15 mg/kg IV q12h for 4-6 wk

Linezolid, 600 mg PO/IV q12h for 6 wk, or levofloxacin,†

  500-750 mg PO/IV daily, plus rifampin,  600-900 mg/day PO for 6 wk if susceptible to both drugs

orDaptomycin 6 mg/kg IV q24h

Penicillin-sensitive streptococci

Aqueous crystalline penicillin G, 20 × 106 U/24 hr IV either continuously or in six equally divided daily doses for 4-6 wk, or ceftriaxone, 1-2 g IV or IM q24h for 4-6 wk or cefazolin, 1-2 g IV q8h for 4-6 wk

Vancomycin, 15 mg/kg IV q12h for 4-6 wk

Enterococci or streptococci with MIC ≥0.5 µg/mL, or Abiotrophia or Granulicatella spp.

Aqueous crystalline penicillin G, 20 × 106 U/24 hr IV either continuously or in six equally divided daily doses for 4-6 wk, or ampicillin sodium, 12 g/24 hr IV either continuously or in 6 equally divided daily doses; the addition of gentamicin sulfate, 1 mg/kg IV or IM q8h for 1-2 wk is optional

Vancomycin,† 15 mg/kg IV q12h for 4-6 wk; the addition of gentamicin sulfate, 1 mg/kg IV or IM q8h for 1-2 wk is optional

Enterobacteriaceae Ceftriaxone, 1-2 g IV q24h for 4-6 wk,  or ertapenem 1 g IV q24h

Ciprofloxacin,† 500-750 mg PO q12h for 4-6 wk, or levofloxacin 500-750 mg PO q24h

Pseudomonas aeruginosa Cefepime, 2 g IV q12h, meropenem, 1 g IV q8h or imipenem, 500 mg IV q6h for 4-6 wk

Ciprofloxacin,† 750 mg PO q12h for 4-6 wk, or ceftazidime, 2 g IV q8h

MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.*Antimicrobial selection should be based on in vitro sensitivity data.†Should be avoided, if possible, in pediatric patients and in osteomyelitis associated with fractures.

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50 Orthopedic Implant–Associated InfectionsWerner Zimmerli and Parham Sendi

PERIPROSTHETIC JOINT INFECTION (PJI)Diagnosis• Determinationthataprostheticjointisinfecteddependsonrecoveryofanorganismfrom

ajointaspirateorsurgicallyobtainedmaterialfromthejoint,althoughinflammation,wounddehiscence,adrainingsinustract,jointeffusion,andlooseningoftheprosthesiscanpointtowardthisdiagnosis.

Microbiology• Mostfrequentmicroorganisms:Staphylococcus aureus,coagulase-negativestaphylococciand

streptococci• Propionibacterium acnes: Most important microorganism in periprosthetic shoulder

infection• Microorganismsestablishabiofilmonthesurfaceoftheimplant

Pathogenesis• Foreigndevicesarecoveredbyhostproteins(e.g.,fibronectin)after implantationfavoring

bacterialadherence.• Minimalinfectingdoseisgreaterthan10,000-foldlowerinthepresencethanabsenceofan

implant.• Granulocytefunctionaroundtheimplantisimpaired(activationanddegranulation).

Clinical Manifestations• Acute exogenous PJI: Local signs of inflammation (wound dehiscence, secretion,

erythema)• AcutehematogenousPJI:New-onsetpainatany timeafter implantation, initiallywithout

localsignsofinfection,new-onsetarticulareffusion• ChronicPJI:Painbecauseofearlyloosening,localinflammation,sinustract,chronicarticu-

lareffusion

Treatment• Cornerstoneofsuccessfultreatmentisearlydiagnosis.• Cureisonlypossiblewithadequatesurgerycombinedwithlong-termantibiotictherapy.• Atreatmentalgorithm(seeFig.50-1)allowschoosingthemostappropriatesurgicalinter-

vention: Débridement with retention, one-stage exchange, two-stage exchange, removalwithoutreplacement,orsuppressivetherapy.

• Guidelines:www.idsociety.org/Organ_System/#Skeletal%20%28Bones%20&%20Joints%29

INTERNAL FIXATION–ASSOCIATED INFECTIONDiagnosis• Diagnosis of infection associated with implanted devices used to stabilize bone fractures,

suchaspinsandrods,requirescultureofthedevice,usuallyfollowingsurgicalremoval.Pain,

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inflammation, wound dehiscence, or loosening of the fixation device often indicatesinfection.

Microbiology• Microbiology is comparable with that of PJI. Staphylococci are the most important

pathogens.• Inopenfractureswithenvironmentalexposureandpreemptivetherapy,considerselection

ofβ-lactam–resistantgram-negativebacillisuchasEnterobacterspp.,nonfermenters.

Pathogenesis• Theexogenousrouteplaysamoreimportantrolethanthehematogenous.• Infectionmayalsooccurviaanadjacentfocus(contiguous).

FIGURE 50-1  Surgical treatment algorithm for prosthetic joint infections. *Difficult-to-treat microorganisms  include  microorganisms  resistant  to  antibiotics  with  good  oral  bioavailability, rifampin-resistant  staphylococci,  enterococci,  and  quinolone-resistant  gram-negative  bacilli  and fungi.  (Modified from Trampuz A, Zimmerli W. Prosthetic  joint  infections: update  in diagnosis and treatment. Swiss Med Wkly. 2005;135:243-251.)

Otherwise

Allyes

Condition Surgical Procedure

Duration of symptoms 3 weeks orinfection within 4 weeks after implantation+ stable implant+ absence of sinus tract+ susceptibility to antibiotics with

activity against surface-adheringmicroorganisms

Intact or only slightlydamaged soft tissue

Damaged soft tissue,abcess, or sinus tract

Microorganism resistant ordifficult to treat*

No functional improvementby exchange of the implant

Inoperable, debilitated, orbedridden

Two-stage exchange with shortinterval (2-4 weeks)

Two-stage exchange with longinterval (8 weeks)

Implant removal withoutreplacement

Long-term suppressiveantimicrobial treatment

One-stage exchange

Débridement with retention

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Clinical Manifestations• Acuteearlypostoperativeinfections:Woundhealingdisturbances,discharge,erythema• Acute symptoms after an uneventful postoperative period: Systemic infection signs are

dominating, pain is the most important local sign. Other local features are absent in thebeginningandbecomeapparentinthecourseofdisease.

• Acutesymptomsmayalsobeduetoreactivationofchronicpost-traumaticosteomyelitisthathasbeensilentformanyyears:Painwithoutprominentsystemicinflammatorysigns.

• Chronicsymptoms:Sinustract,pain,implantloosening.

Treatment• Bonefracturesarelesssusceptibletoinfectionifstabilized.• Inacuteinfections:Retainimplantwithdébridementandantimicrobialtherapy,untilfrac-

tureisconsolidated.• Indelayedinfections,implantmustberemovedafterhealingofbonefracture.

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L  Diseases of the Reproductive Organs and Sexually Transmitted Diseases

51 Genital Skin and Mucous Membrane LesionsMichael H. Augenbraun

DEFINITION• Infectiousgenitalskinandmucousmembranelesionscoverawidespectrumofpathologic

etiologiesandclinicalmanifestations,mostlypresentingasinflammatoryreactionsordefectsintheepitheliumofthegenitaltractinmenandwomen.

EPIDEMIOLOGY• Infectious genital skin and mucous membrane lesions are seen globally without

seasonality.• Theselesionsoccurprimarilyamongindividualswhoaresexuallyactive.• Incubationperiodsmayvaryaccordingtoetiology,thatis,humanpapillomaviruspotentially

weeks,months,oryearsafterexposure;primarysyphilisweekstomonths;herpessimplexoutbreaksyears.

• Diseasemaybemodifiedinpopulationsthatareimmunocompromised.• Someconditionsarecurrentlybeingseenmorefrequentlyinmenwhohavesexwithmen

(early-stagesyphilis,lymphogranulomavenereum[LGV]).

MICROBIOLOGY• Bacteria:Treponema pallidum (spirochete),Haemophilus ducreyi (gram-negativediplococ-

cus), Chlamydia trachomatis L serovars (obligate intracellular pathogen), Klebsiella granulomatis/donovanosis(gram-negativerod)

• Viruses:Herpessimplexvirus,molluscumcontagiosumvirus,humanpapillomavirus• Fungi:Candida albicans

DIAGNOSIS• Clinicalassessmentalonemaybemisleading.• Laboratoryexaminationusingmicroscopyandserologictestingisoftenhelpful.• GramstainingandlightmicroscopyhelptoidentifyH. ducreyiandCandida.• DarkfieldmicroscopyisusedtoidentifyTreponema pallidum.• SerologyhelpstodiagnoseT. pallidumandherpessimplexvirus.• Cellcultureisusedtodiagnoseherpessimplexvirus.• NucleicacidamplificationtestsareusedtoidentifyC. trachomatis.

THERAPY• Therapyisbestchosenbasedonthelikelyorspecificetiologicagent.• Syphilisistreatedwithpenicillinandtetracyclines.• Herpessimplexvirusinfectionistreatedwithacyclovir,valacyclovir,andfamciclovir.• C. trachomatiscausingLGVshouldbetreatedwithtetracyclines.

PREVENTION• Safesex• Partnercontacttracing• Preemptivetreatmentbasedoncontactandrisk

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52 UrethritisMichael H. Augenbraun and William M. McCormack

DEFINITION• Urethritisisaninflammatoryconditioninvolvingthemaleurethrausuallycausedbysexually

transmittedinfectiouspathogens.

EPIDEMIOLOGY• Urethritisoccursworldwide.

MICROBIOLOGY• CommonetiologicagentsincludeChlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas

vaginalis,andMycoplasma genitalium.

DIAGNOSIS• Lightmicroscopyofurethraldischargecanbehelpful.Thepresenceofpolymorphonuclear

leukocytes is highly suggestive of inflammation. Gram stain of this material that revealsintracellular gram-negative diplococci suggests Neisseria gonorrhoeae, which can also becultured using standard agar-based techniques. Nucleic acid amplification techniques arepreferredfordiagnosingtheotheretiologicagentsofthiscondition(seeTable52-1).

THERAPY• Treatment is directed toward the known or suspected pathogen. Infection with Neisseria

gonorrhoeae isgenerally treatedwith third-generationcephalosporins,butresistance isanemerging concern. Infection with Chlamydia trachomatis responds to azalides andtetracyclines.

PREVENTION• Condomuseorabstainingfromhigh-risksexualactivityreducestheriskforurethritis.

TABLE 52-1  Evaluation of Men Who Have Urethral Symptoms

DIAGNOSTIC STUDIES COMMENTSGram-stained urethral smear

Examination of first-void urine specimen for leukocytes

Endourethral cultures or nonculture tests Neisseria gonorrhoeae Culture and NAATs are equally appropriate. Culture

can provide option for susceptibility testing. Chlamydia trachomatis NAATs preferred Trichomonas vaginalis Culture or NAATs Mycoplasma genitalium No currently available commercial test

NAATs, nucleic acid amplification tests.

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53 Vulvovaginitis and CervicitisWilliam M. McCormack and Michael H. Augenbraun

DEFINITION• Vulvovaginitisandcervicitisincludeinfectiousandnoninfectiousconditionsinvolvingthe

vulva,vagina,andcervix.

EPIDEMIOLOGY• Trichomoniasisisasexuallytransmittedcondition.• Bacterialvaginosisandvulvovaginalcandidiasisarenotclassicsexuallytransmitteddiseases

butseldomoccurinsexuallyinexperiencedwomen.• Vulvitisanddesquamativeinflammatoryvaginitisarenotsexuallytransmitted.• Cervicitismaybesexuallytransmittedoridiopathic.

MICROBIOLOGY• TrichomoniasisiscausedbyTrichomonas vaginalis.• CandidiasisiscausedbyCandida albicansandotherfungalspecies.• Bacterialvaginosisisassociatedwithacomplexbacterialmicrobiota.• Infectiouscervicitis isusuallycausedbyNeisseria gonorrhoeae, Mycoplasma genitalium,or

Chlamydia trachomatis.

DIAGNOSIS• TrichomoniasisandcervicalinfectionsduetoN. gonorrhoeae, M. genitalium,andC. tracho-

matiscanbediagnosedbyidentifyingthecausativeorganismswithuseofcultureornon-culturemethodsofwhichnucleicacidamplificationtestingisthemostaccurate.

• Bacterialvaginosisisdiagnosedusingclinicalcriteria,includingvaginalpH,odorproducedwhen potassium hydroxide is added to vaginal fluid, and detection of “clue cells” whenvaginalfluidisexaminedmicroscopically.

• Vulvovaginalcandidiasis isdiagnosedclinicallyandby the identificationofC. albicansorotherfungalspeciesinculturesofvaginalfluid.

• Desquamativeinflammatoryvaginitisisdiagnosedbytheclinicalappearanceofthevaginaandtheidentificationofleukocytesandparabasalcellsinwetpreparationsofvaginalfluid.

THERAPY• Trichomoniasisistreatedwiththeoraladministrationofmetronidazoleortinidazole.• Bacterialvaginosisistreatedwitha7-daycourseoforalmetronidazoleorwithpreparations

forintravaginalusethatcontainmetronidazoleorclindamycin.• Vulvovaginalcandidiasisistreatedwithoralfluconazoleorwithpreparationsforvaginaluse

thatcontainnystatin,miconazole,orotherantifungalagents.• Desquamativeinflammatoryvaginitisisbesttreatedwithintravaginalclindamycin.• Intravaginaladministrationofboricacidorcorticosteroidsprovidessymptomaticrelief.

PREVENTION• Judiciouschoiceofsexualpartnersandregularuseofcondomsispreventative.

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54  Infections of the Female PelvisDavid E. Soper

DEFINITION• Anacuteinflammationoftheepitheliumand/orsofttissueofthepelvicorgans

MICROBIOLOGY• Microorganismsfoundintheendocervixandvagina• Bacterialvaginosismicroorganisms,predominantlyanaerobes• GroupBStreptococcusandEscherichia coli• Sexually transmitted microorganisms, such as Neisseria gonorrhoeae and Chlamydia

trachomatis

DIAGNOSIS• Clinicaldiagnosisbasedonfever,erythema,andtendernessinthepostoperativesetting• Clinicaldiagnosisbasedonriskassessmentforsexuallytransmitteddiseaseandanevalua-

tionforlowergenitaltractinflammationinthecaseofpelvicinflammatorydisease

THERAPY FOR POSTOPERATIVE INFECTIONS• Broad-spectrumantibiotictherapy• Includecoverageofpenicillinase-producinganaerobes• Useantibioticregimenseffectiveinananaerobicenvironment

THERAPY FOR PELVIC INFLAMMATORY DISEASE• BeawareoftheemergingresistanceofN. gonorrhoeaetoquinolones,azithromycin,and,to

somedegree,cephalosporins• Treatconcurrentlyforbacterialvaginosisifthediagnosisismadeconcurrently

PREVENTION• Preoperativeantibioticprophylaxis• Screeningforsexuallytransmittedmicroorganisms

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55 Prostatitis, Epididymitis, and OrchitisCatherine C. McGowan and John Krieger

DEFINITION AND CLASSIFICATION• FortheNationalInstitutesofHealthclassificationofprostatitissyndromes,seeTable55-1.• Acutebacterialprostatitisisassociatedwithlowerurinarytractinfectionandsepsis.• Chronic bacterial prostatitis is associated with recurrent lower urinary tract infections

causedbythesamebacterialclade.• Chronicprostatitis/chronicpelvicpainsyndrome(CP/CPPS)occursinabsenceofuropatho-

genicbacteria.• Acuteepididymitisandorchitisareusuallyduetoinfectiousagentsorlocaltrauma.

EPIDEMIOLOGY• Prostatitis represents the most common urologic diagnosis in healthy young men. Fifty

percentofmenmayexperiencesymptomsintheirlifetimes.Prevalenceis2%to16%.• Nearly90%ofmenevaluatedforgenitourinarysymptomshaveCP/CPPS.• Sexually transmitted epididymitis is most common in young men. Men with bacterial

epididymitis may have underlying urologic pathology or recent genitourinary tractmanipulation.

• Isolatedorchitisisrare.

MICROBIOLOGY• Gram-negativeEnterobacteriaceaecausemostepisodesofbacterialprostatitis.Enterococci

accountforasmallpercentage.• Etiologyofepididymitisandorchitisreflectspatientage.Chlamydia trachomatisandNeisseria

gonorrhoeaepredominateinyoungmen,andcoliformorPseudomonasspeciespredominateinoldermen.

• Mostorchitisiscausedbyviralinfections.

DIAGNOSIS• Carefulhistory,physicalexamination,urinalysis,andurinecultureareessential.• Thelowerurinarytractlocalizationtest(seeTable55-2)isthegoldstandard.• EpididymitisandorchitisshouldbeevaluatedwithaurethralswabforC. trachomatisand

N. gonorrhoeae.AurethralsmearforGramstainandmidstreamurinecultureisusefulforestablishingotheretiologies.

THERAPY• Fluoroquinolonesarepreferredoraltreatment.Quinoloneresistanceisincreasinglycommon,

especiallyaftergenitourinarytractinstrumentation.• Septicpatientsshouldreceiveempiricalbroad-spectrumparenteraltherapy.• Combinationsofantibiotics,α-blockers,anti-inflammatoryagents,andpainmanagement

therapiesrepresentthemosteffectivetreatmentforCP/CPPS.• Combination therapy with intramuscular ceftriaxone plus either azithromycin or doxycy-

clineisrecommendedforN. gonorrhoeaeinfections.

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TABLE 55-1  Classification of Prostatitis Syndromes on the Basis of Lower Urinary Tract Localization Studies

CO

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Acute bacterial prostatitis + + + + +Chronic bacterial prostatitis + + + − −Chronic prostatitis/chronic pelvic pain syndrome − Inflammatory subtypee − − + − − Noninflammatory subtypef − − − − −Asymptomatic inflammatory prostatitis − − + ± −

aDocumented with an identical organism that is shown to localize to a prostatic focus when the midstream urine culture is negative.

bIn expressed prostatic secretions, semen, postmassage urine, or prostate tissue.cAbnormal findings include exquisite tenderness and swelling that may be associated with signs of lower urinary

tract obstruction.dSystemic findings frequently include fever and rigors and may include signs of bacteremia.eFormerly termed nonbacterial prostatitis.fFormerly termed prostatodynia.From Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA.

1999;282:236-237.

TABLE 55-2  Lower Urinary Tract Localization Using Sequential Urine Cultures*

SPECIMEN SYMBOL DESCRIPTIONVoided bladder 1 VB1 Initial 5-10 mL of urinary stream

Voided bladder 2 VB2 Midstream specimen

Expressed prostatic secretions EPS Secretions expressed from prostate by digital massage

Voided bladder 3 VB3 First 5-10 mL of urinary stream immediately after prostatic massage

*Unequivocal diagnosis of bacterial prostatitis requires that the colony count in the VB3 specimen greatly exceed the count in the VB1 specimen, preferably by at least 10-fold. Many patients who have chronic bacterial prostatitis harbor only small numbers of bacteria in the prostate. In these patients, direct culture of prostatic secretions is particularly useful. Microscopic examination of the EPS is useful for identifying white blood cells and oval fat bodies—large lipid-laden macrophages characteristic of the prostatic inflammatory response.

From Stamey T. Pathogenesis and Treatment of Urinary Tract Infections. Baltimore: Williams & Wilkins; 1980.

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M  Eye Infections

56 Microbial ConjunctivitisScott D. Barnes, Nalin M. Kumar, Deborah Pavan-Langston, and Dimitri T. Azar

DEFINITION• Microbialconjunctivitisinvolvesinflammationofthethinliningoftheinnereyelidandfront

oftheeyeball,causedbybacteria,viruses,fungi,orparasites.

EPIDEMIOLOGY• Conjunctivitisaffectsmalesandfemalesofallages.• Bacterialconjunctivitisismoreprevalentinchildren;viralconjunctivitisismoreprevalent

inadults.• Risk factors include contact lens wear, contaminated ocular medications, exposure to an

infectedperson,vaginalversuscesareandelivery,andvisitstocampsandswimmingpools.

MICROBIOLOGY• Common causes of bacterial conjunctivitis include Staphylococcus aureus, Streptococcus

pneumoniae, Haemophilus species, Moraxella, Corynebacterium diphtheriae, Neisseriaspecies,andentericgram-negativerods.

• Themostcommoncauseofviralconjunctivitisisinfectionwithadenovirus,butotherviralcausesincludeherpessimplexvirus(HSV),picornavirus,andherpeszostervirus.

• Neonatal conjunctivitis is commonly due to transmission from the mother during child-birth of sexually transmitted bacteria, including Chlamydia trachomatis and Neisseria gonorrhoeae.

DIAGNOSIS• Symptoms of conjunctivitis include itching, increased ocular secretions, swelling of the

conjunctivaand/oreyelids,pinkcolorinthewhiteoftheeyes,andlightsensitivity.• Clinicalpresentationofacutebacterialconjunctivitis involvesrapidonsetofunilateral lid

edema,conjunctivalinjection,amucopurulentdischarge,andinvolvementofthesecondeyewithin1to2days.Itchingisuncommon.Unlikeviralandchlamydialconjunctivitis,thereisnopreauricularlymphadenopathy.

• Clinicalpresentationofviralconjunctivitis isacute,unilateralconjunctivitiswith involve-ment of the second eye occurring often within 1 week. It is associated with a watery tomucousdischargeandenlargementofpreauricularlymphnodes.

• Routine laboratory evaluation is not usually required except in the first month of lifewhere cultures and smears for bacterial, chlamydial, and herpetic causes need to beperformed.

• Ifbacterial conjunctivitis is suspected, conjunctival scraping for identificationofbacterialspecies by further analysis is recommended for guidance of appropriate antibiotictherapy.

• Viral conjunctivitis can often be diagnosed from signs (e.g., common cold); symptoms(e.g., watery, rather than mucus, discharge); and patient history (e.g., work environmentsuch as if person is a veterinarian or poultry worker). Laboratory tests are not usuallynecessary.

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THERAPY• Acutebacterialconjunctivitisistreatedwithabroad-spectrumtopicalagentsuchassulfa-

cetamide, trimethoprim-polymyxin, or a fluoroquinolone (ciprofloxacin, levofloxacin, ormoxifloxacin) as eyedrops, usually every 3 hours when awake for 7 to 10 days. Topicalazithromycinhasbeenshowntobeeffectiveintreatingbacterialconjunctivitiswitha3-daycourse.

• Viral conjunctivitis spontaneously resolves within days to weeks, usually without adversesequelae to the conjunctiva, but associated keratitis may have long-term sequelae. HSVconjunctivitisinnewbornsshouldbetreatedwithintravenousacyclovir.

• Adult inclusion conjunctivitis involves systemic treatment for 3 weeks with tetracycline,doxycycline,orerythromycin,withthecautiontoavoidtetracyclineinchildrenyoungerthanage8andinpregnantorlactatingwomen.Theuseoforalazithromycinhasalsobeenfoundtobeeffective.

• Forhyperacutebacterialconjunctivitis,theprevalenceofpenicillin-resistantorganismshasmadeceftriaxonethetreatmentofchoice.

• Whentreatingneonatalchlamydialconjunctivitis,iferythromycinortetracyclineointmentisappliedtotheconjunctivalsurfacewithin1hourafterdelivery,thechanceofdevelopingchlamydialconjunctivitisisreportedlyalmostzero.Twoweeksoforalerythromycintherapyisgiventothenewbornwithlaboratory-provenchlamydialconjunctivitis;asecondcoursemaybegivenifadequateresolutionisnotachievedwiththeinitialtreatment.

• Limit spread of conjunctivitis by following good hygiene steps, including washing handsoften,washinganydischargefromaroundtheeyesmultipletimesduringtheday,andusingfreshwashcloths,cottonballs,ortissueseachtime.

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57 Microbial KeratitisScott D. Barnes, Joelle Hallak, Deborah Pavan-Langston, and Dimitri T. Azar

DEFINITION• Microbialkeratitisisavision-threateningcornealinflammatorycondition,causedbybacte-

ria,viruses,fungi,orparasites.

EPIDEMIOLOGY• Diseaseburdenishigherindevelopingthandevelopedcountries.• Riskfactorsincludecontactlenswear,trauma(surgicalandnonsurgical),contaminatedocular

medications,alteredstructureofthecornealsurface,andcontributingsystemicdiseases.• ContactlensuseisthemaincauseforkeratitisintheUnitedStates:poorlensstorageand

hygieneandovernightlensuse.• Nonsurgicaloculartraumaisthemaincauseofkeratitisindevelopingcountries.• Trachomaisencounteredmorecommonlyindevelopingcountries.

MICROBIOLOGY• Pathogenscanbegram-negativeorganisms,suchasPseudomonas aeruginosa.• Pathogenscanbegram-positiveorganisms,suchasStaphylococcusandStreptococcusspp.• Viralpathogensincludeherpessimplexvirus,varicella-zostervirus,adenovirus.• RecentoutbreaksofmicrobialkeratitisincontactlenswearershaveinvolvedAcanthamoeba

andFusariumspp.

DIAGNOSIS• Symptoms include severepainanddiscomfort, tearing,photophobia,blepharospasm,and

decreasedvision.• Clinicalpresentationincludesconjunctivalinjectionanddischarge,decreasedcornealtrans-

parency, corneal infiltrate, epithelial defect and/or stromal inflammation, corneal edema,cornealneovascularization,stromalmelting,lossofvision.

• Knowingthenatureofthestromalinflammation(suppurativeornonsuppurative),anditslocation(focal,multifocal,ordiffuse)ishelpful.

THERAPY• Cornealscrapingsandculturesshouldbeperformedonallsuspectedcaseswithinfectious

keratitis.• Aggressiveantimicrobialtherapyshouldbeinitiatedafterscrapingsandculturesofinfectious

keratitis.• Fortified topical administration is the most common route of antimicrobial therapy.

Subconjunctival injections, parenteral and oral routes, and antibiotic-soaked collagenshields/softlensesareusedinfrequently.

• Fortifiedcefazolinandaminoglycosideshouldbeusedformoreseverebacterialkeratitis.• Monotherapywithafourth-generationfluoroquinoloneisusedforbacterialkeratitis.• Antifungaltherapeuticagentsincludetopicalnatamycin,amphotericinB,flucytosine,fluco-

nazole,anditraconazole.Oralitraconazoleorvoriconazolehavealsoshownfavorableout-comeswhenaddedtotopicaltherapy.

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58  EndophthalmitisMarlene L. Durand

DEFINITION• Endophthalmitisisabacterialorfungalinfectioninsidetheeye,involvingthevitreousand/

oraqueous.Itiseitherexogenous,inwhichinfectionisintroducedfromtheoutsidein,orendogenous,inwhichtheeyeisseededfromthebloodstream.

CLINICAL MANIFESTATIONS• Decreasedvisionandeyepainareusuallypresent.Hypopyon(layerofwhitebloodcellsin

aqueoushumor)iscommonlyseen.Nofeverorleukocytosisispresentinexogenouscasesandmayalsobeabsentinendogenouscasesonpresentation.

CATEGORIES AND MICROBIOLOGY (SEE TABLE 58-1)• Acute postcataract endophthalmitis.Incidenceis0.1%to0.2%ofcataractsurgeries,withonset

within 1 week postoperatively in 75%. Etiology is contamination of aqueous from ocularsurfaceflora.Gram-positivecoccicause95%ofcases,withcoagulase-negativestaphylococcithemajorpathogens(70%ofallcases).

• Chronic postcataract endophthalmitis.Rare,thiscategorypresentsaslow-gradeinflammationinaqueouspostoperativelythatpersistsformonths.Itmayrespondtotopicalcorticosteroidsinitiallybut recursas thedrugdosage is tapered.Thecause isPropionibacterium acnes inmostcases.

• Postinjection endophthalmitis. Incidence is 0.1% after each intravitreal injection of anti–vascularendothelialgrowthfactoragents(treatmentofwetmaculardegeneration).Injectionsaretypicallygivenoncemonthly.Majorpathogensarecoagulase-negativestaphylococciandstreptococci(25%ofcases),thelatterusuallycausingsevereendophthalmitis.

• Bleb-related endophthalmitis.Afilteringblebisa“bleb”ofconjunctivaoverlyingasurgicallycreated defect in the sclera. Endophthalmitis typically occurs suddenly, months to yearspostoperatively; incidence is 1.3% per patient-year. Infection is often fulminant becausestreptococci, including Streptococcus pneumoniae, and Haemophilus influenzae are majorpathogens.

• Post-traumatic endophthalmitis.Incidenceis3%to10%afterpenetratingeyetrauma(“openglobe”)butmaybemuchlowerafterprotocolthatincludes48hoursofprophylacticantibiot-ics.Coagulase-negativestaphylococciandBacillus cereusaremajorpathogens;B. cereus ismostfearedandcausesfulminantinfection.

• Endogenous bacterial endophthalmitis.Sourcesincludeendocarditis(Staphylococcus aureusandstreptococciaremajorpathogens),intraabdominalabscess(liverabscessduetoKlebsiella pneumoniaeinEastAsiannations),transientbacteremia(e.g.,endoscopy,intravenousdrugabuse).

• Candidaendophthalmitis.Thiscategoryisusuallyendogenous,andchorioretinitis,theearli-estmanifestation,isoftenasymptomatic.Chorioretinitisusuallyrespondstosystemicanti-fungaltreatmentalone,butcaseswithendophthalmitis(markedvitreousinflammation)alsorequireintravitrealantifungalinjectionandoftenvitrectomy.

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• Mold endophthalmitis.Usuallyexogenous,thisinfectionoccursaftereyesurgery,eyetrauma,orasanextensionofkeratomycosis(fungalcornealinfection).AspergillusandFusariumarethemostcommonpathogens.

DIAGNOSIS• Exogenous cases, and some endogenous cases, require vitreous aspirate or vitrectomy for

culture(aqueousmayalsobecultured).Endogenouscaseswithpositivebloodculturesareusuallypresumedtobeduetothesameorganism.

THERAPY• Intravitreal antibiotics and often vitrectomy (surgical débridement of the vitreous) are

requiredinallcases.Systemicantibioticsalonearenotusedtotreatendophthalmitis,exceptincasesofCandidachorioretinitis.

TABLE 58-1  Endophthalmitis Categories and the Most Common Pathogens in Each

CATEGORY PATHOGENAcute postcataract Coagulase-negative staphylococci

Chronic postcataract Propionibacterium acnes

Postinjection Viridans streptococci, coagulase-negative staphylococci

Bleb-related Streptococci, Haemophilus influenzae

Post-traumatic Bacillus cereus

Endogenous Staphylococcus aureus, streptococci, gram-negative bacilli

Fungal Candida, Aspergillus, Fusarium

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59  Infectious Causes of UveitisMarlene L. Durand

DEFINITION AND CATEGORIES• Uveitismeansinflammationoftheuvea(iris,ciliarybody,choroid)orretina.• Dividedintocategoriesbysiteofgreatestinflammation:

• Anterior(iritis,iridocyclitis)• Intermediate(parsplanitis)• Posterior(choroiditis,retinitis,chorioretinitis)• Panuveitis

• Noninfectiouscausesofuveitis(idiopathic,autoimmune)aremorecommonthaninfectiouscauses,butthefrequencyofeachvariesdependingoncategory.

• Approximately10%ofanterioruveitiscaseshaveaninfectiousetiology.• Approximately50%ofposterioruveitiscaseshaveaninfectiousetiology.

EPIDEMIOLOGY AND ETIOLOGY• Themost likely infectiousetiologiesvarybyuveitiscategoryandby location in theworld

(seeTable59-1).• Infectiouscausesofanteriorincludeherpessimplexvirus(HSV)(90%ofinfectiousetiolo-

gies),varicella-zostervirus(VZV),syphilis,tuberculosis(TB),andLymedisease.• InfectiouscausesofintermediateuveitisarerareandincludeLymedisease.• Infectious causes of posterior uveitis include ocular toxoplasmosis, acute retinal necrosis

(HSV, VZV, sometimes cytomegalovirus [CMV]), CMV retinitis (severely immuno-compromised patients), ocular Toxocara, syphilis, cat-scratch disease, and Candidaendophthalmitis.

• Infectiouscausesofpanuveitisincludesyphilis,TB,andCandidaendophthalmitis.• Otherinfectiousetiologiesofuveitisseenprimarilyintropicalregionsordevelopingcoun-

triesincludeleptospirosis(panuveitiswithoutretinalorchoroidallesions),leprosy(anterioruveitis),Brucella(chronicrelapsinguveitis),andChikungunyavirus(anterioruveitis,reti-nitis,oropticneuritis).

DIAGNOSIS• Varies by etiology. Ocular syphilis is presumed in cases of uveitis with positive specific

treponemalserology.PolymerasechainreactionofaqueousorvitreousforHSV,VZV,andCMVmaybehelpful in somechronicanterioruveitis cases (aqueous)and in somecasesofacuteretinalnecrosis(vitreoushigheryieldthanaqueous,butvitreoussamplingcarriesmorerisk).

THERAPY• Variesbyetiology.Acuteretinalnecrosisisamedicalemergencyandrequiresantiviraltreat-

ment directed against HSV and VZV and against CMV as well in immunocompromisedpatients.OculartoxoplasmosisisdiscussedinChapter280ofMandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition. Ocular TB and ocular syphilisshouldbetreatedthesamewayasTBmeningitisandneurosyphilis,respectively.

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TABLE 59-1  Classification of Uveitis and Major Infectious Etiologies in Each Category

CATEGORY OCULAR FINDINGS MAJOR INFECTIOUS ETIOLOGIES (%)*Anterior (iritis, cyclitis, iridocyclitis)

WBCs in aqueous, keratic precipitates, iris nodules, synechiae

Herpes simplex (10%); syphilis (<1%); TB (<1%); Lyme disease (<1%); leprosy (<1%)

Intermediate WBCs or snowballs in the vitreous, pars plana snow bank

Lyme disease (<1%)

Posterior (choroiditis, chorioretinitis, retinitis)

Lesions in choroid, retina, or both; vitritis in some

Toxoplasma (25%); CMV (12%)†; ARN (6%); Toxocara (3%); syphilis (2%); Candida (<1%)

Panuveitis WBCs in aqueous and vitreous Syphilis (6%); TB (2%); Candida (2%)

ARN, acute retinal necrosis; CMV, cytomegalovirus; TB, tuberculosis; WBCs, white blood cells.*Percentage of uveitis cases in each category (not of total uveitis cases), based on 1237 cases of uveitis seen at

Massachusetts Eye & Ear Infirmary, Boston, 1982-1992, by Foster’s group (Rodriguez A, Calonge M, Pedoza-Seres M, et al. Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol. 1996;114:593-599).

†Series was before use of highly active antiretroviral therapy, and rate for CMV retinitis would be lower now.

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60  Periocular InfectionsMarlene L. Durand

DEFINITION• Periocularinfectionsincludeinfectionsoftheeyelids,lacrimalsystem,andorbit.• Eyelidinfectionsincludepreseptalcellulitis,infectionsofthemeibomianglandsofthelids

(hordeolum, stye), sterile inflammatory granulomatous nodule in the lid (chalazion), andmarginalblepharitis(inflammationatthelidmargins).

• Lacrimal system infections includedacryoadenitis (infectionof the lacrimalgland),cana­liculitis(infectionofthecanaliculithatcollecttearsinthemedialcanthusanddrainintothelacrimalsac),anddacryocystitis(infectionofthelacrimalsac).

• Orbital infections includeorbital cellulitis, subperiosteal abscess,orbital abscess, andcav­ernous sinus thrombophlebitis. Acute sinusitis is the most common cause of orbitalinfections.

MICROBIOLOGY• Lidinfections: Staphylococcus aureus,streptococci• Canaliculitis:Actinomyces israelii,alsostaphylococci,streptococci• Dacryocystitis:S. aureus,streptococci;alsogram­negativebacilli• Orbitalinfections: S. aureusincludingmethicillin­resistantS. aureus, Streptococcus anginosus

(milleri), other streptococci (including Streptococcus pneumoniae), gram­negative bacilli,anaerobes.Mixedinfectionscommon.

DIAGNOSIS• Clinicalexaminationinlidinfections,lacrimalsysteminfections,supportedbyculture.• Preseptalcellulitismustbedistinguishedfromorbitalinfections(orbitalcellulitis,subperi­

osteal and orbital abscess). Orbital infections usually have one or more of the followingfindings: proptosis (which may not be grossly apparent but can be measured as 2mm ormoredifferenceinHertel’sexophthalmometermeasurements),ophthalmoplegia,andvisionloss.Preseptalcellulitishasnoneofthesefeatures—onlylidedemaanderythema.Computedtomography(CT)scanshouldbeperformedonanypatientwithorbitalfindings.CTshouldbe considered in children who present with what appears to be severe preseptal cellulitisbecausetheymayhavesubperiostealabscess.

THERAPY• Variesbydiagnosis• Orbitalinfectionsaremuchmoreseriousthanpreseptalcellulitis,andallorbitalinfections

mustbetreatedwithintravenousantibiotics.Subperiostealabscessesusuallyrequiresurgicaldrainage,andorbitalabscessesalmostalwaysdo.Drainageofanadjacentinfectedsinusmaybeindicated.

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N  Hepatitis

61 Viral HepatitisJules L. Dienstag and Andrew S. Delemos

ACUTE HEPATITIS• Acuteclinicalillnessescausedbythefivehepatitisviruses(HAV,HBV,HCV,HDV,andHEV)

aresimilar.• Illnessrangesfromasymptomatictofulminant.• Asymptomaticinfectionsare10to30timesmorecommonthansymptomaticones.

CHRONIC HEPATITIS• Chronichepatitisaffectsmorethan500millionpeopleworldwide.• HBV,HCV,andHDVcausechronichepatitis.• HEVcausesprotractedandchronichepatitisonlyinimmunosuppressedpatients.

INDIVIDUAL HEPATITIS VIRUSES (SEE TABLE 61-1)Hepatitis A Virus (HAV)• HAVisanRNAvirusthatisamemberoftheHepatovirusgenus.• HAVistransmittedviathefecal-oralroute.• It typically causesanacute, self-limited illness,moreoften symptomatic inadults than in

children.• HAVismoresevereinpatientswithpreexistingchronichepatitisBorC.• Relapsingandcholestatichepatitismayoccur.• Diagnosisisbyserology(IgManti-HAV)(seeTable61-2).• Treatmentisusuallynotnecessarybeyondsupportivecare.• Prevention—highly effective HAV vaccines that have markedly reduced incidence where

usedareavailable.• Passive immunization with immune globulin intramuscularly is effective in postexposure

prophylaxis.

Hepatitis B Virus (HBV)Virology/Epidemiology• HBVisadouble-strandedDNAvirusintheOrthohepadnavirusgenusandtheHepadnavirus

family;10genotypeshavebeenidentified.• Worldwide,350millionpeopleareinfectedchronicallywithHBV.• Onemilliondeathsannuallyresultfromcomplicationsofchronicinfection—cirrhosis,hepa-

tocellularcarcinoma(HCC).• PrevalenceinAsiaisestimatedatgreaterthan10%,resultingprimarilyfromperinataltrans-

mission,afterwhichthelikelihoodofacquiringchronicinfectionis90%.• Inadults,transmissionofhepatitisBoccursprimarilyfollowinghigh-riskbehaviors(injec-

tion drug use, sexual activity) or after occupational exposure but resolves in greater than95%ofotherwisehealthypersons.

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TABLE 61-1  Hepatitis Viruses and Characteristics of Infection

CHARACTERISTIC A B C D EVirus family Picornaviridae Hepadnaviridae Flaviviridae Unassigned Hepeviridae

Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Hepevirus

Nucleic acid RNA DNA RNA RNA RNA

Incubation period (days) 15-48 (mean 30)

30-180 (mean 60-90)

15-160 (mean 50)

30-180 (mean 60-90)

14-60 (mean 40)

Mode of transmission: Fecal-oral Yes No No No Yes Sexual Possible Yes Rare Yes No Blood Rare Yes Yes Yes No*

Chronic infection No Yes Yes Yes Yes†

Cirrhosis and hepatocellular carcinoma

No Yes Yes With hepatitis B No‡

*Can be bloodborne in endemic areas.†Acute hepatitis in normal hosts, protracted and chronic infection only in immunosuppressed patients.‡Cirrhosis can occur after chronic infection, which is confined to immunosuppressed patients.

TABLE 61-2  Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis

DIAGNOSTIC INTERPRETATION

SEROLOGIC TESTS OF PATIENT’S SERUM

HBsAg IgM Anti-HAV IgM Anti-HBc Anti-HCVAcute hepatitis B + − + −Chronic hepatitis B + − − −Acute hepatitis A superimposed on chronic hepatitis B

+ + − −

Acute hepatitis A and B + + + −Acute hepatitis A − + − −Acute hepatitis A and B (HBsAg below detection threshold)

− + + −

Acute hepatitis B (HBsAg below detection threshold)

− − + −

Acute hepatitis C − − − +

HAV, hepatitis A virus; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.Modified from Longo D, Fauci A, Kasper D, et al. Harrison’s Principles of Internal Medicine. 18th ed. New York:

McGraw Hill; 2011.

Diagnosis• AcutehepatitisBisasymptomaticinfectiontypifiedbyrightupperquadrantpain,nausea,

malaise,jaundice,elevatedalanineaminotransferase(ALT)andaspartateaminotransferase(AST),andIgMantibodytohepatitisBcoreantigen.

• DifferentcategoriesofchronicinfectionarediagnosedonthebasisofserologictestingandHBVDNAlevel(seeTable61-3).

• Liver biopsy is not required for diagnosis but may inform treatment decisions in chronicinfection.

Treatment• Indications(seeTable61-4):

• Hepatitis B e antigen (HBeAg)-positive or HBeAg-negative patients with ALT>2×upperlimitofnormalormoderatetoseverehepatitisonliverbiopsyandHBVDNA>20,000IU/mL

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TABLE 61-3  Viral and Laboratory Markers of Hepatitis B Virus Infection

DIA

GN

OSI

S

HB

sAg

An

ti-H

Bs

IgM

 An

ti-H

Bc

IgG

 An

ti-H

Bc

HB

eAg

An

ti-H

Be

ALT

Acute hepatitis + − + − + − Elevated

Recovered (immune) − + − + − + Normal

HBeAg-positive chronic hepatitis B + − − + + − Elevated

HBeAg-negative chronic hepatitis B + − − + − + Elevated (may be intermittent)

Vaccinated (immune) − + − − − − Normal

Inactive carrier + − − + − + Normal

ALT, alanine aminotransferase; HBc, hepatitis B core (antigen); HBe, HBeAg, hepatitis B e antigen; HBs, HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.

TABLE 61-4  Recommendations/Guidelines of the American Association for the Study of Liver Diseases for the Treatment  of Chronic Hepatitis B

HBeAg HBV DNA (IU/mL) ALT TREATMENT FIRST-LINE AGENTS

Chronic Hepatitis B without Cirrhosis+ >2 × 104 >2 × ULN Recommended PEG IFN, ETV, TDF

+ >2 × 104 ≤2 × ULN Not recommended

− >2 × 104 >2 × ULN Recommended PEG IFN, ETV, TDF

− >2 × 103 1 to >2 × ULN Histology determines*

− ≤2 × 103 Normal Not recommended†

Cirrhosis± Detectable (PCR‡) Normal or ↑ Recommended Compensated: treat with ETV

or TDF for HBV DNA >2 × 103; for HBV DNA <2 × 103, treat if ALT ↑Decompensated§: treat with ETV or combination nucleoside/nucleotide

± Undetectable (PCR‡) Normal or ↑ Not recommended §

ALT, alanine aminotransferase; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IU, international units; PCR, polymerase chain reaction; PEG IFN, pegylated interferon; TDF, tenofovir; ULN, upper limit of normal.

Table is updated to reflect supplanting of the less effective drugs by the best available antiviral drugs.*If liver biopsy reveals advanced necroinflammatory activity or fibrosis, consider treatment.†Inactive carrier.‡>102 to 103 IU/mL.§If decompensated, coordinate care with a liver transplantation center.

• HBeAg-negativepatientswithlow-levelHBVDNAbutevidenceoffibrosisormoderatetoseverehepatitisonliverbiopsy

• CirrhosisassociatedwithchronicHBVirrespectiveofHBVDNAlevel• Inactivecarrier(hepatitisBsurfaceantigen[HBsAg]positive)preemptivelywhenstarting

chemotherapy or other immunosuppressive therapy (including anti–tumor necrosisfactor)

• Therapy(seeTable61-5):• Tenofovir300mgdailyorentecavir0.5mgdaily(1mgdoseapprovedforpriorlamivu-

dineresistancebutnotaviablealternativetoaddingtenofovir)

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TAB

LE 6

1-5

 A

pp

roved

 An

tivir

al 

Dru

gs 

for 

Ch

ron

ic H

ep

ati

tis 

B

IFN

PEG

 IFN

LAM

AD

VET

VTB

VTD

FD

ose

5 M

U/d

ay*

180 µg

/wk

100

mg/

day

10 m

g/da

y0.

5 m

g/da

y60

0 m

g/da

y30

0 m

g/da

y

Rout

eSu

bcut

aneo

usSu

bcut

aneo

usO

ral

Ora

lO

ral

Ora

lO

ral

Dur

atio

n in

tria

ls4

mo

48 w

k48

-52

wk

48 w

k48

wk

52 w

k48

wk

Tole

rabi

lity

Poor

Poor

Exce

llent

Exce

llent

†Ex

celle

ntEx

celle

ntEx

celle

nt†

HBe

Ag

sero

conv

ersi

on18

%-2

0%27

%‡

16%

-21%

12%

21%

22%

21%

Log 1

0 H

BV D

NA

red

uctio

n

HBe

Ag-

posi

tive

?§4.

55.

53.

56.

96.

56.

2

HBe

Ag-

nega

tive

?§4.

14.

73.

95.

05.

24.

6

HBV

DN

A P

CR-

nega

tive

H

BeA

g-po

sitiv

e?

25%

44%

21%

67%

60%

76%

H

BeA

g-ne

gativ

e?

63%

73%

64%

90%

88%

93%

ALT

nor

mal

izat

ion

H

BeA

g-po

sitiv

e?‖

39%

75%

61%

68%

77%

68%

H

BeA

g-ne

gativ

e?‖

38%

79%

77%

78%

74%

76%

HBs

Ag

loss

dur

ing

trea

tmen

tup

to

8%3%

-4%

≤1%

0%2%

<1%

3%

Vira

l res

ista

nce

Non

eN

one

15%

-30%

Non

eN

one

2%-5

%0%

> 1 y

rN

one

Non

e5

yr:

70%

5 yr

: 29

%≤1

%2

yr:

9%-2

2%0%

Cos

t (U

.S.

$)56

00*

18,5

0025

0066

0087

0060

0060

00

AD

V, a

defo

vir;

ALT

, al

anin

e am

inot

rans

fera

se;

ETV,

ent

ecav

ir; H

BeA

g, h

epat

itis

B e

antig

en;

HBs

Ag,

hep

atiti

s B

viru

s su

rfac

e an

tigen

; H

BV,

hepa

titis

B v

irus;

IFN

, in

terf

eron

; LA

M,

lam

i-vu

dine

; PC

R, p

olym

eras

e ch

ain

reac

tion;

PEG

IFN

, pe

gyla

ted

IFN

; M

U,

mill

ion

units

; TB

V, t

elbi

vudi

ne;

TDF,

ten

ofov

ir.D

ata

show

n ar

e m

axim

um r

epor

ted

valu

es f

or u

p to

1 y

r (4

8-52

wk)

of

trea

tmen

t in

reg

istr

atio

n tr

ials

. Th

ese

com

paris

ons

are

head

to

head

onl

y fo

r PE

G I

FN v

s. L

AM

, ET

V v

s. L

AM

, TB

V v

s. L

MV,

and

TD

F vs

. A

DV.

*5 M

U d

aily

to

10 M

U t

hree

tim

es a

wk

for

16 t

o 24

wk;

the

cos

t is

tha

t of

a c

ompl

ete

cour

se,

not

of a

yr

of t

hera

py.

† Cre

atin

ine

mon

itorin

g re

com

men

ded.

‡ At

32%

24

wk

afte

r th

erap

y.§ W

hen

thes

e st

udie

s w

ere

cond

ucte

d, H

BV D

NA

was

mea

sure

d w

ith in

sens

itive

hyb

ridiz

atio

n as

says

.‖ A

LT is

gen

eral

ly n

orm

al in

tho

se w

ith a

dequ

ate

sero

logi

c/vi

rolo

gic

resp

onse

; rep

orts

rar

ely

incl

ude

ALT

leve

ls a

t th

e en

d of

tre

atm

ent.

In H

BeA

g-re

activ

e pa

tient

s, a

met

a-an

alys

is s

how

ed

a 23

% a

dvan

tage

in A

LT n

orm

aliz

atio

n (a

fter

the

rapy

) in

tre

ated

vs.

unt

reat

ed p

atie

nts.

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• 48weeksofpegylatedinterferon(PEGIFN)innoncirrhoticHBeAg-positivepatientsalsoanoption

• ConsiderstoppingoraltherapyinHBeAg-positivepatients6to12monthsafterHBeAgseroconversion (HBeAg-negative and anti-HBe-positive);≥40% chance of seroconver-sionafter5yearsoftherapy

• IndefinitetreatmentforchronicHBeAg-negativehepatitisB;considerstoppingtherapyforHBsAgseroconversion

Prevention• Universalvaccinationofinfantsbeginningatbirth(≥3intramusculardoses)• Prenatal maternal HBsAg screening and if HBsAg positive, hepatitis B immune globulin

0.5mLatbirthalongwithvaccination• Tenofovir 300mg starting in the third trimester in women with HBV DNA

>108IU/mL (some authorities recommend antiviral therapy for mothers with HBVDNA>106IU/mL)

Hepatitis D Virus (HDV)• HDVisapercutaneouslytransmitted,circularRNAvirus(genus:Deltavirus)thatrequires

HBV(orotherhepadnaviruses)toreplicateandpersist.• AcutecoinfectioncanoccurandfollowstheclinicalcourseofacuteHBVinfection.• HDVsuperinfectionresults inchronic infectioninpatientswithpriorchronichepatitisB

and has clinical features similar to chronic hepatitis B infection, although with increasedseverityandriskofprogressiontocirrhosis.

• Thediagnosis ismadebyserologictestingforantibodiestoHDVorbypolymerasechainreaction(PCR)forHDVRNA.

• OralantiviralsforhepatitisBarenotactiveagainstHDV,butprolongedtreatmentwithPEGIFNmaybenefitaproportionofpatients.

Hepatitis C Virus (HCV)Virology/Epidemiology• HCVisasingle-strandedRNAvirus(genus:Hepacivirus)withsixmaingenotypes(1to6);

itexistsasquasi-speciesbecauseofitshighmutationrate.• HCVrequireshostlipidmembraneassembly/secretionapparatusforreplication.• Worldwide,185millionpatientshavechronicHCV,withmorethan4millionresidinginthe

UnitedStates.• Transmission occurs predominantly through injection drug use, but other modes include

bloodtransfusionbeforetheavailabilityofscreeningornonsterilepracticesinwhichblood/body fluids are exchanged [note—the risk of hepatitis C is not increased in people withtattoosorinhealthworkers].

• ChronicHCVinfectiondevelopsinatleast85%ofpatientswithacuteinfectionand,intheabsenceoftreatment,resultsincirrhosisinapproximately20%ofpatientsafter20yearsofinfection.

• TheannualincidenceofHCCinpersonswithHCV-associatedcirrhosisis1%to4%.• HCVistheleadingindicationforlivertransplantationintheUnitedStates.

Diagnosis• Symptomatichepatitisandjaundicedevelopinfewerthan10%to20%ofpatientswithacute

hepatitisC,whichoftenportendsviralclearance.• Chronic hepatitis C tends to be asymptomatic, although patients often complain of

fatigue.• Patients with HCV-associated cirrhosis may present clinically with complications of end-

stageliverdiseasesuchasvaricealbleeding,hepaticencephalopathy,orascites.• Thedetectionofantibody toHCV is the initialdiagnostic test,butPCR testing forHCV

RNAdistinguishesongoingchronicinfection(commonly)frompriorexposurewithsubse-quentclearance(rare).

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Treatment• ThegoaloftherapyinchronichepatitisCistoachieveasustainedvirologicresponse(SVR),

whichisdefinedasundetectableHCVRNA24weeksfollowingcompletionoftherapy(12weekshasbeenadoptedastheSVRendpointinrecentclinicaltrials).

• Standard of care 2011-2013:forgenotypes2and3,24weeksofPEGIFN-α2aor-α2bandribavirin (RBV) 800mg daily; for genotype 1, PEG IFN, weight-based RBV, and eitherboceprevir (BOC) or telaprevir (TVR) (see Fig. 61-1). In prior treatment-naïve patients,treatmentregimensareeither24weeks(TVR),28weeks(BOC,after4weeksofPEGIFN/RBVlead-in),orupto48weeks(withtriple-drugtherapyfor12weeksandPEGIFN/RBVthereafterforTVRorBOC-basedtriple-drugtherapyforuptoweek36andPEGIFN/RBVthereafter)andarebasedonHCVRNAresponsemilestones(i.e.,response-guidedtherapy;see Figs. 61-1 and 61-2), except in cirrhotics, in whom treatment for a full 48 weeks isrecommended. In treatment-experienced patients, relapsers are treated the same way astreatment-naïve patients, while prior nonresponders are treated for up to 48 weeks (withtriple-drug therapy for 12 weeks and PEG IFN/RBV thereafter for TVR or triple-drugtherapyupto44weeksfollowing4weeksofPEGIFN/RBVlead-inforBOC).

• Standard of care 2014• Treatment-naïvepatients:

• Genotype1:sofosbuvir(SOF)400mgdailywithPEGIFN/RBV(weight-based,1000to1200mgdaily)for12weeksorsimeprevir(SMV)150mgwithPEGIFN/RBVfor12 weeks followed by another 12 weeks of PEG IFN/RBV; an alternative for IFN-ineligiblepatientsiscombinationSOF,SMV,andRBVfor12weeks.

• Genotype2:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for12weeks.

• Genotype3:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for24weeks(analternativeisSOFwithPEGIFN/RBVfor12weeks).

• Genotypes 4 to 6: similar to genotype 1 with minor modifications (seewww.hcvguidelines.org).

FIGURE 61-1 Recommended approach to treating patients with chronic hepatitis C virus (HCV),  genotype  1,  with  telaprevir  (TVR)-based  therapy. eRVR, extended rapid virologic response; IU, international units; PEG IFN, pegylated interferon; RBV, ribavirin; RNA, ribonucleic acid. As of January 2015, telaprevir is no longer recommended for treatment of hepatitis C (see Table 61-6).

750 mg (two 375-mg tablets) q8h with food (not low fat)eRVR = HCV negative weeks 4 and 12

Treatment Naïve and Previous Relapsers

TVR + PEG IFN + RBV PEG IFN + RBV

TVR + PEG IFN + RBV PEG IFN + RBV

No eRVR; PEG IFN + RBV

0 4 12

*Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from continuing PEG IFN + RBV to week 48.

24 48

eRVR; stop at week 24*

Previous Partial or Null Responders

Time Point

Week 24

Any

Week 4 or 12 Discontinue all therapyHCV RNA >1000 IU/mLDiscontinue PEG IFN/RBV

Discontinue TVR Discontinuation of PEG IFN/RBV for anyreason

Detectable HCV RNA

Criterion Stopping Rule

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FIGURE 61-2 Recommended approach to treating patients with chronic hepatitis C virus (HCV), genotype 1, with boceprevir (BOC)-based therapy. EU, European Union; IU, international units; LI, lead-in; PEG IFN, pegylated interferon; PR, pegylated; RBV, ribavirin; RGT, response-guided therapy; RNA, ribonucleic acid. As of January 2015, boceprevir is no longer recommended for treat-ment of hepatitis C (see Table 61-6).

800 mg (four 200-mg capsules) q8h with foodEarly response = HCV RNA negative at weeks 8 and 24

Treatment Naïve and Previous RelapsersPEGIFN +RBV

PEGIFN +RBV

PEG IFN + RBV

PEG IFN + RBVBOC + PEG IFN + RBV

BOC + PEG IFN + RBV

BOC + PEG IFN + RBV

BOC + PEG IFN + RBV

0 4 128

Cirrhotics and null responders should receive lead-in and then PEG IFN/RBV + BOC for 44 weeks (no RGT).Week 4 <1 log10 HCV RNA reduction: consider PEG IFN/RBV + BOC for 44 weeks after lead-in (no RGT).EU label: fixed-duration therapy for all treatment-experienced patients: LI + 32 weeks triple + 12 weeks PR (no RGT).

24Weeks

28 36 48

Early response; stop at week 28

Previous Relapsers or Partial Responders (noncirrhotic)

Additional recommendations:

Week 24Any

Week 12 Discontinue all therapyHCV RNA 100 IU/mLDiscontinue all therapy

Discontinue BOCDiscontinuation of PEG/RBV for any reasonDetectable HCV RNA

Time Point Criterion Stopping Rule

• PatientswithpriorPEGIFN/RBVtreatmentfailure:• Genotype1:SOF400mgdaily,SMV150mgdaily,andRBV(1000to1200mgdaily)

for12weeks(analternativeisSOFfor12weekswithPEGIFN/RBVfor12to24weeksorSMV150mgfor12weekswithPEGIFN/RBVfor48weeks).

• Genotype2:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for12weeks(analternativeisSOF400mgdailywithPEGIFN/RBV[weight-based,1000to1200mgdaily]for12weeks).

• Genotype3:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for24weeks(analternativeisSOF400mgdailywithPEGIFN/RBV[weight-based,1000to1200mgdaily]for12weeks).

• Genotypes 4 to 6: SOF 400mg daily with PEG IFN/RBV (weight-based, 1000 to1200mgdaily)for12weeks.

• Patientswithgenotype1andpriorTVRorBOCproteaseinhibitorfailure:SOFfor12weekswithPEGIFN/RBVfor12to24weeks.

• Standard of care: January 2015• The approval of new direct-acting antivirals in October and December 2014 has led

to IFN-free regimens of shorter duration and extraordinarily high efficacy, both intreatment-naïveandtreatment-experiencedpatients(seeTable61-6).

• Newlyrecommendedtreatmentregimens:• Ledipasvir/sofosbuvir(Harvoni):fixed-dosedailycombinationforgenotypes1a,1b,

4,and6• Paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin for genotypes 1a, 1b,

and4

Hepatitis E (HEV)• HEVisanRNAvirus(genus:Hepevirus).• Itspreadsbyfecallycontaminatedwaterinendemicareas.• HEVcausesacute,self-limitedhepatitis,similartoHAV,innormalhosts.

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• Casefatalityratesare0.9%to2.8%inmenand20%inpregnantwomen,particularlyinthethirdtrimester.

• In immunosuppressed patients, particularly solid organ transplants, HEV can cause pro-tractedinfection,chronichepatitis,andcirrhosis.

• Diagnosisisbyserologictests(IgMantibodytoHEV)orPCRinbloodorstool.• Treatment:acutehepatitisEisusuallyself-limited;chronichepatitisErespondstoribavirin

therapy.• Highlyeffectivevaccinesconsistingofrecombinantcapsidproteinshavebeendevelopedfor

useinendemicareas.One(Hecolin)hasbeenrecentlylicensedinChina.

TABLE 61-6  AASLD and IDSA Recommendations for HCV Treatment-Naïve Patients: January 2015

GENOTYPE RECOMMENDATION*1a Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) and weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)

1b Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wkDaily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) for 12 wk; weight-based RBV recommended for patients with cirrhosisDaily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 wk (no cirrhosis) or 24 wk (cirrhosis)

2 Daily sofosbuvir (400 mg) and weight-based RBV for 12 wk (no cirrhosis) or 16 wk (cirrhosis)

3 Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk

4 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wkDaily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 wkDaily sofosbuvir (400 mg) and weight-based RBV for 24 wk

5 Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG IFN for 12 wk

6 Daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; RBV, ribavirin.

*Listed alphabetically—see www.hcvguidelines.org for alternative treatments, treatments in experienced patients, and special populations.

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O  Acquired Immunodeficiency Syndrome

62 Diagnosis of Human Immunodeficiency Virus InfectionFrancesco R. Simonetti, Robin Dewar, and Frank Maldarelli

DEFINITION• Human immunodeficiency virus (HIV) detection is the cornerstone of the medical and

publichealthresponse to theHIVepidemic.HIVdetection isaccurateandsensitive,andpreciseassayshavebeendesignedforthreegeneralpurposes:patientdiagnosisandclinicalmanagement, epidemiologic surveillance, and donor screening for blood and tissueproducts.

EPIDEMIOLOGY• Bytheendof2011,morethan34millionindividualswerelivingwithHIVinfectionthrough-

outtheworld.IntheUnitedStates,thepercentofindividualsevertestedforHIVincreasedfrom36%to45%in2000-2011,buttheyearlytestingratehasremainedrelativelystableat9.6%to10.4%despite thepromotionof rapid testingmodalitiesandexpansionof testingresources.AlthoughtheproportionofpeoplewithHIVawareoftheirstatusisabout80%in the United States, the United Nations estimates that only 30% of infected individualsworldwideareawareoftheirstatus.

MICROBIOLOGY• The genetic diversity of HIV-1 during early infection period is limited, and it is likely

that the majority of individuals are infected with a single variant, with slow, predictableaccumulationingeneticdiversityreflectingboththe intrinsicmutationrateofHIV-1andstrong selection pressure, likely including immune responses. At present, useful tools todetect HIV infection in vivo include viral components (HIV RNA and p24 antigen) andhumoralresponses(detectedbyenzyme-linkedimmunosorbentassay–,Westernblot–,andimmunofluorescence-basedstudies).

DIAGNOSIS• Diagnosisproceedsfromhistory,physicalexamination,andlaboratorystudies.Laboratory

detectionofHIVisatwo-stepsequentialprocessusingahighlysensitivescreeningtestfol-lowedbyahighlyspecificconfirmatoryassay(seeTable62-1).

• Avarietyofformatsareavailable,andrapidtestsarenowU.S.FoodandDrugAdministrationapprovedforHIVscreeningandconfirmation(seeTable62-2).Inmanycircumstances,itisnowpossibletoscreenandconfirmHIVinfectionusingrapidtestswithouthavingpatientsreturnforresults.

• HIVtestingisundergoingexpansionintheUnitedStates;CentersforDiseaseControlandPrevention (CDC) recommendations for opt-out testing for all individuals from 15 to 65yearshavebeenadoptedbytheU.S.PreventiveServicesTaskForce,andthecostforopt-outtestingwillbesubstantiallyunderwrittenthroughtheAffordableCareAct.

• In2014,theCDCissuedupdatedrecommendationsforthediagnosisofHIVinfection(seeTable 62-1). Initial tests are fourth-generation antigen/antibody combination assays, andconfirmatorytestsareHIV-1/HIV-2antibodydifferentiationassays,followedbyanHIV-1nucleicacidtestifneeded.

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TABLE 62-1  CDC-Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens*Step 1: HIV-1/2 antigen/antibody combination immunoassay. If positive, proceed to Step 2.†

Step 2: HIV-1/HIV-2 antibody differentiation immunoassay. If negative or indeterminate for HIV-1 and negative for HIV-2, proceed to Step 3.‡

Step 3: HIV-1 nucleic acid test (NAT). Positive NAT indicates acute HIV-1 infection.§

*This algorithm, starting with the HIV-1/2 antigen/antibody combination immunoassay, should also be used after a reactive result from any rapid HIV test.

†No further testing is required for specimens that are nonreactive on the initial immunoassay.‡Reactive results on the initial antigen/antibody combination immunoassay and the HIV-1/HIV-2 antibody differ-

entiation immunoassay should be interpreted as positive for HIV-1 antibodies, HIV-2 antibodies, or, in the case where both HIV-1 and HIV-2 test results are reactive on the antibody differentiation assay, HIV antibodies, undifferentiated.

§A negative HIV-1 NAT result and nonreactive or indeterminate HIV-1/HIV-2 antibody differentiation immunoassay result indicates a false-positive result on the initial immunoassay.

CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus.

TABLE 62-2  FDA-Approved Formats for HIV Testing

Source for HIV Testing

FDA-APPROVED TESTING MODALITY*

ELISARapid EIA

Western Blot IFA

p24 Antigen Capture

HIV-1 TMA/HPA

Whole blood X X

Dried blood X

Plasma X X X X X X

Serum X X X X X

Oral fluid X X X

Urine X X

Mini-pools (donor screen) X X

Cadaveric serum X X

EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; IFA, indirect immunofluorescence assay; TMA/HPA, transcription-mediated amplification/hybridization protection assay.

*Names and manufacturers of individual testing kits are available at www.fda.gov.

• Noassayorteststrategyisperfect,andfamiliaritywithassaylimitationsisessentialtoensureaccurateidentificationofHIVinfection.

THERAPY• HIVdiagnosisisessentialtointroducespecificantiretroviraltherapyfortreatmentofdisease

andnowaspartofpreexposureprophylaxisstrategies.• Screeningtestsarenecessary,butnotsufficient,tointroducetherapyforHIVinfection,and

confirmationofHIVinfectionisessentialbeforeintroductionofantiretroviraltherapy.• AnonreactiveHIVscreeningtestresulthasbeenusefulinidentifyingpatientsathighrisk

of HIV infection who may undergo preexposure prophylaxis. Regimens for preexposureprophylaxisaredistinctfromandlesspotentthanroutinecombinationantiretroviraltherapy,anditisessentialtoevaluatepatientscarefullyforHIVinfection.

• Specificguidelinesareavailablefortestingfortreatmentandprophylaxispurposes.

PREVENTION• Preexposureprophylaxisrepresentsastrategytotreathigh-riskindividualswithantiretro-

viral therapy to prevent HIV infection. Careful evaluation to rule out HIV infection isnecessary.

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63 

General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)Timothy R. Sterling and Richard E. Chaisson

ACUTE RETROVIRAL SYNDROME• This syndrome is the initial manifestation of human immunodeficiency virus (HIV)

infection.• One half to two thirdsofpatientspresentwithanacute “mononucleosis-like” illness (see

Table63-1),oftenwithatruncalexanthem.• Symptomsgenerallyresolvewithin10to15days.

PERSISTENT GENERALIZED LYMPHADENOPATHY• Thisdisorderoccursin50%to70%ofHIV-infectedindividualsandusuallyaffectsthecervi-

cal,submandibular,occipital,andaxillaryregions.• Inpatientstreatedwithantiretroviraltherapy,previouslyinvolutednodesmayenlarge.

METABOLIC AND ENDOCRINE ABNORMALITIES• Hypogonadism,constitutionalwasting,lipidabnormalities,insulinresistance,andlipodys-

trophyhavebeenreported.

ORAL DISEASE• Oralcandidiasis,oralhairyleukoplakia,gingivitis,andperiodontitismayoccur.

CUTANEOUS DISEASE• Dermatologicconsequences includecutaneous infections (herpes simplexvirus,varicella-

zostervirus,molluscumcontagiosum,scabies,bacillaryangiomatosis,andKaposisarcoma).

RENAL DISEASE• MultiplecausesofrenaldiseasemayafflictpatientswithHIVinfection,aswellasaspecific

HIV-relatednephropathy,whichincludesproteinuria,mildlyelevatedserumcreatininecon-centration,reflectingglomerularinjury,mesangialproliferation,andtubulardegeneration.

CARDIAC DISEASE• AcceleratedatherosclerosiswithmyocardialinfarctionisseeninHIV-infectedpatientswho

havebeentreatedwithantiretroviraltherapyandappearstobeassociatedwithelevationsinproinflammatorycytokinesandprothromboticmarkers.

• Myocarditisandpericarditisarealsofound.

IMMUNE RECONSTITUTION SYNDROMES• Immune reconstitution syndromes are seen after antiretroviral therapy and can involve

Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus, hepatitis BandC,andotheropportunisticinfections.

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TABLE 63-1  Symptoms and Signs of the Acute Retroviral Syndrome in 209 Patients

SYMPTOM OR SIGN NO. WITH FINDING FREQUENCY (%)Fever 200 96

Adenopathy 154 74

Pharyngitis 146 70

Rash 146 70

Myalgia or arthralgia 112 54

Thrombocytopenia 94 45

Leukopenia 80 38

Diarrhea 67 32

Headache 66 32

Nausea, vomiting 56 27

Elevated aminotransferase levels* 38 21

Hepatosplenomegaly 30 14

Thrush 24 12

Neuropathy 13 6

Encephalopathy 12 6

*Based on 178 subjects.Modified from Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review

of pathogenesis and early treatment intervention in human and animal retrovirus infections. J Infect Dis. 1993;168:1490-1501.

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64 Pulmonary Manifestations of Human Immunodeficiency Virus InfectionPaul E. Sax and Kevin L. Ard

EPIDEMIOLOGY• Humanimmunodeficiencyvirus(HIV)infectionincreasestheriskofinfectiousandnonin-

fectiousrespiratoryconditions.• Mostcomplicationsoccurinthosenotreceivingantiretroviraltherapy(ART).• EffectiveARThasreduced,butnoteliminated,theexcessriskofpulmonaryinfectionssuch

asPneumocystis jiroveciipneumonia(PCP)andtoalesserextentbacterialpneumonia.• Noninfectiousconditions,suchaschronicobstructivepulmonarydiseaseandlungcancer,

areassuminggreaterimportanceasHIV-infectedindividualslivelonger.

APPROACH TO THE PATIENT• Thedifferentialdiagnosisisinfluencedbythestageofimmunosuppression,ART,prophylaxis

foropportunisticinfections,andthelocalepidemiologyofconditionssuchastuberculosisandendemicfungalinfections.

• LowerCD4cell counts increase the riskofallpulmonary infections, including those thatalsooccurathigherCD4cellcounts.

• Findingsonchestradiographycanhelpguidethedifferentialdiagnosis(seeTable64-1).

PNEUMOCYSTIS JIROVECII PNEUMONIA• Most cases of PCP occur at CD4 cell counts of fewer than 200 cells/mm3 in patients not

receivingART.• PatientswithPCPtypicallyreportcoughandfeverofatleastseveralweeks’duration.• Radiographic findings include diffuse interstitial infiltrates most commonly, but cavities,

pneumothoraces,pleuraleffusions,andnormalradiographscanoccur.• Diagnosis relieson identificationof theorganism in respiratory secretions,often through

inducedsputumorbronchoalveolarlavage,whichismoresensitive.• Serum(1→3)-β-D-glucanisalsohighlysensitiveforthediagnosisofPCP.

BACTERIAL PNEUMONIA• Streptococcus pneumoniae and Haemophilus influenzae are the most commonly isolated

pathogens.• Withworseningimmunosuppression,pneumoniasduetoStaphylococcus aureus, Pseudomo­

nas aeruginosa (especially in the setting of neutropenia), Nocardia spp., and Rhodococcus equicanoccur.

MYCOBACTERIAL PNEUMONIA• ThefeaturesofMycobacterium tuberculosispulmonaryinfectionvarybasedonthedegreeof

immunosuppression.• HIV-infectedpatientswithrespiratorysymptomswhoarefromtuberculosis-endemicareas

orhaveother risk factors for tuberculosis,whohaveapositive test for latent tuberculosiswithout a history of prophylactic therapy, or who have a personal history of tuberculosis

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withoutdocumentationofappropriatetreatmentshouldbeplacedinnegativeairpressureroomsuntilthediagnosisofpulmonarytuberculosisisexcluded.

• Sputumnucleicacidamplificationtestscanhastendiagnosis,particularlyinsmear-negativecases.

FUNGAL PNEUMONIA• FungalpneumoniatendstooccurwithCD4cellcountfewerthan100cells/mm3,oftenasa

componentofdisseminated fungal infection (cryptococcosis,histoplasmosis, coccidioido-mycosis,blastomycosis).

• Histoplasmosis andcoccidioidomycosis are important causesofpneumonia in thosewhohaveresidedinortraveledtoendemicareas;BlastomycesrarelycausespulmonaryinfectioninpatientswithHIV.

• Pulmonaryaspergillosisisusuallyinseverelyimmunocompromisedindividualswithneu-tropeniaorcorticosteroiduse.

VIRAL PNEUMONIA• During the influenza season, influenza is the most common diagnosis in HIV-infected

patients with fever and respiratory symptoms, although adenovirus, respiratory syncytialvirus,andparainfluenzaviruscancauseasimilarpresentation.

NONINFECTIOUS RESPIRATORY DISORDERS• PulmonaryKaposisarcomausuallyoccurswithcutaneousormucosaldisease.• Pulmonarylymphomacausesnodules,masses,orpleuraleffusionsandisusuallydiagnosed

viavideo-assistedthorascopicsurgery(VATS).• Lymphocyticinterstitialpneumonitis,ararecauseofinterstitialinfiltrates,istypicallydiag-

nosedonbiopsy.Itprimarilyoccursinchildrenbutmaydevelopinadults,particularlythosewithhigherCD4countsthanareseenwithmanyopportunisticinfections.

TABLE 64-1  Radiographic Appearance of Pulmonary Diseases in Human Immunodeficiency Virus Infection

Diffuse Interstitial InfiltratesPneumocystis jiroveciiMycobacterium tuberculosis, especially with advanced

human immunodeficiency virus diseaseHistoplasma capsulatumCoccidioides spp.Cryptococcus neoformansToxoplasma gondiiCytomegalovirusInfluenzaLymphocytic interstitial pneumonitisAbacavir hypersensitivity

Focal ConsolidationPyogenic bacterial pneumonia from Streptococcus

pneumoniae, Haemophilus influenzaeM. tuberculosisLegionella spp.Rhodococcus equi

Hilar AdenopathyM. tuberculosisH. capsulatumCoccidioides spp.Non-Hodgkin’s or Hodgkin’s lymphomaMycobacterium avium complex

Cavitary DiseasePyogenic bacterial pneumonia from Pseudomonas

aeruginosa, Staphylococcus aureus, Enterobacteriaceae

M. tuberculosisC. neoformansR. equiAspergillus spp.Nocardia spp.Mycobacterium avium complexP. jirovecii

Nodules or MassesM. tuberculosisC. neoformansAspergillus spp.H. capsulatumNocardia spp.Non-Hodgkin’s lymphomaKaposi sarcomaLung cancer

Normal RadiographP. jiroveciiM. tuberculosis

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65 Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus InfectionCharles Haines and Mark S. Sulkowski

DEFINITION• Gastrointestinalandhepatobiliarydiseasesareacommoncauseofmorbidityinpersonswith

humanimmunodeficiencyvirus(HIV)infectionandoftenresultfrombothhostfactorsandexposures.

DISORDERS OF THE ESOPHAGUS• Disordersoftheesophagustypicallymanifestasdysphagiaorodynophagiaandaffectupto

onethirdofpatientswithacquiredimmunodeficiencysyndrome(AIDS).• InfectiouscausesincludeCandida,cytomegalovirus(CMV),herpessimplexvirus,varicella-

zostervirus,mycobacteria,Histoplasma,andPneumocystis jirovecii.• Noninfectiouscausesincluderefluxesophagitisandpillesophagitis.• Malignantcausesincludeesophagealcarcinoma,lymphoma,andKaposisarcoma.• Presumptivediagnosescanoftenbemadewithacarefulhistoryandphysicalexamination.• Upperendoscopywithbiopsyoflesionsishighlysensitiveinmanycases.

DISORDERS OF THE STOMACH• Gastric disorders can result from opportunistic infections but more commonly are not

relatedtoHIV-inducedimmunosuppression.• Helicobacter pylori,CMV,andKaposisarcomaarecommoncausesofgastricdisorders.• Upperendoscopyandgastricbiopsiesareoftenneededfordefinitivediagnosis.

DISORDERS OF THE LIVER• Becauseofsharedmodesoftransmission,hepatitiscausedbyacuteorchronicinfectionwith

hepatitisBandCvirusesiscommon.• NewlyavailabledirectlyactingantiviralsagainsthepatitisCvirus(HCV)arerecommended

fortreatmentofpatientscoinfectedwithHIVandHCV.• Drug-inducedliverinjuryhasbeenobservedwithsomeantiretroviralagentsandotherdrugs

usedinpersonswithHIVinfection.

DISORDERS OF THE BILIARY TREE, GALLBLADDER, AND PANCREAS• Acalculous cholecystitis and cholangitis are found primarily in advanced AIDS and may

involvethepancreas.• CMV,Cryptosporidium,andmicrosporidiaaremostcommonlyimplicated.• AIDS-relatedacalculouscholecystitisandcholangitisarerareinsettingswhereantiretroviral

therapy(ART)iswidelyused,andnon–AIDS-relatedgallbladderandbiliarydiseasesmaybemorecommoninsuchsettings.

• Endoscopic retrograde cholangiopancreatography can be used for both diagnosis andtreatment.

• Didanosineandsystemicpentamidinecancausepancreatitis.

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• Pancreatic infectionswithmycobacteria,Cryptococcus,Toxoplasma gondii,P. jirovecii, andCMVhavebeendescribed,oftenindisseminateddisease.

DISORDERS OF THE SMALL AND LARGE INTESTINE• Causesofenterocolitisincludebacterial,protozoal,andviralpathogens(seeTable65-1).• Clostridium difficileisthemostcommoncauseofdiarrheainHIV-infectedpatients.• CMV,Cryptosporidium,andMycobacterium aviumcomplexinfectionsaremorecommonin

thesettingofsevereimmunocompromise.• HIV-associatedenteropathycausesculture-negativediarrheaandmay improvewithART.

Humanpapillomavirus (HPV)andhigh-gradeanaldysplasiaareelevated inHIV,but theutilityofanalHPVscreeningisnotclear.

TABLE 65-1  Causes of Lower Gastrointestinal Tract Disease in Patients with Human Immunodeficiency Virus

Causes of Enterocolitis

Bacteria

Campylobacter jejuni and other spp.Salmonella spp.Shigella flexneriAeromonas hydrophilaPlesiomonas shigelloidesYersinia enterocoliticaVibrio spp.Mycobacterium avium complexMycobacterium tuberculosisEscherichia coli (enterotoxigenic, enteroadherent)Bacterial overgrowthClostridium difficile (toxin)

Parasites

Cryptosporidium parvumMicrosporidia (Enterocytozoon bieneusi, Septata intestinalis)Cystoisospora belliEntamoeba histolyticaGiardia lambliaCyclospora cayetanensis

Viruses

CytomegalovirusAdenovirusCalicivirusAstrovirusPicobirnavirusHuman immunodeficiency virus

Fungi

Histoplasma capsulatum

Causes of Proctitis

Bacteria

Chlamydia trachomatisNeisseria gonorrhoeaeTreponema pallidum

Viruses

Herpes simplexCytomegalovirus

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66 Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic InfectionsOmar K. Siddiqi and Igor J. Koralnik

DEFINITION• Human immunodeficiencyvirus (HIV)andassociated infections canadversely affect any

aspectofthecentralandperipheralnervoussystem.

EPIDEMIOLOGY• TenpercentofHIV-positivepatientsinitiallypresentwithneurologicdisease.• ThirtytofiftypercentofHIV-positivepatientshaveneurologiccomplications.• EightypercentofHIV-positivepatientshavenervoussysteminvolvementatautopsy.

COGNITIVE MANIFESTATIONS• HIV-associatedneurocognitivedisorderoccursin15%ofpatientswithAIDSandcanbethe

firstmanifestationofdiseasein3%to10%ofpatients.

CENTRAL NERVOUS SYSTEM (CNS) MASS LESIONS• Toxoplasmosisisthemostfrequentcerebralmasslesion.Incidencedependsontheseroposi-

tivityofthepopulation.Empiricaltreatmentwithpyrimethamineandsulfadiazineisusefulwhenclinicalandradiologicfindingsareconsistentwiththediagnosis.

• Primary CNS lymphoma is the most common HIV-associated brain malignancy and isassociatedwithEpstein-Barrvirusinfection.

• Progressivemultifocal leukoencephalopathy is causedby JCpolyomavirus,which induceslyticinfectionofoligodendrocytescausingmultifocalCNSdemyelination.

SPINAL CORD• Vacuolarmyelopathyispresentatautopsyin17%to46%ofpatientswithacquiredimmu-

nodeficiencysyndrome.• Presenting symptoms are gait disturbance, weakness, sensory changes, and urinary

dysfunction.• Diagnosisisoneofexclusion.• Etiologyisunclear.

PERIPHERAL NERVOUS SYSTEM• HIV-associateddistalsensorypolyneuropathyisthemostcommonperipheralneuropathy

seen in HIV. Symmetrical paresthesia, numbness, and painful dysesthesia of the lowerextremitiescanoccur.

• Nucleosideneuropathyisassociatedwithnucleosideanaloguereverse-transcriptaseinhibi-torszalcitabine,didanosine,andstavudine.

• ClinicalandelectrophysiologicmanifestationsareindistinguishablefromDSNP.Symptomscanimproveupondiscontinuationofoffendingmedication.

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67 Pediatric Human Immunodeficiency Virus InfectionGeoffrey A. Weinberg and George K. Siberry

EPIDEMIOLOGY• AremarkabledeclineinU.S.pediatrichumanimmunodeficiencyvirus(HIV)infectionhas

occurredasaresultofboththemajorityofcurrentlyinfectedchildrensurvivingintoyoungadulthood and the tremendous success in interrupting new mother-to-child transmission(MTCT). Such success may be achieved globally wherever effective HIV screening andtherapyforpregnantwomenisaccomplished.

• Asmall influxofHIV-infected immigrants,refugees,andadoptees,aswellasuncommondomesticMTCT,will continue tocontribute toaminorbutdefinitepresenceofpediatricHIVinfectionintheUnitedStates.

• AnalarmingincreaseinadolescentacquisitionofHIVinfectionisoccurringamongyoungmenwhohavesexwithmen,especiallyAfrican-AmericanandHispanicmen.

ELIMINATION OF NEW PEDIATRIC HIV INFECTION IN THE UNITED STATES• PreventionofpediatricHIVinfectioncriticallydependsonpreventionofHIVMTCT,which

inturndependsonprimarypreventionofHIVinfectioninwomen,universalHIVtestingofpregnantwomentoidentifythosewhoareHIVinfected,andappropriateantiretroviraltherapyinHIV-infectedwomenandtheirinfants.

• EachepisodeofperinatalHIVinfectionintheUnitedStatesshouldbeviewedasasentinelpublichealtheventindicatingawomanwhoseHIVinfectionwaseitherundiagnosedbeforeor during pregnancy or a woman with a known diagnosis who did not receive adequateprenatalcareincludingappropriateinterventionstopreventMTCT.

• PreventionofadolescentHIVinfectioninvolvessimilarstrategiestothoseusedforadults(safersex,avoidanceofintravenousorinjectiondruguse)butwithspecialattentiontotheadolescent’s unique developmental and biopsychosocial challenges. Additional challengesmaybeposedbyinterruptedhealthinsurance,homelessness,andstigmaamongyoungmenwhohavesexwithmen.

THERAPY FOR AGING HIV-INFECTED YOUTH• DisclosureofthediagnosisofperinatalHIVinfectiontotheagingchildrequiresdiscussion

andplanningand isaprocess thatmay takeplaceovermonths toyearsbasedonseveralfactors,includingthedevelopmentallevelofthechildandtheparent’sorcaretaker’sreadinesstodisclose.Disclosureisbestaccomplishedbyearlyadolescencetomorefullyengageyouthintheirowncare,preferablybeforetheageofsexualdebut.

• Adherence with medical care may suffer during adolescence because of issues revolvingaround psychosocial developmental, confidentiality, peer pressure, and socioeconomicfactors.ThiscontributestothesubstantialpresenceofantiretroviralresistanceofHIVstrainsinagingadolescents.

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• Transition from the pediatric care model to the adult care model is a multifacetedprocessthatrequirestimeandplanningtokeeptheagingadolescentsuccessfullyengagedincare.

• Complications of long-standing perinatal HIV infection and its therapy among maturingyouthincludeimpairedgrowthandbonemineralaccrual,possiblyincreasedcardiovascularriskfactors,increasedincidenceofbehavioralandpsychiatricdisorders,andincreasedriskforcervicaldysplasiaandpretermbirthamongyoungwomen.

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68 Antiretroviral Therapy for Human Immunodeficiency Virus InfectionAthe M. N. Tsibris and Martin S. Hirsch

DEFINITION• Treatmentofhumanimmunodeficiencyvirus(HIV)infectionusesacombinationofatleast

threedrugstoarrestvirusreplicationanddiseaseprogression.

THERAPY CHOICES• AntiretroviraltherapytargetsandinhibitsHIV-specificenzymes.

• Nucleosideandnucleotidereverse-transcriptaseinhibitors(seeTable68-1)• Non-nucleosidereverse-transcriptaseinhibitors(seeTable68-2)• Proteaseinhibitors(seeTable68-3)• Integraseinhibitor(seeTable68-4)

• CCR5antagonistsaretheonlydrugclasstotargetahostprotein.• Entryinhibitors(seeTable68-4)

THERAPY STRATEGIES• Preferredregimenswillusetwonucleosidereverse-transcriptaseinhibitorsincombination

witheitheranon-nucleosidereverse-transcriptaseinhibitor,aproteaseinhibitor,oraninte-grasestrandtransferinhibitor.

THERAPY GOALS• Thegoalofantiretroviraltherapy,inallpatients,isdurablesuppressionofvirusloadtolevels

undetectableincommercialassays.

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TABLE 68-1  Approved Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors

AG

ENT

TRA

DE

NA

ME

OR

AL

BIO

AV

AIL

AB

ILIT

Y

(%)

SER

UM

HA

LF-L

IFE

(hr)

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AC

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SPH

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r)

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S

Zidovudine Retrovir 64 1.1 3-4 Hepatic glucuronidationRenal excretion

300 mg PO q12h or 200 mg PO q8h2 mg/kg IV loading dose, followed by 1 mg/kg/hr until umbilical cord is clamped

300-mg tablets100-mg capsules50-mg/5 mL syrup10-mg/mL solution for IV infusion

Didanosine VidexVidex EC

40 fasted

1.5 25-40 Cellular metabolism

≥60 kg: 400 mg PO qd25 kg < weight < 60 kg: 250 mg PO qd

125-, 200-, 250-, and 400-mg capsules2- and 4-g powder packets (makes 10-mg/mL solution)

Stavudine Zerit 86 1.1 3 Renal excretion ≥60 kg: capsules or solution, 40 mg PO q12h;<60 kg: capsules or solution, 30 mg PO q12h

15-, 20-, 30-, and 40-mg capsules1-mg/mL oral solution

Lamivudine Epivir 86 2.5 12-18 Renal excretion 300 mg PO qd or 150 mg PO q12h

150- and 300-mg tablets10-mg/mL solution

Abacavir Ziagen 83 1.5 3.3 Hepatic glucuronidation and carboxylation

600 mg PO qd or 300 mg PO q12h

300-mg tablets20-mg/mL solution

Tenofovir Viread 39 with meal

12-14 >11* Renal excretion 300 mg PO qd

150-, 200-, 250-, and 300-mg tabletOral powder 40 mg/g

Emtricitabine Emtriva 93 8-10 >24 Renal excretion 200 mg PO qdsolution, 240 mg PO qd

200-mg capsules10-mg/mL solution

Zidovudine + lamivudine

Combivir† One tablet PO q12h

300-mg zidovudine/150-mg lamivudine tablets

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ILIT

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(%)

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UM

HA

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INTR

AC

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LAR

HA

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IFE

OF

TRIP

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SPH

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Abacavir + lamivudine

Epzicom†

KivexaOne tablet PO qd

Abacavir 600-mg/lamivudine 300-mg tablet

Tenofovir + emtricitabine

Truvada† One tablet PO qd

Tenofovir 300-mg/emtricitabine 200-mg tablet

Zidovudine + lamivudine + abacavir

Trizivir† One tablet PO q12h

300-mg zidovudine/ 150-mg lamivudine/300-mg abacavir tablets

Tenofovir + emtricitabine + efavirenz

Atripla† One tablet PO qd on an empty stomach

Tenofovir 300-mg/emtricitabine 200-mg/efavirenz 600-mg tablet

Tenofovir + emtricitabine + rilpivirine

CompleraEviplera†

One tablet PO qd with a meal

Tenofovir 300-mg/emtricitabine 200-mg/rilpivirine 27.5-mg tablet

Tenofovir + emtricitabine + elvitegravir + cobicistat

Stribild† One tablet PO qd with food

Tenofovir 300-mg/emtricitabine 200-mg/elvitegravir 150-mg/cobicistat 150-mg tablet

Abacavir + lamivudine + dolutegravir

Triumeq† One tablet PO qd with or without food

Abacavir 600-mg/lamivudine 300-mg/dolutegravir 50-mg tablet

*Diphosphate form in activated cells.†Pharmacokinetic properties are similar to those of the component drugs used separately.

TABLE 68-1  Approved Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors—cont’d

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TABLE 68-2  Approved Non-Nucleoside Reverse-Transcriptase Inhibitors

AG

ENT

TRA

DE

NA

ME

OR

AL

BIO

AV

AIL

AB

ILIT

Y (

%)

SER

UM

HA

LF-L

IFE

(hr)

ELIM

INA

TIO

N

AD

ULT

DO

SE

DO

SAG

E FO

RM

S

Nevirapine Viramune >90 45 after first dose25-30 after 2 wk

Hepatic cytochrome P-450, CYP3A4 and CYP2B6

200 mg PO qd for 14 days, then, if no rash develops, 200 mg PO q12h or 400 mg XR PO qd

200-mg tablets50 mg/5-mL solution

Delavirdine Rescriptor 85 5.8 Hepatic cytochrome P-450, CYP3A4

400 mg PO q8h 100- and 200-mg tablets

Efavirenz SustivaStocrin

40-45 40-55 Hepatic cytochrome P-450, CYP2B6, and CYP3A4

600 mg PO qd 50- and 200-mg capsules600-mg tablet

Etravirine Intelence Unknown 41 ± 20 Hepatic cytochrome P-450, CYP3A4, 2C9, and 2C19

200 mg PO q12h after meals

25-, 100-, and 200-mg tablets

Rilpivirine Edurant Unknown 50 Hepatic cytochrome P-450, CYP3A

25 mg PO qd with a meal

25-mg tablet

TABLE 68-3  Approved Protease Inhibitors

AG

ENT

TRA

DE

NA

ME

OR

AL

BIO

AV

AIL

AB

ILIT

Y

(%)

SER

UM

HA

LF-L

IFE

(hr)

ELIM

INA

TIO

N

AD

ULT

DO

SE*

DO

SAG

E FO

RM

S

Saquinavir Invirase 4 1-2 Hepatic and intestinal cytochrome P-450, CYP3A4

1000 mg PO q12h with ritonavir 100 mg PO q12h

200-mg capsules500-mg tablets

Ritonavir Norvir 70 3-5 Hepatic cytochrome P-450, CYP3A4, and 2D6

300 mg PO q12h with escalation over 6-9 days to 600 mg PO q12h; rarely used as single agent

100-mg capsules and tablets80 mg/mL solution

Indinavir Crixivan 60-65 1.8 Hepatic cytochrome P-450, CYP3A4

800 mg PO q8hDrink ≥1.5L of water daily

200- and 400-mg capsules

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AV

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AB

ILIT

Y

(%)

SER

UM

HA

LF-L

IFE

(hr)

ELIM

INA

TIO

N

AD

ULT

DO

SE*

DO

SAG

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RM

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Nelfinavir Viracept 70-80 3.5-5 Hepatic cytochrome P-450, CYP2C19, CYP3A4, and CYP2D6

1250 mg PO q12h or 750 mg PO q8h

250- and 625-mg tablets50-mg/g powder

Fosamprenavir LexivaTelzir

— 7-11 Hepatic cytochrome P-450, CYP3A4Biliary excretion

Treatment-naïve: 1400 mg PO q12h without food, or 1400 mg PO qd with ritonavir 200 mg PO qd, or 1400 mg PO qd with ritonavir 100 mg PO qd, or 700 mg PO q12h with ritonavir 100 mg PO q12hPI-experienced: 700 mg PO q12h with ritonavir 100 mg PO q12h

700-mg tablets50-mg/mL suspension

Lopinavir + ritonavir

Kaletra — 5-6 Hepatic cytochrome P-450, CYP3A4

Two tablets PO q12h Lopinavir/ritonavir 100-mg/ 25-mg and 200-mg/50-mg tabletsLopinavir/ritonavir 80-mg/ 20-mg per mL solution

Atazanavir Reyataz — 7 Hepatic cytochrome P-450, CYP3A4

Treatment-naïve: 400 mg PO qd with food or300 mg PO qd with ritonavir 100 mg PO qd with food.Treatment-experienced or with tenofovir: 300 mg PO qd with ritonavir 100 mg PO qd

100-, 150-, 200-, and 300-mg capsules

Tipranavir Aptivus — 5-6 Hepatic cytochrome P-450, CYP3A4

500 mg PO q12h with ritonavir 200 mg PO q12h

250-mg capsules100-mg/mL solution

Darunavir Prezista — 15 (with ritonavir)

Hepatic cytochrome P-450, CYP3A4

Treatment-naïve: 800 mg PO qd with ritonavir 100 mg qd and with food.Treatment-experienced: 800 mg PO qd with ritonavir 100 mg PO qd and with food, or 600 mg PO q12h with ritonavir 100 mg PO q12h and with food

75-, 150-, 400-, 600-, and 800-mg tablets100-mg/mL suspension

PI, protease inhibitor.*Consult product monograph for appropriate dose when low-dose ritonavir is used for pharmacokinetic

enhancement.

TABLE 68-3  Approved Protease Inhibitors—cont’d

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TABLE 68-4  Approved Entry Inhibitors and Integrase InhibitorA

GEN

T

TRA

DE

NA

ME

BIO

AV

AIL

AB

ILIT

Y (

%)

SER

UM

HA

LF-L

IFE

(hr)

ELIM

INA

TIO

N

AD

ULT

DO

SE*

AV

AIL

AB

ILIT

Y

Enfuvirtide Fuzeon 84 3.8 Catabolism to constituent amino acids

90 mg SC q12h 108-mg single-use vials, for reconstitution with 1.1 mL sterile water

Maraviroc SelzentryCelsentri

33 14-18 Hepatic cytochrome P-450, CYP3A

300 mg PO q12h 150- and 300-mg tablets

Raltegravir Isentress Not established

9 UGT1A1-mediated glucuronidation

400 mg PO q12h 400-mg tabletChewable 25- and 100-mg tablets

Dolutegravir Tivicay Not established

14 UGT1A1-mediated glucuronidationHepatic cytochrome P-450, CYP3A

Treatment- or INSTI-naïve: 50 mg PO qdINSTI-experienced or when co-administered with UGT1A/CYP3A inducers: 50 mg PO bid

50-mg tablet

INSTI, integrase strand transfer inhibitor.*Elvitegravir is not available as a single drug.

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69 Management of Opportunistic Infections Associated with Human Immunodeficiency Virus InfectionHenry Masur

DEFINITION• Acquiredimmunodeficiencysyndrome(AIDS)-relatedopportunisticinfectionsaredefined

asthoseinfectionsthatoccurwithincreasedfrequencyorseverityinpatientswithhumanimmunodeficiencyvirus(HIV)infectionorAIDS.

EPIDEMIOLOGY• TheincidenceofHIV-relatedopportunisticinfectionsdependsonthedegreeofimmunosup-

pressionandenvironmentalexposure.• Theoccurrenceofspecificinfectionsinsomecasesisduetoprimaryinfection;inothercases,

diseaseistheresultofreactivationoflatentinfection.

MICROBIOLOGY• TheconstellationofinfectionsthatcharacterizeAIDSisunique:Pneumocystispneumonia,

Toxoplasmaencephalitis,cytomegaloviralretinitis,pneumococcalpneumonia,disseminatedMycobacterium avium complex, cryptosporidiosis, cryptococcal meningitis, and Myco­bacterium tuberculosis infection. The occurrence of these infections individually or in acluster should prompt consideration of underlying HIV infection/AIDS in any patientwithoutaclearpredisposingimmunodeficiency.

• The organisms that cause HIV-related opportunistic infections include bacteria, fungi,viruses,andprotozoa.Somearetransmittedpersontoperson,whereasothersarepresentincertainenvironmentalniches.

DIAGNOSIS• Given thebroadrangeofpathogens that cancause infectious syndromes inpatientswith

HIVinfection/AIDS,andthepotentialtoxicitiesoftherapeuticagents,specificmicrobiologicdiagnoses should be established when possible. AIDS-related opportunistic infections arediagnosedbyawidevarietyoftechniques,includingbacterialandfungalandviralculture,serumorbodyfluidantigenassaysorpolymerasechainreactionassays, colorimetricandimmunofluorescentstainofsecretionsortissue,andhistology.

THERAPY• TherearespecificagentsthatcansuccessfullytreatmostHIV-relatedopportunisticinfections

(seeTable69-1).Prognosisdependsontheseverityoftheacuteillnessaswellasprognosisforcomorbiditiesandavailabilityofeffectiveandwell-tolerated therapies.For someHIV-related opportunistic infections, such as cryptosporidiosis, microsporidiosis, and JC virusencephalitis, thereisnoeffectivespecifictherapy;clinicalresponsedependsonimprovingimmuneresponsebyinitiatingeffectiveantiretroviraltherapy.

PREVENTION• BecausepatientswithHIVinfectionhaveanextraordinarilyhighrateofopportunisticinfec-

tions, and because these opportunistic infections characteristically recur unless patients

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either are reconstituted with antiretroviral therapy (ART) or administered chemoprophy-laxis,bothARTandchemoprophylaxisarebothimportantpreventivestrategies(seeTable69-2).ForsomeinfectionssuchasPneumocystispneumonia,Toxoplasmaencephalitis,anddisseminatedMycobacterium aviumcomplex,primarypreventioniseffective,safe,andwelltolerated and should be part of standard patient management. Immunization is also animportantpartofroutineinfectionpreventionstrategy.

• Recommendationsfordiscontinuingorrestartingprophylacticmedicationsareavailable.

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections

OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Pneumocystis pneumonia (PCP)

Patients who develop PCP despite TMP-SMX prophylaxis can usually be treated with standard doses of TMP-SMX.Duration of PCP treatment: 21 days

Indications for adjunctive corticosteroids:PaO2 <70 mm Hg at room air, orAlveolar-arterial O2 gradient >35 mm HgPrednisone doses (beginning as early as possible and within 72 hr of PCP therapy):Days 1-5: 40 mg PO bidDays 6-10: 40 mg PO dailyDays 11-21: 20 mg PO dailyIV methylprednisolone can be administered as 75% of prednisone dose.Benefit of corticosteroid if started after 72 hr of treatment is unknown, but some clinicians will use it for moderate-to-severe PCP.Whenever possible, patients should be tested for G6PD before use of dapsone or primaquine. Alternative therapy should be used in patients found to have G6PD deficiency.Patients who are receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional PCP prophylaxis.If TMP-SMX is discontinued because of a mild adverse reaction, reinstitution should be considered after the reaction resolves. The dose can be increased gradually (desensitization), reduced, or the frequency modified.TMP-SMX should be permanently discontinued in patients with possible or definite Stevens-Johnson syndrome or toxic epidermal necrosis.

For moderate-to-severe PCP:TMP-SMX: (TMP 15-20 mg and SMX 75-100 mg)/kg/day IV given q6h or q8h; may switch to PO after clinical improvement

For moderate-to-severe PCP:Pentamidine 4 mg/kg IV daily infused over ≥60 min; can reduce dose to 3 mg/kg IV daily because of toxicities, orPrimaquine 30 mg (base) PO daily + clindamycin 600 mg q6h IV, or 900 mg IV q8h, or clindamycin 300 mg PO q6h, or 450 mg PO q8h

For mild-to-moderate PCP:TMP-SMX: (TMP 15-20 mg and SMX 75-100 mg)/kg/day, given PO in three divided doses, orTMP-SMX: (160 mg/800 mg or DS) 2 tablets PO tid

For mild-to-moderate PCP:Dapsone 100 mg PO daily + TMP 5 mg/kg PO tid, orPrimaquine 30 mg (base) PO daily + clindamycin 300 mg PO q6h, or 450 mg PO q8h, orAtovaquone 750 mg PO bid with food

Secondary prophylaxis, after completion of PCP treatment:TMP-SMX DS: 1 tablet PO daily orTMP-SMX (80 mg/400 mg or SS): 1 tablet PO daily

Secondary prophylaxis, after completion of PCP treatment:TMP-SMX DS: 1 tablet PO three times a week, orDapsone 100 mg PO daily, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly, orAerosolized pentamidine 300 mg monthly via Respirgard II nebulizer, orAtovaquone 1500 mg PO daily, orAtovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Toxoplasma gondii encephalitis

Treatment of acute infection:Pyrimethamine 200 mg PO 1 time, followed by weight-based therapy:If <60 kg, pyrimethamine 50 mg PO once daily + sulfadiazine 1000 mg PO q6h + leucovorin 10-25 mg PO once dailyIf ≥60 kg, pyrimethamine 75 mg PO once daily + sulfadiazine 1500 mg PO q6h + leucovorin 10-25 mg PO once dailyLeucovorin dose can be increased to 50 mg daily or bid.Duration for acute therapy:At least 6 wk; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 wk

Treatment of acute infection:Pyrimethamine (leucovorin)* + clindamycin 600 mg IV or PO q6h, orTMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) IV or PO bid, orAtovaquone 1500 mg PO bid with food + pyrimethamine (leucovorin), orAtovaquone 1500 mg PO bid with food + sulfadiazine 1000-1500 mg PO q6h (weight-based dosing, as in preferred therapy), orAtovaquone 1500 mg PO bid with food, orPyrimethamine (leucovorin)* + azithromycin 900-1200 mg PO daily

Adjunctive corticosteroids (e.g., dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible.Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment but should not be used as seizure prophylaxis.If clindamycin is used in place of sulfadiazine, additional therapy must be added to prevent PCP.

Chronic maintenance therapy:Pyrimethamine 25-50 mg PO daily + sulfadiazine 2000-4000 mg PO daily (in two to four divided doses) + leucovorin 10-25 mg PO daily

Chronic maintenance therapy:Clindamycin 600 mg PO q8h + (pyrimethamine 25-50 mg + leucovorin 10-25 mg) PO daily, orTMP-SMX DS 1 tablet bid, orAtovaquone 750-1500 mg PO bid + (pyrimethamine 25 mg + leucovorin 10 mg) PO daily, orAtovaquone 750-1500 mg PO bid + sulfadiazine 2000-4000 mg PO daily (in two to four divided doses), orAtovaquone 750-1500 mg PO bid with food

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Mycobacterium tuberculosis disease

After collecting specimen for culture and molecular diagnostic tests, empirical TB treatment should be started in individuals with clinical and radiographic presentation suggestive of TB.Initial phase (2 mo, given daily, 5-7 times/wk by DOT):INH + [RIF or RFB] + PZA + EMBContinuation phase:INH + (RIF or RFB) daily (5-7 times/wk) or three times a weekTotal duration of therapy (for drug-susceptible TB):Pulmonary TB: 6 moPulmonary TB and culture positive after 2 mo of TB treatment: 9 moExtrapulmonary TB with CNS infection: 9-12 moExtrapulmonary TB with bone or joint involvement: 6 to 9 moExtrapulmonary TB in other sites: 6 moTotal duration of therapy should be based on number of doses received, not on calendar time.

Treatment of drug-resistant TBResistant to INH:(RIF or RFB) + EMB + PZA + (moxifloxacin or levofloxacin) for 2 mo; followed by (RIF or RFB) + EMB + (moxifloxacin or levofloxacin) for 7 moResistant to rifamycins ± other drugs:Regimen and duration of treatment should be individualized based on resistance pattern, clinical and microbiologic responses, and in close consultation with experienced specialists.

Adjunctive corticosteroid improves survival for TB meningitis and pericarditis. RIF is not recommended for patients receiving HIV PI because of its induction of PI metabolism.RFB is a less potent CYP3A4 inducer than RIF and is preferred in patients receiving PIs.Once-weekly rifapentine can result in development of rifamycin resistance in HIV-infected patients and is not recommended.Therapeutic drug monitoring should be considered in patients receiving rifamycin and interacting ART.Paradoxical IRIS that is not severe can be treated with NSAIDs without a change in TB or HIV therapy.For severe IRIS reaction, consider prednisone and taper over 4 wk based on clinical symptoms.For example:If receiving RIF: prednisone 1.5 mg/kg/day for 2 wk, then 0.75 mg/kg/day for 2 wkIf receiving RFB: prednisone 1.0 mg/kg/day for 2 wk, then 0.5 mg/kg/day for 2 wkA more gradual tapering schedule over a few months may be necessary for some patients.

Disseminated Mycobacterium avium complex (MAC) disease

At least two drugs as initial therapy with:Clarithromycin 500 mg PO bid + ethambutol 15 mg/kg PO daily, orAzithromycin 500-600 mg + ethambutol 15 mg/kg PO daily if drug interaction or intolerance precludes the use of clarithromycinDuration:At least 12 mo of therapy, can discontinue if no signs and symptoms of MAC disease and sustained (>6 mo) CD4 count >100 cells/mm3 in response to ART

Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4 counts <50 cells/mm3), high mycobacterial loads (>2 log CFU/mL of blood), or in the absence of effective ART.Third or fourth drug options may include:RFB 300 mg PO daily (dosage adjustment may be necessary based on drug interactions),Amikacin 10-15 mg/kg IV daily or streptomycin 1 g IV or IM daily, orMoxifloxacin 400 mg PO daily or levofloxacin 500 mg PO daily

Testing of susceptibility to clarithromycin and azithromycin is recommended.NSAIDs can be used for patients who experience moderate to severe symptoms attributed to IRIS.If IRIS symptoms persist, short-term (4-8 wk) systemic corticosteroids (equivalent to 20-40 mg prednisone) can be used.

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Bacterial respiratory diseases (with focus on pneumonia)

Empirical antibiotic therapy should be initiated promptly for patients presenting with clinical and radiographic evidence consistent with bacterial pneumonia. The recommendations listed are suggested empirical therapy. The regimen should be modified as needed once microbiologic results are available.

Fluoroquinolones should be used with caution in patients in whom TB is suspected but is not being treated.Empirical therapy with a macrolide alone is not routinely recommended, because of increasing pneumococcal resistance.Patients receiving a macrolide for MAC prophylaxis should not receive macrolide monotherapy for empirical treatment of bacterial pneumonia.For patients begun on IV antibiotic therapy, switching to PO should be considered when they are clinically improved and able to tolerate oral medications.Chemoprophylaxis can be considered for patients with frequent recurrences of serious bacterial pneumonia.Clinicians should be cautious about using antibiotics to prevent recurrences because of the potential for developing drug resistance and drug toxicities.

Empirical outpatient therapy:A PO β-lactam + a PO macrolide (azithromycin or clarithromycin)Preferred β-lactams: High-dose amoxicillin or amoxicillin/clavulanateAlternative β-lactams: Cefpodoxime or cefuroxime, orFor penicillin-allergic patients: Levofloxacin 750 mg PO once daily, or moxifloxacin 400 mg PO once dailyDuration: 7-10 days (a minimum of 5 days). Patients should be afebrile for 48-72 hr and clinically stable before stopping antibiotics.

Empirical outpatient therapy:A PO β-lactam + PO doxycyclinePreferred β-lactams: High-dose amoxicillin or amoxicillin-clavulanateAlternative β-lactams: Cefpodoxime or cefuroxime

Empirical therapy for non-ICU hospitalized patients:An IV β-lactam + a macrolide (azithromycin or clarithromycin)Preferred β-lactams: ceftriaxone, cefotaxime, or ampicillin-sulbactamFor penicillin-allergic patients:Levofloxacin, 750 mg IV once daily, or moxifloxacin, 400 mg IV once daily

Empirical therapy for non-ICU hospitalized patients:An IV β-lactam + doxycycline

Empirical therapy for ICU patients:An IV β-lactam + IV azithromycin, orAn IV β-lactam + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily)Preferred β-lactams: Ceftriaxone, cefotaxime, or ampicillin-sulbactam

Empirical therapy for ICU patients:For penicillin-allergic patients: Aztreonam IV + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily)

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Empirical therapy for patients at risk for Pseudomonas pneumonia:An IV antipneumococcal, antipseudomonal β-lactam + (ciprofloxacin 400 mg IV q8-12h or levofloxacin 750 mg IV once daily)Preferred β-lactams: Piperacillin-tazobactam, cefepime, imipenem, or meropenem

Empirical therapy for patients at risk for Pseudomonas pneumonia:An IV antipneumococcal, antipseudomonal β-lactam + an aminoglycoside + azithromycin, orAbove β-lactam + an aminoglycoside + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily), orFor penicillin-allergic patients: Replace the β-lactam with aztreonam

Empirical therapy for patients at risk for methicillin-resistant Staphylococcus aureus pneumonia:Add vancomycin IV or linezolid (IV or PO) to the baseline regimen.Addition of clindamycin to vancomycin (but not to linezolid) can be considered for severe necrotizing pneumonia to minimize bacterial toxin production.

Salmonellosis Ciprofloxacin 500-750 mg PO (or 400 mg IV) q12h, if susceptibleDuration of therapy:For gastroenteritis without bacteremia:If CD4 count ≥ 200 cells/mm3: 7-14 daysIf CD4 count < 200 cells/mm3: 2-6 wkFor gastroenteritis with bacteremia:If CD4 count ≥ 200/mm3: 14 days; longer duration if bacteremia persists or if the infection is complicated (e.g., if metastatic foci of infection are present)If CD4 count < 200 cells/mm3: 2-6 wkSecondary prophylaxis should be considered for:Patients with recurrent Salmonella gastroenteritis ± bacteremia, orPatients with CD4 <200 cells/mm3 with severe diarrhea

Levofloxacin 750 mg (PO or IV) q24h, orMoxifloxacin 400 mg (PO or IV) q24h, orTMP-SMX (160 mg/800 mg) (PO or IV) q12h, orCeftriaxone 1 g IV q24h, orCefotaxime 1 g IV q8h

Oral or IV rehydration if indicated.Antimotility agents should be avoided.The role of long-term secondary prophylaxis in patients with recurrent Salmonella bacteremia is not well established. Must weigh benefit against risks of long-term antibiotic exposure.Effective ART may reduce the frequency, severity, and recurrence of Salmonella infections.

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Mucocutaneous candidiasis

For oropharyngeal candidiasis; initial episodes (for 7-14 days):Oral therapy:Fluconazole 100 mg PO daily, orTopical therapy:Clotrimazole troches, 10 mg PO five times daily, orMiconazole mucoadhesive buccal 50-mg tablet—apply to mucosal surface over the canine fossa once daily (do not swallow, chew, or crush)

For oropharyngeal candidiasis; initial episodes (for 7-14 days):Oral therapy:Itraconazole oral solution 200 mg PO daily, orPosaconazole oral solution 400 mg PO bid for 1 day, then 400 mg dailyTopical therapy:Nystatin suspension 4-6 mL qid or one to two flavored pastilles four to five times daily

Chronic or prolonged use of azoles may promote development of resistance.Higher relapse rate for esophageal candidiasis seen with echinocandins than with fluconazole use.Suppressive therapy usually not recommended unless patients have frequent or severe recurrences.If decision is to use suppressive therapy:Oropharyngeal candidiasis:Fluconazole 100 mg PO daily or three times a weekItraconazole oral solution 200 mg PO dailyEsophageal candidiasis:Fluconazole 100-200 mg PO dailyPosaconazole 400 mg PO bidVulvovaginal candidiasis:Fluconazole 150 mg PO once weekly

For esophageal candidiasis (for 14-21 days):Fluconazole 100 mg (up to 400 mg) PO or IV daily, orItraconazole oral solution 200 mg PO daily

For esophageal candidiasis (for 14-21 days):Voriconazole 200 mg PO or IV bid, orPosaconazole 400 mg PO bid, orAnidulafungin 100 mg IV one time, then 50 mg IV daily orCaspofungin 50 mg IV daily, orMicafungin 150 mg IV daily, orAmphotericin B deoxycholate 0.6 mg/kg IV daily orLipid formulation of amphotericin B 3-4 mg/kg IV daily

For uncomplicated vulvovaginal candidiasis:Oral fluconazole 150 mg for one dose, orTopical azoles (clotrimazole, butoconazole, miconazole, tioconazole, or terconazole) for 3-7 days

For uncomplicated vulvovaginal candidiasis:Itraconazole oral solution 200 mg PO daily for 3-7 days

For severe or recurrent vulvovaginal candidiasis:Fluconazole 100-200 mg PO daily for ≥7 days, orTopical antifungal ≥7 days

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ALTERNATIVE THERAPY OTHER COMMENTS

Cryptococcosis Cryptococcal meningitis:Induction therapy (for at least 2 wk, followed by consolidation therapy):Liposomal amphotericin B 3-4 mg/kg IV daily + flucytosine 25 mg/kg PO qid (Note: flucytosine dose should be adjusted in patients with renal dysfunction.)

Cryptococcal meningitis:Induction therapy (for at least 2 wk, followed by consolidation therapy):Amphotericin B deoxycholate 0.7 mg/kg IV daily + flucytosine 25 mg/kg PO qid, orAmphotericin B lipid complex 5 mg/kg IV daily + flucytosine 25 mg/kg PO qid, orLiposomal amphotericin B 3-4 mg/kg IV daily + fluconazole 800 mg PO or IV daily, orAmphotericin B deoxycholate 0.7 mg/kg IV daily + fluconazole 800 mg PO or IV daily, orFluconazole 400-800 mg PO or IV daily + flucytosine 25 mg/kg PO qid, orFluconazole 1200 mg PO or IV daily

Addition of flucytosine to amphotericin B has been associated with more rapid sterilization of CSF and decreased risk for subsequent relapse.Patients receiving flucytosine should have either blood levels monitored (peak level 2 hr after dose should be 30-80 µg/mL) or close monitoring of blood cell counts for development of cytopenia. Dosage should be adjusted in patients with renal insufficiency.Opening pressure should always be measured when an LP is performed. Repeated LPs or CSF shunting are essential to effectively manage increased intracranial pressure.Corticosteroids and mannitol are ineffective in reducing ICP and are not recommended.Some specialists recommend a brief course of corticosteroid for management of severe IRIS symptoms.

Consolidation therapy (for at least 8 wk followed by maintenance therapy):Fluconazole 400 mg PO (or IV) daily

Consolidation therapy (for at least 8 wk followed by maintenance therapy):Itraconazole 200 mg PO bid for 8 wk—less effective than fluconazole

Maintenance therapy:Fluconazole 200 mg PO daily for at least 12 mo

Maintenance therapy:No alternative therapy recommendation

For non-CNS, extrapulmonary cryptococcosis and diffuse pulmonary disease:Treatment same as for cryptococcal meningitisNon-CNS cryptococcosis with mild-to-moderate symptoms and focal pulmonary infiltrates:Fluconazole, 400 mg PO daily for 12 mo

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Histoplasmosis Moderately severe to severe disseminated disease:Induction therapy (for at least 2 wk or until clinically improved):Liposomal amphotericin B 3 mg/kg IV dailyMaintenance therapy:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid

Moderately severe to severe disseminated disease:Induction therapy (for at least 2 wk, or until clinically improved):Amphotericin B lipid complex 3 mg/kg IV daily, orAmphotericin B cholesteryl sulfate complete 3 mg/kg IV daily

Itraconazole, posaconazole, and voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bidirectional.Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and ARV efficacy and reduce concentration-related toxicities.Random serum concentration of itraconazole + hydroitraconazole should be >1 µg/mL.Clinical experience with voriconazole or posaconazole in the treatment of histoplasmosis is limited.Acute pulmonary histoplasmosis in HIV-infected patients with CD4 counts >300 cells/mm3 should be managed as nonimmunocompromised host.

Less severe disseminated disease:Induction and maintenance therapy:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bidDuration of therapy:At least 12 mo

Alternatives to itraconazole for maintenance therapy or treatment of less severe disease:Voriconazole 400 mg PO bid for 1 day, then 200 mg bid, orPosaconazole 400 mg PO bid, orFluconazole 800 mg PO daily

Meningitis:Induction therapy (4-6 wk):Liposomal amphotericin B 5 mg/kg/dayMaintenance therapy:Itraconazole 200 mg PO bid to tid for ≥1 year and until resolution of abnormal CSF findings

Meningitis:No alternative therapy recommendation

Long-term suppression therapy:For patients with severe disseminated or CNS infection after completion of at least 12 mo of therapy; and those who relapse despite appropriate therapy:Itraconazole 200 mg PO daily

Long-term suppression therapy:Fluconazole 400 mg PO daily

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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Coccidioidomycosis Clinically mild infections (e.g., focal pneumonia):Fluconazole 400 mg PO daily, orItraconazole 200 mg PO bid

Mild infections (focal pneumonia):For patients who failed to respond to fluconazole or itraconazole:Posaconazole 200 mg PO bid, orVoriconazole 200 mg PO bid)

Some patients with meningitis may develop hydrocephalus and require CSF shunting.Therapy should be continued indefinitely in patients with diffuse pulmonary or disseminated diseases because relapse can occur in 25%-33% of HIV-negative patients. It can also occur in HIV-infected patients with CD4 counts >250 cells/mm3.Therapy should be lifelong in patients with meningeal infections because relapse occurs in 80% of HIV-infected patients after discontinuation of triazole therapy.Itraconazole, posaconazole, and voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bidirectional. Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and antiretroviral efficacy and reduce concentration-related toxicities.Intrathecal amphotericin B should only be given in consultation with a specialist and administered by an individual with experience with the technique.

Severe, nonmeningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease):Amphotericin B deoxycholate 0.7-1.0 mg/kg IV dailyLipid formulation amphotericin B 4-6 mg/kg IV dailyDuration of therapy: Continue until clinical improvement, then switch to an azole.

Severe, nonmeningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease):Some specialists will add a triazole (fluconazole or itraconazole, with itraconazole preferred for bone disease) 400 mg/day to amphotericin B therapy and continue triazole once amphotericin B is stopped.

Meningeal infections:Fluconazole 400-800 mg IV or PO daily

Meningeal infections:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid, orPosaconazole 200 mg PO bid, orVoriconazole 200-400 mg PO bid, orIntrathecal amphotericin B deoxycholate, when triazole antifungal agents are ineffective

Chronic suppressive therapy:Fluconazole 400 mg PO daily, orItraconazole 200 mg PO bid

Chronic suppressive therapy:Posaconazole 200 mg PO bid, orVoriconazole 200 mg PO bid

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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ALTERNATIVE THERAPY OTHER COMMENTS

Cytomegalovirus (CMV) disease

CMV retinitis:Induction therapy for immediate sight-threatening lesions (adjacent to the optic nerve or fovea):Consult ophthalmologist because ganciclovir implant no longer available:Ganciclovir 5 mg/kg IV q12h for 14-21 days followed by valganciclovir 900 mg PO bidFor small peripheral lesions:Valganciclovir 900 mg PO bid for 14-21 daysOne dose of intravitreal ganciclovir can be administered immediately after diagnosis until steady-state plasma ganciclovir concentration is achieved with oral valganciclovir.

CMV retinitis:Induction therapy:Ganciclovir 5 mg/kg IV q12h for 14-21 days, orFoscarnet 90 mg/kg IV q12h or 60 mg q8h for 14-21 days, orCidofovir 5 mg/kg/wk IV for 2 wk; saline hydration before and after therapy and probenecid, 2 g PO 3 hr before dose, followed by 1 g PO 2 hr and 8 hr after the dose (total of 4 g). (Note: This regimen should be avoided in patients with sulfa allergy because of cross-hypersensitivity with probenecid.)

The choice of therapy for CMV retinitis should be individualized, based on location and severity of the lesions, level of immunosuppression, and other factors (e.g., concomitant medications and ability to adhere to treatment).The choice of chronic maintenance therapy (route of administration and drug choices) should be made in consultation with an ophthalmologist. Considerations should include the anatomic location of the retinal lesion, vision in the contralateral eye, the patients’ immunologic and virologic status and response to ART.Patients with CMV retinitis who discontinue maintenance therapy should undergo regular eye examinations (optimally every 3 mo) for early detection of relapse IRU, and then annually after immune reconstitution.IRU may develop in the setting of immune reconstitution.Treatment of IRU:Periocular corticosteroid or short courses of systemic corticosteroid.Initial therapy in patients with CMV retinitis, esophagitis, colitis, and pneumonitis should include initiation or optimization of ART.

Chronic maintenance (secondary prophylaxis):Valganciclovir 900 mg PO daily (for small peripheral lesion)

Chronic maintenance (secondary prophylaxis):Ganciclovir 5 mg/kg IV five to seven times weekly, orFoscarnet 90-120 mg/kg IV once daily, orCidofovir 5 mg/kg IV every other week with saline hydration and probenecid as above

CMV esophagitis or colitis:Ganciclovir 5 mg/kg IV q12h; may switch to valganciclovir 900 mg PO q12h once the patient can tolerate oral therapyDuration: 21-42 days or until symptoms have resolvedMaintenance therapy is usually not necessary, but should be considered after relapses.

CMV esophagitis or colitis:Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for patients with treatment-limiting toxicities to ganciclovir or with ganciclovir resistance, orValganciclovir 900 mg PO q12h in milder disease and if able to tolerate PO therapy, orFor mild cases, if ART can be initiated without delay, consider withholding CMV therapy.Duration: 21-42 days or until symptoms have resolved.

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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ALTERNATIVE THERAPY OTHER COMMENTS

Well-documented, histologically confirmed CMV pneumonia:Experience for treating CMV pneumonitis in HIV patients is limited. Use of IV ganciclovir or IV foscarnet is reasonable (doses same as for CMV retinitis)The optimal duration of therapy and the role of oral valganciclovir have not been established.

Herpes simplex virus (HSV) disease

Orolabial lesions (for 5-10 days):Valacyclovir 1 g PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO tidInitial or recurrent genital HSV (for 5-14 days):Valacyclovir 1 g PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO tidSevere mucocutaneous HSV:Initial therapy, acyclovir 5 mg/kg IV q8hAfter lesions begin to regress, change to PO therapy as above. Continue until lesions are completely healed.Chronic suppressive therapy:For patients with severe recurrences of genital herpes or patients who want to minimize frequency of recurrences:Valacyclovir 500 mg PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO bidContinue indefinitely regardless of CD4 cell count.

For acyclovir-resistant HSV:Preferred therapy:Foscarnet 80-120 mg/kg/day IV in two to three divided doses until clinical responseAlternative therapy:IV cidofovir (dosage as in CMV retinitis), orTopical trifluridine, orTopical cidofovir, orTopical imiquimodDuration of therapy:21-28 days or longer

Patients with HSV infections can be treated with episodic therapy when symptomatic lesions occur or with daily suppressive therapy to prevent recurrences.Topical formulations of trifluridine and cidofovir are not commercially available.Extemporaneous compounding of topical products can be prepared using trifluridine ophthalmic solution and the IV formulation of cidofovir.

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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OPPORTUNISTIC INFECTION PREFERRED THERAPY

ALTERNATIVE THERAPY OTHER COMMENTS

Varicella-zoster virus (VZV) disease

Primary varicella infection (chickenpox):Uncomplicated cases (for 5-7 days):Valacyclovir 1 g PO tid, orFamciclovir 500 mg PO tidSevere or complicated cases:Acyclovir 10-15 mg/kg IV q8h for 7-10 daysMay switch to oral valacyclovir, famciclovir, or acyclovir after defervescence if no evidence of visceral involvement

Primary varicella infection (chickenpox)Uncomplicated cases (for 5-7 days):Acyclovir 800 mg PO five times a day

In managing VZV retinitis consultation with an ophthalmologist experienced in management of VZV retinitis is strongly recommended.Duration of therapy for VZV retinitis is not well defined and should be determined based on clinical, virologic, and immunologic responses and ophthalmologic responses.Optimization of ART is recommended for serious and difficult-to-treat VZV infections (e.g., retinitis, encephalitis).

Herpes zoster (shingles):Acute localized dermatomal:For 7-10 days consider longer duration if lesions are slow to resolve.Valacyclovir 1 g PO tid, orFamciclovir 500 mg tid

Herpes zoster (shingles):Acute localized dermatomal:For 7-10 days consider longer duration if lesions are slow to resolve.Acyclovir 800 mg PO five times a day

Extensive cutaneous lesion or visceral involvement:Acyclovir 10-15 mg/kg IV q8h until clinical improvement is evidentMay switch to PO therapy (valacyclovir, famciclovir, or acyclovir) after clinical improvement (i.e., when no new vesicle formation or improvement of signs and symptoms of visceral VZV), to complete a 10-14 day course.

Progressive outer retinal necrosis (PORN):(Ganciclovir 5 mg/kg + foscarnet 90 mg/kg) IV q12h + (ganciclovir 2 mg/0.05 mL ± foscarnet 1.2 mg/0.05 mL) intravitreal injection twice weekly, orInitiate or optimize ART.

Acute retinal necrosis (ARN):Acyclovir 10 mg/kg IV q8h for 10-14 days, followed by valacyclovir 1 g PO tid for 6 wk

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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ALTERNATIVE THERAPY OTHER COMMENTS

Progressive multifocal leukoencephalopathy (PML) (JC virus infections)

There is no specific antiviral therapy for JC virus infection. The main treatment approach is to reverse the immunosuppression caused by HIV.Initiate ART immediately in ART-naïve patients.Optimize ART in patients who develop PML in phase of HIV viremia on ART.

None Corticosteroids may be used for PML-IRIS characterized by contrast enhancement, edema, or mass effect, and with clinical deterioration.

AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; ARV, antiretroviral; bid, twice daily; CD4, CD4+ lymphocyte cells; CFU, colony-forming unit; CNS, central nervous system; CSF, cerebrospinal fluid; CYP3A4, cytochrome P-450 3A4; DOT, directly observed therapy; DS, double strength; EMB, ethambutol; G6PD, glucose-6-phosphate dehydrogenase; HIV, human immunodeficiency virus; ICP, intracranial pressure; ICU, intensive care unit; IM, intramuscular; INH, isoniazid; IRIS, immune reconstitution inflammatory syndrome; IRU, immune recovery uveitis; IV, intravenous; LP, lumbar puncture; NSAIDs, nonsteroidal anti-inflammatory drugs; PI, protease inhibitor; PO, oral; PZA, pyrazinamide; q(n)h, every “n” hours; RFB, rifabutin; RIF, rifampin; SS, single strength; TB, tubercu-losis; tid, thrice daily; TVR, telaprevir; TMP-SMX, trimethoprim-sulfamethoxazole; ZDV, zidovudine.

*Pyrimethamine and leucovorin doses are the same as for preferred therapy.From Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents:

Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/guidelines. Accessed May 5, 2014.

TABLE 69-2  Prophylaxis to Prevent First Episode of Opportunistic Disease

OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEPneumocystis pneumonia (PCP)

CD4 count <200 cells/mm3, or oropharyngeal candidiasis,or CD4 <14%, or history of AIDS-defining illness, orCD4 count >200 but <250 cells/mm3 if monitoring CD4 cell count every 3 mo is not possibleNote: Patients who are receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional PCP prophylaxis.

TMP-SMX 1 DS tablet PO daily, orTMP-SMX 1 SS tablet PO daily

TMP-SMX 1 DS tablet PO three times a week, orDapsone 100 mg PO daily or 50 mg PO bid, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly; orAerosolized pentamidine 300 mg via Respirgard II nebulizer every month, orAtovaquone 1500 mg PO daily, or Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily

TABLE 69-1  Treatment of AIDS-Associated Opportunistic Infections—cont’d

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TABLE 69-2  Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d

OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEToxoplasma gondii encephalitis

Toxoplasma IgG-positive patients with CD4 count <100 cells/mm3

Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have Toxoplasma serology retested if CD4 count declines to <100 cells/mm3.Prophylaxis should be initiated if seroconversion occurred.Note: All regimens recommended for primary prophylaxis against toxoplasmosis are also effective as PCP prophylaxis.

TMP-SMX 1 DS tablet PO daily

TMP-SMX 1 DS tablet PO three times a week, orTMP-SMX 1 SS tablet PO daily, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly; orAtovaquone 1500 mg PO daily; orAtovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily

Mycobacterium tuberculosis infection (i.e., treatment of LTBI)

Positive screening test for LTBI, with no evidence of active TB, and no prior treatment for active TB or LTBI, orClose contact with a person with infectious TB, with no evidence of active TB, regardless of screening test results.

INH 300 mg + pyridoxine 25 mg PO daily × 9 mo, orINH 900 mg PO twice weekly (by DOT) + pyridoxine 25 mg PO daily × 9 mo.

Rifampin 600 mg PO daily × 4 mo, orRifabutin (dose adjusted based on concomitant ART) × 4 mo.For persons exposed to drug-resistant TB, select anti-TB drugs after consultation with experts or public health authorities.

Disseminated Mycobacterium avium complex (MAC) disease

CD4 count <50 cells/mm3 after ruling out active disseminated MAC disease based on clinical assessment.

Azithromycin 1200 mg PO once weekly, orClarithromycin 500 mg PO bid, orAzithromycin 600 mg PO twice weekly

Rifabutin (dose adjusted based on concomitant ART); rule out active TB before starting rifabutin.

Streptococcus pneumoniae infection

For individuals who have not received any pneumococcal vaccine, regardless of CD4 count, followed by:if CD4 count ≥ 200 cells/mm3

if CD4 count < 200 cells/mm3

PCV13 0.5 mL IM × 1.PPV23 0.5 mL IM at least 8 wk after the PCV13 vaccine.PPV23 can be offered at least 8 wk after receiving PCV13 or can wait until CD4 count increased to >200 cells/mm3.

PPV23 0.5 mL IM × 1

For individuals who have previously received PPV23

One dose of PCV13 should be given at least 1 yr after the last receipt of PPV23.

Revaccination:If age 19-64 yr and ≥5 yr since the first PPV23 doseIf age ≥ 65 yr, and if ≥5 yr since the previous PPV23 dose

PPV23 0.5 mL IM × 1PPV23 0.5 mL IM × 1

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OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEInfluenza A and B virus infection

All HIV-infected patients Inactivated influenza vaccine annually (per recommendation for the season).Live-attenuated influenza vaccine is contraindicated in HIV-infected patients.

Syphilis For individuals exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within past 90 days, orFor individuals exposed to a sex partner >90 days before syphilis diagnosis in the partner, if serologic test results are not available immediately after and the opportunity for follow-up is uncertain (AIII)

Benzathine penicillin G 2.4 million units IM for 1 dose

For pencillin-allergic patients:Doxycycline 100 mg PO bid for 14 days, orCeftriaxone 1 g IM or IV daily for 8-10 days, orAzithromycin 2 g PO for 1 dose: not recommended for MSM or pregnant women

Histoplasma capsulatum infection

CD4 count ≤150 cells/mm3and at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years)

Itraconazole 200 mg PO daily

Coccidioidomycosis A new positive IgM or IgG serologic test in patients who live in a disease-endemic area and with CD4 count <250 cells/mm3

Fluconazole 400 mg PO daily

Varicella-zoster virus Preexposure prevention:Patients with CD4 counts ≥200 cells/mm3 who have not been vaccinated, have no history of varicella or herpes zoster, or who are seronegative for VZVNote: Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.

Preexposure prevention:Primary varicella vaccination (Varivax), two doses (0.5 mL SQ each) administered 3 mo apart.If vaccination results in disease because of vaccine virus, treatment with acyclovir is recommended.

Preexposure prevention:VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts.

TABLE 69-2  Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d

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TABLE 69-2  Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d

OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVE

Postexposure prevention:Close contact with a person with chickenpox or herpes zoster and is susceptible (i.e., no history of vaccination or of either condition, or known to be VZV seronegative)

Postexposure prevention:Varicella-zoster immune globulin (VariZIG) 125 IU/10 kg (maximum 625 IU) IM, administered as soon as possible and within 10 days after exposure.Note: VariZIG is available through Cangene, Canada.Individuals receiving monthly high-dose IVIG (>400 mg/kg) are likely to be protected if the last dose of IVIG was administered <3 wk before exposure.

Alternative postexposure prevention:Acyclovir 800 mg PO five times a day for 5-7 days, orValacyclovir 1 g PO tid for 5-7 daysThese alternatives have not been studied in the HIV population.If antiviral therapy is used, varicella vaccines should not be given until at least 72 hr after the last dose of the antiviral drug.

Hepatitis A virus (HAV) infection

HAV-susceptible patients with chronic liver disease or who are injection drug users or MSM.

Hepatitis A vaccine 1 mL IM × two doses at 0 and 6-12 mo.IgG antibody response should be assessed 1 mo after vaccination; nonresponders should be revaccinated when CD4 count > 200 cells/mm3.

For patients susceptible to both HAV and hepatitis B virus (HBV) infection (see below):Combined HAV and HBV vaccine (Twinrix), 1 mL IM as a three-dose (0, 1, and 6 mo) or four-dose series (days 0, 7, 21 to 30 and at 12 mo)

Hepatitis B virus (HBV) infection

Vaccine nonresponders:Anti-HBs <10 IU/mL 1 mo after vaccination series.For patients with low CD4 counts at time of first vaccine series, some specialists might delay revaccination until after sustained increase in CD4 count with ART.

Revaccinate with a second vaccine series.

Some experts recommend revaccinating with 40-µg doses of either HBV vaccine.

ART, antiretroviral therapy; CD4, CD4+ lymphocyte count; DOT, directly observed treatment; DS, double strength; HBs, hepatitis B surface antibody; HIV, human immunodeficiency virus; IM, intramuscular; INH, isoniazid; IVIG, intravenous immune globulin; LTBI, latent tuberculosis infection; MSM, men who have sex with men; PCV13, 13-valent pneumococcal conjugate vaccine; PO, oral; PPV23, 23-valent pneumococcal polysaccharide vaccine; SQ, subcutaneous; SS, single strength; TB, tuberculosis; TMP-SMX, trimethoprim-sulfamethoxazole; VZV, varicella-zoster virus.

From Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/guidelines. Accessed May 5, 2014.

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70  Chronic Fatigue SyndromeN. Cary Engleberg

DEFINITION• As defined in a 1994 Centers for Disease Control and Prevention/National Institutes of

Healthconsensusconference,chronicfatiguesyndrome(CFS)isadisorderinvolving6ormoremonthsofunexplained,profoundfatiguewithat least fourofeightassociatedsymp-toms(seeTable70-1).

• A new name, “systemic exertion intolerance disease” was proposed by the Institute ofMedicinein2015,alongwithsomewhatmodifieddiagnosticcriteria(seeTable70-2).

• Othernamesusedforthisdisorderinclude“postinfectiousfatigue,”“chronicmononucleosis,”“myalgicencephalomyelitis”(UnitedKingdom/Canada),and“chronicfatigueandimmunedysfunctionsyndrome”(UnitedStates).

EPIDEMIOLOGY• Prevalenceisestimatedat0.2%to1%ofthepopulation,dependingonthedefinitionsused.• CFSoccursinwomenthreetoseventimesmorefrequentlythaninmen.• Itoccursinallsocioeconomicstrataandamongallraces.

ETIOLOGY• CFSmaybeasequelofvariousinfectiousdiseases(e.g.,herpesvirusinfections,influenza,Q

fever, brucellosis, Lyme disease, giardiasis) but is not known to be directly related to anyongoingchronicinfection(seeTable70-3).

• Subtledisturbancesofimmunefunctionarenotconsistentandnotknowntobecausativeofsymptoms.

• Hypothalamus-pituitary-adrenalaxisorautonomicdisturbancesmayoccur,butcorrectingthesesubtleanomaliesdoesnotimprovesymptomsofCFS.

• Priororconcurrenthistoryofpsychiatricdisordersiscommon.

DIAGNOSIS• Diagnosisisclinicalandusuallybasedonthe1994consensusdefinition(seeTable70-1).• ModifieddiagnosticcriteriahavealsobeenproposedbytheInstituteofMedicinein2015

(seeTable70-2).• ThereisnovalidlaboratorytesttoruleinortoruleoutCFS.

THERAPY• Pharmacologic therapiesaredirectedatrelievingsymptomsofpain,sleepdisruption,and

depression.• Noantimicrobialandimmunetherapieshavebeenproventobehelpful.• Nonpharmacologic therapies (cognitive-behavioral therapy and graded exercise therapy)

havebeenrepeatedlyshowntobehelpfulinmostpatients.

PREVENTION• Therearenoknownpreventivemeasures.

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TABLE 70-1  CDC/NIH Consensus Conference Definition of Chronic Fatigue SyndromeClinically evaluated, unexplained chronic fatigue for >6 mo duration, which is not lifelong or the result of

ongoing exertion and is not alleviated substantially by rest. Fatigue is associated with a significant reduction in occupational, educational, social, or personal activities plus ≥4 of the following concurrent symptoms:Impaired memory or concentrationSore throatTender cervical or axillary lymph nodesMuscle painMultijoint painNew headachesUnrefreshing sleepPostexertion malaise

CDC, Centers for Disease Control and Prevention; NIH, National Institutes of Health.Modified from Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach

to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.

TABLE 70-2  IOM Diagnostic Criteria for Systemic Exertion Intolerance DiseaseDiagnosis requires that the patient have the following three symptoms:

1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and

2. Postexertional malaise,* and3. Unrefreshing sleep*

At least one of the following manifestations is also required:1. Cognitive impairment* or2. Orthostatic intolerance

*Frequency and severity of symptoms should be assessed. The diagnosis of systemic intolerance disease (myalgic encephalomyelitis/chronic fatigue syndrome) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.

TABLE 70-3  Proposed Infectious Causes of Chronic Fatigue Syndrome

Proposed Etiologic Agent

REFERENCES

Suggestive Studies Negative StudiesEpstein-Barr virus 6, 7, 173 13, 14, 15, 16, 174-176

Cytomegalovirus 177, 178 13, 14, 174-176

Human herpesvirus 6 45, 46, 179, 180 13, 14, 175, 176, 181, 182

Human herpesvirus 7 183 46, 175, 179, 182

Human herpesvirus 8 — 46, 175, 184

Enteroviruses 185-187 13, 14, 188-191

Parvovirus 39, 192 175, 193, 194

GB virus-C 195

Human spumavirus 196 —

Bornavirus 197, 198 199

Human retrovirus 200 201-203

Xenotropic murine retrovirus (XMRV)

49, 50 54, 56-5859 (retraction of 49)60 (retraction of 50)

Borrelia burgdorferi 204 205, 206

Brucella spp. 207 3

Mycoplasma spp. 208, 209 210

Candida albicans 211, 212 213

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PART II

Infectious Diseases and their Etiologic Agents

176

A  Viral Diseases

71 Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and CowpoxBrett W. Petersen and Inger K. Damon*

DEFINITION• Orthopoxvirus infections can cause a spectrum of febrile rash illnesses in humans, from

fairlybenign,localizedskininfectionstoseveresystemicinfections.• Vaccinia(smallpoxvaccine),variola(smallpox),monkeypox,andcowpoxarethefourortho-

poxvirusspeciesknowntocausehumandisease.

EPIDEMIOLOGY• Mostorthopoxvirusinfectionsarezoonotic,withhumansservingasaccidentalhosts.• Vacciniaviruscontinuestobeusedasavaccine,aswellasasubjectandtoolforbiomedical

research,anditcausessporadicdiseaseinvaccinees,contactsofvaccinees,andlaboratoryworkers.

• Variola,thecausativeagentofsmallpox,causedsignificantmorbidityandmortalityworld-widebeforeitseradicationin1980.

• Monkeypox virus causes intermittent human infections, primarily in Central and WestAfrica,althoughisolatedoutbreakshavebeenidentifiedintheUnitedStatesandSudan.

• Humancowpoxvirusinfectionisclassicallyassociatedwithoccupationalexposuretocattle;however, other animals, including rats, pet cats, and zoo and circus elephants, have beenimplicated.

MICROBIOLOGY• Orthopoxvirusesareagroupoflarge,complex,double-strandedDNAvirusesthatreplicate

inthecytoplasmofthehostcell.

DIAGNOSIS• Diagnostic laboratory testing for orthopoxvirus infections can include polymerase chain

reaction,viralculture,andelectronmicroscopyofrashlesionmaterial,aswellasserologictestingofserum.

THERAPY• Vaccinia Immune Globulin Intravenous (VIGIV) is licensed for the treatment of certain

complicationsofvacciniavaccineadministrationand is available through theCenters forDiseaseControlandPrevention.

• Noantiviraldrugsarecurrentlylicensedforuseinthetreatmentoforthopoxvirusorotherpoxviralillnesses.

• Thedevelopmentandevaluationfor therapeutics fororthopoxvirus infections isanactiveareaofresearch.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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PREVENTION• Orthopoxvirusesinducecross-reactiveantibodiesthatprotectagainstinfectionfromother

orthopoxvirusspecies.• Vaccinationwithsmallpoxvaccine(i.e.,vacciniavirus)canbeusedtoprotectindividualsat

highriskoforthopoxvirusdisease.• Othercontrolmeasures focusoneducationaloutreachtodecreasetheriskofexposureto

likelyzoonoticvectors.

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72 Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and YatapoxvirusesBrett W. Petersen and Inger K. Damon*

DEFINITION• Parapoxviruses,molluscumcontagiosum,andyatapoxvirusesareamongthenonorthopox-

virusinfectionsofhumans.

EPIDEMIOLOGY• Parapoxvirusinfectionsmostcommonlyoccurinindividualswithoccupationalexposures

toinfectedsheep,cattle,orgoats.• Molluscum contagiosum infection occurs worldwide and is spread through mild skin

trauma,fomites,andsexualtransmission.• Yatapoxvirus infections are rarely reported; infections are acquired through exposure to

infectedanimalsandpotentiallyarthropodvectorsandareusuallygeographicallyrestrictedtoCentralandEastAfrica.

MICROBIOLOGY• Poxvirusesareadiversegroupoflarge,complexdouble-strandedDNAvirusesthatreplicate

inthecytoplasmofthehostcell.

DIAGNOSIS• Parapoxvirus, molluscum contagiosum, and yatapoxvirus infections are often diagnosed

clinically based on their characteristic clinical features in combination with appropriateexposureandtravelhistories.

• Diagnostic laboratorytestingforpoxvirusesmayincludepolymerasechainreactionassay,electronmicroscopy,viralculture,andserology.

THERAPY• Parapoxvirus infections are usually self-limited; treatment with topical and intralesional

cidofovir,aswellasimiquimod,hasbeenanecdotallyreported.• Multiplemodalitiesfortreatmentofmolluscumcontagiosumhavebeendescribed,including

cryotherapy, mechanical curettage, and chemical treatments with podophyllin/podofilox,cantharidin,iodine,andtretinoin.

PREVENTION• Transmissionofparapoxviruses,molluscumcontagiosum,andyatapoxvirusescanbepre-

ventedbyavoidingexposures toanimalvectors,properly covering lesions, andobservinggoodhandhygienepractices.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

179

73 Herpes Simplex VirusJoshua T. Schiffer and Lawrence Corey

DEFINITION• Herpessimplexvirus(HSV)isahumanα-herpesvirusoftwotypes,HSV-1andHSV-2.• Bothtypescausecommoninfectionswithvariedclinicalmanifestationsinotherwisehealthy

childrenandadultsthataregenerallymoresevereinpatientswithimmunosuppression.

EPIDEMIOLOGY• HSV-1andHSV-2haveaworldwidedistributionandhavenoknownanimalreservoirs.• HSV-1isacquiredmorefrequentlyandearlierthanHSV-2.Morethan90%ofadultshave

antibodiestoHSV-1bythefifthdecadeoflife.• HSV-2seroprevalencecorrelateswithonsetofsexualactivityandisconsistentlyhigherin

womenthanmen.• GlobalincidenceofHSV-2hasbeenestimatedat23millionnewcasesperyear.

MICROBIOLOGY• HSVisanonenvelopedvirusthatis160nmindiameterandhasalinear,double-stranded

DNAgenome.• HSV-1andHSV-2haveapproximately50%homology,andhomologoussequencesaredis-

tributedthroughoutthegenomemap.• HSVinfectionoccursthroughattachmenttocellsviaubiquitousreceptors,reflectingawide

tissuerangeofinfectionsinthehost,includingsensoryneurons,whichcanresultinlatency.• Viralreplicationoccursthroughnuclearandcytoplasmicphases.• Latency is associated with transcription of only a limited number of virus-encoded ribo-

nucleicacids.

CLINICAL MANIFESTATIONS• HSV has been isolated from nearly all visceral and mucosal sites. Clinical manifestations

dependontheanatomicsite,age,andimmunestatusofthehostandantigenictype(1or2)ofthevirus.

• Initial (primary) infectionsaremoresevere thanrecurrentones,butreactivationof latentinfectioncanresultinfrequentclinicalmanifestations.

• Orofacial infection(gingivostomatitisandpharyngitis) is themost frequent initialclinicalmanifestation of HSV-1 infection. Recurrent lesions on the vermilion border of the lip(herpeslabialis)arethemostfrequentmanifestationoflatentinfection.

• ClinicalaspectsofprimarygenitalinfectionsareclinicallysimilarwithHSV-1orHSV-2,butrecurrencesaremorefrequentwithHSV-2.Complicationsincludeasepticmeningitis,trans-versemyelitis,andsacralradiculopathy.Extragenitallesionsmayoccurduringthecourseofprimarygenitalinfection.

• HSV can cause various eye infections such as keratitis, blepharitis, conjunctivitis, andretinitis.

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TABLE 73-1  Antiviral Chemotherapy for Herpes Simplex Virus Infection

DOSAGE/REGIMEN COMMENT

Mucocutaneous HSV Infections

Infections in Immunosuppressed Patients

Acute symptomatic first or recurrent episodes

IV acyclovir, 5 mg/kg q8h, and oral acyclovir, 400 mg qid, famciclovir, 500 mg PO tid, or valacyclovir, 1 mg PO bid, for 7-10 days are effective

Treatment duration may vary from 7-14 days

Suppression of reactivation disease

IV acyclovir, 5 mg/kg q8h, valacyclovir, 500 mg PO bid, or oral acyclovir, 400-800 mg two to three times per day, prevents recurrences during the immediate 30-day post-transplantation period

Longer-term suppression is often used for persons with continued immunosuppression. In bone marrow and renal transplant recipients, valacyclovir, 2 g four times daily, is also effective in preventing CMV infection. Valacyclovir, 4 g four times daily, has been associated with TTP after extended use in HIV-positive persons. In HIV-infected persons, oral famciclovir, 500 mg bid, is effective in reducing clinical and subclinical reactivations of HSV-1 and HSV-2. If using acyclovir in HIV-infected patients, we generally start with the lower dose of 400 mg twice daily and increase to 800 mg twice daily if breakthrough recurrences occur. Note: Once-daily dosing of valacyclovir, 500 mg to 1 g, should be avoided in HIV-infected patients owing to concerns regarding lower efficacy.

Symptomatic recurrent genital herpes in HIV-1–infected patients

Oral acyclovir, 400 mg tid × 5-10 daysValacyclovir, 1000 mg bid × 5-10 daysFamciclovir, 500 mg PO bid × 5-10 days

• Herpessimplexencephalitisisthemostcommonlyidentifiedcauseofacute,sporadicviralencephalitisintheUnitedStates.Magneticresonanceimagingistheneuroimagingtechniqueofchoicetoidentifyabnormalities.

• EsophagitisandpulmonaryinfectionsmaybecausedbyHSV,mostcommonlyinimmuno-compromisedpatients.

• NeonatalinfectionsmayoccurthroughcontactwithHSVsecretions.Infantsyoungerthan6weekshavethehighestfrequencyofvisualandcentralnervoussysteminvolvement.

DIAGNOSIS• ClinicalcriteriaareutilizedforconsiderationofthediagnosisofHSVinfection,butlabora-

torytestsareneededtoconfirmthediagnosis.• Diagnosis canbemadebydetectionofHSVDNAbypolymerasechain reactionassay in

lesionscrapings,fluids,ortissue.Viralisolationcanalsobemadeintissueculture,butthisisthreetofourtimeslesssensitivethanbyDNAmoleculartechniques.

TREATMENT• Acyclovir,valacyclovir,orfamciclovirisusedtotreatmucocutaneousandvisceralinfections

(seeTable73-1).• Genital infectionsmaybetreatedasaprimary infectionwhenrecognizedorasadiscrete

recurrence.Individualswithfrequentrecurrencesmaybetreatedwithsuppressivetherapy.• Herpessimplexencephalitisistreatedwithhigh-doseacyclovir(10mg/kgIVevery8hours

for14to21days).• Acyclovir-resistantHSVstrainscanbetreatedwithfoscarnetorcidofovir.

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DOSAGE/REGIMEN COMMENT

Infections in Immunocompetent Patients

Genital Herpes

First episodes Oral acyclovir, 400 mg tid (V) or 200 mg five times per day (I) × 7-10 daysOral valacyclovir, 1000 mg bid × 7-10 days (I)Famciclovir, 250 mg tid × 5-10 days (I)IV acyclovir, 5 mg/kg q8h for 5 days, is given for severe disease or neurologic complications such as aseptic meningitis

Symptomatic recurrent genital herpes

Oral acyclovir, 400 mg tid × 5 days (V), 800 mg PO tid × 2 days or bid × 5 days (II)

All these therapies are effective in shortening lesion duration. Short-course options (1, 2, or 3 days of therapy) should be considered based on increased convenience, likelihood of adherence and reduced cost and are listed in bold. Given the brief period of viral replication and rapid evolution of lesions, patients should be given drugs for self-administration when prodromal symptoms occur.

Valacyclovir, 500 mg bid × 3 days (I) or 1 g daily × 5 days (I)

Famciclovir, 125 mg bid for 5 days (I), 1 g bid for 1 day (I), or 500 mg once then 250 mg PO bid × 3 doses (I)

Suppression of recurrent genital herpes

Oral acyclovir, 400 mg bid (I)

Valacyclovir, 500 mg daily (I) or 1000 mg daily (I) or 250-500 mg bid (I) prevents symptomatic reactivation. Persons with frequent reactivation (<9 episodes/yr) can take valacyclovir 500 mg daily; those with >9 episodes/yr should take valacyclovir 1000 mg/daily or 500 mg bid.

Consider for patients with frequent (>6 episodes) or severe recurrences, in immunocompromised patients, or as an adjunct to prevent transmission

Famciclovir, 250 mg bid (I)

Orolabial HSV Infections

First episode Oral acyclovir, 15 mg/kg (up to 200 mg) five times per day (II) or 400 mg tid (V) × 7 daysFamciclovir, 500 mg bid (V)Valacyclovir, 1000 mg bid (V) × 7 days

Recurrent episodes

Oral acyclovir, 400 mg five times per day × 5 days (II)

Self-initiated therapy with topical 1% penciclovir cream q2h during waking hours (I); topical acyclovir cream, 5% five times per day × 4 days (I). Short-course options should be considered based on increased convenience and likelihood of adherence and are listed in bold. Given the brief period of viral replication and rapid evolution of lesions, patients should be given drugs for self-administration when prodromal symptoms occur.

Valacyclovir, 2000 mg bid × 1 day (I)

Famciclovir, 1500 mg once (I)

Suppression of reactivation of orolabial HSV

Oral acyclovir, 400 mg bid (II), or valacyclovir, 500 mg or 1000 mg daily (II), or famciclovir, 500 mg bid (V)

Consider for patients with frequent (>6 episodes) or severe recurrences, in immunocompromised patients, or as an adjunct to prevent transmission

Herpetic Whitlow

Oral acyclovir, 200 mg five times daily for 7-10 days

HSV Proctitis

Oral acyclovir, 400 mg five times per day is useful in shortening the course of infection

In immunosuppressed patients or in patients with severe infection, IV acyclovir, 5 mg/kg q8h, may be useful

TABLE 73-1  Antiviral Chemotherapy for Herpes Simplex Virus Infection—cont’d

Continued

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DOSAGE/REGIMEN COMMENT

Herpetic Eye Infections

In acute keratitis, topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon are all beneficial. Débridement may be required; topical corticosteroids may worsen disease.

CNS HSV InfectionsHSV encephalitis IV acyclovir, 10 mg/kg q8h (30 mg/kg/

day) for 14-21 days

HSV aseptic meningitis

IV acyclovir, 30 mg/kg/day for 7-10 days No studies of systemic antiviral chemotherapy exist

Autonomic radiculopathy

No studies are available

Neonatal HSV Infections

Acyclovir, 60 mg/kg/day (divided into three doses) × 21 days

Monitoring for relapse should be undertaken; most authorities recommend continued suppression with oral acyclovir suspension for 3-4 mo

Visceral HSV Infections

HSV esophagitis IV acyclovir, 15 mg/kg per day In some patients with milder forms of immunosuppression, oral therapy with valacyclovir or famciclovir is effective

HSV pneumonitis

No controlled studies exist. IV acyclovir, 15 mg/kg/day, should be considered.

Disseminated HSV Infections

No controlled studies exist. IV acyclovir, 10 mg/kg q8h, nevertheless should be given. No definite evidence indicates that therapy decreases the risk of death.

Erythema Multiforme–Associated HSV

Anecdotal observations suggest that oral acyclovir, 400 mg bid or tid, or valacyclovir, 500 mg bid, suppresses erythema multiforme

Surgical Prophylaxis

Several surgical procedures such as laser skin resurfacing, trigeminal nerve root decompression, and lumbar disk surgery have been associated with HSV reactivation. IV acyclovir, 3 mg/kg, and oral acyclovir, 800 bid, valacyclovir, 500 bid, or famciclovir, 250 bid, is effective in reducing reactivation. Therapy should be initiated 48 hr before surgery and continued for 3-7 days.

Infections with Acyclovir-Resistant HSV

Foscarnet, 40 mg/kg IV q8h, should be given until lesions heal. IV cidofovir, 5 mg/kg once weekly, might also be effective.

Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days.

CMV, cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; HSV, herpes simplex virus; TTP, thrombotic thrombocytopenic purpura.

Note: I, II, III, IV, and V represent level of evidence.Modified from Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based

review. Arch Intern Med. 2008;168:1137-1144; and Spruance S, Aoki FY, Tyring S, et al. Short-course therapy for recurrent genital herpes and herpes labialis: entering an era of greater convenience, better treatment adherence, and reduced cost. J Fam Pract. 2007;56:30-36.

TABLE 73-1  Antiviral Chemotherapy for Herpes Simplex Virus Infection—cont’d

183

74 Chickenpox and Herpes Zoster (Varicella-Zoster Virus)Richard J. Whitley

DEFINITION• Varicella-zoster virus (VZV) is an alpha herpesvirus that causes chickenpox and herpes

zoster.

EPIDEMIOLOGY• Chickenpoxistheprimaryinfectionoccurringprimarilyinchildhood.• Chickenpoxisusuallyabenigninfectionbutcancauselife-threateningdiseaseintheimmu-

nocompromisedhost.• Diseaseismorelikelytooccurinlatewinterandearlyspring.• Herpes zoster is the consequence of reactivation of latent virus, occurring mainly in the

elderly.• Herpeszostercausessignificantpaininmanyindividuals.• Thereisnoseasonalpredilectionforoccurrenceofherpeszoster.

MICROBIOLOGY• Varicella-zostervirusisadouble-strandedDNAvirus.Followingprimaryinfection,latency

isestablishedinsensoryganglia.

DIAGNOSIS• Thediagnosisofchickenpoxandherpeszosterisusuallyclinical.• Chickenpoxischaracterizedbyamaculopapular,vesicular,andpapularrashinallstagesof

evolution.• Herpes zoster isusuallyaunilateralvesicular rash.Disseminationcanoccur in immuno-

compromisedpatients.• Tzanck smears of lesion scrapings may demonstrate intranuclear inclusions; however, the

sensitivityislow.• Polymerasechainreaction(PCR)canbeappliedtolesionscrapinginordertodetectVZV

DNAandisthediagnosticprocedureofchoice.• Viralculturecanbeusedtomakeadiagnosis,butitislesssensitivethanPCR.

THERAPY• ThreedrugsarelicensedforthetreatmentofVZVinfections.• Chickenpox in children 2 to 16 years of age can be treated with acyclovir at a dosage of

20mg/kg4timesperdayfor5days.Forolderpatients,thedosageofacycloviris800mg5timesaday.

• Byclasseffect,theprodrugsvalacyclovirandfamciclovirareusedbysomeexpertstotreatchickenpox.

• Herpeszostercanbetreatedwithacyclovirat800mgfivetimesdailyfor7to10days.• Herpeszostercanbetreatedwithvalacyclovirat1gthreetimesdailyfor7to10days.• Herpeszostercanbetreatedwithfamciclovirat500mgthreetimesdailyfor7to10days.

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• Herpes zoster will likely require control of pain with analgesics and medications such aspregabalin.

PREVENTION• High-titeredvaricella-zosterimmuneglobulin(VariZIG)canbeadministeredtohigh-risk

patientstoattempttopreventinfection.• A VZV vaccine is available to prevent chickenpox. It is a two-dose series with the first

administeredat12to15monthsofageandthesecondbetween4and6years.Thistwo-doseseries has dramatically decreased the incidence of chickenpox and its associatedcomplications.

• Ahigh-titeredVZVvaccineisavailableforadultsolderthan50yearsofagethatwillreducetheincidenceofherpeszoster,theburdenofillness,andpostherpeticneuralgia.

185

75  Cytomegalovirus (CMV)Clyde S. Crumpacker II

DEFINITION• Human cytomegalovirus (HCMV) is a double-stranded DNA virus, a member of the

Herpesviridaefamily,andinfectsahighpercentageofhumansworldwide.Recentevidencepointstogreatgenomicvariabilityduringreplicationinasinglepatient.HCMVinfectionisusually asymptomatic, but may cause severe congenital infection and severe disease inimmunocompromised transplant and acquired immunodeficiency syndrome (AIDS)patients.

EPIDEMIOLOGY• Infantsinfectedinuteroasaresultofprimarycytomegalovirus(CMV)infectioninapreg-

nantwomanareatriskforseverecongenitalabnormalitiesandsensorineuralhearingloss.Healthy young adults can develop CMV mononucleosis. In immunocompromised AIDSpatients, CMV retinitis leads to vision loss. In solid-organ and hematopoietic stem celltransplant patients, life-threatening CMV pneumonia and hepatitis, meningoencephalitis,colitis, and esophageal ulcers can occur. The potential role of HCMV in cardiovasculardiseaseisbeingincreasinglyinvestigated.

MICROBIOLOGY• HCMVgrowsonlyinhumanepithelial,endothelial,smoothmuscle,neurologic,andfibro-

blastcells.Genomicanalysisusinghigh-throughputdeepsequencingincongenitallyinfectedinfantsrevealsextensivegenomicvariabilityanddiversity.

DIAGNOSIS• TheWorldHealthOrganizationhasstandardizedaCMVDNApolymerasechainreaction

assay(COBASAmplicor/COBASTagmanCMVtest)todetectCMVinbloodandinfectedtissue. This assay uses international units and permits comparison among clinical trials.DetectionofCMVpp65antigenininfectedneutrophilsremainsavaluablediagnostictool.

THERAPY• Ganciclovir(GCV)andvalganciclovir(VGC)are themainstaysof treatment.Foscarnet is

mainly useful for GCV-resistant CMV infection and disease. Cidofovir may be used fortreatment of failures with other anti-CMV drugs. A lipid-coated version of cidofovir(CMX001),maribavir,andletermovirareexperimentaldrugsforCMVundergoingclinicaldevelopment.

PREVENTION• GCVandVGCareusedasprophylaxis in the transplantationsetting.GCVandVGCare

alsousedaspreemptivetherapy.AneffectiveCMVvaccinehasnotyetbeendeveloped.

186

76 Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases)Eric C. Johannsen and Kenneth M. Kaye

DEFINITION• Infectiousmononucleosisisaclinicalsyndromecharacterizedbypharyngitis,fever,lymph-

adenopathy,andthepresenceofatypicallymphocytesonaperipheralbloodsmear.PrimaryEpstein-Barrvirus(EBV)infectionisthemostcommoncauseofthissyndrome.

VIROLOGY AND EPIDEMIOLOGY• EBVisaherpesvirusthatestablisheslifelonglatentinfectioninBlymphocytes.• Replicationoccursinoralepithelium,andinfectiousEBVisfrequentlypresentinthesaliva

ofasymptomaticseropositiveindividuals.• EBVistransmittedpredominantlythroughexposuretoinfectedsaliva,frequentlyasaresult

ofkissing.• Seroprevalenceapproaches95%inadults,andEBVisdistributedthroughouttheworld.• Inchildhood,primaryEBVinfectionisusuallyasymptomaticoranonspecificillness.• Frequencyofpresentationasinfectiousmononucleosisincreaseswithagetoabout50%of

primaryinfectionsbyadolescence.• EBV is tightly linked with several malignancies, including endemic Burkitt’s lymphoma,

nasopharyngealcarcinoma,andlymphoproliferativedisease.

MICROBIOLOGY• EBVisagamma-1herpesvirus,genusLymphocryptovirus.• EBVisadouble-strandedDNAvirusthatisenveloped.• EBVisalsoknownashumanherpesvirus4.

CLINICAL MANIFESTATIONS• Infectiousmononucleosisisgenerallyaself-limited,spontaneouslyremittingsyndrome.• Complications may occur, including splenic rupture, neurologic manifestations such as

encephalitis,autoimmunehemolyticanemia,andmildhepatocellularenzymeelevations.

DIAGNOSIS• Theappearanceofnonspecific,heterophileantibodies(IgMreactingwithsheeporhorsered

blood cells) can distinguish primary EBV infection from other causes of infectiousmononucleosis.

• ThepresenceofIgMviralcapsidantigen(VCA)antibodiesiscloselycorrelatedwithacuteEBVinfection.Heterophileantibodiesinapersonwithclinicalinfectiousmononucleosisissufficienttoestablishthediagnosis.

• EBVserologymaybehelpfulinatypicalcasesandinchildren(whoarefrequentlyhetero-philenegative).

• Primaryhumanimmunodeficiencyvirusinfectionisthemostimportantdifferentialdiag-nosticconsideration.

• Serial measurement of EBV viral loads may be useful in the detection of EBV-associatedmalignanciesinimmunosuppressedindividuals,especiallyforlymphoproliferativedisease.

187C

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align

ant D

iseases, and

 Oth

er Diseases)

THERAPY• Treatmentofmononucleosisisprimarilysupportive.• Corticosteroidsmaybehelpful inmanagingmononucleosis complications suchasairway

impingementfromtonsillarenlargement.• Antiviraltherapyisofnoprovenbenefitininfectiousmononucleosis.

PREVENTION• ThereiscurrentlynoEBVvaccine.

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77 Human Herpesvirus Types 6 and 7 (Exanthem Subitum)Jeffrey I. Cohen*

DEFINITION• Human herpesviruses 6 and 7 (HHV-6 and HHV-7) cause exanthem subitum or febrile

seizuresinyoungchildrenandreactivatefrequentlyinhighlyimmunocompromisedhosts.Theycanalsocauseencephalitisinimmunocompromisedhosts.

EPIDEMIOLOGY• MostadultsareseropositiveforHHV-6andHHV-7.• TheaverageageforinfectionwithHHV-6isabout1yearoldandforHHV-7is2yearsold.• About 50% of hematopoietic transplant recipients and 20% to 33% of organ transplant

recipientshaveHHV-6andHHV-7DNAintheblood.• HHV-6DNAisintegratedinthechromosomesof1%to2%ofpersonsandistransmitted

inthegermlineDNA.

MICROBIOLOGY• HHV-6andHHV-7,likecytomegalovirus,arebetaherpesviruses.

DIAGNOSIS• Exanthemsubitumisusuallydiagnosedclinically,butseroconversiontoHHV-6orHHV-7

antibodypositivitycanbeused.• DiagnosisofHHV-6orHHV-7diseaseinimmunocompromisedpersonsisdifficultdueto

thehighfrequencyofasymptomaticreactivationandthefindingthatupto2%ofpersonshaveHHV-6DNAintegratedintheirchromosomes.

• HHV-6limbicencephalitisisdiagnosedbasedonclinicalsignsandsymptomsandHHV-6DNAinthecerebrospinalfluid.

• DetectionofHHV-6proteinorRNAintissuesismorespecificthanHHV-6DNAfordiag-nosingvirus-associateddiseaseinimmunocompromisedpersons.

THERAPY• No therapy has been shown to be effective for treatment of HHV-6 or HHV-7, but both

virusesaresensitivetoganciclovir,foscarnet,andcidofovirinvitro.• Ganciclovir or foscarnet, or both, have been used to treat immunocompromised persons

withHHV-6orHHV-7disease,especiallywithlimbicencephalitis.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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78 Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)Kenneth M. Kaye

DEFINITION• Kaposi’ssarcoma–associatedherpesvirus(KSHV),orhumanherpesvirus8(HHV-8),isthe

etiologicagentofKaposi’ssarcoma,primaryeffusionlymphoma,andisalsotightlylinkedwithmulticentricCastleman’sdisease.

VIROLOGY AND EPIDEMIOLOGY• KSHV is a herpesvirus that establishes lifelong infection, primarily persisting in latently

infectedBlymphocytes.• Replicationoccursinoralepithelium,andinfectiousKSHVispresentinthesalivaofasymp-

tomaticseropositiveindividuals.• Transmissionispredominantlytheresultofexposuretoinfectedsaliva.• Primaryinfectionisusuallyasymptomaticandrarelyrecognized.• Incontrasttootherherpesviruses,seroprevalencevariessignificantlythroughouttheworld

andishighestinsub-SaharanAfrica,theMediterraneanregion,andinmenwhohavesexwithmenintheUnitedStates.

• KSHVmalignancyusuallyoccursinthesettingofimmunesuppression.

MICROBIOLOGY• KSHVisagamma-2herpesvirus,genusRhadinovirus.• KSHVisanenveloped,double-strandedDNAvirus.• KSHVisalsoknownasHHV-8.

DIAGNOSIS• KScanbediagnosedbyitsclinicalappearanceandconfirmedbybiopsy.• PrimaryeffusionlymphomaandmulticentricCastleman’sdiseasearediagnosedbybiopsy.• KSHVcanbedetectedserologically,althoughassaysarenotstandardized.

THERAPY• AntiviraltherapyisofnoprovenbenefitinthetreatmentofKSHVmalignancies,andtherapy

generallyreliesoncytotoxicapproaches.

PREVENTION• ThereiscurrentlynoKSHVvaccine.

190

79 Herpes B VirusJeffrey I. Cohen*

DEFINITION• HerpesBvirusisamacaquevirusthatcancausefatalencephalitisinhumans.

EPIDEMIOLOGY• Herpes B virus naturally infects Old World macaques, including rhesus and pig-tailed

macaquesandcynomolgusmonkeys.• Humans are infected with herpes B virus after bites, scratches, needlesticks, or mucosal

splasheswithfluidsfromOldWorldmacaques.

MICROBIOLOGY• Herpes B virus is an alphaherpesvirus and is the homolog of herpes simplex virus in

macaques.

DIAGNOSIS• Apositivepolymerasechain reaction (PCR)orculture forherpesBvirus in skin lesions,

conjunctival swabs, or cerebrospinal fluid in the presence of symptoms is diagnostic forherpesBvirusinfection.

• ApositivePCRorcultureforherpesBvirusofwoundsormucosashortlyafterinjuryindi-catesexposuretothevirusbutnotnecessarilyinfection.

• Humanspecimens forPCR,culture,orantibody testing shouldbe sent to theNationalBVirusResourceCenterinAtlanta,Georgia(www2.gsu.edu/~wwwvir/index.html).

THERAPY• PersonswithsignsorsymptomsofBvirus,orpositiveculturesorPCR(otherthanwound

orpostcleansingPCRorculture)andexposuretoOldWorldmacaquesshouldbetreated.• Intravenousacyclovir(12.5to15mg/kgq8h)organciclovir(5mg/kgq12h)isrecommended

forpersonswithoutcentralnervoussystem(CNS)disease.• Intravenousganciclovir(5mg/kgq12h)isrecommendedforpersonswithCNSdisease.• Treatmentiscontinueduntilsymptomsresolveandtwoculturesovera2-weekperiodare

negative;oralvalacycloviroracyclovirareoftengivenafterintravenoustherapyisdiscon-tinuedtopreventreactivationoflatentvirus.

PREVENTION• Firstaid,withthoroughcleansingofwoundsorexposedmucosa,isimportantafterinjuries

ormucosalsplasheswithmacaquefluids.• PersonswhohavehighriskofexposuretoBvirus(seeTable79-1)shouldreceivepostex-

posureprophylaxiswithin5daysofexposurewithvalacyclovir,1gtid,oracyclovir,800mg5timesdailyfor14days.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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TABLE 79-1  Recommendations for Postexposure Prophylaxis for Persons Exposed to Herpes B Virus

Prophylaxis RecommendedSkin exposure* (with loss of skin integrity) or mucosal exposure (with or without injury) to a high-risk source

(e.g., a macaque that is ill, immunocompromised, or known to be shedding virus or that has lesions compatible with herpes B virus disease)

Inadequately cleaned skin exposure (with loss of skin integrity) or mucosal exposure (with or without injury)

Laceration of the head, neck, or torso

Deep puncture bite

Needlestick associated with tissue or fluid from the nervous system, lesions suspicious for herpes B virus, eyelids, or mucosa

Puncture or laceration after exposure to objects (a) contaminated either with fluid from monkey oral or genital lesions or with nervous system tissues, or (b) known to contain herpes B virus

A postcleansing culture is positive for herpes B virus

Prophylaxis ConsideredMucosal splash that has been adequately cleaned

Laceration (with loss of skin integrity) that has been adequately cleaned

Needlestick involving blood from an ill or immunocompromised macaque

Puncture or laceration occurring after exposure to (a) objects contaminated with body fluid (other than that from a lesion), or (b) potentially infected cell culture

Regimen for ProphylaxisValacyclovir, 1 g PO tid, or acyclovir, 800 mg PO 5 times daily × 14 days

Prophylaxis Not RecommendedSkin exposure in which the skin remains intact

Exposure associated with nonmacaque species of nonhuman primates

*Exposures include macaque bites or scratches, or contact with ocular, oral, or genital secretions, nervous system tissues, or materials contaminated by macaques (e.g., cages or equipment).

From Cohen JI, Davenport DS, Stewart JA, et al. Recommendations for prevention and therapy of persons exposed to B virus (Cercopithecine herpesvirus 1). Clin Infect Dis. 2002;35:1191-1203.

192

80 AdenovirusesElizabeth G. Rhee and Dan H. Barouch

DEFINITION• Human adenoviruses (HAdVs) are DNA viruses that can cause a broad range of clinical

syndromes, including respiratory tract infections, ocular disease, gastroenteritis, diarrhea,andcystitis.

EPIDEMIOLOGY• HAdVs are ubiquitous; most humans have serologic evidence of prior infection by age

10years.• Transmission is via respiratory droplets or fecal-oral transmission. Virus secretion may

persistforprolongedperiodsafteracuteinfectionresolves.• Typically,thediseaseissubclinicalormildlysymptomaticandself-limited.• HAdVsareacommoncauseoffebrileillness,respiratorytractinfections(types1to7),and

gastroenteritis(types2to5)inyoungchildren;sporadicpediatricoutbreaksassociatedwithdaycarecentersandsummercamps.

• Acute respiratory disease, including pneumonia, is uncommon; sporadic outbreaks asso-ciated with military recruits (types 4 and 7); recent outbreak occurred in healthy adults(type14).

• Epidemickeratoconjunctivitis(types8,19,and37)hasbeenlinkedtonosocomialtransmis-sionbyinfectedinstruments.

• HAdV is an emerging opportunistic pathogen in immunocompromised hosts, primarilyhematopoieticstemcell transplant(HSCT)andsolidorgantransplant(SOT)recipients; itcanresultindisseminateddiseaseortargetgraftedorgan.

• There is interest inusingHAdVasvectors forgene therapy,asvaccinesbeingstudied forinfectiousdiseases(humanimmunodeficiencyvirus[HIV],malaria);andasimmunomodu-latorytreatmentsforsolidtumors.

MICROBIOLOGY• HAdVsarenonenveloped,lyticDNAviruses,characterizedbyserologicresponsestomajor

capsidproteinsandwhole-genomeanalysis.• HAdVs are classified into 7 groups (A to F); 60 types isolated from clinical specimens

sofar.• HAdVswereoriginallyisolatedfromadenoidtissues,leadingtothevirusname.

DIAGNOSIS• Diagnosisisnotroutinelypursuedbecausemostinfectionsaremildandself-limited.• HAdVs are detected by routine viral tissue culture (except types 40 and 41) and can be

recoveredfromswabs,samples,andtissues;immunofluorescenceassay(IFA),enzyme-linkedimmunosorbentassay,acute/convalescentserumtiterscanestablishdiagnosis.

• Polymerasechainreactionishighlysensitiveandspecific(96%to100%)inimmunocompe-tentadults.

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THERAPY• Therearenoapprovedtherapiesavailable.• CaseseriesreportpartialclinicalresponsebutsubstantialtoxicitiestocidofovirinHSCT/

SOT.Clinicaltrialofbrincidofovirintransplantpatientsisunderway.

PREVENTION• Liveoralvaccines(type4and7)areadministeredtomilitarypersonnelandarehighlyeffec-

tiveinpreventingadenovirus-associatedfebrilerespiratorydiseases.

194

81  PapillomavirusesWilliam Bonnez

DEFINITION• Human papillomavirus (HPV) infects the squamous stratified epithelia of the body and

causestumorsthatcanbebenign(warts,condylomas,papillomas)ormalignant(squamouscellcarcinomas,uterinecervicaladenocarcinoma).

• Theycausetwomaingroupsofdiseases:(1)cutaneous(hand,foot,flat)wartsand(2)lesionsof the mucosal or genital surfaces, such as genital warts, laryngeal papillomas, as well ascancersofthecervix,vagina,vulva,anus,penis,andoropharynx,andtheirrespectiveprecur-sorlesions,calledintraepithelialneoplasias(dysplasias).

EPIDEMIOLOGY• Cutaneous warts are predominantly a disease of school-aged children. They are acquired

fromclosecontacts,predominantlyinthefamilyenvironment.• Genital (ormucosal)HPVinfectionsaremostlysexually transmitted,andtheir incidence

peaksinlateadolescenceandearlyadulthood.• MostofthesexuallyactivepopulationwillhavebeenexposedtogenitalHPVinalifetime.• GenitalHPVinfections inmalesandfemalesareeasilyacquired,butmostalsodisappear

quickly.Persistenceisariskfactorforthedevelopmentofcancer.

MICROBIOLOGY• HPVsaresmall,nonenvelopedDNAviruses,classifiedaccordingtothenucleotidesequence

of the gene coding for the major capsid protein. These viruses are not routinelycultivatable.

• Atleast184typeshavebeenidentified,butonlyasmallnumbercarrythebulkofthehealthburden.

• HPVtypes1,2,and4arethemostcommontypesfoundincutaneouswarts.• HPVtypes6and11accountformostgenitalwarts.• HPVtypes16and18cause thegreatmajorityofcancersof theanogenital tractandoro-

pharynxandaredefinedashigh-riskoncogenic.• The more severe the grade of intraepithelial neoplasia, the more prevalent are high-risk

oncogenicHPVsinthelesion.

DIAGNOSIS• Thediagnosisofcutaneouswartsandofgenitalwartsistypicallyclinical.Abiopsyisindi-

catedwhenthediagnosisisindoubtoramalignancyoritsprecursorisaconsideration.• For the screening of cervical cancer, cytology (Pap smear) is the primary diagnostic

approach.• HPVDNAtestingsupplementsscreeningcytology.

THERAPY• ManytherapeuticmodalitiesexistforthetreatmentofHPV-inducedlesions,noneofthem

fullysatisfactory.Theycanbedividedintomedicalandphysicalapproaches.

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• Thechemicalmethodsincludesalicylicacidsolutionsforcutaneouswartsorpodofiloxorimiquimodforgenitalwarts.

• The physical methods include cryotherapy, cold-blade excision, electrosurgery, and lasertherapy,andtheycanbeappliedtomostlesions.

PREVENTION• Malecondomshavesomeeffectivenessinprotectingagainstgenitalinfections.• Papsmearsareessentialforthepreventionofcervicalcancer.• Vaccination is very effective and safe in preventing genital warts as well as intraepithelial

neoplasiasofthecervix,vagina,vulva,andtheanusinmalesandfemales.• Two highly effective vaccines are available. Gardasil is quadrivalent and protects against

HPV-6,HPV-11,HPV-16,andHPV-18;Cervarixisbivalent,anditonlycoversHPV-16andHPV-18.Thevaccinesaregivenintramuscularlyinthreedoses.

• A9-valentvaccine(Gardasil9)hasbeenapprovedbytheU.S.FoodandDrugAdministrationinDecember2014.ItcoversHPV-31,HPV-33,HPV-45,HPV-52,andHPV-58,inadditiontothefourlistedearlier.

196

82 JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)C. Sabrina Tan and Igor J. Koralnik

JC VIRUSDefinition• JC virus (JCV) is a ubiquitous human polyomavirus that causes central nervous system

diseasesinimmunocompromisedpatients,includingprogressivemultifocalleukoencepha-lopathy(PML),JCVgranulecellneuronopathy,andJCVencephalopathy.

Epidemiology• JCVinfects40%to86%ofthegeneralpopulationworldwide.• JCV can be detected in the urine of one third of healthy and immunosuppressed

individuals.• PML can occur in up to 5% of untreated patients with acquired immunodeficiency

syndrome.• Upto82%ofPMLpatientsareinfectedwithhumanimmunodeficiencyvirus.

Microbiology• JCVisamemberofthePolyomaviridae.• Itisadouble-strandedDNAviruswithoutanenvelope.• Afterprimaryinfection,JCVremainslatentinthekidneyepithelialcells.• Reactivation of JCV causes a lytic infection of oligodendrocytes in the brain, leading

toPML.

Diagnosis• Definitive diagnosis of PML:JCVisdetectedincerebrospinalfluidbypolymerasechainreac-

tion(PCR)assayorJCVproteinsaredetectedinbraintissues.• Possible diagnosis of PML:Magneticresonanceimagingfindingsandclinicalpresentationare

consistentwithPMLintheabsenceofJCVdetectionincerebrospinalfluid.

Therapy• Therearenoeffectiveantiviralmedications.• ImmunereconstitutioncanboosthostcellularimmuneresponsetobettercontrolJCviral

replication.

Prevention• Measuresshouldbetakentopreventimmunosuppression.

BK VIRUSDefinition• BK virus (BKV) is a ubiquitous human polyomavirus that causes hemorrhagic cystitis in

hematopoieticstemcelltransplantationpatientsandnephropathyinkidneytransplantationrecipients.

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Epidemiology• BKVinfects82%to90%ofthegeneralpopulationworldwide.• BKVcanbedetectedintheurineofasymptomatichealthyindividuals.• BKVnephropathyoccursinupto10%ofkidneytransplantpatients.• BKV-associated disease can occur in up to 15.9% of allogeneic stem cell transplant

recipients.

Microbiology• BKVisamemberofthePolyomaviridae.• Itisadouble-strandedDNAviruswithoutanenvelope• Afterprimaryinfection,BKVremainslatentinthekidneyepithelialcells.• ReactivationofBKVcauseshemorrhagiccystitisandnephropathy.

Diagnosis• BKVisdetectedbyPCRassayinbloodandsustainedviruriainurine.• Cytopathologicchangesmaybedetectedonakidneybiopsyspecimen.

Therapy• Thereisnoeffectiveantiviralmedication.• Reductioninimmunosuppressioncanboosthostcellularimmuneresponsetobettercontrol

BKVreplication.

Prevention• EarlydetectionofviralreactivationinurineandbloodbyPCRassaycanbeanindicatorfor

apreemptivereductioninimmunosuppressiontohelpreduceoccurrenceofrenaldisease.

198

83 Hepatitis B Virus and Hepatitis Delta VirusChloe Lynne Thio and Claudia Hawkins

DEFINITION• Hepatitis B virus (HBV) causes chronic hepatitis B, which can lead to progressive liver

disease,includingcirrhosisandhepatocellularcarcinoma.• Hepatitisdeltavirus(HDV)occursasacoinfectionorsuperinfectionwithHBVestablishing

achronicinfectioninhepatocytes.

EPIDEMIOLOGY• Fivepercentoftheworld’spopulationhaschronichepatitisB,butprevalencevarieswidely

(seeTable83-1).• ThehighestHBVprevalenceisinAsia,Africa,andpartsoftheMiddleEast.• ChronichepatitisBistheleadingcauseofend-stageliverdiseaseworldwide.• Transmission of HBV is through percutaneous or sexual routes. Perinatal transmission is

alsocommon.• About5%ofpeoplewithchronichepatitisBhaveevidenceofexposuretoHDV.• HDVhasaworldwideprevalencethatgenerallymirrorsHBVprevalence,althoughthereare

exceptions.• HDVisprimarilytransmittedviatheparenteralroute,butthereissomesexualtransmission.

Perinataltransmissionisuncommon.

MICROBIOLOGY• HBV is apartiallydouble-strandedDNAvirus in theHepadnavirus family thatprimarily

infectshepatocytes.• HBVreplicationisthroughanRNAintermediate,soithasareversetranscriptase.• HDVisasmall,defectiveRNAvirusthatreliesonhostcellmachineryforreplication.• HDVrequirestheenvelopeofHBVforviralassemblyandtransmission.

CLINICAL PRESENTATION AND DIAGNOSIS• Clinical presentation of HBV varies from asymptomatic to fulminant hepatitis with liver

failure.• TheriskofdevelopingchronichepatitisBisinverselyproportionaltoageofacquisitionof

infection.ChronichepatitisBisalsomorelikelyinhigh-riskpatientgroupssuchasinjectiondrug users, men who have sex with men, and human immunodeficiency virus–infectedindividuals.

• LaboratorydiagnosisofHBVisbyenzymeimmunoassays,whichdetectvariousHBVanti-gensandantibodies,andbyreal-timepolymerasechainreaction(PCR)todetectHBVDNA(seeTable83-2).

• ClinicalpresentationofHDVisalsovariablebutcanpresentasacuteseverehepatitis.• LaboratorydiagnosisofHDViswithenzymeimmunoassayforHDVantibodiesandHDV

RNAbyreal-timePCR.

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THERAPY• Anti-HBVagentssignificantlyreducecomplicationsofchronichepatitisB, including liver

cirrhosis and hepatocellular carcinoma. These therapies are also effective in reducing therecurrenceofHBVinfectionintransplantrecipientsandotherimmunocompromisedhosts.

• HBVistreatedwith180µgofpegylatedinterferon-α(PEGIFN-α)weeklyfor48weeksorwithnucleos(t)ideanaloguesoftenindefinitely(seeTable83-3).

• Thefirst-linenucleos(t)ideagentsareentecavir0.5mgdailyortenofovir300mgdaily.• HDVistreatedwith180µgPEGIFN-αweeklyforaminumumof48weeks.

PREVENTION• VaccinationwiththehepatitisBvaccineisrecommendedinallinfantsandchildrenandfor

nonimmuneadultsathighriskforinfection(seeTable83-4).• InfantsborntomotherswithchronichepatitisBshouldreceivethehepatitisBvaccineand

hepatitisBimmuneglobulin(HBIG)atbirth.• Nonimmune individuals who have percutaneous, sexual, ocular, or mucous membrane

exposure toHBV-infectedfluids shouldreceivepostexposureprophylaxiswithHBIGandhepatitisBvaccine.

TABLE 83-1  Global Seroprevalence Rates and Modes of Transmission of Hepatitis B

CHARACTERISTIC HIGH INTERMEDIATE LOWCarrier rate (%) >8 2-7 <2

Distribution Southeast Asia, China, Alaskan Eskimos, sub-Saharan Africa, Middle East except Israel, Haiti, Dominican Republic

Eastern and southern Europe, Mediterranean, central Asia, Latin and South America, Israel

United States, Canada, western Europe, Australia, New Zealand

Age at infection Perinatal and early childhood Childhood Adult

Mode of transmission Maternal and perinatal Percutaneous Sexual, percutaneous

TABLE 83-2  Interpretation of Serologic Tests in Hepatitis B

TESTACUTE HEPATITIS B

IMMUNITY THROUGH INFECTION*

IMMUNITY THROUGH VACCINATION

ACTIVE CHRONIC HEPATITIS B†

INACTIVE CHRONIC HEPATITIS B

HBsAg + – – + +Anti-HBs – + + – –

HBeAg + – – ± –

Anti-HBe – ± – ± +Anti-HBc + + – + +IgM anti-HBc + – – – –

HBV DNA + – – + ± (low)

ALT Elevated Normal Normal Elevated Normal

ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; DNA, deoxyribonucleic acid; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M.

*Occasionally individuals with past infection have isolated anti-HBc only. The presence of an isolated immuno-globulin G anti-HBc may indicate a window period during acute infection or remote prior infection with loss of HBsAg or anti-HBs. In such cases, an HBV DNA test may prove useful.

†Chronic hepatitis B with a pre-core mutant is HBeAg− and anti-HBe+.

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 Ag

ents

TABLE 83-3  Approved Agents for Treatment of Chronic Hepatitis B*

PEG

IFN

-α

LAM

IVU

DIN

E

AD

EFO

VIR

ENTE

CA

VIR

TELB

IVU

DIN

E

TEN

OFO

VIR

Route Subcutaneous Oral Oral Oral Oral Oral

Dose 180 µg/wk 100 mg/day† 10 mg/day† 0.5 mg/day† (1 if lamivudine resistant)

600 mg/day† 300 mg/day†

Duration (wk) 48 ≥48 ≥48 ≥48 ≥48 ≥48

Tolerability Fair-poor: flulike symptoms

Good Good: follow renal function

Good Good Good: follow renal function

HBeAg seroconversion

27% 16%-21% 12% 21% 22% 21%

Undetectable HBV DNA‡

25%-63% 40%-73% 21%-51% 67%-90% 60%-88% 76%-93%

ALT normalization

38% 41%-75% 53% 72% 65% 74%

HBsAg loss 3% <1% 0% 2% <1% 3%

Viral resistance None 15%-30% Minimal None§ 6% 0%

ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; PEG IFN-α, pegylated interferon-α.

*All data are for 1 year unless otherwise noted.†Dose adjustment for creatinine clearance.‡Higher end of range for HBeAg-negative disease.§None; otherwise, 7% if preexisting lamivudine resistance.Modified from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2009;50:661-662.

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TABLE 83-4  Doses and Schedules of Licensed Hepatitis B Vaccines*

HEPATITIS B VACCINES AGE DOSE VOLUME SCHEDULEEngerix-B <20 yr 10 µg 10 µg/

0.5 mLInfants†: birth, 1-4, 6-18 mo

Older children: 0, 1-2, 4 mo

>20 yr 20 µg 20 µg/1 mL 0, 1, 6 mo

Diabetes 19-59 yr¶ 20 µg 20 µg/1 mL 0, 1, 6 mo

Dialysis and other immunocompromised

40 µg 2-20 µg/1 mL doses

0, 1, 2, 6 mo

Recombivax HB <20 yr 5 µg 5 µg/0.5 mL Infants†: birth, 1-4, 6-18 mo

Older children: 0, 1-2, 4 mo

11-15 yr 10 µg 10 µg/1 mL 0, 4-6 mo

>20 yr 10 µg 10 µg/1 mL 0, 1, 6 mo

Diabetes 19-59 yr¶ 10 µg 10 µg/1 mL 0, 1, 6 mo

Dialysis and other immunocompromised

40 µg‡ 40 µg/1 mL 0, 1, 6 mo

COMBINATION VACCINES AGE§ ANTIGEN VOLUME SCHEDULEComvax 6 wk-4 yr PedvaxHIB|| and

Recombivax0.5 mL 2, 4,

12-15 mo

Pediarix 6 wk-6 yr Engerix-B, Infanrix (DTaP), and IPV

0.5 mL 2, 4, 6 mo

Twinrix >18 yr Havrix (HAV) and Engerix-B (20 µg)

1 mL 0, 1, 6 mo

*All vaccines should be administered intramuscularly in the deltoid.†Infants born to hepatitis B surface antigen (HBsAg)-positive mothers should have hepatitis B immune globulin

(HBIG) within 12 hr of delivery, along with vaccine at a separate site. If mother’s HBsAg status is unknown, admin-ister vaccine within 12 hr and test mother. If mother is HBsAg positive, administer HBIG within 1 week.

‡Special formulation.§Birth dose should be monovalent vaccine only; subsequent doses can be combination.||PedvaxHIB, licensed Haemophilus influenzae type b vaccine; Infarix, licensed diphtheria, tetanus, and acellular

pertussis vaccine (DTaP); Havrix, licensed hepatitis A virus (HAV) vaccine.¶Hepatitis B vaccination may be administered at the discretion of the treating clinician to unvaccinated adults with

diabetes mellitus who are aged ≥60 years (see http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a4.htm).

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84 Human Parvoviruses, Including Parvovirus B19V and Human BocaparvovirusesKevin E. Brown

DEFINITION• Atleastfourdifferenttypesofparvovirusinfecthumans.• ParvovirusB19(B19V)cancauseerythemainfectiosum(slappedcheekdisease),transient

aplasticcrisis,andpureredcellaplasiaorfetalhydrops.• Humanbocaparvoviruses(HBoVs)cancauserespiratoryinfectionsandmaybeassociated

withsomecasesofgastroenteritis.• Humandependoparvovirusinfections(adeno-associatedviruses[AAVs])areasymptomatic,

andmodifieddependoparvovirusesareusedasvectorsforgenetherapy.• DiseaseassociationswithParv4infectionarenotclear.

EPIDEMIOLOGY• ParvovirusB19 infection isacommon infection inchildrenandyoungadults.Byage15,

50%ofchildreninAmericaandEuropewillhavebeeninfectedandhaveIgG.• B19Vismainlyspreadthroughtherespiratoryroute,although itmayalsobe transmitted

throughbloodandbloodproducts.• B19V infections in temperateclimatesaremorecommon in latewinter, spring,andearly

summer,withincreasedratesofinfectionevery3to5years.• HBoV infections are ubiquitous in young children, with most if not all children being

infectedwithHBoV1bytheageof6.

DIAGNOSIS• AlthoughtheslappedcheekrashofparvovirusB19infectionisclassic,itisdifficulttoaccu-

ratelydiagnoseoutsideofthecontextofanoutbreak.• DiagnosisofB19VrashisbydetectionofB19VIgMinserum.• Hematologic disease due to B19 can be diagnosed by detection of high-titer B19V DNA

(>106IU/mL)inbloodsamples.• Followinginfection,lowlevelsofB19VDNAmaybedetectedlifelong.Detectionoflow-level

B19VDNAinsamplesthereforedoesnotindicaterecentorcurrentinfection.• Similarly,long-termpersistenceofbocavirusDNAinrespiratoryandfecalsamplesindicates

that detection of viral DNA alone does not correlate with infection. Respiratory HBoV1infectionshouldbediagnosedbydetectionofviralDNAinserumorserology,orboth.

THERAPY• Treatmentforallparvovirusinfectionsismainlysymptomatic.• Intravenous immunoglobulin can be used for treatment of chronic anemia or pure red

aplasiaduetohigh-titerparvovirusB19infection.

PREVENTION• AvaccineforparvovirusB19isindevelopment.

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85 Orthoreoviruses and OrbivirusesRoberta L. DeBiasi and Kenneth L. Tyler

DEFINITION• Reovirusesarelineardouble-strandedRNAviruseswithbroadhostranges.• Thetermreovirusisanacronymforrespiratoryentericorphanvirus,whichemphasizesthe

anatomicsitefromwhichtheseviruseswereinitiallyisolated.

EPIDEMIOLOGY• Infectionofhumansiscommonbutisrarelyassociatedwithsignificantdisease.• Asymptomatic infection is common; symptomatic infection usually consists of mild, self-

limitedupperrespiratorytractandgastrointestinalillness.• Reoviruseshavebeen identifiedas thecausativeagent in rarehumancasesofmeningitis,

encephalitis,pneumonia,andmyocarditisandarepotentiallyassociatedwithbiliaryatresiaandcholedochalcysts.

MICROBIOLOGY• Five genera of the Reoviridae have been etiologically linked with diseases of humans:

Orthoreovirus, Orbivirus, Rotavirus, Coltivirus,andSeadornavirus.• Double-strandedRNAisorganizedinto10to12segments,whicharecapableofreassort-

mentandresultantgenerationofnovelviruses.

DIAGNOSIS• Laboratorydiagnosiscanbemadeserologicallybyafourfoldriseinacuteandconvalescent

serumantibodyresponseorbyvirusisolationfromserum,stool,respiratorysecretions,orcerebrospinalfluid.

THERAPY• Nospecifictherapyisavailable.

PREVENTION• Nospecificpreventativemeasuresarerecommended—reovirusesareubiquitous.

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86  Coltiviruses and SeadornavirusesRoberta L. DeBiasi and Kenneth L. Tyler

DEFINITION• ColtivirusandSeadornavirusaretwooffivegeneraoftheReoviridaevirusfamilythathave

beendocumentedtocausehumandisease.

EPIDEMIOLOGY• Coltiviruses associated with human disease include the type-specific Colorado tick fever

virus(CTFV;NorthAmerica),Eyachvirus(EYAV;France,Germany,CzechRepublic),andSalmonRivervirus(SRV;NorthAmerica).

• TheonlySeadornavirusimplicatedinhumandiseasetodateisBannavirus(BAV;IndonesiaandChina).

• Ticksaretheprincipalvectorsofcoltivirusesbuthavealsobeenisolatedfrommosquitoes,rodents,andhumans.

• ThedistributionofCTFVcoincideswiththerangeoftheprincipaltickvector.Thevirushasbeenisolatedin11states,primarilywithintheRockyMountainregion,aswellassouthwest-ernCanada.

• CTFVhasbeenisolatedfrompatientswithacutefebrilesyndromes,meningitis,andenceph-alitisinNorthAmerica.

MICROBIOLOGY• Coltiviruses and seadornaviruses are nonenveloped double-stranded RNA viruses with a

segmentedgenome.Coltiviruseshave12genesegmentsenclosedwithintwocapsids.

DIAGNOSIS• CTFVshouldbeconsideredinanyonepresentingwithafebrileillnessfollowingtickexpo-

sureinanendemicarea.• Patientsmayhavecerebrospinalfluidpleocytosis.Leukopeniaiscommon.• Serologic methods, including enzyme-linked immunosorbent assay, as well as serum and

cerebrospinal fluid reverse transcriptase–polymerase chain reaction have been used fordiagnosis.

• Viruscanalsobeisolatedincellculture.

THERAPY• Nospecifictherapyisavailable.

PREVENTION• Preventativemeasuresincludetickandmosquitorepellentssuchasdiethyltoluamide,physi-

calbarriers,andreductionofstandingwater.• CTFVpatientsshouldnotbeallowedtoserveasbloodproductorhematopoieticstemcell

donorsuntilinfectionhasfullyresolved.

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87  RotavirusesPhilip R. Dormitzer

DEFINITION• Rotavirusisanonenveloped,double-strandedRNAvirusthatisthemostimportantuniver-

salcauseofdehydratinginfantandchildhoodgastroenteritis.

VIRAL STRUCTURE AND REPLICATION• Theviralparticleisatriple-layeredicosahedron.• Genomeconsistsof11segmentsofdouble-strandedRNA.• TheouterlayerglycoproteinVP7andthespikeproteinVP4mediateentryintocellsandare

theneutralizationdeterminants.• Thevirusbindscellsurfacecarbohydrates.• Cellsareenteredbyviralpenetrationofthecellularmembrane.• Aftertheouterlayerisremoved,asubviralparticletranscribesandextrudesmRNA.• Newsubviralparticlesassembleinviroplasmsinthecytoplasm,andvirionsarecompleted

byadditionoftheouter-layerproteinsintheendoplasmicreticulum.

CLINICAL MANIFESTATIONS• Gastroenteritisduetorotavirusisnotreadilydistinguishedfromgastroenteritiscausedby

otheragentsonclinicalgroundsalone.• Mainsymptomsarediarrheaandvomiting.Severedehydrationanddeathcanresult.

PATHOGENESIS• Thevirusprimarilyinfectsepithelialcellsatthetipsoftheintestinalvilli.• Multifactorial pathogenesis of rotavirus diarrhea includes malabsorption due to loss of

intestinal epithelial cells, an enterotoxin, and enteric nervous system signaling to create asecretorystate.

SEROLOGIC CLASSIFICATION• GroupArotavirusescausemosthumandisease.• Thereisanextensivediversityofantigenictypes.• WithingroupA,rotavirushasadualserologicclassificationsystemwithGtypebasedon

VP7andPtypebasedonVP4.• Geneticclassificationisstartingtoreplaceserologicclassification.

EPIDEMIOLOGY• Infectionisuniversalinthefirstyearsoflife.• Infectionmaybesymptomaticorasymptomatic.• Severeillnessismostcommonbetween6monthsand2yearsofage.• Reinfectionoccursthroughoutlife.• Thereisalargeburdenofillnessinallsocioeconomicsettings,butmortalityisconcentrated

indevelopingcountries.

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• Annually,rotavirusescauseapproximately450,000deathsofchildrenyoungerthantheageof5years.

• Exchangeofstrainsandgenomesegmentsbetweenhumanrotavirusesandanimalrotavi-rusesmaintainsthediversityofcirculatingstrains.

IMMUNITY• Partialprotectionfromreinfectionisprovidedbypreviousinfection,withgenerallydecreas-

ingseverityofsubsequentinfections.• Serotypeinfluencesbutdoesnotdetermineprotectionfromreinfection.• VP4andVP7eachcontainserotype-specificandheterotypicneutralizingepitopes.• Neutralizingantibodiesblockthefunctionsoftheoutercapsidproteinsincellentry.• Non-neutralizingIgAagainstthemiddlelayerprotein,VP6,caninterferewithintracellular

virusreplication,astheantibodyistranscytosedacrossintestinalepithelialcells.• Humoral immunity appears to be the most important determinant of protection from

reinfection.• Cellularimmunitycontributestoclearanceofinfection.• Rotavirusinterfereswiththeinnateimmuneresponsebyseveralmechanisms.

DIAGNOSIS• Specificvirologicdiagnosisisnotnecessaryforroutineclinicalcarebutisusefulforepide-

miologicstudy,incomplicatedorprolongedcases,andtoreduceunnecessaryantibioticuse.• Antigencanbereadilydetectedinthestool,mostcommonlybyenzyme-linkedimmuno-

sorbentassay.• Thereisincreasinguseofnucleicacid–basedtestingforepidemiologicinvestigations.

THERAPY• Therapy is primarily supportive and aimed at maintaining hydration until the infection

resolves.• Nospecificantiviraltherapyisavailable.• Mildandmoderatedehydrationcanbetreatedeffectivelywithoralrehydrationsolutions.• Severedehydrationandtreatmentforpatientswithdepressedconsciousnessorileusrequire

theuseofintravenousfluids.• Inthecontextofmalnutrition,zincsupplementationmaybeausefuladjuncttooralrehydra-

tiontherapy.

IMMUNIZATION• Twolive-attenuated,oralrotavirusvaccineshavebeenlicensedandarecurrentlyinuse—a

monovalentvaccine(Rotarix)andapentavalentvaccine(RotaTeq).• Ararecomplicationofimmunization,intestinalintussusception,ledtothewithdrawalofa

previousrotavirusvaccine,butthereisconsensusthatthebenefitsofimmunizationwiththecurrentrotavirusvaccinesfaroutweightheriskforintussusception.

• Wherethevaccineshavebeenintroduced,theyhavedramaticallydecreasedsevererotavirusgastroenteritis and substantially decreased severe, dehydrating pediatric gastroenteritisoverall.

• Thenextmajorchallengeisdistributingrotavirusvaccinestothedevelopingcountrieswheremortalityisconcentrated.

• Despitelowerefficacyinimpoverishedsettingsthaninaffluentsettings,rotavirusvaccinescouldhavealargeimpactoninfantmortalityworldwide.

• Localproductionofnewrotavirusvaccinecandidatesindevelopingcountriescouldcontrib-utetoincreasedaccess.

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88 AlphavirusesLewis Markoff

DEFINITION• Alphaviruses,whichconstituteagenusofmorethan30viruses intheTogaviridae family,

arelipid-enveloped,positive-senseRNAviruses.• Allhumanpathogenicalphavirusesaremosquitoborne.

EPIDEMIOLOGY• The presence of infected mosquitoes is required for disease outbreak. Human-to-human

transmissiondoesnotoccur.• New World alphaviruses include Eastern, Western, and Venezuelan equine encephalitis

viruses (EEEV, WEEV, and VEEV, respectively), which are found in North and SouthAmerica.

• OldWorldalphaviruses,especiallychikungunya(CHIK),Sindbis,RossRiver,andO’nyong-nyong viruses, found in Europe, Africa, and Asia, cause a fever, arthralgia, and rashsyndrome.

• Inmostcases,exceptforCHIKvirus,thelifecycleofthevirusesrequiresmosquitoesandananimalhostinnature,otherthanhumans.

PATHOGENESIS• Alphaviruses enter cells by receptor-mediated endocytosis and exit by budding from the

plasmamembrane.• Alphavirusesenter thebodyviamosquitobitesandreplicate invarious tissues, including

Langerhanscells,whichthenmigrateto lymphnodes,causingviremia.Viremiaresults ininvasionofthecentralnervoussystem(CNS)byalphavirusesthatcauseencephalitisorofthejointsandinternalorgansbyvirusesthatcausefever,arthralgia,andrash.

• AllalphavirusessuppresstheinnateimmuneresponsebyinhibitingJAK/STATsignaling,amajorearlydeterminantofdiseaseseverity.

• Atlatertimes,recoveryismediatedbyvirus-neutralizingantibodiesandcytotoxicTcells.• In the CNS, virus replication in neurons is suppressed indefinitely by antibody-secreting

Bcells.

DIAGNOSIS• Knowledgeofthepatient’stravelhistoryisofmajorimportanceindiagnosis.• Thefever/arthralgia/rashsyndromecausedbyOldWorldalphavirusescanbeconfusedwith

manyotherviralexanthems.• Alphavirusencephalitisissimilarinpresentationtothatcausedbytheflaviviruses,WestNile

andSt.Louisencephalitisviruses.• Cultureofvirusfrombloodordetectionbyreverse-transcriptasepolymerasechainreaction

isnotrecommendedfordiagnosisofencephalitisbutmayoccasionallyyieldpositiveresultsintheacutephaseoffever/arthralgia/rashsyndrome.

• Detectionofvirus-neutralizingantibodies incombinationwithrecent travelhistory toanendemicareamaybemeaningful.

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• Virus-specificIgMorIgGclassantibodies,orboth,canbedetectedbyenzyme-linkedimmu-nosorbentassay;agreaterthanfourfoldriseintiterbetweenacuteandconvalescentseraorvirus-specificIgMincerebrospinalfluid,orboth,arediagnostic.

THERAPY• Atpresent,therearenoproductslicensedfortreatment.• Experimentaltherapiesthatseempromisingincludetheuseofhumanmonoclonalantibod-

ies,especiallyintreatmentofalphavirusencephalitis.• Forencephalitis,supportivemeasuresandintensivenursingcarearecurrentlyindicated.• Forfever/arthralgia/rashsyndrome,analgesicsandnonsteroidalanti-inflammatorydrugsare

themaintreatmentoptions.

PREVENTION• Veterinaryvaccinesareavailableforhorses,andtheirimmunizationagainstWEE,EEE,and

VEEisrequiredintheUnitedStates.• Thereareno licensedvaccines forpreventionofalphavirusdiseases inhumans,butunli-

censed vaccines against VEE, EEE, WEE, and CHIK are available for at-risk laboratoryworkers.

• Vaccinesareunderdevelopment,particularlyagainstCHIK.OnepromisingapproachistheuseofCHIKvirus–likeparticlesforimmunization.

• Theprimarymethodsfordiseasepreventioninhumansaremosquitoeradicationprograms,avoidance of mosquito-infested areas, and use of protection from mosquito bites, whereexposuretopossiblyinfectedmosquitoesisunavoidable.

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89  Rubella Virus (German Measles)Anne A. Gershon

DEFINITION• Rubellaisaninfectiousillnesscharacterizedbyfeverandmaculopapularrash,whichmay

beaccompaniedbyarthritis.• Manypostnatalinfectionsareasymptomatic.• Postnatalrubellaisaratherbenignillness,butcongenitalrubellacanresultinavarietyof

seriousmedicalproblems.• Manifestationsofcongenitalrubellaincludedeafness,cataractorglaucoma,congenitalheart

disease,andmentalretardation.• Rubellavaccinewasdevelopedprimarilytopreventcongenitalrubellafromoccurring.

EPIDEMIOLOGY• Intemperateclimates,diseaseoccursmainlyinthespring(ifvaccineisnotbeingused).• Rubellaissomewhatlesscontagiousthanmeasles.• WidespreadvaccinationintheAmericasledtotheeliminationofrubellaasof2009.• Globally, rubella and congenital rubella remain serious medical problems, especially in

Africa,someareasofEurope,SoutheastAsia,andtheWesternPacific.

MICROBIOLOGY• RubellaisanRNAvirus,amemberoftheTogaviridaefamilyandthegenusRubivirus.

DIAGNOSIS• Diagnosiscanbemadeserologically(enzyme-linkedimmunosorbentassay)withacuteand

convalescentserumsamples,orbydemonstrationofrubellaIgMantibodyonasingleserumsample.

• ApositivetestforviralRNAusingreverse-transcriptasepolymerasechainreactiononthroatswabs,cerebrospinalfluid,and/oramnioticfluidisespeciallyusefulfordiagnosisofcongeni-talrubella.

THERAPY• Noneisavailable.

PREVENTION• Live-attenuatedrubellavaccineiseffectiveandsafe,usuallyadministeredalongwithmeasles

andmumpsvaccines(MMR).

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90 

Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)Stephen J. Thomas, Timothy P. Endy, Alan L. Rothman, and Alan D. Barrett*

DEFINITION• TheFlaviviridaeincorporatestheFlavivirus, Pestivirus,andHepacivirusgenera,whichcause

systemicfebrile,centralnervoussystem,and/orhemorrhagicfeversyndromes.

EPIDEMIOLOGY• Transmission and disease may occur with endemic, hyperendemic, and/or epidemic

patterns.• Yellow fever (YF) is found in tropical South America and sub-Saharan Africa. Disease is

severewithhighmorbidityandmortality.• Dengueiswidelydistributedthroughoutthetropicsandsubtropics.Severediseaseisinfre-

quent (~2% to 4% of apparent cases) but potentially fatal. Nonsevere disease (outpatient)accountsformuchofdengue’sglobalsocioeconomicimpact.

• Japaneseencephalitis(JE)virusisasignificantcauseofencephalitisinSoutheastandSouthAsia.Chronicmorbidityandmortalityarehighinsymptomaticcases.

• WestNilevirus(WNV),St.Louisencephalitis(SLE)virus,JEvirus,andtick-borneencepha-litis(TBE)virusarethemajorneurotropicmembersofthegenusFlavivirus.InfectionwithWNVisfoundworldwide,SLEisfoundintheAmericas,whereasTBEoccursfromWesternEuropetoRussia,Japan,andChina.Mostinfectionsaresubclinical.Clinicallyapparentcaseswithneurologicmanifestationshaveapredilectionforolderindividuals.

• Alkhurma hemorrhagic fever virus (AHFV), Kyasanur Forest disease virus (KFDV), andZika virus (ZIKV) infections are emerging or reemerging in the Middle East, India, andAfrica/Asia, respectively.All infections initiallyhavenonspecificclinicalfindings;personsinfectedwithAHFVandKFDVmaydevelophemorrhagicmanifestations.

MICROBIOLOGY• Flavivirusesareicosahedral,approximately50nmindiameter,approximately11-kbsingle-

stranded, positive-sense RNA viruses consisting of a lipid envelope covered densely withsurfaceprojectionsconsistingofM(membrane)andE(envelope)glycoproteins.Nonstructuralproteinsmakeuptheremainderofthegenome.

• Mutationsandreplicationerrorsarehigh.

DIAGNOSIS• Diagnosticapproachesaredictatedbythediseasecourse.• Duringtheviremicperiod,viralisolationandnucleicacidorantigendetectionfromblood

arepossible.• Duringthesubacuteperiod,early-phaseIgMantibodiesmaybedetectedinseraorcerebro-

spinalfluidusingvariousassayplatforms(e.g.,enzyme-linkedimmunosorbentassay,hemag-glutinationinhibition).

*Disclaimer:Theopinionsorassertionscontainedhereinaretheprivateviewsoftheauthor(SJT)andarenottobeconstruedasreflectingtheofficialviewsoftheU.S.ArmyortheU.S.DepartmentofDefense.

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• Duringtheconvalescentperiod,ariseinIgGbetweenacuteandconvalescentspecimensismeasuredtoidentifyaseroresponse(plaquereductionneutralizationtest).

THERAPY• Nolicensedorspecificantiviraltherapiesareavailable.• Treatmentissupportive,andoutcomesarevariable.

PREVENTION• U.S.-licensedvaccinesexistforYFandJE.VaccinesexistforTBEandKFDV.• Two recently completed phase III studies in Asia and Latin America of a live-attenuated

denguetetravalentvaccine(CYD-TDV)demonstratedmoderateefficacyagainstanydengueof any severity caused by any serotype and high efficacy against hospitalized and severedengue.

• Numerousvaccinedevelopmenteffortsareunderwayforadditionalflaviviruses.

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91 Hepatitis CStuart C. Ray and David L. Thomas

DEFINITION• HepatitisCvirus(HCV)isanenveloped,positive-strandRNAvirusthatisamemberofthe

Flaviviridaefamily,Hepacivirusgenus.• Itisamajorworldwidecauseofchronicliverdisease,includingcirrhosisandincreasedrisk

ofhepatocellularcarcinoma(HCC).

MICROBIOLOGY• HCVisroughlyspheroidandis55nmindiameter.• TheRNAgenomeis9.6kbinlengthandcontainsasinglelargeopenreadingframe,which

isprocessedintoat least10proteins, including3structuralproteinsand5proteinsof theviralRNAreplicasecomplex(NS3,NS4A,NS4B,NS5A,andNS5B)(seeFig.91-1).

• HCVhassixmajorgenotypesandprovisionallyaseventh.• Extensivequasispeciesvariationispresentineachinfectedindividual.

EPIDEMIOLOGY• Morethan185millionpersonsareHCVantibodypositiveworldwide.• Transmissionoccursmostcommonlybypercutaneousexposuretoblood.• Indevelopedcountries,mostHCVinfectionsareassociatedwithIVdrugabuse.• Inthedevelopingworld,transmissionoccursfromunsafemedicalpractices.• HCVmaybetransmittedsexually,butthisappearstobeinfrequentexceptinhigh-risksexual

activities.

CLINICAL MANIFESTATIONS• Acute illness caused by HCV infection is unusual, but it is typical of acute hepatitis and

consists of malaise, nausea, and right upper quadrant pain, followed by dark urine andjaundice.

• FulminanthepatitisduetoHCVinfectionisuncommoninWesterncountries.• ChronicinfectionwithHCVoccursinapproximately75%ofpatientsafteracuteinfection

withHCV.• Onceestablished,chronicinfectionpersistsfordecadesandcanbeassociatedwithcirrhosis,

metabolicdisorderssuchasinsulinresistanceandsteatosis,andHCC.

DIAGNOSIS• DiagnosisofHCVinfectionisusuallymadebyassaysofserumantibodytoHCVfollowed

bytestingforHCVRNA.• RNAtestsarealsousedtoassesstheeffectsoftreatment.• Liverbiopsiesandnoninvasivelivertestsareusedtoassessthestageofliverdiseases.

TREATMENT (SEE TABLE 91-1)• TheprimaryaimoftreatmentistoeradicateHCVinbloodandliverandthuspreventcom-

plicationsofHCVinfection.

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TABLE 91-1  AASLD and IDSA Recommendations for HCV Treatment-Naïve Patients: January 2015

GENOTYPE RECOMMENDATION*1a Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) and weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)

1b Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) for 12 wk. Weight-based RBV recommended for patients with cirrhosis

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 wk (no cirrhosis) or 24 wk (cirrhosis)

2 Daily sofosbuvir (400 mg) and weight-based RBV for 12 wk (no cirrhosis) or 16 wk (cirrhosis)

3 Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk

4 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 wk

Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk

5 Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG IFN for 12 wk

6 Daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk

AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; RBV, ribavirin.

*Listed alphabetically: see www.hcvguidelines.org for alternative treatments, treatments in experienced patients, and special populations.

FIGURE 91-1 Organization of the hepatitis C virus (HCV) genome and viral polyprotein. The 5′ and 3′ untranslated region (UTR) RNA structures (curves) flank the major open reading frame (ORF). Unlike eukaryotic mRNA, the viral RNA genome has 5′ triphosphate (“ppp”) and no 3′ poly-adenylation. The 5′ UTR contains an internal ribosomal entry site (IRES). Triangles indicate sites of cleavage by host cellular signal peptidase (black, open indicating additional processing by signal peptide peptidase) and viral (blue, open indicating cleavage by the NS2/NS3 cysteine protease) pro-teases are shown as triangles. Putative structural (gray) and nonstructural (blue) mature proteins (boxes) generated by these cleavage events are labeled, below which in blue are viral enzymatic functions NS2/NS3 cysteine protease (Cys Prot), NS3 serine protease (Ser Prot), NS3 helicase, and the NS5B RNA-dependent RNA polymerase (RdRP). Positions of the first and last nucleotides (nt) and amino acids (aa) of the polyprotein ORF are shown, based on reference genome H77 (GenBank accession number AF009606). Above the ORF are positions of the alternate reading frame protein (ARFP), variable regions HVR1 and V3, and (indicated by horizontal lines) the antigens included in the enzyme immunoassay serologic assay.

c200

ppp

IRES

ns5c100c33

SerProt

CysProt

RdRP

c22

nt 342aa1

93743011

3′UTR5′ UTR

Helicase

ARF V3

Core E1 E2 NS2 NS3 NS4B NS5A NS5Bp7

HVR1

4A

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• American Association for the Study of Liver Diseases (AASLD) and Infectious DiseasesSocietyofAmerica(IDSA)treatmentrecommendationsforhepatitisC,January2015:• SeeTable91-1• Genotype1a

• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvir plus dasabuvir and weight-based ribavirin (RBV)

for12weeks(nocirrhosis)or24weeks(cirrhosis)• Sofosbuvir plus simeprevir with or without RBV for 12 weeks (no cirrhosis) or

24weeks(cirrhosis)• Genotype1b

• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvirplusdasabuvirfor12weeks,plusRBVforpatients

withcirrhosis• Sofosbuvirplussimeprevirfor12weeks(nocirrhosis)or24weeks(cirrhosis)

• Genotype2• SofosbuvirandRBVfor12weeks(nocirrhosis)or16weeks(cirrhosis)

• Genotype3• SofosbuvirandRBVfor24weeks

• Genotype4• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvirandRBVfor12weeks• SofosbuvirandRBVfor24weeks

• Genotype5• SofosbuvirandRBVandpolyethyleneglycol(PEG)for12weeks

• Genotype6• Ledipasvir/sofosbuvirfor12weeks

Cliniciansareurgedtoconsultonlineguidelines for the latestrecommendationsonHCVtreatment(www.hcvguidelines.org).

PREVENTION• Strategiesareprimarilydesignedtoreduceexposuretocontaminatedblood,throughscreen-

ingofbloodproducts,applicationofprecautionsinhealthcaresettings,andreductionofIVdrugabuserisks.

• DevelopmentofvaccinesagainstHCVischallengingbecauseofextensiveviraldiversity.

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92 Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)Kenneth McIntosh and Stanley Perlman

DEFINITION• Thecoronaviruses(CoVs)commonlycausemildbutoccasionallymoreseverecommunity-

acquiredacuterespiratoryinfectionsinhumans.CoVsalsoinfectawidevarietyofanimals,andseveralCoVs(e.g.,severeacuterespiratorysyndrome[SARS],MiddleEastrespiratorysyndrome[MERS])havecrossedthespeciesbarrier,producingoutbreaksofsevererespira-torydisease.AsofJanuary23,2015,956casesoflaboratory-confirmedMERSwerereportedtotheWorldHealthOrganization,with351deaths.

EPIDEMIOLOGY• Community-acquiredCoVinfectionscauseabout15%ofcommoncolds.Theyaretypically

epidemic in thewintermonths.MERShasoccurred inpatients in theArabianPeninsulaandthosewhorecentlytraveledfromthislocale.

MICROBIOLOGY• CoVs are members of the Nidovirales order, single-stranded, positive-sense RNA viruses

withalargegenome.Theymutateandalsorecombinefrequently.

DIAGNOSIS• LaboratorydiagnosisisbestaccomplishedbyfindingviralRNAthroughpolymerasechain

reaction.

THERAPY• TherearenoacceptedeffectiveantiviraldrugsforCoVs.

PREVENTION• Prevention is through epidemiologic methods. The SARS epidemic was halted through

carefulcasefinding,quarantine,anduseofbarrierprecautions.

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93  Parainfluenza VirusesMichael G. Ison

DEFINITION• Parainfluenzavirus(PIV)causesacuterespiratoryillness,includingcolds,croup,bronchi-

olitis,andpneumonia.

EPIDEMIOLOGY• PIV-1andPIV-2causeseasonaloutbreaksinthefall,withPIV-1causingepidemicsinodd-

numberedyears.Clinically,PIV-1isstronglyassociatedwithcroupinchildren.• PIV-3causesannualepidemicsinthespring; inyearswherePIV-1doesnotcirculate, the

seasonistypicallymoreactiveandprolonged.PIV-3isassociatedwithmoresevereinfec-tions,particularlyamongimmunocompromisedadultsandchildren.

• PIV-4isassociatedwithmilderdisease,typicallylimitedtotheupperairway.• Although antibodies are produced in response to clinical disease, reinfection is common

throughoutlife.• Disease, particularly associated with PIV-3, frequently progresses to the lower airway in

immunocompromisedadultsandchildrenandisassociatedwithsignificantmorbidityandmortality.

MICROBIOLOGY• Parainfluenzaisasingle-stranded,envelopedRNAvirusbelongingtotheParamyxoviridae

family.ItincludesPIV-1,PIV-2,PIV-3,andPIV-4.

DIAGNOSIS• National parainfluenza virus trends are available at www.cdc.gov/surveillance/nrevss/

human-paraflu/natl-trend.htm.• Laboratorydiagnosiscanbemadebycultureorpolymerasechainreaction(PCR)assay,with

improvedsensitivitywithmoleculardiagnosticmethods.

THERAPY• Croup is generally treated with glucocorticoids and nebulized epinephrine in young

children.• Although ribavirin and intravenous immunoglobulin have been used in the treatment of

immunocompromisedadultsandchildren,theirefficacyisuncertain.• Anumberofnovelantiviralsarecurrentlyunderdevelopment.

PREVENTION• StandardandcontactprecautionsarerecommendedtoavoidnosocomialspreadofPIVin

thehealthcaresetting.• Anumberoflive-attenuatedvaccinecandidatesareundergoingdevelopment.

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94 Mumps VirusNathan Litman and Stephen G. Baum

DEFINITION• Mumpsisanacuteviralinfectionmostcommonlymanifestasnonsuppurativeswellingand

tendernessoftheparotidorothersalivaryglandscausedbythemumpsvirus.• Lesscommonmanifestationsofmumpsincludemeningitis,encephalitis,epididymo-orchitis,

oophoritis,andpancreatitis.

EPIDEMIOLOGY• Mumps is endemic throughout the world, and humans are the only natural hosts for the

virus.• Incubationperiodisusually16to18dayswitharangeof2to4weeks.• Before the introduction of the mumps vaccine in the United States in 1967, epidemics

occurredevery2to5yearswithpeakincidencebetweenJanuaryandMay.• Since1967,therehasbeenmorethana99%declineintheannualU.S.incidenceofmumps.• Outbreaksofmumpshavebeenreportedthroughouttheworld,includingtheUnitedStates,

eveninpopulationswhohavereceivedtherecommendedtwo-dosemeasles-mumps-rubella(MMR)series.

MICROBIOLOGY• Mumpsisanenveloped,single-strandedRNAvirus.• Onlyoneserotypeofmumpsvirusexists,butthereare13genotypes.

DIAGNOSIS• Theclinicaldiagnosisismadeonthebasisofahistoryofexposureandofparotidswelling

andtenderness.• Thediagnosisisconfirmedbyisolationofmumpsvirusordetectionofmumpsnucleicacid

by polymerase chain reaction from clinical specimens or the presence of mumps-specificIgMantibodiesorafourfoldriseinmumpsIgGantibodiesinserum.

THERAPY• Therapyformumpsissymptomaticandsupportive.

PREVENTION• Immunization with live, attenuated mumps virus vaccine as part of the standard MMR

vaccineat12monthsand4to6yearsofageisrecommendedforallchildren;atwo-doseseriesofMMRisrecommendedfor individualsbeyondchildhoodwhohavenotreceivedthechildhoodseries.

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95  Respiratory Syncytial Virus (RSV)Edward E. Walsh and Caroline Breese Hall*

DEFINITION• Respiratorysyncytialvirus(RSV)causesacuteupperandlowertractrespiratoryillnesses.

EPIDEMIOLOGY• RSVcirculatesannuallyduringthewintermonthsintemperateclimates.• RSVistheleadingcauseofbronchiolitisininfants.• Reinfectioniscommonthroughoutlifeandcanbesevereinelderlyandimmunocompro-

misedpersons.• RSVisprimarilytransmittedbydirectcontactwithinfectedpersonsortheirsecretions.

MICROBIOLOGY• RSVisanenvelopednonsegmentedRNAvirusintheParamyxoviridaefamily.• RSVisolatescanbeclassifiedintoantigenicallydistinctgroups,AandB.

DIAGNOSIS• Clinicaldiagnosisininfantsisrelativelyaccurateduringthewintermonths;however,inolder

children and adults, laboratory confirmation by culture, antigen detection, or reverse-transcriptasepolymerasechainreactionisnecessary.

THERAPY• Treatmentformostinfantsandadultsissupportiveonly.• Aerosolizedribavirin,anucleosideanalogue,canbeconsideredforadministrationtohigh-

risk infants. It is also used to treat RSV in highly immunocompromised persons, with orwithoutanti-RSVimmunoglobulin,butitsefficacyisnotestablished.

PREVENTION• Attentiontoinfectioncontrolmeasures,suchashandhygieneandcontactprecautions,can

reducethespreadofRSV.• Palivizumab,ahumanizedneutralizingmonoclonalantibodytoRSV,isbeneficialforspecific

high-riskinfants,includingthosewithunderlyingcardiacandpulmonarydiseaseandlowgestationalage.

*CarenHallpassedawayin2012.Shewastheauthorforthisandotherchaptersforpreviouseditionsofthisbook.Thischapterisdedicatedtohermemory.

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96 Human MetapneumovirusAnn R. Falsey

DEFINITION• Human metapneumovirus (hMPV) is a paramyxovirus that causes acute respiratory tract

infections.

EPIDEMIOLOGY• Distributionisworldwide.• Infectionismostcommoninwinterandspringintemperateclimates.• hMPVcocirculateswithotherseasonalviruses,includinginfluenzaandrespiratorysyncytial

virus(RSV).• Infectionisuniversalbyage5years.• Reinfectionsoccurthroughoutlife.

MICROBIOLOGY• VirusisinfamilyParamyxoviridae,subfamilyPneumovirinae,genusMetapneumovirus;has

nonsegmentedsingle-strandedRNA(ssRNA).• Divergedfromavianmetapneumoviruses200to300yearsago.• Twomajorgenotypes(AandB)andfoursubgroups(A1,A2,B1,andB2).

DIAGNOSIS• Clinicalsyndromeisnotdistinctandrangesfromcommoncoldtoacuterespiratorydistress

syndrome.• Bronchiolitis,asthmaexacerbations,andpneumoniaoccurinchildren.• Diagnosis is best accomplished by reverse-transcriptase polymerase chain reaction (RT-

PCR)ofrespiratorysecretions.• ImmunofluorescenceassayofrespiratorysecretionsislesssensitivethanRT-PCRbutisan

acceptablemethodofdiagnosis.

THERAPY• Therapyissupportive.• Intravenousgammaglobulinandribavirinhavebeenusedinseverelyillimmunocompro-

misedpatients,butefficacy,ifany,isunclear.

PREVENTION• Novaccineisavailable.• Infection control measures include hand hygiene and use of masks, gowns, and gloves in

outbreaksituations.

220

97 Measles Virus (Rubeola)Anne A. Gershon

DEFINITION• Measlesisahighlycontagiousviralinfection,usuallyofchildhood.• Thediseasepresentswithanonpruriticrashthatbeginsontheheadandfaceandspreads

downthebody,withfeverandmalaise.• Initially,beforetherashappears,measlescanresembleinfluenza.• Thereisusuallyaccompanyingconjunctivitis,cough,andcoryza.• Complications include infections of the respiratory tract and central nervous system

involvement.

EPIDEMIOLOGY• Measles is very contagious before the rash appears, which enhances the chance of spread

beforethediseaseisidentified.• Measlesisalsocontagiousforafewdaysafterrashonset.• Thevirusspreadsbydropletsandalsobytheairborneroute.• WidespreadvaccinationwithtwovaccinedosesintheAmericashasreducedtheincidence

ofmeaslessothatthevirusisnolongerendemicintheseregions.• However,measlesoutbreakscontinuetooccurintheUnitedStates(34outbreaksin2013to

2014,andalargeoutbreakin2015relatedtoexposureatDisneylandinCalifornia).• Whenvaccinationratesfallbelow95%,measlesoutbreakscanoccurifthevirusisreintro-

ducedintoapopulation.• Immunosuppressedpatientsareathighrisktodevelopseveremeasleswithoutnecessarily

manifestingarash.• Measlesvaccinationhasbeenshowntobeunrelatedtodevelopmentofautism.

MICROBIOLOGY• MeaslesiscausedbyanRNAvirusclassifiedasaMorbillivirusoftheParamyxoviridaefamily.

DIAGNOSIS• Clinically,measlesmaybeconfusedwithKawasakidisease.• Measlesvirusisdifficulttoculture.• Diagnosis is usually made clinically, particularly if Koplik spots on the oral mucosa are

observed.• Laboratorydiagnosiscanbemadebyreverse-transcriptasepolymerasechainreaction(RT-

PCR)onjustaboutanybodyfluidortissue.

THERAPY• Nospecifictherapyhasbeenproventobeuseful.• AdministrationofvitaminAoncedailybymouthfor2daysshouldbeconsideredforpatients

withmeasles.• ThemechanismofactionofvitaminAisthoughttobebyimmunomodulation.

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irus (R

ub

eola)

PREVENTION• Live-attenuatedmeaslesvaccineisadministeredtohealthychildrenat12to15monthsof

ageandagainatage4to6years.• Passive immunizationwith immunoglobulinGshouldbegiven tohigh-riskchildrenand

adultsexposedtomeaslesbuthavingnohistoryofmeasles.

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98 Zoonotic Paramyxoviruses: Nipah, Hendra, and MenangleAnna R. Thorner and Raphael Dolin

DEFINITION• HendraandNipahvirusesarehighlypathogenic zoonoticparamyxoviruses that emerged

duringthe1990sinAustraliaandSoutheastAsia,respectively.

EPIDEMIOLOGY• In 1994, in Queensland, Australia, Hendra virus caused two outbreaks of fatal illness in

horses and their human caretakers. Additional outbreaks involving humans occurred in2004,2008,and2009.

• Nipahviruswasfirst recognizedwhen it causedanoutbreakof severeencephalitis inpigfarmersinMalaysiaandabattoirworkersinSingaporein1998and1999.MultipleoutbreakshavebeendetectedsubsequentlyinBangladeshandIndia,includingcasesthathaveinvolvedhuman-to-humantransmission.

• Menanglevirus,anotherparamyxovirus,causeddecreasedfarrowingratesandstillbirthsinpigs,aswellasillnessintwohumansinAustraliain1997.

• ThePteropus speciesof fruitbat,alsoknownas theflyingfox, is thereservoirofall threeviruses.

CLASSIFICATION• NipahandHendravirusesaremembersoftheHenipavirusgenuswithintheParamyxovirinae

subfamilyoftheParamyxoviridaefamily.

CLINICAL MANIFESTATIONS• Nipah virus causes a severe and often fatal meningoencephalitis. Clinical manifestations

of Hendra virus infection range from a self-limited influenza-like syndrome to a fatalrespiratory illness or encephalitis. Menangle virus has caused an influenza-like illness intwopeople.

DIAGNOSIS• DiagnosticteststhatcanbeusedtodetectNipahandHendravirusesincludeculture,elec-

tronmicroscopy,immunohistochemistry,serology,andreal-timereverse-transcriptasepoly-merasechainreaction.

THERAPY• BecausenospecificantiviraltherapieshavebeenevaluatedforthetreatmentofNipahvirus

or Hendra virus infection, treatment involves only supportive care, such as intravenoushydrationandmechanicalventilation,whenindicated.

• A recombinant human monoclonal antibody, m102.4, directed against the henipavirusglycoprotein protects animals from disease after inoculation with Hendra virus orNipahvirus.

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viruses: N

ipah

, Hen

dra, an

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enan

gle

PREVENTION• Several vaccines have been developed against Nipah virus and Hendra virus, but none is

currentlyavailableforuseinhumans.• AHendravirussubunitvaccinewasshowntobehighlyeffectiveatpreventingHendravirus

infection in horses following a lethal challenge; it became available for use in horses inAustraliain2012.

224

99 Vesicular Stomatitis Virus and Related VesiculovirusesSteven M. Fine

DEFINITION• Vesicularstomatitisvirus(VSV)isavesiculovirusthatcausesoutbreaksofstomatitis,mainly

inlivestockbutsometimesalsoinhumans.

EPIDEMIOLOGY• Alargepercentageofpeoplewholive inendemicareasare infectedandusuallyhavehad

mildorsubclinicaldisease.• Seasonaloutbreaksamonghorses,cattle,andotherlivestockhavethepotentialtocauselarge

economiclosses,particularlyinthesouthwesternUnitedStates.• EndemicdiseaseoccursinareasofCentralandSouthAmerica.• Themodeoftransmissionisnotknown,althoughthevirusisbelievedtobeintroducedto

aherdbyaninsectvector,anditcanthenspreadfromanimaltoanimalbydirectcontact.

MICROBIOLOGY• VSVisasingle-stranded,negative-strandRNAvirusthatisamemberoftheRhabdoviridae

family,genusVesiculovirus.

DIAGNOSIS• Samples from lesions can be tested by enzyme-linked immunosorbent assay, complement

fixation,orisolationofvirusintissueculture,aswellasbypolymerasechainreactionassays.• Themainpurposeofdiagnosisistoquicklydistinguishthediseasefromthemoredangerous

foot-and-mouthdiseaseinlivestock.

THERAPY• Therapyinhumansisgenerallynotrequired.• Thereisnoknownantiviraltreatment,sotherapyconsistsofsupportivemeasures.

PREVENTION• Quarantineofanimalsfrominfectedranchesiscommonlyinstituted.• Protectiveclothingandglovesshouldbewornwhenhandlinginfectedanimals.• Anexperimentalvaccineisintrials.Akilledvaccineforanimalsisapproved,butitsefficacy

isunknown.

225

100  Rabies (Rhabdoviruses)Kamaljit Singh, Charles E. Rupprecht, and Thomas P. Bleck

DEFINITION• Rabies is a zoonotic encephalitis caused by different species of neurotropic viruses in the

Rhabdoviridaefamily.

EPIDEMIOLOGY• Rabiesisoneoftheoldesthumandiseases,withthehighestcasefatalityrate.• Approximately3.3billionpeopleliveinregionswhererabiesisenzootic.• Anestimated55,000peoplediefromrabieseachyear.• Althoughallagegroupsaresusceptible, rabies ismostcommoninchildrenyounger than

15years.• Bitesbyrabiddogscause99%ofhumandeathsglobally.• IntheUnitedStates,batsaccountformosthumanrabiescases.• Rabiesvirustransmissionmayalsooccurthroughtissueororgantransplantation.

MICROBIOLOGY• Rhabdovirusesarebullet-shaped,single-strandedRNAvirusesoftheorderMononegavirales,

familyRhabdoviridae,andgenusLyssavirus.• RabiesvirusisthetypespeciesoftheLyssavirusgenus.

DIAGNOSIS• Developmentofanacuteneurologicsyndromeafterthebiteofarabidanimalisclassically

recognizedindevelopingcountries.• Encephaliticrabiesoccursinthemajorityofpatientswithfever,hydrophobia,aerophobia,

agitation,autonomicoveractivitywithhypersalivation,coma,andparalysis.• Paralyticrabiesischaracterizedbyascendingflaccidquadriparesisandcoma.• Antemortem diagnosis can be made by direct immunofluorescent staining of skin biopsy

specimens,reverse-transcriptasepolymerasechainreactionofsalivaorskinbiopsy,ordetec-tionofantirabiesvirusantibodiesinserumorcerebrospinalfluid.

THERAPY• Thereisnoprovenantiviraltherapy.• Mostpatientswith rabiesvirus infectiondiewithina fewdays to2weeksafter theonset

ofcoma.

PREVENTION• Annually,morethan10millionpeoplereceiverabiespostexposureprophylaxis.• After exposure to a rabid animal, prevention consists primarily of prompt wound

cleansing.• Postexposureprophylaxisconsistsofpromptadministrationofrabiesimmuneglobulinand

rabiesvaccineaccordingtotheAdvisoryCommitteeonImmunizationPracticesandWorldHealthOrganizationguidelines.

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• BatrabiescausesthemajorityofhumancasesintheUnitedStates,andpostexposurepro-phylaxis depends on the type of exposure and availability of the animal for rabiesdiagnosis.

• Preexposure prophylaxis should be targeted to high-risk groups, including veterinarians,laboratoryworkers,andcertaintravelers.

227

101 Marburg and Ebola Hemorrhagic Fevers (Marburg and Ebola Viral Diseases) (Filoviruses)Thomas W. Geisbert

DEFINITION• MarburgviraldiseaseandEbolaviraldiseasearesevereandoftenfataldiseasescharacterized

byfever,headache,malaise,myalgia,vomiting,diarrhea,coagulationdisorders,andmulti-organfailure.

EPIDEMIOLOGY• HumanoutbreaksoccursporadicallyinregionsofCentralAfrica.

• In2014,anextraordinarilylargeoutbreakofEbolaviraldiseasedevelopedinWestAfricaandstillcontinuesinearly2015.

• Recentevidencesuggeststhatbatsmayplayaroleasareservoirhost.• Themanner inwhichfilovirusoutbreaksare initiated isunknown;however, it is thought

thattheinitialcasesoccurasaresultofcontactwithaninfectedanimal.• Nosocomial transmissionhasoccurred frequentlyduringoutbreaksoffilovirusdisease in

endemicareas.

DIAGNOSIS• Clinicalsymptomsarenonspecific,butaconstellationofsymptoms,includingfever,head-

ache,malaise,myalgia,sorethroat,vomiting,diarrhea,andtheappearanceofamaculopapu-larrashmayindicateinfectionwithafilovirus.

• Reverse-transcriptasepolymerasechainreaction(RT-PCR)isthemostfrequentlyusedassaytodiagnosefilovirusinfection.

TREATMENT• Therearenoapprovedpostexposuretreatmentsforfilovirusinfections.• TreatingpatientsinfectedwithMarburgorEbolavirusesconsistsprimarilyofintensivesup-

portive care that is directed toward maintaining effective blood volume and electrolytebalance.

• Severalexperimentaltreatmentshaveshownpromiseinnonhumanprimatemodelsoffilo-virus infection, including vesicular stomatitis virus–based postexposure vaccines, smallinterferingRNAs,antisenseoligonucleotides,andpoolsofmonoclonalantibodies.

PREVENTION• TherearenoapprovedvaccinesagainstMarburgorEbolaviruses,butsignificantprogress

hasbeenmade in thedevelopmentofChAd3-andrecombinantvesicularstomatitisvirus(rVSV)-basedvaccines.

• Appropriatepersonalprotectionequipment(PPE)isessentialforhealthcareworkers.• Isolationofinfectedpatientsandclosecontactsisessential.• Avoidcontactwithbushmeatandsickanimals,particularlynonhumanprimates,inendemic

regions.

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102 Influenza (Including Avian Influenza and Swine Influenza)John J. Treanor

DEFINITION• Influenzavirusesareenveloped,negative-sense,single-strandedRNAviruseswhosegenome

issegmented.Theycauseepidemicacuterespiratorydiseasecharacterizedbyfever,cough,andsystemicsymptoms.Threetypes(A,B,andC)arerecognized,aswellasmanysubtypeswithinthetypeAviruses.

EPIDEMIOLOGY• Influenzavirusesaretransmittedbytherespiratoryrouteandcauselargeepidemics,which

generallyoccurduringthewinter in temperateclimates. Inadditionto infectinghumans,influenzaAvirusesinfectawidevarietyofanimals,particularlymigratorywaterfowl.NewinfluenzaAvirussubtypessporadicallyemergeinhumanstocausewidespreaddisease,orpandemics.

MICROBIOLOGY• Influenza viruses are readily isolated in eggs or mammalian cell culture at 33°C. They

undergoconstantantigenicevolution,referredtoasantigenicdriftorshiftthatallowsthemtoreinfectindividualswhohavehadpreviousinfections.

DIAGNOSIS• Inthecontextofrecognizedepidemics,influenzaisusuallydiagnosedclinicallyonthebasis

ofcharacteristicsymptomsoffeverandcough.Rapiddetectionofvirusinrespiratorysecre-tionsalsocanbeaccomplishedbyantigendetectionormoleculartechniquessuchaspoly-merasechainreactionassay.

THERAPY• Antiviraltherapywithoseltamivir,zanamivir,orperamivirisavailableandmayshortenthe

durationofillnessandreducetherateofcomplications.Therapyismosteffectivewhenusedearlyinthecourseofillness(seeTable102-1).

PREVENTION• Influenza vaccines are effective in the prevention of influenza illness, although improved

vaccinesareneeded.• Inactivatedandlive-attenuatedvaccinesareavailableintrivalentandquadrivalentformula-

tions(seeTable102-2).• Theobjectivesofvaccination includeprotectionof the individual,aswellasprotectionof

thepopulationthroughherdimmunity.Antiviraldrugscanalsobeusedprophylacticallyinselectedcircumstances.

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uen

za (Inclu

din

g A

vian In

flu

enza an

d Sw

ine In

flu

enza)

TABLE 102-1  Antiviral Chemotherapy and Chemoprophylaxis for Influenza

INFECTION DRUG ROUTE DOSAGEInfluenza A and B: treatment

Oseltamivir Oral Adults: 75 mg bid × 5 daysChildren aged 1-12 years: 30-75 mg bid, depending on weight†, × 5 days

Zanamivir Inhaled orally Adults and children aged ≥7 yr: 10 mg bid × 5 days

Influenza A: treatment

Amantadine* Oral Adults: 100 mg qd or bid × 5-7 daysChildren aged 1-9 yr: 5 mg/kg/day (maximum, 150 mg/day) × 5-7 days

Rimantadine* Oral 100 mg qd or bid × 5-7 days in adults

Influenza A and B: prophylaxis

Oseltamivir Oral Adults: 75 mg/dayChildren aged ≥1 yr: 30-75 mg/day, depending on weight†

Zanamivir Inhaled orally Adults and children aged ≥5 yr: 10 mg/day

Influenza A: prophylaxis

Amantadine* or rimantadine*

Oral Adults: 200 mg/dayChildren aged 1-9 yr: 5 mg/kg/day (maximum, 150 mg/day)

*Amantadine and rimantadine are not considered for use because of widespread resistance in influenza A/H3N2 and A/H1N1 viruses currently circulating (2012-2013). They may be considered if sensitivities become reestablished.

†For detailed dosage recommendations in children aged <1 yr, see www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.

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TABLE 102-2  Influenza Vaccines Available in the United States, 2013-2014 Influenza Season*

VACCINE TRADE NAME MANUFACTURER AGE INDICATIONS ROUTEInactivated influenza vaccine, trivalent (IIV3), standard dose

Afluria CSL Limited ≥9 yr IM†

Fluarix GlaxoSmithKline ≥3 yr IM†

Flucelvax Novartis Vaccines ≥18 yr IM†

FluLaval ID Biomedical Corporation of Quebec (distributed by GlaxoSmithKline)

≥3 yr IM†

Fluvirin Novartis Vaccines ≥4 yr IM†

Fluzone Sanofi Pasteur ≥6 mo IM†

Fluzone Intradermal Sanofi Pasteur 18-64 yr ID

Inactivated influenza vaccine, trivalent (IIV3), high dose

Fluzone High-Dose Sanofi Pasteur ≥65 yr IM†

Inactivated influenza vaccine, quadrivalent (IIV4), standard dose

Fluarix Quadrivalent GlaxoSmithKline ≥3 yr IM†

FluLaval Quadrivalent

ID Biomedical Corporation of Quebec (distributed by GlaxoSmithKline)

≥3 yr IM†

Fluzone Quadrivalent

Sanofi Pasteur ≥6 mo IM†

Recombinant influenza vaccine, trivalent (RIV3)

FluBlok Protein Sciences 18-49 yr IM†

Live-attenuated influenza vaccine, quadrivalent (LAIV4)

FluMist Quadrivalent

MedImmune 2-49 yr IN

ID, intradermal; IIV, Inactivated influenza vaccine; IIV3, inactivated influenza vaccine, trivalent; IIV4, inactivated influenza vaccine, quadrivalent; IM, intramuscular; IN, intranasal; LAIV, live attenuated influenza vaccine; RIV, recombinant influenza vaccine.

*Immunization providers should check U.S. Food and Drug Administration-approved prescribing information for 2013-2014 influenza vaccines for the most complete and updated information, including (but not limited to) indica-tions, contraindications, and precautions. Package inserts for U.S.-licensed vaccines are available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm.

†For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. Specific guidance regarding site and needle length for intramuscular administration may be found in the Advisory Committee on Immunization Practices General Recommendations on Immunization.

Modified from Centers for Disease Control and Prevention. Summary Recommendations: Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United States, 2013-14. Available at http://www.cdc.gov/flu/professionals/acip/2013-summary-recommendations .htm#table1.

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103 California Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirus Hemorrhagic FeversDennis A. Bente

DEFINITION• This largest family of RNA viruses has more than 350 named isolates that can be found

worldwide,anditsmembersareabletoinfectinvertebrates,vertebrates,andplants.

EPIDEMIOLOGY• Multiplemembersaresignificanthumanpathogenswiththeabilitytocauseseveredisease,

rangingfromfebrileillness,encephalitis,andhepatitistohemorrhagicfever.• Withexceptionofhantaviruses,bunyavirusesaretransmittedbyhematophagousarthropods,

includingticks,mosquitoes,andphlebotomineflies.• Hantavirusesaremaintainedinnaturethroughpersistentinfectionofrodents.

DIAGNOSIS• Earlydiagnosisisbasedonreverse-transcriptasepolymerasechainreactionassayofblood

samples.Inmostcases,thediagnosisisbasedonserologicinvestigationofacuteandearlyconvalescentsera.Diagnostictestsaretypicallyperformedinreferencelaboratories.

THERAPY• Nospecific therapy isavailable,andtreatment is typicallysupportive.Ribavirin treatment

has been studied only in some bunyavirus infections, and data from in vitro and in vivomodelsholdpromise.Ribavirinhasshownclinicalbenefitinhemorrhagicfeverwithrenalsyndrome(HFRS)and inCrimean-Congohemorrhagic fever(CCHF).However,compre-hensiveclinicaltrialshavenotbeenconducted.

PREVENTION• Nospecificpreventivemeasuresareavailable,yetexperimentalvaccinesforsomebunyavi-

ruseshavebeendeveloped.Individualprotectivemeasuressuchasarthropodrepellentsandinsecticide-impregnatedmosquitobednetsarerecommendedinendemicareas.

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104 Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)Alexey Seregin, Nadezhda Yun, and Slobodan Paessler

EPIDEMIOLOGY• Lymphocytic choriomeningitis virus (LCMV) is worldwide in distribution; Lassa fever is

foundinAfrica,andtheNewWorldcomplexvirusescirculateinSouthandNorthAmericaandcancausehemorrhagicfevers.

• Transmissionisbyrodents,withgenerallyhighspeciesspecificityofreservoirvectors.

MICROBIOLOGY• Thesepleomorphicvirusesare50to300nmindiameterwithtwosingleRNAsegmentswith

ambisensegeneorganization.

CLINICAL MANIFESTATIONS• LCMV:Febrileillnessisaccompaniedbyheadacheandsystemicsymptoms;coursemaybe

biphasic with meningitis presenting during second phase in 5 to 10 days; full recovery isusual,butimmunosuppressionmayresultindisseminatedandfataldisease.

• Lassa fever:Theillnessisusuallymild,butin5%to10%itmayresultinseveremultisystemdisease,resultingindeathin15%to25%ofhospitalizedpatients;fever,pharyngitis,retroster-nal pain, and proteinuria are the most common features; fatal cases usually occur in thesecondweekofillness,withhypotension,vasoconstriction,mucosalhemorrhages,andcapil-laryleaksyndrome.

• South American hemorrhagic fevers: Argentinean, Bolivian, and Venezuelan hemorrhagicfevershaveprogressivefever,malaise,andmyalgias,mostfrequentlyaffectingthelowerback;petechiaeandsmallvesiclesarefrequent;vasculardisease(capillaryleak),vasoconstriction,and shock may occur; various blood and neurologic abnormalities can be seen; overallmortalityis15%to30%;andconvalescencemaytakeweeks,butrecoveryisusuallywithoutsequelae.

DIAGNOSIS• Detectionofvirusisevidentinacutebloodspecimensbyreverse-transcriptasepolymerase

chainreactionassayorvirusculture,dependingontheparticularviralagent.• IgMantibodiesmaybedetectedbyserology,andincreases inantibodytiters(seroconver-

sion)canbenotedbycomparingacuteandconvalescentserumspecimens.

TREATMENT• Supportivetreatmentmaybelifesaving.• Convalescent human plasma has been shown to be effective in Argentinean hemorrhagic

feverbuthasnotbeenassuccessfulinLassafever.• Ribavirin treatment of patients hospitalized with Lassa fever as well as in patients with

ArgentineanandBolivianhemorrhagicfeversisbeneficial.

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cytic Ch

orio

men

ing

itis, Lassa Fever, and

 the So

uth

 Am

erican H

emo

rrhag

ic Fevers (Aren

aviruses)

PREVENTION• Reductionoftransmissionfromrodentstohumansisneeded.• Person-to-persontransmissioninhospitalsisaproblemwithLassafever,anduseofgloves

andgownsandcarefuldisposalofpatients’wastesandfomitesshouldbe implemented. Ifavailable,singleroomswithnegativepressureshouldbeutilized.

• Stepsshouldbetakentoavoid infectionin laboratoryworkerswhoexaminesamples thatmaycontainarenaviruses.

• Alive-attenuatedvaccineisavailableagainstArgentineanhemorrhagicfeverandislicensedinArgentina.

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105 Human T-Lymphotropic Virus (HTLV)Edward L. Murphy and Roberta L. Bruhn

DEFINITION• HumanT-lymphotropicvirus(HTLV)isahumanretrovirusofthesubfamilyRetroviridae

andgenusDeltaretrovirus.• ItcauseschronichumaninfectionbyintegrationofproviralDNAintothesomaticDNAof

hostTlymphocytes,withexpansionofinfectiousburdenbyproliferationofinfectedlym-phocytesmoreimportantlythanbyproductionoffreevirusparticles.

• Todate,fourtypesofthevirushavebeendiscovered:HTLV-1andHTLV-2infectionsareestimated in millions of humans, and HTLV-3 and HTLV-4 have occurred in only a fewisolatessincetheirdiscoveryinthepastdecade.

• HTLV-1causesadultT-cellleukemia,andbothHTLV-1andHTLV-2causeHTLV-associatedmyelopathy(HAM).

EPIDEMIOLOGY• HTLV-1 is endemic to central Africa, the Caribbean basin, parts of South America, and

southwesternJapanaswellasotherdiscretegeographicareas.Thereislimitedgeneticvaria-tionandclosehomologytoprimateT-lymphotropicviruses,suggestingseveralinstancesofcross-speciestransmission.

• HTLV-2isendemictoAmerindiantribesinNorth,Central,andSouthAmericaaswellasCentralAfricanpygmies.ItishyperendemicamonginjectiondrugusersinNorthAmericaandEurope.

• BothHTLV-1andHTLV-2aretransmittedbymother-to-childtransmissionpredominantlybybreast-feeding,bysexualtransmission,andbyparenteralinfection.

• Inendemicpopulations,bothretrovirusesshowanincreasedprevalenceinolderindividuals,andprevalenceisfrequentlyhigherinfemalesthaninmales.

DIAGNOSIS AND PATHOGENESIS• HTLVantibodiesmaybedetectedusingscreeningenzymeimmunoassaysandsupplemental

Westernblot/recombinantimmunoblot,withdifferentiationofHTLV-1fromHTLV-2usingtype-specificantigensinsupplementalassays.

• Polymerase chain reaction (PCR) assay to detect HTLV-1 or HTLV-2 proviral DNA inperipheralbloodmononuclearcellsmaybeperformedincaseswhereserologyisinconclu-sive. PCR assay is also useful in detecting infection in infants carrying passive maternalantibodies.

• Mostinfectedindividualsareasymptomatic.Twoto4percentofthoseinfectedwithHTLV-1willdevelopadultT-cellleukemia/lymphoma(ATL),characterizedbymonoclonalintegra-tionofHTLV-1provirusintoaT-lymphocyticmalignancy.

• One to 4 percent of those infected with either HTLV-I or HTLV-2 will develop HAM, aspastic paraparesis affecting predominantly the lower limbs and hyperactive bladder in apersoninfectedwithHTLV.

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 T-Lymp

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s (HTLV

)

THERAPY• NotreatmentiscurrentlyrecommendedforpersonswithasymptomaticHTLV-1orHTLV-2

infection.Periodicfollow-upshouldincludephysicalexaminationandcompletebloodcellcounttodetectATLorHAM.

• The lymphoma type of ATL is often treated initially with vincristine, cyclophosphamide,prednisolone,anddoxorubicin;survival ispoor.Chronic,smoldering,andleukemiatypesofATLoftenrespondbettertoacombinationofzidovudineandinterferon-α.

• Therapy for HAM is currently unsatisfactory. Corticosteroids may produce improvement,butsideeffectslimitthedurationoftherapy.Interferon-αandinterferon-1βhavebeenusedwithsomesuccess.Theanabolicsteroiddanazolmayrelievebladdersymptoms.

PREVENTION• Tointerruptmother-to-childtransmission,HTLV-infectedpregnantwomeninmiddle-and

high-incomecountriesshouldnotbreastfeedtheirinfantsifthiscanbeaccomplishedsafely.Limiting the duration of breast-feeding to less than 6 months may be attempted in low-incomecountries.

• Theuseofcondomsshouldberecommendedtopreventsexualtransmission.• InjectiondruguserswithHTLVinfectionshouldbeinstructednottoshareneedles.• TheU.S.FoodandDrugAdministrationrecommendsHTLVtestingofalldonatedblood

andtissue.Novaccineiscurrentlyavailable.

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106 Human Immunodeficiency VirusesMarvin S. Reitz, Jr., and Robert C. Gallo

DEFINITION• Human immunodeficiency virus (HIV) is a Lentivirus, family Retroviridae, that causes

acquired immunodeficiencysyndrome(AIDS).Thereare twotypes,HIV-1andHIV-2,ofwhichHIV-1isthemorewidelydistributedandmorepathogenic.

EPIDEMIOLOGY• HIVinfectionisworldwideindistributionandistransmittedbysexualactivityandintra-

venousdruguse.

MICROBIOLOGY• HIVisasingle-strandedpositive-senseRNAvirusthatcontainsthreestructuralgenes(gag,

pol,env)andsixregulatorygenes.HIVinfectsCD4+TcellsandusesitsreversetranscriptasetotranscribeitsRNAgenomeintodouble-strandedDNA,whichisintegratedintothehostcellgenome.

DIAGNOSIS• InfectionisestablishedbydetectionofviralRNA(virusload)orofimmunologicresponses

toviralproteins(Westernblot).

THERAPY AND PREVENTION• Antiretroviral therapy (ART) has been developed using nucleoside and non-nucleoside

reverse-transcriptase inhibitors,protease inhibitors, integrase inhibitors,andentry inhibi-tors.ARTcanalsodecreasetherateoftransmissionofinfection.VaccinedevelopmentseekstostimulateimmuneresponsestoHIVantigensthatwillinhibittransmissionand/orreplica-tionofvirus.

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107  PoliovirusJosé R. Romero and John F. Modlin

DEFINITION• Polioviruses are the cause of poliomyelitis, a systemic viral infection that predominantly

affectsthecentralnervoussystem,causingparalysis.Onlythreeserotypesexist(1to3).Thename of the disease (polios, “gray”; myelos, “marrow” or “spinal cord”), now commonlyshortenedtopolio,isdescriptiveofthepathologiclesionsthatinvolveneuronsinthegraymatter,especiallyintheanteriorhornsofthespinalcord.

EPIDEMIOLOGY• Wild-type poliovirus type 2 no longer circulates worldwide. Serotypes 1 and 3 have been

eradicatedfrommostoftheworld.Theyremainendemicinthreecountries(Afghanistan,Nigeria,andPakistan)andhaverecentlybeenreintroducedinseveralsub-SaharanAfricanandEasternMediterraneancountries.In2012,theannualnumberofcasesofpoliomyelitis(223)wasthelowestsincetheinitiationoftheglobalpolioviruseradicationeffortin1988.

MICROBIOLOGY• ThepoliovirusesaremembersofthegenusEnterovirus,familyPicornaviridae.Morphologi-

cally, they are small (30nm in diameter), nonenveloped, icosahedral-shaped viruses thatpossessasingle-stranded,positive-senseRNAgenome.

DIAGNOSIS• Poliovirusescanbeisolatedfromthroatsecretionsandfromfecesbutrarelyfromthecere-

brospinalfluid.CharacterizationisaccomplishedbysequencingofthemajorcapsidproteinVP1andisavailableonlyinpublichealthreferencelaboratories.

THERAPY• No specific therapy is available. Supportive measures to ensure airway patency, adequate

respiratoryeffort,andclearanceofsecretionsarethemainstayoftreatmentforseverecasesofparalysis.

PREVENTION• Vaccination using inactivated or live-attenuated oral vaccines has been essential in the

eliminationofthepolioviruses.Publichealthmeasures,suchasprovisionofpotablewaterand proper sewage disposal, play major roles in the community-wide control of thepolioviruses.

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108 Coxsackieviruses, Echoviruses, and Numbered Enteroviruses (EV-D68)José R. Romero and John F. Modlin

DEFINITION• Thecoxsackieviruses,echoviruses,andnumberedenterovirusesaremembersofthegenus

Enterovirus.• Thefourspecies(humanenterovirus[EV]AtoD)withinthegenuscontainmorethan100

serotypes.• Enteroviruses are responsible for a wide array of clinical syndromes involving multiple

organ systems, including acute meningitis, encephalitis, paralysis, exanthems, hand-foot-and-mouth disease, herpangina, myopericarditis, pleurodynia, and acute hemorrhagicconjunctivitis.

EPIDEMIOLOGY• Theenterovirusesarefoundworldwide.• Inregionswithtemperateclimates,themajorityofenteroviralinfectionsoccurduringthe

summerandearlyautumnmonths. In tropical regions, infectionsoccuryear-round,withincreasedfrequencyduringtherainyseason.

• AlargeoutbreakofEV-D68occurredintheUnitedStatesin2014.

MICROBIOLOGY• Morphologically, they are small (30nm in diameter), nonenveloped, icosahedral-shaped

virusesthatpossessasingle-stranded,positive-senseRNAgenome.

DIAGNOSIS• EnterovirusescanbeisolatedortheirgenomicRNAdetectedfromthroatsecretions,feces,

cerebrospinal fluid, and blood, as well as various tissues (heart, brain) and fluids (urine,pericardial,vesicle).

• Nucleicacidamplificationtestinghasbeenshowntobequickerandmoresensitivethancellcultureforenterovirusdetection.

• SerotypeidentificationisaccomplishedbysequencingofthemajorcapsidproteinVP1.

THERAPY• Therapyissupportive.• No specific antiviral therapy is currently available for the treatment of enterovirus

infections.• The investigational compound pleconaril, an inhibitor of viral binding and uncoating,

has undergone clinical studies in enteroviral-associated disease but is no longer underdevelopment.

PREVENTION• Contagioncanbepreventedbyhandwashingand,inthecaseofcertainserotypes,avoidance

ofenterovirus-contaminatedfomites.• Investigational vaccines are under development for the prevention of human EV-A71

infection.

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109 Human ParechovirusesJosé R. Romero and John F. Modlin

DEFINITION• Thehumanparechoviruses(HPeVs)aremembersofarelativelynewlycreatedgenusdesig-

natedParechovirusinthePicornaviridaefamily.Atleast16typeshavebeenidentified.• HPeVs are responsible for multiple clinical syndromes involving many organ systems,

includingundifferentiatedfebrileillness,meningitis,encephalitis,paralysis,andrespiratoryillnesses.

EPIDEMIOLOGY• HPeVsarefoundworldwide.• ThemajorityofHPeVinfectionsoccurduringthesummerandautumnmonths.

MICROBIOLOGY• Morphologically they are small (28nm in diameter), nonenveloped, icosahedral-shaped

virusesthatpossessasingle-stranded,positive-senseRNAgenome.

DIAGNOSIS• HPeVscanbeisolated,ortheirgenomicRNAcanbedetectedfromoralsecretions,feces,

cerebrospinalfluid,andblood.• Nucleic acidamplificationhasbeenquickerandmore sensitive thancell culture for their

detection.• Typeidentificationisaccomplishedbysequencingofthemajorcapsidprotein,VP1.

THERAPY• Therapyissupportive.Nospecificantiviraltherapyisavailable.

PREVENTION• Contagioncanbepreventedbyhandwashing.

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110 Hepatitis A VirusFrancisco Averhoff, Yury Khudyakov, and Beth P. Bell*

DEFINITION• HepatitisAisanacuteinflammatoryconditionofthelivercausedbyhepatitisAvirusand

characterizedbyconstitutionalsymptomsincludinganorexia, fatigueandweight loss,andjaundice.

MICROBIOLOGY• HepatitisAvirus(HAV)isanonenvelopedRNAvirusmemberofthepicornavirusfamily.

Threegenotypesinfecthumans(I,II,andIII).• HAVisrelativelyresistanttoheatbutcanbeinactivatedathighertemperatures.• HAVisresistanttoorganicsolventsanddetergentsandcansurviveinacidicenvironments

toapHof3.• HAVcanbeinactivatedbyhypochlorite(bleach)andquaternaryammoniumformulations

containingHCI(foundinmanytoiletcleaners).

EPIDEMIOLOGY• Transmissionisfecal-oralwithpeakviralsheddingbeforeonsetofsymptoms.• HumansaretheonlyimportantreservoirforHAV.• Spread is most commonly person to person (including sexual contact) but can occur as

foodborneandwaterbornetransmission,amonginjectiondrugusersandmenwhohavesexwithmen,andrarelybyinfectedbloodproducts.

• MostcommonriskfactorsintheUnitedStatesincludeinternationaltravelandclosecontact(sexualorhousehold)withahepatitisA–infectedperson.

• IntheUnitedStates,theincidenceofhepatitisAhasplummetedoverthepast15yearsasaresultofimplementationofroutinevaccinationofchildren.Largecommunity-wideepidem-icspreviouslycommonarenowrare.

• Globally, hepatitis A is one of the leading causes of vaccine-preventable deaths. Diseaseincidenceparadoxicallymayincreaseasimprovementinlivingconditionsdelaysinfectiontoolderages,whensymptomsarelikelytobemoresevere.

DIAGNOSIS• HepatitisAisnotclinicallydistinguishablefromotherformsofviralhepatitis.• LaboratorydiagnosisismadebydetectionofIgMantibodiestoHAVinasingle,acute-phase

serumsample.

THERAPY• Most illnesses are self-limited and can be managed with supportive and symptomatic

measures.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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irus

• Fulminantcasesarerarebutneedtobemanagedappropriatelyandmayrequiretransplanta-tioninextremelyillpatients.

• ChronichepatitisAdoesnotoccur.

PREVENTION• IntheUnitedStates,vaccinationwithhepatitisAvaccineisrecommendedforallchildren

atage12to23months.Vaccinationofolderchildrenandadultsmaybewarranted,includingpatientswithchronichepatitisBandC(seeTable110-1).

• Vaccination of international travelers and persons in selected high-risk groups is recom-mended(seeTable110-1).

• AdministerpostexposureprophylaxiswithhepatitisAvaccine(preferred)orimmuneglobu-linifexposureoccurredwithintheprevious2weeks,ifpatientisimmunosuppressed,orifpatientisyoungerthan1yearofage(seeTable110-2).

TABLE 110-1  Recommendations for Routine Preexposure Use of Hepatitis A Virus Vaccine

GROUP COMMENTSChildren Vaccine should be given to all children at age 1 yr

(12-23 mo).* Vaccination of children 2-18 yr may also be warranted.†

International travelers‡ IG may be given in addition to or instead of vaccine; children <12 mo should receive IG (see Table 176-2)

Close contacts of newly arriving international adopteesMen who have sex with men

All persons who anticipate close personal contact (e.g., household contact or regular babysitter) during the first 60 days after arrivalIncludes adolescents

Illicit drug users Includes adolescents

Persons with chronic liver disease, such as those with hepatitis B or C

Increased risk of fulminant hepatitis A with HAV infection

Persons receiving clotting factor concentrates

Persons who work with HAV in research laboratory settings

HAV, hepatitis A vaccine; IG, immune globulin.*Hepatitis A vaccine is not licensed for children <12 months.†States and communities with existing vaccination programs for children age 2 to 18 years are encouraged to

maintain these programs. Catch-up vaccination for this age group may be warranted elsewhere in the context of ongoing outbreaks among children.

‡Persons traveling to Canada, Western Europe, Japan, Australia, or New Zealand are at no greater risk than in the United States.

From Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immuniza-tion. Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2006;55(RR-7):1-23; and Centers for Disease Control and Prevention. Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees. MMWR Morb Mortal Wkly Rep. 2009;58:1006-1007.

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TABLE 110-2  Recommendations for Hepatitis A Postexposure Prophylaxis

GROUP* RECOMMENDED PROPHYLAXIS†

Persons 12 mo–40 yr Single antigen hepatitis A vaccine at age-appropriate dose

Persons >40 yr IG 0.02 mL/kg is preferred; vaccine can be used if IG cannot be obtained

Children <12 mo IG 0.02 mL/kg‡

Immunocompromised persons, persons who have chronic liver disease, and persons for whom vaccine is contraindicated

IG 0.02 mL/kg‡

IG, immune globulin.*Persons recently exposed to hepatitis A virus who have not previously received hepatitis A vaccine.†Postexposure prophylaxis should be given as soon as possible after exposure. The efficacy of immune globulin

or vaccine administered more than 2 weeks after exposure has not been established.‡In the event of ongoing exposure, persons for whom immune globulin is recommended should receive immune

globulin 0.06 mL/kg, repeated every 5 months during exposure.

243

111  RhinovirusRonald B. Turner

VIROLOGY AND EPIDEMIOLOGY• RhinovirusesareunenvelopedRNAvirusesinthefamilyPicornaviridae.• One-hundredoneserotypeshavebeendetected,nowdividedintotwophylogeneticspecies

(humanrhinovirus[RV]-AandRV-B);athirdspecies,RV-C,alsoexists.• Rhinoviruses are among the most common pathogens of man, with an incidence of 0.5

infectionsperyearinadultsand2infectionsperyearinchildren.• Infections occur year-round, with seasonal peaks in the spring and fall in temperate

climates.

DIAGNOSIS• Thecommoncoldisthecharacteristicclinicalmanifestation.• Exacerbationsofasthmainchildrenarefrequentlyassociatedwithrhinovirusinfection.• Rhinovirusesmaycausebronchiolitisinyoungchildren.• Specificvirologicdiagnosisisbestaccomplishedwithpolymerasechainreactionbutisrarely

usefulforpatientmanagement.

THERAPY• Despitemultiplestudies,nospecificantiviraltherapyhasbeenestablished.

PREVENTION• Thereisnoproveninterventiontopreventrhinovirusinfection.

244

112 Noroviruses and Sapoviruses (Caliciviruses)Raphael Dolin and John J. Treanor

DEFINITION• The genera Norovirus and Sapovirus, of the family Caliciviridae, cause acute

gastroenteritis.

EPIDEMIOLOGY• Noroviruses are the major worldwide cause of viral gastroenteritis, cause both foodborne

andperson-to-personoutbreaks,andcanbespreadviafomites.• Norovirusesaccountfor21millioncasesofgastroenteritisintheUnitedStatesannuallyand

forupto200,000deathsinthedevelopingworldamongchildrenyoungerthan5years.• Sapovirusescausegastroenteritislessfrequentlythannoroviruses.

MICROBIOLOGY• Norovirusesandsapovirusesaresingle-stranded,positive-senseRNAviruses.Eachisdivided

intofivegenogroupsandhasmultiplegenotypes.• Neithernorovirusesnorsapoviruseshavebeencultivatedinvitro.

CLINICAL MANIFESTATIONS• Illness caused by noroviruses and sapoviruses consists of combinations of vomiting and

diarrhea,oftenaccompaniedbyabdominalcramps,nausea,andlow-gradefever.• Illnessusuallylasts12to60hoursandremitsspontaneously.• More severe disease and even fatalities can occur in young children and in the elderly.

Immunocompromisedpatientsmayhaveprolongedsheddingofvirus,alongwithsevereandpersistentgastrointestinalillness.

DIAGNOSIS• Norovirusesmaybesuspectedasacauseofoutbreaksofgastrointestinalillnessiftheabove

clinical features are present, particularly if a large number of individuals are involved.However, the illness is not sufficiently distinctive in individual cases to permit a clinicaldiagnosistobemadeonclinicalgroundsalone.

• Specificdiagnosisismadebydetectionofvirusinstoolspecimensbyreverse-transcriptasepolymerase chain reaction assay. Enzyme immunoassays are also available, but they aregenerallyoflowsensitivity,althoughhighspecificity.

THERAPY• Onlysupportivetherapyisavailable,particularlymaintaininghydration,whichisallthatis

needed.

PREVENTION• Themaincontrolmeasuresaretopreventcontaminationoffoodsuppliesandwaterbygood

hygieneandbyrestrictionoffoodhandlingbyillindividualsuntilatleast2to3daysaftergastrointestinalillnesshasresolved.

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 Sapo

viruses (C

aliciviruses)

• Vigoroushandwashingbyillindividualsshouldbemaintained.• DecontaminationofexposedsurfacesshouldbecarriedoutwithEnvironmentalProtection

Agency–recommendeddisinfectants;forexample,householdbleachshouldbecarriedoutat1:10to1:50dilutions.

• An initial clinical study of an investigational norovirus vaccine, consisting of virus-likeparticles,reducedexperimentallyinducedgastroenteritisby47%.

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113 Astroviruses and PicobirnavirusesRaphael Dolin and John J. Treanor

DEFINITION• Astrovirus causes acute gastroenteritis. Picobirnaviruses have been detected in stools but

havenotbeenestablishedascausesofillnessinhumans.

EPIDEMIOLOGY• Astrovirusesareworldwideindistribution,causediseasemostfrequentlyinyoungchildren,

butcanalsocausegastroenteritisinadultsandinimmunosuppressedpatients.Transmissionislikelybythefecal-oralroute.

MICROBIOLOGY• Astrovirusesaresingle-strandedRNAviruses,comprising8serotypes,withacharacteristic

star-shapedmorphologyseenonelectronmicrographs.Picobirnavirusesaredouble-strandedRNAviruseswithabisegmentedgenome.

CLINICAL MANIFESTATIONS• Illness induced by astroviruses consists of diarrhea, headache, malaise, nausea, low-grade

fever,and,lesscommonly,vomiting.Illnessmaybesomewhatlessseverethanthatseenwithrotaviruses.

DIAGNOSIS• Astroviruses instoolscanbedetectedbyelectronmicroscopy,enzymeimmunoassay,and

by reverse-transcriptase polymerase chain reaction assay, which is the most sensitivetechnique.

THERAPY• Treatmentissupportive.Intravenousimmuneglobulinhasbeenusedinimmunosuppressed

patients,butitsefficacyisnotestablished.

PREVENTION• Althoughvirus-likeparticlesfromastroviruseshavebeenproduced,vaccineshavenotbeen

developed.

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114 Hepatitis E VirusStephen R. Walsh

DEFINITION• Hepatitis E virus (HEV) is a member of the Hepeviridae family, genus Hepevirus, which

causes acute hepatitis in the normal host and chronic hepatitis in immunosuppressedpatients.

EPIDEMIOLOGY• HEVmaybethemostcommonformofacuteviralhepatitisandoccurs inbothsporadic

andepidemicforms.• HEVistransmittedbywaterbornespreadoffecallycontaminatedwaterorbyfecallytrans-

mittedzoonoticinfection.Person-to-persontransmissionisuncommon.• HEVisuniqueamongthehepatitisvirusesbecauseofitsdisproportionatelyhighmortality

rateinpregnantwomen(25%inthethirdtrimester).• HEVinfectionisuncommon,but likelyunderdiagnosedindevelopedcountries,andzoo-

noticinfectionsmayberesponsibleformanyofthecasesthatarelocallyacquiredindevel-opedcountries.

• ChronichepatitisEinfectionhasrecentlybeendescribedinimmunosuppressedpatients.

MICROBIOLOGY• HEVvirionsarenonenveloped,icosahedralparticlesofapproximately32-nmdiameter.• HEV has a single-stranded positive-sense RNA genome that contains three open reading

frames(ORFs).• Fourgenotypesand24subgenotypeshavebeendescribed.

DIAGNOSIS• Diagnosis of HEV had previously been made serologically, but molecular diagnosis via

polymerasechainreactionhasbettersensitivityandspecificityand is thediagnostic tech-niqueofchoice,ifavailable.

THERAPY• AcuteHEVinfectionisgenerallyself-limitedandrequiresonlysupportivecare.Severeacute

caseshavebeentreatedsuccessfullywithribavirin.• RibavirinmonotherapyappearstobehighlyeffectiveintreatmentofchronichepatitisEin

solid-organtransplantrecipients.

PREVENTION• Protecting water supplies from contamination with human feces is the most important

meanstopreventHEVinfection.• AvaccineusingtheORF2capsidproteinthatassemblesintovirus-likeparticles(Hecolin)

hasbeenshowntobesafeandeffectiveandislicensedinChina.

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B  Prion Diseases

115 Prions and Prion Diseases  of the Central Nervous  System (Transmissible Neurodegenerative Diseases)Patrick J. Bosque and Kenneth L. Tyler

DEFINITION• Priondiseasesaretransmissibleneurodegenerativeconditionsofmammalscharacterizedby

arapidlyprogressivedeclineofcognitive,motor,andotherbrainfunctions.• Prion diseases are biochemically defined by the accumulation of an abnormal form of a

normallyexpressedbrainprotein,theprionprotein(PrP).

EPIDEMIOLOGY• Humanpriondiseaseisrare;itsincidenceis1×10−6worldwide.• About90%ofcasesaresporadic.• About10%ofcasesaregenetic.• Infectioustransmissionaccountsforlessthan1%ofhumancases.

MICROBIOLOGY• ThecausativeagentiscomposedofanaggregateofmisfoldedformsofPrP.• The aggregate serves as a catalytic template for the further aggregation of PrP and thus

replicates.• Theprioncontainsnoinformation-bearingnucleicacid.

DIAGNOSIS• Treatablemimicsofpriondiseaseshouldbeexcludedbeforemakingthediagnosis.• CertaindiagnosiscanonlybemadebydetectingabnormalPrPaggregatesintissue,typically

brain.• Diagnosis is usually made by history and clinical signs and supported by ancillary tests,

including magnetic resonance imaging, electroencephalography, and cerebrospinal fluidanalysis.

THERAPY• Noeffectivetherapyexistsforprioninfection.

PREVENTION• Onlystandardprecautionsareneededformostprocedures,topreventiatrogenictransmis-

sionofpriondisease.• Additionalprecautionsareneededforneurosurgicalcases.• Transfusionofredbloodcellsandplasmaproteinproductscantransmitoneformofprion

disease,variantCreutzfeldt-Jakobdisease.• Tissuefrompersonswithpriondiseasemustnotbetransplanted.• Dietaryexposuretoruminantanimalprionsshouldbeavoided.

249

C  Chlamydial Diseases

116 Chlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)Byron E. Batteiger and Ming Tan

DEFINITION• Chlamydia trachomatisisanobligateintracellularbacteriumthatmainlyinfectsocularand

genitourinaryepithelium.• Theoculardiseasetrachomaistheleadinginfectiouscauseofblindnessworldwide.• Chlamydialgenitalinfectionsarethemostcommonbacterialsexuallytransmittedinfections

intheworld.• Lymphogranulomavenereum(LGV),causedbydistinctserovarsofC. trachomatis,isaless

commondiseasecharacterizedbyenlargedinguinallymphnodesorsevereproctocolitis.

EPIDEMIOLOGY• Trachoma is common in poor, rural areas of developing countries, with an estimated 40

millionactivecasesworldwide.• Activeinfectionintrachomalargelyaffectsyoungchildren,oftenthoseyoungerthan1year

ofage,whereasthescarringsequelaethatproduceblindnessoccurlaterinlife.• The sexually transmitted urogenital infections are common worldwide with an estimated

105.7millionnewcasesin2008.• Chlamydialgenitalinfectionsaremostprevalentamongadolescentwomenandmen,where

repeatedinfectionsarecommon.• Chlamydialgenital infectionsareoftenasymptomaticbutcancausereproductivesequelae

inwomen,includinginvoluntaryinfertilityandectopicpregnancy.• Transmissionduringvaginaldeliverycanleadtoneonatalconjunctivitisandpneumonia.• C. trachomatisinfectionsarereportabletotheCentersforDiseaseControlandPrevention

andallstatehealthdepartmentsintheUnitedStates.

PATHOPHYSIOLOGY• Diseasemanifestationsarelargelymediatedbythehostresponsetotheinfection,whichis

initiatedandsustainedbyactivelyinfectednonimmunehostepithelialcells.• Inasubstantialminorityofpersonswithtrachomaandgenitalinfections,thehostinflam-

matoryresponseleadstotissuescarring,resultinginend-organdysfunctionandsequelae.

MICROBIOLOGY• C. trachomatisisagram-negativebacterium,butGramstainisnotusedforidentification.• Theorganismiscultivatedincellculturebecauseitdoesnotgrowanddivideaxenically.• Thebacteriumreplicateswithinacytoplasmicinclusioninthehostcell.• The two morphologic forms are the infectious but nondividing elementary body and the

reticulatebody,whichisanintracellular,replicatingform.

DIAGNOSIS• Diagnosis of trachoma in endemic areas is typically by physical examination of the eye

accordingtocriteriaestablishedbytheWorldHealthOrganization.

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• Diagnosisofgenitalinfectionsrequiresmicrobiologictesting,ideallybynucleicacidampli-ficationtestsoffirst-catchurineinmenandvaginalswabsinwomen.

THERAPY (SEE TABLE 116-1)• Therapy of trachoma is generally provided by repeated mass treatment of hyperendemic

communitieswithsingle-doseazithromycin.• Recommendedtreatmentofuncomplicatedurogenital infectioniseitherazithromycin1g

orallyasasingledoseordoxycycline100mgorallytwicedailyfor7days.Treatmentofsexpartnersiscrucialtopreventrepeatedinfection.

• Treatmentofcomplicatedinfectionsrequireslongerdurationsoftherapy:forsalpingitis,14days;forepididymitis,10days;andforproctitis,7days.

• LGVistreatedwithdoxycyclinefor21days.

PREVENTION• Trachoma can be prevented by face washing, access to clean water, and improvements in

sanitation.• In the United States and other developed countries, prevention of sexually transmitted

genital infectionsandcomplicationsis largelyfocusedonscreeningandtreatingnonpreg-nantsexuallyactivewomenaged25yearsoryoungeronanannualbasis.UptakeofscreeningintheUnitedStatesisrelativelylow.

• Screeningofallpregnantwomenisrecommended.• Screeningandtreatmentofwomenolderthan25yearsofageisrecommendedifriskfactors

areidentified,suchasnewormultiplesexualpartners.• One-timescreeningandtreatmentinwomendecreasesriskofsymptomaticpelvicinflam-

matory disease in the following year. Data are currently lacking as to whether screeningprogramsreducepopulationprevalenceofchlamydialgenitalinfection.

• Screeningofyoungmeninhigh-risksettings(sexuallytransmitteddiseaseandadolescentclinics,correctionalfacilities)shouldbeconsideredifresourcesallow.

• No vaccine is currently available for either trachoma or chlamydial genital infections.Induction of sterilizing immunity appears unlikely, and future vaccine efficacy evaluationmaybebasedondemonstratingreducedriskofinflammatorysequelaeintheeyeandsymp-tomaticpelvicinflammatorydiseaseinwomen.

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lamyd

ia tracho

matis (Trach

om

a, Gen

ital Infectio

ns, Perin

atal Infectio

ns, an

d Lym

ph

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ranu

lom

a Ven

ereum

)

TABLE 116-1  Clinical Characteristics of Common Chlamydia trachomatis Infections

INFECTIONSYMPTOMS AND SIGNS

PRESUMPTIVE DIAGNOSIS

DEFINITIVE DIAGNOSIS TREATMENT

Men Nongonococcal urethritis

Urethral discharge, dysuria

Urethral leukocytosis; no gonococci seen

Urine or urethral NAAT

Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days

Epididymitis Unilateral epididymal tenderness, swelling; pain; fever, presence of NGU

Urine or urethral NAAT

Urethral leukocytosis; pyuria on urinalysis

STI likely: Ceftriaxone 250 mg IM plus doxycycline, 100 mg PO bid, for 10 days

History of insertive anal intercourse:Ceftriaxone, 250 mg IM, plus levofloxacin, 500 mg bid for 10 days

Proctitis (non-LGV)

Rectal pain, discharge and bleeding; history of receptive anal intercourse

≥1 PMN/OIF on rectal Gram stain; no gonococci seen

Urine or urethral NAAT; rectal culture or NAAT

Doxycycline, 100 mg PO bid, for 7 days

LGV Painful, tender inguinal lymphadenopathy, fever

“Groove sign” Urine, urethral, lymph node or rectal NAAT; rectal or lymph node culture; LGV-specific testing if available

Doxycycline, 100 mg PO bid, for 21 days

LGV proctitis Rectal pain, discharge, and bleeding in MSM; absence of inguinal lymphadenopathy

≥1 PMN/OIF on rectal Gram stain; no gonococci seen

Urine, urethral, or rectal NAAT; rectal culture; LGV-specific testing if available

Doxycycline, 100 mg PO bid, for 21 days

Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection

Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear

Rectal culture or NAAT; NAAT of conjunctivae

Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days

Continued

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INFECTIONSYMPTOMS AND SIGNS

PRESUMPTIVE DIAGNOSIS

DEFINITIVE DIAGNOSIS TREATMENT

Women Cervicitis Mucopurulent cervical discharge; ectopy, easily induced bleeding

≥20 PMN/OIF on cervical Gram stain

Urine or cervical NAAT

Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days

Urethritis Dysuria, frequency; no hematuria

Pyuria on UA; negative urine Gram stain and culture

Urine, cervical, or urethral NAAT

Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid for 7 days

PID Lower abdominal pain, adnexal pain, cervical motion tenderness

Evidence of mucopurulent cervicitis

Urine or cervical NAAT

Outpatient: Ceftriaxone 250 mg IM as a single dose, plus doxycycline 100 mg PO bid for 14 days, with or without metronidazole, 500 mg PO bid for 14 days

Adults Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection

Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear

DFA or NAAT on conjunctival swab

Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid for 7 days

Newborns Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection

Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear

DFA or NAAT on conjunctival swab; vagina, rectum, pharynx also often positive

Erythromycin base 50 mg/kg/day, orally divided into four doses daily for 14 days; evaluate and treat parents as well

Pneumonia Staccato cough, tachypnea, hyperinflation

Diffuse interstitial infiltrate, eosinophilia

Nasopharyngeal NAATs or culture; MIF serology (IgM)

Erythromycin base 50 mg/kg/day, orally divided into four doses daily for 14 days; evaluate and treat parents as well

DFA, direct fluorescent antibody; IgM, immunoglobulin M; LGV, lymphogranuloma venereum; MIF, microimmuno-fluorescence; MSM, men who have sex with men; NAAT, nucleic acid amplification test; NGU, nongonococcal urethritis; OIF, oil immersion field; PMN, polymorphonuclear neutrophil; STI, sexually transmitted infection; UA, urinalysis.

TABLE 116-1  Clinical Characteristics of Common Chlamydia trachomatis Infections—cont’d

253

117 Psittacosis (Due to Chlamydia psittaci)David Schlossberg

DEFINITION• Asystemicinfectionthatfrequentlycausespneumonia.

EPIDEMIOLOGY• Acquired by inhalation, after exposure to infected birds, although not all infected birds

appearill,andoccasionalpatientsprovidenohistoryofbirdexposure.

MICROBIOLOGY• TheetiologicagentisChlamydia psittaciofthefamilyChlamydiaceae.

DIAGNOSIS• Diagnosis is made serologically in most cases; when available, polymerase chain reaction

may be positive. Because diagnostic methods are imperfect, treatment should not awaitdefinitivediagnosis.

THERAPY• Doxycycline or tetracycline is treatment of choice. Macrolides and fluoroquinolones have

goodinvitroactivity,butthereislimitedclinicalexperience.

PREVENTION• Treatimportedbirdsandbirdsthathavesuspectedinfection.

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118  Chlamydia pneumoniaeMargaret R. Hammerschlag, Stephan A. Kohlhoff, and Charlotte A. Gaydos

MICROBIOLOGY AND EPIDEMIOLOGY• Obligateintracellularbacterium,mustbegrownintissueculture• Capableofcausingpersistentinfection,oftensubclinical• Worldwidedistribution,infectsmanyanimalsaswellashumans• Primarilyarespiratorypathogeninhumans,causingcommunity-acquiredpneumonia• Cancauseepidemicsinenclosedpopulations:militarybases,schools,nursinghomes

DIAGNOSIS• Chlamydia pneumoniaecausespneumonia;clinicallyitcannotbedifferentiatedfromother

causesofatypicalpneumonia,especiallyMycoplasma pneumoniae.• The most accurate method of diagnosis is identification of the organism in respiratory

samplesbycultureornucleicacidamplificationtest(NAAT).• Serology is of limited value, requires paired sera, and many patients who are positive by

cultureorNAATwillbeseronegative.

THERAPY• C. pneumoniaeissusceptibletomacrolides,quinolones,andtetracyclines.Dataonefficacy

arelimited,includingoptimaldoseanddurationoftherapy.• Ten-to14-daycoursesoferythromycin,clarithromycin,doxycycline,levofloxacin,ormoxi-

floxacinor5daysofazithromycinareclinicallyeffectiveandresult inapproximately80%microbiologiceradication.

255

D  Mycoplasma Diseases

119 Mycoplasma pneumoniae and Atypical PneumoniaRobert S. Holzman and Michael S. Simberkoff

DEFINITION• AtypicalpneumoniacausedbyMycoplasma pneumoniae isasyndromethat incontrast to

lobarpneumoniais:• Slowerinonset• Generallymilder• Notassociatedwithlobarconsolidation• Notassociatedwithresolutionbycrisis

• Manyotherviralandbacterialagentscanproduceanatypicalpneumoniasyndrome.

ETIOLOGIC AGENT• M. pneumoniae

• Bacteriumlackingcellwall• Adhesinsandadhesionorganelleimportantinpathogenesis• Fastidious• Maybecultivablefromsputumaftersymptomsofillnessresolve

EXTRAPULMONARY SITES AND MANIFESTATIONS OF INFECTION• Skin(maculopapularorvesicularrashes,Stevens-Johnsonsyndrome)• Cardiac(pericarditis,myocarditis)• Centralnervoussystem(encephalitisormeningitis,myelitis,radiculopathy)• Musculoskeletal(myalgia/arthralgia,rhabdomyolysis,arthritis)• Raynaud’sphenomenon• Renal(glomerulonephritis,nephroticsyndrome)• Hematologic

DIAGNOSIS• Clinicalsuspicionbysyndrome• Presenceofcoldagglutininsintheabsenceofanotherexplanation• DetectionofrisingtitersofantibodiestoM. pneumoniae• DetectionofM. pneumoniae–specificantigens• DetectionofM. pneumoniae–specificgeneticcomponents

TREATMENT• Macrolides(e.g.,azithromycin,500mgday1,250mgday2to5)

• Macrolideresistanceisincreasingandmaylimitusefulness• Tetracyclines(e.g.,doxycycline,100mgtwicedailyfor14days)• Fluoroquinolones(e.g.,moxifloxacin,400mgdailyfor14days)

256

120 Genital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma SpeciesDavid H. Martin

MICROBIOLOGY AND TAXONOMY• ThegenitalmycoplasmasincludeMycoplasma hominis, Mycoplasma genitalium, Ureaplasma

urealyticum,andUreaplasma parvum.Thelattertwoonlyrecentlywereassignedtoseparatespecies.

• Thegenitalmycoplasmaslackcellwallsandhavethesmallestgenomesofknownfree-livingmicroorganisms.

EPIDEMIOLOGY• All of these organisms are primarily sexually transmitted but also may be transmitted to

infantsatbirth.Thereisevidencethattheymaypersistinchildrenintoadulthood.• TheepidemiologyofinfectionwithM. genitaliumcloselyparallelsthatofChlamydia tracho-

matisandNeisseria gonorrhoeae.

CLINICAL MANIFESTATIONS• U. urealyticumcausesurethritis,whereasU. parvumappearstobeacolonizer.Onlyrelatively

sexuallyinexperiencedmenaresusceptibletoU. urealyticumdisease,whichislikelyduetothedevelopmentofimmunityaftermultipleexposurestothiscommonurethralorganism.

• Althoughthepathogenesisisunclear,theureaplasmasarestronglyassociatedwithbroncho-pulmonarydysplasiainvery-low-birth-weightinfants.

• M. hominisplaysaminorroleingenitaltractdiseasebutisimplicatedinpostpartumfever,bacteremia,andpostoperativemediastinalandwoundinfections.

• M. genitaliumisacauseofurethritisinmenandendocervicitisinwomen.ItislikelyacauseofpelvicinflammatorydiseasebutappearstocausemilderdiseasethanN. gonorrhoeaeand C. trachomatis.

DIAGNOSIS• Mostclinicallaboratoriesarenotequippedtodiagnoseinfectionscausedbytheseorganisms.

OnlyM. hominisisdetectableusingmethodsroutinelyemployedinclinicallaboratories,butsensitivity is poor. The ureaplasmas require special media for growth, and M. genitaliumcannotbeculturedatalloutsideresearchlaboratories.Nucleicacidamplificationassaysforthisorganismhavebeendevelopedbutarenotingeneraluse.

THERAPY• TetracyclineclassdrugsareactiveagainstmostureaplasmasandM. hominisbutnotagainst

M. genitalium.MacrolidesareeffectivefortheureaplasmasbutnotforM. hominisandareonly partially effective for M. genitalium. Quinolones, especially moxifloxacin, are activeagainstallofthegenitalmycoplasmas.

257

E  Rickettsioses, Ehrlichioses, and Anaplasmosis

121 Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers)David H. Walker and Lucas S. Blanton

ETIOLOGY• Spottedfevergroup(SFG)rickettsiaearesmall,gram-negative,obligatelyintracellularbac-

teriathatcausetick-,mite-,andflea-bornehumaninfections.• In humans, rickettsiae infect endothelial cells and exert their pathophysiologic effects

throughendothelialinjury,witharesultantincreaseinvascularpermeability.

EPIDEMIOLOGY• Rickettsia rickettsii is the agent that causes Rocky Mountain spotted fever (RMSF).

Dermacentor variabilis,Dermacentor andersoni,andRhipicephalus sanguineustickstransmittheinfectionintheeasterntwothirds,western,andsouthwesternUnitedStates,respectively.RMSFalsooccursinCentralandSouthAmerica.

• IntheUnitedStates,RMSFismostprevalentintheSouthAtlanticandSouthCentralregions.Infections usually occur during the late spring and summer, when ticks are most active.Other tick-borne SFG rickettsiae with a broad range of distribution include R. conorii(Europe, Africa, and South Asia), R. sibirica (eastern Russia and Asia), R. africae (sub-Saharan Africa and West Indies), R. parkeri (North and South America), and R. slovaca(Europe).

• Rickettsia feliscausesflea-bornespottedfeverandhasaworldwidedistribution.

CLINICAL MANIFESTATIONS• RMSFtypicallymanifestswithfeverearlyinthecourse.Othermanifestationsincludehead-

ache,myalgias,nausea,vomiting,andabdominalpain.• Rashiscommonbutmaynotoccurinthefirstfewdaysofillness.Rashtypicallystartson

thewristsandanklesbeforespreadingproximally.Involvementofthepalmsandsolesoccursin36%to82%butisoftenalatesign.

• Skin necrosis, gangrenous digits, neurologic complications, azotemia, pulmonary edema,andacuterespiratorydistresssyndromearemanifestationsofsevereinfection.

• ThecasefatalityrateofRMSFis23%withoutappropriateantimicrobialtreatmentandupto4%despiteappropriateantimicrobials.

• OtherSFGrickettsiosesmanifestwithawidespectrumofdiseaseseveritybutaregenerallylessseverethanRMSFandoftenhaveanassociatedescharatthetickbitesite.

DIAGNOSIS• Theindirectimmunofluorescenceassayistheserologicmethodofchoice.Afourfoldrisein

immunoglobulin G titer from acute illness to convalescence retrospectively confirms thediagnosis.

• ImmunohistochemicaldetectionofSFGrickettsiaeinskinbiopsycanestablishthediagnosisduringacuteillness.

• Polymerasechainreactionamplificationofrickettsialnucleicacidsinblood,skinorescharbiopsy,orescharswabisausefultoolfordiagnosisandspeciesidentification.

• Treatmentshouldnotbewithheldwhileawaitinglaboratoryconfirmation.

258Part

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Dis

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r Et

iolo

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 Ag

ents

TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10daysisthetreatmentofchoiceforRMSFand

otherSFGrickettsioses.• Chloramphenicolisanalternative,butitsuseisassociatedwithahighercasefatalityinthose

withRMSF.• AzithromycinandclarithromycinarealternativesforlesssevereSFGrickettsioses.• Prevention is aimed toward the avoidance of contact with vectors through repellents and

protectiveclothing.

259

122  Rickettsia akari (Rickettsialpox)Didier Raoult

DEFINITION• Vesicularfeverwithescharcausedbymitebites;maybeconfusedwithanthrax.

EPIDEMIOLOGY• FoundworldwidebutisparticularlycommoninNewYorkCity.

MICROBIOLOGY• InfectioncausedbyintracellularRickettsia akari.

DIAGNOSIS• Basedonserologyandpolymerasechainreactionassayofswabfromavesicleoreschar.

THERAPY• Doxycycline,100mgtwicedailyfor7days.

PREVENTION• Mouseeradicationfrombuildingswillpreventtransmissiontohumans.

260

123  Coxiella burnetii (Q Fever)Thomas J. Marrie and Didier Raoult

DEFINITION• Qfevercanbemanifestasaself-limitedfebrileillness,pneumonia,endocarditis,orhepatitis.

There are many other less common manifestations, such as meningitis, encephalitis, andosteomyelitis.Infectionsaredividedintoacuteandchronicforms.

EPIDEMIOLOGY• Q fever is a zoonosis that is usually acquired by inhalation or, much less commonly, by

ingestingunpasteurizedmilk.• Cattle,sheep,andgoatsarethemostcommonreservoirs.Infectedparturientcatsareimpor-

tantinthespreadofCoxiellainsomeareas.• Thereisanextensivewildlifereservoir.• Theenvironmentiscontaminatedatthetimeofparturitionbyaninfectedanimal.• Windbornespreadfromthecontaminatedenvironmentcanoccuroveradistanceofatleast

10km.• The distribution is worldwide, with the exception of New Zealand, Antarctica, and the

Arctic.

MICROBIOLOGY• Pleomorphicgram-negative(structurally—doesnotstainwithGramstain)coccobacillus• Coxiella burnetii—onlyspeciesinthegenus• Intracellularpathogen• Sporeformer• Undergoesphasevariation;acute infectionleadstoantibodypredominantlyagainstphase

IIantigens,whereaschronicinfections,suchasendocarditis,arecharacterizedbyimmuno-globulinG(IgG)antibodypredominantlyagainstphaseIantigens.

DIAGNOSIS• Inmostinstances,anindirectimmunofluorescentserologictestisthebestone.• A fourfold rise in titer between acute and convalescent samples is diagnostic of acute

disease.• Chronicinfectionisdiagnosedonthebasisofclinicalmanifestations(e.g.,endocarditis)in

conjunction with an IgG phase I titer that is equal to or exceeds phase II and is at least1:1600.

• Isolation of C. burnetii by using a shell vial technique can be done in Biosafety Level 3laboratories.

• PolymerasechainreactionassaycanbeusedtoamplifyC. burnetiiDNAfromavarietyofclinicalspecimens,suchasheartvalvesandjointfluid.Fluorescentinsituhybridizationcanidentifyorganismsintissue,althoughstandardhistopathologicstainsarenegative.

261C

hap

ter 123 Co

xiella bu

rnetii (Q

 Fever)

THERAPY• AcuteQfever:10daysofdoxycycline,afluoroquinoloneoramacrolide• ChronicQfever:DoxycyclineplushydroxychloroquineuntilphaseIIgGantibodytitershave

declinedto1:800orless

PREVENTION• Goodanimalhusbandrypractices• Useofseronegativesheeporgoatsinresearchfacilities

262

124 Rickettsia prowazekii (Epidemic or Louse-Borne Typhus)Lucas S. Blanton and David H. Walker

MICROBIOLOGY• Rickettsia prowazekiiisasmallobligatelyintracellulargram-negativecoccobacillus.• Its1.1-Mbgenomehasundergoneevolutionaryreduction,resultingintherelianceonthe

hostcellcytosolformanybiosyntheticfunctions.• Anextracellulardormantformremainsinfectiousinlousefecesformonthsorlonger.

EPIDEMIOLOGY• The agent is transmitted between patients by the human body louse (Pediculus humanus

corporis).• Licebecomeinfectedwhilefeedingonrickettsemicpatients.Theorganismisinoculatedinto

anewhostbyscratchingrickettsiae-ladenlousefeces into louse-bittenskinorbyrubbingintomucousmembranes.

• Recoveredpatientsremainlatentlyinfected,aresusceptibletoreactivationwithrickettsemia,andcanserveasasourceforanepidemic.

• Epidemics are associated with conditions that promote louse infestations through poorhygiene—poverty, cold climate, jails, and displacement of populations by wars and othercalamities.

• In North America, an extrahuman reservoir of R. prowazekii exists in flying squirrels(Glaucomys volans),withinfectionstransmittedtohumansbymucousmembraneorinha-lationalexposuretothesquirrel’sfleaorlousefeces.

CLINICAL MANIFESTATIONS• Frequentsymptomsincludefever,headache,chills,myalgia,andrash(seeTable124-1).• Untreatedillnessmayprogresstocausepulmonaryedema,encephalitis,anddeath.• Recrudescent typhus and flying squirrel–associated typhus manifest similarly but are less

severe.

DIAGNOSIS• The indirect immunofluorescence assay is the mainstay of serologic diagnosis. A fourfold

rise in immunoglobulin G (IgG) titer from acute illness to convalescence confirms thediagnosis.

• Polymerase chain reaction assay and immunohistochemical detection of R. prowazekii inbloodortissue,respectively,canestablishthediagnosisduringacuteillness.

• Treatmentshouldnotbewithheldwhileawaitinglaboratoryconfirmation.

TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10days,isthetreatmentofchoice.Chloramphenicol

isanalternativetreatment.• Controlofbodylicebychangingandwashinggarmentsinhotwaterisessentialforpreven-

tionandoutbreakcontrol.

263C

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row

azekii (Epid

emic o

r Lou

se-Bo

rne Typ

hu

s)

TABLE 124-1  Clinical Manifestations of Epidemic Typhus

Manifestation

PLACE

Burundi EthiopiaNumber of cases 102 60

Fever >39° C 100% 100%

Headaches 100% 100%

Any rash 25% 38%

Purpuric rash 11% 33%

Stupor 81% 35%

Coma 4% —

Cough 70% 38%

Nausea, vomiting 57% 43%

Conjunctivitis 15% 53%

Diarrhea 13% —

Splenomegaly 8% 13%

Photophobia — 33%

Myalgias 100% 70%

Data for Burundi from Fournier PE, Ndihokubwayo JB, Guidran J, et al. Human pathogens in body and head lice. Emerg Infect Dis. 2002;8:1515-1518; data for Ethiopia from Perine PL, Chandler BP, Krause DK, et al. A clinico-epidemiological study of epidemic typhus in Africa. Clin Infect Dis. 1992;14:1149-1158.

264

125  Rickettsia typhi (Murine Typhus)Lucas S. Blanton, J. Stephen Dumler, and David H. Walker

DEFINITION• MurinetyphusiscausedbyRickettsia typhi.• R. typhiisanobligatelyintracellulargram-negativebacterium.• Theorganisminfectsendothelialcellsinmammalianhostsandmidgutepithelialcellsinflea

hosts.

EPIDEMIOLOGY• Murinetyphusisdistributedworldwideandisprevalentintropicalandsubtropicalseaboard

regionswhererats(Rattusspp.)andtheirfleas(Xenopsylla cheopis)serveasreservoirsandvectors,respectively.

• IntheUnitedStates,mostcasesarereportedinsouthTexasandsouthernCaliforniawherethecatflea (Ctenocephalides felis) is thepredominantvectorandwhereopossumsare thesuspectedreservoir.

• Thediseaseistransmittedbytheinoculationofinfectedfleafecesintoafleabitewound.• Murinetyphusisincreasinglyrecognizedasanillnessintravelersreturningfromendemic

regionsthroughouttheworld.

CLINICAL MANIFESTATIONS• Commonsymptomsinearlyillnessincludefever,headache,nausea,andvomiting.• Rashiscommonasillnessprogresses.Itisusuallydescribedasmacularormaculopapular,

anditismostcommonlyobservedonthetrunk.• Theclinicalcourseisusuallyuncomplicated,but,occasionally,centralnervoussystemabnor-

malities,renalinsufficiency,respiratoryfailure,anddeathoccur.• Elevations in serum hepatic aminotransferase levels are frequent laboratory findings.

Vascular injuryoften leads tohypoproteinemia,hypoalbuminemia,andelectrolyteabnor-malities(e.g.,hyponatremiaandhypocalcemia).

DIAGNOSIS• Earlydiagnosisofmurinetyphusisbasedonclinicalsuspicionandepidemiology.• Immunofluorescenceassayisthemainstayofserologicdiagnosis,whichisgenerallyretro-

spective. A fourfold rise in IgG titer from acute illness to convalescence confirms thediagnosis.

• ImmunohistochemicaldetectionofR. typhiinaskinbiopsyspecimenorpolymerasechainreactionassayamplificationofrickettsialnucleicacidsinbloodorskinbiopsysamplescanestablishthediagnosisduringacuteinfection.

• Toavoidsevereorpotentiallyfatalinfection,treatmentshouldnotbewithheldwhileawait-inglaboratoryconfirmation.

TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10days,isthetreatmentofchoice.Chloramphenicol

isanalternativetreatment.• Preventionisdirectedtowardthecontroloffleavectorsandpotentialfleahosts.

265

126 Orientia tsutsugamushi (Scrub Typhus)Didier Raoult

DEFINITION• Mite-bornerickettsiosis,presentingoneormorepapularlesionsthatformanescharatbite

sites,followedinseveraldaysbyrapidonsetoffever,headache,myalgia,andlocalandthengeneralizedadenopathy,oftenfollowedbyrash

EPIDEMIOLOGY• ExtremelycommoninruralAsiaandwesternAustralia

MICROBIOLOGY• CausedbyintracellularOrientia tsutsugamushi

DIAGNOSIS• Indirectfluorescentantibodyassayisstandardserology.Polymerasechainreactionassayof

swabortissueofescharpretreatmentisverysensitive.TheWeil-Felixtestisunreliablebutwidelyused.

THERAPY• Basedondoxycycline,100mgtwicedailyfor7days

PREVENTION• AvoidingmitebiteinruralAsiawithvectorcontrol

266

127 

Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other AnaplasmataceaeJ. Stephen Dumler and David H. Walker

DEFINITION• InfectionbyintracellularbacteriaintheAnaplasmataceaefamily

MICROBIOLOGY• OrganismsofthefamilyAnaplasmataceaeoftheorderRickettsialesareobligatelyintracel-

lulargram-negativebacteria.• Ehrlichia chaffeensis, Ehrlichia canis, Ehrlichia muris,andNeorickettsia helminthoeca infect

mostlymonocytesandmacrophagesinbloodandtissuesofmammalianhosts.• Anaplasma phagocytophilumandEhrlichia ewingiiinfectmostlyneutrophilsandothergran-

ulocytesinthebloodofmammalianhosts.• ThemammaliantargetcellofNeoehrlichia mikurensisisnotknown.

EPIDEMIOLOGY• Humanmonocytotropicehrlichiosis(HME)andhumanE. ewingiiinfectionaredistributed

predominantly in south-central and eastern North America, where Amblyomma america­num ticks and white-tailed deer (Odocoileus virginianus) serve as vectors and reservoirs,respectively.

• Humangranulocyticanaplasmosis(HGA)isdistributedworldwide,especiallyinnorthernlatitudes of North America, Europe, and Asia, where Ixodes persulcatus clade ticks orHaemaphysalis longicornisticks(China)andmultiplesmallmammalsserveasvectorsandreservoirs.

• HumanE. muris–likeagentinfectionisdistributedintheupperMidwestoftheUnitedStates(WisconsinandMinnesota),whereIxodes scapularisticksandwhite-footedmiceandothersmallmammalsserveasvectorsandreservoirs.

• HumanN. mikurensisinfectionoccursinEuropeandnorthernChina,whereI. persulcatuscladeticksandsmallmammalsserveasvectorsandreservoirs.

• Sennetsuneorickettsiosisoccurs ineasternandsoutheasternAsia,wheredigeneantrema-todesserveasvectorsandaquaticanimals,mostlyfish,serveasreservoirs throughwhichinfection is acquiredbyoral transmission.Allmembersof theAnaplasmataceaeareobli-gatelyintracellularbacteriathatsurvivewithinvacuolesofhostcellsgenerallyderivedfromthebonemarrow,butalsooccasionallyendothelialcells.

CLINICAL MANIFESTATIONS• Frequentearlymanifestationsincludefever,headache,myalgia,nausea,andvomiting.• Rashisinfrequentorrare.• Theclinicalcourseisusuallyuncomplicated,butseverecomplicationscanincludeaseptic

shock–like syndrome, respiratory distress, meningoencephalitis, renal failure, and death,particularlyforHME.

• Leukopenia,thrombocytopenia,andelevationsinserumhepaticaminotransferaselevelsarefrequentfindings.

267C

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ia chaffeen

sis, An

aplasm

a ph

ago

cytop

hilu

m, an

d O

ther A

nap

lasmataceae

DIAGNOSIS• Early diagnosis of HME, HGA, and other human infections caused by bacteria in the

Anaplasmataceaefamilyisbasedonclinicalsuspicionandepidemiologicclues.• Rapidlaboratoryconfirmationcansometimesbeachievedbybloodsmearexaminationfor

morulae(inclusions)incirculatingleukocytesorbydetectionofbacterialDNAinbloodbypolymerasechainreactionassay.

• Seroconversionorfourfoldincreaseinantibodytiterfromacutetoconvalescentphasecon-firmsthediagnosisretrospectively.

• Earlytherapyimprovesoutcomesandpreventsseverecomplicationsorsequelae.

THERAPY• Doxycycline,100mgtwicedailyfor5to10daysuntilfeverisresolved,isthetreatmentof

choice.• Chloramphenicolshouldnotbeused.• Rifampinhasbeensuccessfullyusedinchildren.

PREVENTION• Prevention is directed toward avoidance of tick exposures and bites and early removal of

attachedticks.Neorickettsiosiscouldbepreventedbyavoidanceofuncookedorfermentedfishfoodproductsinregionswherethediseaseoccurs.

268

F  Bacterial Diseases

128 Staphylococcus aureus (Including Staphylococcal  Toxic Shock Syndrome)Yok-Ai Que and Philippe Moreillon

DEFINITION• Gram-positivepathogenresponsibleforsuperficialanddeep-seatedinfections• Frequentcolonizerofasymptomaticcarriers• Responsibleforbothpyogenicandtoxin-relateddiseases• Primarycauseofcommunity-andhospital-acquiredbloodstreaminfections• Firstcauseofinvasiveinfections,includinginfectiveendocarditisandosteomyelitis• Frequentlyresistanttomethicillin(methicillin-resistantS. aureus[MRSA])andallβ-lactam

drugs(inupto50%ofhospitalisolates)• Oftenco-resistanttomanyclinicallyavailableantibiotics

EPIDEMIOLOGY• Colonizeroftheanteriornostrilsin20%to40%ofthenormalpopulation• Numberonepublichealthproblemindrug-resistantnosocomialinfections• ClonalspreadofMRSAfromhealthcare(HCA-MRSA)andotherpermissiveenvironments

(seeFig.128-1)• Polyclonal dispersion of susceptible strains in the community; but successful clones of

community-acquired(CA)-MRSAmayspreadworldwide(e.g.,USA300)• Superantigenproducerresponsiblefortoxicshocksyndromeandfoodpoisoning

MICROBIOLOGY• Mostvirulentspeciesofthemorethan40Staphylococcusspp.taxa• Conservedcoregenomeofapproximately2.8millionbp• Multiple mobile genetic elements (MGEs); pathogenic and genomic islands, transposons,

andprophagesencodingvirulenceandantibiotic-resistancegenes(seeTables128-1,128-2,and128-3)

• EvolutionofsuccessfulclonesviamutationsandacquisitionofMGEs• MethicillinresistanceconferredbyapolymorphfamilyofSCCmeccassettes

DIAGNOSIS• Conventionalculturesmandatoryandcriticaltodetectnewresistancephenotypes• Prolongedincubationneededforsmall-colonyvariantsresponsibleforchronicinfection• Moleculartestsusefulforrapididentificationofknowndrug-resistancegenes• MoleculartypingcriticaltomanageMRSAepidemicsandinfectioncontrol

THERAPY• First choice for methicillin-susceptible S. aureus: penicillinase-resistantβ-lactam or first-

generationcephalosporin,forinstance,cephalexinordicloxacillinorally;nafcillinoroxacil-linintravenously;or,outsidetheUnitedStates,flucloxacillin.Alternativesincludeclindamycinortrimethoprim-sulfamethoxazoleorallyorintravenously).

• FirstchoiceforMRSAwouldbevancomycinordaptomycinintravenously,or,ifsusceptible,trimethoprim-sulfamethoxazoleorclindamycinorallyorintravenously.Alternativesinclude

269C

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ter 128 Staph

yloco

ccus au

reus (In

clud

ing

 Staph

yloco

ccal Toxic Sh

ock Syn

dro

me)

ceftaroline,linezolid,ortelavancin;or,foracutebacterialskinandskinstructureinfections,dalbavancin,oritavancin,ortedizolid.

• Partnerdrugforcombinations:rifampin.• Benefitofaminoglycosidesnotwelldemonstrated.

PREVENTION• Decolonizationofstaphylococcalcarriers(seeTable128-4)• DetectionofHCA-MRSAandepidemicCA-MRSA• Hospitalhygienemeasures• Vaccinesindevelopment

FIGURE  128-1  Evolution  of  methicillin-susceptible  Staphylococcus aureus  (MSSA)  into methicillin-resistant S. aureus (MRSA) as exemplified by sequence type 5 (ST5). ST5 belongs to clonal cluster 5 (CC5), which gathers S. aureus  isolates sharing homologies  in five of the seven genes  (arcC, aroE, glpF, gmk, pta, tpi,  and  yqiL)  compared  with  method  of  multilocus  sequence typing  (MLST).  Parental  ST5  is  an  MSSA  that  has  been  isolated  in  several  countries,  including Denmark, the Netherlands, and the United Kingdom. It acquired various types of SCCmec at several independent occasions, probably  from CoNS donor strains. After SCCmec acquisition, new MRSA clones  followed  their  own  geographic  and  genetic  evolution,  spreading  either  as  HCA-MRSA (SCCmec  I,  II,  or  III)  or CA-MRSA clones  (SCCmec  IV)  and  sometimes  evolving  into new ST  types (e.g., ST222, ST228, and ST308). Three clonal clusters (CC5, CC8, and CC30) generated six of the seven major pandemic MRSA clones described over  the past 3 decades.  (Modified  from Robinson DA,  Enright  MC.  Evolutionary  models  of  the  emergence  of  methicillin-resistant  Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47:3926-3934.)

ST5HCA-MRSA

-Belgium

ST5HCA-MRSA

-USA

ST5CA-MRSAPediatric

-USA

ST5HCA-MRSA

-USA

ST5HCA-MRSA-New York

-Japan

ST5HCA-MRSA

-France-UK

ST5HCA-MRSA

-Slovenia

ST228HCA-MRSA-Germany

ST222HCA-MRSA

-Slovenia

ST5HCA-MRSA

-Ireland

ST308HCA-MRSA

-Ireland

SSCmectype III

SSCmectype II

SSCmectype I

SSCmectype IV

ST5-MSSA-Denmark-Netherlands-UKCC5

270Part

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TABLE 128-1  Staphylococcus aureus Extracellular Factors Involved in Pathogenesis and Response to Global Regulatory Elements during Bacterial Growth

Gen

e

Loca

tio

n

Pro

du

ct

Act

ivit

y/Fu

nct

ion

Tim

ing

*

AC

TIO

N O

F R

EG

ULA

TOR

Y 

GEN

ES

†

agr

saeR

S

rot

sarA

Surface Proteinsspa Chromosome Protein A Anti-immune, anti-PMN Exp − ‡ +cna Chromosome Collagen BP Collagen binding Exp −fnbA Chromosome Fibronectin BPA Fibronectin binding Exp − +fnbB Chromosome Fibronectin BPB Fibronectin binding Exp − +clfA Chromosome Clumping factor A Fibrinogen binding Exp 0

clfB Chromosome Clumping factor B Fibrinogen binding Exp 0 + 0

lfb Chromosome Lactoferrin BP Lactoferrin binding Exp

Capsular Polysaccharidescap5 Chromosome Polysaccharide capsule 

type 5Antiphagocytosis? Pxp + +

cap8 Chromosome Polysaccharide capsule type 8

Antiphagocytosis? Pxp +

Cytotoxinshla Chromosome α-Hemolysin Hemolysin, cytotoxin Pxp + + – ‡

hlb Chromosome β-Hemolysin Hemolysin, cytotoxin Pxp + + – ‡

hld Chromosome δ-Hemolysin Hemolysin, cytotoxin Pxp + 0 +hlg Chromosome γ-Hemolysin Hemolysin, cytotoxin Pxp + – ‡

lukS/F PVL phage PVL Leucolysin Pxp + –

Superantigenssea Bacteriophage Enterotoxin A Food poisoning, TSS Xp 0

seb SaPI3§ Enterotoxin B Food poisoning, TSS Pxp + ‡

sec SaPI4§ Enterotoxin C Food poisoning, TSS Pxp +sed Plasmid Enterotoxin D Food poisoning, TSS Pxp +eta ETA phage Exfoliatin A Scalded skin syndrome Pxp +etb Plasmid Exfoliatin B Scalded skin syndrome Pxp +tst SaPI1,2, bov1§ Toxic shock toxin-1 Toxic shock syndrome Pxp + ‡

EnzymesSplA-F Chromosome Serine protease-like Putative protease + –

ssp Chromosome V8 protease Spreading factor Pxp + 0 –

aur Chromosome Metalloprotease (aureolysin)

Processing enzyme? Pxp + –

sspB Chromosome Cysteine protease Processing enzyme? ? –

scp Chromosome Staphopain (protease II) Spreading, nutrition Pxp + –

geh Chromosome Glycerol ester hydrolase Spreading, nutrition Pxp + 0 – ‡

lip Chromosome Lipase (butyryl esterase) Spreading, nutrition Pxp + 0 ‡

fme Chromosome FAME Fatty acid esterification Pxp + ‡

plc Chromosome PI-phospholipase C Pxp +nuc Chromosome Nuclease Nutrition Pxp + +

271C

hap

ter 128 Staph

yloco

ccus au

reus (In

clud

ing

 Staph

yloco

ccal Toxic Sh

ock Syn

dro

me)

Gen

e

Loca

tio

n

Pro

du

ct

Act

ivit

y/Fu

nct

ion

Tim

ing

*

AC

TIO

N O

F R

EG

ULA

TOR

Y 

GEN

ES

†

agr

saeR

S

rot

sarA

has Chromosome Hyaluronidase Spreading factor Xp ‡

coa Chromosome Coagulase Clotting, clot digestion Exp + + +sak Bacteriophage Staphylokinase Plasminogen activator Pxp + 0

BP, binding protein; FAME, fatty acid modifying enzyme; PMN, polymorphonuclear neutrophil.*Timing: Xp,  throughout exponential phase; Exp, early exponential phase only; Pxp, postexponential phase; 0, 

no effect of gene on. Expression: +, upregulated; –, downregulated.†agr, accessory gene regulator; PVL, Panton-Valentine leukocidin; saeRS, S. aureus exoproteins; rot, repressor of 

toxins; sarA, Staphylococcus accessory regulator.‡Controversial.§SaPI, S. aureus pathogenic island.Modified from Cheung AL, Projan SJ, Gresham H. The genomic aspect of virulence, sepsis, and resistance to killing 

mechanisms in Staphylococcus aureus. Curr Infect Dis Rep. 2002;4:400-410; and Novick RP, Geisinger E. Quorum sensing in staphylococci. Ann Rev Genet. 2008;42:541-564.

TABLE 128-1  Staphylococcus aureus Extracellular Factors Involved in Pathogenesis and Response to Global Regulatory Elements during Bacterial Growth—cont’d

TABLE 128-2  Staphylococcus aureus MSCRAMMs Belonging to Sortase-Mediated Cell Wall–Associated Proteins

GEN

E

PRO

TEIN

AA

SOR

TASE

MO

TIF

LIG

AN

D 

SPEC

IFIC

ITY

POTE

NTI

AL 

IMPL

ICA

TIO

N 

IN D

ISEA

SE

Spa Protein A 508 SrtA LPETG Antibody Fc fragment (IgG, IgM) von Willebrand’s factor, TNFR1, platelets

Experimental sepsis, experimental osteoarthritis

clfA Clumping factor A 933 SrtA LPDTG Fibrinogen, platelets Experimental endocarditis

clfB Clumping factor B 913 SrtA LPETG Fibrinogen, cytokeratin 10, platelets

Colonization of nasal mucosa

cna Collagen-binding protein

1183 SrtA LPKTG Collagen Experimental osteomyelitis, septic arthritis

fnA Fibronectin-binding protein A

1018 SrtA LPETG Fibronectin, fibrinogen, elastin

Experimental endocarditis

Platelets Cell invasion, experimental mastitis

fnB Fibronectin-binding protein B

914 SrtA LPETG Fibronectin, fibrinogen, elastin, platelets

Experimental mastitis

sdrC Serine-aspartate repeat protein

947 SrtA LPETG Undetermined —

sdrD Serine aspartate repeat protein

1315 SrtA LPETG Undetermined —

Continued

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GEN

E

PRO

TEIN

AA

SOR

TASE

MO

TIF

LIG

AN

D 

SPEC

IFIC

ITY

POTE

NTI

AL 

IMPL

ICA

TIO

N 

IN D

ISEA

SE

sdrE Serine aspartate repeat protein

1166 SrtA LPETG Platelets —

pls Plasmin-sensitive protein

1637 SrtA LPDTG Cellular lipids, ganglioside M3; nasal epithelial cells

Colonization of nasal mucosa

sraP Serin-rich adhesin for platelets

2261 SrtA LPDTG Platelets Experimental endocarditis

(sasA)

IsdA Iron-regulated surface determinant A

354 SrtA LPKTG Fibrinogen, fibronectin Nasal colonization

(sasE) Hemoglobin/transferrin

IsdB Iron-regulated surface determinant B

645 SrtA LPQTG Hemoglobin/hemin —

(sasJ)

isdC Iron-regulated surface determinant C

227 SrtB NPQTN Hemin —

isdH Iron-regulated surface determinant H

895 SrtA LPKTG Haptoglobin Nasal colonization

(harA) Haptoglobin/hemoglobin complex

(sasI)

sasB S. aureus surface protein B

937 SrtA LPDTG Undetermined —

sasC S. aureus surface protein C

2186 SrtA LPNTG Undetermined —

sasD S. aureus surface protein D

241 SrtA LPAAG Undetermined —

sasF S. aureus surface protein F

637 SrtA LPKAG Undetermined —

sasG S. aureus surface protein G

1117 SrtA LPKTG Nasal epithelial cells Associated to invasive disease

sash (adsA)

S. aureus surface protein H

308 SrtA LPKTG Cell-wall associated adenosine, synthase

Escape phagocyte-induced killing

sasK S. aureus surface protein K

211 SrtA LPKTG Undetermined —

fmtB Formyl transferase B SrtA LPXTG Cell wall synthesis, β-lactam resistance

Antibiotic resistance

AA, protein length in amino acids; Srt, sortase; IgM, immunoglobulin M; MSCRAMMs, microbial surface compo-nents recognizing adhesive matrix molecules; TNFR1, TNF-receptor 1.

Modified  from Roche FM, Massey R, Peacock SJ, et al. Characterization of novel LPXTG-containing proteins of Staphylococcus aureus  identified from genome sequences. Microbiology. 2003;149:643-654; Clarke S, Foster S. Surface adhesins of Staphylococcus aureus. Adv Microb Physiol. 2006;51:187-224; and Dedent A, Marraffini  L, Schneewind O. Staphylococcal sortases and surface proteins. In: Fischetti V, Novick RP, Ferretti J, et al, eds. Gram-Positive Pathogens. 2nd ed. Washington, DC: ASM Press; 2006:486-495.

TABLE 128-2  Staphylococcus aureus MSCRAMMs Belonging to Sortase-Mediated Cell Wall–Associated Proteins—cont’d

273C

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TABLE 128-3  Summary of Major Mobile Genetic Elements in Sequenced Staphylococcus aureus Strains

S. AUREUS STRAIN

MR

SA25

2

N31

5

Mu

50

CO

L

8325

MW

2

MSS

A47

6

FPR

3757

JH1/

JH9

New

man

RF1

22

Clonal cluster

30 5 5 8 8 1 1 8 5 8 151

BacteriophageΦSa1 NI lukFM

ΦSa2 NI NI (Φ12)

PV-luk PV-luk NI

ΦSa3 chip scin

chip scin

chip sak

chip scin

scin sak

scin sak

chip scin

chip scin chip scin

sak sea

sak sep

sea Sak sea seg

sea seg

sak sak sak sea

sek sek

ΦSa4 NI NI

ΦSa5 NI (Φ11)

NI

ΦSa6 NI (L54a) NI NI NI

ΦSA7 NI

ΦSa8 NI

SAPIsSAPI1 seb ear ear

seq

seq sek sek

SAPI2 sel sec tst

sel sec tst

Mdr

SAPI3 fhuD ear sel sec

SAPI4 NI NI

SAPIbov tst sel

PlasmidsI ble

kn*ble kn*

ble kn*

tet tetK; NI

II cadAC cadDX blaZ cadD

blaZ cadD

blaZ arsR

arsBC* arsBC cadD aac/aph

III aac/aph

erm ileS

qacA

TransposonsTn552 blaZ

Tn554 erm spc

erm spc

erm spc

Tn5801 tetM

Tn976-like

NI NI

Continued

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TABLE 128-4  Example of Decontaminating Scheme for Patients Colonized or Infected with Methicillin-Resistant Staphylococcus aureus (MRSA)

Protective MeasuresPut patient in contact isolation (one or several contaminated patients in single room with restricted access)Use protective gown and glovesUse protective mask and glasses if risk for projection of contaminated liquidsClean hands with alcoholic solution at glove removal and between caregiving proceduresLeave any disposable item in room and discard for sterilization in special containers

Decontamination MeasuresApply nasal mupirocin (2%) every 8 hours for 5-7 daysApply chlorhexidine-based oral spray three to four times a day for 5-7 daysTake daily shower or clean body thoroughly with chlorhexidine-based soap for 5-7 daysIn the case of dental prostheses, clean and soak the prosthesis daily in chlorhexidine-based solution for 5-7 days

Control Cultures and DecisionTake control swabs of any contaminated sites 48 and 96 hours after the end of treatmentKeep isolation measures in force until laboratory results are availableIf no MRSA is present in control cultures, consider patient decontaminated. Relieve isolation and swab weekly 

for follow-up cultures.If MRSA is present in control cultures, pursue isolation measures and repeat whole decontamination scheme

Modified from Current Recommendations at the University Hospital of Lausanne, Switzerland.

S. AUREUS STRAIN

MR

SA25

2

N31

5

Mu

50

CO

L

8325

MW

2

MSS

A47

6

FPR

3757

JH1/

JH9

New

man

RF1

22

SCCmec I mecA

mec II mecA mecA mecA mecA

mec III

mec IV mecA mecA arc

opp

non-mec

far1

aac/aph, aminoglycoside resistance; arc, arginine catabolism; arsBC, arsenic resistance genes; blaZ, penicillin resis-tance;  bsa,  bacteriocin  biosynthesis  genes;  cadACDX,  cadmium  resistance  genes;  chip,  chemotaxis  inhibitory protein;  ear,  putative  β-lactamase  type  protein;  erm,  erythromycin  resistance;  far1,  fusidic  acid  resistance; fhuD, siderophore transporter; ileS, mupiricin resistance; lukFM, leukocidin; mdr, multidrug resistance; opp, oligo-peptide uptake; mecA, penicillin-binding protein 2a conferring resistance to methicillin; qacA, quaternary ammo-nium compound  (antiseptic)  resistance; PV-luk,  Panton-Valentine  leukocidin;  sak,  staphylokinase; SaPI, S. aureus pathogenicity island; SCC, staphylococcal cassette chromosome; scin, staphylococcal chemotaxis inhibitory protein; sea  to  sep,  enterotoxin  A  to  enterotoxin  P;  spc,  spectinomycin  resistance;  tst,  toxic  shock  syndrome  toxin-1; tet and tetM, tetracycline resistance.

Note: Phage and SaPI families based on homology of integrase genes and insertion site. NI, Element present but no  identified virulence or  resistance gene. FPR3757 SCCmec  is  fused  to ACME element; SaPIS belongs  to SaPI1 family based on integrase and insertion site. RF122 has two phage fragments.

*Integrated plasmid.Modified  from Lindsay  J. S. aureus  evolution:  lineages  and mobile genetic  elements  (MGEs).  In:  Lindsay  J,  ed. 

Staphylococcus aureus Molecular Genetics. Norfolk, UK: Casiter Academic Press; 2008:45-69.

TABLE 128-3  Summary of Major Mobile Genetic Elements in Sequenced Staphylococcus aureus Strains—cont’d

275

129 Staphylococcus epidermidis and Other Coagulase-Negative StaphylococciMark E. Rupp and Paul D. Fey

MICROBIOLOGY• More than40speciesofcoagulase-negativestaphylococciaregram-positivecocci thatare

closely related to the intrinsically more virulent Staphylococcus aureus and differentiatedfromS. aureusbytheirinabilitytoproducecoagulase.

• Staphylococcus epidermidis, themostcommonclinicallyencounteredspeciesofcoagulase-negativestaphylococci,isaprominentpartofthenormalcommensalfloraofhumanskin.S. epidermidisowesitspathogenicsuccesstothreefactors:(1)itsnormalnicheonhumanskin,givingitaccesstoanydeviceinsertedorpassedthroughtheskin;(2)itsabilitytoadheretobiomaterialsandelaboratebiofilm;and(3)changesinthehumanhostpopulationresult-ing in greater numbers of immunosuppressed patients and greater use of bioprostheticdevices.

• Other noteworthy species of coagulase-negative staphylococci include S. saprophyticus, acommoncauseofuncomplicatedurinarytract infectioninsexuallyactivewomen;S. hae-molyticus, often resistant to glycopeptides; and S. lugdunensis, a more virulent coagulase-negativestaphylococcusthatmimicsinfectionsduetoS. aureus.

EPIDEMIOLOGY• S. epidermidisisaprominentcauseofintravascularcatheter-relatedinfectionandinfection

ofavarietyofmedicaldevices,suchasprostheticjoints,artificialheartvalves,andcerebro-spinalfluidshunts.

• StrainsofS. epidermidis canestablishpredominance inhospitalenvironmentsandspreadfromunittounit,hospitaltohospital,andcountrytocountry.

DIAGNOSIS• Differentiating“true”infection-causingcoagulase-negativestaphylococcifromcontaminants

can, at times, be a diagnostic challenge. Finding coagulase-negative staphylococci at highnumbersorrepetitivelyinsituationsclinicallyconsistentwithinfectionisindicativeofatrueinfection.Unfortunately,insomesituations,infectionsduetocoagulase-negativestaphylo-coccicanbeindolentanddiagnosisisdifficult.

THERAPY• MostnosocomialS. epidermidisstrainsaremultidrugresistant,andglycopeptideoralterna-

tiveantistaphylococcal antibioticsdirectedatmethicillin-resistant strainsareemployed intreatment. Isolates of S. epidermidis with an oxacillin minimal inhibitory concentration(MIC)of0.25µg/mLor lessmaybetreatedwithoxacillinornafcillin.Vancomycinis thedrugwithwhichthereisthemostclinicalexperienceincoagulase-negativestaphylococcalinfections,althoughcasereportssupportuseofdaptomycinandlinezolid.Mostspeciesaresusceptibleinvitrototheneweragents:telavancin,dalbavancin,oritavancin,ceftaroline,andtedizolid,aswellastotheolderagents,quinupristin-dalfopristin,andtigecycline,buttheirclinicalutilityforcoagulase-negativestaphylococcalinfectionsremainstobedefined.

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• In some situations, rifampin is added to the regimen for better activity against biofilm-associatedorganisms.

• Information isaccruingwithregard to treatmentofbiomaterial-based infectionswith thedeviceinsitu,butmostofthesedataareanecdotal.Ingeneral, infecteddevicesshouldberemovedwheneverpossible.Anumberofbiofilm-directedtherapeuticmodalitiesappeartoholdpromise.

PREVENTION• Biomedicaldevicesmustbeinsertedorimplantedwithscrupulousattentiontoasepticprac-

tices.Thereisgreatinterestindevelopingbiomedicaldevicesthatarelesspronetobacterialadherenceandinfection.

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130  Streptococcus pyogenesAmy E. Bryant and Dennis L. Stevens

DEFINITION• Streptococcus pyogenesisanimportantglobalhumanpathogenthatcausesawidevarietyof

acuteinfections,suchassofttissueinfectionsandpharyngitis;severelife-threateninginfec-tions,suchasstreptococcaltoxicshocksyndrome;anddevastatingpostinfectioussequelae,suchasrheumaticfeverandglomerulonephritis.

EPIDEMIOLOGY• Themostcommoninfectionisstreptococcalpharyngitis.• Superficialskinandsofttissueinfectionsincludeimpetigo,erysipelas,andcellulitis.• Severelife-threateninginfectionsincludescarletfever,bacteremia,pneumonia,necrotizing

fasciitis,myonecrosis,andstreptococcaltoxicshocksyndrome.• Postinfectioussequelae includeacuterheumatic feverandpoststreptococcalglomerulone-

phritis.

MICROBIOLOGY• S. pyogenesisagram-positive,β-hemolyticstreptococcusthatiscatalasenegative.Morethan

150differentstrainshavebeenidentifiedbasedondifferentM-proteintypes.ItisagroupAstreptococcus based on its carbohydrate structure, according to Lancefield typing ofβ-hemolyticstrains.Mucoidstrainsarerichinhyaluronicacidcapsule,andnumerousextra-cellular toxins are produced by most strains, which include streptolysin O, a cholesterol-specific cytolysin, streptolysin S, a cell-associated hemolysin, fibrinogen-binding proteins,streptokinase, numerous pyrogenic exotoxins that act as superantigens, and a cysteine-proteasecalledpyrogenicexotoxinB.

DIAGNOSIS• DiagnosisofS. pyogenespharyngitisissuspectedbasedonspecificclinicalcriteriaandcan

besubstantiatedbyrapidtestsorculture.• Similarly,impetigo,cellulitis,anderysipelasaresuspectedbasedonuniqueclinicalpresenta-

tions. Cultures of impetiginous lesions will distinguish Streptococcus from Staphylococcus aureus as the cause. Cultures of lesions associated with cellulitis and erysipelas are usefulonly20%ofthetime,andbloodculturesarerarelypositive.

• InvasiveS. pyogenesismoredifficulttodiagnoseearlyinthecourse,althoughbloodculturesare positive in more than 50% of cases. In the 50% of patients with necrotizing fasciitisassociatedwithaportalofentrysuchassurgicalincision,postpartumsepsis,orinsectbites,culturesofthesesitesarepositiveinthevastmajorityofcases.Inthe50%ofpatientswithnoportalofentry,infectionbeginsdeepinthefasciaandmuscle,andthesepatientspresentwithahistoryofpreviousnonpenetratingtrauma,severepain,andsystemictoxicity.Classicsigns of necrotizing infections are not apparent until late in the course at a time that thepatienthassystemicshockandorganfailure.

• Rheumatic fever is diagnosed based on clinical suspicion of patients with an antecedentpharyngitiswhopresentwithcarditis,Sydenham’schorea,migratoryarthritis,andevidence

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thatthepharyngitiswasduetoS. pyogenesbypositivecultureorrisinganti–streptolysinOtitersandusingtheJonescriteria,whicharereviewedelsewhere.

• Poststreptococcalglomerulonephritis isdiagnosedbasedonevidenceofrenal failurewithglomerular damage, as indicated by red blood cell casts and an antecedent streptococcalinfection,whichcanbeeitherpharyngitisorimpetigo.

THERAPY• Penicillinremainsthedrugofchoiceforthetreatmentofallstreptococcalinfections.• Mostcasesof impetigocanbe treatedwith topicalbacitracin,mupirocin,or retapamulin,

and only in severe cases or in epidemic situations is oral or parenteral administration ofpenicillinnecessary.

• SeverecasesofS. pyogenesinfections,suchasnecrotizingfasciitis,myonecrosis,andstrep-tococcaltoxicshocksyndrome,maybenefitfromclindamycin,whichsuppressestoxinpro-ductionandinanimalstudiesandlimitedhumanstudiesissuperiortopenicillin.Intensivecaresupport,aggressivefluidresuscitation,ventilatorsupport,andsurgicalinterventionarecommonlyrequired.

PREVENTION• Epidemics of streptococcal pharyngitis have been prevented in military recruits by the

administrationofmonthlybenzathinepenicillingivenintramuscularly.• Rheumaticfevercanbepreventedbyadministrationofpenicillinwithin9daysoftheonset

ofstreptococcalpharyngitis.Secondaryprophylaxisshouldbeconsideredinpatientswithrheumaticheartdiseasebasedonage,smallchildreninthehousehold,andexposuretocasesofstreptococcalinfection.

• Improvedlivingconditions,improvedpersonalhygiene,andtopicaltreatmentofimpetigi-nouslesionscanpreventspreadtosusceptibleindividuals.

• Prevention of secondary cases should be considered in health care workers and familymembers with prolonged, intimate contact with patients with necrotizing fasciitis/streptococcaltoxicshocksyndrome,particularlythosewhoareimmunocompromised,havevaricella,havehadrecentsurgery,orhaverecentlygivenbirth.Theriskforsecondarysevereinfectionislow,butcolonizationandstreptococcalpharyngitiscanoccurcommonly.Oralpenicillinfor7to10daysisreasonable,althoughnodefinitivestudieshavebeendone.

279

131 Nonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and GlomerulonephritisStanford T. Shulman and Alan L. Bisno

DEFINITIONS• Acuterheumaticfever(ARF)andacutepoststreptococcalglomerulonephritis(APSGN)are

immune-mediatedillnessesthatdevelopaftersomegroupAstreptococcalinfections.• ARF predominantly affects the heart and joints and can lead to chronic rheumatic heart

disease,whereasAPSGNisanimmune-complexnephritis.

EPIDEMIOLOGY• ARFcanfollowanuntreatedgroupAstreptococcalinfectionofthepharynxinindividuals

whoappeartobegeneticallysusceptible.• ARFismostfrequentinchildren5to15yearsofageandoccursmostcommonlyinwinter

orspring.• ARF now is much less common in developed areas of the world, compared with several

decadesago.MostcasesnowoccurindevelopingcountriesorinminoritypopulationswithinAustraliaandNewZealand.

• APSGNcanfollowgroupAstreptococcalinfectionsoftheskinorthroat.• PostpharyngealAPSGNoccursmainlyinschool-agedchildreninwinterorspring,whereas

postpyodermaAPSGNismostcommoninpre–school-agedchildreninlatesummerorfall.

MICROBIOLOGY• CertainMtypesofgroupAstreptococci(GAS;M-1,M-3,M-5,M-6,M-14,M-18,M-19)

areconsideredrheumatogenic,thatis,theyhavemuchgreaterabilitytotriggertheimmuneeventsthatresultinARFwhencomparedtononrheumatogenictypes.Themolecularbasisofrheumatogenicityisunknown.

• NephritogenicMtypesofGASarethosewithgreatpropensitytoleadtoAPSGN,specificallyM-1,M-4,M-12,andM-25afterpharyngitisandM-2,M-9,M-55,M-57,M-59,M-60,andM-61afterpyoderma.Thespecificantigen(s)involvedinthisimmune-complexnephritisisstillsomewhatunclear.

DIAGNOSIS• Diagnosis of ARF is based upon the Jones criteria, comprising five major criteria, four

minor criteria, and a requirement for evidence of antecedent group A streptococcalinfection.

• ThefivemajorJonescriteriaarecarditis,arthritis,chorea,erythemamarginatum,andsub-cutaneousnodules.Thefourminorcriteriaarefever,arthralgia,elevatedacute-phasereac-tants (erythrocyte sedimentation rate, C-reactive protein), and prolonged P-R interval.DiagnosisofARFrequiresonemajorplusatleasttwominorcriteriaortwomajorcriteriaplusevidenceofantecedentgroupAstreptococcalinfection.

• ThediagnosisofAPSGNisgenerallybaseduponacuteonsetofhematuriawithhypertension,azotemia,hypocomplementemia,andwithevidenceofrecentstreptococcalpharyngitisorpyoderma.

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THERAPY• Treatment of ARF includes an anti-inflammatory agent (aspirin for those with arthritis

and/or mild carditis; corticosteroids for those with moderate or severe carditis [see Table131-1]);anagentsuchasphenobarbital,diazepam,haloperidol,valproate,orrisperidoneforthosewithchorea;andaprophylacticantibiotic.Asingledoseofintramuscular(IM)ben-zathinepenicillin(oranalternativeagentforpenicillin-allergicindividuals)isindicated.

• TreatmentofAPSGNincludescorrectionofcirculatoryoverloadandhypertensionbysaltandfluidrestriction,diureticsasneeded,antihypertensivesonly if severehypertensionorhypertensiveencephalopathyispresent.Immunosuppressivesarenotbeneficial.

PREVENTION• BecauseARFfrequentlyrecurswithsubsequentgroupAstreptococcalpharyngitisepisodes,

long-term prophylaxis is indicated with IM benzathine penicillin every 4 weeks or oralpenicillinVtwicedaily,orforpenicillin-allergicindividualswithdailysulfadiazine,macro-lide,orazalide(seeTable131-2),usuallyatleastuntilage21.

• BecauseAPSGNonlyveryrarelyrecurs,nopreventativeantibiotictherapyisindicated.

TABLE 131-1  Suggested Schedule of Anti-inflammatory Therapy in Rheumatic Fever

CLINICAL SEVERITY TREATMENTArthralgia or mild arthritis; no carditis Analgesics only, such as codeine or propoxyphene

Moderate or severe arthritis; no carditis, or carditis with or without cardiomegaly, but without failure

Aspirin, 50-70 mg/kg/day for 3 wk, increased if necessary; 25-35 mg/kg/day for the subsequent 6 wk

Carditis with congestive failure, with or without joint manifestations

Prednisone, 2 mg/kg, max 60 mg/day; methylprednisone sodium succinate intravenous in fulminating cases; after 2-3 wk, slow withdrawal to be completed in 3 more wk; aspirin to be continued for 1 mo after discontinuation of prednisone

From Stollerman GH. Rheumatic Fever and Streptococcal Infection. New York: Grune & Stratton; 1975.

TABLE 131-2  Secondary Prevention of Rheumatic Fever (Prevention of Recurrent Attacks)

AGENT DOSE MODEBenzathine penicillin G 600,000 U for children ≤27 kg (60 lb), 1.2 million U

for those >27 kg (60 lb) every 4 wk*Intramuscular

Penicillin V 250 mg twice daily Oral

Sulfadiazine 0.5 g once daily for patients ≤27 kg (60 lb) Oral

1.0 g once daily for patients >27 kg (60 lb)

For Individuals Allergic to Penicillin and SulfadiazineMacrolide or azalide Variable Oral

*In high-risk situations, administration every 3 weeks is justified and recommended.From Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of

acute streptococcal pharyngitis. Circulation. 2009;191:1541-1551.

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132  Streptococcus pneumoniaeEdward N. Janoff and Daniel M. Musher

EPIDEMIOLOGY• Streptococcus pneumoniae is the leading cause of pneumonia and bacterial meningitis in

childrenyoungerthan5yearsandolderadultsworldwide.• The incidence ishighest inchildrenyounger than2yearsandadultsolder than65years;

mortalityishighestinolderadults.• Asymptomatic colonization is common and precedes almost all symptomatic clinical

infections.• Large outbreaks are uncommon, but smaller outbreaks occur under crowded conditions

(prisons,nursinghomes,militarytraining).• Groupsatincreasedriskforseriouspneumococcaldiseaseincludeindividualsattheextremes

ofage(particularly<2yearsand>65yearsofage),thosewithunderlyingorgandysfunction(aspleniaandsplenicdysfunction,chronicheart,lung,liver,andkidneydisease),andimmu-nocompromisingconditions (particularlyantibodydefects, complementdeficiencies,neu-tropenia,andmalignancies).

MICROBIOLOGY• Streptococcus pneumoniaeisagram-positive,α-hemolytic,lancet-shapeddiplococcusandis

bilesolubleandoptochinsensitive.• Streptococcus pneumoniaeiscatalase-negativebutproduceshydrogenperoxide.• Therearemorethan92capsularpolysaccharideserotypesthatconferresistancetophago-

cytosis;serotypeisdeterminedbytheQuellungreaction.• Effectivephagocytosisandkillingtypicallyrequireantibodies,mostoftentocapsularpoly-

saccharides,complement,andphagocytes(neutrophilsandmacrophages).• Pneumolysin is thecholesterol-binding,pore-formingprimarytoxinthatcausesbothepi-

thelialandendothelialdamageandperturbscomplementactivity.

DIAGNOSIS• PerformGramstainandcultureofgood-qualitysputum(<10epithelialcells,>25neutrophils/

high-powerfieldor>10neutrophils/epithelialcell)frompatientswithpneumonia,ofcere-brospinalfluidfrompatientswithmeningitis,andofmiddleearfluidbytympanocentesisfrom patients with otitis media. Among adults with pneumonia, approximately 10% havepositivebloodcultures,halfofwhichgrowS. pneumoniae.

• Perform urine antigen detection in adults (≈70% sensitive in adults with bacteremia; notspecificinchildren).

CLINICAL MANIFESTATIONS• Otitismediaisthemostcommonclinicalsyndrome,butpneumococcalpneumoniainchil-

drenandadultsunderliesmostseriousinfectionsanddeath.• Thespectrumof infectionranges fromasymptomaticpharyngealcolonizationtomucosal

disease(otitismedia,sinusitis,pneumonia)toinvasivedisease(bacteriainanormallysterilesite;bacteremia,meningitis,empyema,endocarditis,arthritis).

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• Most invasivedisease results frombacteremic seeding,butmeningitis andempyemamayalsoresultfromextensionoflocalinfection.

THERAPY• A β-lactam antibiotic is the mainstay of therapy for pneumococcal infection. Decreased

sensitivitytopenicillinderivesfromstructuralmodificationsofpenicillin-bindingproteins,effectsthatcompromisetheefficacyofpenicillinintreatmentofmeningitisandotitismedia,buttypicallynotpneumonia.

• Intravenoustherapy,particularlyceftriaxoneandcefotaxime,arerecommendedfortherapyofbacteremiaandmostoften,withtheinitialadditionofvancomycin,meningitis.

• Respiratory quinolones, linezolid, vancomycin, and macrolides all show clinical activityagainst S. pneumoniae. Combined therapy with a β-lactam and macrolide may improveoutcomes.

PREVENTION• Two vaccines provide protection against invasive pneumococcal disease: a pneumococcal

polysaccharide-protein conjugate vaccine (PCV13) with the 13 most common pediatriccapsular serotypes for children (>90%protection)anda23-valentpolysaccharidevaccineforadults(PPSV23)(54%to81%protection).ThechildhoodPCV13alsopreventsuptoonethirdofchildhoodbacterialpneumoniaandsomeproportionofmeningitisandotitismedia.Theefficacyof the23-valentpolysaccharidevaccineagainstadultpneumonia is lessclear.Both PPSV23 and PCV13 are now approved independently for use in older adults. Forimmunocompromised adults, vaccination with the 13-valent conjugate, followed greaterthanorequalto8weekslaterwiththe23-valentpolysaccharidevaccine,isrecommended.Widespread pneumococcal vaccination of children has reduced the overall incidence ofinvasivediseaseandhospitalizationforpneumoniainallagegroupsintheUnitedStates.

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133 Enterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc SpeciesCesar A. Arias and Barbara E. Murray

MICROBIOLOGY AND TAXONOMY• Enterococci are gram-positive facultatively anaerobic bacteria that usually appear oval in

shapeandcanbeseenassinglecells,pairs,shortchains,orevenverylongchains.• Enterococci are capable of growing in medium containing 6.5% sodium chloride and at

temperaturesbetween10°and45°Candareabletohydrolyzeesculininthepresenceof40%bilesalts.

• Enterococcus faecalisandEnterococcus faeciumarethemostclinicallyrelevantspecies.• Most clinically relevant species of enterococci produce a leucine aminopeptidase and a

pyrrolidonylarylamidase.• TheformerStreptococcus bovisgroupisnowdividedintothreemainspecies:S. gallolyticus,

S. pasteurianus,andS. infantarius.• TheLeuconostocgenuscomprisescatalase-negative,gram-positivecocci,usuallyarrangedin

pairsorchainsandareintrinsicallyresistanttovancomycin.

COLONIZATION, VIRULENCE, AND GENOMICS• Enterococciarenormalcommensalsofthegastrointestinaltract.• Enterococci are capable of dominating the gut microbiota of hospitalized patients who

receivebroad-spectrumantibiotics.• Specific hospital-associated genetic lineages of E. faecium and E. faecalis have evolved to

becomesuccessfulinthenosocomialenvironment.• TheStreptococcus gallolyticusgroupoforganismsalsocarriesgenesencodingpotentialcell

surfacedeterminantsthatinteractwithhostproteins.

EPIDEMIOLOGY• Enterococciareorganismsknowntocausehospital-associatedinfectionsinpatientswhoare

criticallyillorimmunosuppressed.• Enterococci are among the most common organisms causing infective endocarditis, both

hospital-andcommunity-associated.• Enterococciareabletospreadinthehospitalusuallyviathehandsofhealthcareworkers

andtheenvironment.• Infectioncontrolmeasuresarecriticaltopreventacquisitionofthesemicroorganisms.• Infective endocarditis and bacteremia caused by S. gallolyticus is highly associated with

gastrointestinalmalignancies.

CLINICAL PRESENTATIONS• Enterococciarecapableofcausingbloodstreaminfections,bothincommunity-andhospital-

associatedclinicalsettings.• Infectiveendocarditis isoneof themost seriousand life-threatening infectionscausedby

enterococci.• Enterococciareoneoftheleadingcausesofnosocomialurinarytractinfections.

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• Enterococci have been described in soft tissue infections, intra-abdominal infections andmeningitis.

• S. gallolyticusgroupoforganismshavebeenassociatedwithinfectiveendocarditis.• Leuconostoc causes opportunistic infections mainly in immunocompromised patients,

althoughcasesinimmunocompetentpatientshavebeenreported.

THERAPY AND ANTIMICROBIAL RESISTANCE• WhereasmostE. faecalis isolatesaresusceptibletoampicillinandvancomycin,E. faecium

oftenexhibithighminimalinhibitoryconcentrationsofampicillin,andmostclinicalisolatesintheUnitedStatesarevancomycin-resistant.

• Bactericidaltherapyforenterococcioftenrequirestheuseofacellwallagentplusanami-noglycosideorceftriaxone.

• Therapyofchoiceforsevereinfectionscausedbyenterococciisthecombinationofampicillinplusaminoglycoside(gentamicinandstreptomycin).

• AmpicillinplusceftriaxoneisanalternativetherapyforE. faecalisendocarditis.• TherapyofsevereinfectionscausedbyE. faeciumischallenging,andnoreliabletherapyis

currentlyavailable.• Linezolid and quinupristin-dalfopristin are two U.S. Food and Drug Administration–

approved drugs for multidrug resistant E. faecium, but these compounds have importantlimitationsbecauseofthelackofbactericidaleffect,toxicity,sideeffects,andemergenceofresistance.

• Daptomycinisalipopeptideantibioticwithinvitrobactericidalactivityagainstenterococci,but development of resistance during therapy seems to be a limitation for the use of thisantibiotic.

• Daptomycincombinations(withβ-lactams,aminoglycosides,and/ortigecycline)mayoffersome promise in the future for the treatment of multidrug-resistant enterococcalinfections.

• The therapy of choice for endocarditis caused by S. gallolyticus group of organisms is aβ-lactamincombinationwithanaminoglycosideforatleastpartofthetherapy.

• AmpicillinorpenicillinisthedrugofchoiceforthetreatmentofLeuconostocinfections.

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134 Streptococcus agalactiae (Group B Streptococcus)Morven S. Edwards and Carol J. Baker

DEFINITION• Group B streptococci (GBS) are gram-positive bacteria that cause invasive hematogenous

infectioninat-riskindividuals.

EPIDEMIOLOGY• GBSasymptomaticallycolonizethelowergastrointestinalorgenitaltractinapproximately

onefourthtoonethirdofadultmenandwomen.• Distributionisworldwide,butratesvarygeographically.• Invasiveinfectionriskisenhancedinneonatesandinfantsyoungerthan3months;pregnant

womenandadultswithdiabetesmellitus;andpersonswithliverorkidneydisease,cancer,heartorvasculardisease,orneurologicimpairment.

MICROBIOLOGY• β-Hemolyticstreptococciexhibitanarrowzoneofhemolysisonbloodagar.• GBShaveapolysaccharidecapsulewithpilus-like structures that enhanceadherenceand

invasion.• GBSgrowreadilyinbloodculturemediaandspecimensfromcerebrospinalfluidandother

sitesofinfection.

DIAGNOSIS• Inadults,onsetisacute,withchillsandfever,oracute-on-chronic,withindolentsymptoms,

especiallyinassociationwithskinandsofttissuemanifestations.• In infants younger than 3 months, bacteremia without a focus; meningitis; or, less often,

otherfocalinfections,suchaspneumoniaorsofttissueinfection,occur.• GrowthofGBSfrombloodoranothernormallysterilesiteisdiagnostic.

TREATMENT• Penicillinisthedrugofchoice;isolatesareuniformlysusceptibletoβ-lactamsandmerope-

nem.Isolatesaregenerallysusceptibletovancomycin;therehavebeenonlyafewcasereportsofresistance.

• Thedurationoftreatmentrangesfrom10daysforuncomplicatedbacteremiatoa4-weekminimumtreatmentcourseforendocarditis.

PREVENTION• Intrapartum antibiotic prophylaxis given to colonized parturients during labor prevents

early-onsetinfectionsinneonates,thusreducingtheoverallrateofneonatalsepsis(seeTable134-1).

• Aglycoconjugatevaccineisinclinicaltrialsandoffersthepotentialforpreventionofinfec-tionsinpregnantwomenandyounginfants,aswellas invasiveinfectionsinnonpregnantadults.

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TABLE 134-1  Indications and Nonindications for Intrapartum Antibiotic Prophylaxis to Prevent Early-Onset GBS Disease

INTRAPARTUM GBS PROPHYLAXIS INDICATED

INTRAPARTUM GBS PROPHYLAXIS NOT INDICATED

Previous infant with invasive GBS disease Colonization with GBS during a previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy)

GBS bacteriuria during any trimester of the current pregnancy*

GBS bacteriuria during previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy)

Positive GBS vaginal-rectal screening culture in late gestation† during current pregnancy*

Negative vaginal and rectal GBS screening culture in late gestation† during the current pregnancy, regardless of intrapartum risk factors

Unknown GBS status at the onset of labor (culture not done, incomplete, or results unknown) and any of the following:• Delivery at <37 wk gestation• Amniotic membrane rupture ≥18 hr• Intrapartum temperature ≥100.4° F (≥38.0° C)‡

• Intrapartum NAAT§ positive for GBS

Cesarean delivery performed before onset of labor on a woman with intact amniotic membranes, regardless of GBS colonization status or gestational age

GBS, group B streptococci/streptococcal; NAAT, nucleic acid amplification test.*Intrapartum antibiotic prophylaxis is not indicated in this circumstance if a cesarean delivery is performed before

onset of labor on a woman with intact amniotic membranes.†Optimal timing for prenatal GBS screening is at 35-37 weeks’ gestation.‡If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be active against

GBS should replace GBS prophylaxis.§NAAT for GBS is optional and might not be available in all settings. If intrapartum NAAT is negative for GBS but

any other intrapartum risk factor (delivery at <37 weeks’ gestation, amniotic rupture at ≥18 hours, or temperature ≥100.4° F [≥38.0° C]) is present, then intrapartum antibiotic prophylaxis is indicated.

From Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1-32.

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135 Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related OrganismsScott W. Sinner and Allan R. Tunkel

DEFINITION• Discussedinthischapterarethemajorhumanviridansstreptococci,groupsCandGstrep-

tococci, Streptococcus iniae and Streptococcus suis, and the genera Gemella, Abiotrophia, Granulicatella, Rothia,andPediococcus.

EPIDEMIOLOGY• Many of these streptococci exist as normal microbiota on various mucosal surfaces of

humans,particularlytheoralcavity.• Although generally considered to be bacteria of low virulence, they can cause significant

infections,oftenasaresultofweakhostdefenses,highinoculaatthesitesofcolonization,andvulnerablehumantissuesthatmaybepronetoinfectionaftertransientbacteremia.

• SomespeciesofgroupsCandGstreptococci,alongwithS. iniae,aremoreoftencommensalsorpathogensofanimalsbutcancausehumaninfectionaftersignificantcontactofhumanswiththeanimalsinquestion.

MICROBIOLOGY• The viridans streptococci are typically facultatively anaerobic, nonmotile, non–spore-

forminggram-positivecoccithatarebothcatalaseandcoagulasenegativeandeitherα-orγ-hemolyticonbloodagar.

• The nutritionally variant genera Abiotrophia and Granulicatella need either supplementalpyridoxalorcysteineforgrowthonagar.

• GroupsCandGstreptococcidonotalwaysreliablyfitintopredictablespeciationschemesandformrelativelylargecoloniesthatareoftenβ-hemolytic.

DIAGNOSIS• Clinicaldiagnosisofinfectionscausedbytheseorganismsdependsonthesiteofinfection

andthestatusofthehost.• Someofthemostcommonorsignificantsyndromesincludepharyngitis,softtissueinfec-

tions,primarybacteremiainneutropenichosts,endocarditis,andmeningitis.• Microbiologicdiagnosisbeginswithtypicalbacterialculturemethodsinvirtuallyallcases,

but these may be supplemented by latex agglutination studies, automated speciation andsusceptibilitytechniques,culturesonnutrient-enrichedagar,ormoleculartechniquessuchaspolymerasechainreactionassay.

THERAPY• First-linetherapyformostinfectionscausedbytheseorganismsispenicillin,iftheisolateis

susceptible.• Cephalosporinsandvancomycinarethemoststudiedsecond-linetherapies,foruseincases

ofdrugresistanceorallergyorintolerance.• Useandoveruseofβ-lactams,macrolides,andfluoroquinolonesinrecentdecadeshasled

toaslowbutclearincreaseindrugresistance.

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• Therouteanddurationoftherapydependlargelyonthesiteofinfectionandthestatusofthehost.

PREVENTION• Becausemostoftheseorganismsareconsideredpartofthenormalmicrobiotaofhumans,

preventionofinfectionislargelyaccomplishedbymaintainingarobustimmunesystem,aswellasmaintaininghealthymucosalsurfaces(e.g.,practicinggooddentalhygiene).

• Fortheoccasionalorganismthatcanbeacquiredfromanimals,avoidanceofspecificanimalcontactisthebestprevention.

• Certaingroupsofpatientsmayenjoythebenefitsofthefollowingadditionalspecificpreven-tive strategies: antimicrobial prophylaxis for certain dental procedures in patients at thehighest risk for endocarditis, antimicrobial prophylaxis for high-risk neutropenic patientsreceiving cytotoxic chemotherapy for malignancy, and appropriate surgical prophylaxis atthetimeofimplantationofvariousforeignbodies.

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136  Streptococcus anginosus GroupCathy A. Petti and Charles W. Stratton IV

DEFINITION• The Streptococcus anginosus (milleri) group comprises three distinct species: S. anginosus,

S. constellatus,andS. intermedius.

EPIDEMIOLOGY• TheStreptococcus anginosusgroupcomprisesnormalmicrobiotaofthegastrointestinaltract

and oropharynx, and when pathogenic, is often associated with abscess formation andendocarditis.

MICROBIOLOGY• These microorganisms are microaerophilic, catalase-negative, gram-positive cocci and

are easily identified by conventional methods. They are generally susceptible toβ-lactamantibiotics.

DIAGNOSIS• Dependingontheclinicalpresentation,infectionsareusuallydiagnosedbyculturingaspeci-

menfromthesourceofinfection.

THERAPY• β-Lactam antibiotics are generally used; abscesses may require incision and drainage as

well as antimicrobial therapy with broader coverage, such as that provided by ampicillin/sulbactamorpiperacillin/tazobactam.

PREVENTION• Notapplicable.

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137 Corynebacterium diphtheriae (Diphtheria)Rob Roy MacGregor

DEFINITION• Corynebacterium diphtheriae,agram-positivebacillus,classicallyproducesepidemicupper

respiratorytractinfectionswithhighmortalityratesinunimmunizedsubjects.

EPIDEMIOLOGY• Humansare theonlyknownreservoir, and thedisease spreadsviaairanddirect contact.

Asymptomaticcarriageisimportantintransmission.DiphtheriaisnowrareintheWestandendemicintheThirdWorld,especiallySoutheastAsia.Fewerthan5000annualcaseshavebeenreportedworldwidesince2000.

MICROBIOLOGY• Thebacillusisnonsporulating,unencapsulated,andnonmotile.Itproducesbrowncolonies

andhalosontelluritemediumandrequireslysogenicβ-phagetoproducetoxinresponsibleforthedisease.Fourbiovarsand86ribotypeshavebeenidentifiedfortracking.Nontoxigenicstrainsoccasionallycausedisease,asdotoxin-producingCorynebacterium ulceransstrains.

CLINICAL MANIFESTATIONS• Subacutefaucialinfectioncauseslow-gradefever,hoarseness,pain,andanecroticpseudo-

membrane that can extend to larynx and cause stridor and fatal obstruction. Circulatingtoxin causes potentially fatal carditis and motor neuropathy. Cutaneous infection causesindolentulcers.

DIAGNOSIS• Diagnosisispresumptive,basedontonsillitis/pharyngitiswithnecroticmembrane,hoarse-

ness,palatalparalysis,low-gradefever,andrecenttraveltoanendemicarea.Confirmationis made by observing brown colonies on tellurite medium, a distinctive Gram stain, andbiochemicaltests.Polymerasechainreactionshowsatoxingene,whichisthekeytoalertthelaboratoryforculture.

THERAPY• Diphtheriaantitoxin(DAT),producedinhorsesandobtainedfromtheCentersforDisease

ControlandPrevention,mustbegivenintravenouslywithoutwaitingfordiagnosisconfir-mation.Thedosedependsonthedurationandextentofdisease.Testpatientsfirstforhorseproteinhypersensitivity.Considertracheostomytoprotectairway.Cardiographicmonitor-ingiswisebecauseoftoxincardiotoxicity.Antibioticsaregivenorallyorparenterallyfor14days tostop toxinproductionanderadicate throatcarriage.Adultscanbegivenprocainepenicillin600,000units IMevery12hoursuntiloralmedication is tolerated, followedbypenicillinV250mgorerythromycin500mgevery6hours.

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PREVENTION• ToxoidimmunizationconsistsofTDaP5timesupto7yearsofage.Tdboostersshouldbe

givenat10-yearintervals.Penicillinorerythromycinshouldbegivenfor14daystocarriersto prevent clinical infection or spread. Close contacts of cases should be cultured, givenantimicrobialprophylaxis,and,ifnotfullyimmunized,vaccinated.

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138 Other Coryneform Bacteria and RhodococciRose Kim and Annette C. Reboli

DEFINITION• Coryneformbacteriaencompassseveralgenera,ofwhichCorynebacteriumisthemostfre-

quentlyencounteredinclinicalinfections.• Coryneformbacteriaarecharacterizedas irregularlyshaped,non–spore-forming,aerobic,

gram-positiverods.

EPIDEMIOLOGY• Coryneformbacteriaareubiquitousintheenvironment(soilandwater),commensalcolo-

nizersofskinandmucousmembranesinhumans,andcommensalsinanimals.• Infectionscausedbycoryneformbacteriaarebroadlycategorizedascommunityacquiredor

nosocomial;sporadiccasesofzoonoseshavebeenreported.• Rhodococcus equiusuallyoccursinindividualswithdefectivecell-mediatedimmunity,par-

ticularlywithhumanimmunodeficiencyvirusinfection,withorwithoutahistoryofanimalexposure.

MICROBIOLOGY• Coryneformbacteriareadilygrowonstandardculturemedia.Forlipophilicstrains,growth

isenhancedwithadditionofTween80.• Species identification and antimicrobial testing of coryneform bacteria is recommended

whenspecimensarecollectedfromnormallysterilesites, there ispresenceofhighcolonycounts with a strong leukocyte reaction, or there is recovery of high colony counts ofCorynebacterium urealyticumfromurineculture.

• Moleculartests,suchas16sribosomalRNAsequencing,andmatrix-assistedlaserdesorption/ionizationtime-of-flightmassspectrometryareusedforspeciesidentificationofcoryneformbacteria,includingRhodococcus, Gordonia,andTsukamurella.

DIAGNOSIS• Coryneformbacteriaareconsideredclinicallysignificantwhenpatientspresentwithsymp-

toms consistent with infection, along with recovery of bacteria as outlined above(“Microbiology”).

THERAPY• Coryneformbacteriaareuniformly susceptible toglycopeptides, suchasvancomycinand

teicoplanin,andmoststrainsaresusceptibletodaptomycinandlinezolid.• Rhodococcus equi is usually susceptible to vancomycin, teicoplanin, erythromycin, fluoro-

quinolones,rifampin,carbapenems,aminoglycosides,andlinezolid.

PREVENTION• Prevention of infections caused by coryneform bacteria includes proper skin antisepsis

beforeinvasiveproceduresandcautionwhenhandlinganimals.

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139  Listeria monocytogenesBennett Lorber

DIAGNOSIS• Clinical settings inwhich listeriosis shouldget strongconsideration include immunosup-

pressionandpregnancy(seeTable139-1).• Cultureofblood,cerebrospinalfluid,orothernormallysterilebodyfluidor,inthecaseof

gastroenteritis,fromstool.• Serologynotusefulforinvasivedisease.

MICROBIOLOGY• Short,gram-positiverod;growsreadilyonbloodagar;tumblingmotility.• Maybemistakenfordiphtheroidcontaminant.• Willgrowinrefrigeratedfood.

EPIDEMIOLOGY• Zoonosis,particularlyherdanimals.• Human transmission from contaminated food or from pregnant woman to fetus or

newborn.• Highestfoodrisksfromdelicatessen-stylemeatsandunpasteurizedcheeses.• Mostcasesoccurinneonates,pregnantwomen,persons60yearsorolder,andthosewith

impairedcell-mediatedimmunityresultingfromunderlyingcondition(hematologicmalig-nancy, organ or bone marrow transplantation, acquired immunodeficiency syndrome) ortherapy(corticosteroids,antitumornecrosisfactoragents).Notifylaboratoryforspecialstoolculturesifoutbreakoffebrilegastroenteritis.

CLINICAL SETTINGS• Neonatalsepsisormeningitis.• Meningitisorfocalcentralnervoussystem(CNS)lesionsinimmunosuppressedpatientsor

thoseolderthan50years.• Rhombencephalitisoccurs inpreviouslyhealthypatientswhodevelop fever,cranialnerve

palsies,cerebellarsignsandhemiparesis,hemisensorydeficits,orboth.• Feverinpregnancy,especiallythirdtrimester.• Outbreakoffoodbornefebrilegastroenteritis.

TREATMENT• Ampicillin(2gIVevery4hours).Addgentamicin(5mg/kgperday)forCNSinfectionor

endocarditis.• Trimethoprim-sulfamethoxazole(5/25mg/kgIVevery8hours)forpenicillinallergic.

• Add one of the above to vancomycin and ceftriaxone regimen for suspected bacterialmeningitisinpersonsolderthan50yearsbecausevancomycinandceftriaxoneareinad-equateforlisterialmeningitis.

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PREVENTION• Isolationnotnecessary.• Foodsafetyrecommendationsforthoseatrisk(seeTable139-2).• Pneumocystisprophylaxiswithtrimethoprim-sulfamethoxazolepreventslisteriosis.

TABLE 139-1  Clinical Settings in Which Listeriosis Should Be Considered Strongly in the Differential Diagnosis• Neonatalsepsisormeningitis• Meningitisorparenchymalbraininfectionin:

• Patientswithhematologicmalignancies,AIDS,organtransplantation,corticosteroidimmunosuppression,andthosereceivinganti-TNFagents

• Patientswithasubacutepresentationofmeningitis• Adultsolderthan50years

• Simultaneousinfectionofthemeningesandbrainparenchyma• Subcorticalbrainabscess• Spinalsymptomsinthesettingofacutebacterialmeningitisofuncertainetiology• Feverduringpregnancy,particularlyinthethirdtrimester• Blood,CSF,orothernormallysterilespecimenreportedtohave“diphtheroids”onGramstainorculture• Foodborneoutbreakoffebrilegastroenteritiswhenroutineculturesfailtoidentifyapathogen

AIDS,acquiredimmunodeficiencysyndrome;CSF,cerebrospinalfluid;TNF,tumornecrosisfactor.

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TABLE 139-2  Dietary Recommendations for Preventing Foodborne Listeriosis

General RecommendationsWashing and Handling Food

Rinserawproducethoroughlyunderrunningtapwaterbeforeeating,cutting,orcooking.Eveniftheproducewillbepeeled,itshouldstillbewashedfirst.

Scrubfirmproduce,suchasmelonsandcucumbers,withacleanproducebrush.Drytheproducewithacleanclothorpapertowel.

Keep Your Kitchen Cleaner and Safer

Washhands,knives,countertops,andcuttingboardsafterhandlingandpreparinguncookedfoods.BeawarethatListeria monocytogenescangrowinfoodsintherefrigerator.Therefrigeratorshouldbe40°F

orlowerandthefreezer0°Forlower.Cleanupallspillsinyourrefrigeratorrightaway,especiallyjuicesfromhotdogandlunchmeatpackages,

rawmeat,andrawpoultry.

Cook Meat and Poultry Thoroughly

Thoroughlycookrawfoodfromanimalsources,suchasbeef,pork,orpoultrytoasafeinternaltemperature.Useprecookedorready-to-eatfoodassoonasyoucan.Donotstoretheproductintherefrigeratorbeyond

theuse-bydate.Useleftoverswithin3to4days.

Choose Safer Foods

Donotdrinkraw (unpasteurized) milk,anddonoteatfoodsthathaveunpasteurizedmilkinthem.

Recommendations for Persons at Higher Risk*Meats

Donoteathotdogs,luncheonmeats,coldcuts,otherdelicatessenmeats(e.g.,bologna),orfermentedordrysausages,unlesstheyareheatedtoaninternaltemperatureof165°Foruntilsteaminghotjustbeforeserving.

Avoidgettingfluidfromhotdogandlunchmeatpackagesonotherfoods,utensils,andfoodpreparationsurfaces,andwashhandsafterhandlinghotdogs,luncheonmeats,anddelicatessenmeats.

Donoteatrefrigeratedpâtéormeatspreadsfromadelicatessenormeatcounterorfromtherefrigeratedsectionofastore.Foodsthatdonotneedrefrigeration,suchascannedorshelf-stablepâtéandmeatspreads,aresafetoeat.Refrigerateafteropening.

Cheeses

Donoteatsoftcheesesuchasfeta,quesoblanco,quesofresco,brie,Camembert,blue-veined,orpanela(quesopanela)unlessitislabeledas“MADEWITHPASTEURIZEDMILK.”

Seafood

Donoteatrefrigeratedsmokedseafood,unlessitiscontainedinacookeddish,suchasacasserole,orunlessitisacannedorshelf-stableproduct.

Cannedandshelfstabletuna,salmon,andotherfishproductsaresafetoeat.

Melons

Washhandswithwarmwaterandsoapforatleast20secondsbeforeandafterhandlinganywholemelon.Scrubthesurfaceofmelonswithacleanproducebrushunderrunningwateranddrythemwithaclean

clothorpapertowelbeforecutting.Besurethatyourscrubbrushissanitizedaftereachuse.Promptlyconsumecutmelonorrefrigeratepromptly.Keepyourcutmelonrefrigeratedfornomorethan

7days.Discardcutmelonsleftatroomtemperatureformorethan4hours.

*Recommendationsforpersonsathigherrisk,suchaspregnantwomen,personswithweakenedimmunesystems,andolderadults,inadditiontotherecommendationslistedunderGeneralRecommendations.

296

140  Bacillus anthracis (Anthrax)Gregory J. Martin and Arthur M. Friedlander*

EPIDEMIOLOGY AND MICROBIOLOGY• Sporadicworldwide,anthraxismostcommoninAfrica,theMiddleEast,andLatinAmerica.• Naturallyacquiredhumancasesareusuallyassociatedwithanimalproducts.• Spore-forminggram-positivebacillusgrowsreadilyinthelaboratory.• Spores,whenprotectedfromultravioletlight,remainviablefordecadesorlonger.• Pathogenicityisassociatedwithedemaandlethaltoxinsandacapsule.

CLINICAL MANIFESTATIONS AND DIAGNOSIS• Cutaneous anthrax:95%ofnaturallyacquiredcasesarethisform.Afterskininoculation,a

pruriticpapuleformsin2to5days.Vesiclesrupture,leadingtoformationofablackescharat the base of a shallow ulcer. An injectional form has been newly described in injectionheroin users and associated with a more aggressive course. Surgical débridement may berequired.Gramstainofvesiclefluid,scrapingofbaseofulcer,orpunchbiopsymayshowgram-positivebacilliandapaucityofpolymorphonuclearneutrophils.Cultureofmaterialisfrequentlypositive.Directfluorescentantibody(DFA)testandpolymerasechainreaction(PCR)assayalsomaybeused.

• Inhalational anthrax:resultsfromhandlingofanimalproducts,suchaswool,hides,orbonesorafterintentionalsporereleaseinbioterrorism.Thisformhasthemostdangerouspresenta-tion,withnear100%mortalitywithoutearlyantibiotics.It isprimarilyamediastinal(notanairspace)process.Bloodandpleuralfluidculturesarepositive.PleuralfluidGramstainmaybepositive.DFAtestorPCRassaymaygivemostrapidresults.

• Gastrointestinal anthrax:responsibleforapproximately1%ofhumancasesandoccurstypi-cally1to5daysafteringestionofcontaminatedmeat.Blood,stool,andascitesshouldallbeobtainedforculture,DFAtesting,andPCRassay.Gramstainingofasciticfluidmayrevealgram-positivebacilli.

• Anthrax meningitis:secondaryseedingofthemeningesoccursduringbacteremiainfulmi-nant disease. Death occurs within 24 hours in 75% of cases. Cerebrospinal fluid revealsgram-positive bacilli, and cultures are positive. DFA test and PCR assay may provide themostrapiddiagnosis.

THERAPY• Rapidinitiationofantibioticsforallstagesiscrucial(seeTable140-1).• Forcutaneousanthrax,ciprofloxacinordoxycyclinealoneisused.• Inhalational, gastrointestinal, and injectional anthrax and anthrax meningitis should be

treated with two bactericidal agents, preferably a quinolone such as ciprofloxacin and aβ-lactamsuchasmeropenem,combinedwithaproteinsynthesisinhibitorsuchaslinezolid,

*The opinions and assertions herein are those of the authors and should not be construed as official orrepresenting the views of the Office of Medical Services of the Department of State, the Department ofDefense,ortheU.S.government.

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TABLE 140-1  Intravenous Triple Therapya for Severe Anthraxb with Possible or Confirmed Meningitis

1. A Bactericidal Agent (Fluoroquinolone)Ciprofloxacin 400 mg q8h

or

Levofloxacin 750 mg q24h

or

Moxifloxacin 400 mg q24h

plus

2. A Bactericidal Agent (β-Lactam)

a. For All Strains, Regardless of Penicillin Susceptibility or if Susceptibility Is Unknown

Meropenem 2 g q8h

or

Imipenemc 1 g q6h

or

Doripenem 500 mg q8h

or

b. Alternatives for Penicillin-Susceptible Strains

Penicillin G 4 million units q4h

or

Ampicillin 3 g q6h

plus

3. A Protein Synthesis InhibitorLinezolidd 600 mg q12h

or

Clindamycin 900 mg q8h

or

Rifampine 600 mg q12h

or

Chloramphenicolf 1 g q6-8h

Duration of TherapyFor 2-3 weeks or longer, until clinically stable. Will require prophylaxis to complete an antibiotic course of up to 60 days from onset of illness.

aDrug names in boldface are preferred agents. Alternative selections are listed in order of preference for therapy for patients who cannot tolerate first-line therapy or if first-line therapy is unavailable.

bSevere anthrax includes meningitis; inhalational, injectional, and gastrointestinal; and cutaneous with systemic involvement, extensive edema, or lesions of the head or neck.

cIncreased risk for seizures associated with imipenem/cilastatin therapy.dLinezolid may exacerbate thrombocytopenia; use for >14 days carries additional hematopoietic toxicity.eRifampin is not a protein synthesis inhibitor but may be used based on in vitro synergy.fShould only be used if other options are not available, owing to toxicity concerns.Data from Hendricks KA, Wright ME, Shadomy SV, et al; Workgroup on Anthrax Clinical Guidelines. Centers for

Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis. 2014;20. doi: 10.3201/eid2002.130687.

clindamycin,rifampin,orchloramphenicol.Considercentralnervoussystempenetrationofantibioticsfortreatmentofpotentialmeningitis.

• Immunotherapeuticssuchasanthraximmuneglobulinandraxibacumabshouldbeconsid-eredinconjunctionwithantibioticsinseverecasesandinsomesporeexposures.

PREVENTION• Current vaccines are cell-free supernatants of protective antigen adsorbed to aluminum

hydroxide.• PostexposurevaccinationmustbedoneunderCentersforDiseaseControlandPrevention

InvestigationalNewDrugprotocol(intheUnitedStates)at0,2,and4weeksandadminis-teredsubcutaneously.

ANTHRAX AS AN AGENT OF BIOTERRORISM• Anthraxisgenerallyconsideredthemostlikelyagentforbioterrorismviaanaerosolroute.• Gramquantitiesofstablesporesareeasytotransportandcouldcausethousandsofcases.• Earlyidentificationofthefirstcasesisdifficultowingtothepresentationwithnonspecific

flulikesymptoms.• Nasalswabsareusedtoidentifyexposureareas,nottodetermineindividualexposures.• Exposed patients should be given antibiotic prophylaxis with 60 days of ciprofloxacin or

doxycyclineandanthraximmunizationat0,2,and4weeks.• Exposedpatientsshouldbedecontaminatedwithsoapandwater.Surfacesmayberemedi-

atedwithanumberofdifferentchloride-containingcompounds,includinghouseholdbleach.• Anthraxisnottransmissiblefrompatientsaftertheyhavebeendecontaminated,andisola-

tionisnotrequired.

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141 Bacillus Species and Related Genera Other Than Bacillus anthracisThomas Fekete

DEFINITION• Gram-positivespore-formingbacilli

EPIDEMIOLOGY• Worldwidedistribution• Commonlyfoundinsoilandwater• Majorpathogensofinsects• Infrequentcauseofinfectioninmammals(includinghumans)• Normalflorainchildrenandadults

MICROBIOLOGY• Aerobicorfacultativelyanaerobic• Easilycultivatedwithstandardculturetechnique• Numerousgenera(>56)andspecies(>545)• Frequentlytoxinproducing,andtoxincontributestomanyclinicalmanifestationsofdisease• Susceptibilitytestsnotstandardizedbutcanbehelpful

DIAGNOSIS• Cultureonroutinemediaatstandardtemperatures(25°to37°C)• Canbechallengingtodistinguishtruepathogenfromcontaminant• CharacteristicGramstainpropertiesbutcanbeconfusedwithClostridium• Forfoodpoisoning,canbeisolatedfromfoodproducts• Shouldbesuspectedwhensterilizationofequipmentisinadequate• Infectionmayfollowtraumaticinjury

THERAPY• Foodpoisoningisnormallyself-limitedandrequiresonlysupportivetreatment• Deepinfectionrequiresantibiotics• Vancomycinandfluoroquinolonesusuallyactive• Mayrequireremovalofforeignbodysuchasvascularcatheter

PREVENTION• Optimalmanagementandstorageoffood• Carefulattentiontosterilizationtechniques• Earlyremovalofunneededdevices

299

142  Erysipelothrix rhusiopathiaeAnnette C. Reboli

DEFINITION• Erysipelothrix rhusiopathiaeisapleomorphic,nonsporulatinggram-positivebacillus.• It causes three major forms of disease in humans: erysipeloid (localized cutaneous infec-

tion), diffuse cutaneous infection, and systemic infection (bacteremia with or withoutendocarditis).

EPIDEMIOLOGY• A zoonosis, it is widespread in nature and infects wild and domestic animals, including

swine,poultry,sheep,andfish.• Infectioninhumansisusuallyduetooccupationalexposure.• Portalofentryisusuallythroughabrasionsorpuncturewoundsoftheskin,butinfection

mayalsofollowingestionofundercookedporkorseafood.

MICROBIOLOGY• Itisanaerobeorfacultativeanaerobe.• Moststrainsproducehydrogensulfide,adiagnosticallyimportantreaction.• Itissometimesconfusedwithothergram-positivebacilli.• Vitek2andtheAPICorynesystemarereliableforidentification.

DIAGNOSIS• Aprovisionaldiagnosiscanoftenbemadebasedonahistoryofappropriateepidemiologic

exposureand,inthecaseoferysipeloid,characteristicphysicalfindings.• Definitivediagnosisrequiresisolationoftheorganismfromblood,othersterilebodyfluid,

orabiopsyspecimen.• Standardmethodsforculturingbloodorbiopsytissuesuffice.• Thepolymerasechainreactionassayhasbeenusedforrapiddiagnosisinswineandhasbeen

appliedsuccessfullytohumanandenvironmentalsamples.

THERAPY• E. rhusiopathiaeishighlysusceptibletopenicillins,cephalosporins,clindamycin,imipenem,

linezolid,daptomycin,andciprofloxacin.• Moststrainsareresistanttovancomycin,sulfadrugs,andaminoglycosides.• Erysipeloidmayresolveintheabsenceoftherapy;however,appropriatetherapyshortensthe

illnessandreducestheriskforrelapse.• Penicillinisthedrugofchoiceforallformsofinfection.Whenβ-lactamsarecontraindicated,

useoffluoroquinolones,daptomycin,linezolid,orclindamycinmaybeconsidered.

PREVENTION• Handhygiene,useofprotectiveattiresuchasgloves,anddisinfectionofcontaminatedsur-

facesareessential.• Commercialvaccinesareavailableforveterinaryuse.

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143 Whipple’s DiseaseThomas Marth and Thomas Schneider

DEFINITION• Whipple’sdisease (WD) isa raresystemic infectiousdisordercausedby theactinomycete

Tropheryma whipplei.

EPIDEMIOLOGY• ClassicWDisrareandisfoundinmiddle-agedindividuals,approximatelythreetimesmore

ofteninmenthaninwomen.• T. whippleiisfoundfrequentlyinthestoolsofchildrenwithacutediarrhea.• T. whippleicancauseculture-negativeendocarditis.

MICROBIOLOGY AND PATHOGENESIS• T. whippleiisagram-positivebacteriumwithhighguanineandcytosinecontent.• T. whippleiisresistanttoglutaraldehyde.• ThehallmarkofWDistheinvasionoftheintestinalmucosawithmacrophagesincompetent

todegradeT. whipplei.• An immunologicdefect in thepathogenesisofWDisevidentand includesmacrophages,

Tcells,andanimpairedhumoralimmuneresponse.

CLINICAL FEATURES AND DIAGNOSIS• WD occurs as an acute transient disease (presenting, e.g., with fever and diarrhea in

children).• WDoccursinalocalizedform(e.g.,endocarditisorcentralnervoussystemdisease).• WDoccursinvariousclinicalmanifestationsinassociationwithimmunosuppression.• WDoccursasaclassicsystemicdiseasewithweightloss,arthralgia,diarrhea,andapossible

broadspectrumofclinicalsignsandsymptoms.• Diagnosis is established usually by duodenal biopsy showing typical periodic acid–Schiff

positivecellsinthelaminapropria.• Diagnosisshouldbeconfirmedbypolymerasechainreactionassayorimmunohistochem-

istry,whichcanbeperformedalternativelyfromvariousorgansamplesorbodyfluids.

THERAPY• IVinductiontherapywithceftriaxonefor2to4weeks.• Followedbylong-termtherapywithoraltrimethoprim-sulfamethoxazolefor1year.• Closefollow-upoftreatmentsuccessoverseveralyears.• Complications:relapses,neurologicdefects,heartvalvedestruction,immunereconstitution

inflammatorysyndrome.

PREVENTION• Ubiquitousbacterialagent,preventionnotyetpossible.

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144 Neisseria meningitidisDavid S. Stephens and Michael A. Apicella

DEFINITION• Neisseria meningitidis,thecauseofepidemiccerebrospinalfever(firstdescribedin1805),is

anobligatehumanbacterialpathogenmostoftenpresentingasacutebacterialmeningitis,mildbacteremiatodevastatingsepticemia,andpneumonia.

MICROBIOLOGY• N. meningitidisisagram-negativediplococcus(0.6×0.8µm)andmemberofthebacterial

familyNeisseriaceaethatincludesthehumanpathogenNeisseria gonorrhoeae.

BIOLOGY AND PATHOGENESIS• Meningococcalbiologyandpathogenesisaredefinedby(1)N. meningitidiscolonizationand

virulencefactors,(2)transmissionandacquisitionamonghumans,and(3)humansuscep-tibility to invasive meningococcal disease. These factors influence disease incidence andseverityandpreventionstrategies.

EPIDEMIOLOGY• Diseaseoccursworldwide,butincidenceisvariable.ClonalcomplexesST-5andST-7(cap-

sularserogroupA);ST-41/44,ST-32,ST-18,ST-269,ST-8,andST-35(serogroupB);ST-11(serogroups C or W-135); ST-23 and ST-167 (serogroup Y); and ST-181 (serogroup X)meningococcicurrentlycausealmostallinvasivemeningococcaldisease(seeFig.144-1).

CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY• Commonpresentationsofinvasivemeningococcaldiseasearemeningococcemiaandacute

meningitis.Lesscommonpresentationsareprimarypneumonia(upto10%,especiallywithserogroupY), septic arthritis (2%),purulentpericarditis, chronicmeningococcemia, con-junctivitis,epiglottitis,sinusitis,otitis,urethritis,andproctitis.

• Meningococcemia: In20%to30%ofcases, septicemiawithshock is thedominantclinicalfindingwithsuddenonsetoffever,generalizedmalaise,weakness,coldextremitiesandskinpallor,leukocytosisorleukopenia,rash,headacheand/ordrowsiness,andhypotension.

• Meningitis:Meningitisisthemostcommonpresentationofinvasivemeningococcaldiseaseand occurs in 40% to 65% of cases, reflecting the meningeal tropism of N. meningitidis.Findingsincludesudden-onsetheadache,fever,vomiting,myalgias,photophobia,irritability,decreasedabilitytoconcentrate,agitation,drowsinessandmeningealsigns(neckstiffness,Kernig’s or Brudzinski’s sign), and cloudy cerebrospinal fluid. Rash may or may not bepresent.

• Rash:Skinlesionsarepresentin28%to77%ofpatientswithinvasivemeningococcaldiseaseonadmissionbutmaynotalwaysbepetechialorpurpuric.

• Complement system deficiencies increase risk for meningococcal disease, in particularC5-C9terminalpathwaydeficiencies,properdindeficiency,andC3deficiency.

• Chronic meningococcemia manifests as intermittent fever (often low grade), migratoryarthralgiasorarthritis,andanonspecific,oftenmaculopapularrash.

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COMPLICATIONS• Immunecomplex–mediatedcomplicationsmayfollowmeningococcaldisease.• Long-termsequelaeoccurin11%to19%ofcases.• Familyandcommunityimpactissignificant.

DIAGNOSIS• Thedefinitivediagnosisofinvasivemeningococcaldiseaseisbasedonbacteriologicisolation

orantigenorDNAidentification(bypolymerasechainreactionassay)ofN. meningitidisinausuallysterilebodyfluid,suchasblood,cerebrospinalfluid,synovialfluid,pleuralfluid,urine,orpericardialfluid.

TREATMENT• Invasive meningococcal disease is a medical emergency, and early antibiotic treatment

shouldbetheprimarygoal(seeTable144-1).• Adjuvanttherapyandsupportivecareshouldbeprovided.

FIGURE 144-1  Epidemiology of meningococcal disease by serogroup. Group B outbreaks are noted by country and year of onset. Clonal complexes ST-5 and ST-7  (serogroup A); ST-41/44, ST-32,  ST-18,  ST-269,  ST-8,  and  ST-35  (serogroup  B);  ST-11  (serogroups  C  or  W-135);  ST-23  and ST-167  (serogroup  Y);  and  ST-181  (serogroup  X)  meningococci  currently  cause  almost  all  invasive meningococcal disease.  (Modified from Stephens DS, Greenwood B, Brandtzaeg P. Epidemic men-ingitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196-2210.)

Chile 1985

Brazil 1985

South Africa 1980

New Zealand 1992

Australia 1982

Japan 1979

Cuba 1980

Spain 1974

Norway 1969

Oregon 1994 B, Y, C

A, W-135, C, X

B, A, W-135, Y, C

W-135, B, Y, A

A, B, C

A, C

B, C

B, C, Y

B, C, Y

TABLE 144-1  Antibiotic Treatment of Meningococcal Meningitis and MeningococcemiaCeftriaxone*: in children age >3 mo: 50 mg/kg IV q12h; adults: 1-2 g IV q12h

orCefotaxime 50-75 mg/kg q6-8h, maximum dose 12 g/day

orPenicillin G, 50,000 U/kg IV q4h, up to 4 million U q4h

orMeropenem, 2 g IV q8h, 6 g/dayIf patient is allergic to penicillin and cephalosporins, use chloramphenicol, 25 mg/kg IV q6h up to 1 g q6h.

*Because of concerns in neonates from calcium/ceftriaxone precipitates and displacement of bilirubin from albumin by ceftriaxone, neonates younger  than 3 months of age should be started on cefotaxime, 50 mg/kg every 6  to  8 hours.

Modified from Shin SH, Kwang Kim SK. Treatment of bacterial meningitis: an update. Exp Opin Pharmacother. 2012;13:2189-2206.

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TABLE 144-2  Antibiotic Chemoprophylaxis for Household or Intimate Contacts*

ANTIBIOTIC DOSAGE COMMENTRifampin Adults: 600 mg q12h for 2 days

Children <1 mo: 5 mg/kg q12h for 2 daysChildren >1 mo: 10 mg/kg q12h (maximum, 600 mg) orally for 2 days

Rifampin can interfere with efficacy of oral contraceptives and some seizure prevention and anticoagulant medications; may stain soft contact lenses. Not recommended for pregnant women.

Ceftriaxone Children <15 yr: 125 mg, single IM doseChildren >15 yr and adults: 250 mg, single IM dose

Ceftriaxone is recommended for prophylaxis in pregnant women.

Ciprofloxacin Adults: 500 mg, single dose Not recommended routinely for persons <18 yr, but use in infants and children (20 mg/kg) may be justified after careful assessment of the risks and benefits. Not recommended for pregnant or lactating women. Cases of ciprofloxacin resistance have been reported, and use for prophylaxis should be based on local sensitivity of the meningococcus to the drug.

Azithromycin 10 mg/kg (maximum, 500 mg) single dose

Equivalent to rifampin for eradication of meningococci from nasopharynx, but data are limited.

*Recommended groups for chemoprophylaxis, based on exposure to the index patient in the week before onset of illness:

•  Household contacts and persons sharing the same living quarters, particularly young children•  Daycare center, nursery school or child care contacts, frequent playmates of young children•  Close social contacts that were exposed to oral secretions in week before onset, such as by kissing or sharing 

eating or drinking utensils or toothbrushes•  For airline travel  lasting more than 8 hours, passengers who are seated directly next to an  infected person 

should receive prophylaxis.•  Routine prophylaxis is not recommended for health care professionals unless they have had intimate exposure 

to respiratory secretions of an infected person.•  Because  the  risk  for  secondary cases  is highest during  the first  few days after exposure, chemoprophylaxis 

should be initiated as soon as possible, ideally <24 hours after identification of the index patient.•  If more than 14 days have passed since the last contact with the index patient, chemoprophylaxis is not likely 

to be of benefit.•  Pharyngeal  cultures  are  not  helpful  in  determining  the  need  for  chemoprophylaxis  and  may  unnecessarily 

delay the use of effective chemoprophylaxis.•  Chemoprophylaxis has also been recommended for patients given penicillin or chloramphenicol for treatment 

since pharyngeal carriage may not be eliminated with these antibiotics and the patient could remain colonized with a virulent strain.

•  Ceftriaxone is recommended for pregnant women.•  May want to avoid ciprofloxacin or azithromycin in individuals at risk of QT-prolongation.

PREVENTION• Chemoprophylaxiseliminatesmeningococcifromclosecontactsofconfirmedorpresump-

tivecases,protectssusceptibleindividuals,anddisruptsthefurtherspreadofmeningococci.Recommended antibiotics are rifampin, ceftriaxone, ciprofloxacin, and azithromycin (seeTable144-2).

• Meningococcalpolysaccharide-conjugatevaccinesarelicensedforpreventionofmeningo-coccaldisease(seeTable144-3)andarerecommendedforadolescentsandothersatriskformeningococcaldisease.

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TABLE 144-3  Conjugate Vaccines for Neisseria meningitidis: United States, 2015Menveo (Novartis) Meningococcal (groups A, C, Y, and W-135) 

Oligosaccharide Diphtheria CRM197 Conjugate

Menactra (Sanofi Pasteur) Meningococcal (groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine

MenHibrix (GlaxoSmithKline) Meningococcal groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine

Bexsero (Novartis) Meningococcal group B Recombinant Protein Vaccine

Trumenba (Pfizer) Meningococcal group B Recombinant Protein Vaccine

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145 Neisseria gonorrhoeae (Gonorrhea)Jeanne M. Marrazzo and Michael A. Apicella

DEFINITION• Gonorrhea is a sexually transmitted infection caused by the organism Neisseria

gonorrhoeae.

EPIDEMIOLOGY• Gonorrheaoccursmostcommonlyinadolescentsandyoungadultsworldwide.• Overall, incidencehasbeendeclining;however,anexceptionisamongmenwhohavesex

withmen.• N. gonorrhoeaeisthecausativeagenttoconsiderinevaluationofgenitalinflammatorysyn-

dromes,includingcervicitis,urethritis,andpelvicinflammatorydisease.• Most infections, however, involve neither signs nor symptoms; thus, routine screening of

youngwomen(≤25years)orolderwomenwithkeyriskfactorsisrecommended.• Untreatedmaternalinfectionmayresultinophthalmianeonatorum,whichmaybeavoided

byneonatalprophylaxis.

MICROBIOLOGY• Thisgram-negative,intracellulardiplococcusisafastidiousmicroorganismthatgrowsonly

invitroinanarrowtemperaturerange(35°Cand38°C)oncomplexmedia.• Ithasamarkedabilitytodevelopresistancetoantibiotics;recentlytherehasbeentheglobal

appearanceofstrainswithincreasingresistancetothird-generationcephalosporins.• Thegonococcusisnaturallycompetent.Thisisafactorthathasledtotherapidacquisition

ofantimicrobialresistance.• N. gonorrhoeaeisanexclusivehumanpathogen.Itutilizesdifferentpathogenicmechanisms

toinfecttheepitheliumofmenandwomen.Inmen,theasialoglycoproteinreceptorpresenton the urethral epithelia interacts with the terminal galactose of the lipo-oligosaccharide(LOS)toenterhumancells.Inwomen,acooperativeinteractionoccursbetweenC3bcova-lentlylinkedtotheLOS,gonococcalporinandpilus,andcomplementreceptor3(CR3)onthesurfaceofthecervicalepithelialcell.

DIAGNOSIS• Cultureornucleicacidamplificationtestingaresensitiveandspecificandcanbeperformed

atallpotentiallyinfectedanatomicsites.

THERAPY• Optionsarelimited,givenwidespreadresistancetonumerousantibioticclasses.• Parenteral therapy with a third-generation cephalosporin is currently recommended and

shouldbeaccompaniedbytreatmentwithazithromycinordoxycyclineforadditionalcover-age(seeTable145-1).

• Sexpartnersofinfectedpeopleshouldbetreatedpresumptively,regardlessofdiagnostictestresults.

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• Patientswhofailtreatmentwithstandardregimensshouldundergoassessmentforreinfec-tion;ifreinfectionisunlikely,antibioticresistanceshouldbeconsidered.

PREVENTION• Becauseoftheasymptomaticnatureofmostinfections,routinescreeningofyoungwomen

(≤25years)andpregnantwomenisrecommended.• Condomsareveryeffectiveinpreventingtransmission.

TABLE 145-1  Options for the Treatment of Gonorrhea*

Uncomplicated Infection of the Cervix, Urethra, and RectumCeftriaxone, 250 mg IM single dose

Infection of the PharynxCeftriaxone, 250 mg IM single dose

Conjunctivitis (Not Ophthalmia Neonatorum)Ceftriaxone, 1 g IM single dose

Disseminated Gonococcal InfectionCeftriaxone, 1 g IM or IV every 24 hr for 24-48 hr† after improvement, with switch to oral therapy for completion of 1 wk total antibiotic therapy, including cefixime, 400 mg PO twice daily

Meningitis and EndocarditisCeftriaxone, 1-2 g IV every 12 hr for 10-14 days (meningitis) or ≥4 wk (endocarditis)

Ophthalmia NeonatorumCeftriaxone, 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg‡

IM, intramuscular; IV, intravenous; PO, orally.*Treatment of gonorrhea in the adult should always be accompanied by treatment of chlamydial infection, and

patients should abstain from sex during treatment. Azithromycin, given as a single oral dose of 1 g, is preferred. Test of cure at 7 days is recommended if the ceftriaxone regimen is not used.

†Ceftriaxone administered IM may be reconstituted in 1% lidocaine solution to minimize injection pain. Alternative parenteral regimens include cefotaxime, ceftizoxime, and spectinomycin. See www.cdc.gov/std/treatment for specific regimens.

‡Topical antibiotic therapy alone is inadequate for treatment of ophthalmia neonatorum.Modified from Centers for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treat-

ment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012;61:590-594; and www.cdc.gov/std/treatment.

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146 Moraxella catarrhalis, Kingella, and Other Gram-Negative CocciTimothy F. Murphy

DEFINITION• Moraxella catarrhalis is a gram-negative diplococcus that colonizes the upper respiratory

tractofchildren.• It isacommoncauseofotitismedia inchildrenandexacerbationsofchronicobstructive

pulmonarydisease(COPD)inadults.• Kingella kingaeisanincreasinglyrecognizedpathogenthatcausesosteoarticularinfections

andbacteremiainyoungchildren.

EPIDEMIOLOGY• M. catarrhalisisrecoveredexclusivelyfromhumans.• Nasopharyngealcolonizationiscommonininfancyandchildhoodanddecreaseswithage.• K. kingaecolonizestheoropharynxofchildrenandismoreoftenisolatedfromthosewho

attenddaycarecenters.Infectionsoccursporadically,butoccasionalclustersareseen.

MICROBIOLOGY• M. catarrhalisiseasilyoverlookedinculturebecauseitisphenotypicallyidenticaltoNeisseria

inGramstainandoncultureplates.• M. catarrhalisproducesoxidase,catalase,andDNAse,whichareusedforspeciation.

DIAGNOSIS• AnetiologicdiagnosisofthemostcommonclinicalmanifestationsofM. catarrhalis(otitis

media inchildrenandexacerbationsofCOPDinadults) isnotmaderoutinely inclinicalpractice. Rather, these infections are usually treated empirically, based on a presumptivediagnosisusingclinicalmanifestations.

• A diagnosis of K. kingae infections is made by recovering the organism in culture fromnormally sterile body fluid, including blood and joint fluid aspirate. Polymerase chainreaction–basedassaysaremoresensitivethancultureindetectingtheorganisminjointfluid.

THERAPY• Most isolates of M. catarrhalis produceβ-lactamase and are thus resistant to ampicillin.

Isolates are susceptible to amoxicillin/clavulanic acid, macrolides, fluoroquinolones, andextended-spectrumcephalosporins.

• OtitismediaandexacerbationsofCOPDaretreatedwithoralantimicrobialagents,withthechoicegenerallyguidedbyexpertguidelines.

• K. kingaeisolatesaresusceptibletopenicillinsandcephalosporins.

PREVENTION• Novaccinesareavailablecurrently,butresearchisinprogresstodevelopvaccinestoprevent

M. catarrhalisinfections,includingotitismediaandexacerbationsofCOPD.

308

147 Vibrio choleraeMatthew K. Waldor and Edward T. Ryan

MICROBIOLOGY AND EPIDEMIOLOGY• Vibrio choleraeisacurvedmotilegram-negativebacillus.• V. choleraeisanoninvasiveintestinalpathogen.• V. choleraeO1andO139serogrouporganismsarethecausesofepidemiccholera.• Non-O1andnon-O139V. choleraecancauseisolatedcasesofusuallymildgastroenteritis.• Cholera results from secretory diarrhea caused by the actions of cholera toxin (CT) on

intestinalepithelialcells.• CT is an adenosine diphosphate–ribosylating enzyme that leads to chloride, sodium, and

waterlossfromintestinalepithelialcells.• V. choleraehasanaquaticreservoir,particularlyinbrackishestuarinewater.• Thefecal-oraltransmissionisassociatedwithunsafewaterandinadequatesanitation.• Thereareanestimatedthreetofivemillioncholeracases,resultinginapproximately100,000

deathseachyear.• Thecurrentcholeraglobalpandemicbeganin1961andrepresentstheseventhinthehistori-

calrecord.• Choleraisnowendemicinmorethan50countries.• Choleracanleadtoexplosiveepidemicsandoutbreaks.• ThecurrentpandemiciscausedbyV. choleraeO1ElTororganisms,withthelargestburdens

inSouthAsia,sub-SaharanAfrica,andHaiti.

CLINICAL MANIFESTATIONS• Acuteseverewaterydiarrheacanresultindeathfromdehydrationwithin6to12hoursof

onsetofclinicalsymptoms.• Bowelmovementsduringcholeracanbecomeprogressivelymorewatery,eventuallyresem-

blingricewaterwithafishyodor.• Vomiting,ileus,andmusclecrampsarecommon.• Thepresenceoffevershouldpromptconsiderationofadditionaldiagnoses.• Complicationsofcholeralargelyreflectthoseresultingfromhypotensionandhypoperfusion

and may include acute renal tubular necrosis and stroke, usually in older individuals.Aspiration pneumonia from vomiting may also occur. Death from cholera almost alwaysresultsfromdehydration.

DIAGNOSIS• Cholerashouldbeconsideredwhenanadultorchildaged5yearsorolderdevelopssevere

dehydrationordiesofacutewaterydiarrheainanyarea,orwhenanindividualaged2yearsorolderdevelopsacutewaterydiarrheainanareaknowntobeendemicforcholera.

• Rapidantigentestsareavailable,includingdipstickstoolassays.• Confirmatory microbiologic culturing permits definitive identification and assessment of

antimicrobialresistanceprofiles.

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TABLE 147-1  Composition of Cholera Stools and Therapeutic Fluids for Cholera

CONCENTRATION (MMOLES/L)

Na+ K+ Cl− HCO3− Carbohydrate Comments

Intravenous fluid

LRS 130 4 109 28 — (278 if D5LR available)

LRS contains potassium and bicarbonate and is preferred over normal saline. Both LRS and NS can be supplemented with dextrose. Dhaka solution more closely approximates losses during cholera, but is not readily available.

Normal saline 154 0 154 0 —

Cholera saline (“Dhaka solution”)

133 13 154 48 140

Oral rehydration therapy

ORS (WHO, 2002)*

75 20 65 10 (citrate)

75 (glucose) WHO ORS uses glucose as a carbohydrate source. Rice-based ORS formulations have been found in randomized trials to reduce the duration of diarrhea and stool losses in severe cholera.A homemade preparation of ORS could be used in an emergency situation.

Rice-based ORS(e.g., CeraORS 75)

75 20 65 10 (citrate)

27 g rice syrup solids

Homemade ORS: 12 tsp table salt

and 6 tsp table sugar in1 L of safe water

≈75 0 ≈75 0 ≈75

Electrolyte losses in stools (composite estimates)

Cholera stool, adult

130 20 100 45 — Mean maximal rate of purging in severe cholera may exceed 10 mL/kg/hr. Sodium losses in cholera stools exceed those seen in other causes of diarrheal illness.

Cholera stool, child

100 30 90 30 —

Noncholera stool, child (ETEC)

50 35 25 20 —

Cl−, chloride ion; D5LR, 5% dextrose in lactated Ringer’s solution; ETEC, enterotoxigenic Escherichia coli; HCO3−,

bicarbonate ion; K+, potassium ion; LRS, lactated Ringer’s solution; Na+, sodium ion; NS, normal saline; ORS, oral rehydration solution; WHO, World Health Organization.

*In 2002, the WHO replaced its previous formulation of ORS with the current lower osmolarity formulation to reflect the broad use of ORS for treating dehydration from all-cause gastroenteritis.

Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.

MANAGEMENT• Thecornerstoneofmanagementisrapidassessmentofthedegreeofdehydration,followed

bypromptfluidrestoration(seeTable147-1)aswellasvigorousmonitoringandmatchingofongoingfluidlosses.

• Severedehydration(>10%fluidloss),mayrequiregreaterthan100mL/kgoffluidreplace-ment to restore euvolemia, ideally administered within the first 3 to 4 hours of clinicalpresentation.

• Additional stool losses shouldbematchedatapproximately10 to20mL/kgperdiarrhealstoolorvomitingepisode.

• Moderatedehydration(5%to10%fluidloss)mayrequire75to100mL/kgoffluidresuscita-tionwithinthefirst3to4hoursofclinicalpresentation.Individualswithnoormilddehy-drationmaybetreatedwithoralrehydrationsolution(ORS)aloneorliquidadlibitum.

• IntravenousfluidsareindicatedforseveredehydrationandinthoseunabletoingestadequateORS. Lactated Ringer’s solution supplemented with 5% dextrose (D5LR) (ideally supple-mentedwithadditionalpotassium)isanoptimalchoiceforpatientswithcholera,althoughintravenous normal saline or normal saline supplemented with dextrose (and potassium)canalsobeused.

• Oral rehydration treatment should be encouraged among all individuals able to ingest,regardlessofdegreeofdehydration,andregardlessofpotentialongoingadministrationofintravenousfluid.

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TABLE 147-2  Antimicrobial Options for Treating Patients with Cholera

CLASS ANTIBIOTIC PEDIATRIC DOSE* ADULT DOSE COMMENTSMacrolides Erythromycin 12.5 mg/kg/dose qid

× 3 days250 mg qid × 3 days

Single-dose azithromycin is often the preferred therapy, especially in children, and has been shown to be more effective than ciprofloxacin in randomized trials in regions where reduced susceptibility to fluoroquinolones are common. Rare reports of macrolide resistance.

Azithromycin 20 mg/kg × single dose

1 g × single dose

Fluoroquinolones Ciprofloxacin 15 mg/kg/dose bid × 3 days

500 mg bid × 3 days

In highly susceptible strains, single-dose ciprofloxacin compares favorably against erythromycin and doxycycline in randomized trials. Reduced susceptibility to fluoroquinolones has become common in endemic areas and is associated with treatment failure.

Tetracyclines Tetracycline 12.5 mg/kg/dose qid × 3 days

500 mg qid × 3 days

Antibiotic resistance to all tetracyclines is common. Empirical use often reserved for outbreaks caused by documented susceptible isolates. Tetracyclines are not recommended for pregnant women or children less than 8 yr.

Doxycycline 4-6 mg/kg × single dose

300 mg × single dose

bid, twice a day; qid: four times a day.*Pediatric doses, based on weight; should not exceed maximum adult dose.Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.

• ORScanbemadeinresource-limitedsettingsbyadding 12 tspoftablesaltto6tspoftablesugar in 1L of safe water, ideally supplemented with locally available potassium sources,suchascoconutmilk,bananas,ororangejuice.

• Antibioticsplayasecondaryrole in the treatmentof individualswithcholeraandusuallyinvolve administration of a macrolide or fluoroquinolone antibiotic. Tetracyclines can beused innonpregnant individualsolder than7years inareaswithconfirmedsusceptibility(seeTable147-2).

• Antibioticsdecreasethedurationofdiarrheaandmaylimitsecondarytransmission.

PREVENTION• Controlprimarily focusesonsurveillance,casedetection,fluidresuscitationandmanage-

ment,vaccination,andprovisionofsafewaterandadequatesanitation.• Twooralkilledcholeravaccinesarecurrentlycommerciallyavailableandapprovedbythe

WorldHealthOrganization(seeTable147-3).• Additionalcholeravaccinesareunderdevelopment.

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TABLE 147-3  Internationally Available and WHO Prequalified Oral Killed Cholera Vaccines

VA

CC

INE

DO

SES*

DO

SIN

G

INTE

RV

AL*

DO

SIN

G

VO

LUM

E*

BO

OST

ERS*

PRO

TEC

TIV

E EF

FIC

AC

Y

CO

MM

ENTS

REF

EREN

CES

Shanchol (Shantha Biotechnics–Sanofi Pasteur) Possible longer term protection than that afforded by Dukoral.Does not require buffer to administer vaccine.Currently more affordable than Dukoral.Currently undergoing field studies in Kolkata/Orissa, India, and Dhaka, Bangladesh, and pilot roll out in a number of countries, including Haiti.

82-88

≥1 yr of age

2 14 days (7-42 probably permissible)

1.5 mL Every 2 yr

60%-70% protective efficacy decreasing to baseline over 36-60 mo in older children and adults; 40% protective efficacy and shorter duration in younger children

Dukoral† (Crucell) Licensed in many countries.Has been safely administered to individuals infected with HIV.Provides short-term protection against diarrhea caused by heat-labile toxin expressing strains of ETEC.

89-96

Children 2 to <6 yr of age

3 14 days (7-42 permissible)

3 mL vaccine and 75 mL buffer

Every 6 mo

60%-85% protective efficacy within 6 mo of vaccination, decreasing to baseline over 24-36 mo

≥6 yr of age

2 14 days (7-42 permissible)

3 mL vaccine and 150 mL buffer

Every 2 yr

ETEC, enterotoxigenic Escherichia coli; HIV, human immunodeficiency virus; WHO, World Health Organization.*Per manufacturer.†Field studies have involved both the current preparation of WC-rBS vaccine, supplemented with recombinant

cholera toxin B subunit (rBS), and an initial preparation of WC-BS containing nonrecombinant B subunit (BS).Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.

312

148 Other Pathogenic VibriosMarguerite A. Neill and Charles C. J. Carpenter

DEFINITION• Vibriosaregram-negativerodswhoseenvironmentalnicheisprimarilymarineandestuarine

waters.• Theymayalsobefoundinfreshwatersources.• Thehalophilicvibriosrequirehigherconcentrationsofsaltforgrowth.

EPIDEMIOLOGY• The most common Vibrio species causing human illness are Vibrio parahemolyticus and

Vibrio vulnificus.• The incidence of vibriosis in the United States has been increasing in the past 15 years,

indicatingthatcurrentpreventioneffortsarenoteffective.• IllnessismorecommoninthewarmersummermonthswhenVibriopopulationsarehigher

andthereisincreasedhumanexposurefromshellfishconsumptionandrecreationalwaterexposure.

• Vibrio species primarily cause diarrhea of varying severity, soft tissue infection, and/orbacteremia.

• V. vulnificus causes a distinct soft tissue infection with rapidly developing hemorrhagicbullae.

• Vibrioinfectionsaremoresevereandmoreoftenfatalinpeoplewithcirrhosisorunderlyingliverdisease.

MICROBIOLOGY• Themajorpathogenicvibriosgrowwellinbloodculturemediaandcommonnonselective

mediausedforwoundcultures.• Selectivemediasuchasthiosulfatecitratebilesaltssucrosefacilitatesidentificationfromfecal

specimens.

DIAGNOSIS• Vibrioinfectionshouldbesuspectedinpeoplewithdiarrhea,sepsis,orwoundinfectionafter

seafoodconsumptionormarinewaterexposure.

THERAPY• RapidrecognitionofpossibleV. vulnificusinfectioniskeytoimprovingsurvivalandrequires

antimicrobialtreatmentaswellassurgicaldébridement• Survival is improved in V. vulnificus infection when a third-generation cephalosporin

is added to doxycycline or a quinolone, provided débridement of necrotic tissueisdone.

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• Treatmentwithdoxycyclineoraquinolonecandecreasesymptomsandfecal shedding inpeoplewithdiarrheacontinuingfor5days.

PREVENTION• Novaccineisavailableforthenoncholeravibrios.• Thorough cooking of seafood with prompt consumption or refrigeration is needed to

decreasetheriskforVibrioinfection.

314

149 Campylobacter jejuni and Related SpeciesBan Mishu Allos, Nicole M. Iovine, and Martin J. Blaser

DEFINITION• Campylobacterspp.aresmall,curved,gram-negativerodsthatcauseacutegastrointestinal

illnessthattypicallylastsfrom1to7days.Thediarrheaisfrequentlybloodyandisassociatedwithabdominalpain.C. jejuniisthemostcommonhumanclinicalisolate,butmanyotherCampylobacterspp.havebeenidentified.

EPIDEMIOLOGY• Campylobacter spp. are found inavarietyof animals andarea commoncauseofhuman

diarrhealdiseaseworldwide.Indevelopednations,theincidencepeaksinlatesummerandfall,butinfectionsoccuryear-roundindevelopingcountries.Transmissiontohumansoccursmostcommonlyfromconsumptionorhandlingofpoultry.

MICROBIOLOGY• Many,butnotall,Campylobacterspp.thriveat42°C.Theorganismsarequitesmall(0.3to

0.6µmindiameter)andmotile.Theyaremicroaerophilicandgrowbestatanoxygencon-centrationof5%to10%.

DIAGNOSIS• Thegoldstandardfordiagnosisisviaisolationoftheorganismfromastooloroccasionally

abloodculture.

THERAPY• Themostimportanttenetoftreatmentistoreplacefluidandelectrolytestopreventdehydra-

tion.Antibioticsmayshortenthedurationofsymptoms.Erythromycin,250mgfourtimesperdayfor5to7days,willtreatmostinfections.Extended-spectrummacrolidesareequallyefficacious.

PREVENTION• Thebestwaytopreventinfectionisbythoroughlycookingpoultryandotherfoodsofanimal

originbeforeconsuming them.Meticulousattention toavoidcross-contaminationduringfood preparation may also prevent some infections. No effective vaccine is currentlyavailable.

315

150 Helicobacter pylori and Other Gastric Helicobacter SpeciesTimothy L. Cover and Martin J. Blaser

DEFINITION• Helicobacter pylori is a gram-negative bacterium that persistently colonizes the human

stomach.• Most H. pylori–colonized persons remain asymptomatic, but the presence of H. pylori is

associatedwithanincreasedriskofpepticulcerationandgastriccancer.

EPIDEMIOLOGY• H. pylori is present in humans throughout the world, but the prevalence is variable and

dependsonageandgeography.• TheprevalenceofH. pyloriindevelopedcountrieshasbeendecliningoverthepastseveral

decades.

MICROBIOLOGY• H. pyloriisaurease-positive,gram-negative,spiral-shapedbacterium.

DIAGNOSIS• Noninvasiveapproachesareserology,ureabreathtest,andstoolantigentest.• Invasiveapproachesareendoscopyandanalysisofgastrictissue.

THERAPY• Treatmentisnotindicatedexceptinpatientswithpepticulcerationorpatientsconsidered

tohaveahighrelativeriskofgastriccancer.

PREVENTION• PreventionofH. pyloriacquisitionbyimmunizationisnotroutinelypracticed.

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151  EnterobacteriaceaeMichael S. Donnenberg

DEFINITION• Family of gram-negative, non–spore-forming facultative anaerobes that ferment glucose,

reducenitratetonitrite,andproducecatalase

EPIDEMIOLOGY• Cause a wide variety of diseases in humans of all ages, the spectrum of which varies by

organismandsubtype

MICROBIOLOGY• IncludesEscherichia coli, Proteusspp.,Klebsiellaspp.,andCitrobacterspp.amongothers• Salmonellaspp.,Shigellaspp.,Yersiniaspp.(seediscussionsinotherchapters)

DIAGNOSIS• Standardculturetechniques• Specific subtypes identified by immunoassays for toxin production or polymerase chain

reactionassayforvirulencegenes• Pulsed-fieldgelelectrophoresishelpfulinidentifyingoutbreaks

THERAPY• Variesbyorganism,site,andsusceptibilitypatternandcanincludearangefromantimicro-

bialagentsbeingcontraindicatedtobeinguntreatablewithcurrentlyavailableantimicrobialagents

PREVENTION• Strict adherence to infection control measures for nosocomial spread of highly resistant

strains• Reduceriskforfoodborneinfectionsbyobservinggoodfoodhygiene• Nocurrentlylicensedvaccine

317

152 Pseudomonas aeruginosa and Other Pseudomonas SpeciesErika D’Agata

EPIDEMIOLOGY• Pseudomonasspeciesaregram-negativebacteriathatinhabitdiverseenvironments,includ-

ingsoil,water,plants,insects,andanimals.• P. aeruginosaisthemostimportantPseudomonasspeciesaffectinghumans,causingserious

infectionsassociatedwithsubstantialmorbidityandmortality.• OtherPseudomonasspecies,includingP. fluorescens, P. luteola, P. putida,andP. stutzeri,are

lessvirulentbutarestillimplicatedinawidevarietyofinfections,primarilyoccurringamongimmunocompromisedpatients.

• P. aeruginosahasmanyvirulencefactors,includingpili,flagella,enzymesecretionsystems,andquorum-sensingmolecules.

• P. aeruginosa isoneofthemostfrequentpathogensimplicatedinhospital-acquiredinfec-tions, including ventilator-associated pneumonia and catheter-associated urinary tractinfections. Long-term acute care hospitals have very high rates of infections causedbyP. aeruginosa

• CharacteristicinfectionscausedbyP. aeruginosaincludeecthymagangrenosum,malignantotitisexterna,hothand-footsyndrome,andhottubfolliculitis.

• Resistancetosingleandmultipleantimicrobialagentsisrisingrapidly.

MICROBIOLOGY OF P. AERUGINOSA• P. aeruginosaisanaerobicrod-shapedbacteria.• Growthoccursinavarietyofculturemediaformingsmoothroundcolonies,withacharac-

teristicgrapelikeor“corn-taco”odor,andagreen-bluecoloration.• Identificationisbasedoncolonymorphology,coloration,oxidasepositivity,andgrowthat

42°C.

THERAPY• The efficacy of treatment with two antipseudomonal antimicrobial agents versus mono-

therapyhasnotbeendefinitivelyanswered.• The majority of evidence suggests that empirical treatment with combination therapy is

indicatedifantimicrobialresistanceratesarehigh.• Streamlining to a single antimicrobial agent, once antimicrobial susceptibility profiles are

available,shouldthenbeconsidered.

318

153 Stenotrophomonas maltophilia and Burkholderia cepaciaAmar Safdar

MICROBIOLOGY AND EPIDEMIOLOGY• Stenotrophomonas maltophilia and Burkholderia cepacia are gram-negative bacteria that

acquire motility via multitrichous polar flagella. They do not ferment glucose, and manyclinicalisolatestendtogiveaweakoxidasereaction.

• Slow-growingmorphotypes,knownassmall-colonyvariantsofB. cepaciaandS. maltophilia,mayappearandexhibitahighdegreeofresistancetoantibioticsandmaygoundetectedinroutinecultures.

• Thesefree-livingorganismsarepresentinmostaquaticandhumidenvironments,includinghospitaldrinkingwater.

• Burkholderia cenocepaciaandBurkholderia multivoransaretheprominentbacterialstrainsisolated from patients with cystic fibrosis. Patient-to-patient transmission is believed tocontributetocolonization.

• Community-acquiredS. maltophiliapneumoniahasemergedasaseriousconcerninpatientswithnoknownriskfactors,suchascriticalunitstay;mechanicalventilationorprolongedtreatment-induced neutropenia; recent carbapenem, higher-generation cephalosporin, orfluoroquinolonetherapy;orextendedhospitalstays.

CLINICAL MANIFESTATIONS• S. maltophiliamayinvolveanyorgan.Lungsarefrequentsitesofinfection.Pulmonaryinfec-

tion is often preceded by respiratory tract colonization. Lobular or lobar consolidation iscommon,whereaspleuraleffusionsareseldomnoted.

• Most S. maltophilia bloodstream infections arise from infected indwelling intravascu-lar devices. Non–catheter-related bacteremia is often seen in patients with prolongedneutropenia.

• S. maltophilia wound infections in burn patients are being reported as the second mostcommon gram-negative bacterial infections after those caused by Aeromonas hydrophila.Skinlesionsinmostlyneutropenicpatientsaredifficulttodistinguishfrompyodermagan-grenosum, leukemiacutis, vasculitis, anddisseminatedPseudomonas, Fusarium, Candida,andrapidlygrowingmycobacterialinfections.

• Inpatientswithcysticfibrosis,afterinitialB. cepaciainfection,50%ofpatientswithB. mul-tivoransmaydevelopchronicasymptomaticbacterialcolonization,whereasnearlyall(94%)patientswithB. cenocepaciaretainbacterialpresenceaftertheinitialinfectionepisode.

COMPLICATIONS• LackofacuteinflammationmayunderwhelminitialclinicalpresentationofS. maltophilia

pneumoniaintheimmunosuppressedpatient.Patientsmaypresentwithseriouspulmonaryhemorrhage at the time of diagnosis owing to high propensity for tissue necrosis andhemorrhage.

• Non–catheter-related S. maltophilia bacteremia is a serious complication associated withhighrateof treatmentfailureanddeath.Patientsoftenhaveprofoundneutropenia lastinglongerthan10days;andinnearly70%ofpatients,hematogenousdisseminationarisesfrom

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lungorsofttissueinfection.Indicatorsforpooroutcomeincancerpatientsincludeneutro-peniamorethan10days,bacteremicpneumonia,shocksyndrome,severethrombocytope-nia,anddelayinappropriatetherapy.

• B. cenocepacia isassociatedwithprolongedrespiratorytractcolonization,andtheriskfordeathwithinvasivediseaseismorethanfivefoldhighercomparedwithinfectionsduetotheothereightB. cepaciacomplexgenomovars.

• B. cepaciacomplexinfectioninpatientswithcysticfibrosiswithdiminishedforcedexpira-toryvolumein1secondhassteadilybeenassociatedwithpoorprognosis.Infectionincriti-callyillpatients,presenceofsepticshock,andadvancedunderlyingconditionsalsoheraldhighermortality.

DIAGNOSIS• EarlydiagnosisrequiresahighlevelofsuspicionforS. maltophilialunginfection.• Up to 36% of Burkholderia species may be misidentified by automated systems as other

nonfermentativebacteria,suchasAchromobacterorRalstonia.• Swiftandaccuratemolecularmethodsusing16Sor23SribosomalRNAgenesequencing

mayreplaceconventionalmethods.• Whole-cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

holdspromiseasarapid,accurateidentificationmethodforB. cepaciaandS. maltophilia.

THERAPY• Monotherapyisnotrecommended,owingtohighfrequencyoftreatmentfailureandinfec-

tionrelapse.• Trimethoprim-sulfamethoxazole(TMP/SMX)hasthemostpotentandreliableinvitroactiv-

ityagainstclinicalisolatesofS. maltophilia;however,drugresistancehasincreasedamong30%to40%ofdisease-associatedisolatesworldwide.

• Thenewerfluoroquinolones,suchasmoxifloxacin,showimprovedactivityagainstS. malto-philia.However,resistancehasdevelopedaftersingle-drugtherapy,whichcanbepreventedbydrugcombinationsincludingticarcillin-clavulanicacidand/orTMP/SMX.

• Carbapenems, TMP/SMX, chloramphenicol, and tetracycline are active against mostB. cepaciacomplexisolates.Treatmentpendingsusceptibilitytestingwilldependonexperi-enceoftheinstitution.

• Most active drugs against B. cepacia include minocycline (38%), meropenem (26%), andceftazidime(23%).Ceftazidime,tobramycin,andciprofloxacinretainantimicrobialactivityagainstplanktonicandbiofilm-embeddedorganisms.

PREVENTION• Nosocomialoutbreaksunderscore thecurrentpracticeofstrict infectionpreventionmea-

sures with main emphasis on decreasing transmission on health care workers’ hands andcohort segregation of infected or colonized hospitalized patients with multidrug-resistantbacteria.

• Continuedsurveillanceofhospitalwatersupplyremainscriticalinpreventingiatrogenicandhospital-relatedacquisitionofthesefreeliving,nearlyubiquitousbacteria.

• Immunization:preclinicalexperimentsusingoutermembraneprotein immunogenicepit-opesagainstB. multivoransandB. cenocepaciaappearpromising.

• Immunotherapy: various strategies to boost innate local immune response against gram-negativebacteriaarebeinginvestigated.

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154 Burkholderia pseudomallei and Burkholderia mallei:Melioidosis and GlandersBart J. Currie

DEFINITION• Melioidosis isadiseaseofhumansandanimalsresulting frominfectionwiththesoiland

waterbacteriumBurkholderia pseudomallei.• GlandersisadiseaseprimarilyofhorsesresultingfrominfectionwithBurkholderia mallei.

EPIDEMIOLOGY: MELIOIDOSIS• ThemajorendemicregionsformelioidosisareSoutheastAsiaandnorthernAustralia.• Caseshaveoccurredinothertropicalandsubtropicallocations,suchastheIndiansubcon-

tinent,China,Africa,theCaribbean,andCentralandSouthAmerica.• Mostcasesoccurduringtherainyseason,andclusterscanfollowsevereweatherevents.• Exposure occurs through percutaneous inoculation, inhalation, and ingestion (more

commonwithglanders).• Zoonoticandnosocomialinfectionsareexceedinglyrarewithmelioidosis(morecommon

withglanders).• Disease and outcomes are tightly linked to risk factors, especially diabetes (see

Table154-1).

MICROBIOLOGY• B. pseudomalleiisasmall,gram-negative,oxidase-positive,motile,aerobicbacillus.• B. malleiisasmall,gram-negative,oxidase-positive,nonmotileaerobicbacillus.• B. mallei does not persist in the environment outside its equine host, and genetic studies

suggest that B. mallei evolved in animals from the environmental pathogen B. pseudomallei.

DIAGNOSIS: MELIOIDOSIS• MostinfectionswithB. pseudomalleiareasymptomatic.• Eighty-fivepercentofcasesareacuteillnessafterrecentinfection;11%arechronicinfections

(sick more than 2 months), and activation from latency is rare (longest is 62 years afterinfection).

• Over half are bacteremic, and up to one quarter present with septic shock with highmortality.

• Presentationispneumoniainabouthalfofcases,buttherearediverseotherpresentations(seeTable154-2).

• Cultureisrequiredfordiagnosisbyusingblood,sputum,urine,pus,anditisfacilitatedbyinoculatingswabsfrompus,throat,andrectumdirectlyontoselectivemedium.

• IdentificationofB. pseudomalleiandB. malleibyvariousmethodscanbeproblematic.• LocallydevelopedantigenandDNAdetection techniquesareavailable insome locations.

Serologyhaspoorspecificitybecauseofbackgroundpositivityinendemicregions.

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ido

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 Glan

ders

TABLE 154-1  Risk Factors for Melioidosis

RISK FACTOR* THAILAND (% OF CASES) AUSTRALIA (% OF CASES)Diabetes 23-60 37

Alcohol excess 12 39

Renal disease 20-27 10

Chronic lung disease NR 27

Thalassemia 7 0

No risk factors 24-36 20

NR, not reported.Australia data from Currie BJ, Fisher DA, Howard DM, et al. Endemic melioidosis in tropical northern Australia: a

10-year prospective study and review of the literature. Clin Infect Dis. 2000;31:981-986.*Not listed: malignancy, steroid therapy, iron overload, cardiac failure.Thailand data from Punyagupta S. Melioidosis: review of 686 cases and presentation of a new clinical classifica-

tion. In: Punyagupta S, Sirisanthana T, Stapatayavong B, eds. Melioidosis. Bangkok: Bangkok Medical; 1989:217-229; Chaowagul W, White NJ, Dance DA, et al. Melioidosis: a major cause of community-acquired septicemia in northeastern Thailand. J Infect Dis. 1989;159:890-899; Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis. 1999;29:408-413; and Limmathurotsakul D, Chaowagul W, Chierakul W, et al. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis. 2006;43:979-986.

TABLE 154-2  Clinical Presentations and Outcomes of Melioidosis in Northern Australia

TOTAL BACTEREMIC NONBACTEREMIC

NumberDeaths (Mortality) Number

Deaths (Mortality) Number

Deaths (Mortality)

Septic Shock Present

116 (21%) 58 (50%) 103 48 (47%) 13 10 (77%)

Pneumonia 88 43 (49%) 78 35 (45%) 10* 8 (80%)

No evident focus 13 8 (62%) 12 7 (58%) 1† 1 (100%)

Genitourinary 10 5 (50%) 9 4 (44%) 1‡ 1 (100%)

Osteomyelitis/septic arthritis

4 2 (50%) 4 2 (50%) 0 0 (0%)

Soft tissue abscess 1 0 (0%) 0 0 1 0 (0%)

Not Septic Shock 424 (79%) 19 (4%) 195 13 (7%) 229 6 (3%)

Pneumonia 190 12 (6%) 89 9 (10%) 101 3 (3%)

Skin infection 68 0 (0%) 1 0 (0%) 67 0 (0%)

Genitourinary 66 2 (3%) 41 2 (5%) 25 0 (0%)

No evident focus 52 2 (4%) 47 2 (4%) 5 0 (0%)

Soft tissue abscess(es)

18 0 (0%) 4 0 (0%) 14 0 (0%)

Osteomyelitis/septic arthritis

16 0 (0%) 10 0 (0%) 6 0 (0%)

Neurologic 14 3 (21%) 3 0 (0%) 11 3 (27%)

Total 540 77 (14%) 298 (55%) 61 (20%) 242 (45%) 16 (7%)

*Seven blood cultures not done; three blood cultures negative.†Culture was positive for Burkholderia pseudomallei only from rectal swab, although fatal septic shock.‡Blood culture not done.From Currie BJ, Ward L, Cheng AC. The epidemiology and clinical spectrum of melioidosis: 540 cases from the

20-year Darwin prospective study. PLoS Negl Trop Dis. 2010;4:e900.

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THERAPY• Ceftazidimeoracarbapenem± trimethoprim-sulfamethoxazole(TMP-SMX) isgiven ini-

tially,followedbyTMP-SMX(seeTables154-3and154-4).• Therapyofglandersisasformelioidosis,althoughgentamicin,azithromycin,orclarithro-

mycinmayhavearole.

PREVENTION• Melioidosis:Educationisneededinendemicareasaboutminimizingexposuretowetseason

soils, surface water, and potential aerosols during windy monsoonal rains, especially fordiabetics.

• Cysticfibrosispatientsshouldconsideravoidingtraveltohigh-riskareas.• Glanders: Control of glanders in the equine species and strict precautions to prevent

laboratory-acquiredinfectionarecrucial.• Vaccinesareunderdevelopmentforbothmelioidosisandglanders.

TABLE 154-3  Antibiotic Therapy for Melioidosis

Initial Intensive Therapy (Minimum of 10-14 Days)Ceftazidime (50 mg/kg, up to 2 g) q6horMeropenem (25 mg/kg, up to 1 g) q8horImipenem (25 mg/kg, up to 1 g) q6hAny one of the three may be combined with TMP-SMX (6/30 mg/kg, up to 320/1600 mg) q12h

(recommended for neurologic, cutaneous, bone, joint, and prostatic melioidosis)

Eradication Therapy (Minimum of 3 Months)TMP-SMX (6/30 mg/kg, up to 320/1600 mg) q12h

TMP-SMX, trimethoprim-sulfamethoxazole.

TABLE 154-4  Duration of Antibiotic Therapy for Melioidosis

ANTIBIOTIC DURATION-DETERMINING FOCUS

MINIMUM INTENSIVE PHASE DURATION (WK)*

ERADICATION PHASE DURATION (MO)

Skin abscess 2 3

Bacteremia with no focus 2 3

Pneumonia Without lymphadenopathy† or ICU admission

2 3

With either lymphadenopathy† or ICU admission

4 3

Deep-seated collection‡ 4§ 3

Osteomyelitis 6 6

Central nervous system (CNS) infection 8 6

Arterial infection‖ 8§ 6

CNS, central nervous system; ICU, intensive care unit.*Clinical judgement to guide prolongation of intensive phase if improvement is slow or if blood cultures remain

positive at 7 days.†Defined as enlargement of any hilar or mediastinal lymph node to greater than 10-mm diameter.‡Defined as abscess anywhere other than skin, lungs, bone, CNS, or vasculature; septic arthritis is considered a

deep-seated collection.§Intensive phase duration is timed from date of most recent drainage or resection where culture of the drainage

specimen or resected material grew Burkholderia pseudomallei or where no specimen was sent for culture; clock is not reset if specimen is culture-negative.‖Most commonly presenting as mycotic aneurysm.

323

155 Acinetobacter SpeciesMichael Phillips

DEFINITION AND EPIDEMIOLOGY• Acinetobacterspeciesareassociatedwithspecificecologicniches.• A. baumannii and the closely related and phenotypically indistinguishable A. pittii and

A. nosocomialiscausethebulkofhumaninfectionsandaretypicallyacquiredinthehealthcaresetting.

• Acinetobacterspeciesreadilyincorporatemultipleresistancemechanisms,andpan-resistantstrainshaveemerged.

THERAPY• Antimicrobial treatment isbasedonantimicrobialsusceptibility testing.Potentialoptions,

withadultdosagefornormalrenalfunction,includethefollowing:• Cefepime,2gIVevery8hours• Imipenem,1gIVevery6hours• Meropenem,1gIVevery8hours• Ampicillin/sulbactam,3g/1.5gevery6hours(sulbactamistheactivecomponent)• Tigecycline,100mgIVloadingdose,then50mgIVevery12hours• Colistin(colistimethatesodium),5mg/kgloadingdose,then2.5mg/kgevery12hours• Polymyxin B, 2.5mg/kg on day 1, then either 2.5mg/kg daily or 1.25mg/kg every 12

hours(polymyxinB1mg=10,000units)

PREVENTION• Prevention of Acinetobacter transmission in health care settings requires a multifactorial

approach,withenvironmentaldisinfectionandhandhygieneasthecornerstone.• TheemergenceofA. baumanniistrainsresistanttoessentiallyallpotentantimicrobialagents,

coupledwithadearthofantibioticsindevelopment,constitutesasignificantpublichealththreat.

324

156  Salmonella SpeciesDavid A. Pegues and Samuel I. Miller

DEFINITION• SalmonellosisincludesgastroenteritisandotherinfectionscausedbynontyphoidalSalmonella

(NTS).

EPIDEMIOLOGY• Thereareapproximately1millioncasesofNTSinfectionannuallyintheUnitedStates.• Nontyphoidal salmonellosis isassociatedwithdiverse reservoirs, including freshandpre-

paredfooditemsandotheranimalsources.

MICROBIOLOGY• Therearemorethan2500Salmonellaserotypes.• Strains with multidrug resistance and decreased susceptibility to fluoroquinolones are

increasinglyprevalent.

DIAGNOSIS• FreshlypassedstoolshouldbeplateddirectlyonMacConkeyagarormoreselectivemedia.• Obtainbloodculturesforpatientssuspectedofbacteremiaorvascularinfection.• Serogroupingisperformedwithcommerciallyavailableantisera.

THERAPY• Antimicrobial therapy is not indicated for uncomplicated Salmonella gastroenteritis and

prolongsthedurationoffecalcarriage.• Ceftriaxoneorfluoroquinolonesshouldbeadministeredempiricallyfortreatmentofsevere

gastroenteritisorwhenoccurringinhigh-riskpatientsandfordirectedtherapyofbacteremiaorfocalinfectionswithNTS.

PREVENTION• ControloffoodborneoutbreaksofNTSdependonacoordinatedpublichealthresponseand

identificationofcontrollablehazardsfromthefarmtothetable.

325

157 Bacillary Dysentery: Shigella and Enteroinvasive Escherichia coliHerbert L. DuPont

DEFINITION• Diarrhea illnesscausedbystrainsof invasive formsofShigellaor invasiveEscherichia coli

comprisesbacillarydysentery.

EPIDEMIOLOGY• Shigellosis is the most infectious (communicable from person to person) of the bacterial

enteropathogens.

MICROBIOLOGY• Shigellaspp.aresmallgram-negativerodsinthefamilyEnterobacteriaceae.• SimilartostrainsofShigella,enteroinvasiveE. colipossessessomaticantigensandaplasmid

thatcontrolsinvasiveness.

DIAGNOSIS• Patientspassingbloodystoolsorthoseassociatedwithothercasesofshigellosisshouldhave

stoolsprocessedforShigella.• Thesoonerastoolspecimeniscultured,thehighertheyieldforShigella.• Once specimens are plated on gram-negative media at 37°C and incubated overnight,

lactose-negativecoloniesaretestedbiochemicallyandserologicallyforShigella.

THERAPY• Antibioticsareusefulinthemanagementofshigellosisandcanbelivesavingforinfection

causedbytheShigabacillus(S. dysenteriae1).• Thetreatmentofchoiceforadultsisafluoroquinoloneantibioticgivenfor3days.• Forchildren,cephalosporin,ciprofloxacin,orazithromycinmaybeused.

PREVENTION• Because person-to-person spread is so important in Shigella infection, hand washing and

otherhygienicmethodsshouldbeusedtopreventspread.• VaccinesareindevelopmenttopreventShigellainfection.

326

158 Haemophilus Species, Including H. influenzae and H. ducreyi (Chancroid)Timothy F. Murphy

DEFINITION• Gram-negativecoccobacilluswithfastidiousgrowthrequirements.• Nontypeable(nonencapsulated)Haemophilus influenzaeisacommoncauseofotitismedia

inchildrenandexacerbationsofchronicobstructivepulmonarydisease(COPD)inadults.• EncapsulatedH. influenzaetypebcausesinvasiveinfections,includingmeningitisandepi-

glottitis,inchildrenyoungerthan6years.• Haemophilus ducreyicauseschancroid,agenitalulcerdiseasethatfacilitateshumanimmu-

nodeficiencyvirustransmission.• OtherHaemophilusspeciesareunusualcausesofhumandisease.

EPIDEMIOLOGY• Theecologicnicheisthehumanrespiratorytract.• ColonizationofthenasopharynxbynontypeableH. influenzaebeginsininfancy,iscommon

duringchildhood,andpersistsatalowerrateinadults.• InvasiveH. influenzaetypebinfectionsarerareinregionsoftheworldwhereH. influenzae

typebconjugatevaccinesareusedwidelybutareprevalentinregionswherethevaccineisnotused.

• The prevalence of chancroid appears to be decreasing, based on the number of reportedcases,butthedifficultyindiagnosismayresultinunderestimatesofprevalence.

MICROBIOLOGY• ManymembersofthegenusHaemophilusarepartofthenormalbacterialfloraofthehuman

upperrespiratorytract.• Fastidiousgrowthrequirementsareusedtodistinguishthespeciesinthelaboratory.

DIAGNOSIS• Anetiologicdiagnosisofmostcommonclinicalmanifestationsofnontypeablestrains(otitis

media inchildrenandexacerbationsofCOPDinadults) isnotmaderoutinely inclinicalpractice. Rather, these infections are usually treated empirically, based on a presumptivediagnosisbyusingclinicalmanifestations.

• InvasiveinfectionscausedbyH. influenzaetypebareestablishedbyisolatingtheorganismordetectingcapsularantigenfromnormallysterilebodyfluids,includingcerebrospinalfluidorblood.

THERAPY• OtitismediaandexacerbationsofCOPDaretreatedwithoralantimicrobialagents,withthe

choicegenerallyguidedbyexpertguidelines.• H. influenzaetypebmeningitis:ceftriaxone,75to100mg/kgdividedinto12hourlydoses

orcefotaxime,200mg/kg/day,divided into sixhourlydoses.Alsoadministerdexametha-sone,0.6mg/kg/dayIVinfourdivideddosesfor4daystochildrenolderthan2months.

• Chancroid:azithromycin,1gorally(singledose)orceftriaxone,250mgIM(singledose).

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 H. in

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d H

. du

creyi (Ch

ancro

id)

PREVENTION• Allchildrenshouldreceive theH. influenzae typebconjugatevaccineseriesbeginningat

2monthsaspartofroutinechildhoodvaccination.• Incompletelyimmunizedhouseholdcontactsofcasesofmeningitisshouldreceiverifampin

prophylaxis(20mg/kgoncedaily[600mgmaximum]for4days).• Sexualcontactsofpatientswithchancroidshouldbetreated,evenifasymptomatic.

328

159  Brucellosis (Brucella Species)H. Cem Gul and Hakan Erdem

DIAGNOSIS• Brucellosis isdiagnosedbyisolationofBrucella fromblood,bonemarrow,ortissueorby

serology,althoughthepolymerasechainreactionassayisavailableinafewlaboratories.Thepreferredserologyisthetubeagglutinationtestwithatiterofatleast1:160.TheRose-Bengalcardagglutinationtestisusefulforscreening.Brucella canisrequiresaseparateserology.

MICROBIOLOGY• Brucella melitensis, Brucella suis, Brucella abortus,and,rarely,B. caniscausebrucellosisand

arenonmotilegram-negativecoccobacilli.

EPIDEMIOLOGY• AlthoughuncommonintheUnitedStates,brucellosisisaworldwidezoonosisofwildand

domesticanimals,principallycattle,swine,goats,andsheep.Infectionisacquiredbycontactwith infected animals, their tissues, or ingestion of unpasteurized milk or dairy productsfrominfectedcows,goats,andsheep.

CLINICAL SETTINGS• Fever, sweating,myalgia,weight loss,headache,andmalaisewithout localizingsymptoms

are evident. Lymphadenopathy or hepatosplenomegaly may occur. Onset can be acute orinsidiousandpersistforweeksormonthsifuntreated.

• Focal infections include osteomyelitis (particularly spondylitis or sacroiliitis), epididymo-orchitis,endocarditis,meningitis,meningoencephalitis,andmyeloradiculitis.

TREATMENT• Doxycyclinewithstreptomycin is thestandardregimen.Foralternativesand treatmentof

neurobrucellosis,seeTable159-1.

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rucella Sp

ecies)

TABLE 159-1  Treatment of Brucellosis

CLINICAL FORM PREFERRED REGIMEN ALTERNATIVE REGIMENUncomplicated Doxycycline 100 mg PO twice daily

for at least 6 wkDoxycycline 100 mg PO twice daily for at least 6 wk

plus plus

Streptomycin 1 g IM daily for 2-3 wk Gentamicin 5 mg/kg IM daily for 1 wk

or

Doxycycline 100 mg PO twice daily for at least 6 wk

plus

Rifampin 600-900 mg (15 mg/kg) once daily for at least 6 wk

Neurobrucellosis Ceftriaxone 2 mg IV twice daily for at least 1 mo

Trimethoprim-sulfamethoxazole 160/800 mg PO twice daily for 5-6 mo

plus plus

Doxycycline 100 mg PO twice daily; for 4-5 mo

Doxycycline 100 mg PO twice daily; for 5-6 mo

plus plus

Rifampin 600-900 mg (15 mg/kg) PO once daily for 4-5 mo

Rifampin 600-900 mg (15 mg/kg) PO once daily for 5-6 mo

330

160  Francisella tularensis (Tularemia)Robert L. Penn

DEFINITION• TularemiaisthezoonoticdiseasecausedbyFrancisella tularensis.

EPIDEMIOLOGY• TularemiaiswidelydistributedbutisprimarilyadiseaseoftheNorthernHemisphere.• IntheUnitedStatesthemajorityofcasesreportedin2010occurredinArkansas,Missouri,

Kansas,SouthDakota,California,andOklahoma.• TularemiapeaksinthelatespringandsummerintheUnitedStates.• Lagomorphsandrodentsareimportantanimalreservoirs.• MajorvectorsoftransmissionincludeticksandbitingfliesintheUnitedStatesandmosqui-

toesinEurope.• Other routes of transmission include aerosol droplets, contaminated mud or water, and

animalbites.• Occupations that have an increased risk for tularemia include laboratory worker, farmer,

landscaper,veterinarian,sheepworker,hunterortrapper,andcookormeathandler.• Tularemiaspreadbyaerosolisapotentialbioterroristweapon.

MICROBIOLOGY• Francisellaorganismsaresmall,aerobic,pleomorphicgram-negativecoccobacilli.• F. tularensisrequirescysteineorcystine(oranothersulfhydrylsource)forgrowthandthere-

forewillnotgrowwellonmostroutinesolidmedia.• Although thereare three species in thegenusFrancisella and fourF. tularensis subspecies

(seeTable160-1),onlyF. tularensis subsp. tularensisandF. tularensis subsp.holarcticaarerelativelycommon.

• Infections caused by F. tularensis subsp. tularensis are generally more severe than thosecausedbyF. tularensissubsp.holarctica.

• Theinfectiousdoseinhumansis10to50organismswheninjectedintradermallyorwheninhaled.

• F. tularensisisafacultativeintracellularpathogenthatsurviveswithinhostmacrophagesbyimpairingphagosome-lysosome fusion,and it is capableof suppressingoravoidingmanyotherhumoralandcellularhostdefenses.

• Recoveryfrominfectiondependsondevelopmentofhostcell-mediatedimmunity.

CLINICAL MANIFESTATIONS• Tularemiastartsabruptlywithfever,chills,headache,anorexia,andfatigueafteranaverage

incubationperiodof3to5days.• Therearesixmajorpatternsofillness:ulceroglandular(seeFig.160-1),glandular,oculoglan-

dular, pharyngeal, typhoidal, and pneumonic (see Fig. 160-2); pneumonic and typhoidaltularemiaareexpectedtobetheprimaryformsresultingfromabioterrorismevent.

• Secondaryrashesarerelativelycommon.

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laremia)

• Themostcommoncomplicationsoftularemiaarelymphnodesuppurationandpersistentdebility.

DIAGNOSIS• Diagnosisrestsonclinicalsuspicion,andbecauseofitspotentialdanger,laboratoryperson-

nelshouldbenotifiedwhenevertularemiaissuspected.• F. tularensisisaTier1selectagent,anditspossessionandshipmentaretightlyrestricted.• Routineculturesandsmearsareoftennegative,andthediagnosisisusuallyconfirmedsero-

logically;directfluorescentantibodyandpolymerasechainreactiontestsforrapiddiagnosisareavailableinspecializedlaboratories.

THERAPY• Streptomycinandgentamicinarethedrugsofchoiceforallformsoftularemiaexceptmen-

ingitis(seeTable160-2).• Selectedadultsandchildrenwithmildtomoderatediseasemaybetreatedwithoralagents

(seeTable160-2).• Surgicaltherapyislimitedtodrainageofsuppuratednodesorofempyemas.

TABLE 160-1  Characterization of Francisella Species

FEA

TUR

E

F. TULARENSIS SUBSPECIES

F. P

HIL

OM

IRA

GIA

F. H

ISPA

NIE

NSI

S

tula

ren

sis

ho

larc

tica

no

vici

da

Cysteine growth requirement + + – – –

Growth in broth plus 6% NaCl – – +* +† NA

Motility – – – – NA

Oxidase – – – +† +Nitrate reduction – – – – NA

Acid from:

Glucose +* +* +* +* + Glycerol + – + + +Gelatin hydrolysis – – – * NA

Relative virulence

Humans High Intermediate Low Low Low

Rabbits High Low Low NA NA

NA, not available; NaCl, sodium chloride.*Variable or delayed.†Using Kovacs test; negative using cytochrome-oxidase test.Data from Huber B, Escudero R, Busse HJ, et al. Description of Francisella hispaniensis sp. nov., isolated from

human blood, reclassification of Francisella novicida (Larson et al. 1955) Olsufiev et al. 1959 as Francisella tularensis subsp. novicida comb. nov. and emended description of the genus Francisella. Int J Syst Evol Microbiol. 2010;60(pt 8):1887-1896; Petersen JM, Schriefer ME, Araj GF. Francisella and Brucella. In: Versalovic J, Carroll KC, Funke G, et al, eds. Manual of Clinical Microbiology. Vol 1. 10th ed. Washington, DC: ASM Press; 2011:751-769; Sjöstedt AB. Francisella. In: Brenner DJ, Krieg NR, Staley JT, et al, eds. Bergey’s Manual of Systematic Bacteriology. Vol 2. 2nd ed. New York: Springer-Verlag; 2005:200-210; and Escudero R, Elia M, Saez-Nieto JA, et al. A possible novel Francisella genomic species isolated from blood and urine of a patient with severe illness. Clin Microbiol Infect. 2010;16:1026-1030.

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C

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laremia)

PREVENTION• The best prevention is avoiding exposure to the organism; a vaccine for tularemia is not

available.• Patientswithtularemiadonotneedspecialisolationbecauseperson-to-personspreaddoes

notoccur.Standardprecautionsforhandlingcontaminatedsecretionsareadequate.• Antibiotic prophylaxis after potential exposures of unknown risk such as tick bites is not

recommended.• Eitherciprofloxacin,500mg,ordoxycycline,100mg,givenorallytwicedailyfor14daysis

recommendedforadultswithsuspectedorprovenhigh-riskexposuretoF. tularensis.• Observation without prophylactic antibiotics is appropriate for exposed children (except

duringabioterroristevent)andforadultswithlowerriskexposures.

FIGURE  160-1 Examples of primary lesions seen in ulceroglandular tularemia. A, Large cervical and submandibular lymph nodes in a young child; an ulcer was found under the hairline on her forehead at the site of a tick bite. B, Papule undergoing central necrosis with desquamation on the thigh of a middle-aged man. C, Inguinal adenopathy and suppurative mass in a young hunter who had carried a dead hare at his side. D, Penile ulcer that was suspected of being syphilis or another sexually transmitted disease until the history of a recent tick bite was obtained by the infec-tious diseases consultant. E, Cervical ulcer and nodular adenopathy with a sporotrichoid appearance in a 6-year-old girl who had a tick removed from the area of the ulcer 2 weeks before presentation. The nodes coalesced, suppurated, and required drainage after 3 days of gentamicin therapy. Cultures of the ulcer and node drainage both grew F. tularensis. (A and C courtesy Dr. Joseph A. Bocchini, Louisiana State University Health Sciences Center, Shreveport, LA; D courtesy Dr. John W. King, Louisiana State University Health Sciences Center, Shreveport, LA; and E courtesy Dr. Robin Trotman, CoxHealth Infectious Diseases Specialty Clinic, Springfield, MO.)

FIGURE 160-2 Chest radiograph of untreated tularemia pneumonia. This patient remained symptomatic for more than 3 months. The diagnosis was established serologically when poorly developed granulomas were found in a transbronchial biopsy specimen, other causes were excluded, and the exposure history was finally obtained. (From Penn RL, Kinasewitz GT. Factors associated with a poor outcome in tularemia. Arch Intern Med. 1987;147:265-268.)

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INDICATION AND PATIENT GROUP RECOMMENDED ANTIBIOTICS AND DOSAGES

Moderate to Serious DiseaseAdults Streptomycin,* 10 mg/kg IM q12h for 7-10 days (not to

exceed 2 g/day), orGentamicin,* 5 mg/kg/day IM or IV divided q8h for 7-10 days

Children Streptomycin,* 15 mg/kg IM q12h for 7-10 days (not to exceed 2 g/day), orGentamicin,* 2.5 mg/kg IM or IV q8-12h for 7-10 days

Mild DiseaseAdults Ciprofloxacin,† 500 mg orally twice daily for 14 days, or

Doxycycline, 100 mg orally twice daily for 14 days

Children Doxycycline,‡ 2-4 mg/kg/day orally divided q12h or once daily for 14 days (not to exceed 200 mg/day)

MeningitisAdults Streptomycin or gentamicin in the doses given for moderate

to serious disease plus either chloramphenicol, 15-25 mg/kg IV q6h (not to exceed 4 g/day), or doxycycline, 100 mg IV twice daily for 14-21 days

Children Streptomycin or gentamicin in the doses for moderate to serious disease plus either chloramphenicol, 15 mg/kg IV q6h (not to exceed 4 g/day), or doxycycline, 2-4 mg/kg/day IV divided q12h or once daily (not to exceed 200 mg/day) for 14-21 days

*The streptomycin and gentamicin doses listed are for patients with normal renal function, and they need to be adjusted for renal impairment. In adults with normal renal function, once-daily administration of gentamicin also is acceptable.

†A ciprofloxacin dose of 750 mg twice daily also has been used in some reports.‡Doxycycline should be used in patients younger than 8 years of age only if the risks are outweighed by the

benefits.

335

161  Pasteurella SpeciesJohn J. Zurlo

DEFINITION• Frequentcauseofskinandsofttissueinfectionsfollowingananimalbiteorscratch• Oftenpartofamixedbacterialinfection• Complicationsincludesepticarthritisandosteomyelitis• Lessfrequentlycausespneumoniainpatientswithunderlyinglungdisease• Otherdeep-seatedcomplicationsareuncommonbutcarryhighmorbidityandmortality

EPIDEMIOLOGY• Worldwidedistribution• Principalreservoirisanimals• Infectionmostoftenoccursfollowingbitesorscratchesfromdogsandespeciallycats• Infections have been reported following bites or scratches from a large number of other

animals• Infectionsalsooccurinindividualswithanimalexposurewithoutbitesorscratches

MICROBIOLOGY• Nonmotile,facultativelyanaerobic,gram-negativecoccobacilli• Growsbestonsheepbloodandchocolateagar,notusuallyonMacConkeyagar• Somewhatfastidious• Canbedifficulttoisolatefromnonsterilespecimens,especiallysputum• P. multocida with three subspecies: multocida, septica, gallicida (least common)

(seeTable161-1)• SeveralotherrelatedspeciesofgenusPasteurellacausehumandisease

DIAGNOSIS• Progressiveskinandsofttissueinflammationfollowingananimalbiteinjury,especiallyfol-

lowingpuncturewounds• Isolation of the organism from wound/tissue culture, often as part of a mixed bacterial

infection• Sputumorpleuralfluid isolates frompatientswithunderlying lungconditionspresenting

withlowerrespiratorytractinfections

THERAPY• Treatinfectedbitewoundsempiricallywithbroad-spectrumantibioticsuntilmicrobiology

isestablished:ampicillin/sulbactam3gIVq6horpiperacillin/tazobactam3.375gIVq6h• For patients withβ-lactam allergy, use a fluoroquinolone, doxycycline, or trimethoprim/

sulfamethoxazolealongwithanaerobiccoverage(metronidazoleorclindamycin)• OncedefinedasPasteurellaspecies,penicillinistheagentofchoice• β-lactamresistanceisrare,mostlydescribedinrespiratoryisolates• Aggressivesurgicaldébridementofsofttissueinfections

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PREVENTION• Antimicrobialprophylaxisforselectedbitewounds,usuallywithamoxicillin/clavulanicacid

875mgorallytwicedailyfor5days

TABLE 161-1  Pasteurella Species

Pasteurella sensu strictoP. multocida

  Subspecies multocida

  Subspecies septicum

  Subspecies gallicida

P. canis

P. dagmatis

P. stomatis

Pasteurella-related SpeciesP. aerogenes

P. bettyae

P. caballi

P. pneumotropica

Data from Versalovic J, Carroll KC, Jorgensen JH, et al, eds. Manual of Clinical Microbiology, 10th ed. Washington, DC: ASM Press; 2011:574-587.

337

162 Yersinia Species (Including Plague)Paul S. Mead

DEFINITION• Threehumanpathogens:Yersiniaenterocolitica,Y.pseudotuberculosis,Y.pestis• Zoonoseswithmultipleanimalhosts,widespreadinenvironment• Allhavetropismforlymphnodes,butclinicalillnessandecologydiffer

EPIDEMIOLOGY• GloballydistributedbutY. pestisusuallyfoundwithindistinctecologicfoci• Y. enterocolitica, Y. pseudotuberculosis: fecal-oral transmission, enteric pathogens, more

commoninchildren,illnessoftenself-limited• Y. pestis:vectorborne,highlyinvasive,allages,frequentlyfatal,potentialbioterrorismagent

MICROBIOLOGY• Aerobic,gram-negativemembersofEnterobacteriaceae• Growthat37°ConMacConkeyagar,sheepblood(Y. pestis, Y. pseudotuberculosis), Salmonella-

Shigellamedia(Y. enterocolitica),andbrain-heartinfusion• Automatedidentificationsystemsmaymisidentify

CLINICAL MANIFESTATIONS AND DIAGNOSIS• Regionalsuppurativelymphadenitis,sepsis,orfulminantpneumoniawithplague• Bioterrorismmassexposure:fulminantpneumonia• EnteritisandpseudoappendicitiswithY. enterocolitica, Y. pseudotuberculosis• Reactivearthritisorerythemanodosummayfollowdiarrhea;HLA-B27predisposes• Cultureofblood,stool,bubo,orsputum• Acuteandconvalescentserology

THERAPY• Immediateuseofantimicrobialagents:lifesavingforplagueorYersiniabacteremia• Plague:streptomycin,1gtwicedaily;gentamicin,5mg/kgoncedaily;orlevofloxacin,500

to750mgoncedaily,preferred(seeTable162-1foroptions)• Y. enterocolitica, Y. pseudotuberculosis(aminoglycosides,tetracycline,fluoroquinolones)• Antimicrobialagentsgenerallyunnecessaryforenteritisormesentericlymphadenitis

PREVENTION• Safehandlingandpreparationofporkproducts• Avoidunpasteurizedmilkanddairyproducts• Reducerodentharborage;controlfleasonpets• Avoidcontactwithrodentsandsickanimals• Bioterrorismexposure:doxycycline100mgtwicedailyorlevofloxacin500mg,oncedaily

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TABLE 162-1  Working Group on Civilian Biodefense Recommendations for Treatment of Adult Patients with Pneumonic Plague

Contained Casualty SettingPreferred Choices

Streptomycin, 1 g IM twice daily

Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV three times daily

Alternative Choices

Doxycycline, 100 mg IV twice daily or 200 mg IV once daily*

Ciprofloxacin, 400 mg IV twice daily†

Chloramphenicol, 25 mg/kg IV four times daily

Mass Casualty Setting or Postexposure ProphylaxisPreferred Choices

Doxycycline, 100 mg orally twice daily*

Ciprofloxacin, 500 mg orally twice daily†

Alternative Choice

Chloramphenicol, 25 mg/kg orally four times daily

*Doxycycline and ciprofloxacin are pregnancy categories D and C, respectively.†Ciprofloxacin has not been approved by the U.S. Food and Drug Administration (FDA) for this indication. Since

the publication of the Working Group Recommendations, levofloxacin has been approved by FDA treatment of plague. Therefore, levofloxacin, at adult dosages of 500 to 750 mg once daily, should be considered the fluoro-quinolone of choice for treatment and prophylaxis of plague.

Modified from Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 2000;283:2281-2290.

339

163  Bordetella pertussisValerie Waters and Scott A. Halperin

DEFINITION• Pertussis,infectionwithBordetella pertussis,isdividedinthreestages:

• Catarrhal stage: rhinorrhea, nonpurulent conjunctivitis, occasional cough, low-gradefever

• Paroxysmalstage:paroxysmsorfitsofcoughing,inspiratorywhoop• Convalescentstage:graduallydiminishingcoughlastingupto8weeks

• Clinicalcasedefinition:coughgreaterthanorequalto14daysandoneormoreofthefol-lowing:paroxysmalcough,inspiratorywhoop,orpost-tussivevomiting

EPIDEMIOLOGY• With introduction of whole-cell pertussis vaccine in 1940s, pertussis rates dropped

dramatically.• Peaksofdiseasecontinuetooccurevery3to5years.• Most cases, hospitalizations, and deaths occur in unimmunized infants younger than 6

monthsofage.• Outbreaksinchildrenwithhighvaccineratesmaybepartlyduetowaningimmunityfrom

acellularpertussisvaccine.

MICROBIOLOGY• Bordetellaspeciesaresmallgram-negativecoccobacilli;growthisfastidious.• Filamentoushemagglutininandfimbriaearetwomajoradhesins.• Pertussistoxin(PT)helpsorganismevadehostdefensesandcausessystemicmanifestations;

italsoactsasanadhesin.

DIAGNOSIS• Diagnosisistraditionallymadebyculturefromnasopharyngealswabsoraspirates;specific

swabs,transportmedia,andgrowthmediashouldbeusedtoenhancerecovery.• NewerpolymerasechainreactionassaysaremoresensitivefordetectionofB. pertussisand

aretheprocedureofchoice.• AntibodiestoB. pertussisPTcanbeusedfordiagnosis.• Directfluorescentantibodyisavailablebutnotrecommended.

THERAPY• Erythromycin, 40 to 50mg/kg/day in four divided doses, is recommended for children

(maximum 2g/day) or clarithromycin, 15mg/kg/day in two divided doses (maximum1g/day)for7to14days.Azithromycinisrecommendedforinfantsyoungerthan1monthofage.Fivedaysofazithromycinisprobablyeffectivefortreatmentorprophylaxisinadults(500mg first day, then 250mg daily) and is better tolerated and has fewer serious druginteractionsthanerythromycin,500mgfourtimesdailyfor14days.

• Supportivecareisparamountinmanagementofpertussis,especiallyininfants.

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PREVENTION• Immunizationisthesinglemosteffectivemeansofpreventingpertussis.• PertussisimmunizationscheduleintheUnitedStatesandCanadaforchildrenandadoles-

cents:DTaP(diphtheriatoxoid,tetanustoxoid,acellularpertussisvaccine,pediatricformula-tion)2,4,6,and18months,withboosterat4to6years;andTdap(tetanustoxoid,diphtheriatoxoid,acellularpertussisvaccine,adultformulation[reduceddosesof“d”and“ap”compo-nents])forpreadolescents/adolescents.

• In the United States and Canada, all adults age 19 years and older are recommended toreceiveasingledoseofTdap.Theexceptionispregnantwomenwho,intheUnitedStates,arerecommendedtoreceiveTdapforeachpregnancy, ideally in the27thto36thweekofpregnancy,toprotecttheirnewbornsfrompertussis.

• AllhealthcareworkerswithpatientcontactshouldbegivenasingledoseofTdapif theyhave not been vaccinated as an adult, irrespective of when they received the last dose oftetanustoxoid.

• Prophylaxiscanbeconsideredforclosecontactsexposedwithin21daysofonsetofcoughinthe indexcase.Adultsandadolescentsaregivenerythromycin500mgfourtimesdailyfor7to14days,azithromycin500mgthefirstdayand250mgdailyfor4additionaldays,orclarithromycin500mgtwicedailyfor7days.

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164 Rat-Bite Fever: Streptobacillus moniliformis and Spirillum minusRonald G. Washburn

DEFINITION• Rat-bitefeverisanacutefebrileillnesscharacterizedbyrashandrelapsingfever.

EPIDEMIOLOGY• The infection is transmittedbybitesor scratches fromrodentsorcarnivores thatpreyon

rodentsorbyingestionofcontaminatedmilkorwater.Rat-bitefeverisnotgenerallyreport-able,andtheincidenceisprobablyhigherthantheliteraturereflects.

MICROBIOLOGY• In the United States and Europe, rat-bite fever is caused by Streptobacillus moniliformis,

a fastidious gram-negative bacillus. In Asia, the causative organism is Spirillum minus, aspirochetethathasneverbeengrowninculture.

DIAGNOSIS• S. moniliformisisdiagnosedbyclinicalpresentationpluscultureinenrichedmediaorpoly-

merasechainreaction.S. minusisdiagnosedbyclinicalpresentationplusdirectvisualizationorxenodiagnosis.

THERAPY• Penicillinisthetreatmentofchoiceforbothtypesofrat-bitefever.

PREVENTION• Preventivemeasuresincludeeradicationofrats,avoidanceofnonpasteurizedmilkandwater,

anduseofglovesbylaboratoryworkerswhenhandlingrats.

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165 Legionnaires’ Disease and Pontiac FeverPaul H. Edelstein and Craig R. Roy

DEFINITION• Legionnaires’diseaseisanoncontagioustypeofbacterialpneumoniacausedbyLegionella

spp.bacteria,mostcommonlyL. pneumophila.• Pontiacfeverisaseveralday–long,nonpneumonic,febrile,influenza-likeillnessassociated

withexposuretoLegionellaspp.thatresolvesspontaneously.• Legionellosis includesLegionnaires’disease,Pontiac fever, andextrapulmonaryLegionella

spp.infectionnotassociatedwithpneumonia.

EPIDEMIOLOGY• Legionnaires’diseaseisacquiredbyinhalingawateraerosolcontainingLegionellaspp.bac-

teria,andpossiblybymicroaspiratingLegionellaspp.–containingwater.• About 20 to 80 cases annually per million population occur in most developed coun-

tries, with the elderly, males, cigarette smokers, and immunosuppressed patients mostatrisk.

• About 1% to 5% of patients hospitalized for community-acquired pneumonia haveLegionnaires’disease.

• PontiacfeverisassociatedwithinhalationofLegionellaspp.–containingwaterbutnotneces-sarilycausedbythebacterium.Itoccursinsporadicandepidemicformatapparentlylowincidencebutmaybemorecommonthanisreported.

MICROBIOLOGY• Constituted of more than 58 known species, the Legionella bacteria are ubiquitous in the

aqueousenvironmentandprobablymoistsoils.• Optimalbacterialgrowthrequiresspecializedmediathatcontaincysteineandiron.• Thebacteriaarefacultativeintracellularparasitesoffree-livingamebasandhumanmono-

cytesandmacrophagesthatusehostlikeproteinstomasqueradeashostandtoavailthem-selvesofintracellularresources.

DIAGNOSIS• ClinicalandroentgenographicdifferentiationofLegionnaires’diseasefromcommoncauses

ofpneumoniaisnotgenerallypossible.• Specific and specialized laboratory testing can be helpful for disease diagnosis but is

not highly sensitive in all settings. Urine antigen testing, the most commonly used test,is about 70% and 30% sensitive in community-acquired and nosocomial disease,respectively.

THERAPY• Macrolides,tetracyclines,andquinoloneantimicrobialscanallbeusedtosuccessfullytreat

thedisease,withazithromycinandlevofloxacinbeingthemostactive.

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• Forcure,3to14days’therapyisrequired,dependingondiseaseseverity,hostfactors,andtypeoftherapyused.

PREVENTION• Novaccineisavailable.• Properenvironmentaldesignandmaintenancereducediseaserisk.

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166  CapnocytophagaJ. Michael Janda

DEFINITION• Endogenousorzoonotic-associatedinfectionshavebeenreported,dependingonthespecies

ofCapnocytophagainvolved.• Symptomsrangefromsepsis(mostoften)withandwithoutcentralnervoussysteminvolve-

menttooculardisease,illnessesassociatedwithpregnancy,andthoseinvolvingbone,joints,andsofttissues.

EPIDEMIOLOGY• Endogenous infections arise in children or adults with blood dyscrasias and significant

neutropenia.• Sepsis arises fromhumanspecies seeding into thecirculatory system throughabradedor

damagedgumsorgingivalpocketsintheoralcavity.• Mortalityrateislow(<5%)withappropriatetreatment.• Zoonotic infections arise primarily in males from a dog bite or intimate contact with

dogs.• Persons most at risk include dog owners, breeders, veterinarians, kennel workers, or

hunters.• Individualsathighest risk fordeveloping serious life-threatening infectionswithdissemi-

nated intravascular coagulation include splenectomized persons or functionally asplenicpatientsandthosewithethanolabuseorimmunosuppression.

• Reportedmortalityratesrangefrom20%to33%.

MICROBIOLOGY• Bacilliaregramnegativewithtaperedends.• Theyare slowgrowingand fastidious, requiring3 to10daysof incubationonsupportive

media.• Nostandardizedmethodofdeterminingdrugsusceptibilitiesexists,but testingshouldbe

attempted,ifpossible.

DIAGNOSIS• IshistorycompatiblewithCapnocytophagainfection(dogbite)?• DoesGramorWright-Giemsastainofbloodorother sterile specimensshowbacilliwith

taperedendssometimeswithinpolymorphonuclearleukocytes?• Conventional tests that include catalase, oxidase, and arginine dihydrolase are slow but

reliable.• Rapidmoleculartestsinclude16SrRNAgenesequencingforrapiddiagnosisonspecimens

oridentificationofisolatedorganismsandmatrix-assistedlaserdesorption/ionizationtime-of-flight(MALDI-TOF)massspectrometryforfutureorganismcharacterization.

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THERAPY• Infectionisbroadlysusceptibletomanyantimicrobialagents.• Penicillin/β-lactamaseinhibitorcombinationorextended-spectrumcephalosporinisdrug

offirstchoice.• Acquireddrugresistancehasbeenreportedinsomeisolates.

PREVENTION• Cliniciansmustbemadeawareoftheseorganisms,thediseasestheycause,andthepatients

atrisk.• Laboratoriesmayrequireextra incubationtime,aspecializedincubationatmosphere,and

richermediatoisolatetheseorganisms.• Userapidtestingmethodstodecreasetimetodiagnosis.

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167 Bartonella, Including Cat-Scratch DiseaseTejal N. Gandhi, Leonard N. Slater, David F. Welch, and Jane E. Koehler

EPIDEMIOLOGY AND MICROBIOLOGY• Fastidious,facultativelyintracellular,pleomorphicgram-negativebacilli• Transmissionviafecesofarthropodvectorsorbydirectinoculationintononintactskin• Bartonella bacilliformis: endemic only in the Andes mountains; reservoir—humans, and

possibly,ananimalreservoir• Bartonella henselae: globally endemic; reservoir—cats; vector—cat flea; transmitted to

humansusuallyviacatscratch• Bartonella quintana:sporadicoutbreaksworldwide;associatedwithhomelessnessandother

conditionsofpoorsanitation;reservoir—humans;vector—humanbodylouse

CLINICAL FEATURES• Chronicbloodstreaminfections(formonths)isahallmarkofBartonellainfections• B. bacilliformis:biphasicillness;Oroyafever(acutephase)characterizedbyfever,hemolytic

anemia,andhigh fatalityratewhenuntreated;verrugaperuana(latephase)characterizedbycropsofangioproliferativeskinlesionswithanevolutionofstages

• B. henselae:cat-scratchdisease(CSD):self-limitedregionallymphadenopathy• B. henselae:bacillaryangiomatosis(BA):vascularproliferativedisorderobservedinpatients

withadvancedhumanimmunodeficiencyvirus(HIV)infectionandotherimmunocompro-misingconditions;cutaneousBA,hepatic,andsplenicbacillarypeliosis(BP)

• B. henselae:bloodculture–negativeendocarditis,usuallyinpatientswithpreexistingvalvularlesions

• B. henselae:causeoffeverofunknownorigin(FUO)inimmunocompetentchildren,andinimmunocompromisedpatients(HIV-infectedandtransplantrecipients)

• B. quintana:trenchfever:usuallyaself-limitedfebrileillness• B. quintana:bloodculture–negativeendocarditis;canoccur inpatientswithnormalheart

valves• B. quintana:bacillaryangiomatosis(cutaneous,subcutaneous,osseous)• B. quintana:causeofFUOinHIV-infectedpatients

DIAGNOSIS• Difficulttoculture• Serology:mainstayfordiagnosis,butcross-reactivityamongBartonellaspeciescommon• Histopathology:CSD—granulomatousinflammation;BA—vascularproliferation;Warthin-

StarryorSteinerstaindemonstratesBartonellabacilliintissue• Polymerasechainreactiontestingontissueorblood

THERAPY• CSD:notreatment(self-limited);possiblyazithromycinforsevereCSD• Endocarditis:doxycyclinefor6weeksandgentamicinforfirst2weeks;renalinsufficiency

commoninBartonellaendocarditis,thusrifampincanbesubstitutedforgentamicininthesettingofrenalinsufficiency

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• Bacteremia:doxycyclinefor4weeksandgentamicinforfirst2weeks• BA/BP:doxycycline isfirst choiceanderythromycinorazithromycin is secondchoice; in

HIV-infectedandtransplantrecipients,doxycyclineispreferredduetotolerabilityissuesanddrug-drug interaction potential with erythromycin; duration of 3 months or longer forcutaneousdiseaseand6monthsor longerforsevereBartonella infection(e.g.,BP,centralnervoussystem)

• Neuroretinitis:doxycyclineandrifampinfor4to6weeks

PREVENTION• Avoidarthropodvectors;eradicatebodylicetoreduceriskofB. quintana• Avoidcatscratches,bites,licks,andcatfleastoreduceriskofB. henselae;controlofcatflea

infestationisimportant

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168 Klebsiella granulomatis (Donovanosis, Granuloma Inguinale)Ronald C. Ballard

DEFINITION• Donovanosisisanulcerativesexuallytransmittedinfectioncausedbyanintracellularbac-

terium,Klebsiella granulomatis.

EPIDEMIOLOGY• Donovanosisislargelyconfinedtodiscretegeographicareasofthetropics.• Donovanosisissexuallytransmittedbutoflowinfectivity.

MICROBIOLOGY• Klebsiella granulomatisisagram-negative,encapsulated,intracellularbacteriumexhibiting

bipolardensities.

DIAGNOSIS• For microscopic examination, biopsies or smears are obtained from the margin of active

lesionsfor“Donovanbodies.”

THERAPY• Thetreatmentofchoiceisazithromycin,1gweeklyforupto4to6weeks.• Treatmentshouldbecontinueduntilcompleteepithelializationhasoccurred.

349

169 Other Gram-Negative and Gram-Variable BacilliJames P. Steinberg and Eileen M. Burd

SHORT VIEW SUMMARYDefinition• Gram-negative and gram-variable aerobic bacilli that are less commonly encountered as

causesofinfectionandarenotdiscussedinotherchaptersareconsideredhere.• Thetaxonomyofmanyoftheseorganismshasbeenandcontinuestobeinastateofflux.• The organisms considered are broadly divided into those that ferment glucose and

those that weakly ferment or do not ferment glucose. Specific genera considered includeAggregatibacter, Aeromonas, Cardiobacterium, Chromobacterium, Dysgonomonas, Plesiomo­nas, Achromobacter, Alcaligenes, Chryseobacterium, Elizabethkingia, Comamonas, Delftia, Eikenella, Flavobacterium, Myroides, Ochrobactrum, Oligella, lesscommonspeciesofPseu­domonas, Ralstonia, Cupriavidus, Rhizobium, Roseomonas, Shewanella, Sphingobacterium, Sphingomonas, Bergeyella, Weeksella, Gardnerella, Mobiluncus,uncommonNeisseriaspecies,and Centers for Disease Control and Prevention Groups NO-1, WO-1, WO-2, O-1, O-2,andO-3.

Epidemiology• Someofthesegram-negativebacilliareubiquitousintheenvironment.• Manyaregenerallyconsideredtobeoflowvirulencebutmaybeopportunisticpathogens

undercertaincircumstances.• Some infections have been linked to hospital sources, particularly unclean water sources,

nonsterileenvironmentalsurfaces,orcontaminatedsolutions.

Microbiology• Manyoftheseorganismsarefastidiousanddifficulttogrow.• Identificationofglucosenonfermentinggram-negativebacilliposesachallengetoclinical

laboratories because conventional biochemical systems frequently fail to provide accurateidentification.Accurateidentification,especiallytospecieslevel,oftenrequirescellwallfattyacid analysis, 16S rRNA gene sequencing–based technologies, or matrix-assisted laserdesorption/ionization-timeofflightmassspectrometry.

Diagnosis• The types of infections caused by these organisms are quite varied and are diagnosed by

analysisofculturesofsamplestakenfromtheinfectionsite.• Becausetheseorganismsareinfrequentlyencounteredandareoftenoflowvirulence,inter-

pretationofcultureresultsmustbecorrelatedwithclinicalfindings.

Therapy• Thesmallnumberofpatientsreportedandthevarietyofantibioticregimensuseddonot

permitidentificationoftheoptimaltherapeuticregimenformostoftheseorganisms.

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• MethodsforantibioticsusceptibilitytestingformanyoftheseorganismsarenotstandardizedandClinicalandLaboratoryStandardsInstitutebreakpointsforinterpretationmaynotbeavailable.

• Someoftheenvironmentalbacteriaareofconcernbecausetheycarryresistancegenesontransferablegeneticelementsandcouldserveasreservoirsofresistancegeneswhenintro-ducedintotheclinicalsetting.

• Someof these infectionsmaybedifficult toeradicatewhenthecausativebacteriaexist inwell-developedbiofilms.

Prevention• Attentionshouldbegiven topractices topreventdevice-related infections,particularly in

immunocompromisedindividuals.• Hospital-basedprogramsofsurveillanceandmethodsforpreventionandcontroltoelimi-

natehealthcare–associatedinfectionsshouldbeimplemented.

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170  Syphilis (Treponema pallidum)Justin D. Radolf, Edmund C. Tramont, and Juan C. Salazar

DEFINITION• Syphilis is a chronic, multistage sexually transmitted disease caused by the spirochete

Treponema pallidum.

EPIDEMIOLOGY• AccordingtotheWorldHealthOrganization,11millionnewcasesofvenerealsyphilisoccur

globallyeachyear.• Globally,1.5millionpregnantwomenareestimatedtobeinfectedeachyear;approximately

one third of these infections will result in stillbirths or other adverse outcomes ofpregnancy.

• Indevelopingcountries,transmissionislargelyheterosexual,whiletransmissionamongmenwhohavesexwithmenpredominatesinindustrializednations.

• Genitalulcerscausedbysyphilisareamajorcofactorforbidirectionaltransmissionofhumanimmunodeficiencyvirus(HIV).

MICROBIOLOGY• T. pallidumsubspeciespallidum, pertenue,andendemicumcausevenerealsyphilis,yaws,and

endemicsyphilis,respectively.Treponema carateumcausespinta.• Allpathogenictreponemesarenoncultivableandindistinguishablebyroutineclinicallabo-

ratorytests.• HumansaretheonlynaturalhostsforT. pallidumsubsp.pallidum.• T. pallidumpossessesbothinnerandoutermembranes;itsoutermembranelackslipopoly-

saccharideandcontainsapaucityofintegralmembraneproteinsandsurface-exposedlipo-proteins,henceitsdesignationas“thestealthpathogen.”

• T. pallidummustacquireessentiallyallnutrientsfromitsobligatehumanhostandgeneratesadenosinetriphosphateprimarilybyglycolysis.

• T. pallidumdisseminatesearlyduringthecourseofinfectionandinvadesthecentralnervoussysteminasubstantialpercentageofpersonswithearlysyphilis.

DIAGNOSIS• BecauseT. pallidum cannotbecultivated invitro,diagnosisof syphilisdependsondirect

demonstrationoftreponemesinclinicalsamplesorreactivityinserologictests,orboth.• Darkfieldmicroscopyandpolymerasechainreactionareusefulfordetectingtreponemesin

exudativelesions,principallychancres.• Serodiagnosisofsyphilisinvolvestwotypesofserologictests:nontreponemalandtrepone-

mal.Theformerdetectsantibodiesagainstlipoidalantigens(primarilycardiolipin),whereasthelatterdetectsantibodiesagainstT. pallidumproteins.

• Nontreponemalantibodytestsareusedasindicatorsofdiseaseactivity;nontreponemaltiterstendtodeclinewiththerapy.Treponemaltestsremainreactiveforlife.

• Treponemaltestsareusedtoconfirmthatreactivityinnontreponemaltestsisduetosyphilisasopposedtobeingabiologicfalsepositive.

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THERAPY• PenicillinGisthepreferredformoftherapyforallstagesandtypesofinfection.• 2.4 million units of IM benzathine penicillin is the Centers for Disease Control and

Prevention–recommendedregimenforearlysyphilisregardlessofHIVstatus.• Doxycyclineisthepreferredalternativefornonpregnant,penicillin-allergicpatients.• Penicillin-allergicpregnantfemalesshouldbedesensitized.

PREVENTION• Prophylactic treatment is indicatedforpartnersexposedtoknownactivecaseswithinthe

past90daysregardlessofwhetherlesionsarepresentorserologiesarereactive.• Earlyidentificationandtreatmentofgestationalsyphilispreventscongenitalinfection.

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171  Endemic TreponematosesEdward W. Hook III

DEFINITION• Theendemictreponematosesincludeyaws,endemicsyphilis,andpinta.Allarecutaneous

diseasesmostcommoninchildrenandcausedbytreponemescloselyrelatedtoTreponema pallidum,thecausativeagentofsyphilis.

EPIDEMIOLOGY• Theendemictreponematosesarespreadonlyfromhumantohumanbydirectcontact.The

infectionsaremostcommoninchildrenbutifuntreatedmayprogresstocausechronicskinandbonedisease.Overthepast2decades,yawsrateshaveincreasedworldwide.Endemicsyphilisandpintaremainveryuncommon.

MICROBIOLOGY• Thetreponemalspeciesthatcausetheendemictreponematosescannotbeeasilyculturedfor

diagnosis.Microbiologicdiagnosisismostoftenbasedonnontreponemalandtreponemalserologicreactivityintestsdesignedforsyphilisdiagnosis.

DIAGNOSIS• Thediagnosisofendemictreponematosesisbasedonclinicalrecognitionofcompatibleskin

lesions,confirmedbyserologictesting.

THERAPY• Untilrecently,benzathinepenicillinwasthemainstayoftherapyoftheendemictreponema-

toses.Recently,azithromycinhasbeenprovenasaneasy-to-administeralternativetopenicil-lininjectionsfortherapyofyaws.

PREVENTION• Yawsappearstobeamenabletomasstherapyasacontrolandpreventionmeasure.In2012,

the World Health Organization announced plans to embark on mass therapy initiativesdesignedtoeliminateyawsby2020.

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172  Leptospira Species (Leptospirosis)David A. Haake and Paul N. Levett

DEFINITION• LeptospirosisiscausedbyinfectionwithpathogenicspirochetesofthegenusLeptospira.

EPIDEMIOLOGY• Leptospirosisisazoonosisofglobaldistribution.• Leptospirosisismaintainedinnaturebychronicrenalinfectionofcarrieranimals,especially

rodents.• Infections typicallyoccur followingoccupationalorrecreationalexposure towaterorsoil

contaminatedwithrodenturine.• Indevelopingcountrieswithpoorhousingstandards,leptospirosisoutbreaksoccurregularly

inurbansettingsafterheavyrainfallandflooding.

MICROBIOLOGY• Twenty-onenamed leptospiral specieshavebeendescribed,ofwhich11areknown tobe

pathogenic(seeTable172-1).

DIAGNOSIS• Clinicaldiagnosisrequiresahighindexofsuspicionbasedonepidemiologicexposure.• Serologictestsarehelpfulwhenpositivebutmayhavepoorsensitivityduringthefirstweek

ofillness.• Thesignsandsymptomsofearlyleptospirosisarenonspecific.

THERAPY• Antibiotictherapy(seeTable172-2)shouldbeinitiatedasearlyinthecourseofthedisease

assuspicionallows.Formilddisease,doxycycline,amoxicillin,ororalampicillinisrecom-mended.Formoreseveredisease,intravenousceftriaxone,ampicillin,orpenicillinisused.

• Patientswithearlyrenaldiseasewithhigh-outputrenaldysfunctionandhypokalemiashouldreceiveaggressivevolumerepletionandpotassiumsupplementation.

• Patientswhoprogresstooliguricrenalfailureshouldundergorapidinitiationofhemodialy-sisorperitonealdialysis,whichistypicallyrequiredononlyashort-termbasis.

PREVENTION• Themosteffectivepreventivestrategy is toreducedirectcontactwithpotentially infected

animalsandindirectcontactwithurine-contaminatedsoilandwater.• Chemoprophylaxiswithdoxycycline200mgonceaweekisrecommendedfor individuals

whowillbeunavoidablyexposedtoendemicenvironments.

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TABLE 172-1  Species of Leptospira and Some Pathogenic Serovars

SPECIES SELECTED PATHOGENIC SEROVARSL. interrogans Icterohaemorrhagiae, Copenhageni, Canicola, Pomona,

Australis, Autumnalis, Pyrogenes, Bratislava, Lai

L. noguchii Panama, Pomona

L. borgpetersenii Ballum, Hardjo, Javanica

L. santarosai Bataviae

L. kirschneri Bim, Bulgarica, Grippotyphosa, Cynopteri

L. weilii Celledoni, Sarmin

L. alexanderi Manhao 3

L. alstonii Sichuan

L. meyeri Sofia

L. wolffii Khorat

L. kmetyi Manilae

L. wolbachii Nonpathogen

L. biflexa Nonpathogen

L. vanthielii Nonpathogen

L. terpstrae Nonpathogen

L. yanagawae Nonpathogen

L. idonii Nonpathogen

L. inadai Indeterminate

L. fainei Indeterminate

L. broomii Indeterminate

L. licerasiae Indeterminate

TABLE 172-2  Antimicrobial Agents Recommended for Treatment and Chemoprophylaxis of Leptospirosis

INDICATION COMPOUND DOSAGEChemoprophylaxis Doxycycline 200 mg PO orally once per week

Treatment of mild leptospirosis Doxycycline 100 mg bid PO

Ampicillin 500-750 mg q6h PO

Amoxicillin 500 mg q6h PO

Treatment of moderate to severe leptospirosis

Penicillin 1.5 MU IV q6h

Ceftriaxone 1 g IV q24h

Ampicillin 0.5-1 g IV q6h

356

173 Relapsing Fever Caused by Borrelia SpeciesJames M. Horton

DEFINITION• RelapsingfeveriscausedbyspirochetesoftheBorreliagenus.• Theillnessischaracterizedbyrelapsingfeverswithspirochetesevidentonabloodsmear.

ORGANISM• Borrelia species are divided between B. burgdorferi, which causes Lyme disease, and the

Borreliaspeciesthatcauserelapsingfever.• Therelapsingfeverspeciesaredividedbetweenthelouse-borneandtick-bornespecies.

EPIDEMIOLOGY• Tick-bornerelapsingfeveroccursonalmosteverycontinent,butintheUnitedStatesit is

endemicintheRockyMountains.

PATHOPHYSIOLOGY• The spirochete changes surface antigens about every 7 days, causing the cyclic, relapsing

fever.

CLINICAL MANIFESTATIONS• The patient presents with fever for 3 days alternating with afebrile periods lasting about

7days.

DIAGNOSIS• Spirochetescanbeseenontheperipheralbloodsmearduringfebrileperiods.

THERAPY• Doxycyclineorpenicilliniseffectivetreatment.• Jarisch-Herxheimerreactionsarecommon,andthepatientshouldbeobservedinaclinic

orhospitalforabout3hoursafterstartingantibiotictherapy.

PREVENTION• Postexposuretherapywithdoxycyclineispreventive.

357

174 Lyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferiAllen C. Steere

DEFINITION• Atick-borneinfectioncausedbythespirocheteBorrelia burgdorferisensulatoleadingtoa

multisystemillnessprimarilyintheskin,joints,nervoussystem,heart,oracombinationofthese.

EPIDEMIOLOGY• The vectors of Lyme disease are 14 closely related ixodid tick species that are part of the

Ixodes ricinuscomplex.• ThediseaseoccursinpartsofNorthAmerica,Europe,andAsia.• Thedisorder in theUnitedStatesoccursprimarily in threedistinct foci: in theNortheast

fromMainetoNorthCarolina;intheMidwestinWisconsin,Minnesota,andMichigan;andintheWest,primarilyinnorthernCalifornia.

• Thepeakonsetofearlyinfectionisinthesummermonths.• About30,000casesarereportedyearlyintheUnitedStates,mostlyfromthenortheastern

UnitedStates.

MICROBIOLOGY• ThegenusBorreliacurrentlyincludes13closelyrelatedspeciesknowncollectivelyasBorrelia

burgdorferisensulato(B. burgdorferiinthegeneralsense).• Thehumaninfectioniscausedprimarilybythreepathogenicspecies:B. burgdorferisensu

stricto (B. burgdorferi in the strict sense) is the sole cause in the United States, whereasBorrelia afzeliiandBorrelia gariniiaretheprimarycausesoftheinfectioninEurope.

DIAGNOSIS• CultureofB. burgdorferiinBarbour-Stoenner-Kelly(BSK)mediumpermitsdefinitivediag-

nosisbuthasbeenpossiblereliablyonlyfrombiopsiesoferythemamigransskinlesions,anearlydiseasemanifestation.

• DiagnosisisusuallybasedoncharacteristicclinicalfindingsandapositiveIgGserologictestresult,usingatwo-testapproachofenzyme-linkedimmunosorbentassayandWesternblot.

THERAPY• Forearly infection,appropriateoralantibiotic therapy (usuallydoxycycline,100mg twice

dailyoramoxicillin,500mgthreetimesdaily)for14to21daysisusuallysuccessful.• Forneurologicinvolvementorsomecasesofarthritis,intravenousantibiotictherapy(often

ceftriaxone,2gdaily)for28daysmaybenecessary.

PREVENTION• Personalprotectionmethodstoavoidtickbitesandtickchecksafterexposureinendemic

areasarethemajorpreventionstrategies.• AvaccineforLymediseaseconsistingofrecombinantOspAwithadjuvantwasshowntobe

safeandeffective,butthevaccineisnotnowavailable.

358

175  Clostridium difficile InfectionDale N. Gerding and Vincent B. Young

DEFINITION• Clostridium difficileinfection(CDI)isacutediarrheaandcolitisthatismostoftenpreceded

by antimicrobial use and is caused by an anaerobic spore-forming, toxin-producingbacterium.

EPIDEMIOLOGY• C. difficileisfoundinwater,soil,meats,andvegetablesandisparticularlycommoninhealth

careenvironments,wherethesporesaredifficult toeradicate.Patientsareexposedtoandingest C. difficile spores in the health care setting from contact with the environment orhealthcareworkerswhodonotpracticegoodhandhygiene.

• Ifthepatienthastakenantibioticsrecently,thenormalmicrobiotaislikelytobedisrupted;andinthisdisruptedmicrobiota,theingestedspores,whichareresistanttostomachacid,cangerminateandproliferateinthecolon,producingtwomajortoxins:TcdAandTcdB.

• Thetwotoxinsproduceamarkedneutrophilicinflammatoryresponseinthecolon,resultingin diarrhea, erosion of the mucosa, and formation of pseudomembranes composed ofnecroticcellsandproteinaceousmaterialthatextendoverthemucosalsurface.

• Recurrenceofdiarrheaaftertreatmentoccursin25%ofpatientsandrequiresre-treatment.

MICROBIOLOGY• C. difficileisanobligategram-positiveanaerobicbacteriumthatcansurviveinenvironments

underaerobicconditionsbyformingspores.• ThemajorityofstrainsproducebothtoxinsAandB.Athirdtoxin,binarytoxin,isproduced

by recent epidemic strains that have caused outbreaks with increased severity andmortality.

• SomestrainsofC. difficilelackthegenesfortoxinproductionandarenontoxigenicandnotbelievedtocauseCDI.

DIAGNOSIS• DiagnosisofCDI isbasedon thepresenceofclinical symptoms(usuallydefinedasmore

thanthreewatery,looseorunformedstoolswithin≤24hours)coupledwithadiagnostictest(usuallyofastoolspecimen)thateitherdetectsthepresenceoftheC. difficileorganismoritstoxingenesordetectsC. difficiletoxinusinganenzymeimmunoassayorcellcytotoxinassay.

THERAPY• Thefirststepsineffectivetreatmentaretostopanytherapywiththeoffendingantibioticand

providefluidandelectrolytesupport,ifneeded.• Specific treatment consists of metronidazole or vancomycin orally for mild-to-moderate

disease,vancomycinorallyforseveredisease(whitebloodcellcount>15,000/mLorcreati-nineconcentration>1.5timesbaseline),andvancomycinorallyorbynasogastrictubeplus

359C

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stridiu

m d

ifficile In

fection

intravenousmetronidazoleforseverecomplicated(alsocalledfulminant)CDIthatpresentsashypotension,shock,ileus,ormegacolon.

• Patients with recurrent CDI may benefit from fidaxomicin treatment, and multiple CDIrecurrencesareeffectivelytreatedbyfecalmicrobiotatransplant(FMT).

PREVENTION• Prevention in the health care environment is focused on preventing patient exposure to

sporesofC. difficilebyutilizingisolation,cohorting,glovesandgowns,andhandwashing(alcoholrubsareineffectiveagainstspores).Bleachisusedintheenvironmenttoeradicatespores.

• Itisexceedinglydifficulttopreventsporeexposure,soantimicrobialstewardshipprogramstoreduceunnecessaryantimicrobialuseareextremelyeffective in limitingthenumberofsusceptiblepatients.

• A number of new preventive approaches are undergoing clinical investigation, includingvaccinestoinduceantibodiestotoxinsAandB,monoclonalantibodiestoprovidepassiveimmunity,andbiotherapeutics thatare livebacterialorganismssuchasFMTorsporesofnontoxigenicC. difficile.

360

176  Tetanus (Clostridium tetani)Aimee Hodowanec and Thomas P. Bleck

DEFINITION• Tetanus is a nervous system disease caused by a toxin (tetanospasmin) produced by

Clostridium tetani.• Tetanusisdividedintofourclinicaltypes:generalized, localized, cephalic,andneonatal.

EPIDEMIOLOGY• Acuteinjuryandinjectiondruguseareriskfactorsfortetanus.• Tetanusisrareindevelopedcountriesduetotheavailabilityofeffectivevaccines.• Indevelopingcountries,neonataltetanuscanoccurwhenthereisfailureofaseptictechnique

andmothersareinadequatelyimmunized.• IntheUnitedStates, tetanusismorecommoninpeopleolderthan60years, likelydueto

waningimmunity.

MICROBIOLOGY• C. tetaniisanobligatelyanaerobicbacillus.• Tetanusproducestwotoxins:tetanospasminandtetanolysin.• Itdevelopsaterminalsporethatisextremelystableintheenvironment,retainingtheability

togerminateandcausediseaseindefinitely.

DIAGNOSIS• Diagnosisoftetanusreliesonhistoryandexaminationfindings.• CulturingC. tetaniisdifficultandnothelpful.

THERAPY• Theairwaymustbesecuredatthetimeofpresentation.• Benzodiazepinesprovidethemainstayofsymptomatictherapy.• Passive immunizationwithhumantetanus immuneglobulin(HTIG)shortens thedisease

courseandmaylessendiseaseseverity.• Antibiotictherapywithmetronidazole(Flagyl)mayimproveoutcomes.

PREVENTION• AllchildrenshouldbevaccinatedagainsttetanusthroughDTaPvaccineseries.• Adultsshouldreceiveatetanusbooster(Td)every10years.OneoftheTddosesshouldbe

replacedwithTdap.• Woundmanagementofminor,cleanwoundsshouldincludecompletionoftetanusimmu-

nizationifincomplete,oraboosterdoseofvaccine(Td),ifthelastdosewasgivenmorethan10yearsbefore.PatientswithseriouscontaminatedwoundsshouldalsoreceiveHTIG.

361

177  Botulism (Clostridium botulinum)Aimee Hodowanec and Thomas P. Bleck

DEFINITION• Botulismisatoxin-mediatedparalyticillnesscausedbyClostridium botulinum.Itisclassified

asfoodbornebotulism,infantbotulism,woundbotulism,iatrogenicbotulism,botulismofundeterminedetiology,orinhalationalbotulism.

EPIDEMIOLOGY• Foodbornebotulismoccursinoutbreaks,whereasotherformsaresporadic.• Foodbornebotulismisassociatedwithhome-cannedorfermentedfoods.• Infantbotulismhistoricallyisassociatedwithhoneyingestion.• Woundbotulismisassociatedwithinjectiondruguseof“black-tar”heroin.• BotulinumtoxinsAandBareusedfortherapeuticandcosmeticpurposesandmaycause

iatrogenicbotulism.• Botulismisapotentialbioterrorismagentdeployedbyaerosoloringestion.

MICROBIOLOGY• C. botulinumisagram-positive,strictlyanaerobicbacillusthatformsasubterminalspore.• C. botulinumproducessevendistincttoxins,designatedtypesAthroughG.

DIAGNOSIS• Presumptivediagnosisbasedonclinicalpresentation:acute,bilateralcranialneuropathies

withsymmetricaldescendingweakness.• Mousebioassayisthegoldstandardforbotulinumtoxin.• Cultureofserum,stool,andenvironmentalsamplesrequiresstrictanaerobicconditionsand

islowyield.• Characteristicelectrophysiologicstudyfindingsaresuggestiveofbotulism.

THERAPY• Supportivecareremainsthemainstayofbotulismtreatment.• HeptavalentbotulinumantitoxinisavailablefornoninfantbotulismintheUnitedStates.• Human botulinum immune globulin (BabyBIG) is available for the treatment of

infant (younger than 1 year) botulism. To obtain, contact the California Department ofHealth Services, Infant Botulism Treatment and Prevention Program (510-540-2646;www.infantbotulism.org).

PREVENTION• Properfoodpreparationpreventsfoodbornebotulism.• Thereisnocurrentlyavailablevaccine.

362

178 Gas Gangrene and Other Clostridium-Associated DiseasesAndrew B. Onderdonk and Wendy S. Garrett

CHARACTERISTICS OF CLOSTRIDIUM SPP.• MemberofthephylumFirmicutes• Anaerobicgram-positiverodscapableofformingendospores• Ubiquitousinnature• Phenotypic classification methods include carbohydrate fermentation, detection of short-

chainfattyacidendproductsoffermentation,Gram-stainmorphology,colonymorphology,anddetectionofspecifictoxins

• Variousspeciesassociatedwithhumandisease(seeTable178-1)

CLOSTRIDIUM PERFRINGENS AND CLOSTRIDIAL MYONECROSIS (GAS GANGRENE)• C. perfringensproducesavarietyoftoxins(seeTable178-2)• Most common following traumatic crushing injuries that result in lowered tissue oxygen

levels,penetratingtraumainvolvingforeignbodiescontaminatedwithsoil,gastrointestinalorbiliarytractsurgery,andsepticabortion

• Diagnosis: Initial symptoms include severe pain, redness at the wound site followed byrapidlyspreadingbrowntopurplediscoloration,edemaandgas,andserosanguineousdis-chargewithacharacteristic“mousy”odor.Full-blownsepsiswithhypotension,renalfailure,andmetabolicacidosisoccursrapidly.

• Treatmentinvolvespromptsurgicaldébridementofinfectedtissues, includingamputationforextremities,orhysterectomyinuterinegasgangrene.Antibiotictreatmentisalsoimpor-tant, and most strains are sensitive to penicillin, metronidazole, clindamycin, and thecarbapenems.

FOOD POISONING CAUSED BY CLOSTRIDIUM PERFRINGENS• C. perfringenstypeAinvolvedinmostcases• Involvestheingestionofatleast108viableenterotoxin-producingcells• Periodofincubationis7to15hours;casesresolvespontaneouslywithin24to48hours

OTHER CLOSTRIDIAL INFECTIONS• Bacteremia—clostridia account for 1% of all positive blood cultures. Risk factors include

hemodialysis,intestinalmalignancy,andinflammatoryboweldisease.• Biliarytractinfections—clostridiacanbeisolatedfrommorethan20%ofdiseasedgallblad-

ders,andC. perfringensaccountsfor50%.• Femalegenitaltractinfections—clostridiaarepresentinupto20%ofnon–sexuallytransmit-

teddiseasegenitalinfectionsandmaybepresentaspartofbacterialvaginosis.C. perfringensandC. sordelliicanbeisolatedfrompostpartumandpostabortioninfections.

• Pleuropulmonaryinfections—clostridiaarerecoveredfromupto10%ofpulmonaryinfec-tionswithC. perfringensaccountingforthemajority.

363C

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ang

rene an

d O

ther C

lostrid

ium

-Asso

ciated D

iseases

TABLE 178-1  Clostridial Species Commonly Associated with Human Disease

SPEC

IES

SPO

RE

LOC

ATI

ON

LEC

ITH

INA

SE

PRO

DU

CED

LIPA

SE

ENTE

RO

TOX

INS

PRO

DU

CED

HIS

TOTO

XIN

S,

HEM

OLY

SIN

S,

PRO

TEA

SES

NEU

RO

TOX

INS

PRO

DU

CED

Tissue InfectionsC. perfringens ST, C + − Yes Yes No

C. ramosum T − − No Yes No

C. septicum ST − − No Yes No

C. sordellii ST + − No Yes No

C. bifermentans ST + − No Yes No

C. tertium T − − No Yes No

C. sphenoides ST − − No Yes No

C. baratii ST − − No Yes No

C. novyi ST + + No Yes No

C. histolyticum ST − − No Yes No

IntoxicationsC. difficile ST − − Yes Yes No

C. botulinum ST, T − + No Yes Yes

C. tetani T − − No Yes Yes

C, centrally; ST, subterminally; T, terminally.

TABLE 178-2  Toxins Produced by Clostridium perfringens

TOXIN STRAIN TYPES BIOLOGIC ACTIVITYα All strains Lecithinase

β B and C Necrotoxin, necrosis of the bowel

ε B and D Lethal, hemorrhagic

ι E Adenosine diphosphate ribosylating; lethal

cpe enterotoxin A, C, and D Cytopathic

Neuraminidase All strains Hydrolyzes N-acetylneuraminic acid

δ B and C Hemolysins

κ All strains Collagenase

λ B, D, and E Protease

µ All strains Hyaluronidase

ν All strains DNAase

364

179 Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)Wendy S. Garrett and Andrew B. Onderdonk

DEFINITION• Bacteroides, Porphyromonas, Prevotella,andFusobacteriumspp.accountforthemajorityof

infectionscausedbyanaerobicgram-negativerods.BilophilaandSutterellaspp.alsocausehumaninfections,althoughtheyarelessfrequentlyencountered.

EPIDEMIOLOGY• Theseorganismsarepartof thenormalhumanmicrobiomeandcanbe isolated fromthe

oralcavity,gastrointestinaltract,andvaginalvaultofhumans.

MICROBIOLOGY• Theorganismsareobligatelyanaerobic,gram-negative,non–spore-formingrods.Members

ofthisgroupcanbeproteolytic,saccharolytic,orboth.Somespeciesproducecatalaseandsuperoxide dismutase in low concentrations. Some species have capsular polysaccharidesthat have been shown to be potent immunomodulators, whereas other species produceabundantproteasesthatcandegradetissue.

DIAGNOSIS• Identification in theclinical laboratory includescolonymorphology,Gramstain,pigment

productionvisualizedinnaturallightandasfluorescenceemissionafterexposuretoultra-violetlight,andnumerousbiochemicaltests(e.g.,Vitek).

THERAPY• Treatmentisdirectedbycultureandsensitivitytestresults(seeTable179-1).

TABLE 179-1  Antibiotic Sensitivities of Medically Important Gram-Negative Anaerobic Rods

PEN

ICIL

LIN

β-LA

CTA

M

PIPE

RA

CIL

LIN

/TA

ZOB

AC

TAM

AM

OX

ICIL

LIN

/C

LAV

ULA

NIC

AC

ID

CLI

ND

AM

YC

IN

CA

RB

APE

NEM

MET

RO

NID

AZO

LE

MO

XIF

LOX

AC

IN

Bacteroides fragilis group R V S S V S S S

Prevotella R V S S S S S S

Porphyromonas R V S S S S S S

Fusobacterium S V S S S S S S

R, resistant >30%; S, sensitive <5%; V, variable >5%.

365

180 Mycobacterium tuberculosisDaniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas

MICROBIOLOGY• HumansaretheonlyreservoirforMycobacterium tuberculosis.• Theorganismisanacid-fast,aerobicbacilluswithahighcellwallcontentofhigh-molecular-

weightlipids.• Visiblegrowthtakes3to8weeksonsolidmedia.• Anestimated10,000organisms/mLarerequiredforsputumsmearpositivity.• Incompletenecrosisproducescheesy,acellularmaterial(i.e.,caseousnecrosis).• Pulmonarycavitiescontainhugenumbersoforganisms.

EPIDEMIOLOGY• M. tuberculosis infects one third of the world’s population, with 8.7 million new cases

reportedeachyear.• Almostallinfectionsareduetoinhalationofdropletnuclei.• Keydeterminantsof infectionof tuberculin-negativepersonsareclosenessofcontactand

infectiousnessofthesource.• Thestrongestriskfactorforprogressiontoactivetuberculosisisacquiredimmunodeficiency

syndrome(AIDS).• GreatestcaseratesareincountriesheavilyaffectedbyAIDS.• Drugresistancecanbeprimaryorsecondary.• Multidrug-resistant tuberculosis (MDR-TB) indicates resistance to both isoniazid and

rifampin.• Extensivelydrug-resistanttuberculosis(XDR-TB)indicatesresistancetoisoniazid,rifampin,

afluoroquinolone,andasecond-lineinjectabledrug.• TransmissionofXDR-TBisofimmenseconcern.

IMMUNOLOGY AND PATHOGENESIS• Infectionrequiresacellularimmuneresponse.• Airbornedropletnuclei reach the terminal air-spaceswhere theyare ingestedbyalveolar

macrophagesandthencarriedbylymphaticstoregionallymphnodes.• Occult preallergic lymphohematogenous dissemination occurs to the lung apices and

elsewhere.• Granulomasformwhenantigenloadissmallandtissuehypersensitivityishigh.• Ageinfluenceslikelihoodandpatternofdisease.• Tuberculosis in advanced AIDS is characterized by middle or lower lung field location,

absenceofcavitation,increasedextrapulmonarydisease,andanegativetuberculintest.

TUBERCULIN SKIN TESTING AND INTERFERON-γ RELEASE ASSAYS• TodetectlatentM. tuberculosisinfection,apositiveskintestisdefinedbyinduration.• Skintestingisrecommendedforpersonsathighriskfordevelopingtuberculosisandthose

withpossiblelatentinfectionwhocanbetreatedifthetestispositive.

366Part

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Infe

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Dis

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s an

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hei

r Et

iolo

gic

 Ag

ents

• Theskintestisnegativeinatleast20%ofactivetuberculosiscases.• Interferon-γreleaseassaysmaybeusedinsteadofskintesting.

DIAGNOSIS• Cultureisthegoldstandard.• Liquidbrothculturesrequire1to3weekstodetectorganisms.• Nucleicacidamplificationtestshavesensitivitiesandspecificitiesthatapproachculture.• Threesputumspecimensincreasesensitivity.• Aradiographshowingapatchyornodularinfiltrateinthelungapicesishighlysuggestive,

especiallyiftheinfiltrateiscavitary.• Pulmonarytuberculosiscanoccurinpersonswithnormalchestradiographs.

THERAPY (SEE TABLES 180-1 AND 180-2)• Multidrugregimens,typicallystartingwithatleastfouractivedrugs,arerecommended.• Atleast6monthsoftherapyisusuallyrequired.• Isoniazid(INH)isthecornerstoneoftherapy;rifampin,thesecondmajorantituberculous

agent, causes many drug-drug interactions; pyrazinamide is essential for 6-monthregimens.

• Adjustmentofdosesofantiretroviralagentsduringtreatmentoftuberculosiswithrifampinand rifabutin is discussed in Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases,8thEdition,Chapter38.

• Directlyobservedtherapyiscrucial.• Susceptibilitytestingisimportanttoguidetherapy.• Withappropriatechemotherapy,patientsbecomenoninfectiouswithin2weeks.• TreatmentofXDR-TBisusuallyassociatedwithpooroutcomes.• BedaquilineisarecentlyapproveddrugforMDR-TB.

THERAPY FOR LATENT INFECTION• IntheUnitedStates,9monthsofINHiswidelyprescribedforlatentinfection.• Twelve weeks of directly observed, once-weekly INH plus rifapentine is as effective as

9monthsofINH.Foradultsweighingmorethan50kg,thedoseofbothdrugsis900mgonceaweek.

PREVENTION• Casefindingandtreatmentisthemosteffectivemethodoftuberculosiscontrol.• Hospitalizedhumanimmunodeficiencyvirus–positivepatientswithrespiratorysymptoms

shouldbeadmittedtonegative-pressureisolationrooms.N95masksareusedforhealthcareworkers.

• ChildhoodbacillusCalmette-Guérinvaccination inhigh-burdencountriesdecreases inci-denttuberculosis.

367C

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bacteriu

m tu

bercu

losis

TABLE 180-1  Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

INITIAL PHASE CONTINUATION PHASE

Reg

imen

Dru

gs

Inte

rval

an

d

Do

ses*

(M

inim

al

Du

rati

on

)

Reg

imen

Dru

gs

Inte

rval

an

d

Do

ses*

† (M

inim

al

Du

rati

on

)

Ran

ge

of

Tota

l D

ose

s (M

inim

al

Du

rati

on

)

1 INHRIFPZAEMB

7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)‡

1a INH/RIF 7 days/wk for 126 doses (18 wk) or 5 days/wk for 90 doses (18 wk)‡

182-130 (26 wk)

1b INH/RIF Twice weekly for 36 doses (18 wk)§

92-76 (26 wk)

1c‖ INH/RPT Once weekly for 18 doses (18 wk)

74-58 (26 wk)

2 INHRIFPZAEMB

7 days/wk for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 days/wk for 10 doses (2 wk),‡ then twice weekly for 12 doses (6 wk)

2a INH/RIF Twice weekly for 36 doses (18 wk)§

62-58 (26 wk)

2b‖ INH/RPT Once weekly for 18 doses (18 wk)

44-40 (26 wk)

3 INHRIFPZAEMB

Three times weekly for 24 doses (8 wk)

3a INH/RIF Three times weekly for 54 doses (18 wk)

78 (26 wk)

4 INHRIFEMB

7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)§

4a INH/RIF 7 days/wk for 217 doses (31 wk) or 5 days/wk for 155 doses (31 wk)§

273-195 (39 wk)

4b INH/RIF Twice weekly for 62 doses (31 wk)§

118-102 (39 wk)

EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.*When directly observed therapy is used, drugs may be given 5 days/wk and the necessary number of doses

adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice.

†Patients with cavitation on an initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 weeks; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase.

‡Five-day-a-week administration is always given by directly observed therapy.§Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/mm3.‖Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time

of completion of 2 months of therapy and who do not have cavitation on an initial chest radiograph. For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.

Modified from Centers for Disease Control and Prevention. Treatment of tuberculosis. American Thoracic Society, CDC and Infectious Diseases Society of America. MMWR Recomm Rep. 2003;52(RR-11):1-88.

368Part

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Dis

ease

s an

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hei

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 Ag

ents

TAB

LE 1

80

-2 

Firs

t-Li

ne T

ub

erc

ulo

sis 

Med

icati

on

s*

DR

UG

DO

SE

(MA

XIM

UM

)M

AJO

R A

DV

ERSE

REA

CTI

ON

SR

ECO

MM

END

ED

MO

NIT

OR

ING

DO

SAG

E FO

RM

SC

OM

MEN

TS

Iso

nia

zid

* (I

NH

)D

aily

C:

10-1

5 m

g/kg

(30

0 m

g)A

: 5

mg/

kg (

300

mg)

Onc

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

15 m

g/kg

(90

0 m

g)Tw

ice

wee

kly

C:

20-3

0 m

g/kg

(90

0 m

g)A

: 15

mg/

kg (

900

mg)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

15 m

g/kg

(90

0 m

g)

Hep

atic

enz

yme

elev

atio

n, p

erip

hera

l ne

urop

athy

, he

patit

is,

rash

, C

NS

effe

cts,

in

crea

sed

phen

ytoi

n, (

Dila

ntin

), an

d di

sulfi

ram

(A

ntab

use)

leve

ls

Base

line

hepa

tic e

nzym

es.

Repe

at m

onth

ly if

bas

elin

e ab

norm

al,

risk

fact

ors

for

hepa

titis

, or

sym

ptom

s of

ad

vers

e re

actio

ns.

Scor

ed t

able

ts:

50 m

g,

100

mg,

and

300

mg

Syru

p: 5

0 m

g/5

mL

Aqu

eous

sol

utio

n (IV

/IM):

scar

ce a

nd m

ay n

ot b

e av

aila

ble

Hep

atiti

s ris

k in

crea

ses

with

age

and

al

coho

l con

sum

ptio

n. O

verd

ose

may

be

fata

l. A

lum

inum

-con

tain

ing

anta

cids

re

duce

abs

orpt

ion.

Pyr

idox

ine

(vita

min

B6)

m

ay d

ecre

ase

perip

hera

l neu

ritis

and

CN

S ef

fect

s.

Rif

amp

in*

(RIF

)D

aily

C:

10-2

0 m

g/kg

(60

0 m

g)A

: 10

mg/

kg (

600

mg)

Onc

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

Not

rec

omm

ende

dTw

ice

wee

kly

C:

10-2

0 m

g/kg

(60

0 m

g)A

: 10

mg/

kg (

600

mg)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

10 m

g/kg

(60

0 m

g)

Hep

atiti

s, f

ever

, th

rom

bocy

tope

nia,

flul

ike

synd

rom

e, r

ash,

gas

troi

ntes

tinal

ups

et,

rena

l fai

lure

. Re

duce

s le

vels

of

man

y dr

ugs,

in

clud

ing

met

hado

ne,

war

farin

(C

oum

adin

), bi

rth

cont

rol p

ills,

the

ophy

lline

, da

pson

e,

keto

cona

zole

, PI

s, a

nd s

ome

NN

RTIs

. O

rang

e di

scol

orat

ion

of s

ecre

tions

(sp

utum

, ur

ine,

sw

eat,

tea

rs)

and

may

per

man

ently

st

ain

soft

con

tact

lens

es.

CD

C n

o lo

nger

rec

omm

ends

ro

utin

e m

onito

ring

test

s.

How

ever

, m

any

clin

icia

ns

cont

inue

to

orde

r ba

selin

e C

BC,

plat

elet

s, h

epat

ic

enzy

mes

. Re

peat

if b

asel

ine

abno

rmal

, ris

k fa

ctor

s fo

r he

patit

is o

r sy

mpt

oms

of

adve

rse

reac

tions

.

Cap

sule

s: 1

50 m

g an

d 30

0 m

gSy

rup:

can

be

form

ulat

ed

from

cap

sule

s by

pha

rmac

yA

queo

us s

olut

ion

(IV/IM

): sc

arce

and

may

not

be

avai

labl

e

Patie

nts

on m

etha

done

will

nee

d an

in

crea

sed

dose

of

met

hado

ne (

aver

age

50%

) to

avo

id o

piat

e w

ithdr

awal

. In

tera

ctio

n w

ith m

any

drug

s le

ads

to

decr

ease

d le

vels

of

one

or b

oth.

May

m

ake

gluc

ose

cont

rol m

ore

diffi

cult

in

diab

etic

s. C

ontr

aind

icat

ed f

or p

atie

nts

taki

ng P

Is a

nd s

ome

NN

RTIs

. W

omen

on

birt

h co

ntro

l pill

s ne

ed a

bar

rier

met

hod

whi

le o

n rif

ampi

n.

Pyra

zin

amid

e (P

ZA)

Dai

lyC

: 15

-30

mg/

kg (

2 g)

A:

15-3

0 m

g/kg

(2

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: 50

mg/

kg (

2 g)

A:

50-7

0 m

g/kg

(4

g)Th

ree

times

wee

kly

C:

Not

rec

omm

ende

dA

: 50

-70

mg/

kg (

3 g)

Gas

troi

ntes

tinal

ups

et,

hepa

toto

xici

ty,

hype

ruric

emia

, ar

thra

lgia

s, r

ash,

gou

t (r

are)

Scor

ed t

able

ts:

500

mg

May

com

plic

ate

man

agem

ent

of d

iabe

tes

mel

litus

. Tr

eat

incr

ease

d ur

ic a

cid

only

if

sym

ptom

atic

. M

ost

com

mon

rea

son

for

TB p

atie

nts

expe

rienc

ing

GI u

pset

.

Eth

amb

uto

l† (EM

B)

Dai

lyC

: 15

-20

mg/

kg (

1000

mg)

A:

15-2

5 m

g/kg

(16

00 m

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: 50

mg/

kg (

2.5

g)A

: 50

mg/

kg (

4 g)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

25-3

0 m

g/kg

(24

00 m

g)

Dec

reas

ed r

ed-g

reen

col

or d

iscr

imin

atio

n,

decr

ease

d vi

sual

acu

ity (

optic

neu

ritis

), ra

shBa

selin

e te

sts

of v

isua

l acu

ity

and

colo

r vi

sion

. M

onth

ly

test

ing

for

patie

nts

taki

ng

>15-

25 m

g/kg

, fo

r th

ose

taki

ng E

MB

for >2

mo,

and

fo

r pa

tient

s w

ith r

enal

in

suffi

cien

cy.

Tabl

ets:

100

mg

and

400

mg

Opt

ic n

eurit

is m

ay b

e un

ilate

ral;

chec

k ea

ch e

ye s

epar

atel

y. N

ot r

ecom

men

ded

for

child

ren

too

youn

g to

mon

itor

visi

on

unle

ss d

rug

resi

stan

t. U

se lo

wes

t po

ssib

le

dose

in r

ange

(ex

cept

for

dru

g-re

sist

ant

patie

nts)

. EM

B sh

ould

be

disc

ontin

ued

imm

edia

tely

and

per

man

ently

for

any

si

gns

of v

isua

l tox

icity

.

Rif

abu

tin

(R

BT)

Dai

lyC

: N

ot r

ecom

men

ded

A:

5 m

g/kg

(30

0 m

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

5 m

g/kg

(30

0 m

g)Th

ree

times

wee

kly

C:

Not

rec

omm

ende

dA

: 5

mg/

kg (

300

mg)

Hep

atiti

s fe

ver,

thro

mbo

cyto

peni

a,

neut

rope

nia,

leuk

open

ia,

flulik

e sy

mpt

oms,

hy

peru

ricem

ia.

Ora

nge

disc

olor

atio

n of

se

cret

ions

(sp

utum

, ur

ine,

sw

eat,

tea

rs)

and

may

per

man

ently

sta

in s

oft

cont

act

lens

es.

Redu

ces

leve

ls o

f m

any

drug

s, in

clud

ing

met

hado

ne,

war

farin

(C

oum

adin

), bi

rth

cont

rol p

ills,

the

ophy

lline

, da

pson

e,

keto

cona

zole

, PI

s, a

nd N

NRT

Is.

With

in

crea

sed

rifab

utin

leve

ls,

seve

re a

rthr

algi

as,

uvei

tis,

leuk

open

ia o

ccur

.

Base

line

hepa

tic e

nzym

es.

Repe

at if

bas

elin

e va

lues

ab

norm

al,

risk

fact

ors

for

hepa

titis

, or

sym

ptom

s of

ad

vers

e re

actio

ns.

Cap

sule

s: 1

50 m

gPa

tient

s on

met

hado

ne m

ay n

eed

an

incr

ease

d do

se t

o av

oid

opia

te

with

draw

al.

Inte

ract

ion

with

man

y dr

ugs

lead

s to

dec

reas

ed le

vels

of

one

or b

oth.

M

ay m

ake

gluc

ose

cont

rol m

ore

diffi

cult

in d

iabe

tics.

Wom

en o

n bi

rth

cont

rol p

ills

need

to

use

a ba

rrie

r m

etho

d w

hile

on

rifab

utin

.In

com

bina

tion

with

NN

RTIs

or

PIs,

do

sage

s ch

ange

sig

nific

antly

.

369C

hap

ter 180 Myco

bacteriu

m tu

bercu

losis

TAB

LE 1

80

-2 

Firs

t-Li

ne T

ub

erc

ulo

sis 

Med

icati

on

s*

DR

UG

DO

SE

(MA

XIM

UM

)M

AJO

R A

DV

ERSE

REA

CTI

ON

SR

ECO

MM

END

ED

MO

NIT

OR

ING

DO

SAG

E FO

RM

SC

OM

MEN

TS

Iso

nia

zid

* (I

NH

)D

aily

C:

10-1

5 m

g/kg

(30

0 m

g)A

: 5

mg/

kg (

300

mg)

Onc

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

15 m

g/kg

(90

0 m

g)Tw

ice

wee

kly

C:

20-3

0 m

g/kg

(90

0 m

g)A

: 15

mg/

kg (

900

mg)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

15 m

g/kg

(90

0 m

g)

Hep

atic

enz

yme

elev

atio

n, p

erip

hera

l ne

urop

athy

, he

patit

is,

rash

, C

NS

effe

cts,

in

crea

sed

phen

ytoi

n, (

Dila

ntin

), an

d di

sulfi

ram

(A

ntab

use)

leve

ls

Base

line

hepa

tic e

nzym

es.

Repe

at m

onth

ly if

bas

elin

e ab

norm

al,

risk

fact

ors

for

hepa

titis

, or

sym

ptom

s of

ad

vers

e re

actio

ns.

Scor

ed t

able

ts:

50 m

g,

100

mg,

and

300

mg

Syru

p: 5

0 m

g/5

mL

Aqu

eous

sol

utio

n (IV

/IM):

scar

ce a

nd m

ay n

ot b

e av

aila

ble

Hep

atiti

s ris

k in

crea

ses

with

age

and

al

coho

l con

sum

ptio

n. O

verd

ose

may

be

fata

l. A

lum

inum

-con

tain

ing

anta

cids

re

duce

abs

orpt

ion.

Pyr

idox

ine

(vita

min

B6)

m

ay d

ecre

ase

perip

hera

l neu

ritis

and

CN

S ef

fect

s.

Rif

amp

in*

(RIF

)D

aily

C:

10-2

0 m

g/kg

(60

0 m

g)A

: 10

mg/

kg (

600

mg)

Onc

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

Not

rec

omm

ende

dTw

ice

wee

kly

C:

10-2

0 m

g/kg

(60

0 m

g)A

: 10

mg/

kg (

600

mg)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

10 m

g/kg

(60

0 m

g)

Hep

atiti

s, f

ever

, th

rom

bocy

tope

nia,

flul

ike

synd

rom

e, r

ash,

gas

troi

ntes

tinal

ups

et,

rena

l fai

lure

. Re

duce

s le

vels

of

man

y dr

ugs,

in

clud

ing

met

hado

ne,

war

farin

(C

oum

adin

), bi

rth

cont

rol p

ills,

the

ophy

lline

, da

pson

e,

keto

cona

zole

, PI

s, a

nd s

ome

NN

RTIs

. O

rang

e di

scol

orat

ion

of s

ecre

tions

(sp

utum

, ur

ine,

sw

eat,

tea

rs)

and

may

per

man

ently

st

ain

soft

con

tact

lens

es.

CD

C n

o lo

nger

rec

omm

ends

ro

utin

e m

onito

ring

test

s.

How

ever

, m

any

clin

icia

ns

cont

inue

to

orde

r ba

selin

e C

BC,

plat

elet

s, h

epat

ic

enzy

mes

. Re

peat

if b

asel

ine

abno

rmal

, ris

k fa

ctor

s fo

r he

patit

is o

r sy

mpt

oms

of

adve

rse

reac

tions

.

Cap

sule

s: 1

50 m

g an

d 30

0 m

gSy

rup:

can

be

form

ulat

ed

from

cap

sule

s by

pha

rmac

yA

queo

us s

olut

ion

(IV/IM

): sc

arce

and

may

not

be

avai

labl

e

Patie

nts

on m

etha

done

will

nee

d an

in

crea

sed

dose

of

met

hado

ne (

aver

age

50%

) to

avo

id o

piat

e w

ithdr

awal

. In

tera

ctio

n w

ith m

any

drug

s le

ads

to

decr

ease

d le

vels

of

one

or b

oth.

May

m

ake

gluc

ose

cont

rol m

ore

diffi

cult

in

diab

etic

s. C

ontr

aind

icat

ed f

or p

atie

nts

taki

ng P

Is a

nd s

ome

NN

RTIs

. W

omen

on

birt

h co

ntro

l pill

s ne

ed a

bar

rier

met

hod

whi

le o

n rif

ampi

n.

Pyra

zin

amid

e (P

ZA)

Dai

lyC

: 15

-30

mg/

kg (

2 g)

A:

15-3

0 m

g/kg

(2

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: 50

mg/

kg (

2 g)

A:

50-7

0 m

g/kg

(4

g)Th

ree

times

wee

kly

C:

Not

rec

omm

ende

dA

: 50

-70

mg/

kg (

3 g)

Gas

troi

ntes

tinal

ups

et,

hepa

toto

xici

ty,

hype

ruric

emia

, ar

thra

lgia

s, r

ash,

gou

t (r

are)

Scor

ed t

able

ts:

500

mg

May

com

plic

ate

man

agem

ent

of d

iabe

tes

mel

litus

. Tr

eat

incr

ease

d ur

ic a

cid

only

if

sym

ptom

atic

. M

ost

com

mon

rea

son

for

TB p

atie

nts

expe

rienc

ing

GI u

pset

.

Eth

amb

uto

l† (EM

B)

Dai

lyC

: 15

-20

mg/

kg (

1000

mg)

A:

15-2

5 m

g/kg

(16

00 m

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: 50

mg/

kg (

2.5

g)A

: 50

mg/

kg (

4 g)

Thre

e tim

es w

eekl

yC

: N

ot r

ecom

men

ded

A:

25-3

0 m

g/kg

(24

00 m

g)

Dec

reas

ed r

ed-g

reen

col

or d

iscr

imin

atio

n,

decr

ease

d vi

sual

acu

ity (

optic

neu

ritis

), ra

shBa

selin

e te

sts

of v

isua

l acu

ity

and

colo

r vi

sion

. M

onth

ly

test

ing

for

patie

nts

taki

ng

>15-

25 m

g/kg

, fo

r th

ose

taki

ng E

MB

for >2

mo,

and

fo

r pa

tient

s w

ith r

enal

in

suffi

cien

cy.

Tabl

ets:

100

mg

and

400

mg

Opt

ic n

eurit

is m

ay b

e un

ilate

ral;

chec

k ea

ch e

ye s

epar

atel

y. N

ot r

ecom

men

ded

for

child

ren

too

youn

g to

mon

itor

visi

on

unle

ss d

rug

resi

stan

t. U

se lo

wes

t po

ssib

le

dose

in r

ange

(ex

cept

for

dru

g-re

sist

ant

patie

nts)

. EM

B sh

ould

be

disc

ontin

ued

imm

edia

tely

and

per

man

ently

for

any

si

gns

of v

isua

l tox

icity

.

Rif

abu

tin

(R

BT)

Dai

lyC

: N

ot r

ecom

men

ded

A:

5 m

g/kg

(30

0 m

g)O

nce

wee

kly

C:

Not

rec

omm

ende

dA

: N

ot r

ecom

men

ded

Twic

e w

eekl

yC

: N

ot r

ecom

men

ded

A:

5 m

g/kg

(30

0 m

g)Th

ree

times

wee

kly

C:

Not

rec

omm

ende

dA

: 5

mg/

kg (

300

mg)

Hep

atiti

s fe

ver,

thro

mbo

cyto

peni

a,

neut

rope

nia,

leuk

open

ia,

flulik

e sy

mpt

oms,

hy

peru

ricem

ia.

Ora

nge

disc

olor

atio

n of

se

cret

ions

(sp

utum

, ur

ine,

sw

eat,

tea

rs)

and

may

per

man

ently

sta

in s

oft

cont

act

lens

es.

Redu

ces

leve

ls o

f m

any

drug

s, in

clud

ing

met

hado

ne,

war

farin

(C

oum

adin

), bi

rth

cont

rol p

ills,

the

ophy

lline

, da

pson

e,

keto

cona

zole

, PI

s, a

nd N

NRT

Is.

With

in

crea

sed

rifab

utin

leve

ls,

seve

re a

rthr

algi

as,

uvei

tis,

leuk

open

ia o

ccur

.

Base

line

hepa

tic e

nzym

es.

Repe

at if

bas

elin

e va

lues

ab

norm

al,

risk

fact

ors

for

hepa

titis

, or

sym

ptom

s of

ad

vers

e re

actio

ns.

Cap

sule

s: 1

50 m

gPa

tient

s on

met

hado

ne m

ay n

eed

an

incr

ease

d do

se t

o av

oid

opia

te

with

draw

al.

Inte

ract

ion

with

man

y dr

ugs

lead

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371

181 Mycobacterium leprae (Leprosy)Cybèle A. Renault and Joel D. Ernst

MICROBIOLOGY AND EPIDEMIOLOGY• Acid-fast–andGramstain–positiveMycobacterium lepraecannotbeculturedinvitro.• Predominantmodeoftransmissionislikelythroughrespiratorydropletsornasalsecretions,

althoughtransmissionmayalsooccurthroughskincontact,transplacentally,viabreastmilk,andafterzoonotic(particularlyarmadillo)exposure.

• Risk factors for clinical disease include age (bimodal distribution: adolescents and adultsolderthan30yearsareathighestrisk),gender(nodifferencesnotedinchildren,althoughadultmenhavedoubletheriskcomparedwithadultwomen),anddegreeofcontact(indi-vidualsincontactwithpatientswithmultibacillarydiseaseareathighestrisk).

• Estimates of leprosy incidence and prevalence are underestimated owing to difficulty indiagnosingsubclinicaldisease(themajorityofthoseinfected)andinlightoftheassociatedstigmatizationofinfectedindividuals.

CLINICAL MANIFESTATIONS AND IMMUNOLOGIC SPECTRUM OF DISEASE• Clinicalandpathologicmanifestationsarise inadistinctandwell-characterizedspectrum

basedonhostimmuneresponsetotheorganism.Spectrumrangesfromtuberculoidleprosy(smallnumberofskinlesions,fewbacilli inlesions,andarobustT-lymphocyteresponse)to lepromatous leprosy (larger number of skin lesions, clinically apparent infiltration ofperipheralnerves,largenumberofbacilli,andalowT-lymphocyteresponse).

• Clinicalmanifestationsvarysignificantly,dependingonthesubtypeofdisease.Therearetwoclinicalclassificationsystems:WorldHealthOrganization(WHO)(usedinresource-limitedsettings)andRidley-Jopling(usedwhenhistopathologyisavailable).

• Skin lesions are hypopigmented, erythematous, or infiltrative with or without neurologicsignsorsymptoms,includinghypoesthesia,weakness,autonomicdysfunction,orperipheralnervethickening.

• Peripheralsensorynervedamage(mediateddirectlybyM. lepraeorbytheimmuneresponseto the organism) is the leading cause of functional morbidity and is seen throughout thediseasespectrum.

• Reactions include reversal reactions, which present most often as increased erythema ofpreexisting skin lesions and progressive peripheral neuropathy, and erythema nodosumleprosum(ENL),whichpresentsassystemicsignsandpainfulerythematousskinnodules.

DIAGNOSIS• Leprosy isdiagnosedusinga combinationof clinical examinationand skin slit smearsor

skinbiopsy.• Skinslitsmear:HeatfixationandZiehl-NeelsenorFitestainingareusedtoevaluatebacillary

loadandtypicallydoneinsixsites.• Skinbiopsy:Histopathologyisthegoldstandardforestablishingadefinitivediagnosisand

for accurately classifying the subtype of disease but is often not available in endemiccountries.

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• M. lepraepolymerasechainreactionassayisnotcurrentlyavailableforcommercialusebutcanbeperformedinspecializedcenters(e.g.,NationalHansen’sDiseaseProgram[NHDP])to identify the organism in skin specimens that stain positive for acid-fast organisms butwherecultureresultsarenegative.

THERAPY (SEE TABLE 181-1)• Dapsone,rifampin,andclofaziminearethethreeestablishedantimicrobialagents.Alternative

agents includeofloxacin,minocycline,andclarithromycin.Standardtherapyusesmultipledrugstoincreasecurerateandpreventemergenceofdrugresistanceandtreatmentfailure.

• Recommendedtreatmentcoursesvarybasedonsubtypeofdiseaseandresourcesavailable.Althoughboth theWHOandNHDPrecommendmultipledrug therapy, theU.S. recom-mendationsincludedailyrifampin(incontrasttomonthlydosing)andrecommendlongerdurationsoftherapycomparedwithWHOrecommendations.

• Choiceof therapy for reversal reactions shouldbemadebasedon the severityofdisease.TreatmentofchoiceforbothreversalandENLreactions,particularlyinthesettingofacuteneuritis,iscorticosteroids.Thalidomide(forENLonly)andclofaziminearecorticosteroid-sparingagents thatcanbeused inchroniccases.Multipledrug therapy shouldalwaysbecontinuedinpatientspresentingwithreactions.

TABLE 181-1  Recommended Regimens to Treat Leprosy in Adults

Disease Stage Agent

WHO RECOMMENDATIONS

U.S. (NHDP) RECOMMENDATIONS

Dose Duration Dose DurationPaucibacillary or “tuberculoid” disease (TT, BT)

Dapsone 100 mg/day 6 mo 100 mg/day 12 mo

Rifampin 600 mg/mo 600 mg/day

Multibacillary or “lepromatous” disease (BB, BL, LL)

Dapsone 100 mg/day 12 mo 100 mg/day 24 mo

Rifampin 600 mg/ mo 600 mg/day

Clofazimine 50 mg/day, 300 mg/mo

50 mg/day

BB, mid-borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous leprosy; NHDP, National Hansen’s Disease Program; TT, tuberculoid; WHO, World Health Organization.

373

182 Mycobacterium avium ComplexFred M. Gordin and C. Robert Horsburgh, Jr.

MICROBIOLOGY AND EPIDEMIOLOGY• Mycobacterium avium and Mycobacterium intracellulare are closely related in a complex

(MAC).• MACisfoundinwater,soil,andanimalsbutnotspreadfrompersontoperson.• Thesourcefromwhichpatientsacquirethediseaseisusuallyunknown.• MACcausespulmonarydisease,lymphadenitis,anddisseminateddisease.• Pulmonary disease occurs in older patients with chronic obstructive pulmonary disease,

priorpneumonia,cysticfibrosis,andsteroiduse,aswellasolderwomenwithnopredispos-ingfactors.

• Lymphadenitisismostlyinchildrenyoungerthan5yearsofage.• Disseminateddiseaseoccursmostlyinpatientswithacquiredimmunodeficiencysyndrome

andaCD4+cellcountlessthan50/mm3.

CLINICAL MANIFESTATIONS AND DIAGNOSIS• Pulmonarydiseasecanbe infiltrativewithorwithoutcavities,nodular (solitaryormulti-

nodular), pleural, or as a hypersensitivity pneumonitis. It can closely mimic tuberculosis.Diagnosisrequiresatriadofclinicalsymptoms,radiographicabnormalities,andculture.

• Lymphadenitisisusuallycervicofacial,unilateral,andpainless.Diagnosisisvialymphnodeaspirationorexcision.

• Disseminated disease is usually accompanied by fever, weight loss, and night sweats.Diagnosis ismade inmore than90%ofpatientsbybloodcultures forM. aviumcomplex(MAC).

TREATMENT (SEE TABLES 182-1 AND 182-2)• Forpulmonarydisease:

• Starttreatmentforpulmonarydiseasewithclarithromycinorazithromycin,plusetham-butolandeitherrifampinorrifabutin.Moreadvanceddiseasemayrequiretheadditionofaminoglycosides,usuallyamikacin.

• Treat pulmonary disease until cultures have been negative for at least 12 months; theusualtotaldurationis18to24months.

• Hypersensitivitypneumonitismaybetreatedwithavoidanceofexposureorshort-terminhaledsteroids,orboth.

• Lymphadenitiscanbetreatedwithsurgicalexcisionorclarithromycinplusethambutoluntilthenoderesolves.

• Humanimmunodeficiencyvirus(HIV)-infectedpatientswithdisseminateddiseaseshouldbe treated with clarithromycin plus ethambutol and possibly rifabutin or rifampin. Theseindividualsshouldhaveantiretroviraltherapyinitiatedafter2to4weeks.AntibiotictherapyfordisseminatedMACshouldbecontinuedfor1yearandmaythenbediscontinuediftheCD4+cellcountisgreaterthan100/mm3.Immunereconstitutioninflammatorysyndromemaycomplicaterecovery.

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PREVENTION• HIV-infected persons with fewer than 50 CD4+ cells/mm3 should be given azithromycin

1200mg once weekly to prevent disseminated MAC. This can be stopped once sustainedCD4+cellcountsabove100/mm3haveoccurred.

TABLE 182-1  Drugs Employed in the Treatment of Mycobacterium avium Complex Disease

DRUG USUAL DAILY DOSE*USUAL INTERMITTENT DOSE

COMMON ADVERSE EFFECTS

Clarithromycin 500 mg bid 1 g tiw GI distress, bitter taste, rash, hearing loss, drug interactions

Azithromycin 250 mg qd 500-600 mg tiw GI distress, hearing loss

Ethambutol 15 mg/kg qd 25 mg/kg tiw At high doses: optic neuritis, GI distress

Rifabutin 300 mg qd 300 mg tiw GI distress, hepatitis, neutropenia, drug interactions; at high doses: uveitis, arthralgias

Rifampin 600 mg qd 600 mg tiw GI distress, hepatitis, neutropenia, drug interactions

Amikacin Not recommended 15 mg/kg IV tiw Vestibular and auditory abnormalities, renal toxicity

Streptomycin Not recommended 15 mg/kg IM (maximum tiw 1 g)

Vestibular and auditory abnormalities, renal toxicity

GI, gastrointestinal; tiw, three times weekly; IM, intramuscularly; IV, intravenously.*Oral dosing unless otherwise indicated.

TABLE 182-2  Regimens for Pulmonary Mycobacterium avium Complex

INITIAL THERAPY FOR NODULAR/BRONCHIECTATIC DISEASE

INITIAL THERAPY FOR CAVITARY DISEASE

ADVANCED (SEVERE) OR PREVIOUSLY TREATED DISEASE

Clarithromycin 1000 mg tiw orAzithromycin 500-600 mg tiw plus

Clarithromycin 500-1000 mg/day orAzithromycin 250-300 mg/day plus

Clarithromycin 500-1000 mg/day orAzithromycin 250-300 mg/day plus

Ethambutol 25 mg/kg tiw plus Ethambutol 15 mg/kg/day plus Ethambutol 15 mg/kg/day plus

Rifampin 600 mg tiw Rifampin 600 mg/day with or without

Rifabutin 300 mg/day orRifampin 600 mg/day plus

Streptomycin orAmikacin

Streptomycin orAmikacin

tiw, three times weekly.Modified  from An official ATS/IDSA  statement: diagnosis,  treatment,  and prevention of nontuberculous myco-

bacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416.

375

183 Infections Caused by Nontuberculous Mycobacteria Other Than Mycobacterium Avium ComplexBarbara A. Brown-Elliott and Richard J. Wallace, Jr.

DEFINITION• ComposedofspeciesotherthanMycobacterium tuberculosiscomplex(MTBC)• Previouslyknownas“atypicalmycobacteria”or“mycobacteriaotherthanM. tuberculosis”• Morethan150speciesofnontuberculousmycobacteria(NTM)• Dividedintorapidly,intermediate,andslowlygrowingspecies

EPIDEMIOLOGY• Mostspeciesareworldwideandubiquitousintheenvironment,includinghouseholdwater,

pottingsoil,vegetablematter,animals,andbirds.• NTMincludepathogensandnonpathogens.• Casesinchronic(e.g.,pulmonary)infectionsinvolvepatientswithunderlyingdiseasesuch

asbronchiectasisandcysticfibrosis.• Othercasesinvolveextrapulmonarysites,includingskinandsofttissue,bones,joints,bursae,

tendonsheaths,lymphnodes,eyes,ears,blood,brain,andcerebrospinalfluid.

MICROBIOLOGY• Acid-fastbacilli(AFB)stainpoorlywithGramstaining.• Identification of definitive species level is only accomplished by molecular or proteomic

methodsatpresent.

Rapidly Growing Mycobacteria• Rapidly growing mycobacteria (RGM) produce mature colonies on solid media within

7days.• Routineculturemediasuchasbloodagar,chocolateagar,trypticasesoyagar,mostMTBC

media(Middlebrook7H10or7H11agarandLowenstein-Jensenagar),andvariousbroths,includingrapidbrothdetectionsystems,supportthegrowthofmostspecies.

• Preferenceisfor28°to30°Cincubationforsomespecies,althoughmanyspeciesalsogrowat35°C.

• SomeRGM,especiallyMycobacterium abscessus,areadverselyaffectedbyharshdecontami-nationmethodsthatareusedforisolationofMTBC.

• Currently six groups of pathogenic species are defined based on presence or absence ofpigmentandgeneticrelatedness.

Intermediately Growing Mycobacteria• MostMTBCmediaincludingMiddlebrook7H10or7H11agarandLowenstein-Jensenagar

supportgrowthofspecies.• Theyrequire7to10daystoreachmaturegrowth.• Primarilytwopigmentedspeciesareinvolved:

• Mycobacterium marinum (pathogen) grows optimally at 28° to 30°C and is associatedwithmarinewaterandmarineanimals.

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• Mycobacterium gordonae(nonpathogen)growsoptimallyat35°to37°Candisacommontapwatercontaminant.

Slowly Growing Mycobacteria• Producematurecoloniesinmorethan7daysonsolidmedia• Most MTBC media, including Middlebrook 7H10 or 7H11 agar, Lowenstein-Jensen agar,

Middlebrookbroth,andrapiddetectionbrothsystems,supportgrowthofspecies,exceptforfastidious species such as Mycobacterium haemophilum (requires hemin or iron) andMycobacterium genavense(requiresMycobactinJ).

• MostspeciesexceptM. haemophilum (28°to30°C),Mycobacterium xenopi (42°to45°C),andsomeenvironmentalspeciesgrowoptimallyat35°to37°C.

DIAGNOSISPulmonary• SignsandsymptomsofNTMlungdiseasearevariableandnonspecific.• Patientsoftenpresentwithchroniccoughorthroatclearing,withorwithoutsputumproduc-

tionandseverefatigue.Lessfrequentlymalaise,dyspnea,fever,hemoptysis,andweightlossmayoccur.

• ClinicaldiagnosisdependsonmultiplepositivemicrobiologicculturesofrespiratorysamplesforAFB.

• FollowtheAmericanThoracicSocietyguidelinesfordiagnosis.• High-resolutionchestcomputedtomographyisuseful.• Routinechestradiographsarerecommended.• SinglepositivesputumculturesarenotdefinitiveforNTMdisease.• ExpertconsultationisrequiredforpatientswithinfrequentlyencounteredspeciesofNTM.

Extrapulmonary• Infectionmayinvolvefever,drainage,bacteremia,granulomatoussystemicinfections,necro-

sis,etc.dependingonthesiteofinfection.• Clinicaldiagnosisdependsonpositivemicrobiologicsmearsandculturesformycobacteria

ofdrainage,biopsytissue,orbodyfluid,leadingtoisolationofspecificNTM.

THERAPYRapidly Growing Mycobacteria• Pulmonary disease

• MostpulmonarydiseaseiscausedbyM. abscessusorM. abscessussubsp.massiliense.• Antimicrobial therapy alone is generally unsuccessful for microbiologic eradication of

M. abscessus.• Rifampin, rifabutin, ethambutol, isoniazid, streptomycin, and pyrazinamide are not

effective.• Multidrugregimensofmacrolides(azithromycinorclarithromycin),high-doseIVcefox-

itin(8to12g/dayindivideddoses)orimipenem(1gtwicedaily),andlow-doseparen-teral amikacin (peaks in the 20 to 25µg/mL range on once-daily dosing) probablyoptimalforM. abscessus.DailyIVtigecyclineoftenincluded;dosageadjustmentisusuallynecessary for clinical improvement, not cure. The role of inhaled amikacin is not yetestablished.

• PatientswithM. abscessusare treated forseveralmonthsuntilclinically improvedandmayrequireseveralcoursesoftreatment.

• Macrolides may not be useful for isolates of M. abscessus (but not M. massiliense), Mycobacterium fortuitum,andMycobacterium smegmatisthatcontainfunctionalinduc-ibleermgenes.

• OtherantimicrobialsareoftenusefulforspeciesotherthanM. abscessus(minocycline,doxycycline, trimethoprim/sulfamethoxazole [TMP-SMX], quinolones, linezolid, and,forMycobacterium chelonae,tobramycin).

• Extrapulmonary disease

377C

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• Generallycliniciansprescribeamultidrugregimenbasedoninvitrosusceptibilitytesting,includingamacrolide(exceptincaseoferm-positivespecies).

• Rifampin,rifabutin,ethambutol,andisoniazidarenoteffective.• Patientswithsignificantdiseasearetreatedfor6months,dependingontheseverityof

infection.• OtherantimicrobialsoftenusefulforspeciesoftheM. fortuitumgroupareminocycline,

doxycycline,TMP-SMX,quinolones,linezolid,and,forM. chelonae,tobramycin.

Intermediately Growing Mycobacteria• M. marinumisfoundonskinandinsofttissueinfections(usuallyhands).• Treatmentoptionsincludemacrolides,rifampin,TMP-SMX,oracombinationofrifampin

andethambutol.

Slowly Growing Mycobacteria• Pulmonary disease

• Antibiotic treatmentgenerally follows theregimen forMycobacterium avium complex:rifampin, ethambutol, and a macrolide (clarithromycin or azithromycin) with adjust-mentsdependingoninvitroantimicrobialsusceptibilitytesting.

• Patientsaregenerallytreatedfor12monthsofculturenegativity.• Extrapulmonary disease

• Treatment is the same as for pulmonary disease except that it is usually for 6 monthsdependingontheseverityofinfection.

PREVENTION• Noevidenceofperson-to-personspreadofNTMexists.• Tap(household)waterisconsideredthemajorreservoirformostcommonNTMspecies.• BiofilmsmayrenderNTMlesssusceptibletodisinfectantsandantimicrobials.• Publichealthconcernsareincreasing.

378

184 Nocardia SpeciesTania C. Sorrell, David H. Mitchell, Jonathan R. Iredell, and Sharon C-A. Chen

DEFINITION• NocardiosisresultsfrominfectionbymembersofthegenusNocardia,whichareubiquitous

environmental saprophytes that cause localized or disseminated disease in humans andanimals.

MICROBIOLOGY AND EPIDEMIOLOGY• Microscopically,Nocardiaappearasgram-positive,beaded,weaklyacid-fast,branchingrods.• Molecular speciation has revolutionized taxonomy by identifying several new species

and reassigning species, especially from the commonest pathogenic group, the formerN. asteroidescomplex.

• Infectionarisesbydirectinoculationthroughtheskinorbyinhalation.• MycetomasfromNocardiaspecies,mostoftencausedbyN. brasiliensis,affectimmunocom-

petenthostsintropicalcountries.• Immunocompromise,alcoholism,andcertain lungdiseasespredisposepatientstopulmo-

nary and disseminated nocardiosis, most often due to N. cyriacigeorgica, N. nova, orN. farcinica.

CLINICAL MANIFESTATIONS• Primaryskininfectioncancausesporotrichoidlesionsandleadtopyogenicabscessesorto

chronicallyprogressive,destructivediseasewithsinustractformation(mycetoma)usuallyonadistallimb.

• Presentationoflungdiseasemaybesubacuteorchronicwithproductiveornonproductivecough, dyspnea, hemoptysis, and fever and other systemic symptoms. Cavity formationwithinthepneumoniaorspreadtothecentralnervoussystem(CNS),orboth,aresuggestiveofnocardiosis.IsolatedCNSlesionsalsooccurandtheirpresentationcanbeinsidious.

DIAGNOSIS• Cerebralimaging,preferablymagneticresonanceimaging,shouldbeperformedinallcases

ofpulmonaryanddisseminatednocardiosistoruleoutinsidiousCNSdisease.• Themicrobiology laboratoryshouldbe informedof suspectednocardiosisbecause itmay

not be detected by routine laboratory methods. Respiratory secretions, skin biopsies, oraspiratesfromdeepcollectionsarethemostusefulandaretypicallypositiveonGramstain.Modifiedacid-faststainofsputumorpusishelpfulinsuggestingthediagnosis.GrowthofNocardiaspeciesmaytake48hourstoseveralweeksbutusually3to5days.

• Speciesidentificationispredictiveofantimicrobialsusceptibility;itrequiresmoleculariden-tificationtestsbasedonnucleicacidtechnology(NAT).

• Recentlymassspectrometryanalysisusingmatrix-assistedlaserdesorption/ionizationtime-of-flightmass spectrometryhasbeen reported tobea reliable andmore rapidalternativetoNAT.

379C

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THERAPY AND FOLLOW-UP• Trimethoprim-sulfamethoxazole(TMP-SMX)isthemainstayoftreatment,andmonother-

apyisusuallysuccessfulinpatientswithisolatedskininfectionormycetomasthatarenotextensive(seeTable184-1).

• In systemicdisease, speciationand/or susceptibility testing results shouldguidedefinitivecombinationtherapy.

• EmpiricaltherapywithamikacinandimipenemormeropenemoramikacinandTMP-SMXarerecommendedinimmunocompromisedpatientsorthosewithdisseminateddiseasebutnobraininvolvement.

• For isolated cerebral disease, empirical TMP-SMX plus imipenem or meropenem aresuitable.

• When additional sites are involved or the patient has life-threatening disease, empiricalthree-drugregimenssuchasTMP-SMX,imipenemormeropenem,andamikacin(orceftri-axone,inpatientswithrenalfailure)arepreferred.Initialadjunctivetherapywithlinezolidisanoption,especiallyifoneoftheseclassesofdrugiscontraindicated.

• Clinical improvement isgenerallyevidentwithin3 to5daysor,at themost,7 to10daysafterinitiationofappropriatetherapy.

• Prolongedtherapyisnecessarytopreventrelapse.• Surgical excision may be required depending on the extent and site of the lesions or the

responsetomedicaltherapy,orboth.• Patientswithdeep-seatedinfectionshouldbemonitoredclinicallyandradiologicallyduring

andforupto12monthsaftercessationoftherapy.

TABLE 184-1  Antimicrobial Susceptibility of Selected Nocardia Species

N.

cyri

acig

eorg

ica

N.

farc

inic

a

N.

no

va c

om

ple

x

N.

tran

sval

ensi

s co

mp

lex

N.

bra

silie

nsi

s

Trimethoprim-sulfamethoxazole S R S S S

Amoxicillin clavulanate R V R V S

Ceftriaxone S R S S R

Imipenem S S S S R

Amikacin S S S R S

Linezolid S S S S S

Moxifloxacin V S R ND R

Clarithromycin R R R S R

Minocycline V R V R R

Tigecycline V R V ND S

ND, no data; R, generally inactive; S, generally active (some isolates may be resistant); V, may be active but resistance common.

Data taken from multiple published sources.

380

185 Agents of ActinomycosisThomas A. Russo

DEFINITION• Indolentinfection• Chronicity,crossestissueboundaries,masslikefeatures• Mimicsmalignancy• Sinustract(s)maydevelop,resolve,andrecur• Refractoryorrelapsinginfectionmayoccurafterashortcourseoftherapy

MICROBIOLOGY• PrimarilycausedbyActinomycesspp.• Gram-positive,primarilyfilamentousbacteria• Mostareanaerobes,fewaremicroaerophilic• “Companionorganisms”areusuallypresent

EPIDEMIOLOGY/PATHOGENESIS• Humancommensaloforal,gastrointestinal,pelvicmucosa• Disruptionofmucosalsurfaceinitiatingfactor• Allagesandnormalhostsinfected• Associationwithintrauterinedevicesandbisphosphonates

CLINICAL MANIFESTATIONS• Allorgansandsitescouldbeinvolved• Orocervicofacialmostcommon• Classicpresentationaspainlessmassatangleofthejaw• Alternativepresentationsaremyriad

DIAGNOSIS• Challenging,oftenmissed,mistakenforcancer• Sulfurgranules• Informlaboratory• Priorantibioticscaninhibitgrowthonculture• Increasingroleforpolymerasechainreaction• Oftenmadeviapathologyafterpotentiallyunnecessarysurgery

THERAPY• Basedonclinicalexperience,individualized• Highdoseandprolongedcourseofantibiotics• Standard2to6weeksintravenously,followedby6to12monthsorally• Imaginghelpfulindefiningduration• Penicillin,tetracyclines,erythromycin,andclindamycinhavegreatestexperience• Ashortcourseoftreatmentdirectedagainst“companionorganisms”maybewarranted• Medicaltherapyusuallycurative,evenwithextensivedisease• Interventionalradiologyfordrainageofaccessibleabscess• Surgeryreservedforcriticalsites(e.g.,centralnervoussystem)andrefractorydisease

381

G  Mycoses

186 Aspergillus SpeciesThomas F. Patterson

DEFINITION• AspergillosisiscausedbyspeciesofthemoldAspergillus.• Syndromesrangefromcolonization;fungusballduetoAspergillus(aspergilloma);allergic

responsestoAspergillus,includingallergicbronchopulmonaryaspergillosis;tosemi-invasiveorinvasiveinfections,fromchronicnecrotizingpneumoniatoinvasivepulmonaryaspergil-losisandotherinvasivesyndromes.

EPIDEMIOLOGY• The highest incidence of infection occurs in patients undergoing hematopoietic stem cell

transplantationorsolid-organtransplantation(seeTable186-1).• Infection is more likely in patients with extensive immunosuppression or in those with

relapseorrecurrenceofunderlyingmalignancy.• Improvedsurvivalhasbeennotedwithearlydiagnosisandnewertherapies,butmortality

ratesinseverelyorpersistentlyimmunosuppressedpatientsaresubstantial.

MICROBIOLOGY• Culture-baseddiagnosisisusefultoestablishthespecificdiagnosis.• Aspergillusspeciescomplexesexhibitdistinctantifungalsusceptibilitiessothatculture-based

diagnosisisclinicallyrelevant(seeTable186-2).• Molecularanalysisisrequiredtoestablishspecies-levelidentity.• Increasingratesofantifungalresistancearereportedinsomesettingswithaglobalcloneof

antifungal-resistantspecies.

DIAGNOSIS• Proveninfectionisestablishedbycultureoftheorganism.• Biomarkers such as galactomannan,β-D-glucan, and polymerase chain reaction assay are

usefulforestablishingprobablediagnosis.• Serialassessmentofbiomarkersmaybeusefulformeasuringresponsetotherapy.

THERAPY• Voriconazoleisrecommendedforprimarytherapyinmostpatients(seeTable186-3).• LiposomalamphotericinBcanbeusedasprimarytherapyinpatientsinwhomvoriconazole

isnottoleratedorcontraindicatedbecauseofdruginteractionsorotherreasons.• AlternativeagentsforsalvagetherapyincludeamphotericinBlipidcomplex,theechinocan-

dins(caspofungin,micafungin,oranidulafungin),posaconazole,oritraconazole.• Combinationtherapyisnotrecommendedforroutineuse,butsomesubgroupsofpatients

(e.g.,thosewithearlydiagnosisofinfectionbasedondetectionofgalactomannanorthosewithfailureofprimarytherapywithasingleagent)maybenefitfromsuchanapproach.

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PREVENTION• Antifungalprophylaxiswithposaconazoleorpossiblyvoriconazoleisrecommendedinhigh-

riskpatients.• Therisk-benefitratioofprophylaxisinindividualpatientsatriskshouldbeconsidered.• Infectioncontrol is importanttoreducerisk inhospitalizedpatients,but longdurationof

risk (>180days) inhigh-riskhematopoietic stemcell transplantor solid-organ transplantpatientsmakescommunity-acquiredinfectionlikely.

TABLE 186-1  Incidence and Mortality of Invasive Aspergillosis in Transplantation

Type of Transplant

INCIDENCE (%)

12-Week Mortality (%)Range MeanAllogeneic stem cell 2.3-11 7 40-75

Autologous stem cell 0.5-2 1 50

Lung 2.4-9 6 5-21

Liver 1-8 4 45-59

Heart 0.3-6 2 15-21

Kidney 0.1-2 0.5 25-48

Data from the following sources:Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic

stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091-1100.

Neofytos D, Treadway S, Ostrander D, et al. Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis. 2013;15: 233-242.

Steinbach WJ, Marr KA, Anaissie EJ, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012;65:453-464.

Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50: 1101-1111.

Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18:44-69.Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ

transplant recipients. Transpl Infect Dis. 2010;12:220-229.Baddley JW, Andes DR, Marr KA, et al. Factors associated with mortality in transplant patients with invasive asper-

gillosis. Clin Infect Dis. 2010;50:1559-1567.

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ter 186 Asp

ergillu

s Species

TABLE 186-2  Characteristics of Aspergillus Species Associated with Invasive Infection

ASP

ERG

ILLU

S SP

ECIE

S

FREQ

UEN

CY

 OF 

SPEC

IES 

CO

MPL

EX I

SOLA

TED

 IN

 C

LIN

ICA

L IN

FEC

TIO

N (

%)

CO

LON

Y C

HA

RA

CTE

RIS

TIC

S

MIC

RO

SCO

PIC

 FEA

TUR

ES

CLI

NIC

AL 

SIG

NIF

ICA

NC

E

A. fumigatus 50-67 Smoky gray-green; may have pale yellow or lavender reverse; grows at 50° C

Columnar; uniseriate; smooth to finely roughened conidia 2-3.5 µm

Most common invasive species; most pathogenic

A. flavus 8-14 Olive to lime green Radiate to loosely columnar; uniseriate or biseriate; rough conidiophore; conidia 3-6 µm

Sinusitis; skin infection; produces aflatoxin

A. terreus 3-5 Beige to cinnamon buff

Columnar; biseriate; globose; small 2-2.5 µm conidia; globose accessory conidia along hyphae

Increasingly detected; resistant to amphotericin B; more susceptible to newer azoles

A. niger 5-9 Initially white, rapidly turning black with yellow reverse

Radiate; biseriate; globose, black, very rough conidia 4-5 µm

Uncommon in invasive infections; superficial agent of otic disease; colonization

Data from the following references:Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis: disease spectrum, treatment practices, and

outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000;79:250-260.Alastruey-Izquierdo A, Mellado E, Cuenca-Estrella M. Current section and species complex concepts in Aspergillus:

recommendations for routine daily practice. Ann N Y Acad Sci. 2012;1273:18-24.Balajee SA, Kano R, Baddley JW, et al. Molecular identification of Aspergillus species collected for the Transplant-

Associated Infection Surveillance Network. J Clin Microbiol. 2009;47:3138-3141.Sutton DA, Fothergill AW, Rinaldi MG, eds. Guide to Clinically Significant Fungi. Baltimore: Williams & Wilkins;

1998.

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ents

TABLE 186-3  Antifungal Agents for Invasive Aspergillosis

AG

ENT

CLA

SS

RO

UTE

 OF 

AD

MIN

ISTR

ATI

ON

DO

SE

CO

MM

ENTS

Primary TherapyVoriconazole Azole IV/

oral6 mg/kg (IV) q12h × 2 doses, followed by 4 mg/kg (IV) q12h or 200 mg (PO) q12h. Some experts advise oral dosing as 4 mg/kg (PO) q12h.

Recommended for primary therapy in most patients due to randomized trial demonstrating improved survival as compared with amphotericin B deoxycholate; caution for use in patients with potential liver toxicity and for drug interactions; measurement of serum levels advocated for efficacy and avoidance of toxicity (controversial)

Alternative Primary TherapyLiposomal amphotericin B

Polyene IV 3 mg/kg/day Well tolerated; minimal infusion reactions or nephrotoxicity; initial doses of 10 mg/kg/day more toxic and not more effective

Other AgentsAmphotericin B Polyene IV 1-1.5 mg/kg/day Previous gold standard; significant

toxicity in higher doses; limited efficacy in high-risk patients

Amphotericin B lipid complex

Polyene IV 5 mg/kg/day Indicated for patients intolerant or refractory to standard therapy; case-controlled data suggest better efficacy than amphotericin B deoxycholate

Amphotericin B colloidal dispersion

Polyene IV 3-6 mg/kg/day More infusion-related toxicity than other lipid formulations; efficacy similar to amphotericin B in primary treatment

Posaconazole Azole Oral Investigational in United States for Aspergillus treatment: 400 mg (PO) bid; prophylaxis 200 mg (PO) tid

Oral formulation; efficacy in salvage therapy and prophylaxis

Itraconazole Azole Oral 200 mg bid (PO) Erratic bioavailability improved with oral solution; serious cardiac adverse events with higher doses, drug interactions common; intravenous formulation not currently available

Caspofungin Echinocandin IV 50-70 mg/day Approved for refractory infection and intolerance to standard therapy; well tolerated; limited efficacy as monotherapy for primary infection; preclinical and anecdotal data showing improved efficacy in combination with azoles

Micafungin Echinocandin IV Investigational in United States for Aspergillus treatment (50-100 mg/day)

Efficacy for prevention and salvage treatment of aspergillosis

Anidulafungin Echinocandin IV Investigational for Aspergillus (100 mg/day)

Combination trial data showing improved outcomes in patients with galactomannan diagnosis of invasive pulmonary aspergillosis

385

187 Agents of Mucormycosis and EntomophthoramycosisDimitrios P. Kontoyiannis and Russell E. Lewis

DEFINITION• Mucormycosisisanaggressive,angioinvasivefungalinfectioncausedbyfilamentousfungi

inthesubphylumMucormycotina,whichafflictimmunocompromisedorseverelyhypergly-cemicpatients.Skinandsofttissueinfectionsinimmunocompetentpatientsmaybeencoun-teredinpatientswithseveresofttissuetrauma(e.g.,tornadoes,combatinjuries).

• Entomophthoramycosisisarareinfectionoftheparanasalsinuses,subcutaneoustissues,orgastrointestinaltractcausedbyfilamentousfungiinthesubphylumEntomophthoramycotina,whichareprincipallyencounteredinthetropics.

EPIDEMIOLOGY• Mucormycosis is acquired primarily via inhalation of environmental sporangiospores in

immunocompromisedhosts.Theinfectionmaybreakthroughantifungalprophylaxisregi-mensusedtoreducetheriskofaspergillosis.

• Entomophthoramycosis typically causes indolent subcutaneous infections localized to thesinuses,headandface(conidiobolomycosis),ortrunkandarms(basidiobolomycosis)frominhalationorminortrauma.Gastrointestinalbasidiobolomycosishasoccurred inArizonaandtheNearEastandisperhapsacquiredbyingestion.

MICROBIOLOGY• Mostcommonculture-confirmedcasesintheliteratureareRhizopusspecies(47%),Mucor

species(18%),Cunninghamella bertholletiae (7%),Apophysomyces elegans (5%),Lictheimia (Absidia) species (5%), Saksenaea species (5%), and Rhizomucor pusillus (4%), with otherspecies(8%)accountingfortheremainingcases.

• Conidiobolus coronatusandConidiobolus incongruuscauseconidiobolomycosis.Basidiobolus ranarumcausesbasidiobolomycosis.

DIAGNOSIS• Ahighindexofsuspicioninimmunocompromisedpatientsisessentialbecausemostsigns,

symptoms,andradiographicsignsarenonspecific.Cultureshaveapoorsensitivity.Diagnosisis typically established by histopathologic documentation of “ribbon-like” angioinvasivehyphaeintissue,thoughthisispronetoerror.

TREATMENT• Lipid formulations of amphotericin B are the drug of choice. Some patients can then be

transitionedtooralposaconazoleifabsorptionisadequate.

PREVENTION• Giventherarityofmucormycosisandentomophthoramycosis,primaryprophylaxis isnot

recommended. Secondary or potentially indefinite prophylaxis should be considered forimmunocompromisedpatientswithpreviousepisodesofmucormycosis,dependingonthestatusofunderlyingimmunosuppression.

386

188  Sporothrix schenckiiJohn H. Rex and Pablo C. Okhuysen

MICROBIOLOGY AND EPIDEMIOLOGY• Adimorphicfungus,withbuddingyeastintissueandamoldinculture• Worldwidedistribution,especiallyintropicalandsubtropicalregions• Acquisitionisassociatedwithexposuretosoil,plants,plantproducts(hay,straw,sphagnum

moss),andavarietyofanimals(especiallycats)• Growsslowlyonfungalculturefrominvolvedtissues

DIAGNOSIS• Lymphocutaneousdiseases:presentationwithanindolentpapulonodularlesion,sometimes

ulcerating,shouldsuggestthediagnosis.Secondarylesionsalonglymphangiticchannelsarecharacteristic. Biopsy will show pyogranulomas without visible organisms; culture will bepositive.

• Themostcommonextracutaneousformisosteoarticular.Pulmonarydisease(usuallycavi-tary)andmeningealdiseasearealsowelldescribed.Allarediagnosedbyculturewithorgan-ismsnotcommonlyseenonexaminationoftissuesandfluidsexceptincavitarypulmonarydisease.

• Multifocaldisseminationmayalsooccur,inimmunocompromisedsubjects:culturesofskinlesions and joints are usually positive, whereas blood and bone marrow cultures are onlyoccasionallypositive.

• Serodiagnosticmethodsremainexperimental.

THERAPY• Itraconazoleat200mg/dayorally is thetreatmentofchoicefor lymphocutaneousdisease,

with3to6monthsoftherapytypicallyneededforcompleteresolution.• Therapywithasaturatedsolutionofpotassiumiodideisalsoeffectiveforlymphocutaneous

disease,althoughassociatedwithmanysideeffects.• Itraconazoleisalsoactiveinextracutaneousdisease,butextendedtherapymayberequired.

Indifficultsettings,amphotericinBisalsoemployed.Improvementofimmunestatus(e.g.,introductionofantiretroviraltherapyinsubjectswithhumanimmunodeficiencyviruscoin-fection,reductionofimmunosuppressiveagents)isuseful.

387

189 Agents of ChromoblastomycosisDuane R. Hospenthal

DEFINITION• Chronicfungalinfectionlimitedtotheskinandsubcutaneoustissue• Scalynodular,tumorous,verrucous,plaque,orcicatriciallesions,typicallyaffectingthelower

extremities• Definedbythemicroscopicpresenceofmuriformcells

EPIDEMIOLOGY• Worldwidedistribution,withmostcasesoccurringintropicalandsubtropicalregions• LargestnumbersofcasesreportedfromMadagascar,Brazil,Mexico,Venezuela,andCosta

Rica• Male predominance, ages 40 to 69; commonly associated with outdoor activities such as

farmingorwoodcuttingandwithabsenceoffootwear

MICROBIOLOGY• MostcommonlycausedbyFonsecaea pedrosoi• Less commonly caused by Cladophialophora carrionii, Fonsecaea monophora, Fonsecaea

nubica, Phialophora verrucosa,orRhinocladiella aquaspersa• Otherdark-walledfungirarelyreportedascausativeagents

DIAGNOSIS• Presence of muriform cells (also called sclerotic, copper penny, or Medlar bodies)

pathognomonic• Muriformcellsobservedmicroscopicallyinskinscrapingspreparedwithpotassiumhydrox-

ideorinroutinelystainedskinbiopsyspecimens• Cultureonstandardmycologicmediapossiblebutnotalwaysnecessary

THERAPY• Noproventreatmentidentified• Small lesions treated successfully with surgical excision, liquid nitrogen or topical heat

application,orphotocoagulation;useofcurettageandelectrocauterydiscouragedbecauseofreportsofdiseasespreadaftertheiruse

• Oral itraconazole or terbinafine in combination with local liquid nitrogen therapy mosteffectivetherapy

• Posaconazole used successfully in small number of patients refractory to itraconazole orterbinafine

PREVENTION• Novaccineavailable• Needforfootwearandproperprotectiveclothing

388

190 Agents of MycetomaDuane R. Hospenthal

DEFINITION• Mycetoma is an infection of the skin and subcutaneous tissue characterized by a triad of

localizedswelling,drainingsinuses,andgrains(aggregatesofinfectingorganisms).• Itmostcommonlyaffectsasinglesite,typicallyinvolvingthelowerextremity,andespecially

thefoot.• Eumycetoma (eumycotic mycetoma) is mycetoma caused by fungi, most commonly

Madurella mycetomatis.• Actinomycetoma (actinomycotic mycetoma) is mycetoma caused by bacteria, most com-

monlyNocardia brasiliensis.

EPIDEMIOLOGY• Distributionisworldwidewithmostcasesoccurringintropicalandsubtropicalregions.• Largest numbers of cases are reported from Africa, Latin America, and the Indian

subcontinent.• Mycetoma occurs predominantly in men, ages 20 to 40, typically with occupations that

exposethemtotheenvironment.

MICROBIOLOGY• M. mycetomatis, Madurella grisea,andPseudallescheria boydiiarethemostcommoncauses

ofeumycetoma,althoughmanyothergeneraandspeciesoffungihavebeenreportedasetio-logicagents.

• N. brasiliensis, Actinomadura madurae, Streptomyces somaliensis,andActinomadura pelletieriare the most common causes of actinomycetoma, although disease secondary to otherspeciesofActinomadura, Nocardia,andStreptomyceshasbeendescribed.

DIAGNOSIS• Clinicalpresentationoftheclassictriadofchronic,painless,softtissueswellingwithdraining

sinusesthatdischargegrainsispathognomonic.• Microscopic examination of the grains can differentiate between eumycetoma and

actinomycetoma.• Cultureofcausativeagentfromgrainscanbetterdirectselectionofantimicrobialtherapy.• Radiographictechniques(plainradiographs,ultrasound,computedtomography,andmag-

neticresonanceimaging)canbeusedadjunctivelyinmaking(orexcluding)thediagnosisanddeterminingitsextent.

THERAPY• Smalllesionsmaybetreatedsuccessfullywithsurgicalexcisionalone.• Actinomycetomaistypicallytreatedwithmedicaltherapyalone.• Eumycetomacommonlyrequirescombinedmedicalandsurgicaltherapy.• Nosingletherapyhasprovedmosteffectiveforeitherformofmycetoma.• Mostactinomycetomaregimensincludeparenteralaminoglycosidesandoralsulfadrugs.

389C

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ma

• Less severe actinomycetoma may be treated with 6 to 24 months of trimethoprim-sulfamethoxazole.

• Eumycetomaistypicallytreatedwitharegimenofanoralazoleantifungaldrugfor6to24monthscombinedwithdebulkingsurgery.

PREVENTION• Novaccineisavailable.• Useoffootwearandproperprotectiveclothingshouldprotectagainstthisinfection.

390

191 Cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii )John R. Perfect

HISTORY• Thelifecyclerepresentsbothasexual(clinical)andsexual(recombination)cycleswiththe

impactofsexualcycleonpathogenesis.

TAXONOMY• There are 19 cryptococcal species with two major pathogenic species, C. neoformans and

C. gattii.• Atpresent,thefollowingtaxonomicdivisionshavebeenproposed:Cryptococcus neoformans

var.grubii(serotypeA),withthreegenotypes(VNI,VNII,VNB);Cryptococcus neoformansvar.neoformans (serotypeDorVNIV);andfiveothercrypticspecies:Cryptococcus gattii, Cryptococcus bacillisporus, Cryptococcus deuterogattii, Cryptococcus tetragattii, andCryptococcus decagattii(serotypesB/CorVGl-lV).

IDENTIFICATION• Biochemicaltests,includingurease,melaninproduction,andappearanceofcapsule• CulturesorDNA-basedtests

ECOLOGY• C. neoformans(serotypesAandD)foundinpigeonguanotorottingtrees• C. gattiifoundineucalyptustoconiferoustrees(landscapeofnichemaybechanging)

EPIDEMIOLOGY• Notroutineconstituentofhumanbiotabutcancolonizehumanswithoutdisease• Widespreadasymptomaticinfectionsintheexposedpopulations• Risk factors for disease (acquired immunodeficiency syndrome [AIDS], corticosteroid

treatment, transplantation, cancer, monoclonal antibodies, sarcoidosis, autoantibodies togranulocyte-macrophagecolony-stimulatingfactor,idiopathicCD4lymphocytopenia);pri-marilycell-mediatedimmunitydefect(seeTable191-1)

• Antiretroviraltherapy(ART)impactonclinicalcryptococcosisisimpressiveinpatientswithAIDS.

• Amillionnewcasesofcryptococcosisperyear,withmorethan600,000deathsworldwideat thepeakof thehuman immunodeficiencyvirus (HIV)epidemicandprobablyreducedwithARTavailability

PATHOGENICITY• Virulencefactors(capsule,melanin,hightemperaturegrowth,urease,phospholipase)• Understandingatthegeneticandmolecularlevel

HOST RESPONSES• Efficientprotectionrequiresintactcell-mediated,innate,andhumoralimmunity.

391C

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ter 191 Cryp

toco

ccosis (C

rypto

coccu

s neo

form

ans an

d C

rypto

coccu

s gattii)

PATHOGENESIS• Threefactors:(1)hostdefenses,(2)virulenceofstrain,and(3)sizeofinocula• Cryptococcosisconsideredprimarilyareactivationdisease

CLINICAL MANIFESTATIONS (SEE TABLE 191-2)• Majorsitesarethecentralnervoussystemandlung.• Othersiteswithuniqueconsiderationsaretheskin,prostate,peritoneum,andeye.• Cryptococcicaninfectanyorganofthehumanbody.• Diseaseprimarilydependsonhostimmunity(eitherfromtoolittleortoomuch[immune

reconstitutioninflammatorysyndrome,IRIS]).

LABORATORY DIAGNOSIS• Microscopy(Indiainkandhistopathologicstainsincludingmucicarmine)• Cultureofcerebrospinalfluid(CSF),blood,bronchoalveolarlavage• CryptococcalantigenonCSFandserumissensitiveandspecificasdetectedbylatexagglu-

tination,enzyme-linkedimmunosorbentassay,andlateralflow

MANAGEMENT• TheInfectiousDiseasesSocietyofAmericanGuidelinesin2010establishedroadmapsfor

therapiesandstrategies(www.idsociety.org/Organism/#Fungi).• Directantifungaldrugresistanceuncommonlyarisesduringtherapy.• TreatmentisbeststudiedforcryptococcalmeningitisinHIV-infectedpatients(2013guide-

lines at http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/333/cryptococcosis).TreatmentisinitiatedwithamphotericinB,pref-erablywiththeliposomalformulationat3to4mg/kgdaily,thealternativesbeingthelipidcomplexat5mg/kgorconventionalamphotericinBat0.7mg/kg/day.Anyoneofthesecanbeusedplusflucytosine25mg/kgevery6hours(100mg/kgperday) forat least2weeksanduntilclinicallyimproved.Inseverelyillpatientsorthosewithhighintracranialpressure,delaying ART during these 2 weeks may prevent IRIS from complicating management.PatientswhorespondtoamphotericinBmaybeswitchedtofluconazole,400to800mg/day,for8to10weeksasaconsolidationphase.Finally,asuppressivephaseisbegunwithfluco-nazole200mgoncedaily.Antifungaltherapycanbestoppedafter1to2yearsinpatientswhorespondtoARTwithaCD4countabove100/µLforatleast3months,anondetectableviralload,andanegativeorlowserumcryptococcalantigen.

TABLE 191-1  Conditions Known or Possibly Associated with Predisposition to Cryptococcus neoformans InfectionsHIV infectionLymphoproliferative disordersSarcoidosisCorticosteroid therapyHyper-IgM syndromeHyper-IgE syndrome

Autoantibodies to GM-CSFMonoclonal antibodies (e.g., infliximab intercept, adalimumab, alemtuzumab)Systemic lupus erythematosus*HIV-negative CD4+ T-cell lymphocytopeniaDiabetes mellitus†

Organ transplantation*Peritoneal dialysisCirrhosis

GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus.*Immunosuppressive therapy may account for the predisposition.†Diabetes mellitus has historically been considered a risk factor for cryptococcal infection. However, diabetes is a

common disease, and it is unclear whether this condition is truly a specific risk factor for cryptococcosis.Modified from Casadevall A, Perfect JR. Cryptococcus neoformans. Washington, DC: ASM Press; 1998:410.

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• Complicationsofcryptococcalmeningitisrequiringspecialattentionare(1)increasedintra-cranialpressure,whichcan leadtoblindness,permanentdementia,anddeath;(2)hydro-cephalus, which may require placement of a ventriculoperitoneal shunt; and (3) immunereconstitutionsyndrome,whichmaybemistakenfortherapeuticfailure.

TABLE 191-2  Clinical Manifestations of Cryptococcosis

Central Nervous SystemAcute, subacute, chronic meningitis

Cryptococcomas of brain (abscesses)

Spinal cord granuloma

Chronic dementia (from hydrocephalus)

LungNodules (single or multiple)

Lobar infiltrates

Interstitial infiltrates

Cavities

Endobronchial masses

Endobronchial colonization

Acute respiratory distress syndrome

Mediastinal adenopathy

Hilar adenopathy

Pneumothorax

Pleural effusions/empyema

Miliary pattern

SkinPapules and maculopapules

Subcutaneous abscess

Vesicles

Plaques

Cellulitis

Purpura

Acne

Draining sinuses

Ulcers

Bullae

Herpetiformis-like

Molluscum contagiosum–like

EyePapilledema

Extraocular muscle paresis

Keratitis

Chorioretinitis

Endophthalmitis

Optic nerve atrophy

Genitourinary TractProstatitis

Renal cortical abscess

Positive urine culture from occult source

Genital lesions

Bone and JointsOsteolytic lesion (single or multiple sites)

Arthritis (acute/chronic)

MuscleMyositis

Heart, Blood VesselsCryptococcemia

Endocarditis (native and prosthetic)

Mycotic aneurysm

Myocarditis

Pericarditis

Infected vascular graft

Gastrointestinal TractEsophageal nodule

Nodular or ulcerated lesions in stomach or intestines (may resemble Crohn’s disease)

Hepatitis

Peritonitis

Pancreatic mass

BreastBreast abscess

Lymph nodes

Lymphadenopathy

ThyroidThyroiditis

Thyroid mass

Adrenal GlandAdrenal insufficiency

Adrenal mass

Head and NeckGingivitis

Sinusitis

Salivary gland enlargement

Modified from Casadevall A, Perfect JR. Cryptococcus neoformans. Washington, DC: ASM Press; 1998:409.

393

192 Histoplasma capsulatum (Histoplasmosis)George S. Deepe, Jr.

DEFINITION• Histoplasmosis is themost frequentcauseof fungal respiratory infectionandhasabroad

spectrumofclinicalmanifestationsrangingfromaself-limited,acute,influenza-likeillnesstoaprogressivedisseminatedinfectionthatislifethreatening.

EPIDEMIOLOGY• The fungus is typically found in the midwestern and southeastern United States and in

CentralandSouthAmerica.• Indigenouscaseshavebeenreportedworldwide.• Thefungusthrivesindecayingbirdguano(starlingsandblackbirds)andbatguano.• Patientswithacquiredimmunodeficiencysyndrome(AIDS)orreceivingimmunosuppres-

sive drugs, including tumor necrosis factor-α inhibitors, are predisposed to disseminatedinfection.

MICROBIOLOGY• Thefungusexistsinthemycelialforminnature.• The mycelia produce two sizes of conidia—micro and macro. The former are thought to

inducediseasebecausetheyaresmallenoughtoreachthebronchiolesandalveoli.• Conversiontotheyeastphaseisdrivenbytemperature.

DIAGNOSIS• SerologyisusefulforallbutAIDSpatients.Complement-fixationtitersof1:32orgreater

areindicativeofactivedisease.ThepresenceoftheHimmunodiffusionbandsignifiesactivedisease.AnMbanddoesnotdiscriminatebetweencurrentorremoteinfection.

• TheHistoplasmaantigentesteitherfromurineorserumisparticularlyusefulindiagnosisofextrapulmonarydisease.Itisalsousefulforfollowingresponsetotherapy.

• Tissueandbuffycoatexaminationisusefulfordetectingtheorganism.• SeeTable192-1fordiagnostictests.

THERAPY• Pulmonaryhistoplasmosis:mildtomoderate—notreatmentoritraconazole200mg3times

daily,followedby200mgtwiceadayfor6to12weeks;moderatetosevere—lipid-formulatedamphotericin B, 3 to 5mg/kg or deoxycholate amphotericin B, 0.7 to 1mg/kg, for 1 to 2weeks, followed by itraconazole for total of 10 to 11 weeks; cavitary—itraconazole asdescribedabove.

• Disseminateddisease:moderatetosevere—sameasmoderate-to-severepulmonarydisease;inchildrencanusedeoxycholateamphotericinB,1mg/kgfor4to6weeks.

• Rheumatologicmanifestations—nonsteroidals• Mediastinal lymphadenitis—no treatment or, if symptomatic, itraconazole as described

above• SeeTable192-2fortreatmentoptions.

394Part

 II 

Infe

ctio

us 

Dis

ease

s an

d t

hei

r Et

iolo

gic

 Ag

ents

PREVENTION• Prophylaxisforimmunosuppressedpatients—itraconazole200mgdaily• Avoid construction sites, spelunking, and remodeling of unoccupied homes or farm

habitats.

TABLE 192-1  Diagnostics for Histoplasmosis

INFECTION SITE DISEASE SEVERITY DIAGNOSTICLung

  Acute Mild-moderate H and M bands and complement fixation.

Moderate to severe As above. Serum or urine antigen, or both, also may be positive in up to 70%. Bronchoalveolar fluid antigen may be useful. Culture of bronchoalveolar lavage fluid and silver stain of concentrated lavage fluid. Sputum culture.

  Chronic cavitary H and M bands and complement fixation. Culture  of bronchoalveolar lavage fluid and silver stain of concentrated lavage fluid. Sputum cultures.

Disseminated

Acute Serum or urine antigen, or both. H and M bands and complement fixation. These are not useful in AIDS patients. Examination of the buffy coat for yeast cells in phagocytes. Biopsy of bone marrow or liver with silver stain and culture. Blood culture.

Chronic Serum or urine antigen, or both. H and M bands and complement fixation. Biopsy of tissue with silver stain and culture.

Central nervous system Serum or urine antigen, or both. CSF antigen. Culture of CSF. H and M bands and complement fixation are not as useful.

Mediastinal

Lymphadenitis H and M bands and complement fixation.

Granuloma H and M bands and complement fixation.

Fibrosis H and M bands and complement fixation.

Rheumatologic Arthralgias H and M bands and complement fixation.

Pericarditis H and M bands and complement fixation.

Endocarditis/Endovascular H and M bands and complement fixation. Serum or urine antigen, or both. Culture and silver stain of valve.

AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.

395C

hap

ter 192 Histo

plasm

a capsu

latum

 (Histo

plasm

osis)

TABLE 192-2  Treatment of Histoplasmosis

INFECTION SITE DISEASE SEVERITY TREATMENTLung

  Acute Mild-Moderate None or itraconazole 200 mg 3 times daily for 3 days followed by 200 mg twice a day for 6-12 wk.

Moderate-Severe Lipid-formulated amphotericin B, 3-5 mg/kg, or deoxycholate amphotericin B, 0.7-1 mg/kg, daily for 1-2 wk followed  by itraconazole 200 mg 3 times a day for 3 days followed by 200 mg twice a day for a total duration of 12 wk.  For children, itraconazole 5-10 mg/kg or deoxycholate amphotericin B, 1 mg/kg daily.

  Chronic cavitary Itraconazole 200 mg 3 times a day for 3 days followed by twice daily for at least 1 yr and as long as 2 yr.

Disseminated

Acute Lipid-formulated amphotericin B, 3-5 mg/kg, or deoxycholate amphotericin B, 0.7-1 mg/kg, daily for 1-2 wk followed by itraconazole 200 mg 3 times a day for 3 days followed  by 200 mg twice a day for at least 12 mo. For children, deoxycholate amphotericin B (1 mg/kg) daily for 4-6 wk or 2-4 wk followed by itraconazole 5-10 mg/kg daily. Total duration = 3 mo.

Chronic Itraconazole 200 mg 3 times a day for 3 days followed by 200 mg twice a day for at least 1 yr. Serum levels should be monitored to ensure adequate concentrations.

Central nervous system

Liposomal amphotericin B, 5 mg/kg daily for 4-6 wk followed by itraconazole administered as above for at least 1 yr and resolution of symptoms and negative cerebrospinal fluid antigen.

Mediastinal

Lymphadenitis No treatment. If symptomatic (e.g., dysphagia), itraconazole 200 mg twice daily for 12 wk. Corticosteroids (60 mg with a rapid taper) may be used to diminish lymph node size.

Granuloma Same as lymphadenitis. Corticosteroids are not necessary.

Fibrosis Surgical intervention with stents. Antifungals are not useful.

Rheumatologic Arthralgias, etc. Nonsteroidals

Pericarditis Nonsteroidals or corticosteroids. If the latter, treat with itraconazole (200 mg × 3 for 3 days and then once a day) until corticosteroids have been discontinued.

Endocarditis/Endovascular

Surgical removal of the valve combined with lipid-formulated amphotericin B, 5 mg/kg daily for 6 wk. Lifelong suppression may be considered in some who are not surgical candidates with itraconazole 200 mg once or twice a day.

Data from Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with  histoplasmosis:  2007  update  by  the  Infectious  Diseases  Society  of  America.  Clin Infect Dis.  2007;45:807-825.

396

193  BlastomycosisRobert W. Bradsher, Jr.

DEFINITION• InfectionbyBlastomycesdermatitidis

MICROBIOLOGY AND EPIDEMIOLOGY• Broad-basedsinglebuddingyeast• Blastomyces dermatitidis:dimorphic;grows25°to28°Casamoldandat37°Casyeast• Visible in wet preparations of potassium hydroxide or calcofluor white by fluorescent

microscopy• PrimarilyinNorthAmerica—Mississippi,Ohio,andSt.LawrenceRiverValleysandGreat

Lakesregions• Point source outbreaks, often around lakes or rivers with recreational or occupational

exposures• Endemicorsporadiccasesmostcommonlyinnormalhosts,althoughimmune-suppressed

hostscanbeinfectedandcouldreactivateinfectionfrompriorsubclinicalinfection• Cellularimmunityistheprimaryhostdefensetocontroltheinfection

CLINICAL MANIFESTATIONS• Pulmonaryportalofinfectionwithpneumoniathemostcommonfinding• Extrapulmonary infection to skin and subcutaneous tissue most common but also bone,

prostate,centralnervoussystem(CNS),oressentiallyanyorgan

DIAGNOSIS• Diagnosis by visualization of organism with fungal stains or by culture of specimens. No

colonizationorcontaminationwiththisfungus• Antibodytestslackofsensitivity• Antigentestingofurinemaybeuseful fordiagnosis,butcross-reactionsoccurwithother

dimorphicfungalinfections

TREATMENT (SEE TABLE 193-1)• Itraconazoleisthedrugofchoiceformild-to-moderatepulmonaryornon-CNSextrapul-

monaryinfection• AmphotericinB(usuallylipid)isthetreatmentforsevereinfectionuntilimprovementand

thenitraconazole• CNSinfectionwithlipidamphotericinB,followedbyvoriconazoleorfluconazole

397C

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myco

sis

TABLE 193-1  Treatment of Blastomycosis*

INDICATION THERAPYModerately severe or severe pulmonary blastomycosis or immunosuppressed patients

Liposomal amphotericin B 3-5 mg/kg or conventional amphotericin B 0.7-1 mg/kg once daily for 6-8 wk.After improvement, consider switching to itraconazole 200 mg PO once or twice daily.†

Pregnant Liposomal amphotericin B 3-5 mg/kg or conventional amphotericin B 0.7-1 mg/kg once daily for 6-8 wk.

Brain abscess or meningitis Amphotericin B as above until improved. For step-down treatment, consider itraconazole 200 mg PO 2-3 times daily, fluconazole 800 mg daily, or voriconazole 6 mg/kg for 2 doses, then 4 mg/kg q12h, IV or PO.

Mild-to-moderate pulmonary blastomycosis Itraconazole 200 mg PO once or twice daily.†

IV, intravenous; PO, by mouth.*Total duration of therapy at least 6 months. Disseminated, central nervous system, osteoarticular, or cavitary

pulmonary manifestations may require longer treatment.†Consider monitoring trough levels of native drug in patients not responding to itraconazole. Levels above

1 µg/mL by high-performance liquid chromatography are considered desirable, although data are scant.

398

194 Coccidioidomycosis (Coccidioides Species)John N. Galgiani

DEFINITION• Thedimorphicfungi,Coccidioides immitisandCoccidioides posadasii,causeasystemicfungal

infection,coccidioidomycosis,alsoknownasSan Joaquin Valley fever.

EPIDEMIOLOGY• CoccidioidomycosisisendemictoaridregionsoftheWesternHemisphere.• Approximately150,000newU.S.infectionsoccurannuallywith60%originatinginArizona

and30%inCalifornia.Ofthese,50,000producesignificantillness.• Infectionsmostfrequentlyoccurduringdryseasons,andtheincubationperioduntilfirst

symptomsrangesfrom1to3weeks.• The most common illness is a community-acquired pneumonia, lasting weeks to months

whether treated or not with antifungal agents. Progressive pneumonia or hematogenousdisseminationtootherorgansisaseriouscomplicationthatrequirestreatment.

• Patientswithdiabetesaremorelikelytosufferpulmonarycomplications.• Disseminationisfrequentinpatientswithimpairedcellularimmunity.

MICROBIOLOGY• Coccidioideshasbeenfoundindesertsoilandassociatedwithanimalburrowsbutissparsely

distributed,evenwithinthemosthighlyendemicregions.• Throughout the 20th century, coccidioidomycosis was recognized as caused by a single

fungalspecies,C. immitis.Thispopulationcontainstwogeneticallyandgeographicallydis-tinctclades,nowrecognizedasseparatespecies:C. immitispredominantlyfoundinCaliforniaandC. posadasiiinallotherendemicregions.

• Onmostlaboratorymedia,growthbyapicalmycelialelongationisvisiblewithinaweek.• Alternatehyphalcellsautolyze,leavingbehindsingle3-to5-µmcells(arthroconidia)that

canbecomeairborneandcapableofbeinginhaleddeepintoairways.• Inmammaliantissue,anarthroconidiumremodelsintoasphericalcellthatenlargesisotro-

picallytoformlargematurespheruleswithscoresofendosporesdevelopingwithin.• Endospores,whenreleasedduringspherulerupture,candevelopintoanewspherulewithin

hosttissueorreverttomycelialgrowthifremovedfromtheinfection.• A sexual phase has not been observed, but population genetics suggest that one exists.

SequenceanalysisindicatesthatCoccidioidesisanascomycete.

DIAGNOSIS• IsolationofCoccidioidesinculturefromaclinicalspecimenisdiagnosticofinfection.• Recognizing endospore-containing spherules in wet mounts or histologic sections is also

definitive.• Diagnosisinmostpatientsismadepresumptivelybydetectinganticoccidioidalantibodies

inserumorcerebrospinalfluid.

399C

hap

ter 194 Co

ccidio

ido

myco

sis (Co

ccidio

ides Sp

ecies)

• Complement-fixinganticoccidioidal antibodiesarequantitatedby serialdilution titration.Moreextensiveinfectionsarefrequentlyassociatedwithhighertiters,andclinicalimprove-mentisassociatedwithdecreasingtiters.

• Immunodiffusion techniques are routinely used to provide a qualitative mimic of thecomplement-fixing antibody test and also to detect other Coccidioides-specific antibodies,oftenIgM,whichoccurearlier.

• ProprietaryenzymeimmunoassaykitsthatmeasureanticoccidioidalIgMandIgGantibodiesareinwideuse.Theyaremoresensitiveindetectingearlycoccidioidalinfectionsbutmaynotbeasspecific.

• Atestforcoccidioidalantigensiscommerciallyavailableandismostfrequentlypositiveinpatientswithextensiveinfection.

THERAPY• Healthypatientswithuncomplicatedcoccidioidalpneumoniausuallyimprovewithgeneral

supportivemanagementwhetherornotantifungaldrugsareused.Ifantifungaltreatmentisinitiatedforsuchpatients,itusuallyconsistsoffluconazolegivenorallyatadoseof400mgperdayforperiodsrangingfrom3monthsto1year.

• PatientswithsevereearlypneumoniasufficienttorequireintensivecarehospitalizationareoftentreatedwithintravenousamphotericinBinitiallyuntiltherespiratorystatusstabilizesorimproves.

• Wheninfectionresults inchronicfibrocavitarypneumoniaorextrapulmonarydissemina-tion,antifungal therapyinvolvesoralfluconazole(400mgdailyorhigher)or itraconazole(200mgtwiceorthreetimesdaily).Treatmentwouldnormallybecontinuedforatleast1year.Insuchpatients,itisnotinfrequentfortreatmenttocontinueforseveralyearsbecauserelapseofftreatmentiscommon.

• Insomepatients,surgeryisessentialinadditiontoantifungaldrugstocontrolinfection.• Treatmentofcoccidioidalmeningitis ismost frequentlymanagedwithoralfluconazole in

dosesof400to800mgdaily.Thistreatmentislifelongforallpatients.Patientswhodevelophydrocephalususuallyrequiretheplacementofaninternalventricularshunt.

PREVENTION• Apreventivevaccineforcoccidioidomycosisisnotavailable.

400

195 Dermatophytosis (Ringworm) and Other Superficial MycosesRoderick J. Hay

DEFINITION• Dermatophyteinfectionsaresuperficialinfectionsofthestratumcorneumoftheskinorof

keratinizedappendages,suchashairornails,arisingfromit.OthersuperficialinfectionsarecausedbyCandidaandMalasseziaspp.orlesscommonorganisms(e.g.,Piedraia).

EPIDEMIOLOGY• Globally,thesuperficialfungalinfectionsoftheskinaffectmorethan900,000millionindi-

viduals.Mosthavenounderlyingabnormality,althoughindividualconditionssuchassebor-rheicdermatitisandoropharyngealcandidiasismaybeearlysignsofhumanimmunodeficiencyvirusinfection.

MICROBIOLOGY• ThemainfungiinvolvedaredermatophytespeciesofthegeneraTrichophyton, Microsporum,

andEpidermophytonandyeastssuchasCandidaorMalasseziaspp.Lesscommonly,othermoldfungi(e.g.,Scytalidium)areimplicated.

DIAGNOSIS• Directmicroscopyoftheskinandcultureisdiagnostic.Moleculardiagnostictechniquesare

indevelopment.

THERAPY• Topicaltreatmentsincludeazoleantifungalagentsandterbinafine.Seleniumsulfideandzinc

pyrithione have specific activity against Malassezia. Oral therapies are itraconazole andfluconazole;oralterbinafineisusedmainlyfordermatophyteinfections(seeTable195-1).

PREVENTION• There are no major preventive programs, although early identification of infection limits

spreadincommunities,suchasschools.

401C

hap

ter 195 Derm

atop

hyto

sis (Rin

gw

orm

) and

 Oth

er Sup

erficial M

ycoses

TABLE 195-1  Treatment of Dermatophytosis

DERMATOPHYTOSIS, CLINICAL DISEASE PATTERN TREATMENTTinea pedis

Interdigital Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole, etc.), undecenoic acid, tolnaftate

“Dry type” Oral: terbinafine, 250 mg/day for 2-4 wk; itraconazole, 400 mg/day for 1 wk per month (repeated if necessary); fluconazole 200 mg weekly for 4-8 wk

Tinea corporis

Small, well-defined lesions Topical cream/ointment: terbinafine, imidazoles (e.g., miconazole, econazole, clotrimazole)

Larger lesions Oral: terbinafine, 250 mg/day for 2 weeks; itraconazole, 200 mg/day for 1 wk; fluconazole, 250 mg weekly for 2-4 wk

Tinea capitis Griseofulvin, 10-20 mg/kg/day for minimum 6 wk

Terbinafine

<20 kg: 62.5 mg/day

20-40 kg: 125 mg/day

>40 kg: 250 mg/day

Itraconazole, 4-6 mg/kg pulsed dose weekly

Onychomycosis Fluconazole, 3-8 mg/kg pulsed dose weekly

Fingernails Terbinafine, 250 mg daily for 6 wk

Itraconazole, 400 mg/day for 1 wk each month, repeated for 2-3 mo

Fluconazole, 200 mg weekly for 8-16 wk

Toenails Terbinafine, 250 mg daily for 12 wk

Itraconazole, 400 mg/day for 1 wk each month, repeated for 2-4 mo

Fluconazole, 200 mg weekly for 12-24 wk

402

196  ParacoccidioidomycosisAngela Restrepo, Angela María Tobón, and Luz Elena Cano

MICROBIOLOGY AND EPIDEMIOLOGY• Paracoccidioidomycosis iscausedbyParacoccidioides brasiliensis,whichcontains fourdif-

ferentphylogeneticlineages(S1,PS2,PS3,andPS4).Anewspecies,Paracoccidioides lutzii,hasbeenrecognizedwithinP. brasiliensisandalsocausesparacoccidioidomycosis.

• Paracoccidioides spp. are thermally dimorphic fungi, identified by multiple-budding yeastcells(pilot’swheel).

• Thesefungiexhibitslowmycelialgrowthformorethan20daysat22°to24°C.Theyeastformappears±10daysat36°to37°C.

• Directmicroscopyandhistopathologyallowpromptdiagnosis.• ThesefungiarerestrictedtoLatinAmericancountriesinunknownhabitats.• ThelargestendemicareasarefoundinBrazil.• Mostpatientsaremalesandwork(orhaveworked)inagriculturewithintheendemicareas.• Twoprogressivediseaseformsexist:(1)acute/subacuteinchildren,adolescents,andimmu-

nocompromisedindividualsand(2)chronicinadultsatleast30yearsofage.

CLINICAL MANIFESTATIONS• In theacute/subacute form,a severedisease, there is fever,weight loss, lymphadenopathy

andhepatosplenomegaly.Multipleskinandmucosallesionsoccurinhalfofthecases.• Inthechronicform,therearepulmonaryinfiltratesonchestradiographs(>90%ofthecases)

andlesionsinmucousmembranesandskin.Adrenallesionswithadrenalinsufficiencyarecommon.

• Specificdiagnosisisusuallylateduetoconfusionwithothermoreprevalentdiseases(e.g.,tuberculosis).Lackofphysicians’awarenessisaproblem.

• Lung imaging studies are essential in adult patients. Healing by fibrosis creates seriouscomplications.

• Intissues,granulomaformationisan importantcluetodiagnosis.Buddingyeastcellsarefoundinlesions.

• Serologyshowsthatanti–P. brasiliensisantibodiesaredetectableinmostpatients.Quantitativetestsallowtreatmentfollow-up.Antigendeterminationalsoisusefulincertainpatients.

• Humanimmunodeficiencyviruscomorbidityisuncommon.

TREATMENT (SEE TABLE 196-1)• Itraconazole is the treatment of choice for most patients, at 200 to 400mg/day for 9 to

12months.• AmphotericinBdeoxycholateisreservedforseverecases,at1mg/kg/dayuntilachievinga

2-gtotaldose.Thisshouldbefollowedbyoralmedications.• Trimethoprim-sulfamethoxazole(TMP-SMX)isgivenasTMP,160to240mg,andSMX,800

to1200mgperdayfor12to24months,dependingondiseaseseverity.• Regularfollow-upobservations(clinical,laboratoryoriented)aremandatory.

403C

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ioid

om

ycosis

TABLE 196-1  Antifungal Therapy for ParacoccidioidomycosisA

NTI

FUN

GA

L PR

ESC

RIB

ED

(AD

MIN

ISTR

ATI

ON

R

OU

TE)

MIN

IMA

L TR

EATM

ENT

DU

RA

TIO

N B

ASE

D

ON

OR

GA

N

INV

OLV

EMEN

T*

DO

SE

AD

VER

SE E

FFEC

TS

RES

PON

SE (

%)

REL

APS

ES (

%)

TMP-SMX (PO/IV)

Minor: 12 moModerate: 18-24 mo

AdultsTMP: 160-240 mg/daySMX: 800-1200 mg/dayDivided into two doses per dayChildrenTMP: 8-10 mg/kgSMX: 40-50 mg/kgDivided into two doses per day

LeukopeniaHypersensitivity-reactions, such as rash

80 20

Amphotericin B deoxycholate (IV)

Until patient improves and can be treated by the oral routeAchieve a total dose of 2 g†

1 mg/kg/day NephrotoxicityHypokalemiaNausea/vomitingFeverAnemia

70 25

Ketoconazole (PO)

9-12 mo 200-400 mg/day Hormonal alterationsIncrease in hepatic enzymesNausea/vomiting

90 11

Itraconazole (PO)

6-9 mo Adults600 mg/day for 3 days; continue 200 mg/dayChildren (<30/kg and >5 yr)5-10 mg/kg/day

Nausea/vomiting↑ Hepatic enzymesDrug interactions

94-98 3-5

Voriconazole (PO/IV)

6 mo Initial dose: 400 mg each 12 hr for one day, then 200 mg each 12 hrDiminish the dose to 50% if weight is <40 kg

Visual alterations↑ Hepatic enzymesSkin rashPhotosensitivityHallucinationsPeriostitis

88 No data

IV, intravenous; PO, orally; TMP-SMX, trimethoprim-sulfamethoxazole.*Shown only with the aim of guiding therapy. Total duration must be defined in accordance with clinical and

immune-based tests, as well with the mycosis clinical form.†Should always be continued with TMP-SMX or itraconazole oral therapy, once clinical improvement has been

obtained.

404

197 Uncommon Fungi and Related SpeciesDuane R. Hospenthal

PSEUDALLESCHERIA BOYDIIDefinition• Infection of the lungs, bones and joints, or central nervous system (CNS); may be

disseminated• Alsocausesmycetoma

Epidemiology• Typicallyoccursintheimmunocompromisedorfollowingtrauma• CNSinfectioninimmunocompetentpersonsafternear-drowning• Organismcanbefoundinsoilandfreshwater,especiallystagnantorpolluted

Microbiology• P. boydii (Scedosporium apiospermum)isagroupofatleastfivespecies.• Identificationistypicallymadebyidentificationofmicroscopicstructuresfromculture.

Diagnosis• Diagnosisismadebyculturerecoveryfrominfectedsite.• BecauseP. boydiimaycolonizeairways,sputumculturesmaynotreflectinfection.

Therapy• Voriconazoleislikelythemosteffectiveagent.

SCEDOSPORIUM PROLIFICANSDefinition• Disseminatedinfectionandboneandjointinfectionsaremostcommon.• S. prolificansmaycauseonychomycosisandinfectionsoftheeyeandwounds.

Epidemiology• Disseminatedinfectioncommonlyoccursintheseverelyimmunocompromised.• Localizedinfectionoccursinimmunocompetentindividualsaftertrauma.• Theorganismcanbefoundinsoilandcolonizingtherespiratorytract.

Microbiology• Identificationismadebyculture.

Diagnosis• Diagnosisismadebyculturerecoveryfromtheinfectedsite.• BecauseS. prolificansmaycolonizeairways,sputumculturesmaynotreflectinfection.

Therapy• Noeffectivetherapy.ConsidervoriconazolewithamphotericinB.

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com

mo

n Fu

ng

i and

 Related

 Species

DARK-WALLED FUNGI (BIPOLARIS, EXOPHIALA, EXSEROHILUM, PHIALOPHORA, CURVULARIA, OTHERS)Definition• Thisinfectioninvolvesfungithathavemelaninintheircellwallandmayappeardarkwalled

intissue.• Infectionisoftentermedphaeohyphomycosisandtypicallypresentsaslocalizedskinandsoft

tissueinfections,CNSinfections,orallergicsinusitis.• Dark-walledfungithatcausechromoblastomycosisandmycetomaarenotincludedinthe

agentsofphaeohyphomycosis.

Epidemiology• Infectioniscommonlyacquiredfromminortraumaorinhalation.• Fungiarefoundinsoil,organicmaterial,plants,andair.• Theymaybespreadthroughcontaminatedproducts(e.g.,injectablesteroids).

Microbiology• ThemostcommonagentsofphaeohyphomycosisareAlternaria, Bipolaris, Cladophialophora,

Curvularia, Exophiala, Exserohilum,andWangiella

Diagnosis• Diagnosisismadebyrecoveryoftheseorganismsinculturefromthesiteofinfection.• Cell walls may appear dark brown or golden on histopathology (hematoxylin and eosin).

UseofaFontana-Massonstainmayalloweasieridentificationofthesefungi.

Therapy• Surgicaldébridementoflesionsorcolonizingfungiinthecaseofallergicfungalsinusitis• AmphotericinBinlife-threateninginfections• Voriconazoleanditraconazolearetypicallyeffectivebutprolongedtherapyneeded

FUSARIUM SPP.Definition• Cancausedisseminatedinfectioninimmunocompromisedpatients• Commoncauseofkeratitisandothereyeinfectionsincontact lenswearersandfollowing

trauma• Skinandsofttissueinfectionaftertrauma,onychomycosis;cancausemycetoma

Epidemiology• Commonplantpathogens;foundinsoilandorganicdebris• Hasbeenrecoveredinhospitalwatersupplies

Microbiology• F. solaniisthemostcommonpathogen,althoughotherspeciesmayalsocauseinfection.• Fusariumproducesbanana-(orcrescent)-shapedmulticellularmacroconidiainculture.

Diagnosis• Recoveryofthefungusfromcultureofanotherwisesterilesite• Oneofthefewmoldsthatarecommonlyrecoveredfrombloodculture

Therapy• Optimumtherapyisnotknown.• Recoveryfromneutropeniaisessentialinresponsetotherapyofdisseminatedinfection.• AmphotericinBorvoriconazoleissuggested.

TRICHOSPORON SPP.Definition• Mostcommonlypresentsasdisseminatedinfection

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Epidemiology• Typicallyaninfectionoftheimmunocompromised;maybeassociatedwithcentralvenous

catheter• Fungifoundcolonizingtheskin,gastrointestinal,respiratory,orgenitaltract• Foundinsoilandwater• Breakthroughinfectionsinpatientsreceivingechinocandins

Microbiology• MostcommonpathogenisT. asahii.• Trichosporonareidentifiedbytheiruniqueabilitytoproduceseptatehyphae,arthroconidia,

andbuddingyeast.• Appearsyeastlikeoninitialculture

Diagnosis• Byrecoveryoftheorganismfromthebloodorlesionbiopsy

Therapy• Azoleantifungal(voriconazole,itraconazole,isavuconazole,posaconazole,orfluconazole)

MALASSEZIA FURFURDefinition• Catheter-relatedbloodstreaminfection• Alsocausespityriasisversicolor

Epidemiology• Typicallyassociatedwithparenterallipidinfusion• Commonlyreportedinneonates

Microbiology• Maybedifficulttogrowfrompositivebloodcultureswithoutlipidsupplementation

Diagnosis• Recoveryoffungusfrombloodculture

Therapy• Catheterremovalanddiscontinuationofparenterallipids• Susceptibletomostantifungals(voriconazole,fluconazole,oramphotericinB)

Prevention• Limitinguseofparenterallipids

OTHER UNCOMMON YEASTSDefinition• Otherlesscommonyeastsmayalsocausecatheter-relatedbloodstreaminfection.

Epidemiology• Typicallyassociatedwithuseofcentralvenouscathetersandimmunocompromise

Microbiology• Include Saprochaete capitata (Blastoschizomyces capitatus), Pichia anomala, Rhodotorula

species,andSaccharomyces cerevisiae

Diagnosis• Madebyrecoveryoftheyeastinbloodculture

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Therapy• Removalofcentralvenouscatheter• Antifungalsbasedonrecoveredyeast

PENICILLIUM MARNEFFEIDefinition• Acute disseminated infection of persons infected with human immunodeficiency virus

(HIV)inSoutheastAsia• Infectionsimilartoacutedisseminatedhistoplasmosis inpatientswithacquiredimmuno-

deficiencysyndrome• Rarely,localizedinfectioninapparentlyimmunocompetentpersons

Epidemiology• LimitedtoSoutheastAsia.Morecommoninrainyseason,inyoungadultmaleswithHIV

infection,typicallywithlowCD4cellcounts

Microbiology• TypicalPenicillium-likestructuresonmicroscopicexaminationofculture• Culturesproduceredpigmentthatdiffusesintotheagar.

Diagnosis• Typicallymadefromrecoveryoftheorganisminblood• Mayalsoberecoveredincultureofskinlesions,lymphnodes,orbonemarrowaspirates• Serologictestingmaybeavailableinendemicregions.

Therapy• AmphotericinBinlife-threateningpresentations• Itraconazoleorvoriconazoleininitialtherapy(notlife-threatening)• ItraconazolesecondaryprophylaxisinHIV-infectedpatients

LACAZIA LOBOIDefinition• Chronicnodularorkeloidalskininfection,commonlyoftheearsorface

Epidemiology• LimitedtoCentralandSouthAmerica• Infectionalsofoundindolphins

Microbiology• Hasnotbeenrecoveredinculture• IdentifiedascloselyrelatedtoParacoccidioides brasiliensisbymoleculartechniques

Diagnosis• Basedonclinicalpresentationandfindingtypicalstructuresonhistopathology• Globose(yeast)cellsend-to-endinshort“strings”

Therapy• Surgicalremoval

AGENTS OF ADIASPIROMYCOSIS (EMMONSIA SPP.)Definition• Disease secondary to host immune response to nonreplicating fungal conidia, termed

adiaspores• Chieflyapulmonarydisease;mayrangefromasymptomatictorapidlyleadingtorespiratory

failureandoccasionallydeath• Mayalsopresentasocularnodules

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Epidemiology• Seenwithoccupationalinhalationtodustsinmen,averageage40• OutbreakinBrazilianchildreninassociationwithdivingandfreshwatersponges

Microbiology• SecondarytoEmmonsiaspecies,usuallyE. crescens• DimorphicfungicloselyrelatedtoBlastomyces dermatitidis

Diagnosis• Identificationislimitedtoobservationoftypicalstructuresonhistopathologyshowingadia-

spores,upto500µmindiameter,nondividing,andsurroundedbygranulomatacomposedofepithelioidandgiantcells.

Therapy• Corticosteroidsappeartobeuseful.

EMMONSIA PASTEURIANADefinition• DisseminatedinfectionmostcommonlyafflictingHIV-infectedpersons

Epidemiology• Severelyimmunocompromisedpersons• LargestreportfromSouthAfrica

Microbiology• Emmonsia pasteurianaorcloselyrelatedfungus• Thermallydimorphicfungus

Diagnosis• Recoveryofthedimorphicfungusfromskinbiopsyorbloodculture

Therapy• ResponsestoamphotericinBandtriazoleantifungalshavebeenreported

PROTOTHECA SPP.Definition• Localizedskinorsubcutaneousinfectioncausedbyalgalpathogen• Rarereportsofdisseminatedordeepinfection

Epidemiology• Likelycauseinfectionaftertraumaticinoculation• Organismscolonizeskin,gastrointestinalandrespiratorytract

Microbiology• DiseaseistypicallyduetoP. wickerhamiiorP. zopfii.• Unicellularalgaelackchlorophyll.• Protothecaspp.growonfungalculturemediawithyeastlikecolonialmorphology.• Microscopicappearanceintissueisdiagnostic.

Diagnosis• Recoveryofalgaeincultureisdiagnostic.• YeastbiochemicalpanelscommonlyidentifyPrototheca.

Therapy• SurgicalexcisionwithamphotericinBoritraconazole

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PYTHIUM SPP.Definition• Vascular infectionsinpersonswithironoverloadsuchasthalassemiaorocularinfections

followingtrauma• Skinandsubcutaneousanddisseminatedinfectionpossible

Epidemiology• Worldwidedistribution,butmostcommonlyreportedfromThailand• Riskfactors:thalassemia-hemoglobinopathysyndromeandtrauma• Presumedassociationwithworkinswampy(e.g.,ricepaddy)environment• Highmorbidity(eyeorlimbloss)andmortality

Microbiology• Fungus-likeprotist,Pythium,growsrapidlyasmoldonfungalculture.

Diagnosis• Recoveryoftheorganismfromcultureisdiagnostic.• Localserologictestingmaybeavailable.

Therapy• Canperformsurgicalresectionoramputation.• Nosatisfactorymedicaltherapyisknown.• Doxycycline,minocycline,tigecycline,linezolid,andmacrolideshaveactivityinvitro.

RHINOSPORIDIUM SEEBERIDefinition• Localizedpolypoidalinfection,chieflyofthenose,upperairway,andconjunctiva

Epidemiology• Worldwidedistribution,butmostcommonlyreportedfromsouthernIndiaandSriLanka

Microbiology• Hasnotbeengrowninculture• Identifiedasaprotistbymolecularmethods

Diagnosis• Madebymicroscopicobservationoftypicalstructures—thick-walledcysts(100to350µm)

filledwithnumerousspores

Therapy• Surgicalexcisionwithelectrocauteryoflesionbase

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198  Pneumocystis SpeciesPeter D. Walzer, A. George Smulian, and Robert F. Miller*

DEFINITION• Pneumocystis spp. are genetically distinct, host-specific opportunistic fungal pathogens

widelyfoundinnature.• Pneumocystis jirovecii,foundinhumans,causespneumonia(“Pneumocystispneumonia”or

“PCP”)inimmunocompromisedpatients.

EPIDEMIOLOGY• Infectionisacquiredbyinhalationofthecystformoftheorganism.• Primaryinfectionoccursinthefirst2yearsoflifeinmostpeople.• Person-to-persontransmissionandoutbreaksofPCPin immunosuppressedpatientshave

beenreported.• EnvironmentalfactorsinfluencePCPhospitalizations.• Colonizationiscommon,associatedwithobstructiveairwaydisease.

DIAGNOSIS• PCP in patients with human immunodeficiency virus (HIV): slow development, milder

disease,10%to12%mortality• PCPinnon-HIVpatients:rapiddevelopment,severedisease,30%to50%mortality• Gold standard: microscopic demonstration of organism in respiratory tract specimens by

immunofluorescenceorspecialstains• Othermethods(polymerasechainreaction,β-D-glucanlevels)arepromisingbutarecon-

sideredinvestigational

TREATMENT• Trimethoprim-sulfamethoxazole(TMP-SMX)15to20mg/kg/day(TMP)and75to100mg/

kg/day(SMX)IVorPOindivideddosesevery6to8hoursfor14to21daysisthetreatmentofchoiceformild,moderate,orseverePCP.

• Mild-to-moderate PCP:OraldosecanbegivenasTMP-SMXdoublestrength2tabletsorallythreetimesaday.

• SeveralalternativeregimensareavailabledependingontheseverityofPCP.• Prednisone40mgPOtwicedailyondays1to5,40mgPOeverydayondays6to10,and

20mgPOeverydayondays11to21aregivenasadjunctivetherapyformoderate-to-severePCP(PaO2≤70mmHg,oralveolar-arterialO2gradient>35mmHg).

• Startprednisoneassoonaspossibleorwithinthefirst3daysafterbeginningantimicrobialtherapy.

• PrednisoneismainlyindicatedforHIV-positivepatients.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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PREVENTION• TMP-SMX1DStabletorallyeverydayor1SStabletorallyeverydayisthedrugofchoice

forprimaryandsecondaryprophylaxis.• Alternativeregimensareavailable.• Strongevidencesupports isolationofPCPpatientsfromcontactwithotherimmunocom-

promisedhosts.

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199 MicrosporidiosisLouis M. Weiss

DEFINITION• Microsporidiaareobligateeukaryoticintracellularpathogensrelatedtofungi.• Taxonomyofthephylumisbasedonultrastructuraldescriptionsofthesporesandlifecycle.• Molecularphylogeny,basedonrRNAsequences,isalsoutilizedforclassification.

EPIDEMIOLOGY• The phylum Microsporidia contains at least 1200 species distributed into more than 190

genera.• Several different genera and species of microsporidia cause disease in humans, including

Nosema, Vittaforma, Pleistophora, Encephalitozoon, Enterocytozoon, Trachipleistophora, Anncaliia, Tubulinosema, Endoreticulatus,andMicrosporidium.

• Microsporidiosisoccursinbothimmunocompromisedandimmune-competenthosts.• Thesepathogenscanbetransmittedbyfoodorwaterandarelikelyzoonotic.• Diarrheaorkeratoconjunctivitisarethemostcommonpresentingmanifestationsofinfec-

tion,butinfectioncanoccurinanyorgansystem.

DIAGNOSIS• Diagnosis can be made by finding characteristic spores in body fluids (e.g., stool, urine,

conjunctivalscraping,etc.,usingstains,suchaschromotrope2RorUvitex2B).• Definitiveidentificationofthemicrosporidiacausinganinfectioncanbedoneusingultra-

structuralexaminationormoleculartechniques.• Patientswithdiarrheaorkeratoconjunctivitisshouldhaveurineexaminedtolookfordis-

seminatedinfection.• Species-specificdiagnosisisusefulforguidingtreatment.

THERAPY• Systemic albendazole and fumagillin are active therapeutic agents for the treatment of

microsporidiosis.• Topicalfumagillinisusefulformicrosporidiankeratoconjunctivitis.• Immunerestorationsuchascombinationantiretroviraltreatmentinpatientswithacquired

immunodeficiencysyndromeoftenresultsinresolutionofinfection.

PREVENTION• Therearelimiteddataoneffectivepreventivestrategiesformicrosporidiosis,butthemost

effectiveprophylaxisisrestorationofimmunefunctioninimmunocompromisedhosts.• Theusualsanitarymeasuresthatpreventcontaminationoffoodandwaterwilldecreasethe

chanceofinfection.• Handwashingandgeneralhygienichabitsreducethechanceofcontaminationofthecon-

junctivaandcorneawithmicrosporidianspores.

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H  Protozoal Diseases

200 Entamoeba Species, Including Amebic Colitis and Liver AbscessWilliam A. Petri, Jr., and Rashidul Haque

DEFINITION• Amebiasis is defined as human infection by Entamoeba species, including E. histolytica,

whichisthecauseofamebiccolitis,liverabscess,and,rarely,brainabscess;E. moshkovskii,whichcausesdiarrhea;andE. dispar,whichisnonpathogenic.

EPIDEMIOLOGY• Amebiasisisspreadbyfecal-oraltransmission,andinadditiontopersontopersoncanbe

waterborneandfoodborne.• Mostinfectionsareinimpoverishedcommunitiesinthedevelopingworld.• Amebic colonization, diarrhea, and colitis are most common in infants through the pre-

schoolyears.• Amebicliverandbrainabscessoccur90%ofthetimeinyoungmen.• E. histolyticaisacommoncauseofdiarrheainreturninginternationaltravelers.• Men who have sex with men (MSM) are at risk of both human immunodeficiency virus

(HIV)andamebiasis,andoneshouldconsiderthepossibilityofHIVinthesettingofamebia-sisinMSM.

MICROBIOLOGY• Cystformisinfectious,environmentallystable,andresistanttochlorination.• Trophozoiteisthetissue-invasivestage.

DIAGNOSIS• Stoolovaandparasiteexamshouldnotbeusedbecausetheyareinsensitiveandnonspecific.

Instead, diagnosis is best accomplished in the laboratory through a combination of fecalantigendetectionorquantitativepolymerasechainreactionforfecalparasiteDNA,incombi-nationwithserologictestsforantiamebicantibodies(whichcanbenegativeearlyinillness).

• Colonoscopyandabdominal imagingtechniques(ultrasound,computedtomography,andmagneticresonanceimaging)areusefuladjunctsfordiagnosisofintestinalandextraintes-tinaldisease,respectively.

THERAPY (SEE TABLE 200-1)• Noninvasive infection is treatedwithparomomycin:30mg/kg/dayorally in threedivided

dosesperday×5to10days.• Invasiveinfectionistreatedwithtinidazole2goncedailyfor5days,followedbyparomo-

mycin(topreventrelapsefromgutlumenparasites).• Considerpercutaneousdrainageforliverabscessesof5cmorgreaterindiameterorifthey

areintheleftlobe.

PREVENTION• Preventionisaccomplishedbysanitationandcleanwater.• Vaccineisunderdevelopment.

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TABLE 200-1  Drug Therapy for Treatment of Amebiasis

DRUG ADULT DOSAGE SIDE EFFECTS

Amebic Liver Abscess*Metronidazole† 750 mg PO tid × 10 days Primarily GI side effects: anorexia, nausea, 

vomiting, diarrhea, abdominal discomfort, or unpleasant metallic taste; disulfiram-like intolerance reaction to alcoholic beverages; neurotoxicity, including seizures, peripheral neuropathy, dizziness, confusion, irritability

or

Tinidazole 2 g PO once daily × 5 days Primarily GI side effects and disulfiram-like intolerance reaction to alcoholic beverages for  5 days

Followed by a luminal agent

Paromomycin 30 mg/kg/day PO in three divided doses per day × 5-10 days

Primarily GI side effects: diarrhea, GI upset

or

Diloxanide furoate 500 mg PO tid × 10 days Primarily GI side effects: flatulence, nausea, vomitingPruritus, urticaria

Amebic Colitis‡

Tinidazole 2 g PO once daily × 5 days Same as for amebic liver abscess

Plus a luminal agent (same as for amebic liver abscess)

Asymptomatic Intestinal ColonizationTreatment with luminal agent as for amebic liver abscess

GI, gastrointestinal; PO, by mouth.*Amebic liver abscess may necessitate antiparasitic treatment plus percutaneous or surgical drainage. Nitazoxanide 

may be effective therapy as well, but clinical experience is limited.†Drug of choice for treatment of amebic liver abscess.‡Amebic colitis may necessitate antiparasitic treatment plus surgical treatment.Modified  from Haque R, Huston CD, Hughes M, et al. Current  concepts: amebiasis. N Engl J Med. 2003;348:

1565-1573.

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201  Free-Living AmebaeAnita A. Koshy, Brian G. Blackburn, and Upinder Singh

MICROBIOLOGY AND EPIDEMIOLOGY• Free-livingamebaeareprotiststhatarecommonintheenvironmentworldwidebutrarely

causerecognizedhumaninfections.Thetrophozoitestagesoftheseorganismsfeedonbac-teriaanddebrisintheenvironment.• Naegleria fowleri iswidelydistributedgloballyandhasbeen isolated fromfreshwater,

mostcommonlyinwarmenvironments.• Acanthamoebaspp.areubiquitousmembersoftheenvironmentandarefoundworldwide

insoilandfreshwater.• Balamuthia mandrillaris is also likely widely distributed and has been isolated

fromsoil.

CLINICAL MANIFESTATIONS AND DIAGNOSIS• N. fowleritypicallycausesafulminantmeningoencephalitisinhealthy,immunocompetent

young patients, in association with swimming in warm fresh water. The disease is nearlyalwaysfatal.• Thecerebrospinalfluid(CSF)profileofpatientswithN. fowleriprimaryamebicmenin-

goencephalitis (PAM) is similar to that seen inbacterialmeningitis (highwhitebloodcellcount,lowglucose,highprotein),butwithanegativeGramstainandculture.MotiletrophozoitescansometimesbeseenonwetmountoftheCSF.

• NeuroimagingstudiesinpatientswithPAMareusuallynonspecific.• Acanthamoebaspp.andB. mandrillariscausethesubacuteonsetoffocalneurologicdeficits

and mental status changes (granulomatous amebic encephalitis [GAE]) related to centralnervous system mass lesions. Acanthamoeba is mostly seen in immunocompromised anddebilitated individuals, whereas Balamuthia occurs in both immunocompromised andimmunocompetentpatients.Thecase-fatalityratefortheseinfectionsisalsohigh.• IntheUnitedStates,BalamuthiaGAEmaybemorecommoninmaleHispanicpatients

thaninothergroups.• CSFstudiesofpatientswithGAEareusuallynonspecific,anditisraretoisolateorgan-

ismsfromtheCSF.• Neuroimagingstudiesgenerallyrevealmultiplespace-occupyinglesionsinthebrain,with

orwithoutcontrastenhancement.• Biopsyofinvolvedtissues(skin,brain,etc.)canbediagnostic,usuallyviahistopathologic

examination/immunohistochemicalstainingorpolymerasechainreaction(PCR).• Acanthamoebaspp.andB. mandrillariscaninvolveothersites(lungs,sinuses,adrenals,and

skin).• Acanthamoebaspp.alsocausesight-threateningkeratitisinotherwisehealthyindividualsin

associationwithcontactlensuse.Diagnosisdependsonahighclinicalsuspicion,inconjunc-tionwithinvivoconfocalmicroscopyordemonstrationofAcanthamoebaincornealscrap-ingsorbiopsyspecimensbyhistopathologicexamination,culture,orPCR.

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THERAPY• Therapeuticregimensforfree-livingamebicinfectionsofhumansarenotwelldefined.• TreatmentforN. fowleriPAMshouldincludehigh-doseintravenousamphotericinproducts;

intrathecalamphotericinmayalsoprovidesomebenefit,andtheadditionofazoles,rifampin,miltefosine,orotherantimicrobialsshouldbeconsidered.

• Acanthamoebakeratitisshouldbetreatedwithtopicalchlorhexidineorpolyhexamethylenebiguanide;adjunctivesurgicaltherapymayalsobenecessary.

• AcanthamoebaGAEshouldbe treatedwithcombinationantimicrobial regimens,possiblyincludingpentamidine,anazole,asulfonamide,miltefosine,andflucytosine.However,themostefficaciousregimenisnotcurrentlyknown.

• B. mandrillarisGAEshouldbetreatedwithcombinationantimicrobialregimens,possiblyincluding pentamidine, flucytosine, a sulfonamide, albendazole, an azole, a macrolide,amphotericin, and/or miltefosine. However, the most efficacious regimen is not currentlyknown.

• SurgicaldébridementmayplayanadjunctiveroleinthemanagementofbothformsofGAE.

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202 Malaria (Plasmodium Species)Rick M. Fairhurst* and Thomas E. Wellems

DEFINITION• Thehistoryoftravelandexposureinamalaria-endemicareaistypical.• Uncomplicatedmalariaisoftenconfusedwiththe“flu”:fever,accompaniedbyheadaches,

bodyaches,andmalaise.• Severemalariacanpresentwithanyoneofthefollowing:diminishedconsciousness,convul-

sions, respiratory distress, prostration, hyperparasitemia, severe anemia, hypoglycemia,jaundice,renalinsufficiency,hemoglobinuria,shock,cessationofeatinganddrinking,repeti-tivevomiting,orhyperpyrexia.

EPIDEMIOLOGY• Malaria is endemic in tropical and subtropical areas of Africa, South America, Asia, and

Oceania.• MalariaistransmittedbythebiteofafemaleAnophelesmosquito.• Transmissioncanalsooccurbybloodtransfusion,importedmosquitoes,orautochthonous

mosquitoesinfectedbyimmigrants.

MICROBIOLOGY• PlasmodiaareparasiticprotozoaoftheApicomplexaphylum.• Plasmodium falciparum,Plasmodium vivax,Plasmodium ovale,Plasmodium malariae, and

Plasmodium knowlesiarethemajorhumanmalariaparasites.

LABORATORY DIAGNOSIS• IdentificationofparasitesisthroughGiemsa-stainedthickandthinbloodsmears.• Rapiddiagnostictestsareavailable(e.g.,BinaxNOWintheUnitedStates).

THERAPY• Treatmentdependsprimarilyondiseaseseverity,drug-resistanceepidemiology,patientage,

andpregnancystatus.• Uncomplicatedmalariadueto:

• Chloroquine-sensitiveP. falciparum(Mexico,CentralAmericawestofthePanamaCanal,Haiti, the Dominican Republic, and most areas of the Middle East), P. vivax, P. ovale,P. malariae,andP. knowlesi,aswellasuncomplicatedmalaria,dueto:• Oraltreatmentwithchloroquinephosphate

• Chloroquine-resistant P. falciparum (most areas of the world) or chloroquine-resistantP. vivax(PapuaNewGuineaandIndonesia)• Oral treatment with atovaquone-proguanil, artemether-lumefantrine, quinine plus

doxycycline,ormefloquine(dihydroartemisinin-piperaquineisregisteredandavail-ableinsomecountriesoutsidetheUnitedStates)

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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• PreventrelapsingP. vivaxandP. ovalemalariawithprimaquinephosphate(contraindi-cated in pregnant/breast-feeding women and glucose-6-phosphate dehydrogenase[G6PD]-deficientpersons)

• Severemalaria• Intravenoustreatmentwithquinidinegluconate(onlydrugcommerciallyavailableinthe

United States), artesunate (available only from the Centers for Disease Control andPreventionintheUnitedStates),orquininedihydrochloride(notavailableintheUnitedStates)

PREVENTION• Chemoprophylaxisdecisionsshouldbebasedondrug-resistanceepidemiology,patientage,

andpregnancystatus.• Areaswithchloroquine-sensitivemalaria:chloroquinephosphate• Areaswithmefloquine-sensitivemalaria:mefloquine• Allareas:atovaquone-proguanilordoxycycline• AreaswithmostlyP. vivax:primaquine(contraindicatedinpregnantwomenandG6PD-

deficientpersons)• Mosquitorepellentsandavoidancemeasures

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203 Leishmania Species: Visceral (Kala-Azar), Cutaneous, and Mucosal LeishmaniasisAlan J. Magill

DEFINITION• Leishmaniasis is infection with Leishmania species of protozoa acquired by the bite of a

PhlebotomusorLutzomyiasandfly.

CLINICAL MANIFESTATIONS• The syndrome classifications of leishmaniasis are cutaneous, mucosal (mucocutaneous),

and visceral (kala-azar). Uncommon skin manifestations are diffuse cutaneous leish-maniasis,post–kala-azardermal leishmaniasis, leishmaniasisrecidivans,anddisseminatedleishmaniasis.

DIAGNOSIS• Giemsastain,culture,andpolymerasechainreactionassayareperformed.

TREATMENT• Treatmentofskinlesionsincludestopical,oral,andsystemicregimens.Visceralleishmani-

asis andNewWorldmucosal leishmaniasis are treatedparenterallybyanamphotericinBformulation,pentavalentantimony,andmiltefosine.

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204 Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of TrypanosomesLouis V. Kirchhoff*

DEFINITION• Chagas’disease,orAmericantrypanosomiasis,isaninfectioncausedbythesingle-cellpro-

tozoanparasiteTrypanosoma cruzi.

MICROBIOLOGY• T. cruziisspreadamongitsvariousmammalianhosts,includingdomesticandwildanimals

as well as humans, by bloodsucking triatomine insects, also called cone-nosed or kissingbugs.

• Theparasitesmultiplyinthegutoftheseinsects,andtheirfecescontainformsthatcaninfectmammals.Whencontaminatedfecestouchvulnerablemammaliantissuessuchasthecon-junctivae,oralandnasalmucosalsurfaces,orskinabrasions,transmissioncantakeplace.

• Oncetheparasitesgainafootholdinamammalianhost,theyalternatebetweenmultiplyingintracellularformsandfree-swimmingformsinthebloodstreamthatspreadtheinfectioninternallyorgetsweptupbyfeedingvectors,thuscompletingthecycle.

• T. cruzicanalsobetransmittedfrommothertofetus,throughbloodproductsandorgansobtainedfrominfecteddonors,andinlaboratoryaccidents.

• InfectionwithT. cruziinhumansislifelong.

EPIDEMIOLOGY• Chagas’diseaseisendemicinallSouthandCentralAmericancountriesandalsoinMexico.• TheinfectionisnotendemicinanyoftheCaribbeanislands.• About8millionpersonsarechronicallyinfectedwithT. cruzi,roughly56,000newinfections

occureachyear,andabout12,000personsdieoftheillnessannually.Anestimated300,000immigrantswithChagas’diseasecurrentlyliveintheUnitedStates.

• Duringrecentdecades,largenumbersofpeopleintheendemiccountrieshavebeenmigrat-ingfromruralareastothecities,andatthesametimemanymillionsofpeoplehaveemi-grated from the endemic countries to industrialized regions, particularly the EuropeanUnionandtheUnitedStates,thusurbanizingandglobalizingthedisease.

CLINICAL MANIFESTATIONS• Between 10% and 30% of persons who are chronically infected with T. cruzi ultimately

developcardiacorgastrointestinalsymptomsthatarecausedbypathologicprocessesrelatedtothepersistentpresenceoftheparasite.

• ChroniccardiacChagas’diseasetypicallyinvolvesrhythmdisturbancesandcardiomyopathy.• Gastrointestinalproblemscanincludemegaesophagusandmegacolon.• ImmunosuppressionofpersonswhoharborT. cruzichronicallycanresultinlife-threatening

reactivationoftheinfection.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofborrowedfigures.

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DIAGNOSIS• ThediagnosisofacuteorcongenitalChagas’diseaseismadebyparasitologicmethods,typi-

callydirectmicroscopicexaminationofblood,hemoculture,orpolymerasechainreaction–basedassays.

• ChronicT. cruziinfectionisdiagnosedserologically,andmanyenzyme-linkedimmunosor-bent assays, immunofluorescence assays, and chemiluminescence tests are available com-merciallyforthispurpose.

THERAPY• NifurtimoxandbenznidazolearetheonlytwodrugsavailablefortreatingT. cruziinfections

(availablefromtheCentersforDiseaseControlandPreventionDrugService).• Parasitologic cure rates for these drugs are high for acute and congenital infections but

unfortunatelyverylowinpersonswithlong-standinginfections.• Therearenoconvincingdatafromrandomizedcontrolledtrialsindicatingthattreatmentof

chronically infected persons with either drug significantly delays pathogenesis or affectslong-termoutcomes.

PREVENTION• NovaccineorprophylacticdrugsareavailableforreducingtransmissionofT. cruzi.• In the endemic countries, reducing transmission depends primarily on educating at-risk

populations, housing improvement, and spraying insecticides to eliminate vectors indwellings.

• SerologicscreeningofbloodandorgandonorsisalsoakeyelementinthecontrolofChagas’disease.

• Inmanyoftheendemiccountries,enormousprogresshasbeenmadeinbothvectorcontrolandbloodscreeningand in theUnitedStates,Canada,and theEuropeanUnionwith thelatter.

422

205 Agents of African Trypanosomiasis (Sleeping Sickness)Louis V. Kirchhoff*

DEFINITION• HumanAfricantrypanosomiasis(HAT),alsoknownassleepingsickness,iscausedbytwo

protozoanparasitesubspecies:Trypanosoma brucei gambiense(WestAfricantrypanosomia-sis)andTrypanosoma brucei rhodesiense(EastAfricantrypanosomiasis).

MICROBIOLOGY• ThetrypanosomesthatcauseHATaretransmittedamongtheirmammalianhostsbytsetse

flies.Thefliesbecomeinfectedwhentheytakeabloodmealfromaninfectedmammal.Thereisadevelopmentalcycle intheflies,afterwhichinfectiveparasitesmigratetothesalivaryglandsandareinjectedintoanewhostwhenthefliestakesubsequentbloodmeals.IntheirmammalianhostsAfricantrypanosomesarefoundprimarilyinthebloodstreamand,toalesserextent,inperivascularareasofthebrainandothertissues.IncontrasttoTrypanosoma cruzi,theparasitethatcausesChagas’disease,Africantrypanosomesdonothaveanintracel-lular phase. They avoid immune destruction by antibodies by periodically changing theirglycoproteincoatsthroughamolecularprocesscalledantigenic variation.

EPIDEMIOLOGY• HAT occurs only in sub-Saharan Africa, where endemic foci are found in about 20

countries.• HAT is much less of a problem today than in the past. Fewer than 10,000 new cases are

reportedannuallytotheWorldHealthOrganization.Althoughthisnumberreflectssubstan-tial underreporting, there is no doubt that control efforts implemented in many endemiccountriesduringthepast15yearshaveachievedconsiderablesuccess.Eachyearinindus-trializedcountriesHATisdiagnosedinasprinklingofpersonswhohavetraveledtoendemicareas,butgiventhe largenumbersofpersonswhomakesuchtrips, the incidenceofsuchcasesisextremelylow.

CLINICAL MANIFESTATIONS• Twoclinicalstagesexist.Stage1(hemolymphaticdisease)ischaracterizedbyfever,adenopa-

thy,andheadache.Stage2(centralnervoussystemorencephaliticdisease)involvesmainlyneuropsychiatricsignsandsymptoms.

• TheprimarydifferencebetweentheclinicalpatternsofgambienseandrhodesienseHATisthatthelatterfollowsamuchmorerapidcourseandcanleadtodeathinamatterofmonths,whereasgambienseHATtypicallydevelopsachronicpatternthatcanlastforyears.

• UntreatedHATalmostinevitablyendsindeath.• Itisimportantforcaregiversattendingtotravelerswithfeverandothernonspecificsymp-

tomswhohavebeeninendemicareastoincludeHATinthedifferentialdiagnosis.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofborrowedfigures.

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ents o

f African

 Trypan

oso

miasis (Sleep

ing

 Sickness)

DIAGNOSIS• Given the life-threatening nature of untreated HAT, a high index of suspicion should be

maintainedwithpersonswhohavebeeninareasendemicforHAT.• Numerousotherillnessescommoninthetropicscausesymptomssimilartothoseseenin

boththeearlyandlatestagesofsleepingsickness.• A definitive diagnosis of African trypanosomiasis requires demonstration of the parasite.

ExaminationofbloodsmearsandcerebrospinalfluidforparasitesisthecornerstoneofHATdiagnosis.

• ThereisagrowingroleforpolymerasechainreactionandrelatedmolecularmethodsinthediagnosisofHAT.

• DiagnosticapproachesandtreatmentshouldbediscussedindetailwithappropriatestaffattheCentersforDiseaseControlandPrevention.

THERAPY• Treatmentiscomplicatedbecauseitvariesaccordingtotheclinicalstageofthediseaseand

thetrypanosomesubspeciescausingtheinfection.• ToxicityofthedrugsusedtotreatHATisamajorproblem.

PREVENTION• Individuals can reduce their risk of acquiring infections with African trypanosomes by

avoidingareasknowntoharborinfectedinsects,wearingclothingthatreducesthebitingoftheflies,andusinginsectrepellent.

• Chemoprophylaxis isnotrecommendedbecauseof thehightoxicityof thedrugs thatareactiveagainstAfricantrypanosomes,andnovaccineisavailabletopreventtransmissionoftheparasites.

424

206  Toxoplasma gondiiJosé G. Montoya, John C. Boothroyd, and Joseph A. Kovacs

DEFINITION• Toxoplasma gondii is a ubiquitous coccidian protozoan that usually causes asymptomatic

infection inhumansbut cancause significantdisease incongenitally infected infantsandimmunodeficientpatientsandoccasionallyinimmunocompetentindividuals.

EPIDEMIOLOGY• Toxoplasmosisisaworldwidezoonosisthatcaninfectawiderangeofanimalsandbirds.• Transmissiontohumansismainlybyingestionofviabletissuecystsinmeatoroffoodor

watercontaminatedwithoocysts.Lesscommonly,thereiscongenitaltransmissionortrans­plantationofaninfectedorgan.

• PositiveimmunoglobulinG(IgG)representingpriorinfectionincreaseswithage;seropreva­lenceis≈11%intheUnitedStatesandupto≈78%inotherpartsoftheworld.

• Congenital transmission occurs almost exclusively when the mother becomes infectedduringpregnancy.Retinochoroiditiscanoccuraftercongenitalinfectionorrecentlyacquiredinfection.Infectioninhumanimmunodeficiencyvirus(HIV)/acquiredimmunodeficiencysyndromepatientsalmostalwaysresultsfromreactivationoflatentinfection.Amongorgantransplantpatients,diseasecanresultfromeithernewlyacquiredinfectionfromthetrans­plantedorganorfromreactivationoflatentinfection.

MICROBIOLOGY• Toxoplasma organisms are exclusively intracellular. The sexual phase occurs in felines.

Excretedoocystsrequire1to5daystobecomeinfectious.Tachyzoitesactivelyreplicateinessentiallyallcelltypes.Tissuecystswithintracysticbradyzoitesmaintainorganismviabilityduringlatentinfection.

• Tachyzoites replicate well in tissue culture and are responsible for clinical manifestationsduringprimaryinfectionorreactivationoflatentinfection.

• Multiplestrainsareidentifiedbygenotyping.Strainsdifferinvirulence,withthemostviru­lentstrainssofarreportedbeingfoundinSouthAmerica.

DIAGNOSIS• Direct detection of the organism is by polymerase chain reaction (PCR) assay, histopa­

thology with immunoperoxidase staining, or, less commonly, by tissue culture or mouseinoculation.

• Serologicassayscanhelpdistinguishacutefromchronicinfectionandcanidentifypatientsatriskforreactivation.ImmunoglobulinM(IgM)­positivetestresultsshouldbeconfirmedat a reference laboratory (e.g., the Palo Alto Medical Foundation–Toxoplasma SerologyLaboratory[PAMF­TSL];www.pamf.org/serology/).

• Maternalinfectionisoftenasymptomatic;serologyshowsacuteinfection,andIgM­positivetestresultsmustbeconfirmedatareferencelaboratory.Congenitalinfectionmaybeasymp­tomaticorappearwithneurologicorocularmanifestations;thisformisdiagnosedinuterobyPCRofamnioticfluidorafterbirthbyserologyorPCR.

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plasm

a go

nd

ii

• Chorioretinitismaybeasymptomaticorshowvisualloss;ophthalmologicexaminationandPCRofvitreousoraqueousfluidareperformed.TheGoldmann­Witmercoefficient(anti­Toxoplasma IgG/total IgG in aqueous fluid divided by anti­Toxoplasma IgG/total IgG inserum)canbehelpful.

• HIV­infectedpatientsusuallypresentwithfocalneurologicsymptoms.PatientsareusuallyIgGpositiveandIgMnegative,computedtomographyormagneticresonanceimagingmayshow one or more contrast­enhancing lesions, cerebrospinal fluid PCR is specific but notsensitive,brainbiopsysensitivityisimprovedbyimmunoperoxidasestaining,anddiagnosisisoftenpresumptiveandextendstoaresponsetoempiricaltherapy.

• Immunodeficient patients present with encephalopathy, seizures, pneumonia, and fever.DiagnosisisbasedonpositivePCRorhistopathology.Hematopoieticstemcelltransplanta­tion(HSCT)requirespretransplantserology;solid­organtransplantationrequirespretrans­plantserologyinthedonorandrecipient.

THERAPY• Immunocompetentpatients:Thesepatientsusuallyrequirenotherapyifasymptomatic;they

maybenefitfromtreatmentifsymptomsaresevereorpersist.• Immunocompromised patients: The therapy dosage is pyrimethamine (200­mg load,

then50 to75mg/day)plus sulfadiazine (1000 to1500mgevery6hours)plus leucovorin(10to20mg/day).Thedosageisthendecreasedtomaintenancedosingofpyrimethamine(25 to 50mg/day) plus sulfadiazine (500 to 1000mg every 6 hours) plus leucovorin (10to 20mg/day) after 3 to 6 weeks if a clinical response occurs. Alternatives include pyri­methamine,asabove,plusleucovorinpluseitherclindamycin(intravenous[IV]ororal[PO];600mg every 6 hours) or atovaquone (1500mg every 12 hours). Another alternative istrimethoprim­sulfamethoxazole(TMP­SMX)(IVorPO;5mg/kgofTMPevery12hours).Corticosteroidsaregivenonlyforclinicallysignificantedemaormasseffect,andanticon­vulsantsaregivenonlyafteraseizure.

• HIV patients: Start antiretroviral therapy (ART) after 2 to 3 weeks; stop anti­ToxoplasmamedicationsiftheCD4countisgreaterthan200cells/mm3formorethan6months.HighrelapserateoccurswithoutARTandmaintenancetherapy.

• Acuteinfectioninpregnantwomenlessthanorequalto18weeksofgestation:Givespira­mycin (1g every 8 hours; available at no cost through the PAMF­TSL and the U.S. FoodandDrugAdministration)untildelivery.Ifinfectioninthefetusisdocumentedorsuspected,or ifatgreaterthan18weeksofgestation,givepyrimethamine(50mgevery12hoursfor2days,then50mg/day)plussulfadiazine(initialdose75mg/kg,followedby50mg/kgevery12hours;maximum,4g/day),plusfolinicacid(10to20mg/day).Before14to18weeksofgestation,givenopyrimethamineorleucovorin.

• Congenitallyinfectedinfant:Givepyrimethamine(1mg/kgevery12hoursfor2days,then1mg/kg/day for 2 or 6 months); then this dose is given every Monday, Wednesday, andFriday; plus sulfadiazine (50mg/kg every 12 hours) plus folinic acid (10mg three timesweekly)foratleast12months.

• Chorioretinitis patients: If therapy is clinically indicated, give pyrimethamine (100­mgloadingdoseover24hours,then25to50mg/day)plussulfadiazine(1gevery6hours)plusleucovorin(10to20mg/day)for4to6weeks.TMP­SMX,onedouble­strengthtabletevery3days,canpreventrelapse.

PREVENTION AND PROPHYLAXIS• Avoidundercookedmeatandpotentiallycontaminatedfoodorwater;cleancatlitterdaily.• Immunocompromised patients: Give TMP­SMX, one double­strength or single­strength

tablet daily. An alternative is dapsone (50mg/day) plus pyrimethamine (50mg/wk) plusleucovorin (25mg/wk). If the patient has HIV, start if the CD4 count is less than 100 to200 cells/mm3; discontinue if the patient is on ART and the CD4 count is greater than200cells/mm3foratleast3months(primaryprophylaxis)or6months(secondaryprophy­laxis).ForHSCTrecipients,startTMP­SMXafterengraftment.Ifthepatientisasolid­organtransplantrecipient,startattransplantationifclassifiedasD+orR+.

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207 Giardia lambliaDavid R. Hill and Theodore E. Nash

DEFINITION• Giardiasis,causedbytheprotozoanGiardia lamblia,isacommoncauseofsporadic,endemic,

andepidemicdiarrheathroughouttheworld.• Infected persons can have acute diarrhea with malaise, cramping and bloating, chronic

diarrhea with malabsorption, or asymptomatic infection. Asymptomatic infection is mostcommon in children, particularly in low-income settings, and may contribute to poornutrition.

EPIDEMIOLOGY• Giardiaisoneofthemostwidelydistributedentericparasites.• IntheUnitedStates,thereareapproximately20,000documentedinfectionsannually,with

estimatedinfectionsofmorethan100,000;itismostfrequentlyreportedinchildrenaged1to9yearsandadultsaged35to45years.

• Inlow-incomecountries,Giardiainfectsnearlyallchildrenbytheageof10years.• Transmissionofthisfecal-oralparasiteismostcommonthroughpersontopersontransmis-

sionandthroughuntreatedorinadequatelytreatedsurfacewater.• Although specific human genotypes (assemblages A and B) are found in some animals,

epidemicsofgiardiasiscausedbyanimalshavenotbeenreliablyobserved.Animalstypicallyharborotherassemblages.

DIAGNOSIS• Aclinicalsyndromeofdiarrhealasting7to10days,andoftenassociatedwithweightloss,

ishelpfulindistinguishinggiardiasisfromotherentericinfections.• Usefulepidemiologicrisk factorsareahistoryof travel,drinkinguntreatedsurfacewater,

having young children in daycare, or engaging in sexual practices with the potential forfecal-oraltransmission.

• Stoolexaminationforovaandparasitesisthetraditionalmethodofdiagnosis.• Antigendetectioniswidelyavailableandismoresensitiveandspecificthanstoolexamina-

tionforovaandparasites.Polymerasechainreactionassayisbecomingmorewidelyusedandcanidentifytheassemblage.

THERAPY• Tinidazoleisthedrugofchoice,takeninasingledose(seeTable207-1).• Alternativesaremetronidazole,nitazoxanide,andalbendazole.• Potentialadverseeventsassociatedwithtreatmentshouldbediscussedwiththepatient.• Treatmentduringpregnancyrequiresspecialconsiderations.• Post-Giardialactoseintoleranceshouldbeconsiderediftreatmentappearstofail.Ifparasites

arepresent,thenre-treatmentwithadrugofadifferentclassisusuallysuccessful.

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ia lamb

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PREVENTION• Preventionofgiardiasisrequirestheproperhandlingandtreatmentofdrinkingandrecre-

ational water supplies, good personal hygiene, and protection of food supplies fromcontamination.

• Bringingwatertoaboil,filtration,andcarefulhalogenationcanbeeffectivemeasurestotreatsmallvolumesofwater.

TABLE 207-1  Treatment of Giardiasis

Drug (FDA Pregnancy Category)*

DOSAGE

Adult PediatricTinidazole (C) 2 g, single dose 50 mg/kg, single dose (maximum, 2 g)

Metronidazole† (B) 250 mg tid × 5-7 days 5 mg/kg tid × 7 days

Nitazoxanide (B) 500 mg bid × 3 days Age 12-47 mo: 100 mg bid × 3 days

Age 4-11 yr: 200 mg bid × 3 days

Albendazole† (C) 400 mg qd × 5 days 15 mg/kg/day × 5-7 days (maximum, 400 mg)

Paromomycin† (NC) 500 mg tid × 5-10 days 30 mg/kg/day in 3 doses × 5-10 days

Quinacrine‡ (C) 100 mg tid × 5-7 days 2 mg/kg tid × 7 days

Furazolidone‡ (C) 100 mg qid × 7-10 days 2 mg/kg qid × 10 days

FDA, U.S. Food and Drug Administration; NC, not categorized.*FDA pregnancy categories: B, Animal reproduction studies have failed to demonstrate a risk to the fetus, and

there are no adequate and well-controlled studies in pregnant women. C, Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

†Not an FDA-approved indication.‡No longer produced in the United States; may be obtained from some compounding pharmacies.

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208  Trichomonas vaginalisJane R. Schwebke

MICROBIOLOGY AND EPIDEMIOLOGY• Trichomonas vaginalisisaflagellatedparasite.• Infectionisthroughsexualtransmission.• Susceptibilitytohumanimmunodeficiencyvirus(HIV)infectionmaybeincreased.

DIAGNOSIS• Infection causes vaginitis in women and may cause urethritis in men; it is often

asymptomatic.• Inwomen,mostcasesarediagnosedusingwetprepmicroscopyofvaginalfluidasthepoint

ofcaretest,butthislackssensitivity.• Goldstandardfordiagnosisisnucleicacidamplificationtesting.

THERAPY• Metronidazoleistheusualtherapy.• Resistancetometronidazolemayoccur.• Tinidazolemaybemoreeffective.

PREVENTION• Sexualpartnersshouldbetreated.• Condomspreventinfection.

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209  Babesia SpeciesJeffrey A. Gelfand and Edouard G. Vannier

DEFINITION• Babesiosisisanemerginginfectiousdiseasecausedbyhemoprotozoanparasitesofthegenus

Babesia.

EPIDEMIOLOGY AND MICROBIOLOGY• ThemainetiologicagentofbabesiosisintheUnitedStatesisBabesia microti,aparasitetypi-

callyfoundinwhite-footedmiceandprimarilytransmittedtohumansduringthebloodmealofaninfectedIxodes scapularisnymphaltick.

• B. microticanalsobetransmittedviatransfusionofbloodproducts,primarilypackedredbloodcells.Transplacentaltransmissionisrare.

• Babesiosis is a nationally notifiable disease in seven highly endemic states (Connecticut,Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin) and 12otherjurisdictions.

• Risk factors for severe babesiosis include age older than 50 years, splenectomy, humanimmunodeficiencyvirusinfection,malignancy,andimmunosuppressiontherapiesfortrans-plantationorcancer.

DIAGNOSIS• Feveristhesalientsymptom.Chillsandsweatsarecommon.Lessfrequentsymptomsinclude

headache,myalgia,anorexia,arthralgia,andnausea.• DiagnosisismadeonGiemsa-stainedthinbloodsmears.Trophozoitesoftenappearasrings.

Tetradsofmerozoitesarepathognomonic.Other features thatdistinguishbabesiosis frommalariaincludethelackofbrownishdepositinrings,theabsenceofgametocytes,andthepresenceofextracellularmerozoites.

• Ifparasitesarenotvisualizedonasmearandbabesiosisissuspected,polymerasechainreac-tionassay–basedamplificationofparasiteDNAshouldbeperformed.Serologyconfirmsthediagnosis.

• Laboratory findings are consistent with hemolytic anemia and include low hematocrit,low hemoglobin, elevated lactate dehydrogenase level, and elevated reticulocyte count.Thrombocytopeniaandelevatedliverenzymevaluesarecommon.

THERAPY (SEE TABLE 209-1)• MildB. microtiillnessshouldbetreatedwithasingle7-to10-daycourseoforalatovaquone

(750mg orally every 12 hours) plus oral azithromycin (500mg orally once, then 250mgdaily). Symptoms should be expected to abate within 48 hours and to resolve within3months.

• Severe B. microti illness requires hospitalization. Initial therapy should consist of a 7-to10-daycourseofclindamycin(300to600mgintravenouslyevery6hoursor600mgorallyevery 8 hours) plus oral quinine (650mg orally every 8 hours). Despite therapy, half ofhospitalizedpatientsdevelopcomplicationsandabout10%die.

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• Ifsymptomspersistorrelapse,antimicrobialtherapyshouldlast6weeks,including2weeksduringwhichparasitesarenolongerseenonbloodsmear.

• Partialorcompleteredbloodcellexchangetransfusionisrecommendedwhenhigh-gradeparasitemia (≥10%) or severe anemia (≤10g/dL) occurs, or when pulmonary, renal, orhepaticsystemsarecompromised.

PREVENTION• Novaccineisavailable.Individualsatriskshouldavoidhighlyendemicareas.

TABLE 209-1  Treatment of Human Babesiosis

ORGANISM SEVERITY ADULTS CHILDRENBabesia microti* Mild† Atovaquone 750 mg

q12h PO plus azithromycin 500 mg PO on day 1 and 250 mg/day PO from day 2 on

Atovaquone 20 mg/kg q12h PO (maximum 750 mg/dose) plus azithromycin 10 mg/kg PO on day 1 (maximum 500 mg/dose) and 5 mg/kg/day PO from day 2 on (maximum 250 mg/dose)

SevereठClindamycin 300-600 mg q6h IV or 600 mg q8h PO plus quinine 650 mg q8h PO

Clindamycin 7-10 mg/kg q6-8h IV or 7-10 mg/kg q6-8h PO (maximum 600 mg/dose) plus quinine 8 mg/kg q8h PO (maximum 650 mg/dose)

Babesia divergens* Immediate complete RBC exchange transfusion plus clindamycin 600 mg q6-8h IV plus quinine 650 mg q8h PO

Immediate complete RBC exchange transfusion plus clindamycin 7-10 mg/kg q6-8h IV (maximum 600 mg/dose) plus quinine 8 mg/kg q8h PO (maximum 650 mg/dose)

Note: Monitor patients on quinine with electrocardiography; monitor quinine serum levels in the setting of hepatic or renal disease.

IV, intravenously; PO, orally; RBC, red blood cell.*Treatment for 7 to 10 days, but duration may vary.†Atovaquone (750 mg twice daily) combined with higher doses of azithromycin (600 to 1000 mg/day) has been

used in immunocompromised patients. With this regimen, symptoms and parasitemia resolve faster.‡Consider partial or complete RBC exchange transfusion in cases of high-grade parasitemia (≥10%), severe anemia

(<10 g/dL), or pulmonary, renal, or hepatic compromise. Even when parasitemia is less than 10%, consider exchange transfusion if acute respiratory distress syndrome or syndrome resembling a systemic inflammatory response syndrome is present.

§In asplenic individuals and in immunocompromised patients, persistent or relapsing babesiosis should be treated for at least 6 weeks, including 2 weeks during which parasites are no longer detected.

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210 Cryptosporidiosis (Cryptosporidium Species)A. Clinton White, Jr.

DEFINITION• CryptosporidiosisiscausedbyinfectionwithoocystsofCryptosporidiumspecies.

EPIDEMIOLOGY• Cryptosporidiosis has a global distribution with a higher prevalence in resource-poor

countries.• Cryptosporidiosis is amajorcauseofprolongeddiarrheaandmalnutrition inchildren in

resource-poorcountries.• Cryptosporidiosis is a major cause of diarrhea in adults infected by human immunodefi-

ciencyvirus(HIV).• Cryptosporidiosis is associated with person-to-person and waterborne transmission in

wealthycountries.• Themajorspecies,Cryptosporidium hominis,primarilyinfectshumans.• Zoonoticspecies,includingCryptosporidium parvum,arealsocommoninhumans.

MICROBIOLOGY• Cryptosporidiumspeciesareapicocomplexanprotozoanparasites.

CLINICAL MANIFESTATIONS• Mostpatientspresentwithdiarrheathatisfrequentlyprolonged.

DIAGNOSIS• Diagnosisdependsondemonstrationoftheorganisminstoolbyantigendetection,nucleic

acidamplification,ormicroscopywithacid-fastorfluorescentstains.

MANAGEMENT• Forimmunocompromisedhosts,thereisnoeffectivetherapy,butreversalofimmunedefects

iscritical(e.g.,treatingunderlyingHIVwithantiretroviraltherapy).• Nitazoxanidealoneiseffectiveinimmunocompetenthostsbutnotinseverelyimmunocom-

promisedpatients.

PREVENTION• Watertreatmentandhandhygienearekeymeasurestopreventinfection.

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211 Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis SpeciesKathryn N. Suh, Phyllis Kozarsky, and Jay S. Keystone

CYCLOSPORA AND CYSTOISOSPORA (ISOSPORA)Epidemiology• Bothareopportunisticpathogens in immunocompromisedhostsbutalso infectnoncom-

promisedpatients.• Cyclospora:distributionisworldwideandisendemicindevelopingareas,withoutbreaksin

developedareas.• Cystoisospora: occurrence is primarily in tropical and subtropical climes, especially South

America,Africa,andSoutheastAsia.• Contaminatedfoodandwaterareprimarysources.• Oocystscansurviveinenvironmentformonthsbutmustsporulatetobecomeinfective.

Diagnosis• Acuteorchronicdiarrheaoccurswithotherconstitutionalandgastrointestinalsymptoms.• Oocystsinstoolmaybevisualizedusingmodifiedacid-faststain.• Multiplestoolexaminationsmayberequired.

Therapy• Trimethoprim-sulfamethoxazole, 1 double-strength tablet twice daily for 7 to 10 days,

or ciprofloxacin, 500mg orally twice daily for 7 days, is effective (see Tables 211-1 and211-2).

SARCOCYSTIS SPECIESEpidemiology• Distributionismainlytropicalandsubtropical,especiallyinSoutheastAsiaandMalaysia.• Infectioniswidelydistributedinvariousanimals;humandiseaseisveryrareafterconsump-

tionofinfectedraworundercookedanimalflesh.• Sarcocystis suihominisandSarcocystis hominisarethemaincausesofhumandisease.

Diagnosis• Infectionisgenerallyasymptomatic.• Rarely,self-limitedgastrointestinalillnessormyositis(fever,myalgias)occursafterexposure

inendemicareas.• Sporocystsoroocystsmaybevisibleinstool;musclebiopsymayberequired.

Therapy• None;albendazolehasbeenused.

BALANTIDIUM COLIEpidemiology• Distribution is worldwide, with infections in Latin America, Southeast Asia, Papua New

Guinea,andtheMiddleEastmostcommon.

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spo

ra cayetanen

sis, Cysto

isosp

ora (Iso

spo

ra) belli, Sarco

cystis Species, B

alantid

ium

coli, an

d B

lastocystis Sp

ecies

• Pigsareprimaryreservoirsandshedcystsinstool.• Cystsincontaminatedfoodorwaterareinfective.

Diagnosis• Theinfectionisgenerallyasymptomatic;occasionallyadiarrhealillnessisreported.• Trophozoitesarevisibleinstool.

Therapy• Tetracycline,metronidazole,oriodoquinolisused(seeTable211-3).

BLASTOCYSTIS SPECIESEpidemiology• Distribution is worldwide, primarily in developing countries, but prevalence varies

markedly.

Diagnosis• Roleinhumandiseaseisunclear;diarrhea,flatulence,andabdominaldiscomfortaremost

commonlyreportedsymptoms.• Microscopicdiagnosisischallenging;trichromestainisthemostsensitive.• Polymerasechainreactionassayismoresensitiveandspecificbutnotwidelyavailable.

Therapy• Therapyisoftenunsatisfactory.• Trimethoprim-sulfamethoxazole,metronidazole,oriodoquinolisused(seeTable211-4).

TABLE 211-1  Therapy (Adult) for Cyclosporiasis

DRUG* THERAPEUTIC DOSAGE PROPHYLACTIC DOSAGETrimethoprim-sulfamethoxazole One DS tablet† PO bid for 7-10 days One DS tablet PO three times weekly

Ciprofloxacin 500 mg PO bid for 7 days 500 mg PO three times weekly

Nitazoxanide 500 mg PO bid for 7 days

DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.

TABLE 211-2  Therapy (Adult) for Cystoisosporiasis

DRUG* THERAPEUTIC DOSAGE PROPHYLACTIC DOSAGETrimethoprim-sulfamethoxazole One DS tablet† PO bid for 10 days One DS tablet PO daily or three times

weekly

Ciprofloxacin 500 mg PO bid for 7 days 500 mg PO daily or three times weekly

DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.

TABLE 211-3  Therapy (Adult) for Balantidiasis

DRUG* DOSAGETetracycline 500 mg PO qid for 10 days

Metronidazole 750 mg PO tid for 5 days

Iodoquinol 650 mg PO tid for 20 days

PO, orally.*Drugs are listed in order of preference.

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TABLE 211-4  Therapy (Adult) for Blastocystosis

DRUG* DOSAGEMetronidazole 750 mg PO tid or 1.5 g daily, for 10 days

Trimethoprim-sulfamethoxazole One DS tablet† bid or two DS tablets daily for 7 days

Iodoquinol 650 mg PO tid for 20 days

Nitazoxanide 500 mg bid for 3 days

Paromomycin 25-35 mg/kg divided tid for 7 days

DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.

435

I  Diseases Due to Toxic Algae

212 Human Illness Associated with Harmful Algal BloomsJ. Glenn Morris, Jr.

DEFINITION• Illnessesofprimaryconcerncausedbypreformedtoxinsproducedbyalgalspeciesinclude

ciguaterafishpoisoning,paralyticshellfishpoisoning,andamnesicshellfishpoisoning.

EPIDEMIOLOGY AND MICROBIOLOGY• Dependingontheagent,illnessiscausedbyingestionoftoxinsinseafoodorbyinhalation

orskincontact.• Occurrenceofillnessisusuallylinkedwithbloomsofspecifictoxicalgalspecies(seeTable

212-1).Harmfulalgalbloom–relatedillnessesintheUnitedStateshavebeenreportedfromAtlantic,Pacific,andGulfCoasts,HawaiiandAlaska,andtheCaribbean(seeFig.212-1).

DIAGNOSIS• Diagnosisisbasedonclinicalpresentation(seeTable212-1).

THERAPY• Therapy is supportive. The syndrome of hypotension/bradycardia seen in severe cases of

ciguaterafishpoisoningmayrequireatropine;respiratorysupportmaybenecessaryinseverecasesofparalyticshellfishpoisoning.

PREVENTION• Prevention is based on avoidance of fish or shellfish that contain toxins. Environmental

monitoringofshellfishfortoxinsresponsibleforparalytic,amnesic,andneurotoxicshellfishpoisoningisconductedbystateandlocalhealthdepartments.

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TABLE 212-1  Human Illness Associated with Harmful Algal Blooms

SYNDROMECAUSATIVE ORGANISMS

TOXIN PRODUCED CLINICAL MANIFESTATIONS

Ciguatera fish poisoning

Gambierdiscus spp. and others

Ciguatoxin Acute gastroenteritis, followed by paresthesias and other neurologic symptoms

Paralytic shellfish poisoning

Alexandrium spp. and others

Saxitoxins Acute paresthesias and other neurologic manifestations; may progress rapidly to respiratory paralysis

Neurotoxic shellfish poisoning

Karenia brevis Brevetoxins Gastrointestinal and neurologic symptoms; formation of toxic aerosols by wave action can produce respiratory irritation and asthma-like symptoms

Diarrhetic shellfish poisoning

Dinophysis spp. Okadaic acid and others

Acute gastroenteritis, abdominal pain

Amnesic shellfish poisoning

Pseudonitzschia spp.

Domoic acid Gastroenteritis, followed by memory loss, neurologic manifestations; may progress to amnesia, coma, and death

Azaspiracid shellfish poisoning

Azadinium spp. and others

Azaspiracid Acute gastroenteritis, abdominal pain

Lyngbya or Cyanobacteria exposure syndromes

Lyngbya spp. Lyngbyatoxin A, debromaplysiatoxin

“Swimmers’ itch,” particularly in inguinal area; sore eyes, ears; headache; possibly gastrointestinal symptoms

Microcystis spp. Microcystins (??)

Pfiesteria-associated syndrome

Pfiesteria spp. (?) Unidentified to date

Deficiencies in learning and memory; acute respiratory and eye irritation; acute confusional syndrome

FIGURE 212-1 Sites and types of harmful algal blooms along the U.S. coast. ASP, amnesic shellfish poisoning; CFP, ciguatera fish poisoning; CyanoHABs, cyanobacterial harmful algal bloom; DSP, diarrhetic shellfish poisoning; NSP, neurotoxic shellfish poisoning; PSP, paralytic shellfish poison-ing. (From U.S. National Office for Harmful Algal Blooms/Woods Hole Oceanographic Institution.)

Puerto Rico

HawaiiAlaska

Harmful algae blooms

PSP

ASP

CFP

NSP

Brown tide

CyanoHABs

Golden algae

DSP

Karlodinium and Pfiesteria

437

J  Diseases Due to Helminths

213 Intestinal Nematodes (Roundworms)James H. Maguire

DEFINITION• Intestinalnematodesorroundwormsarehelminthicparasitesofthehumangastrointestinal

tract(seeTable213-1).• AscarisandTrichuris(whipworm)areacquiredbyingestionofcontaminatedsoil.• Strongyloidesandhookworms(Ancylostoma, Necator)areacquiredbyexposuretolarvaein

soil.• OnlyEnterobius(pinworm)istransmittedfrompersontopersonbyingestionofeggsorby

contactwithfomites.

EPIDEMIOLOGY• Soil-transmittedhelminthscalledStrongyloidesareprevalentintropicsandsubtropics.They

infectmorethan1billionpersons,primarily thosewith limitedaccess tocleanwaterandsanitation.

• In temperate areas and industrialized countries, Strongyloides are found primarily amongimmigrantsandtravelersreturningfromthetropicsandsubtropics.

MICROBIOLOGY• Ascarisnematodes,hookworms,andTrichuriswhipwormscannotreplicateinahumanhost;

hence,thereisnoperson-to-persontransmission.Thedurationofinfectionisthelifespanofadultworms,usuallylessthanafewyears.

• Strongyloidescanreplicateinhumanhosts;hence,infectionisacquiredviaperson-to-personcontactandcontactwithlarvaeonsoil.Infectionpersistsfordecades,andnumbersofwormscanincreasewithoutexogenousreinfection,especiallyinpersonsreceivingcorticosteroidsorwithhumanT-celllymphotropicvirus-1infection.

• Pinwormsarecommoninallpartsoftheworld,particularlyinchildren.• Pinworms spread readily by person-to-person contact and ingestion of eggs shed in the

environment,andinfectedpersonsfrequentlyreinfectthemselvesandothersinfamily.• Hookworms,Ascaris,andStrongyloidesmigratethroughthelung,butwhipwormsandpin-

wormsdonot.

DIAGNOSIS• Intestinalparasiteinfections:usuallycauselight,few,ornosymptomsbutoftenelicitperiph-

eralbloodeosinophilia• Soil-transmitted helminths: in children with moderate infections and those at risk of

malnutrition• Suggestive clinical syndromes: Ascaris: intestinal or biliary obstruction; hookworm: iron-

deficiencyanemia;Trichuris: intestinalprolapse,dysentery;Strongyloides:abdominalpain,diarrhea, larva currens, disseminated infection (immune compromised); pinworm: analitching

• Ascaris nematodes, hookworms, and Trichuris whipworms: readily diagnosed by micro-scopicexaminationofthestoolforcharacteristiceggs

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• Strongyloides:serologymoresensitivethanstoolexamination• Pinworm:cellophanetapemethod

THERAPY• Soil-transmittedhelminthsandpinworms;albendazole,mebendazole,orpyrantel• SingledoseeffectiveforAscaris,hookworm;multipledosesforTrichuris;repeatsingledose

after2weeksforpinworm• Strongyloides: two daily doses of ivermectin; prolonged therapy for hyperinfection or dis-

seminatedinfection

PREVENTION• Sanitation,provisionofcleanwater,wearingshoes,handwashing• Periodicmassdrugadministrationforsoil-transmittedhelminths• Strongyloides:suspect,diagnose,andtreatbeforeimmunosuppressivetherapy

TABLE 213-1  Features of Major Intestinal NematodesN

EMA

TOD

E

TRA

NSM

ISSI

ON

DIR

ECT 

PER

SON

-TO

-PER

SON

 TR

AN

SMIS

SIO

N

GEO

GR

APH

IC 

DIS

TRIB

UTI

ON

DU

RA

TIO

N O

F IN

FEC

TIO

N

LOC

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ON

 OF 

AD

ULT

 W

OR

M(S

)

TREA

TMEN

T*

Ascaris lumbricoides

Ingestion of infective eggs

No Warm, humid areas; temperate zones in warmer months

1-2 yr Free in lumen of small bowel, primarily jejunum

Albendazole MebendazolePyrantel Ivermectin Levamisole Piperazine

Trichuris trichiura (whipworm)

Ingestion of infective eggs

No Warm, humid areas; temperate zones in warmer months

1-3 yr Anchored in superficial mucosa of cecum and colon

Albendazole Mebendazole

Necator americanus, Ancylostoma duodenale (hookworm)

Penetration of skin by filariform larvae

No Warm, humid areas; temperate zones in warmer months

3-5 yr (Necator); 1 yr (Ancylostoma)

Attached to mucosa of mid to upper portion of small bowel

Albendazole Mebendazole LevamisolePyrantel

Strongyloides stercoralis

Penetration of skin or bowel mucosa by filariform larvae

Yes Primarily warm, humid areas, but can be worldwide

Lifetime of host

Embedded in mucosa of duodenum, jejunum

Ivermectin† Albendazole Thiabendazole

Enterobius vermicularis (pinworm)

Ingestion of infective eggs

Yes Worldwide 1 mo Free in lumen of cecum, appendix, adjacent colon

Albendazole MebendazolePyrantel Ivermectin Levamisole Piperazine

*Nitazoxanide has been shown to be effective in the treatment of ascariasis, trichuriasis, and enterobiasis in several trials in Mexico. Tribendimidine, which is licensed in China, was shown to be efficacious against Ascaris and had moderate efficacy against Strongyloides in a randomized trial.

†Drug of choice.

439

214 Tissue Nematodes (Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis)James W. Kazura

DEFINITION• Tissuenematodeinfectionscauseaspectrumofdiseasemanifestationsrangingfromasymp-

tomaticcasestochronicpathologicprocessesand,occasionally,severeillnessanddeath.

EPIDEMIOLOGY• Infectionswithtissuenematodesoccurthroughouttheworldandhavethehighestpreva-

lenceintropicalregionswhereobligatoryinsectvectorsarepresent.• Trichinellosis• Dracunculiais• Filariases

MICROBIOLOGY• Thelifecyclesoftheseparasitesarecomplexwithfivedistinctstagesthatinvolvetheirhuman

hostand,whereapplicable,insectvectors.• Trichinellosis• Dracunculiais• Filariases

DIAGNOSIS• Parasitesareidentifiedmicroscopicallyinbodyfluids,ordiagnosticassaysareusedtodetect

parasiteantigens.

THERAPY• Anthelminticdrugsareavailableformanyinfections.• Fortrichinellosis,nodrugsareavailablefortreatmentofnewbornlarvaeormaturingfirst-

stage larvae. Corticosteroids and mebendazole are sometimes utilized in severe disease.Duringtheenteralstageofinfection(1to2weeksaftereatingcontaminatedmeat),meben-dazoleoralbendazolecanbeusedtoeliminateadultwormsfromthesmallintestine.

• Forlymphaticfilariasis,diethylcarbamazineismoreactiveagainstWuchereria bancroftithanBrugia malayi.

• Diethylcarbamazineisalsousedtotreattropicalpulmonaryeosinophiliaandloiasis.• Ivermectinisusedtotreatonchocerciasis.

PREVENTION• Controllinginsectvectorsandmassadministrationofanthelminticdrugstoendemicpopu-

lations reduces and may potentially eliminate transmission of medically significant tissuenematodeinfections.

440

215 Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes)James H. Maguire*

DEFINITION• Trematodesorflukesareflatworms that live inbloodvessels,biliary tract, intestines, and

lungsofhumansandloweranimals.• Included are the schistosomes and the foodborne trematodes—liver flukes (Fasciola,

Clonorchis, Opisthorchis),intestinalflukes(variousspecies),andlungfluke(Paragonimus).

EPIDEMIOLOGY• Schistosomes are prevalent in tropical and subtropical Africa, the Middle East, Southeast

Asia,EastAsia,thePhilippines,andlimitedareasintheCaribbeanandSouthAmericainareaswithinadequatesanitationoraccesstocleanwater.

• FoodbornetrematodesaremostprevalentinSoutheastandEastAsiabutalsoinotherpartsoftheworldwherepersonsingestraworundercookedfish,crayfish,orplantsproducedinfreshwatercontaminatedwithhumanoranimalfecesor(forParagonimus)sputum.

MICROBIOLOGY• Persons become infected with schistosomes when the larval parasites (cercariae) shed by

freshwatersnails(intermediatehosts)penetratebareskin.• Personsbecomeinfectedwithfoodbornetrematodesbyingestingthelarvalparasites(meta-

cercariae)encystedinfish,aquaticvegetation,orcrustaceans(secondintermediatehost)thatwereinfectedwithcercariaeshedfromsnails(firstintermediatehost).

DIAGNOSIS• Trematodeinfectionsarefrequentlylightandmaycausefewornosymptomsbutoftenelicit

peripheralbloodeosinophilia.• Suggestive clinical syndromes during the first weeks after initial infection include acute

illnesswithfever,urticaria,eosinophilia,andothersymptomswhenlarvalflukesaremigrat-ing through the body and maturing; ectopic migration can lead to disease of the centralnervoussystem,theskin,andotherpartsofthebody.

• Suggestive clinical syndromes during chronic infections include intestinal schistosomes(diarrhea,intestinalpolyps,portalhypertension),urinaryschistosomes(hematuria,bladdercancer),liverflukes(biliaryobstruction),intestinalflukes(diarrhea,abdominaldiscomfort),andlungflukes(cough,hemoptysis,cavitarylunglesions).

• Diagnosis is made by microscopic identification of characteristic eggs in stool, urine, orsputumorbyidentificationoflarvaloradultwormsintissue.

• Serology,availableforsometrematodeinfections,maybemoresensitivethanmicroscopicexamination,especiallyduringacuteinfections.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

441C

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des (Sch

istoso

mes an

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testinal, an

d Lu

ng

 Flukes)

THERAPY• Praziquantelisthedrugofchoiceforalltrematodeinfectionsexceptfascioliasis,forwhich

triclabendazoleispreferred(seeTable215-1).

PREVENTION• Forschistosomiasis,preventivemethods includesanitation,provisionofcleanwater, snail

control,andavoidanceofcontactwithcontaminatedfreshwater.• Forfoodbornetrematodes,preventionofinfectionincludesmaintainingfreshwaterbodies

freeofcontaminationbyhumansandloweranimals,snailcontrol,andpropercookingofaquaticfish,plants,andcrustaceans.

• Periodic screening and treatment or mass drug administration for populations at risk forinfectionareessential.

TABLE 215-1  Features of Schistosomes and Other Important Trematodes

PAR

ASI

TE

SNA

IL

INTE

RM

EDIA

TE

HO

ST (

GEN

US)

SEC

ON

D

INTE

RM

EDIA

TE

HO

ST

GEO

GR

APH

IC

DIS

TRIB

UTI

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OF

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TREA

TMEN

T

Schistosomes*Schistosoma mansoni

Biomphalaria None South America, Africa, Caribbean, Arabian peninsula

Mesenteric venules

Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 dayOxamniquine†

Schistosoma japonicum

Onchomelania None China, Philippines, Indonesia, Thailand

Mesenteric venules

Praziquantel, 60 mg/kg/day in 3 doses × 1 day

Schistosoma mekongi

Neotricula None Cambodia, Laos

Mesenteric venules

Praziquantel, 60 mg/kg/day in 3 doses × 1 day

Schistosoma intercalatum, Schistosoma guineensis

Bulinus None Central and West Africa

Mesenteric venules

Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 day

Schistosoma haematobium

Bulinus None Africa, Middle East

Venules of lower urinary tract

Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 dayMetriphonate†

Liver FlukesClonorchis sinensis

Bithynia, Parafossarulus

Freshwater fish

China, Taiwan, Korea, Japan, Vietnam

Bile, pancreatic ducts

Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days

Opisthorchis viverrini

Bithynia Freshwater fish

Thailand, Laos, Cambodia

Bile, pancreatic ducts

Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days

Opisthorchis felineus

Bithynia Freshwater fish

Eastern Europe, former Soviet Union

Bile, pancreatic ducts

Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days

Fasciola hepatica

Lymnaea Watercress, other aquatic plants

Americas, Europe, Asia, western Pacific, North Africa

Bile ducts Triclabendazole,§ × 10 mg/kg × 1 dayNitazoxanide¶

Continued

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PAR

ASI

TE

SNA

IL

INTE

RM

EDIA

TE

HO

ST (

GEN

US)

SEC

ON

D

INTE

RM

EDIA

TE

HO

ST

GEO

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DIS

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TREA

TMEN

T

Intestinal FlukesFasciolopsis buski

Segmentina Aquatic plants

Far East, India Small intestine

Praziquantel, 25 mg/kg/day × 1 dayNiclosamide,‡ 1 g × 1 dayTriclabendazole¶

Heterophyes heterophyes

Pirenella, Cerithidea

Freshwater fish

Far East, Egypt, Middle East, southern Europe

Small intestine

Praziquantel, 25 mg/kg/day × 1 dayTriclabendazole¶

Metagonimus yokogawai

Semisulcospira Freshwater fish

Far East, Russia, southern Europe

Small intestine

Praziquantel, 25 mg/kg/day × 1 dayTriclabendazole¶

Lung FlukesParagonimus westermani; other species

Semisulcospira, Onchomelania, Thiara

Freshwater crabs, crayfish

Far East, South Asia, Philippines, West Africa, South and Central America

Lungs Praziquantel, 75 mg/kg/day in 3 doses × 2 daysTriclabendazole,‡ 10 mg/kg day × 3 days

*Some experts recommend higher doses (e.g., praziquantel 60 mg/kg/day in divided doses for all species), multiple doses (e.g., for 2 or 3 days), or a repeated dose at 4 to 6 weeks to achieve higher rates of cure in persons not exposed to reinfection.

†Not available or limited availability.‡Alternative drug.§In the United States it is available (from the manufacturer, Novartis, from Victoria Pharmacy in Zurich, Switzerland)

for compassionate use after approval of patient Investigational New Drug (IND) by the U.S. Food and Drug Administration.

¶Limited data.

TABLE 215-1  Features of Schistosomes and Other Important Trematodes—cont’d

443

216  Tapeworms (Cestodes)Charles H. King and Jessica K. Fairley

DEFINITION• Cestodesareflatworms(platyhelminths)thatcausehumanparasiticinfectionintheformof

intestinaltapewormsorinvasivelarvalcysts(i.e.,neurocysticercosisorechinococcosis)(seeTable216-1).

EPIDEMIOLOGY• Diphyllobothrium latum,fishtapeworm,isassociatedwitheatingundercookedfresh-water

fishandendemicworldwide.• Hymenolepis nana is the most common tapeworm worldwide and transmitted person to

person.• Taenia saginata(beeftapeworm)occursincattle-breedingareasoftheworld.• Taenia solium(porktapeworm),andconsequentlyneurocysticercosis,isendemictoresource-

limitedareas,includingMexico,CentralandSouthAmerica,Asia,andAfrica.• Echinococcus granulosusinfectionoccursworldwideinlivestock-raisingareasandprimarily

isassociatedwithdomesticdogs.• Echinococcus multilocularishasalifecyclethatinvolveswildcaninesandisendemiconlyin

theNorthernHemisphere.

MICROBIOLOGY• Maturetapewormsresideinintestinesofcarnivorousanimals.• Eggsareshedandthenpasstoanintermediatehost,causingcysticinfectionviadissemina-

tionofoncospheresintohosttissues.• Definitive carnivore host ingests cyst-infected tissue, and tapeworm then develops in

intestines.

DIAGNOSIS• Diagnosis of intestinal tapeworms relies on examination of stool for evidence of eggs or

tapewormsegments(proglottids).• Neurocysticercosisisdiagnosedbytypicalappearanceonimagingscansandsupportedby

clinicalsymptomsandserologictesting.• Echinococcosisisdiagnosedbytypicalscanimageryandsupportedbyserology.

THERAPY• Mainstayoftherapyforintestinaltapewormsispraziquantelorniclosamide.• Neurocysticercosistherapydependsonthelocationandstageofthecyst.• Parenchymal neurocysticercosis is generally treated with a combination of anthelmintic

agentsandcorticosteroids(albendazoleorpraziquantel).• Echinococcosis,dependingonthestageandspecies,oftenrequiressurgeryincombination

withanthelminticagents.

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PREVENTION• Improvedsanitationisessential.• Educationprogramsonsymptomsofinfectionandkeepinglivestockincorralsawayfrom

humansshouldbeimplemented.• Livestockatmarketorslaughterhouseshouldbescreenedforcysts.• DogsshouldbescreenedandtreatedtoeliminateEchinococcus granulosus.• Prolongedfreezingorthoroughcookingwillkillcystsintissue.

TABLE 216-1  Common Cestode Parasites of Humans, Their Typical Vectors, and Their Usual Symptoms

PARASITE SPECIES

DEVELOPMENTAL STAGE FOUND IN HUMANS

COMMON NAME

TRANSMISSION SOURCE

SYMPTOMS ASSOCIATED WITH INFECTION

Diphyllobothrium latum

Tapeworm Fish tapeworm Plerocercoid cysts in freshwater fish

Usually minimal; with prolonged or heavy infection, vitamin B12 deficiency

Hymenolepis nana

Tapeworm, cysticercoids

Dwarf tapeworm

Infected humans Mild abdominal discomfort

Taenia saginata Tapeworm Beef tapeworm Cysts in beef Abdominal discomfort, proglottid migration

Taenia solium Tapeworm Pork tapeworm Cysticerci in pork Minimal

Taenia solium (Cysticercus cellulosae)

Cysticerci Cysticercosis Eggs from infected humans

Local inflammation, mass effect; if in central nervous system, seizures, hydrocephalus, arachnoiditis

Echinococcus granulosus

Larval cysts Hydatid cyst disease

Eggs from infected dogs

Mass effect leading to pain, obstruction of adjacent organs; less commonly, secondary bacterial infection, distal spread of daughter cysts

Echinococcus multilocularis

Larval cysts Alveolar cyst disease

Eggs from infected canines

Local invasion and mass effect leading to organ dysfunction; distal metastasis possible

Taenia multiceps Larval cysts Coenurosis, bladder worm

Eggs from infected dogs

Local inflammation and mass effect

Spirometra mansonoides

Larval cysts Sparganosis Cysts from infected copepods, frogs, snakes

Local inflammation and mass effect

445

217 Visceral Larva Migrans and Other Uncommon Helminth InfectionsTheodore E. Nash*

VISCERAL LARVA MIGRANSDefinition• Visceral larva migrans (toxocariasis) is caused by Toxocara canis and less frequently by

Toxocara catiandotherhelminths.Itcommonlyoccursinchildrenandmaybemanifestedbyfever,wheezing,hepatomegaly,andothergeneralizedsymptoms.

Diagnosis• Diagnosis is based on the finding of larvae in affected tissues and the presence of

eosinophilia.

Treatment• Mostpatientsrecoverwithouttherapy.• Anti-inflammatorydrugsmaybeconsidered,andalbendazole,mebendazole,anddiethyl-

carbamazinehavebeentriedbutareofuncertainefficacy.

OCULAR LARVA MIGRANSDefinition• OcularlarvamigransiscausedbyToxocara canislarvaeintheeyeandresultsinachorio-

retinalgranulomaoroccasionallyinpanuveitis.Retinaldetachmentmayalsooccur.Thereisnospecifictherapy.

OTHER UNCOMMON HELMINTHS• Otherhelminthicinfectionsdiscussedinthechapterareanisakiasis,cutaneouslarvamigrans,

eosinophilic meningitis, gnathostomiasis, angiostrongyliasis, eosinophilic gastroenteritis,dirofilariasis,capillariasis,nanophyetiasis,andswimmer’sitch.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

446

K  Ectoparasitic Diseases

218  Lice (Pediculosis)James H. Diaz

DEFINITION• Pediculosisisacomplexofthreedifferenthumaninfestations(headlice,bodylice,andpubic

lice)with twospeciesofbloodsucking lice:Pediculus humanusvar.capitisorcorporis andPhthirus pubis.

EPIDEMIOLOGY• Headlice,orpediculosiscapitis,aretransmittedprimarilybyhead-to-headcontactrather

thanbyfomites.• Headliceafflictmillionsofpeopleannually,mostlyschool-agedchildren.• Bodylice,orpediculosiscorporis,aretransmittedprimarilybybodilycontactratherthan

byfomites.• Bodyliceareassociatedwithpoorhygieneandprimarilyinfesttheindigent,institutional-

ized,homeless,refugees,andimmunocompromised.• Pubic lice infestations (phthiriasis) are transmitted primarily during sexual contacts and

oftencoexistwithothersexuallytransmitteddiseases.

MICROBIOLOGY• Body lice can transmit several bacterial diseases, including (1) relapsing fever caused by

Borrelia recurrentis,(2)trenchfevercausedbyBartonella quintana,and(3)epidemictyphuscausedbyRickettsia prowazekii. B. quintanahasbeen isolated inhead lice fromhomelesspersonsintheUnitedStates,establishingthepotential fortransmissionoftrenchfeverbyheadliceinadditiontobodylice.

DIAGNOSIS• Liceinfestationsarediagnosedbyclinicalinspectiondemonstratingliveadultlice,nymphs,

andviableeggs,ornits,intheirprecisehumananatomicniches.• Recently,dermoscopyhasbeenused to immediatelydistinguishviablenits fromhatched,

emptynits.• Dermoscopy may provide a more sensitive screening tool for head lice infestations than

inspectionalone.

THERAPY• Acombinationofpharmacologictherapywithtopicalororal(ivermectin)pediculicidesand

physicalremovalofviablenitsbywetcombingisrequired.• Pharmacotherapyshouldbeginwiththeleasttoxicpediculicides,suchaspyrethrins.• Topicalororalivermectinpreparationsshouldbereservedforpyrethrin-resistantcases.

447C

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losis)

PREVENTION• Combinationsofsanitizingtheenvironmentandeliminatingallhumanreservoirsofhead

lice in households, apartments, housing complexes, homeless shelters, classrooms, andschoolsarerecommended.

• Preventionstrategiesforpubiclicearesimilartothepreventionstrategiesforbodyliceandshouldincludehotcyclewashinganddryingofallclothingandbedding;institutionofbasicpersonalhygieneandsanitationmeasures;andtreatmentofsexualcontactswithactivebodyorpubicliceinfestations.

448

219  ScabiesJames H. Diaz

DEFINITION• Scabies is an infestation by the itch or scabies miteSarcoptes scabiei var.hominis and has

become a significant reemerging ectoparasitosis in its most severe form as crusted orNorwegianscabiesamongthehomeless,institutionalizedolderadults,thementallyretarded,andtheimmunocompromised.

EPIDEMIOLOGY• Theworldwideannualprevalenceofscabieshasbeenestimatedtobeabout300millioncases.• Scabiesoccursworldwideinbothgenders,atallages,andamongallethnicandsocioeco-

nomicgroups.Scabiesishyperendemicthroughoutthedevelopingworld,especiallyinsub-SaharanAfrica, India, theAboriginalregionsofnorthernAustralia,andtheSouthPacificIslands,especiallytheSolomonIslands.

• CrustedorNorwegianscabiesishighlytransmissibleinthehospitalenvironment.

MICROBIOLOGY• Thehumanscabiesmiteisanobligateparasiteandcompletesitsentirelifecycleonitshuman

hostsasfemalesburrowintradermallytolayeggsandlarvaeemergeandmaturetoreinfestthesameornewhosts.Theentireincubationperiodfromeggstofull-grownmiteslasts14to15days.

• The human incubation period from initial infestation to symptom development is 3 to 6weeksininitialinfestationsandasshortas1to3daysinreinfestationsasaresultofpriorsensitizationtomiteantigens.

DIAGNOSIS• The diagnosis of scabies is made by epidemiologic considerations and clinical

observations.• Aclinicaldiagnosismaybeconfirmedbylow-powermicroscopicexaminationofaburrow

skinscrapingthatexcavatesthefemalemite.• Skinbiopsymayhelpconfirmthediagnosisinatypicalcases.• Newerdiagnosticmethodsforscabiesincludeenhancedmicroscopictechniques(dermos-

copy),immunologicdetectionofspecificscabiesantibodies,andmolecularidentificationofscabiesDNA.

THERAPY• Bothtopical5%permethrinandoralivermectinappearmosteffectiveforindividualclassic

scabies.• Themanagementofcrusted(Norwegian)scabiesmayrequirecombined,intensescabicidal

therapieswithbothtopical5%permethrinandoralivermectin,especiallyinhigh-riskcom-munityandinstitutionaloutbreaks.

449C

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PREVENTION• Aggressivetreatmentof infestedpatientsandallclosehousehold, institutional,andsexual

contacts,especiallyincasesofhighlyinfectiouscrusted(Norwegian)scabies,isrequired.• Disposalorhotwash-drysterilization(bymachinewashinganddryingat60°C[140°F]or

higher)ofallcontaminatedclothingandbeddingofindexcasesisessential.• Provisionofimprovedaccessforpersonalhygieneandhealthcareforalldisplaced,homeless,

orinstitutionalizedpersonsshouldbeimplemented.

450

220 Myiasis and TungiasisJames H. Diaz

MYIASISDefinition• Myiasisisanectoparasiticinfestationofviableornecrotictissuesbythedipterouslarvaeof

higherflies.Furuncularmyiasisisthemostcommonclinicalmanifestationofmyiasisandoccurswhenoneormoreflylarvaepenetratetheskin,causingpustularlesionsthatresembleboilsorfuruncles.

Epidemiology• Myiasisisanopportunisticinfestationthatoccursintravelersreturningfromtropicaljungles

andinvulnerablepopulationslivinginendemicareasofthetropics.

Microbiology• Inhumanbotflyfuruncularmyiasis,botflylarvaerapidlyburrowintotheskinwithsharp

mandiblestobegintheirdevelopmentalinstarstages,whichcanlast6to12weeksandcausedraining,boil-likelesions,orfuruncles.

Diagnosis• Thediagnosisofmyiasisisusuallybyclinicalinspectionandexamination,oftenwithmicros-

copy. Some immunodiagnostic tests have been developed to detect the antibodies to theantigensofspecificflyspeciescausingmyiasis.

Therapy• Furuncularmyiasismaybetreatedconservativelybycoaxingembeddedlarvaefromfurun-

clesbysmotheringtheirrespiratoryspiracleswithocclusivecoatingsofpetrolatum(Vaseline),clearfingernailpolish,tobaccotar,porkfat,rawbeefsteak,orbaconstrips.However,unsuc-cessful occlusive therapy may asphyxiate larvae and necessitate their surgical or vacuumextraction.Alongwithlarvalremoval,myiasiswoundsshouldbecleansedandconservativelydébrided,tetanusprophylaxisadministered,andbacterialsecondaryinfectionstreatedwithantibiotics.

Prevention• Methodsincludecontrolofdomesticandlivestockanimallarvalinfestations;sanitarydis-

posal of animal carcasses and offal to deny flies their preferred breeding grounds; propermanagementofanyopenhumanwoundsorcutaneousinfections;cementingfloorstodenyfloor maggot flies their preferred egg-laying surfaces; sleeping on raised beds or cots inscreenedhutsor tents;wearing long-sleevedshirtsandpants,whichcanbepyrethrin-orpyrethroid-impregnated;sprayingexposedskinwithdiethyltoluamide(N,N-diethyl-meta-toluamide[DEET])–containingrepellents;andironingbothsidesofallclothesanddiapersleftoutsidetodryintumbuflyhabitats.

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ng

iasis

TUNGIASISDefinition• Tungiasis isapainful,cutaneous infestationwiththegravidfemale jiggerfleathatusually

occursonthefeetbutmayoccuranywherewherebareskintouchessoilcontaininggravidfemalefleas.

Epidemiology• Intravelersreturningtoaccessiblehealthcareinfrastructuresindevelopednations,tungiasis

isanexotic infestation,withaminimalparasiteburdenandasimplesurgicalcure,but intheimpoverishedandunderservedcommunitiesofdevelopingtropicalnations,tungiasisisarecurrentinfestationofthefeetwithahighparasiteburdencausingsignificantmorbidity,includingautoamputation.

Microbiology• Intungiasis, thegravidfemale jigger(chigoe)fleapenetratesbareskinusuallyonthe feet

(orheels),underornearthetoenailsorintheinterdigitalwebspaces,tofeedonbloodandtissuejuicesandtoincubatehundredsofdevelopingeggswithindays;itswellsto2000timesits sizeand thenexpelseggsoveraperiodof3weeksor lessbeforedyingand leaving itsshriveledcarcassinacontaminatedwoundtract.

Diagnosis• The diagnosis of tungiasis is usually by clinical inspection and examination, often with

microscopy.

Therapy• Tungiasis is treated by extracting all embedded fleas immediately with sterile needles or

curets, administering tetanus prophylaxis, and treating secondary wound infections withappropriatetopicalororalantibiotics.

Prevention• Methodsincludewearingshoes,whichcanbesprayedwithpyrethroidordiethyltoluamide–

containingsolutions;notsittingnakedonbareground;insecticidetreatmentofflea-infesteddomesticandstrayanimalsandpetswith10%pyrethrinorpyrethroidsprays,or1%to4%malathion powder; bathing the feet of domestic and stray dogs and pigs with insecticidesolutions,suchas2%trichlorfon(Neguvon);andsprayingordustinghouseholds,especiallythosewithdirtfloors,with1%to4%malathion.

452

221 Mites, Including ChiggersJames H. Diaz

DEFINITION• Mites are among the smallest arthropods, with more than 3000 species, only about 25 of

which,mostlychigger,animal,plant,andscabiesmites,areofanymedicalimportance.

EPIDEMIOLOGY• Mostmitesaresimplybitingnuisancesthatcancausehighlysymptomaticmaculopapular

eruptionsanddonottransmitinfectiousdiseases.

MICROBIOLOGY• Only biting larvae of Asian scrub typhus chiggers (Leptotrombidium spp.) can transmit

scrubtyphuscausedbyOrientia tsutsugamushi(formerlyRickettsia tsutsugamushi),andonlybitinghousemousemites(Liponyssoides sanguineus)cantransmitrickettsialpoxcausedbyRickettsia akari.

DIAGNOSIS• Clinicaldiagnosesarehighlysensitiveandspecificinthepresenceofamite-biteoutbreak.• Mite-transmittedscrubtyphusandrickettsialpoxpresentclinicallyinasimilarfashionwith

fever,biteeschar,regionallymphadenopathy,conjunctivalinjection,centralnervoussystemsymptomsinseverescrubtyphus(e.g.,confusion,delirium,coma,ortransienthearingloss),andcentrifugalrashinscrubtyphus.

THERAPY• Treatmentofchiggerbitesissupportivewithsoapandwatercleansing,warmwatersoaks,

andtopicalandlocalanestheticsandantihistamines.Impetigoandsecondaryinfectionsarepotentialcomplicationsthatwouldnecessitateantibiotictreatment.

• Bothscrubtyphusandrickettsialpoxrespondtotreatmentwithoraldoxycycline.

PREVENTION• Chiggerbitescanbepreventedwithcampsitesprayingofpyrethrinorpyrethroid-containing

insecticides;bysprayingorimpregnatingpyrethrinandpyrethroid-containingrepellentsonclothingandsleepingbags;andbyapplyingdiethyltoluamide–containinginsectrepellents(N,N-diethyl-meta-toluamide[DEET])toexposedskin.

• Rickettsialpox can be prevented by improving rodent reservoir control in campgrounds,homes,apartments,barns,sheds,and,especially,crowdedpublichousing.

• Therearenovaccinesforscrubtyphusorrickettsialpox.• Weeklydosesof200mgofdoxycyclinecanpreventO. tsutsugamushiinfectionsinendemic

regions.

453

222  Ticks, Including Tick ParalysisJames H. Diaz

DEFINITION• Tickscantransmitthebroadestrangeofinfectiousmicrobesamongallarthropods,including

bacteria,viruses,andparasites.• Gravidticksmayalsotransmitparalyticsalivarytoxinsduringblood-feeding.

EPIDEMIOLOGY• Ticks are among the most competent and versatile of all arthropod vectors of infectious

diseases.• Tick-transmitted Lyme borreliosis or Lyme disease is now the most common arthropod-

borneinfectiousdiseaseintheUnitedStatesandEurope.• Mosttick-borneinfectiousdiseasescanalsobetransmittedtohumansbybloodtransfusions

andorgantransplants,andbabesiosiscanbetransmittedcongenitally.

MICROBIOLOGY• Ticksofallagesandbothgendersmayremaininfectiousforgenerationswithouthavingto

reacquireinfectionsfromhostreservoirs.• Newtick-transmittedpathogenicspeciesareconstantlybeingdescribedintheUnitedStates.

DIAGNOSIS• Tickscantransmitseveralpathogensduringoneblood-feeding,resultingincoinfectionsthat

cancomplicatedifferentialdiagnosisandtreatment.• Thediagnosisof tick-transmittedinfectiousdiseases isbasedoncombinationsoftick-bite

historyandcharacteristiclesions,suchaserythemamigransandeschars,microscopiciden-tificationofpathogensinbloodandtissuebiopsyspecimens,serologicandimmunocytologictests,andnucleicacidserotyping.

THERAPY• Most tick-transmitted bacterial diseases remain sensitive to doxycycline, amoxicillin, and

chloramphenicol.• Thetick-transmittedviraldiseasescanbemanagedonlysupportively.• Babesiosis is caused by a malaria-like parasite and must be treated with combinations of

antimalarialagentsandazithromycinorclindamycin.

PREVENTION• Combinations of immunization, prophylactic antibiotics, personal protective measures,

landscapemanagement,andwildlifemanagementarealleffectivestrategiesforthepreven-tionandcontroloftick-borneinfectiousdiseases.

• Asingle200-mgdoseofdoxycyclineadministeredwithin72hoursofatickbiteismorethan80%effectiveinpreventingLymedisease.

454

L  Diseases of Unknown Etiology

223 Kawasaki DiseaseJane C. Burns

DEFINITION• Kawasakidisease(KD)isanacute,self-limitedpediatricvasculitisthatisthemostcommon

causeofacquiredheartdiseaseinchildren.Coronaryarteryaneurysmsdevelopin25%ofuntreatedpatients.

EPIDEMIOLOGY• KDaffectschildrenofallethnicitiesworldwide.ChildrenofAsianandAfrican-American

descentaredisproportionatelyaffected.Thereisnoevidenceforperson-to-persontransmis-sion.Temporospatialclusteringofcaseshasbeenobserved.

ETIOLOGY• ThecauseofKDisunknown.Accordingtothecurrentparadigm,KDistriggeredingeneti-

callysusceptiblechildrenafterexposuretoawidelydispersedagent.

DIAGNOSIS• Thediagnosisisestablishedbyfulfillmentoffouroffiveclinicalcriteriainachildwithfever

and no other apparent cause. Clinical criteria include bilateral conjunctival injection;a polymorphous rash; oropharyngeal changes including erythematous, fissured lips, ery-thematousoropharynxwithoutdiscretelesions,andstrawberrytongue;extremitychangesincluding edema of the dorsa of the hands and feet, palm and sole erythema, and peri-ungual desquamation during the convalescent phase; and a cervical lymph node massmeasuring at least 1.5cm. Coronary artery abnormalities are detected by transthoracicechocardiography.

THERAPY• High-doseintravenousimmuneglobulin(IVIG,2g/kg)plusaspirinisthestandardtherapy

forKD.Ifadministeredwithinthefirst10daysafterfeveronset,theincidenceofcoronaryarteryaneurysms is reduced from25% to5%.A subsetofpatients (10% to20%)mayberelativelyresistanttoIVIGandrequireadditionalanti-inflammatorytherapy.

PREVENTION• ThereisnoknowninterventionthatcanpreventKD.

PART III

Special Problems

456

A  Nosocomial Infections

224 Infections Caused  by Percutaneous Intravascular DevicesSusan E. Beekmann and David K. Henderson*

DEFINITION• Infections caused by peripheral and central intravenous catheters, including nontunneled

centralcathetersandtunneled(HickmanorBroviac)catheterswithorwithouttheGroshongtip,peripherally insertedcentralvenouscatheters(PICCs), totally implantedintravascularaccessdevices(ports),pulmonaryarterycatheters,andarteriallines

EPIDEMIOLOGY• Ratesofcentralline–associatedbloodstreaminfections(CLABSIs)in2009rangedfrom1.05

(pooledmeanhemodialysisrate)to1.14(pooledmeaninpatientwardrate)to1.65(pooledmeanintensivecareunitrate)bacteremiasper1000centralvenouscatheter(CVC)days.

• These rates reflect a 58% reduction in total estimated CLABSIs from 2001 to 2009; thereduction in incidence of Staphylococcus aureus CLABSIs was greater than for any otherpathogen.

• ThemajorityofCLABSIsnowoccurininpatientwardsandoutpatienthemodialysiscenters.

MICROBIOLOGY• Staphylococcipredominateasthemostfrequentlyencounteredpathogensindevice-related

infections; coagulase-negative staphylococci are the single most common cause of theseinfections,whereasS. aureusbacteremiashavedecreased.

• CLABSIsincreasinglyarecausedbymultiresistantgram-negativerods.

DIAGNOSIS• Clinicalmarkersshowapoorcorrelationwithintravenousdevice–relatedbacteremia.• Blood culture results positive for coagulase-negative staphylococci, S. aureus, or Candida

spp.,intheabsenceofanyotheridentifiablesourceofinfection,increasethepossibilityofintravenousdevice–relatedbacteremia.

• Quantitativeorsemiquantitativecultureofthecathetercombinedwithtwobloodcultures(one peripheral and one through the catheter) is most accurate for short-term centralcatheters.

• Pairedquantitativebloodculturewasdeterminedtobethemostaccuratediagnosticmethodforlong-termdevices,includingtunneledandtotallyimplantedcatheters.

• Differentialtimetopositivity(betweenculturesdrawnthroughthecatheterandperipher-ally)comparesfavorablywithquantitativebloodculturesforthediagnosisofCLABSIs.

PREVENTION• ManyCLABSIscanbepreventedusingsimultaneousimplementationofanarrayofpractice

improvements(i.e.,“bundles”).

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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 by Percu

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evices

• Allhealthcarepersonnelinvolvedincatheterinsertionandmaintenanceshouldcompleteaneducationalprogramregardingcatheter-associatedinfections.

• Chlorhexidinesolutionsshouldbeusedforskinpreparationbeforecatheterinsertion.• MaximalsterilebarriersshouldbeusedduringinsertionofCVCs.• DonotroutinelyreplaceCVCs,PICCs,hemodialysiscatheters,peripheralarterialcatheters,

orpulmonaryarterycatheterstopreventinfection.• Antimicrobial-impregnatedcatheters,ifused,shouldonlybeusedaspartofacomprehensive

nosocomialbacteremiapreventionstrategy.

458

225 Nosocomial PneumoniaMichael Klompas

DIAGNOSIS• Classic clinical signs for ventilator-assisted pneumonia (VAP) include fever, leukocytosis,

purulentsecretions,worseningoxygenation,infiltrates,andpathogeniccultures.Thesesignsareneithersensitivenorspecific.PaucityofneutrophilsorlackoforganismsonGramstainmakeVAPunlikely,buttheirpresenceisnotspecific.Stableoxygenation/ventilatorsettingsargueagainstclinicallysignificantdisease.

• Quantitativebronchoalveolarlavage(BAL)culturesare51%sensitive,are77%specific,andhaveapositivepredictivevalueof67%forhistologicallyconfirmedVAP.

• RandomizedcontrolledtrialsofquantitativeBALculturesversusendotrachealaspiratesfordiagnosis have found no difference in duration of mechanical ventilation, length of stay,mortality,superinfection,oracquiredresistancerates.Endotrachealaspiratesarethereforepreferred.

• Obtaindiagnosticstudiestoguidetherapy:bloodandendotrachealaspiratecultures,urinepneumococcalandlegionellaantigens,±viralstudies.

MICROBIOLOGY• Most common pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella sp.,

andAcinetobactersp.Drugresistanceiscommon:50%ofS. aureusisolatesaremethicillin-resistant,25%to30%ofPseudomonasandKlebsiella isolatesareceftazidimeandcefepimeresistant,and60%ofAcinetobacterisolatesarecarbapenemresistant.

• Risk factors for methicillin-resistant S. aureus (MRSA) and multidrug-resistant gram-negative pathogens include recent broad-spectrum antibiotics, prolonged hospitalization,poorfunctionalstatus,hemodialysis,andsevereillness.

TREATMENT• Initiatebroad-spectrumantibioticsassoonaspneumoniaissuspected.Usevancomycinor

linezolidplustwoantipseudomonalagentsforempirictherapy.Consideraloadingdoseofvancomycin25to30mg/kgforseriouslyillpatients.Includeanaerobiccoverageifthereisfrankaspiration.

• Reassessthelikelihoodofpneumoniadaily;ifthediagnosisnolongerseemslikely,thenstopantibiotics.

• Narrowtreatmentassoonassusceptibilitiesareavailable.Avoiddoublecoverage.Ifculturesarenegativeandthepatientisimproving,trimorstopantibiotics.

• Vancomycin and linezolid are similarly effective for MRSA. Dose vancomycin 15 to20mg/kgevery8to12hours.Thegoaltroughis15to20mg/L.Thereisanincreasedriskofclinicalfailureifthevancomycinminimalinhibitoryconcentrationisgreaterthan1mg/L.

• Treat7 to8days,but shorter forpatientswith rapidclinical improvementand longer forpatientswhoareslowtoimproveorwhohavecomplicationssuchasbacteremia,abscess,orempyema.Dailyprocalcitoninmonitoringcansafelyshortenthedurationofantibiotics.

• Adjunctiveaerosolizedantibioticsinadditiontointravenoustherapyenhanceclearanceofpulmonaryculturesbuthavenoimpactonclinicalcureratesorpatientoutcomes.Vibrating

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meshplateispreferredfordelivery.Aerosolizationmaybeaseffectiveasintravenousdrugdelivery,butnephrotoxicityisequallylikely.Dataaresparse.

PREVENTION• VAPratesaresubjectiveandnonspecific.Therefore,preferentiallyselectinterventionsproven

toimproveconcreteoutcomes.• Noninvasivepositivepressureventilation,continuousaspirationofsubglotticsecretions,and

ventilator-weaningprotocols(especiallypaireddailyspontaneousawakeningandbreathingtrials)shortentheaveragedurationofmechanicalventilation.

• Digestive decontamination decreases mortality, but there are ongoing concerns about thepotential impactonantibioticresistancerates,especially inunitswithhighbaselineresis-tancerates.

460

226 Nosocomial Urinary Tract InfectionsThomas M. Hooton

DEFINITION• Nosocomialurinarytractinfection(UTI)referstoUTIacquiredinanyinstitutionalsetting

providinghealthcare.• Catheter-associated(CA)-bacteriuriaiscomposedmostlyofCA-asymptomaticbacteriuria

(CA-ASB).• CA-ASBshouldbedistinguishedfromCA-UTIbecausetreatmentisusuallyindicatedonly

forthelatter.• Significantbacteriuria:≥103CFU/mLinasymptomaticpersonisanindicatorofCA-UTI,

whereas≥105CFU/mLinanasymptomaticpersonisanindicatorofCA-ASB.

EPIDEMIOLOGY• NosocomialUTIs,97%ofwhicharecatheterassociated,accountforupto40%ofnosocomial

infectionsinU.S.hospitalseachyear.• Approximately15%to25%ofpatientsingeneralhospitalshaveacatheterinsertedatsome

timeduringtheirstay.• About 5% to 10% of long-term care facility residents are managed with urethral

catheterization.• Theincidenceofbacteriuriaassociatedwithindwellingurethralcatheterizationwithaclosed

drainagesystemisapproximately3%to8%perday.• ThedurationofcatheterizationisthemostimportantriskfactorforCA-bacteriuria.• CA-bacteriuriacomprisesalargereservoirofantibiotic-resistantorganismsandisafrequent

targetforinappropriateantimicrobialtherapy.

MICROBIOLOGY• A broad range of bacteria can cause nosocomial UTI, and many are resistant to multiple

antimicrobialagents.• CA-bacteriuria is caused by a broad range of bacteria, including Escherichia coli, other

Enterobacteriaceae, nonfermenters such as Pseudomonas aeruginosa, and gram-positivecocci,includingcoagulase-negativestaphylococciandEnterococcusspp.

• Funguria,mostlycandiduria,isreportedin3%to32%ofcatheterizedpatients.

DIAGNOSIS• The majority of patients with CA-bacteriuria are asymptomatic, and signs and symptoms

commonlyassociatedwithUTI,suchasfever,dysuria,urgency,flankpain,orleukocytosis,arenonspecific.

• In the catheterized patient, pyuria does not differentiate CA-ASB from CA-UTI, but itsabsencesuggeststhatCA-UTIisnotthecauseofsymptoms.

THERAPY (SEE TABLE 226-1)• ScreeningandtreatmentofASBarenotrecommendedexceptinpregnantwomenandsome

patientswhoundergogenitourinarysurgery.

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s

• UrineculturesshouldbeobtainedbeforetreatmentofnosocomialUTI.• RecommendedtreatmentdurationforCA-UTIrangesfrom7to21days,dependingonthe

severity.• Asymptomaticnosocomialcandiduriararelyrequirestreatment.

PREVENTION• Reducing exposure to urinary catheterization is the most effective way to prevent

CA-bacteriuria.• IndwellingurethralcatheterizationplacesthepatientatgreaterriskforCA-bacteriuriathan

condomorintermittentcatheterization.• Aclosedcatheterdrainagesystemisindicatedinallcatheterizedpatients.• Routineuseofantimicrobial-coatedurinarycathetersisnotsupportedbyavailabledata.• Routine use of systemic antimicrobial agents to prevent CA-bacteriuria should be

discouraged.• Use of multiple infection control techniques and strategies simultaneously (bundling) is

recommendedtopreventCA-bacteriuria.

TABLE 226-1  Empirical Management of Catheter-associated Urinary Tract Infection

Antimicrobial Agent* and Dosing

Mild to Moderate, Afebrile (Dosage Duration: 5-7 Days)

Ciprofloxacin 500 mg PO twice daily or 1 g (extended release) PO once daily†

Levofloxacin 750 mg PO once daily†

Severe Illness or Febrile, or Both (Dosage Duration: 5-14 Days)

Ciprofloxacin 400 mg IV twice daily†

Levofloxacin 500-750 mg IV once daily†

Ceftriaxone 1-2 g IV once daily‡

Cefepime 1 g IV twice daily‡

Piperacillin-tazobactam 3.375 g IV q6h‡

Meropenem 500 mg–1 g IV q8h‡

Imipenem-cilastatin 500 mg IV q6-8h†

Doripenem 500 mg IV q8h‡

Ertapenem 1 g IV once daily‡

Gentamicin 5-7 mg/kg IV once daily† ± ampicillin 1-2 g IV q6h§

In Choosing an Empirical Agent, Consider the FollowingSeverity of illness and comorbiditiesAntimicrobial susceptibility of prior urinary tract infection strainsLocal resistance dataExposure to same class in past 3-6 mo—choose alternative agentConsider adding vancomycin if Gram stain shows gram-positive cocciUse a carbapenem (meropenem, imipenem, doripenem, or ertapenem) if an extended-spectrum β-lactamase

strain is known or suspectedTailor regimen based on susceptibility data, and transition to oral medications (usually a fluoroquinolone), as

soon as condition allows

*If resistance to the antimicrobial agent is a concern because of the prevalence of resistance in the community, especially in a severely ill patient, an initial intravenous dose of a broader-spectrum agent, such as meropenem, should be given.

†Pregnancy category C—animal studies have shown an adverse effect on the fetus; use only if potential benefit justifies the potential risk to the fetus.

‡Pregnancy category B—no clear risk to fetus based on animal or human studies, or both.§Pregnancy category D—associated with human fetal risk; use only if the potential benefit justifies the potential

risk to the fetus.Modified from Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 2012;366:

1028-1037.

462

227 Health Care–Acquired HepatitisKent A. Sepkowitz

DEFINITION• Viralhepatitiscanbeacquiredbypatientsorhealthcareworkers(HCWs)duringtheprocess

ofhealthcaredelivery.

EPIDEMIOLOGY• TransmissionbetweenpatientsandHCWsisrare,buttheriskremains.• DialysispatientsandworkersareatparticularriskforhepatitisCvirus(HCV)and,ifunvac-

cinated,forhepatitisBvirus(HBV).• Increasingly,transmissionstopatientsareseeninlong-termcareandcanbetracedtounsafe

injectionpractices.

DIAGNOSIS• Identificationofanoutbreakisdifficultunlessaclusterofcasesoccurs.• Mostinvestigationsareidentifiedinconjunctionwithpublichealthauthorities.• Useofagenotypetodeterminehomologyisusefulininvestigation.

POSTEXPOSURE TREATMENT• HepatitisA:BothimmuneglobulinandhepatitisAvaccinehavebeenusedeffectively.• HepatitisB:Treatallexposednonimmunepersons.IfexposedbutwithoutHBVantibody,

administerhepatitisBimmuneglobulinwithorwithoutinitiationofvaccineseries.Theroleofantiviralshasnotbeendetermined.Useasimilarapproachforexposedpatients.

• HepatitisC:Treatonlyiftheexposedpersonhasevidenceofacuteinfection.Useofcurrentlyapprovedtherapieshasnotbeenstudiedinthiscontextbutislikelyeffective.

VACCINATION• HepatitisAvaccineisnotroutinelyrecommendedforHCWs.• HepatitisBvaccineorformaldeclinationismandatedforHCWs.• NovaccineisavailableforHCV.

463

228 Transfusion- and Transplantation-Transmitted InfectionsMatthew J. Kuehnert and Sridhar V. Basavaraju*

DEFINITION• Transfusion-andtransplant-transmittedinfectionsoccurwhenapathogenisspreadfrom

thedonortorecipientsthroughblood,organs,orothertissue.

EPIDEMIOLOGY• Transfusion-andtransplant-transmittedinfectionsareunusualbutoccurwhenadonorhas

aninfectionbutscreeningisnoteffectiveorwhenapathogenisnotscreened.Theriskofinfectiontransmittedthroughorgantransplantationislikelygreaterthanthroughbloodortissue,duetothelackofinclusioncriteriafororgandonors.

MICROBIOLOGY• Transfusionofbloodproducthastransmittedinfectionsbybacteria,viruses,parasites,and

prions.• Solid organ transplantation has transmitted infections caused by viruses, bacteria, fungi,

mycobacteria,andparasites.• Encephalitis followingsolidorgan transplantationhasresulted fromtransmissionofWest

NileVirus,lymphocyticchoriomeningitisvirus,rabies,andBalamuthia mandrillaris.

DIAGNOSIS• Diagnosis isdependentonclinicalrecognitionthatarecipienthasaninfectionthatcould

havebeenfromatransfusionortransplant.

THERAPY AND PREVENTION• Betterdonorscreening,orpromptrecognitionwhentransfusion-ortransplant-transmitted

infectionoccurs,canimproverecipientoutcomes.

*ThefindingsandconclusionsinthischapterarethoseoftheauthorsanddonotnecessarilyrepresenttheofficialpositionoftheCentersforDiseaseControlandPrevention.

464

B  Infections in Special Hosts

229 Prophylaxis and Empirical Therapy of Infection in Cancer PatientsElio Castagnola, Małgorzata Mikulska, and Claudio Viscoli

RISK FACTORS FOR INFECTIONS IN CANCER PATIENTS• Neutropeniaisthemostimportant,particularlyifsevere(<100polymorphonuclearneutro-

phils)andprolonged(7to10days).• Otherriskfactorsincludemucositis;underlyingdiseaseanditsstatus;intensityofchemo-

therapy; theuseofbiologicresponsemodifiers,especiallymonoclonalantibodies, suchasalemtuzumaborrituximab;presenceofcentralvenouscatheter;andgeneticfactors.

EPIDEMIOLOGY AND ETIOLOGY• Epidemiology of bloodstream infections in neutropenia is constantly changing, and after

yearsofthepredominanceofgram-positivecocci,gram-negativerodshavebeenemerginginmanycentersasthemostfrequentpathogens.

• This shift has been accompanied by an increasing rate of resistant pathogens, suchas extended-spectrum β-lactamase–producing Enterobacteriaceae, carbapenem-resistantgram-negative pathogens, methicillin-resistant Staphylococcus aureus, methicillin-resistantStaphylococcus epidermidis,orvancomycin-resistantenterococci.

• Themainchallengeisthemanagementofmultidrug-resistant(MDR)gram-negativebacteriaforwhichfewtherapeuticoptionsexist.

• Invasivefungaldiseases(IFDs)inhematologypatientsarecausedmainlybyAspergillus,inturncausedbyawidespreaduseofCandida-activefluconazoleprophylaxis(theemergenceoffluconazole-resistantstrainsisthenaturalconsequence),whereasinsolid-organtumors,candidemiaremainsthemostfrequentIFD.

PROPHYLAXIS (SEE TABLE 229-1)• Ingeneral,antibacterial,antifungal,andantiviralprophylaxisisindicatedinpatientsreceiv-

inginductionchemotherapyforacutemyelogenousleukemia(AML).• Influenza and varicella vaccination of household contact and health care workers is

recommended.• Influenzaandpneumococcalvaccinationofpatients,especiallyduringlessaggressivetreat-

mentphases,isrecommended.• Fluoroquinolonesarerecommendedonlyforpatientswithprolonged(7to10days)neutro-

peniaincenterswhereresistancetofluoroquinolonesislessthan20%.• Primaryantifungalprophylaxisincancerpatientsisusuallyrecommendediftheincidence

ofIFDishigherthan15%.• Fluconazole is recommended as yeast-active prophylaxis in AML patients receiving

anthracyclineregimens.• Posaconazoleasmold-activeprophylaxisisrecommendedforpatientsreceivingchemo-

therapyforAMLormyelodysplasticsyndrome.• SecondaryantifungalprophylaxisshouldbeadministeredtopatientswithpreviousIFDwho

receivehigh-intensitychemotherapyoratransplant.• Prophylaxis against Pneumocystis jirovecii (usually with trimethoprim-sulfamethoxazole

three times per week) is beneficial in patients with deficits of T-cellular immunity,

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n in

 Can

cer Patients

TABLE 229-1  Suggested Prophylaxis for Infections in Cancer Patients

DRUG SCHEDULE COMMENTSAntibacterial Ciprofloxacin 500 mg bid Adults receiving chemotherapy for acute 

leukemia or autologous HSCT; starting with chemotherapy and continuing until resolution of neutropenia or initiation of empirical antibacterial therapy for febrile neutropenia

Levofloxacin 500 mg once daily

Amoxicillin-clavulanate

25 mg/kg (max., 1000 mg) bid

Children receiving chemotherapy for acute leukemia

Antifungal Posaconazole Oral solution 200 mg tid orally with a (fatty) meal

Patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome

Fluconazole 400 mg once daily Patients receiving chemotherapy for acute myelogenous leukemia with cytarabine plus anthracycline regimens (administered for 7 and 3 days, respectively) and high-dose cytarabine-containing regimens

Other Secondary prophylaxis according to isolated pathogen and/or clinical presentation

Pneumocystis jirovecii

Trimethoprim-sulfamethoxazole

One-double strength tablet (160/800 mg) three times weekly, or25 mg/kg of TMP-SMX (5 mg/kg of TMP), max., 1920 mg (two double-strength capsules) in 2 divided doses for 3 consecutive days/wk

All patients receiving chemotherapy with steroids, including those with  solid tumors (e.g., brain cancer)

Dapsone 2 mg/kg/day (max., 100 mg), on alternate days three  times/wk

In patients who cannot tolerate TMP-SMX

Aerosolized pentamidine

300 mg once a month with nebulizer

In patients who cannot tolerate TMP-SMX; effective, but it is more difficult to administer

Atovaquone 750 mg twice daily or 1500 mg once daily

In patients who cannot tolerate TMP-SMX

Antiviral Acycloviror

2000 mg (40 mg/kg in children) in 4-5 divided doses or in adult >40 kg: 800 mg twice daily

Patients with positive anti-HSV antibodies and severe mucositis or receiving treatment for acute leukemia

Valacyclovir 500 mg twice daily for HSV prophylaxisFor VZV exposure 1 g three times daily

VZV-susceptible patients exposed  to chickenpox who did not receive prompt administration of specific immunoglobulins

Lamivudine 100 mg once daily Patients with chronic inactive HBV infection (HBsAg-positive, HBV DNA low level or negative)Patients with resolved HBV infection (HBsAg-negative and HBcAb-positive) if receiving rituximab or allogeneic HSCT

Tuberculosis Isoniazid 300 mg once daily Patients with latent tuberculosisEfficacy not specifically evaluated in cancer patients

Central venous catheter

None Good skin preparation and the use of sterile technique  at time of device insertionGood maintenance procedures

All patients with indwelling central venous catheter

Continued

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DRUG SCHEDULE COMMENTSOthers Growth factors Filgrastim 300 µg/day (in 

children: 5 µg/kg/day) either subcutaneously or as an intravenous infusion over at least 1 hr, or pegylated filgrastim, 6 mg every 14 days

For the prevention of febrile neutropenia in patients who have a high risk of this complication based  on age, medical history, disease characteristics, and myelotoxicity  of the chemotherapy regimenSecondary prophylaxis with G-CSFs  is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose  of chemotherapy may compromise disease-free or overall survival or treatment outcomeEfficacy not fully demonstrated for pegylated filgrastim

Immunoglobulins Polyclonal immunoglobulins: 400 mg/kg every 21-28 days

Patients with chronic lymphocytic leukemia after the second episode  of severe bacterial infectionPatients with leukemia or lymphoma with hypogammaglobulinemia (<400 mg/dL) and severe bacterial infections (reasonable, but not proved)

Specific anti-VZV (VariZIG) 125 IU for every 10 kg of body weight (max., 625 IU)

In high-risk contact with a negative history of varicella within 96 hours after exposure to chickenpox

Vaccines InfluenzaVaricella

Influenza and varicella (negative contacts) vaccination of household contact and health care workersInfluenza vaccination of patients, especially during less aggressive treatment phases

Pneumococcus Conjugated-polysaccharide 13-valent antipneumococcal vaccine

Isolation procedures

Perform hand hygiene with an alcohol-based hand rub or by washing hands with soap and water if soiled, before and after all patient contacts or contact with the patients’ potentially contaminated equipment or environmentUse contact precautions (gowns and gloves)Ensure adherence to standard environmental cleaning with an effective disinfectant

Patients colonized or infected with multidrug-resistant pathogens (such as VRE, KPC, etc.) or infected with other pathogens for which contact isolation precautions are advisable (Clostridum difficile, norovirus, etc.); of note, alcohol-based hand rubs are not sporicidal

G-CSFs,  granulocyte  colony-stimulating  factors;  HBcAb,  hepatitis  B  core  antibody;  HBsAg,  hepatitis  B  surface antigen;  HBV,  hepatitis  B  virus;  HSCT,  hematopoietic  stem  cell  transplantation;  HSV,  herpes  simplex  virus;  IU,  international  unit;  KPC,  Klebsiella pneumoniae  carbapenemase;  max.,  maximum;  TMP-SMX,  trimethoprim-sulfamethoxazole; VRE, vancomycin-resistant enterococci; VZV, varicella-zoster virus.

TABLE 229-1  Suggested Prophylaxis for Infections in Cancer Patients—cont’d

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particularlywithchroniclymphocyticleukemia,orinthosereceivinghigh-dosecorticoste-roidsoralemtuzumab.

• Antiherpesprophylaxiswithacyclovirorvalacyclovirshouldbeofferedtopatientswithacuteleukemiaorreceivingalemtuzumab.

• Varicella postexposure prophylaxis with specific immunoglobulins or acyclovir is recom-mendedforhigh-riskvaricella-zostervirus–susceptiblepatients.

• LamivudineisrecommendedforcancerpatientswithchronicinactivehepatitisBreceivinghigh-dosechemotherapy,particularlyifcontainingrituximab,andforselectedpatientswitharesolvedhepatitisBvirusinfection.

MANAGEMENT OF FEBRILE NEUTROPENIA (SEE FIGS. 229-1 AND 229-2)• Bloodcultures• Assessment of the risk of severe infection (e.g., Multinational Association for Supportive

CareinCancerscore;seeTable229-2)• Assessmentoftheriskofinfectioncausedbyresistantpathogens;riskishighincaseof

• Colonizationorpreviousinfectioncausedbyresistantbacteria• Localepidemiologywithhighincidenceofinfectionscausedbyresistantpathogens

• Choiceoftheappropriatetherapy• Oralversusintravenous• Inpatientversusoutpatientsetting

FIGURE 229-1  Possible initial approach to a patient with febrile neutropenia. 

At onset of febrile neutropenia consider: 1. Type of patient: underlying disease, time from chemotherapy, previous history of

infectious complications, particularly caused by resistant pathogens. 2. Type of center: knowledge of epidemiology of infections and susceptibility patterns.If available, use a risk stratification system. For antibiotic choice, consider the local resistance patterns. Perform blood cultures (at least 3) and other cultures from sites of suspected infection.

Yes

No

Yes

Clinical signs ofa localizedinfection

Signs of septic shockStart empirical therapy activeagainst gram-negatives (considercombination of β-lactam +aminoglycoside), AND gram-positives(according to local epidemiology andsusceptibility patterns) AND considerantifungal therapy (an echinocandin).

Use antibiotics active againstgram-negatives AND add otheragents according to the mostprobable pathogen (if different)AND the site of infection.

Start empirical therapy according to risk stratification(consider oral therapy) AND local epidemiologic patterns.In any case, use antibiotics active against gram-negatives.

Discontinue anti–gram-positive and antifungal drugs if these infections are not confirmed.Discontinue aminoglycoside if gram-negatives are not isolated or susceptible to the chosen β-lactam.Adjust treatment according to isolated pathogens and the site of infection.

Revise anti-infective regimen usually after 72 hours of treatment:

Consider chest computed tomography scan or other imaging according to clinical features.

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FIGURE 229-2  Management of persistently febrile neutropenic patient. 

infection or colonization by resistant

Signs or cultures suggesting a “new”bacterial infection or a viral infection

Treat accordingly Treat accordingly

No

Patient at high risk of invasive fungal disease

Wait and see Availability ofdiagnostic workup

Yes NoYes

YesNo

YesNo

YesNo

Septic shock or rapid worsening

Diagnostic workup1. Lung computed tomography scan (repeat at least 1/wk, unless clinical signs or

acute deterioration) 2. Serum galactomannan testing for 3 consecutive days3.4. Blood cultures5. Other imaging and/or invasive diagnostic procedures, with culture, microscopic

examination and antigen search, according to clinical features

Positive result of any

Patient at high risk of infection caused by resistant pathogens (e.g., previous

bacteria)

Start antifungal therapy

All negative

Persistent fever andneutropenia in spite of

broad-spectrum antibiotics

Empirical antifungaltherapy

Empirical antifungaltherapy AND

Do not start antifungalsor discontinue

empirical antifungal therapy

Serum (1,3)-�-D-glucan testing for 3 consecutive days

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• Escalationversusdeescalationstrategy• Escalationstrategyusuallystartswithanti-Pseudomonasβ-lactammonotherapy.• Deescalationstrategystartswithacombinationofanti-Pseudomonasβ-lactamplus

otheragentscoveringthemostprobableresistantpathogens;theseotheragentsshouldbediscontinuedifnoresistantpathogenisisolated.

• Empiricalantifungaltherapy(addingantifungalagentinpatientspersistentlyfebriledespitebroad-spectrumantibiotics) couldbe replacedbydiagnostic-driven strategybasedon theuseofdiagnostictools,suchasachestcomputedtomographyscanandfungalserummarkers(galactomannanandβ-D-glucan).

• IntheeraofincreasingantibioticresistanceandfewagentsactiveagainstMDRpathogens,antimicrobialstewardshipincancercentersismandatoryandshouldinclude• Infection-controlpractices• Local surveillance of antibiotic resistance, antibiotic consumption, and patient

outcomes• Promotingappropriateantibioticuse(timelydeescalation,appropriatedosing)• Establishing antibiotic regiments for empirical therapy appropriate for local

epidemiology

TABLE 229-2  Factors Associated with Low Risk of Severe Infection or Associated with an Uncomplicated Clinical Course in Febrile Neutropenic Cancer Patients

MASCC SCORE

Clinical Parameters ScoreClinical data available at onset of febrile neutropenia or soon after admission

1.  Burden of illness: no or mild symptoms 5

2.  No hypotension 5

3.  No chronic obstructive pulmonary disease 4

4.  Solid tumor or no previous fungal infection 4

5.  No dehydration 3

6.  Outpatient status 3

7.  Burden of illness: moderate symptoms 3

8.  Patient’s age <60 yr 2

MASCC, Multinational Association for Supportive Care in Cancer.Points attributed to the variable “burden of illness” are not cumulative. The maximal theoretical score is therefore 

26.Low-risk patient: score ≥21.

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230 Infections in Recipients of Hematopoietic Stem Cell TransplantsJo-Anne H. Young and Daniel J. Weisdorf

TYPES OF DONORS OF STEM CELLS FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)• Syngeneic:donorisanidenticaltwinsibling• Autologous:therecipientdonatestoself• Allogeneic:thedonatedmaterialcomesfromadifferentindividualthantherecipient

SPECIFIC TYPES OF ALLOGENEIC DONORS• Matchedrelatedorpartiallymatchedrelateddonor,suchasasiblingwiththesameorsimilar

humanleukocyteantigen(HLA)type• Unrelateddonorormatchedunrelateddonor• Haploidentical:parent,cousin,sibling,orchildisthedonor;oneHLAhaplotypematched.

AlthoughhaploidenticalorotherHLAmismatchedtransplantsmayleadtoahighincidenceof graft-versus-host disease (GVHD), administration of cyclophosphamide early post-transplantandT-celldepletionofthegraftsmaylimitrisksofGVHD.

• Cord: umbilical cord blood usually partially HLA matched, not matched for blood type;sometimestwocordsusedtoprovidebloodwithsufficientcells

• Haplo-cord: haploidentical peripheral blood stem cells plus cord blood cells; haplo-cordengraftsrapidlybutmaynotbesustainedyetprovidesneutrophilproductionuntilthecordengrafts

TYPES OF CELLS USED IN HSCT• Peripheralbloodstemcells,usuallyfilgrastim(granulocytecolony-stimulatingfactor)mobi-

lized;maybeCD34selectedforT-celldepletion• Umbilicalcordblood:usuallyassociatedwithdelayedengraftmentbutlessGVHD• Bonemarrow:collectedbyaspirationharvest frommatchedrelatedormatchedunrelated

donor;associatedwithlesschronicGVHD• Donorlymphocyteinfusion:donorcellssortedforlymphocytes;givenafterengraftmentor

afterrelapseforantitumororantiviraleffectbutcanstimulateGVHD

PREPARATION OF PATIENT FOR CELL INFUSION (“CONDITIONING REGIMEN”)• Myeloablative: total-body irradiation plus cyclophosphamide or busulfan; can be without

irradiation• Nonmyeloablative(reducedintensity):usinglower-dosetotal-bodyirradiationorwithanti-

thymocyteglobulin,mostoftenwithfludarabine

OUTCOMES• Engraftment:absoluteneutrophilcountrisestomorethan500cells/µLbyday42• Primarygraftfailure:noengraftmentbyday42• Mixedchimerism:persistenceofhostanddonorhematopoiesis• Relapse:returnoftheunderlyingmalignantcondition

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COMPLICATIONS• Mucositis:mucosalinflammationthatservesasaportalofentryfororalorintestinalinfec-

tions;commonwithmethotrexate-containingregimens.Paliferminmayreducemucositis.• Hemorrhagiccystitis:oftenoccursinconjunctionwithcyclophosphamideearlyaftertrans-

plant,despite theuseofmesnaand forceddiuresis;viral causesmorecommon lateraftertransplant,includingadenovirusorBKvirus

• Engraftmentsyndrome(immunereconstitutionsyndrome):feverwithorwithoutrashand/orpulmonaryinfiltratesatengraftment

• Veno-occlusive disease, also called sinusoidal obstruction syndrome: triad of jaundice,weightgain,andascites leadingtomultiorganfailure,usuallyoccurring in thefirst3 to4weeksaftertransplantation

• Diffusealveolarhemorrhage:bleedingintoalveoli,usuallyduringthesecondorthirdweekafter transplant;diagnosedbyprogressivebloody returnson lung lavageand treatedwithcorticosteroids

• Graft-versus-hostdisease:inflammationandcelldeath(apoptosis)inskin,liver,gut,orlung.Acuteformusuallyoccursuntilday100.Chronicformgenerallyoccurslaterandhasfeaturesresemblingbutdistinctfromscleroderma.Theriskishigherintheelderlyandwithgraftsfrompartiallymatcheddonors.Calcineurininhibitors(cyclosporine,tacrolimus),lessoftensirolimus,andmycophenolatemofetilarestartedsoonaftertransplanttodecreasetheinci-denceandseverityofGVHD.High-dosecorticosteroids(andotheragents)areusedtotreatGVHD.

• Posteriorreversibleencephalopathysyndrome:neurotoxicityfromhypertension,calcineurininhibitors,orfludarabine

• Bronchiolitisobliteransorganizingpneumoniaandobliterativebronchiolitis:pneumonitisassociatedwithsmallairwayinjury,sometimesassociatedwithchronicGVHD

ANTIMICROBIAL AGENTS FOR PROPHYLAXIS• Acyclovir: low dose for herpes simplex virus, high dose for cytomegalovirus (see

Table230-1)• Levofloxacin:usedforpreventionofbacterialinfections,untilfeversorinfectiondevelop• Fluconazole:forpreventionofcandidiasis,startingwithneutropenia• Trimethoprim-sulfamethoxazole:agentofchoiceforPneumocystis;alsocoversToxoplasma

andsomebacteria,suchasNocardia.Alternativesincludeaerosolizedpentamidine,atova-quone,anddapsone.

• PenicillinVK:preventionagainstStreptococcus pneumoniaeduringactivechronicGVHD.Regionalpenicillinresistancemayleadtotheuseoflevofloxacinforthisindication.

• Voriconazoleorposaconazole:giveninplaceoffluconazoletopreventmoldinfections• Echinocandins(micafunginorcaspofungin):intravenouslyadministeredagentsthatmaybe

substitutedforazoles• Lamivudine:preventionofhepatitisBvirusreactivationinanti–hepatitisBcoreantibody–

positive, hepatitis B surface antigen–negative, and hepatitis B DNA–negative patient withhepatitisB–positivedonors.Entecavirortenofovirmaybesubstitutedforlamivudine.

• Entecavir or tenofovir: prevention of hepatitis B virus reactivation in hepatitis B surfaceantigen–positivepatient

• Ivermectin:twodosesforpatientsfromcountrieswithhighriskforStrongyloidesinfestation

PREEMPTIVE THERAPY• Ganciclovir, valganciclovir, or foscarnet: given to patients with cytomegalovirus reactiva-

tion based on polymerase chain reaction assay of blood or pp65 neutrophil antigen (seeTable230-1)

EMPIRICAL ANTIBACTERIAL THERAPY DURING FEVER AND NEUTROPENIA WITH NEGATIVE WORKUP• Designatedbroad-spectrumagentsuchasceftazidime,piperacillin-tazobactam,orcefepime• Addition of an aminoglycoside possibly required for institutional antibiotic resistance

patterns

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TABLE 230-1  Suggestions for Management of Possible CMV Infection after HSCT

INDICATION STRATEGY* COMMENT

Prevention

Allogeneic Transplant

Seropositive recipient Preemptive ganciclovir† induction for subclinical viremia, 5 mg/kg bid for 7-14 days, followed by 5 mg/kg daily until the end of maintenanceorGanciclovir prophylaxis‡ at engraftment

Some cases of CMV disease may occur shortly after ganciclovir discontinuation.

CMV reactivation might be delayed, occurring later after HSCT.

Seronegative recipient with seropositive donor

Preemptive ganciclovir induction for subclinical viremia, 5 mg/kg bid for 7-14 days, followed by 5 mg/kg daily until the end of maintenanceandSeronegative or filtered blood products

Prophylaxis at engraftment is not recommended because of the low incidence of post-transplantation infection.

Seronegative recipient with seronegative donor

Seronegative or filtered blood products

Autologous Transplant

Seropositive recipient Early ganciclovir induction of subclinical viremia, 5 mg/kg ganciclovir bid for 7 days, followed by 5 mg/kg daily for 14 days of maintenance

Because of the very low risk in some settings, monitoring is not uniformly advocated.

Seronegative recipient Seronegative or filtered blood products

Treatment of DiseaseCMV pneumonitis Ganciclovir induction, 5 mg/kg bid for 14-21

days, followed by 5 mg/kg daily for at least 3-4 wk of maintenanceplusIVIG every other day for the duration of induction

Extended maintenance throughout periods of severe immunosuppression (i.e., GVHD treatment) may be considered.

Gastrointestinal disease Ganciclovir induction, 5 mg/kg bid for 14-21 days, followed by 5 mg/kg daily for at least 3-4 wk of maintenance

If deep ulcerations are present, maintenance may be required for a longer time.

Marrow failure Foscarnet, 90 mg/kg bid for 14 days, followed by 90 mg/kg daily for 2 wkplusG-CSF

Ganciclovir plus IVIG has also been used.

Retinitis Ganciclovir, 5 mg/kg bid for 14-21 days, followed by 5 mg/kg daily for at least 3-4 wk

Extended maintenance may be required.

CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; IVIG, intravenous immune globulin; PCR, polymerase chain reaction.

*Regimens should be accompanied by weekly monitoring with antigenemia or PCR-based nucleic acid testing.†Oral 900-mg doses of valganciclovir produce blood levels that are similar to those for the standard intravenous

dose (5 mg/kg) of ganciclovir. Foscarnet and cidofovir are acceptable alternatives. Renal dose adjustment is required for all antiviral agents.

‡Foscarnet, high-dose acyclovir, or valacyclovir are acceptable alternatives. Renal dose adjustment required for all antiviral agents.

• Vancomycin if any cellulitis, dysfunction with an indwelling catheter, or hemodynamicinstabilityorcolonizedwithmethicillin-resistantStaphylococcus aureus.

VIRAL DISEASES IN THE TRANSPLANT RECIPIENT• Herpessimplexvirus:oral,esophageal,vaginalulcers;autoinoculatonofotherskinsites• Varicella-zostervirus:dermatomalzoster;maydisseminate;rarelyseverehepatitisorvisceral

zoster• Cytomegalovirus: fever, viremia, cytopenias, pneumonitis, gastrointestinal disorders (e.g.,

hepatitis,esophagealulcers,mucosalchangesintheduodenumorcolon),retinitis

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• Humanherpesvirus6:viremia,pneumonitis,encephalitis;maybeassociatedwithdelayedneutrophilrecoveryorprolongedthrombocytopenia

• Adenovirus:hemorrhagiccystitis,pneumonitis,hepatitis• BKpolyomavirus:hemorrhagiccystitis• HepatitisBandC:hepatitis• Majorrespiratoryviruses:influenza,respiratorysyncytialvirusinthewinter;parainfluenza

virusandrhinovirusyear-round.• JCpolyomavirus:progressivemultifocalleukoencephalopathy• Epstein-Barrvirus:viremiaorpost-transplantlymphoproliferativedisorder

OTHER INFECTIONS• Clostridium difficile diarrhea: stool toxin polymerase chain reaction assay considered the

besttest• Intravascularcentralcatheter–relatedbacteremiaortunnelinfection• Typhlitis:abdominalpainandcecaledemaduringneutropenia• Pneumocystisinfection:diffusepneumonitisamongthosenottakingprophylaxis• Candidiasis:candidemiaoriginatingfromthegut• InfectionwithAspergillusandothermolds:lungfieldabnormalities,sinusitis• Toxoplasmosis:brainlesions

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231 Infections in Solid-Organ Transplant RecipientsNina Singh and Ajit P. Limaye

EPIDEMIOLOGY• Infectionsinorgantransplantrecipientstypicallyrepresentopportunisticinfections,reacti-

vation of latent organisms, and complications related to surgery, health care–associatedinfections,orboth.Infectionsmayalsobedonorderived.

• Advancesinmedicalpracticesandpreventivestrategieshavemodifiedtherisksandtimelineofmanyinfectionsinthecurrentera.

TYPES OF INFECTIONS• Bacterialinfectionsarethemostfrequentlyoccurringinfections.Bacteremiaoccursin5%

to25%oftransplantrecipients.• Fungalinfectionsoccurin0.7%to23%ofpatients.AmajorityoftheseareduetoCandida

orAspergillus spp.,withCryptococcus,endemicmycoses,andothernon-Aspergillusmoldsaccountingformostoftheothers.

• Cytomegalovirus(CMV)isamajorviralinfection.Intheeraofroutineantiviralprophylaxis,CMVdiseasetypicallyoccursinthelatepost-transplantperiod.Otherherpesviruses(herpessimplexvirus,varicella-zostervirus,Epstein-Barrvirus,humanherpesvirus6)arealsoseenwithgreaterfrequencyandseverityintransplantpatients.

• Influenzaandotherrespiratoryvirusesareamajorcauseofmorbidityandmortality,espe-ciallyinlungtransplantrecipients.

• BKvirusnephropathyhasemergedasanimportantcauseofallograftdysfunctionandlossinkidneytransplantpatients.

MANAGEMENT• Asageneralprinciple,serologicassays,althoughvaluableintheassessmentofpastexposure,

arenotreliableforthediagnosisofacuteinfections.• Quantitativemolecularassayshaveprovedtobevaluabletoolsfordiagnosis,guidingpre-

emptivetherapy,andmonitoringresponsetotreatmentforseveralviralpathogens(CMV,BKvirus).

• ProphylaxisagainstPneumocystisandToxoplasma(hearttransplantrecipients)isconsideredstandard.PreventiveapproachesarealsoroutinelyusedforCMV,BKvirus,fungalinfections,andherpessimplexvirusinselectedtransplantpatients,basedonriskfactors.

• Evaluation should take into consideration the time elapsed since transplant, exposures,receiptofpriorantimicrobialprophylacticagents,graftfunction,andtheoverallimmuno-suppressivestateofthetransplantrecipient.

475

232 Infections in Patients with Spinal Cord InjuryRabih O. Darouiche

DEFINITION• Spinalcordinjury(SCI)resultsfrommechanicalcompression,vascularinsult,orboth.

PREVALENCE AND ETIOLOGY• SCIaffectsalmost1per1000persons.• CausesofSCIincludevehicularaccidents,falls,violence,sports,andinfection.• InfectioncancauseorresultfromSCI.

URINARY TRACT INFECTION• Urinary tract infection (UTI) is the most common infection and leading cause of

rehospitalization.• UTIs are mostly caused by usual bowel microbiota (gram-negative bacteria and

enterococci).• Intermittentcatheterizationispreferredtoindwellingbladdercatheters.• Preventionisineffective.• FrequentunnecessarytherapyisundertakenforfailuretodistinguishbetweenclinicalUTI

andasymptomaticpyuria.

PNEUMONIA• Pneumoniahasthehighestinfection-relatedmortality.• Itoccursmostlyinpatientswithtetraplegia.• Community-andhospital-acquiredmicrobesarecomparabletothosefoundinthegeneral

population.

INFECTION OF PRESSURE SORES AND BONE• Thisdiagnosisisveryproblematic.• The broadest microbial etiology includes gram-positive cocci, gram-negative bacilli, and

anaerobes.• Multidisciplinarymanagementisdifficultandrequireslongandrepeatedhospitalstays.

MULTIRESISTANT ORGANISMS IN SPINAL CORD INJURY UNITS• Multiresistant organisms include methicillin-resistant Staphylococcus aureus, vancomycin-

resistantEnterococcus, Clostridium difficile,andmultiresistantgram-negativebacteria.• TheseorganismsaremoreprevalentinSCIunitsthaningeneralhospitalwards.• Properinfectioncontrolmeasuresreducebothcolonizationandinfection.

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233  Infections in the ElderlyKent B. Crossley* and Phillip K. Peterson

GENERAL CONSIDERATIONS• Peoplelivingpast65yearsofagearerapidlyincreasinginnumber.• Individuals older than age 65 years have a higher incidence of most infections than do

youngerpeople.• Fornearlyallinfections,clinicalmanifestationsaremoresubtleintheelderly.

URINARY TRACT INFECTION• Asymptomaticbacteriuriashouldnotbetreated.• SymptomaticinfectionisoftencausedbyorganismsotherthanEscherichia coli.• Extended-durationtherapy(i.e.,>7days)ofsymptomaticinfectionisnotneededineither

menorwomen.

PNEUMONIA• Pneumoniaiscommonandoftenfollowedbydeathintheyearafterapneumonicillness.• Nonbacterial causes (e.g., metapneumovirus, respiratory syncytial virus) are relatively

frequent.• Managementofnursinghome–associatedpneumoniaremainscontroversial.• Immunizationwithinfluenzaandpneumococcalvaccinesisofsignificantbutlesserbenefit.

BACTEREMIA AND ENDOCARDITIS• Botharemorecommonintheelderly.• Multidrug-resistantgram-negativeorganismsarecommonlyrecoveredfrombloodcultures

ofresidentsinlong-termcarefacilities.

CENTRAL NERVOUS SYSTEM INFECTIONS• Viralmeningitisisuncommoninelderlyindividuals.• WestNilevirusinfectionhasrecentlyincreasedinfrequencyandismorecommonandmore

severeintheaged.

IMMUNIZATIONS• Immunizationwithaserialcombinationofbothpneumococcalvaccinesissuggestedforall

individualsaged65yearsandolder.• Ahigh-doseinfluenzavaccineisavailablefortheelderly.• Yellow fevervaccine isassociatedwithprolongedviremiaanddelayedantibodyresponse,

withmoresevereadverseeffectsafterimmunization.• Immunizationagainstherpeszosterhasbeenshowntoreducetheincidenceofdiseaseand

ofpostherpeticneuralgia.Recentstudieshavevalidatedthesafetyofthevaccine.

*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.

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234  Infections in Asplenic PatientsJanet R. Gilsdorf

EPIDEMIOLOGY• Infectionoccursinpatientswithcongenitalasplenia(rare),acquiredaspleniasecondaryto

splenectomyorsicklecellanemia,andacquiredhypospleniasecondarytoinflammatoryorautoimmune disorders or human immunodeficiency virus–acquired immunodeficiencysyndrome.

• Theincidenceisseventoeightsevere infectionsper100person-years inpostsplenectomyadults.

• Riskfactorsforinfectionincludeyoungoroldage,lessthan1yearaftersplenectomy,indica-tionforsplenectomy(immunecytopenias>trauma> incidental),lackofappropriatevac-cines,andlackofprophylacticantibioticsinyoungchildren.

MICROBIOLOGY• Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria

meningitidis)aretheclassicalpathogensofpostsplenectomysepsis.• Withwidespreaduseofvaccinesagainstencapsulatedbacteria,Staphylococcus aureus and

gram-negativeentericbacteriaareseenmorecommonly.• Asplenic patients are at risk for increased severity of malaria, babesiosis, and

anaplasmosis.

DIAGNOSIS• Blood culture is the most important test to identify postsplenectomy sepsis and must be

obtainedattheearliestsignofinfection.• Whitebloodcellcountmaybeelevatedordepressed.• Cerebrospinalfluidexaminationmaybeindicatedinseveresepsis.• Evidence of disseminated intravascular coagulation or vascular collapse may accompany

sepsis.

TREATMENT• Immediateempiricalantibiotictherapyiskeytopreventingfulminantbacterialinfection.• Self-administered,oralantibiotics(amoxicillin-clavulanate,cefuroxime,orfluoroquinolone)

maybeusedbyasplenicpatientsathomeatfirstsignofinfection,followedbyimmediatevisittoanemergencyfacility.

• Empirical systemic antibiotics (vancomycin + ceftriaxone or fluoroquinolone) must bestartedimmediatelyatanemergencyfacility(afterbloodculturebutbeforeotherdiagnostictests).

• Definitiveantibiotictherapywilldependontheidentificationandantibioticsusceptibilityoftheinfectingpathogen.

PREVENTION• Patienteducation,repeatedlyreinforced,istheresponsibilityofallhealthcareproviders.• Avoidsplenectomyifpossible.

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• Administerappropriatevaccines(Hib,PCV13,PPSV23,MCV4,MenB,influenza),asrecom-mendedbytheAdvisoryCommitteeonImmunizationPracticesoftheCentersforDiseaseControlandPrevention.

• Prophylacticantibioticsarerecommendedforchildrenyounger than5yearsofage, thosewhoareimmunocompromised,orpatientswithpasthistoryofsepsis.

• Avoidvectorsthatcarrytheparasitescausingmalaria,babesiosis,andanaplasmosis.

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235  Infections in Injection Drug UsersDonald P. Levine and Patricia D. Brown

HOST DEFENSES• Direct effects of opioids on the immune system include impairment of chemotaxis,

phagocytosis, cytokine and chemokine production, natural killer cell activity, lymphocyteproliferationinresponsetomitogens,andantigenpresentationbyBlymphocytes.Indirecteffects through the neuroendocrine system and the autonomic nervous system are alsopostulated.

• IgMandIgGlevelsareoftenelevated,givingrisetoahighfrequencyofautoantibodiesaswellasantibodiesagainstvariousmicroorganisms;thismaycausediagnosticconfusion(e.g.,ininterpretationofsyphilisserology).

• Morphine-mediateddepressionofmonocytefunctionsimportanttoantiviraldefensemaycontributetothehighefficiencyoftransmissionofvirusessuchashepatitisBandCvirusesandhumanimmunodeficiencyvirus(HIV).

SKIN AND SOFT TISSUE INFECTIONS• Location of infection is related to the preferred location of injection; abscesses are most

common,followedbycellulitisandskinulcers.• InfectionwithStaphylococcus aureus(particularlycommunity-acquiredmethicillin-resistant

S. aureus[MRSA])ismostcommon,followedbystreptococci,eitheraloneorincombinationwith other pathogens; infection with Eikenella corrodens occurs in injection drug users(IDUs)wholicktheirneedlesorcontaminatetheirdrugswithsaliva;anaerobesandgram-negativebacilliarefoundinmixedinfections.

• Incisionanddrainageisthemainstayoftherapyforabscesses;forcellulitis,antibioticselec-tionandneedforhospitalizationmustbeindividualizedbasedonseverityofillness;ahighindexofsuspicionfornecrotizingfasciitisshouldbemaintainedinthesettingofseverepainorseveresignsofsystemictoxicityorboth.

BONE AND JOINT INFECTIONS• Theseinfectionsarecommon,mainlyaffecttheaxialskeleton,andoccurbythehematoge-

nousroute;contiguousspreadfromadjacentskinandsofttissueinfectionalsooccurs.• Bacterial infection with S. aureus and group A and G streptococci are most common;

infectionwithPseudomonas isalsoreported; infectionwithEikenellaoccurs inIDUswholicktheirneedles;andinfectionwithCandidaspeciesisincreasinglyreported.

• Joint infections typically involve the extremities (most commonly the knee), althoughinvolvementofunusualsites(costochondralandsternoclavicularjoints,pubicsymphysis)isfrequent;thereisahighincidenceofcervicalspineinvolvementinpersonswithvertebralosteomyelitis.

• Microbiologicdiagnosisshouldbeconfirmedinallcases;theuseofhighbioavailabilityoralantibiotictherapyforprolongedtreatmentisincreasing.

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INFECTIVE ENDOCARDITIS• IncidenceamongIDUsappearstobeincreasing,perhapsowingtoincreasedmethamphet-

amine use (increased number of injections); IDUs with HIV are at even higher risk forinfectiveendocarditis(IE).

• InfectionwithS. aureus ismostcommon(theincidenceofMRSAisincreasing),followedbygroupsA,B,andGstreptococci;outbreaksofgram-negative IE(causedbySerratiaorPseudomonas)arewelldescribed;andinfectionwithCandidaspecies(mainlynon-C. albi-cans)havebeenreported.

• TricuspidvalveIE isassociatedwith injectiondruguse,but the incidenceof left-sidedIEnowexceedsthatofright-sidedinfectioninsomeseries;multiplevalvesmaybeinvolved;infectionofthepulmonaryvalveisrare.

• IDUstendtopresentacutely inthefirstweekof illness;diagnosis isusuallyeasytomakebasedontheclinicalsignsandsymptomsandsupportedbytheresultsofbloodculturesandcardiacimaging.

• InitialempiricaltherapyshouldbedirectedagainstS. aureus(withvancomycinornafcillininsettingswhereMRSAisknowntoberare);optimaltherapyforMRSAisolateswithvan-comycin minimal inhibitory concentration of 2.0µg/mL is not yet defined; many expertsrecommenddaptomycin.

• Cefepimeplushigh-dosetobramycinhasbeenusedsuccessfullyinthetreatmentofpseudo-monalIE;surgicaltherapyalongwithamphotericinplusflucytosineisthestandardrecom-mendationforcandidalIE;theroleofazolesandechinocandinsisnotyetdefined;indefinitesuppressive therapy with oral azoles is recommended if the patient is not a candidate forsurgery.

NONCARDIAC VASCULAR INFECTIONS• InfectionwithS. aureusmostcommon;infectionwithPseudomonasisalsoreported;poly-

microbialinfectionsarecommon.• Septic thrombophlebitis presents as local pain, swelling, and fever, with bacteremia and

sepsis;septicpulmonaryembolimayoccur;antibiotictherapyshouldbegivenforatleast4weeks;theroleofanticoagulationremainscontroversial—short-termanticoagulationwhilethepatientishospitalizedmaybesufficient.

• Mycoticaneurysmsfrequentlyinvolvethefemoralveinsandpresentasatender,enlargingandpulsatilemass;Dopplerultrasonography,computedtomography(CT),ormagneticreso-nanceangiography(MRA)canbeusedfordiagnosis;surgicalmanagementisrequired,alongwithantibiotictherapyfor4to6weeks.

PULMONARY INFECTIONS• Community-acquired pneumonia caused by common respiratory pathogens is most

common;patientsareatriskforbacteremia,parapneumoniceffusions,andempyema.• PulmonarytuberculosisisamajorproblemamongIDUs,especiallythoseinfectedwithHIV;

treatment for latent tuberculous infection is challenging; material incentives and directlyobservedtherapycanincreaseadherence.

HEPATITIS• Cocaine,methamphetamine,andbuprenorphine(injectedorsublingual)canbehepatotoxic;

heroinisnot.• IDUs are at risk for hepatitis B virus infection and should be vaccinated if nonimmune;

spontaneousreactivationofinfectioncanoccur.• InnonendemicareassuchastheUnitedStates,hepatitisDvirusoccursalmostexclusively

inIDUs;althoughtheoverallprevalenceofhepatitisDvirushasdecreased,theprevalenceamongthosewithchronichepatitisBvirusinfectionhasincreased.

• SuperinfectionofhepatitisDvirusonchronichepatitisBvirusismostcommon;however,simultaneousinfectionoccursinIDUsandcanresultinfulminanthepatitis.

• IDUsaccount for themajorityofhepatitisC infections in theUnitedStates,although theoverallprevalenceofinfectionsinthispopulationisdecreasing;chronicinfectiondevelops

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in60%to80%ofpatients;treatmentischallengingandshouldbecoupledwithtreatmentforsubstanceabuse.

• IDUs are at increased risk for infection with hepatitis A virus, but socioeconomic factorsratherthandrugusearethelargerrisk;nonimmuneIDUsshouldbevaccinated.

SPLENIC ABSCESS• Splenic abscess occurs most commonly as a complication of IE; secondary infection of a

cocaine-inducedsplenicinfarctorinfectionoccurringaftertraumaalsoisreported;staphy-lococciandstreptococciarethemostcommoncausativeagents.

• Ultrasonography, CT, and magnetic resonance imaging can all be utilized for diagnosis;althoughsplenectomyisgenerallyconsideredthemanagementofchoice,especially inthesetting of IE necessitating valve replacement, there is an increasing role for percutaneousdrainage.

CENTRAL NERVOUS SYSTEM INFECTION• InfectionofthecentralnervoussystemoccursmostcommonlyasacomplicationofIE(e.g.,

meningitis,brainabscess,mycoticaneurysms).• MycoticaneurysmmaybediagnosedbyCT,CTangiography,orMRA;optimalmanagement

isnotdefined;manyaneurysmshealwithantibiotic therapy; rupturedaneurysmsrequiresurgeryoranendovascularprocedure.

• Thedifferentialdiagnosisofbrainabscessisbroad,especiallyinIDUswithHIVinfection;microbiologicdiagnosisshouldalwaysbeconfirmed.

• SpinalepiduralabscessshouldbesuspectedinIDUswhopresentwithbackpainaccompa-niedbyradicularsymptomsorneurologicfindings;S. aureusisthemostcommonetiologicagent.

• IDUsareatincreasedriskfortetanusandwoundbotulism.

OCULAR INFECTIONS• Bacterialandfungalendophthalmitisareseen,frequentlyasacomplicationofIE;Aspergillus

endophthalmitisisalsoreported.• Intravitrealantimicrobialagentswithorwithoutparsplanavitrectomymayberequired.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION• IncidenceofHIVinfectionamongIDUsintheUnitedStateshassteadilydeclined;however,

injectiondruguseremainsamajorriskfactorforHIVacquisitioninotherpartsoftheworld.• NeedleexchangeprogramsareeffectiveatreducingHIVtransmissionbutshouldideallybe

coupled with access to voluntary counseling and testing, opioid substitution therapy, andcombinationantiretroviraltherapyforthosealreadyinfected.

• Injection drug use is associated with delayed entry into care and receipt of antiretroviraltherapy;periodsofincarcerationareassociatedwithvirologicfailure,buttheprevalenceofdrugresistanceisnohigherthaninnon-IDUs.

SEXUALLY TRANSMITTED DISEASES• Injectiondruguseisassociatedwithhigh-risksexualbehavior,andreductioninriskysexual

behaviorismoredifficulttoachievethanreductionsinriskyinjectionbehavior.• Theprevalenceofcommonsexuallytransmittedinfectionsappearstobenohigherthanin

thegeneralpopulation,butbecause theyplaya role in the transmissionofHIV, reducinginfections in this population could reduce the transmission of HIV from IDUs to sexualpartners.

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236 Surgical Site Infections and Antimicrobial ProphylaxisThomas R. Talbot

BACKGROUND• Surgical site infections (SSIs) are a common and unwanted outcome from most types of

surgicalprocedures.• The development of an SSI depends on patient-related, procedure-related, and pathogen-

relatedfactors,aswellastheapplicationofevidence-basedpreventionmethods.• CausativeorganismsofSSIarepredominantlytheflorapresentattheincisionsite.

RISK FACTORS FOR SURGICAL SITE INFECTIONS (SEE TABLE 236-1)• Patientfactorsincludecomorbidillness,colonizationwithpathogenicbacteria,perioperative

hyperglycemia,andtobaccouse.• Proceduralfactorsincludebreaksinsteriletechnique,operatingroomventilation,andtraffic.• Proceduralistfactorsincludesurgicaltechnique,improperapplicationofskinantisepsis,and

providerimpairment.

PREVENTION OF SURGICAL SITE INFECTIONS (SEE TABLE 236-2)• Practices to reducebacterial inoculation intowounds includeantisepticuse, sterile attire,

decolonizationstrategies,andproperhairremoval.• Practicestoimprovehostcontainmentofintroducedbacteriaincludemaintenanceofnor-

mothermia,minimizingtissuehypoxia,glucosecontrol,andantimicrobialprophylaxis.

SURGICAL ANTIMICROBIAL PROPHYLAXIS• Keyprinciples:

• Maintaintissueconcentrationofdrugaboveminimalinhibitoryconcentration(MIC)ofcommonflora(seeFig.236-1).

• Provide“right”drug:thus,targetfloraatsurgicalsite,penetratesurgicalincisionsite,andachieveminimaladverseevents.

• Provide“right”doseatthe“right”time:providedoseinthewindowbeforeincisiontoallowpenetrationintotissues(seeFig.236-2);considerhigherdoseforobesepatients;redoseinprolongedprocedures.

• Provide“right”durationofdrug:stoponceincisionclosedorby24hoursatthelatest.• Prophylaxistargetingresistantorganismsmaybewarrantedinselectsituations(e.g.,known

colonizationwithorganism).• Adherencetokeyprinciplesofantimicrobialprophylaxisisusedtoassessoverallqualityof

careandreimbursementfromthird-partypayers.

SSI SURVEILLANCE• SSIsurveillancerequiresstandardizeddefinitions.• PostdischargesurveillanceofSSIsmayleadtovariabilityinreportedoutcomesandmustbe

addressedaspartofanysurveillancesystem.

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TABLE 236-1  Selected Factors Associated with an Increased Risk for Surgical Site Infection

Patient FactorsDiabetes mellitus/perioperative hyperglycemiaConcurrent tobacco useRemote infection at time of surgeryObesityLow preoperative serum albuminMalnutritionConcurrent steroid useProlonged preoperative stay*Prior site irradiationColonization with Staphylococcus aureus

Procedural FactorsShaving of site the night before procedureUse of razor for hair removalImproper preoperative skin preparation/use of non–alcohol-based skin preparationImproper antimicrobial prophylaxis (wrong drug, wrong dose, wrong time of administration)Failure to timely redose antibiotics in prolonged proceduresInadequate OR ventilationIncreased OR trafficPerioperative hypothermiaPerioperative hypoxia

Proceduralist FactorsSurgical technique (poor hemostasis, tissue trauma)Lapses in sterile technique and asepsisGlove micropenetrationsBehavioral factors/proceduralist impairment

OR, operating room.*Likely a surrogate marker for severity of underlying illness and comorbidities.Modified from Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection,

1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;20:250-278; quiz 279-280.

TABLE 236-2  Interventional Maneuvers of Proven or Theoretical Benefit in Diminishing the Risk of Surgical Site Infection

Maneuvers to Diminish Inoculation of Bacteria into Wound

Preoperative Factors

Avoid preoperative antibiotic use (excluding surgical prophylaxis)Minimize preoperative hospitalizationTreat remote sites of infection before surgeryAvoid shaving or razor use at operative siteDelay hair removal at operative site until time of surgery and remove hair (only if necessary) with electric

clippers or depilatoriesEnsure timely administration (including appropriate dose) of prophylactic antibioticsConsider elimination of Staphylococcus aureus nasal carriage via decolonization techniquesUse standardized checklist for implementation at preprocedural time-out

Intraoperative and Postoperative Factors

Carefully prepare patient’s skin with antiseptic + alcohol-based skin preparation agent (e.g., povidone-iodine-alcohol or chlorhexidine-alcohol–containing solution)

Rigorously adhere to aseptic techniquesIsolate clean from contaminated surgical fields (e.g., reglove and change instruments used to harvest

saphenous vein before working in intrathoracic field)Maintain high flow of filtered airRedose prophylactic antibiotics in prolonged proceduresMinimize operative personnel trafficMinimize immediate use steam sterilization of surgical instrumentsMinimize use of drainsBring drains, if used, through a separate stab wound

Continued

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FIGURE 236-1 Tissue antibiotic concentration over time. Dynamics of tissue antibiotic con-centration during the course of a surgical procedure. After an initial dose of antibiotic (noted on the far left of the x axis), tissue concentrations reach their peak rapidly, with a subsequent decline over time. As illustrated, the goal of antibiotic prophylaxis is to have tissue concentrations above the minimal inhibitory concentration (MIC) for the specific pathogens of concern at the time of the inci-sion and throughout the procedure. Antibiotics should be redosed in prolonged procedures to prevent a period with tissue levels below the MIC (light blue arrow). Failure to redose antibiotics appropriately (dark blue arrow) may result in a period during which the wound is vulnerable.

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TABLE 10-2  Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck—cont’d

Maneuvers to Improve Host Containment of Contaminating Bacteria

Preoperative Factors

Resolve malnutrition or obesityDiscontinue tobacco use for at least 30 days preoperativelyMaximize diabetes control

Intraoperative and Postoperative Factors

Minimize dead space, devitalized tissue, and hematomasConsider use of supplemental oxygen therapyMaintain perioperative normothermia (core temperature at or above 36.0° C)Maintain adequate hydration and nutritionIdentify and minimize hyperglycemia (through 48 hours postprocedure)

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FIGURE  236-2 Timing of administration and infection rate. Relationship between timing of administration of prophylactic antibiotics and surgical site infection rate from two large studies. A, Data from 2847 elective surgical patients. B, Data from 3656 cardiac, orthopedic, and gynecologic surgical patients. (A from Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326:281-286. B from Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10-16.)

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237  BurnsClinton K. Murray*

DEFINITIONS• Annually,500,000burninjuriesreceivemedicaltreatment,andapproximately40,000require

hospitalization,ofwhichapproximately55%areadmittedtospecializedburncenters.• Theprimaryinsultfromaburnisthewounditself.

EPIDEMIOLOGY• Burnpatientpopulation:almost70%ofpatientsaremen,withmeanage32years,with19%

ofpatientsyoungerthan5years,and12%age60yearsorolder.Thetotalburnsizeistypi-callylessthan10%oftotalbodysurfacearea(TBSA)in72%ofcases.

*TheopinionsorassertionscontainedhereinaretheprivateviewsoftheauthorandarenottobeconstruedasofficialorreflectingtheviewsoftheU.S.DepartmentoftheArmy,theU.S.DepartmentofDefense,orthefederalgovernment.TheauthorisanemployeeoftheU.S.government,andthisworkwasperformedaspartofofficialduties.Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanybor-rowedfiguresortables.

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238  BitesEllie J. C. Goldstein and Fredrick M. Abrahamian

DEFINITION• Bitewoundsarecommoninjuriescausedbyawidevarietyofdomesticandwildanimals,as

wellashumans.

EPIDEMIOLOGY• Bitesoccurin4.7millionAmericansyearlyandaccountfor800,000medicalvisits,including

approximately1%ofallemergencydepartmentvisits.

MICROBIOLOGY• Thebacteriaassociatedwithbite infectionsmaycome fromtheenvironment, thevictim’s

skinflora,ormostfrequently,theoralfloraofthebiter,whichcanalsobeinfluencedbythemicrobiomeoftheiringestedpreyandotherfood.

DIAGNOSIS• Thediagnosisismadebythepatient’sreportedhistoryofevents.Ultimatelyamicrobiologic

assessmentofinfectedwoundsisperformedthroughaerobicandanaerobiccultures.• Plainradiographsshouldbeobtainedifthereisahighlikelihoodofbonyinjury.

THERAPY• Irrigatewoundswithcopiousamountsofnormalsaline.• Cautiouslydébridedevitalizedornecrotictissue.• Primarywoundclosure isnotusuallyadvocated;delayedprimaryclosureorallowing the

woundtoclosebysecondaryintentionisrecommended.• Looseapproximationofwoundedgeswithadhesivestripsorsuturesmaybenecessaryfor

selected,fresh,uninfectedwounds.Closureoffacialwoundsmaybeconsideredifcoupledwithcopiousirrigationandantimicrobialpreemptivetherapy.

• Inmostcasesofterrestrialanimalbites,antimicrobialtherapywhenindicatedshouldincludecoverageforPasteurella(Eikenellainhumanbites),Streptococcus, Staphylococcus,andanaer-obesincludingFusobacterium, Porphyromonas, Prevotella,andBacteroidesspecies.

• Oralantimicrobialchoicescanincludethefollowing(seeTable238-1):• Amoxicillin/clavulanicacid875/125mgonetabletbymouthtwicedaily• Clindamycin300mgbymouthfourtimesdailyplusciprofloxacin500mgbymouthtwice

daily• Clindamycin300mgbymouthfourtimesdailyplustrimethoprim-sulfamethoxazoleone

double-strengthtabletbymouthtwicedaily• Moxifloxacin400mgbymouthdaily• Doxycycline100mgbymouthtwicedaily

• Intravenousantimicrobialchoicescanincludethefollowing:• Ampicillin/sulbactam1.5to3gIVevery6hours• Cefoxitin1to2gIVevery6to8hours

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TABLE 238-1  Management of Bite Wounds

HistoryAnimal bite: Ascertain the type of animal, whether the bite was provoked or unprovoked, and the situation/

environment in which the bite occurred. Follow rabies guidelines for details on management of bites that carry a risk of rabies.

Patient: Obtain information on antimicrobial allergies, current medications, splenectomy, mastectomy, liver disease, or immunosuppressive conditions.

Physical ExaminationIf possible record a diagram of the wound with the location, type, and approximate depth of injury; range of

motion; possibility of joint penetration; presence of edema or crush injury; nerve and tendon function; signs of infection; and odor of exudate.

CultureAerobic and anaerobic cultures should be taken from infected wounds.

IrrigationCopious amounts of normal saline should be used for irrigation.

DébridementDevitalized or necrotic tissue should be cautiously débrided.

RadiographsPlain radiographs should be obtained if bony penetration is possible and to provide a baseline for future

evaluation of osteomyelitis.

Wound ClosurePrimary wound closure is not usually advocated. Wound closure may be necessary for selected, fresh,

uninfected wounds, especially large facial wounds. For larger wounds, edges may be approximated with adhesive strips in selected cases.

Antimicrobial TherapyEarly presenting (uninfected) wounds: Provide antimicrobial therapy for (1) moderate-to-severe injuries less

than 8 hours old, especially if edema or significant crush injury is present; (2) bone or joint space penetration; (3) deep hand wounds; (4) immunocompromised patients (including those with mastectomy, advanced liver disease, asplenia, or chronic steroid therapy); (5) wounds adjacent to a prosthetic joint; and (6) wounds in close proximity to the genital area. In most cases, coverage should include Pasteurella (Eikenella in human bites), Staphylococcus, Streptococcus, and anaerobes including Fusobacterium, Porphyromonas, Prevotella, and Bacteroides species.

Infected wounds: Cover Pasteurella (Eikenella in human bites), Staphylococcus, Streptococcus, and anaerobes including Fusobacterium, Porphyromonas, Prevotella, and Bacteroides spp. The following antimicrobials can be considered for most terrestrial animal and human bites in adults:• First choice: Amoxicillin/clavulanic acid 875/125 mg one tablet bid with food.• Penicillin allergy: No alternative treatment for animal bites has been established for penicillin-allergic

patients. The following regimens can be considered for adults:• Clindamycin 300 mg PO qid plus either ciprofloxacin 500 mg PO bid or levofloxacin 500 mg PO daily

or trimethoprim-sulfamethoxazole one double-strength tablet PO bid• Doxycycline 100 mg PO bid• Moxifloxacin 400 mg PO daily• In highly penicillin-allergic pregnant patients, macrolides have been used, but because of poor

antimicrobial coverage against anaerobic pathogens, the wounds must be closely followed.• In cases where intravenous antibiotics are deemed necessary, single antimicrobial choices can include

ampicillin/sulbactam, cefoxitin, ertapenem, or moxifloxacin.• Empirical regimens for marine- and freshwater-acquired infection should also cover Vibrio and

Aeromonas species, respectively, with agents such as third-generation cephalosporins (e.g., cefotaxime) and fluoroquinolones.

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HospitalizationIndications include signs and symptoms of systemic toxicity and worsening infection.

ImmunizationsProvide tetanus and rabies immunization, if indicated.

ElevationElevation may be required if any edema is present. Lack of elevation is a common cause of therapeutic

failure.

ImmobilizationFor significant injuries, immobilize the extremity, especially the hands, with a splint.

Follow-upPatients should be reminded to follow up within 48 hours or sooner for worsening or unresolved infections

and continuous pain.

ReportingReporting the incident to a local health department may be required.

bid, two times a day; PO, orally; qid, four times a day; tid, three times a day.

• Moxifloxacin400mgIVdaily• Ertapenem1gIVdaily

• Empiricalregimensformarine-andfreshwater-acquiredinfectionsshouldcoverVibrioandAeromonasspecies,respectively,withagentssuchasthird-generationcephalosporins(e.g.,cefotaxime)andfluoroquinolones.

PREVENTION• Asaroutine,antimicrobialsarenotadvocatedforeveryuninfectedanimalbiteinjury.• In general, antimicrobial preemptive therapy is advocated for 3 to 5 days for uninfected

animalbites(e.g.,<24hoursafterinjury)inmoderate-to-severeinjuries,especiallythosetothehandorface,deepinjuriespenetratingbonystructures,inthepresenceofedema,andinimmunocompromisedhosts.

• Providetetanusandrabiesimmunization,asindicated.

TABLE 238-1  Management of Bite Wounds—cont’d

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D  Zoonoses

239  ZoonosesW. Ian Lipkin

DEFINITION• Azoonosisisaninfectiousdiseaseofhumansthatoriginatesinanimals.

EPIDEMIOLOGY• Zoonosesaccountformorethanhalfofallemerginginfectiousdiseasesandincludesuch

variedexamplesashumanimmunodeficiencyvirus/acquiredimmunodeficiencysyndrome(HIV/AIDS),Ebolavirus,severeacuterespiratorysyndrome,plague,rabies,influenza,andnew-variantCreutzfeldt-Jakobdisease.

DIAGNOSIS• Themajorityofzoonoticdiseasesarediagnosedusingmolecularmethods.Manyappearin

unexpectedcontexts;thus,acomprehensivetravelandexposurehistorycanbecritical.

TREATMENT• WiththenotableexceptionofHIV/AIDSandinfluenza,mostviralzoonoseshavenotbeen

a focus for drug development. Thus, treatment is primarily supportive. In contrast, manybacterialzoonosescanbetreatedwithantibiotics.

PREVENTION• Vaccinesareestablished foronlyaminorityofzoonoticdiseases.Thus,prevention isbest

achievedbylimitingexposuretoreservoirsandvectorsfortransmissionofinfection.

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E  Protection of Travelers

240  Protection of TravelersDavid O. Freedman

The pretravel office visit with an adult traveler to the developing world should follow a structured approach.

PERFORM RISK ASSESSMENT• Exact itinerary, including regions within each country to be visited, dates of travel to assess

risk of seasonal diseases, age, past vaccination history, underlying illness(es), current medica-tions, pregnancy status, allergies, purpose of trip, risk exposures—blood, body fluids, adven-ture or extensive outdoor exposures, urban versus rural travel, type of accommodations, level of aversion to risk, and financial limitations that may necessitate prioritization of interventions

ADMINISTER IMMUNIZATIONS• Routine vaccinations that are not up to date, including measles-mumps-rubella (MMR),

tetanus-diphtheria–acellular pertussis (Tdap), pneumococcal, varicella, zoster• Indicated routine travel vaccines, including hepatitis A, hepatitis B, typhoid, and

influenza• Indicated specialized vaccines, including yellow fever, rabies, polio, meningococcal, and, in

certain countries, tick-borne encephalitis and cholera

PROVIDE MALARIA PREVENTION (IF INDICATED)• Several equally effective drugs of choice may be indicated, including atovaquone/proguanil,

mefloquine, and doxycycline. Ascertain which is best suited to the individual patient and itinerary.

• Educate on personal protection against arthropods.

TRAVELER’S DIARRHEA• Recommend food and water precautions.• Prescribe and educate on standby therapy with a quinolone antibiotic or azithromycin, and

advise on use of loperamide and oral hydration if needed.

TEACH ESSENTIAL PREVENTIVE BEHAVIORS• Most travel-related health problems, including vaccine-preventable diseases, can be avoided

through simple behaviors initiated by the traveler.• Educate on appropriate strategies in the following categories (some topics are not applicable

to all destinations): blood-borne and sexually transmitted diseases, safety and crime avoid-ance, injury prevention, swimming safety, rabies, skin/wound care, tuberculosis, packing for healthy travel, and obtaining health care abroad.

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DISCUSS OTHER APPLICABLE HEALTH ISSUES• Advise and prescribe for altitude illness, motion sickness, or jet lag.• Discuss prevention of specific travel-related infections that are of some risk to the traveler

and have a possible preventive strategy not included in the strategies given above.• Discuss any minimal-risk conditions (e.g., hemorrhagic fevers) that are a frequent cause of

patient anxiety.

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241  Infections in Returning TravelersDavid O. Freedman

MAJOR SYNDROMES IN RETURNED TRAVELERS• Fever,diarrhea(acuteorpersistent),skinproblems,eosinophilia

TROPICAL DISEASES WITH POSITIVE PERIPHERAL BLOOD FILMS• Malaria,babesiosis,filariasis,Africantrypanosomiasis,Americantrypanosomiasis,relapsing

fever,bartonellosis

INCUBATION PERIODS OF TROPICAL DISEASES• Short (<10 days):arboviralinfectionsincludingdengueandyellowfever,hemorrhagicfevers,

respiratoryvirusinfections,typhoid,infectionwithgastrointestinalpathogens,spottedfeverrickettsioses,relapsingfever,leptospirosis

• Intermediate (10 to 20 days):malaria,hemorrhagicfever,Qfever,typhus,typhoid,brucellosis,Africantrypanosomiasis,rabies,tick-borneencephalitis,Japaneseencephalitis

• Prolonged (>21 days):viralhepatitis,malaria,rabies,tuberculosis,schistosomiasis,filariasis,amebicabscess,Qfever,Epstein-Barrvirusinfection

EVALUATION OF SIGNIFICANT TROPICAL FEVER• Any hemorrhagic manifestations?Ifviralhemorrhagicfeverispossible,isolateandcallpublic

healthauthorities;considermeningococcemia,rickettsiosis,sepsis,dengue.• Is malaria possible?Ifthereisend-organdamage,initiateempiricaltherapy.• Utilize a “rule out malaria protocol,” and use empirical therapy if no local expertise is

available.• Aretherelocalizingfindings?Gotosyndromicapproachanddifferentialdiagnosis.• Aretherenolocalizingfindings?Considertyphoid,dengue,rickettsiosis,humanimmuno-

deficiencyvirusinfection,leptospirosis,schistosomiasis(eosinophilia),amebicdisease.• ConsultTable241-1forconstellationsofexposuresandclinicalpresentationssuggestiveof

particulardiagnosesinreturnedtravelers.• Eosinophilia iscausedbytissue-invasivehelminthsandisproportionaltodegreeoftissue

invasion.

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TABLE 241-1  Constellations of Exposures and Clinical Presentations Suggestive of Particular Diagnoses in Returned Travelers*

EXPOSURE SCENARIO DISTINCTIVE FINDINGS DIAGNOSISAny exposure in any area with documented malaria transmission

Fever with or without any other finding

Malaria

Most tropical countries Fever and altered mental status Malaria, meningococcal meningitis, rabies, West Nile virus

Budget travel to India, Nepal, Pakistan, or Bangladesh

Insidious-onset, high unremitting fever, toxic patient, paucity of physical findings

Enteric fever due to Salmonella Typhi or Salmonella Paratyphi

Freshwater recreational exposure in Africa Fever, eosinophilia, hepatomegaly, negative malaria smear

Acute schistosomiasis (Katayama fever)

Bitten by Aedes aegypti in Central America, Southeast Asia, or the South Pacific

Fever, headache, myalgia, diffuse macular rash, mild to moderate thrombocytopenia

Dengue

Bitten by A. aegypti or Aedes albopictus in India, Malaysia, Singapore, the Caribbean, or an island in the Indian Ocean

Fever, headache, myalgia, diffuse macular rash, arthralgia, tenosynovitis often followed by chronic polyarthritis after the fever resolves

Chikungunya fever

Hunting or visiting game reserves in southern Africa

Fever, eschar, diffuse petechial rash African tick typhus due to Rickettsia africae

Travel to Southeast Asia Fever, eschar, diffuse petechial rash Scrub typhus due to Orientia tsutsugamushi

Hiking, biking, swimming, rafting with exposure to fresh surface water

Fever, myalgia, conjunctival suffusion, mild to severe jaundice, variable rash

Leptospirosis

Cruise, elderly traveler Influenza-like illness Influenza A or B

Outdoor exposure anywhere in the Americas

Large, single furuncular lesion anywhere on body, with sense of movement inside

Myiasis due to Dermatobia hominis (botfly)

Clothing washed or dried out of doors in Africa

Multiple furuncular lesions around clothing contact points with skin

Myiasis due to Cordylobia anthropophaga (tumbu fly)

New sexual partner during travel Fever, rash, mononucleosis-like illness Acute human immunodeficiency virus infection

Travel to any developing country or to Western Europe

Coryza, conjunctivitis, Koplik spots, rash

Measles

Longer visit to humid areas of Africa, the Americas, or Southeast Asia

Asymptomatic eosinophilia or with periodic cough or wheezing

Strongyloidiasis

Sand fly bite in either New or Old World tropical area

Painless skin ulcer with clean, moist base in exposed area

Cutaneous leishmaniasis

Resort hotel in southern Europe, ± exposure to whirlpool spas

Pneumonia Legionnaires’ disease

Explored a cave in the Americas Fever, cough, retrosternal chest pain, hilar adenopathy

Histoplasmosis

Ingestion of unpasteurized goat cheese Chronic fever, fatigue Brucella melitensis

Long trip to West/Central Africa Afebrile, intensely pruritic, evanescent truncal maculopapular rash

Onchocerciasis

Long trip to West/Central Africa Migratory localized angioedema or swellings over large joints, eosinophilia

Loiasis

Safari to game parks of East Africa Fever, nongenital chancre, fine macular rash

East African trypanosomiasis

Travel to Australia Fever, fatigue, polyarthritis Ross River virus

Farming areas of India and Southeast Asia Fever, altered mental status, paralysis Japanese encephalitis

Forested areas of central and eastern Europe and across Russia

Fever, altered mental status, paralysis Tick-borne encephalitis

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EXPOSURE SCENARIO DISTINCTIVE FINDINGS DIAGNOSISRodent exposure in West Africa Fever, sore throat, jaundice,

hemorrhagic manifestationsLassa fever

Ingestion of sushi, ceviche, or raw freshwater fish

Migratory nodules in truncal areas with overlying erythema or mild hemorrhage

Gnathostomiasis

Returning Hajj pilgrim or family contact Fever, meningitis Meningococcal meningitis

Ingestion of snails, fish, or shellfish in Asia or Australia

Eosinophilic meningitis Angiostrongyliasis, gnathostomiasis

Diabetic or compromised host with exposure to moist terrain in Asia or Australia

Fever, sepsis, pneumonia or multifocal abscesses

Melioidosis

Summertime exposure to rodent droppings in Scandinavia

Fever with decreased renal function Puumala virus

Ingestion of undercooked meat of any animal in any country

Fever, facial edema, myositis, increased creatine phosphokinase, massive eosinophilia, normal erythrocyte sedimentation rate

Trichinosis

Unvaccinated, returning from sub-Saharan Africa or forested areas of Amazonia

Fever, jaundice, proteinuria, hemorrhage

Yellow fever

Exposure to farm animals Pneumonia, mild hepatitis Q fever

Possible tick exposure almost anywhere Fever, headache, rash, conjunctival injection, hepatosplenomegaly

Tick-borne relapsing fever

Poor hygienic conditions with possible body louse exposure in Ethiopia or Sudan

Fever, headache, rash, conjunctival injection, hepatosplenomegaly

Louse-borne relapsing fever

*The table includes illnesses of travelers (listed first) as well as less common diseases with presentations that should suggest the possibility of the appropriate diagnosis. Many diseases have a spectrum of presentation, and the table describes the most common presentations of these diseases. Many diseases have a spectrum of geographic origins, and the table describes the most common exposures seen in daily practice.

TABLE 241-1  Constellations of Exposures and Clinical Presentations Suggestive of Particular Diagnoses in Returned Travelers*—cont’d

496

Index

AAbacavir, for human immunodeficiency virus infection,

150t-151tAbdominal imaging techniques, in amebiasis, 413Abiotrophia, 287Abscess

brain, 84-85caused by Streptococcus anginosus group, 289epidural, 86-87intraperitoneal, peritonitis and, 42-47liver, 48lung, bacterial, 30pancreatic, 49, 50tsplenic, 54

in injection drug users, 481Acalculous cholecystitis, 48Acanthamoeba spp., 415-416Acid, hepatitis A virus and, 240Acinetobacter baumannii, 323Acinetobacter nosocomialis, 323Acinetobacter pittii, 323Acinetobacter species, 323Acquired immunodeficiency syndrome (AIDS), 138-139

histoplasmosis and, 393tuberculosis and, 365zoonoses and, 490

Acquired immunodeficiency syndrome (AIDS)-related opportunistic infections, 155

treatment of, 156t-168tActinomycetoma, 388Actinomycosis, agents of, 380Acute appendicitis, 55Acute bacterial sinusitis, 14Acute bronchitis, 22Acute diverticulitis, 56Acute exacerbations, of chronic obstructive pulmonary

disease, 23Acute fluid collection, 50tAcute illness, in HCV infection, 212Acute laryngitis, 10Acute laryngotracheobronchitis, 11Acute mediastinitis, 72

causes of, 73t

Acute meningitis, 75-77Acute necrotizing ulcerative gingivitis, antimicrobial

regimens for, 18t-19tAcute otitis media (AOM), 12Acute pancreatitis, 49, 50t

definitions derived from the International Symposium on, 50t

severe, 50tAcute pharyngitis, microbial causes of, 7tAcute pneumonia, 25-26Acute postcataract endophthalmitis, 125-126Acute poststreptococcal glomerulonephritis (APSGN)

definition of, 279diagnosis of, 279treatment of, 280

Acute pseudocyst, 50tAcute pulmonary exacerbations, in cystic fibrosis, 33, 36tAcute respiratory disease, adenoviruses and, 192Acute retinal necrosis (ARN), treatment of, 156t-168tAcute retroviral syndrome, 140

symptoms and signs of, 141tAcute rheumatic fever (ARF)

anti-inflammatory therapy for, 280, 280tdefinition of, 279diagnosis of, 279prevention of, 280, 280t

Acute simple gingivitis, antimicrobial regimens for, 18t-19t

Acute transient disease, 300Acute uncomplicated diverticulitis, 56-57Acutely ill patient, with fever and rash, 3-4Acyclovir

for HSV conjunctivitis, 123for infections

in cancer patients, 465t-466t, 467in HSCT, 471

Adefovir, for chronic hepatitis B, 200tAdenoviruses, 81t-83t, 192-193

human, 192Adiaspiromycosis, 407-408Adiaspores, 407β2-adrenergic receptor agonists, 34t-36tAdult epiglottitis, 15

clinical manifestations of, 15therapy for, 16

Adult T-cell leukemia (ATL), lymphoma type of, 235Advisory Committee on Immunization Practices, 77Aeromonas hydrophila, 318

Page numbers followed by f indicate figures and t indicate tables.

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Aerosolized pentamidine, for infections in cancer patients, 465t-466t

Aerosolized ribavirin, for respiratory syncytial virus, 218African trypanosomiasis, 422-423Age, burn and, 486Albendazole

for cestodes, 443for giardiasis, 427tfor microsporidiosis, 412for tissue nematodes, 439

Algal blooms, harmfulillness associated with, 435, 436tsites and types of, 436f

Alkhurma hemorrhagic fever virus (AHFV), 210Allergic bronchopulmonary aspergillosis, 381Allogeneic donors, for HSCT, types of, 470Alphavirus encephalitis, 207Alphaviruses, 207-208Alveolar hemorrhage, diffuse, in HSCT, 471Amebae, free-living, 415-416Amebiasis, 413

treatment of, 414tAmebic colitis, 413

treatment of, 414tAmebic liver abscess, 48, 413

treatment of, 414tAmerican trypanosomiasis, 420-421Aminoglycoside, for bacterial keratitis, 124Aminotransferase levels, hepatic, in murine typhus,

264Amnesic shellfish poisoning, harmful algal blooms and,

436tAmoxicillin

for bites, 487for group A streptococcal pharyngitis, 9t

Amoxicillin-clavulanate, for infections in cancer patients, 465t-466t

Amphotericin Bfor entomophthoramycosis and mucormycosis, 385liposomal, for aspergillosis, 381, 384tfor Sporothrix schenckii, 386

Amphotericin B deoxycholate, for paracoccidioidomycosis, 402, 403t

Ampicillinfor bites, 487for listeriosis, 293

Anaplasma phagocytophilum, 266-267Anaplasmataceae, 266-267Ancylostoma, 437, 438tAnidulafungin, for aspergillosis, 384tAnopheles mosquito, malaria transmitted by, 417Anterior uveitis, 127, 128tAnthelmintic agents

for cestodes, 443for tissue nematodes, 439

Anthrax, 296-297, 297tAnthrax meningitis, 296Anti-HBV agents, 199Antibiotic prophylaxis, of infective endocarditis,

regimens for, 68tAntibiotic susceptibility testing, for gram-negative and

gram-variable bacilli, 350

Antibiotic therapyfor leptospirosis, 354, 355tfor melioidosis, 322tfor tularemia, 334t

Antibiotics, 34t-36tbroad-spectrum, for pneumonia, 458-459for infections, in asplenic patients, 477intravitreal, for endophthalmitis, 126for myiasis, 450for septic bursitis, 110for shigellosis, 325for tungiasis, 451for zoonoses, 490

Anticholinergics, 34t-36tAntifungal therapeutic agents, for microbial keratitis, 124Antigen detection, in Giardia lamblia, 426Antigenic variation, of African trypanosomiasis, 422Antimicrobial agents

for Capnocytophaga, 345for fever of unknown origin, 2for foodborne disease, 105guide to empirical choice of, for treating adult patients

with community-acquired pneumonia or health care-acquired pneumonia, 26t-27t

for plague, 337Antimicrobial prophylaxis, 288, 482

for Pasteurella species, 336surgical, 482, 484f-485f

Antimicrobial therapyfor bites, 487, 488t-489t, 489for CSF shunt infections, 88-89empirical, for brain abscess, 85tfor epidural abscess, 86-87for group A streptococcal pharyngitis, 9tfor microbial keratitis, 124for osteomyelitis, 112tfor Salmonella gastroenteritis, 324for suppurative intracranial thrombophlebitis, 87

Antiretroviral therapy (ART)for cryptococcosis, 390for human immunodeficiency virus infection, 149

entry inhibitors for, 154tintegrase inhibitor for, 154tnon-nucleoside reverse-transcriptase inhibitors for,

152tnucleoside and nucleotide reverse-transcriptase

inhibitors for, 150t-151tprotease inhibitors for, 152t-153t

for human immunodeficiency viruses, 236for toxoplasmosis, 425

Antistaphylococcal antibiotics, 34t-36tAntiviral chemotherapy

for herpes simplex virus infection, 180t-182tfor influenza, 229t

Antiviral drugsfor chronic hepatitis B, 133tfor influenza, 228

Antiviral therapyfor infectious mononucleosis, 187for influenza, 228for Kaposi’s sarcoma-associated herpesvirus, 189

Aphthous ulceration, esophagitis from, 99t

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Apnea, bronchiolitis and, 24Appendicitis, 55Appendix, vermiform, 55Arenaviruses, 232-233ART. see Antiretroviral therapy (ART).Arthritis

bacterial, 108fungal, 109gonococcal, 108infectious, of native joints, 108-110

empirical therapy for, 109treactive, foodborne diseases and, 105viral, 108

Ascaris, 437-438, 438tAsialoglycoprotein receptor, 305Asian scrub typhus chiggers, larvae of, in scrub typhus,

452Aspergilloma, 381Aspergillosis, pulmonary, in human immunodeficiency

virus infection, 143Aspergillus, 59t, 381-382

characteristics of, 383tdefinition of, 381diagnosis of, 381epidemiology of, 381, 382tmicrobiology of, 381prevention of, 382therapy for, 381, 384t

Aspirin, for KD, 454Asplenic patients, infections in, 477-478Asthma, rhinovirus and, 243Astroviruses, 246Asymptomatic bacteriuria, 37

of pregnancy, 38Asymptomatic infection, of reoviruses, 203Atazanavir, for human immunodeficiency virus infection,

152t-153tAtovaquone

for Babesia microti, 429-430, 430tfor infections, in cancer patients, 465t-466tfor malaria prevention, in travelers, 491

Atropine, for hypotension/bradycardia, syndrome of, 435

Attenuated mumps virus vaccine, immunization with, 217

Atypical pneumonia, 255Avian influenza, 228Azaspiracid shellfish poisoning, harmful algal blooms

and, 436tAzithromycin

for Babesia microti, 429-430, 430tfor babesiosis, 453for chancroid, 326for conjunctivitis, 123for diarrhea, in travelers, 491for donovanosis, 348with P. aeruginosa, 34t-36tfor pertussis, 339for SFG rickettsioses, 258for trachoma, 250without P. aeruginosa, 34t-36t

Aztreonam, 34t-36t

BBabesia divergens, treatment of babesiosis from, 430tBabesia microti, 429

treatment of babesiosis from, 430tBabesia species, 429-430Babesiosis, 429

treatment of, 430t, 453Bacillary angiomatosis, from Bartonella henselae, 346Bacillary dysentery, 325Bacillary peliosis, from Bartonella henselae, 346Bacilli

gram-negative, 349-350brain abscess and, 84

gram-variable, 349-350Bacillus anthracis, 296-297

related genera to, 298Bacillus species, 298Bacteremia, 56

from Clostridium, 362in elderly, 476non-catheter-related S. maltophilia, 318-319

Bacteriawith bite infections, 487chronic pneumonia and, 31conjunctivitis from, 122encapsulated, in postsplenectomy sepsis, 477inflammatory enteritides from, 102-103mucous membrane lesions, 116noninflammatory gastroenteritis from, 100prostatitis from, 120

Bacterial arthritis, acute, 108Bacterial diseases, body lice and, 446Bacterial infection

in injection drug users, 479in solid-organ transplant recipients, 474

Bacterial lung abscess, 30Bacterial lymphadenitis, 95t-96tBacterial meningitis, Streptococcus pneumoniae in, 281Bacterial pneumonia, in human immunodeficiency virus

infection, 142Bacterial respiratory diseases, treatment of, 156t-168tBacterial sinusitis, acute, 14Bacteriuria, asymptomatic, 37

of pregnancy, 38Bacteroides, 364

brain abscess and, 84definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t

BAL. see Bronchoalveolar lavage (BAL).Balamuthia mandrillaris, 415-416Balantidiasis, therapy for, 433tBalantidium coli, 432-433Banna virus (BAV), 204Bartonella bacilliformis, 346Bartonella henselae, 346Bartonella quintana, 346Bartonella spp., 58, 59tBasidiobolomycosis, 385Basidiobolus ranarum, 385

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Bat rabies, 226BAV. see Banna virus (BAV).Benzathine penicillin

for S. pyogenes infections, 278for syphilis, 352

Benzathine penicillin G, for group A streptococcal pharyngitis, 9t

Benznidazole, for T. cruzi, 421Benzodiazepines, for tetanus, 360Biliary tract infections, from Clostridium, 362Biliary tree, disorders of, from human immunodeficiency

virus infection, 144-145Binary toxin, from Clostridium difficile, 358Biopsy, for cutaneous warts and genital warts, 194Bioterrorism, anthrax for, 296Birds, psittacosis from, 253Bites, 487-489

dog, Capnocytophaga from, 344management of, 488t-489tPasteurella infection from, 335

BK virus (BKV), 196-197in solid-organ transplant recipients, 474

Blastocystis species, 432-433Blastocystosis, therapy for, 434tBlastomyces dermatitidis, 396Blastomycosis, 396

clinical manifestations of, 396definition of, 396diagnosis of, 396microbiology and epidemiology of, 396treatment for, 396, 397t

Bleb-related endophthalmitis, 125Blepharitis, marginal, 129Blood, donors of, transfusion- and transplantation-

transmitted infections in, 463Blood culture

for enteric fever, 104in postsplenectomy sepsis, 477

Blood films, positive peripheral, tropical diseases with, in returning travelers, 493

Blood stem cells, peripheral, in HSCT, 470Bloodstream infections, in cancer patients, 464Boceprevir, for hepatitis C virus, 136fBody lice, 446-447Bone fractures, internal fixation-associated infection and,

115Bone infection

in injection drug users, 479SCI and, 475

Bone marrow, in HSCT, 470Bone marrow cultures, for enteric fever, 104Bordetella pertussis, 339-340Borrelia afzelii, 357Borrelia burgdorferi, Lyme disease due to, 357Borrelia garinii, 357Borrelia species, relapsing fever caused by, 356Botfly furuncular myiasis, 450Botulism, 361Brain abscess, 84-85Bronchiolitis, 24

posterior, in HSCT, 471Bronchitis, acute, 22

Bronchoalveolar lavage (BAL), 458Brucella species, 59t, 328Brucellosis, 328

treatment of, 329tBullous lesions, in acutely ill patients, 3-4Bunyavirus hemorrhagic fevers, 231Burkholderia cenocepacia, 318Burkholderia cepacia, 318-319Burkholderia mallei, 320-322Burkholderia multivorans, 318Burkholderia pseudomallei, 320-322Burns, 486Bursitis, septic, 110

CCA-asymptomatic bacteriuria (CA-ASB), 460CA-UTI. see Catheter-associated urinary tract infection

(CA-UTI).Caliciviruses, 244-245California encephalitis, 231Campylobacter jejuni, and related species, 314Campylobacter spp., inflammatory enteritides from, 102Canaliculitis, 129Candida, esophagitis from, 99tCandida endophthalmitis, 125Candidiasis

esophageal, treatment of, 156t-168tmucocutaneous, treatment of, 156t-168toropharyngeal, treatment of, 156t-168tvulvovaginal, 118

treatment of, 156t-168tCapnocytophaga, 344-345Capsular polysaccharides, of Staphylococcus aureus,

270t-271tCardiac disease, from human immunodeficiency virus

infection, 140Cardiomyopathy, trypanosomiasis and, 420Cardiovascular devices, nonvalvular, infections of,

65-66Cardiovascular implantable electronic device (CIED)

infections, 65Caspofungin, for aspergillosis, 384tCat-scratch disease, 346-347Catheter-associated (CA)-bacteriuria, 460-461Catheter-associated urinary tract infection (CA-UTI),

460-461management of, 461t

Catheterization, in CA-bacteriuria, 460Catheters, infections caused by, 456-457Cats, parturient, Q fever from, 260Cefazolin, for bacterial keratitis, 124Cefepime, for infective endocarditis, in injection drug

users, 480Cefotaxime, for H. influenzae type b meningitis, 326Cefoxitin, for bites, 487Ceftazidime, for melioidosis, 322Ceftriaxone

for brucellosis, 329tfor conjunctivitis, 123for H. influenzae type b meningitis, 326for Salmonella gastroenteritis, 324

Cell infusion, preparation of patient for, 470

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Cell wall fatty acid analysis, for gram-negative and gram-variable bacilli, 349

Cellular immunity, in rotaviruses, 206Cellulitis, 90-91Centers for Disease Control and Prevention (CDC), 75

for human immunodeficiency virus, 138, 139tCenters for Disease Control and Prevention/National

Institutes of Health consensus conference, definition of chronic fatigue syndrome, 172, 173t

Central line-associated bloodstream infections (CLABSIs), 456

Central nervous system (CNS)infection of

in elderly, 476in injection drug users, 481

mass lesions in, human immunodeficiency virus and, 146

prion diseases of, 248Cephalosporin, for Capnocytophaga, 345Cerebrospinal fluid (CSF)

of patients with N. fowleri, 415shunt and drain infections of, 88-89

Cervicitis, 118from Chlamydia trachomatis, clinical characteristics of,

251t-252tCervicofacial actinomycosis, initial empirical

antimicrobial regimens for, 20t-21tCestodes, 443-444, 444tCFS. see Chronic fatigue syndrome (CFS).Chagas’ disease, 420-421Chalazion, 129Chancroid, 326-327Chemicals, causing foodborne illnesses, 105Chemoprophylaxis

for acute meningitis, 76-77for influenza, 229tfor Neisseria meningitidis, 303, 303t

Chickenpox, 183-184Chiggers, mites and, 452Chikungunya virus, 81t-83tChildren

croup in, 11cryptosporidiosis in, 431human immunodeficiency virus infection in, 147KD in, 454visceral larva migrans in, 445

Chlamydia pneumoniae, 254Chlamydia psittaci, 59t, 253Chlamydia trachomatis, 249-250

clinical characteristics of, 251t-252tepididymitis from, 120urethritis from, 117

Chlamydial conjunctivitis, neonatal, 123Chlamydial lymphadenitis, 95t-96tChloramphenicol

for louse-borne typhus, 262for murine typhus, 264for Rocky Mountain spotted fever, 258

Cholangitis, 48Cholecystitis, 48Cholera, caused by Vibrio cholerae, 308Chorioretinitis, 125, 425

Chromoblastomycosis, 387Chronic airway infection, 33Chronic airway inflammation, 33Chronic fatigue syndrome (CFS), 172

CDC/NIH consensus conference definition of, 172, 173t

proposed infectious causes of, 173tChronic fibrocavitary pneumonia, 399Chronic hepatitis B, 198

approved agents for treatment of, 200tChronic infection, with hepatitis C, 212Chronic infectious arthritis, 109Chronic mediastinitis, 72Chronic obstructive pulmonary disease (COPD)

acute exacerbations of, 23Haemophilus influenzae and, 326Moraxella catarrhalis causing, 307

Chronic pneumonia, 31-32Chronic postcataract endophthalmitis, 125Chronic prostatitis/chronic pelvic pain syndrome (CP/

CPPS), 120Chronic pulmonary therapies, for patients with cystic

fibrosis, 34t-36tCIED infections. see Cardiovascular implantable

electronic device (CIED) infections.Cierny and Mader classification, of osteomyelitis, 111Ciguatera fish poisoning, harmful algal blooms and, 436tCiprofloxacin

for bites, 487for Cyclospora and Cystoisospora, 432, 433tfor infections, in cancer patients, 465t-466tfor tularemia, 334t

Cirrhosis, HCV-associated, 134Citrobacter spp., 316Cladophialophora carrionii, 387Clarithromycin

for pertussis, 339for SFG rickettsioses, 258

Clindamycinfor Babesia microti, 429, 430tfor babesiosis, 453for bites, 487for S. pyogenes infections, 278

Clonorchis sinensis, 441t-442tClostridial myonecrosis, 92, 362Clostridium difficile infection, 358-359

definition of, 358diagnosis of, 358epidemiology of, 358microbiology of, 358prevention of, 359therapy for, 358-359

Clostridium perfringensand clostridial myonecrosis, 362food poisoning by, 362myonecrosis from, 92toxins produced by, 363t

Clostridium spp.characteristics of, 362, 363tother diseases associated with, 362

Clostridium tetani, 360CMV. see Cytomegalovirus (CMV).

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CMV colitis, treatment of, 156t-168tCMV esophagitis, treatment of, 156t-168tCMV retinitis, treatment of, 156t-168tCoagulase-negative staphylococci, 275-276Cobicistat, for human immunodeficiency virus infection,

150t-151tCoccidioides immitis, 398Coccidioidomycosis, 398-399

diagnosis of, 398epidemiology of, 398in human immunodeficiency virus infection, 143microbiology of, 398prevention of, 399prophylaxis of, 168t-171ttherapy for, 399treatment of, 156t-168t

Colchicine, with NSAIDs, for pericarditis, 70Cold

common, 5rhinovirus and, 243

Colonoscopy, in amebiasis, 413Colorado tick fever virus (CTFV), 204Coltiviruses, 204Common cold, 5Common respiratory pathogens, frequency of laryngitis

associated with, 10tCommunity, MRSA from, 268Community-acquired CoV infections, 215Community-acquired pneumonia, guide to empirical

choice of antimicrobial agent for treating adult patients with, 26t-27t

Complement-fixing anticoccidioidal antibodies, 399Complicated diverticulitis, 56Computed tomography (CT)

for brain abscess, 85for empyema, 28

Comvax, 201tCondom

for gonorrhea prevention, 306urethritis and, 117

Confirmatory assay, for human immunodeficiency virus, 138-139, 139t

Congenital asplenia, patients with, infections in, 477Congenital rubella, 209Conidiobolomycosis, 385Conidiobolus coronatus, 385Conidiobolus incongruus, 385Conjunctivitis

from Chlamydia trachomatis, clinical characteristics of, 251t-252t

microbial, 122-123Contact lens, keratitis and, 124Contamination, of food, 105Continuous ambulatory peritoneal dialysis (CAPD),

polymicrobial peritonitis in, 44Continuous ambulatory peritoneal dialysis (CAPD)

peritonitis, 42, 44, 47indications for catheter removal, 47t

Convalescent human plasma, for arenaviruses, 232Cornea, inflammatory condition of, 124Coronary artery aneurysm, KD and, 454Coronaviruses (CoVs), 215

Corticosteroids, 34t-36tfor cestodes, 443for infectious mononucleosis, 187for tissue nematodes, 439for toxoplasmosis, 425

Corynebacterium diphtheriae, 290-291Corynebacterium ulcerans, 290Corynebacterium urealyticum, 292Coryneform bacteria, 292Cough, Bordetella pertussis and, 339CoVs. see Coronaviruses (CoVs).Coxiella burnetii, 59t, 260-261Coxsackieviruses, 238Craniotomy, for subdural empyema, 86-87Croup, in children, 11Crusted, 448-449Cryptococcal meningitis, treatment of, 156t-168tCryptococcosis, 390-392

clinical manifestations of, 391, 392tcomplications of, 392conditions associated with, 391tepidemiology of, 390history of, 390laboratory diagnosis for, 391management of, 391-392pathogenesis of, 391risk factors for, 390treatment of, 156t-168t

Cryptococcus gattii, 390-392Cryptococcus neoformans, 390-392Cryptosporidiosis, 431Cryptosporidium species, 431CTFV. see Colorado tick fever virus (CTFV).Culture

from cerebrospinal fluid shunt, 88for herpes B virus, 190for management of bite wounds, 488t-489t

Culture-negative endocarditis, causes of, 59tCutaneous anthrax, 296Cutaneous disease, from human immunodeficiency virus

infection, 140Cutaneous leishmaniasis, 419Cutaneous warts, 194Cyclospora cayetanensis, 432-433Cyclosporiasis, therapy for, 433tCystic fibrosis (CF), 33-36

caused by Burkholderia species, 318chronic pulmonary therapies for patients with, 34t-36t

Cystitis, hemorrhagic, in HSCT, 471Cystoisospora (Isospora) belli, 432-433Cystoisosporiasis, therapy for, 433tCysts, thick-walled, from Rhinosporidium seeberi, 409Cytomegalovirus (CMV), 185

esophagitis from, 99tin solid-organ transplant recipients, 474

Cytomegalovirus (CMV) disease, treatment of, 156t-168tCytotoxins, of Staphylococcus aureus, 270t-271t

DDacryoadenitis, 129Dacryocystitis, 129Dapsone, for infections, in cancer patients, 465t-466t

502In

dex

Daptomycin, 284Dark-walled fungi, 405Darkfield microscopy, for treponemes, 351Darunavir, for human immunodeficiency virus infection,

152t-153tDébridement

for management of bite wounds, 488t-489tfor necrotizing infections, 91

Decontamination, for prevention of norovirus infection, 245

Definitive antibiotic therapy, for infections, in asplenic patients, 477

Delavirdine, for human immunodeficiency virus infection, 152t

Deltavirus, 134Dengue, 210Dermatophytosis, 400

definition of, 400diagnosis of, 400epidemiology of, 400microbiology of, 400prevention of, 400therapy for, 400, 401t

Dermoscopy, in lice, 446Desquamative inflammatory vaginitis, 118Detergents, hepatitis A virus and, 240Dexamethasone, for H. influenzae type b meningitis, 326Diabetes mellitus, osteomyelitis and, 112Diagnostic laboratory testing, for poxviruses, 178Dialysis, in hepatitis, 462Diarrhea

caused by Campylobacter spp., 314cryptosporidiosis in, 431enteropathy and, 107Giardia lamblia in, 426microsporidiosis and, 412noninflammatory, with nausea and vomiting, 100-101in travelers, 491

Diarrhetic shellfish poisoning, harmful algal blooms and, 436t

Didanosine, for human immunodeficiency virus infection, 150t-151t

Diethylcarbamazine, for tissue nematodes, 439Diffuse alveolar hemorrhage, in HSCT, 471Diloxanide furoate, for amebiasis, 414tDiphtheria, 290-291Diphtheria antitoxin (DAT), 290Diphtheroids, in CSF shunt infections, 88Diphyllobothrium latum, 443, 444tDisseminated disease, with human immunodeficiency

virus (HIV) infection, 373Disseminated Mycobacterium avium complex (MAC)

disease, 373prophylaxis of, 168t-171ttreatment of, 156t-168t

Diverticulitis, 56-57Dog bite, Capnocytophaga from, 344Dolutegravir, for human immunodeficiency virus

infection, 150t-151t, 154tDonors, transfusion- and transplantation-transmitted

infections in, 463“Donovan bodies,” 348

Donovanosis, 348Dornase alfa, 34t-36tDoxycycline

for Anaplasmataceae infection, 267for Bartonella infection, 347for bites, 487chemoprophylaxis with, for leptospirosis, 354for louse-borne typhus, 262for lymphogranuloma venereum, 250for malaria prevention, in travelers, 491for murine typhus, 264for plague, 337for Q fever, 261for rickettsialpox, 259for Rocky Mountain spotted fever, 258for scrub typhus, 265

and rickettsialpox, 452with streptomycin, for brucellosis, 328, 329tfor syphilis, 352for ticks, 453for tularemia, 334t

Dracunculiasis, 439Drain infections, of cerebrospinal fluid, 88-89Drainage, infections of, in injection drug users, 479Drug users, injection of, infections in, 479-481Drugs, toxicity of, for HAT, 423DTaP, for pertussis, 340Duodenal biopsy, for Whipple’s disease, 300Dysenteric syndromes, acute, 102Dysentery, bacillary, 325

EEbola hemorrhagic fevers, 227Ebola viral diseases, 227EBV. see Epstein-Barr virus (EBV).Echinocandins, for infections, in HSCT, 471Echinococcosis, 443Echinococcus granulosus, 443, 444tEchinococcus multilocularis, 443, 444tEchoviruses, 238Efavirenz, for human immunodeficiency virus infection,

150t-151tEhrlichia chaffeensis, 266-267Ehrlichia ewingii, 266Ehrlichia muris, 266Elderly, infections in, 476Elevation, for management of bite wounds, 488t-489tElvitegravir, for human immunodeficiency virus

infection, 150t-151tEmmonsia pasteuriana, 408Empirical antibiotic therapy, 41t

for infections, in asplenic patients, 477Empirical antifungal therapy, for febrile neutropenia, 469Empirical regimens, for bites, 489Empirical therapy, for suspected tuberculous meningitis,

78Empyema, 28

source of, 28subdural, 86-87

Emtricitabine, for human immunodeficiency virus infection, 150t-151t

Encapsulated bacteria, in asplenic patients, 477

503In

dex

Encephalitic disease, African trypanosomiasis and, 422Encephalitic rabies, 225Encephalitis, 80

alphavirus, 207comparison of encephalopathy and, 81tToxoplasma gondii

prophylaxis of, 168t-171ttreatment of, 156t-168t

Encephalopathy, comparison of encephalitis and, 81tEndemic treponematoses, 353Endocarditis, 58-59

Bartonella, 346caused by S. gallolyticus group, 284causes of culture-negative, 59tin elderly, 476infective

in injection drug users, 480preexisting cardiac conditions associated with, 68tprevention of, 67prophylaxis of, 67regimens for antibiotic prophylaxis of, 68t

prosthetic valve, 63-64caused by staphylococci, therapy for, 64tindications for consideration of surgical

intervention, 64tsummary of treatment options for, 60t-62t

Endocrine abnormalities, from human immunodeficiency virus infection, 140

Endogenous bacterial endophthalmitis, 125Endophthalmitis, 125-126

categories of, 126tEnfuvirtide, for human immunodeficiency virus

infection, 154tEngerix-B, 201tEngraftment syndrome, in HSCT, 471Entamoeba histolytica, amebiasis and, 413Entamoeba species, including amebic colitis, liver abscess

and, 413, 414tEntecavir

for chronic hepatitis B, 200tfor hepatitis B virus, 132for infections, in HSCT, 471

Enteric fever, 104Enteritides, bacterial inflammatory, 102-103Enterobacteriaceae, 316

prostatitis from, 120Enterobius, 437, 438tEnterococcus faecalis, 283Enterococcus faecium, 283Enterococcus species, 283-284Enterocolitis

from human immunodeficiency virus infection, 145tneutropenic, 56

Enteropathy, 107HIV-associated, 145

Enteroviruses, 75-76Entomophthoramycosis, agents of, 385Entry inhibitors, for human immunodeficiency virus

infection, 154tEnzymes, of Staphylococcus aureus, 270t-271tEosinophilia, in returning travelers, 493Epidemic keratoconjunctivitis, 192

Epidermophyton, 400Epididymitis, 120

from Chlamydia trachomatis, clinical characteristics of, 251t-252t

Epidural abscess, 86-87Epiglottitis, 15-16

empirical therapy for, 16Epstein-Barr virus (EBV), 186-187Ertapenem, for bites, 489Erysipelas, 90Erysipeloid, 299Erysipelothrix rhusiopathiae, 299Erythromycin, 314

for chlamydial conjunctivitis, 123for group A streptococcal pharyngitis, 9tfor pertussis, 339

Eschar, vesicular fever with, 259Escherichia coli, 316

enteroinvasive, 325inflammatory enteritides from, 102urinary tract infections and, 37-38

Esophageal candidiasis, treatment of, 156t-168tEsophageal perforation, acute mediastinitis and, 73tEsophageal rupture, 72Esophagitis, 98

in herpes simplex virus, 180treatment of, 99t

Esophagusdisorders of, from human immunodeficiency virus

infection, 144inflammation of, 98

Ethambutol, for tuberculosis, 369t-370tEumycetoma, 388Exanthem subitum, 188Excretory urography, 38Extensively drug-resistant tuberculosis (XDR-TB), 365Extragenital lesions, in herpes simplex virus, 179Eye infections, 122-123Eyedrops, for conjunctivitis, 123Eyelid

infections of, 129inner, inflammation of, 122

FFasciitis, necrotizing, 90-91Fasciola hepatica, 441t-442tFasciolopsis buski, 441t-442tFebrile neutropenia, management of, 467-469, 467f-468fFecal microbiota transplant, for Clostridium difficile

infections, 359Fecal-oral transmission, of adenoviruses, 192Female genital tract infections, from Clostridium, 362Female jigger flea, gravid, 451Fever

acutely ill patient with, 3-4enteric, 104Pontiac, 342-343rat-bite, 341relapsing, caused by Borrelia species, 356tropical, evaluation of, in returning travelers, 493,

494t-495tFever/arthralgia/rash syndrome, 207

504In

dex

Fever of unknown origin (FUO), 2from Bartonella henselae, 346definition of, 2diagnosis of, 2etiology and epidemiology of, 2prognosis of, 2therapy of, 2

Fibrinolytic therapy, for pleural effusion and empyema, 28

Fibrosing mediastinitis, 72Fidaxomicin, for Clostridium difficile infections, 359Filariasis, 439Filoviruses, 227First-generation cephalosporins, for group A

streptococcal pharyngitis, 9tFish, harmful algal blooms in, 435Flaviviruses, 210-211Fleas, murine typhus from, 264Flies, Francisella tularensis from, 330Fluconazole, for infections

in cancer patients, 464, 465t-466tin HSCT, 471

Flukes. see Trematodes.Fluorescent antibody assay, indirect, for scrub typhus,

265Fluorescent in situ hybridization, for Coxiella burnetii,

260Fluoroquinolones

for atypical pneumonia, 255for Salmonella gastroenteritis, 324

Flying fox, 222Flying squirrels, Rickettsia prowazekii in, 262Folate, for enteropathy, 107Folliculitis, 90Follow-up, for management of bite wounds, 488t-489tFonsecaea monophora, 387Fonsecaea nubica, 387Fonsecaea pedrosoi, 387Food poisoning, 298

due to Clostridium perfringens, 362Foodborne botulism, 361Foodborne disease, 105-106Foodborne trematodes, 440-441Foreign bodies, swallowed, acute mediastinitis and,

73tFosamprenavir, for human immunodeficiency virus

infection, 152t-153tFoscarnet

for human herpesvirus types 6 and 7, 188for infections, in HSCT, 471

Fracture, open, contaminated, osteomyelitis after, 111Francisella tularensis, 330-333

characterization of, 331tsubspecies of, 330, 331t

Free-living amebae, 415-416Fruit bat, Pteropus species of, 222Fulminant hepatitis, due to HCV infection, 212Fulminant meningoencephalitis, N. fowleri and, 415Fumagillin, for microsporidiosis, 412Fungal arthritides, 109Fungal infections, in solid-organ transplant recipients,

474

Fungal pneumonia, in human immunodeficiency virus infection, 143

Fungemia, 56Fungi

brain abscess and, 84chronic pneumonia and, 31mucous membrane lesions, 116noncandidal, 59t

Furazolidone, for giardiasis, 427tFuruncular myiasis, 450Fusarium spp., 405Fusobacterium necrophorum, pharyngitis and, 6Fusobacterium species, 364

definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t

GGalactomannan, 381Gallbladder, disorders of, from human

immunodeficiency virus infection, 144-145Ganciclovir

for cytomegalovirus infection, 185for human herpesvirus types 6 and 7, 188for infections, in HSCT, 471

Gangrenous stomatitis (noma), antimicrobial regimens for, 18t-19t

Gas gangrene, 362and Clostridium perfringens, 362

Gastric cancer, risk of, 315Gastric Helicobacter species, 315Gastroenteritis

from astroviruses, 246due to rotaviruses, 205noninflammatory, 100from noroviruses, 244from Salmonella, 324

Gastroesophageal reflux disease, esophagitis from, 98Gastrointestinal anthrax, 296Gastrointestinal problems, trypanosomiasis and, 420Gemella, 287Genital infections, chlamydial, 249-250Genital mycoplasmas, 256Genital (or mucosal) HPV infections, 194Genital skin, lesions of, 116Genital ulcers, caused by syphilis, 351Genome

of hepatitis C virus, 213fof rotaviruses, 205

Gentamicinfor listeriosis, 293for plague, 337for tularemia, 331, 334t

German measles, 209Giardia lamblia, 426-427Giardiasis, 426

prevention of, 427treatment of, 427t

Giemsa-stained blood smears, for malaria, 417Gingivostomatitis, in herpes simplex virus, 179

505In

dex

Glanders, 320-322Glaucomys volans, 262Glomerulonephritis

nonsuppurative poststreptococcal sequelae of, 279-280

from Streptococcus pyogenes, 277Glucocorticoids, for croup, 216Glucose nonfermenting gram-negative bacilli, 349Glycoconjugate vaccine, for group B streptococci, 285Gonorrhea, 305-306Graft-versus-host disease (GVHD), in HSCT, 470-471Gram-negative bacilli, 349-350

acute bacterial arthritis from, 108Gram-negative bacteria, peritonitis and intraperitoneal

abscesses and, 44Gram-negative cocci, 307Gram-negative species, in CSF shunt infections, 88Gram-positive organisms, acute bacterial arthritis from,

108Gram-positive spore-forming bacilli, 298Gram-variable bacilli, 349-350Granulicatella, 287Granuloma inguinale, 348Granulomatous amebic encephalitis (GAE), 415Gravid female jigger flea, 451Gravid ticks, 453Group A streptococcal pharyngitis

antimicrobial therapy for, 9tclinical and epidemiologic findings associated with,

8tsigns and symptoms of, 6

Group A Streptococcus (GAS), 6Group B Streptococcus (GBS), 76, 285Groups C and G streptococci, 287-288Growth factors, for infections, in cancer patients,

465t-466tGuillain-Barré syndrome, foodborne diseases and,

105

HHACEK spp., 59tHAdVs. see Human adenoviruses (HAdVs).Haemophilus ducreyi, 326-327Haemophilus influenzae, 326-327Haemophilus species, 326-327Hand hygiene, 299Handwashing

human parechoviruses and, 239for prevention of norovirus infection, 245

Hantavirus pulmonary syndrome, 231HAT. see Human African trypanosomiasis (HAT).HAV. see Hepatitis A virus (HAV).HBoVs. see Human bocaparvoviruses (HBoVs).HBV. see Hepatitis B virus (HBV).HCMV. see Human cytomegalovirus (HCMV).HCV. see Hepatitis C virus (HCV).HDV. see Hepatitis D virus (HDV).Head, infections of, 17-18

initial empirical antimicrobial regimens for suppurative, 20t-21t

Head lice, 446-447Health care, MRSA from, 268

Health care-acquired hepatitis, 462Health care-acquired pneumonia

antibiotic treatment for, 26guide to empirical choice of antimicrobial agent for

treating adult patients with, 26t-27tHealth care-associated intra-abdominal infections,

42Health care workers (HCWs), hepatitis in, 462Heat, hepatitis A virus and, 240Helicobacter pylori, 315Helminth infections, 445Helminthic lymphadenitis, 95t-96tHematogenous osteomyelitis, acute, 112Hematopoietic stem cell transplantation (HSCT)

cell infusion in, preparation of, 470cells used in, types of, 470complications of, 471donors of, types of, 470outcomes of, 470prophylaxis of, antimicrobial agents for, 471, 472trecipients of

infections in, 470-473viral diseases in, 472-473

Hemolymphatic disease, African trypanosomiasis and, 422

β-hemolytic streptococci, 285Hemorrhagic cystitis, in HSCT, 471Hemorrhagic fever, evaluation of, in returning travelers,

493Hendra virus, 81t-83t, 222Hendra virus subunit vaccine, 223Hepacivirus, 134Hepadnavirus, 130Hepatitis, 130-137

acute, 130chronic, 130diagnostic approach for, 131tHAV, 130HBV, 130-134HCV, 134-136, 135f-136f, 137tHDV, 134health care-acquired, 462HEV, 136-137in injection drug users, 480-481viruses causing, 130-137, 131t

Hepatitis A virus (HAV), 130, 240-241infection, prophylaxis of, 168t-171tpostexposure prophylaxis for, 242tvaccine for, 241t

Hepatitis B vaccines, doses and schedules of, 201tHepatitis B virus (HBV), 130-134, 198-199, 462

chronic, 198diagnosis of, 131, 132tepidemiology of, 130global seroprevalence rates and modes of transmission

of, 199tinfection, prophylaxis of, 168t-171tinterpretation of serologic tests in, 199tprevention of, 134replication of, 198treatment of, 131-134, 132t-133tvirology of, 130

506In

dex

Hepatitis C virus (HCV), 134-136, 212-214, 462genome and viral polyprotein organization of, 213ftreatment-naïve patients in, 213ttreatment of, 135f-136f, 137t

Hepatitis D virus (HDV), 134, 198-199Hepatitis E virus (HEV), 136-137, 247Hepatovirus, 130Hepevirus, 136-137, 247Heptavalent botulinum antitoxin, 361Herpes B virus, 190

postexposure prophylaxis for, 191tHerpes labialis, in herpes simplex virus, 179Herpes simplex encephalitis, 180Herpes simplex virus (HSV), 179-180

esophagitis from, 99tinfection, therapy for, 116

Herpes simplex virus (HSV)-1, 179Herpes simplex virus (HSV)-2, 179Herpes simplex virus (HSV) disease, treatment of,

156t-168tHerpes zoster, 183-184

treatment of, 156t-168tHeterophile antibodies, in infectious mononucleosis, 186Heterophyes heterophyes, 441t-442tHEV. see Hepatitis E virus (HEV).HGA. see Human granulocytotropic anaplasmosis

(HGA).HHV-8. see Human herpesvirus 8 (HHV-8).High-dose intravenous immune globulin, for KD, 454Higher-order bacteria, chronic pneumonia and, 31Histoplasma capsulatum, 393-394

infection, prophylaxis of, 168t-171tHistoplasmosis, 393-394

definition of, 393diagnosis of, 393, 394tepidemiology of, 393in human immunodeficiency virus infection, 143microbiology of, 393prevention of, 394therapy for, 393, 395ttreatment of, 156t-168t

History, for management of bite wounds, 488t-489tHIV. see Human immunodeficiency virus (HIV).HME. see Human monocytotropic ehrlichiosis (HME).hMPV. see Human metapneumovirus (hMPV).Hookworms, 437-438, 438tHordeolum, 129Hospitalization, for management of bite wounds,

488t-489tHost defenses, infections of, in injection drug users, 479House mouse mites, in rickettsialpox, 452HPeVs. see Human parechoviruses (HPeVs).HPV. see Human papillomavirus (HPV).HSV. see Herpes simplex virus (HSV).HTIG. see Human tetanus immune globulin (HTIG).HTLV. see Human T-lymphotropic virus (HTLV).HTLV antibodies, 234HTLV-associated myelopathy (HAM), therapy for, 235Human adenoviruses (HAdVs), 192Human African trypanosomiasis (HAT), 422-423Human bocaparvoviruses (HBoVs), 202

infections of, 202

Human botulinum immune globulin (BabyBIG), 361Human cowpox virus infection, 176Human cytomegalovirus (HCMV), 185Human granulocytotropic anaplasmosis (HGA), 266-267Human herpesvirus

type 6, 188type 7, 188

Human herpesvirus 8 (HHV-8), 189Human immunodeficiency virus (HIV), 81t-83t, 236

cryptosporidiosis in, 431infected patients, with disseminated disease, 373patient with, PCP and, 410and Penicillium marneffei, 407type 1, neurologic diseases caused by, 146zoonoses and, 490

Human immunodeficiency virus (HIV) infection, 138-139

antiretroviral therapy for, 149entry inhibitors for, 154tintegrase inhibitor for, 154tnon-nucleoside reverse-transcriptase inhibitors for,

152tnucleoside and nucleotide reverse-transcriptase

inhibitors for, 150t-151tprotease inhibitors for, 152t-153t

clinical manifestations of, 140gastrointestinal manifestations of, 144-145, 145thepatobiliary manifestations of, 144-145in injection drug users, 481management of opportunistic infections associated

with, 155-156pancreatic manifestations of, 144-145pediatric, 147-148primary, EBV and, 186pulmonary manifestations of, 142-143, 143ttoxoplasmosis and, 424Trichomonas vaginalis and, 428

Human metapneumovirus (hMPV), 219Human monocytotropic ehrlichiosis (HME), 266-267Human or animal bites, initial empirical antimicrobial

regimens for, 20t-21tHuman papillomavirus (HPV), 194

and human immunodeficiency virus infection, 145two main groups of, 194

Human parechoviruses (HPeVs), 239Human parvoviruses, 202Human T-lymphotropic virus (HTLV), 234-235Human T-lymphotropic virus (HTLV)-1, 234Human T-lymphotropic virus (HTLV)-2, 234Human tetanus immune globulin (HTIG), 360Humoral immunity, in rotaviruses, 206Hydrocephalus, from cryptococcosis, 392Hygiene, conjunctivitis and, 123Hymenolepis nana, 443, 444tHypertonic saline aerosols, for bronchiolitis, 24Hypochlorite, hepatitis A virus and, 240Hypopyon, in endophthalmitis, 125

IIbuprofen, 34t-36tIgM antibodies, of arenaviruses, 232IgM viral capsid antigen (VCA) antibodies, 186

507In

dex

Immobilization, for management of bite wounds, 488t-489t

Immune reconstitution, of JC virus, 196Immune reconstitution syndrome

from cryptococcosis, 392from human immunodeficiency virus infection, 140

Immunity, of rotaviruses, 206Immunization

in elderly, 476with live, attenuated mumps virus vaccine, 217for management of bite wounds, 488t-489tfor opportunistic infections associated with human

immunodeficiency virus infection, 155-156for pertussis, 340for rotaviruses, 206for travelers, 491

Immunodiffusion, 399Immunofluorescence assay

indirect, for Rocky Mountain spotted fever, 257for murine typhus, 264of respiratory secretions, 219

Immunofluorescent serologic test, indirect, for Q fever, 260

Immunoglobulin G (IgG)passive immunization with, in measles, 221positive, toxoplasmosis and, 424

Immunoglobulin M (IgM), positive test results of, in toxoplasmosis, 424

Immunoglobulins, for infections, in cancer patients, 465t-466t, 467

Immunohistochemical detectionof Rickettsia prowazekii, 262of Rickettsia typhi, 264of SFG rickettsiae, 257

Immunosuppression, reduction in, in BK virus, 197Impetigo, 90Implant, orthopedic, infections associated with, 113-115Inactivated vaccines

for influenza, 228of poliovirus, 237

Incision, infections of, in injection drug users, 479Indinavir, for human immunodeficiency virus infection,

152t-153tInfant botulism, 361Infants, amebiasis in, 413Infected embryologic cysts, initial empirical

antimicrobial regimens for, 20t-21tInfections

see also specific infectionin asplenic patients, 477-478in cancer patients, 464-469

epidemiology and etiology of, 464prophylaxis of, 464-467, 465t-466trisk factors for, 464, 469t

cardiovascular implantable electronic device, 65caused by nontuberculous mycobacteria, 375-377

definition of, 375diagnosis of, 376epidemiology of, 375microbiology of, 375-376prevention of, 377therapy for, 376-377

caused by P. aeruginosa, 317in elderly, 476head and neck, acute mediastinitis and, 73thuman immunodeficiency virus, 236human metapneumovirus, 219in injection drug users, 479-481internal fixation-associated, 113-115intravascular, 58-59left ventricular assist device, 65of liver and biliary system, 48of nonvalvular cardiovascular devices, 65-66of oral cavity, neck, and head, 17-18orthopedic implant-associated, 113-115pancreatic, 49

incidence and mortality rate in controlled trials with antibiotics and meta-analyses, 51t-53t

in patients with spinal cord injury, 475of pelvis, female, 119periprosthetic joint, 113, 114fprosthetic vascular graft, 65-66rate of, administration and, timing of, 485fin recipients of hematopoietic stem cell transplants,

470-473in returning travelers, 493, 494t-495tfrom rhinovirus, 243rotaviruses, 205-206shunt and drain, of cerebrospinal fluid, 88-89in solid-organ transplant recipients, 474of subcutaneous tissue, 90-91in surgical site, 482transfusion- and transplantation-transmitted, 463uncomplicated, 42urinary tract, 37-38

recommendations for initial therapy of, 39tInfectious arthritis, of native joints, 108-110

empirical therapy for, 109tInfectious mononucleosis, 186Infective endocarditis, 58

preexisting cardiac conditions associated with, 68tprevention of, 67prophylaxis of, 67regimens for antibiotic prophylaxis of, 68t

Infective peritonitis, 42Inflammation, pelvic, in female, 119Inflammatory enteritides, bacterial, 102-103Influenza, 81t-83t, 228Influenza A, prophylaxis of, 168t-171tInfluenza B, prophylaxis of, 168t-171tInfluenza vaccines, 228, 230tInfluenza viruses, 228Inhalational anthrax, 296Inhaled hypertonic saline, 34t-36tInjection drug users, infections in, 479-481Integrase inhibitor, for human immunodeficiency virus

infection, 154tInterferon-γ release assays, 365-366Intermediate uveitis, 127, 128tInternal fixation, infection associated with, 113-115

clinical manifestations of, 115diagnosis of, 113-114microbiology in, 114

Infections (Continued)

508In

dex

pathogenesis of, 114treatment of, 115

Intestinal flukes, 440-441features of, 441t-442t

Intestinal nematodes, 437-438, 438tIntra-abdominal infections, complicated

organisms causing, 44trecommended agents for treatment of, 45t

Intraepithelial neoplasia, human papillomavirus and, 194

Intramuscular regimens, for group A streptococcal pharyngitis, 9t

Intrapartum antibiotic prophylaxis, for group B streptococci, 285, 286t

Intraperitoneal abscesses, 42-47Intravascular devices, percutaneous, infections caused by,

456-457Intravascular infections, 58-59Intravenous acyclovir, for herpes B virus, 190Intravenous catheters, infections caused by, 456Intravenous gamma globulin, for human

metapneumovirus, 219Intravenous ganciclovir, for herpes B virus, 190Intravenous immunoglobulin

for chronic anemia or pure red aplasia, 202for parainfluenza virus, 216

Intravenous pyelography, 38Invasive fungal diseases (IFDs), in cancer patients, 464Iodoquinol

for balantidiasis, 433tfor blastocystosis, 434t

Irrigation, for management of bite wounds, 488t-489tIrritable bowel syndrome, foodborne diseases and, 105Isolation procedures, for infections, in cancer patients,

465t-466tIsoniazid

for infections, in cancer patients, 465t-466tfor tuberculosis, 366, 369t-370t

Itraconazolefor aspergillosis, 384tfor chromoblastomycosis, 387for paracoccidioidomycosis, 402, 403tfor Penicillium marneffei infections, 407for Sporothrix schenckii, 386

Ivacaftor, 34t-36tIvermectin

for infections, in HSCT, 471for lice, 446for scabies, 448for tissue nematodes, 439

Ixodes ricinus, 357

JJapanese encephalitis, 81t-83tJapanese encephalitis (JE) virus, 210Jarisch-Herxheimer reactions, in relapsing fever, 356JC virus infections, treatment of, 156t-168tJC virus (JCV), 81t-83t, 196JCV. see JC virus (JCV).JE virus, 210Jigger flea, gravid female, 451

Joint infections, in injection drug users, 479Joints, native, infectious arthritis of, 108-110

empirical therapy for, 109tJones criteria, 279

KKaposi sarcoma, pulmonary, in human

immunodeficiency virus infection, 143Kaposi’s sarcoma-associated herpesvirus (KSHV), 189Kawasaki disease (KD), 454KD. see Kawasaki disease (KD).Keratitis

associated with viral conjunctivitis, 123microbial, 124

Keratoconjunctivitis, microsporidiosis and, 412Ketoconazole, for paracoccidioidomycosis, 403tKFDV. see Kyasanur Forest disease virus (KFDV).Kidney, impaired function of, foodborne diseases and,

105Killed vaccine, for vesicular stomatitis virus, 224Kingella kingae, 307Klebsiella granulomatis, 348Klebsiella pneumoniae, 48Klebsiella spp., 316KSHV. see Kaposi’s sarcoma-associated herpesvirus

(KSHV).Kyasanur Forest disease virus (KFDV), 210

LLacazia loboi, 407Lacrimal system, infections of, 129β-lactam, for anthrax, 296-297, 297tβ-lactam antibiotics

for S. pneumoniae, 282for Streptococcus anginosus group, 289

Lagomorphs, Francisella tularensis from, 330Lamivudine

for chronic hepatitis B, 200tfor human immunodeficiency virus infection,

150t-151tfor infections

in cancer patients, 465t-466t, 467in HSCT, 471

Large intestine, disorders of, from human immunodeficiency virus infection, 145

Laryngitisacute, 10frequency of, associated with common respiratory

pathogens, 10tLaryngotracheobronchitis, acute, 11Lassa fever, 232-233Latency, in herpes simplex virus, 179Lateral pharyngeal or retropharyngeal space infections,

initial empirical antimicrobial regimens for, 20t-21t

LCMV. see Lymphocytic choriomeningitis virus (LCMV).Left ventricular assist device (LVAD) infections, 65Legionella spp., 59t, 342Legionellosis, 342Legionnaires’ disease, 342-343Leishmania species, 419Leishmaniasis, 419

Internal fixation, infection associated with (Continued)

509In

dex

Leprosy, 371-372clinical manifestations and immunologic spectrum of,

371diagnosis of, 371-372therapy for, 372, 372t

Leptospira species, 354, 355tdefinition of, 354diagnosis of, 354epidemiology of, 354microbiology of, 354prevention of, 354therapy of, 354, 355t

Leptospirosis, 354definition of, 354diagnosis of, 354epidemiology of, 354microbiology of, 354prevention of, 354in returning travelers, 493therapy of, 354, 355t

Lesions, of genital skin and mucous membrane, 116Leuconostoc species, 283-284Leukoencephalopathy, progressive multifocal

human immunodeficiency virus and, 146treatment of, 156t-168t

Leukotriene modifiers, 34t-36tLevofloxacin

for infectionsin cancer patients, 465t-466tin HSCT, 471

for plague, 337Lew and Waldvogel classification, of osteomyelitis, 111LGV. see Lymphogranuloma venereum (LGV).Lice, 446-447Linezolid, 284

for pneumonia, 458-459Listeria monocytogenes, 293-294Listeriosis

clinical settings for, 293, 294tfood safety recommendations for, 294, 295t

Live-attenuated measles vaccine, 221Live-attenuated oral vaccines, of poliovirus, 237Live-attenuated rubella vaccine, 209Live-attenuated vaccines

of arenaviruses, 233for influenza, 228

Live oral vaccines, for prevention of adenoviruses, 193Liver, disorders of, from human immunodeficiency virus

infection, 144Liver biopsies, 212Liver flukes, 440-441

features of, 441t-442tLoiasis, 439Loperamide, for diarrhea, in travelers, 491Lopinavir, for human immunodeficiency virus infection,

152t-153tLouping ill virus, 81t-83tLouse-borne typhus, 262Lower urinary tract localization test, for prostatitis, 121tLung abscess, bacterial, 30Lung flukes, 440-441

features of, 441t-442t

Lutzomyia sand fly, 419LVAD infections. see Left ventricular assist device

(LVAD) infections.Lyme borreliosis, 357

definition of, 357diagnosis of, 357epidemiology of, 357microbiology of, 357prevention of, 357therapy for, 357tick-transmitted, 453

Lyme disease, 357Lymph nodes, inflammation of, 94Lymphadenitis, 94

forms of, 95t-96tfrom Mycobacterium avium complex, 373

Lymphadenopathy, persistent generalized, from human immunodeficiency virus infection, 140

Lymphangitis, 94causes of, 97t

Lymphatic channels, inflammation of, 94Lymphocutaneous disease, from Sporothrix schenckii, 386Lymphocyte infusion, in HSCT, 470Lymphocytic choriomeningitis, 232-233Lymphocytic choriomeningitis virus (LCMV), 232Lymphocytic interstitial pneumonitis, in human

immunodeficiency virus infection, 143Lymphogranuloma venereum (LGV), 249-250

clinical characteristics of, 251t-252ttherapy for, 116

Lymphomaprimary CNS, human immunodeficiency virus and,

146pulmonary, in human immunodeficiency virus

infection, 143Lyngbya or Cyanobacteria exposure syndromes, harmful

algal blooms and, 436t

MMacrolides

for atypical pneumonia, 255for ureaplasmas, 256

Maculopapular eruptions, mites in, 452Maculopapular rashes, in acutely ill patients, 3-4Madurella mycetomatis, 388Magnetic resonance imaging (MRI)

for brain abscess, 84-85for subdural empyema, 86

Major commensal microorganisms, 41tMajor community-acquired pathogens, 41tMalaria, 417-418

prevention of, in travelers, 491in returning travelers, 493

Malassezia furfur, 406Male condoms, in human papillomavirus, 195Malignant otitis externa, 13Malnutrition, cryptosporidiosis in, 431Mandibular osteomyelitis, initial empirical antimicrobial

regimens for, 20t-21tMaraviroc, for human immunodeficiency virus infection,

154tMarburg hemorrhagic fevers, 227

510In

dex

Marburg viral diseases, 227Mass spectrometry, matrix-assisted laser desorption/

ionization time-of-flight, for Capnocytophaga, 344Mastoiditis, 12-13

definition of, 12diagnosis of, 13epidemiology of, 12microbiology of, 13prevention of, 13therapy of, 13

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry

for Capnocytophaga, 344for diagnosis of Nocardia infection, 378for gram-negative and gram-variable bacilli, 349

Maxillofacial trauma, initial empirical antimicrobial regimens for, 20t-21t

Me Tri virus, 81t-83tMeasles, 220

vaccination, 220Measles virus, 220-221Mebendazole, for tissue nematodes, 439Median sternotomy, acute mediastinitis and, 73tMediastinitis, 72-74Mediastinum, anatomic boundaries and divisions of, 73fMefloquine, for malaria prevention, in travelers, 491Melioidosis, 320-322

antibiotic therapy for, 322tclinical presentations and outcomes of, 321tdefinition of, 320diagnosis of, 320epidemiology of, 320microbiology of, 320prevention of, 322risk factors for, 321ttherapy for, 322

Men, burn in, 486Menangle virus, 222Meningeal infections, treatment of, 156t-168tMeningitis

acute, 75-77anthrax, 296chronic, 78

diagnostic tests for, 79tdifferential diagnosis of, 79t

cryptococcal, treatment of, 156t-168tH. influenzae type b, 326

Meningococcal conjugate vaccine, 77Meningococcal disease, Neisseria meningitidis in, 301,

302fMeningococcal meningitis, antibiotic treatment for, 302tMeningococcemia

antibiotic treatment for, 302tNeisseria meningitidis in, 301

MERS. see Middle East respiratory syndrome (MERS).Metabolic abnormalities, from human immunodeficiency

virus infection, 140Metagonimus yokogawai, 441t-442tMethicillin-resistant Staphylococcus aureus (MRSA), 268,

269fdecontaminating scheme for, 274trisk factors for, 458

Methicillin-resistant Staphylococcus aureus pneumonia, treatment of, 156t-168t

Methicillin-susceptible Staphylococcus aureus (MSSA), evolution of, 269f

Metronidazolefor amebiasis, 414tfor balantidiasis, 433tfor blastocystosis, 434tfor Clostridium difficile infections, 358-359for giardiasis, 427tfor Trichomonas vaginalis, 428

Micafungin, for aspergillosis, 384tMicrobes, in appendicitis, 55Microbial conjunctivitis, 122-123Microbial keratitis, 124Microsporidiosis, 412Middle East respiratory syndrome (MERS), 215Milk, unpasteurized, Q fever from, 260Mite-borne rickettsiosis, 265Mites, 452

vesicular fever with eschar from, 259Mixtures of benzathine and procaine penicillin G, for

group A streptococcal pharyngitis, 9tMobile genetic elements (MGEs), Staphylococcus aureus

and, 268, 273t-274tMold endophthalmitis, 126Molluscum contagiosum infection, 178Monkeypox, 81t-83tMonkeypox virus, 176Monoclonal antibody prophylaxis, for bronchiolitis, 24Monotherapy, for bacterial keratitis, 124Moraxella catarrhalis, 307Morphine-mediated depression, in injection drug users,

479Mosquitoes, Francisella tularensis from, 330Mother-to-child transmission (MTCT), of human

immunodeficiency virus, 147Moxifloxacin, 319

for bites, 487, 489for genital mycoplasmas, 256

MTCT. see Mother-to-child transmission (MTCT).Mucocutaneous candidiasis, treatment of, 156t-168tMucormycosis, agents of, 385Mucosal leishmaniasis, 419Mucositis, in HSCT, 471Mucous membrane, lesions of, 116Multidrug-resistant tuberculosis (MDR-TB), 365Multifocal leukoencephalopathy, progressive, treatment

of, 156t-168tMultiresistant organisms, in SCI units, 475Mumps, 217Mumps virus, 81t-83t, 217Muriform cells, 387Murine typhus, 264Murray Valley encephalitis virus, 81t-83tMycetoma, 388-389Mycobacteria

intermediately growing, 375-376therapy for, 377

nontuberculous, infections caused by, 375-377rapidly growing, 375

therapy for, 376-377

511In

dex

slowly growing, 376therapy for, 377

Mycobacterial pneumonia, in human immunodeficiency virus infection, 142-143

Mycobacterium abscessus, 375Mycobacterium avium complex, 373-374

clinical manifestations and diagnosis of, 373microbiology and epidemiology of, 373prevention of, 374treatment of, 373, 374t

Mycobacterium avium complex (MAC) disease, disseminated

prophylaxis of, 168t-171ttreatment of, 156t-168t

Mycobacterium chelonae, 376Mycobacterium fortuitum, 376Mycobacterium genavense, 376Mycobacterium gordonae, 376Mycobacterium leprae, 371-372Mycobacterium marinum, 375Mycobacterium smegmatis, 376Mycobacterium tuberculosis, 69, 365-366

diagnosis of, 366drug regimens for, 367tepidemiology of, 365first-line tuberculosis medications for, 369t-370thuman immunodeficiency virus infection and,

142-143immunology and pathogenesis of, 365lymphadenitis from, 94microbiology of, 365prevention of, 366prophylaxis of, 168t-171ttherapy for, 366

latent infection, 366treatment of, 156t-168t

Mycoplasma genitalium, 256urethritis from, 117

Mycoplasma hominis, 256Mycoplasma pneumoniae, 255Mycoplasmas, genital, 256Mycoses, superficial, 400Mycotic aneurysms, in injection drug users, 480Mycotic lymphadenitis, 95t-96tMyelopathy, vacuolar, human immunodeficiency virus

and, 146Myiasis, 450Myocarditis, 69

infectious causes of, 70tMyonecrosis, 92-93Myositis, 92-93

NNAAT. see Nucleic acid amplification test (NAAT).Naegleria fowleri, 415-416Nafcillin, for Staphylococcus epidermidis, 275-276Narrow-spectrum therapy, for myonecrosis, 92-93Nausea, vomiting and noninflammatory diarrhea,

100-101Nebulized epinephrine, for croup, 216Necator, 437, 438t

Neck, infections of, 17-18initial empirical antimicrobial regimens for

suppurative, 20t-21tNecrosis

pancreatic, 50tsterile, 49

retinal, acute, 127Necrotizing fasciitis, 90-91Neisseria gonorrhoeae, 301, 305-306

epididymitis from, 120pelvic inflammatory disease from, 119urethritis from, 117

Neisseria meningitidis, 301-303Nelfinavir, for human immunodeficiency virus infection,

152t-153tNematodes

intestinal, 437-438, 438tin tissue, 439

Neoehrlichia mikurensis, 266Neonatal infections, in herpes simplex virus, 180Neonate, conjunctivitis in, 122Neurobrucellosis, treatment of, 329tNeurocognitive disorder, human immunodeficiency

virus and, 146Neurocysticercosis, 443Neurodegenerative diseases, transmissible, 248Neurologic diseases, caused by human

immunodeficiency virus, 146Neuropathy, nucleoside, human immunodeficiency virus

and, 146Neurotoxic shellfish poisoning, harmful algal blooms

and, 436tNeutralizing antibodies, in rotaviruses, 206Neutropenia, 464

febrile, management of, 467-469, 467f-468f, 469tNeutropenic enterocolitis, 56Nevirapine, for human immunodeficiency virus

infection, 152tNew World alphaviruses, 207Nifurtimox, for T. cruzi, 421Nipah virus, 81t-83t, 222Nitazoxanide

for blastocystosis, 434tfor cryptosporidiosis, 431for cyclosporiasis, 433tfor giardiasis, 427t

Nocardia brasiliensis, 388Nocardia species, 378-379

clinical manifestations of, 378definition of, 378diagnosis of, 378microbiology and epidemiology of, 378therapy and follow-up, 379, 379t

Nocardial brain abscess, 84Nodular lesions, in acutely ill patients, 3-4Non-nucleoside reverse-transcriptase inhibitors, for

human immunodeficiency virus infection, 152tNoncandidal fungi, 59tNoncardiac vascular infections, in injection drug users,

480Nongonococcal urethritis, clinical characteristics of,

251t-252t

Mycobacteria (Continued)

512In

dex

Noninfectious causes, of chronic pneumonia, 31Noninfectious respiratory disorders, in human

immunodeficiency virus infection, 143Noninflammatory diarrhea, with nausea and vomiting,

100-101Noninflammatory gastroenteritides, 100Noninvasive liver tests, 212Nonpharmacologic therapies, for chronic fatigue

syndrome, 172Nontreponemal antibody tests, for syphilis, 351Nontyphoidal salmonellosis, 324Nonvalvular cardiovascular devices, infections of, 65-66Noroviruses, 244-245Norwegian scabies, 448-449Nosocomial microorganisms, 41tNosocomial pneumonia, 458-459Nosocomial urinary tract infections, 460-461Nucleic acid amplification assays, for enteric fever, 104Nucleic acid amplification test (NAAT), for Chlamydia

pneumoniae, 254Nucleoside and nucleotide reverse-transcriptase

inhibitors, for human immunodeficiency virus infection, 150t-151t

Numbered enteroviruses (EV-D68), 238Nutritionally variant streptococci, 59t, 287-288

OOcular infections, in injection drug users, 481Ocular larva migrans, definition of, 445Odontogenic infections, initial empirical antimicrobial

regimens for, 20t-21tOld World alphaviruses, 207Onchocerciasis, 439Open reading frames (ORFs), in hepatitis E virus, 247Opioids, effects of, in injection drug users, 479Opisthorchis felineus, 441t-442tOpisthorchis viverrini, 441t-442tOpportunistic infections

acquired immunodeficiency syndrome (AIDS)-related, 155

treatment of, 156t-168tmanagement of, associated with human

immunodeficiency virus infection, 155-156Oral antipseudomonal antibiotics, 34t-36tOral cavity, infections of, 17-18Oral corticosteroids, 34t-36tOral disease, from human immunodeficiency virus

infection, 140Oral mucositis, in immunocompromised hosts,

antimicrobial regimens for, 18t-19tOral N-acetylcysteine, 34t-36tOral therapy, for cutaneous infections, 91Orbit, infections of, 129Orbiviruses, 203Orchitis, 120Organ donors, transfusion- and transplantation-

transmitted infections in, 463Orientia tsutsugamushi, 265Orofacial infections

antimicrobial regimens for various odontogenic and nonodontogenic, 18t-19t

in herpes simplex virus, 179

Oropharyngeal candidiasis, treatment of, 156t-168tOroya fever, 346Orthohepadnavirus, 130Orthopedic implant, infections associated with,

113-115Orthopoxviruses, 176-177Orthoreoviruses, 203Osteomyelitis, 111-112

antimicrobial therapy for, 112textension of, from prevertebral space infection,

initial empirical antimicrobial regimens for, 20t-21t

Otitis externa, 12-13definition of, 12diagnosis of, 13epidemiology of, 12microbiology of, 12prevention of, 13therapy of, 13

Otitis media, 12-13, 281-282definition of, 12diagnosis of, 13epidemiology of, 12Haemophilus influenzae and, 326microbiology of, 12Moraxella catarrhalis causing, 307prevention of, 13therapy of, 13

Otogenic infections, initial empirical antimicrobial regimens for, 20t-21t

Outbreak, of foodborne diseases, 105Oxacillin, for Staphylococcus epidermidis, 275-276

PPain

in eye, in endophthalmitis, 125internal fixation-associated infection and, 115

Palivizumab, for respiratory syncytial virus, 218Pancreas, disorders of, from human immunodeficiency

virus infection, 144-145Pancreatic abscess, 49, 50tPancreatic infection, 49

incidence and mortality rate in controlled trials with antibiotics and meta-analyses, 51t-53t

Pancreatic necrosis, 50tsterile, 49

Panuveitis, 127, 128tPap smear, for cervical cancer, 194-195Papillomaviruses, 194-195Paracoccidioides brasiliensis, 402Paracoccidioides lutzii, 402Paracoccidioidomycosis, 402

clinical manifestations of, 402microbiology and epidemiology of, 402treatment of, 402, 403t

Paragonimus westermani, 441t-442tParainfluenza viruses (PIV), 216Paralytic rabies, 225Paralytic shellfish poisoning, harmful algal blooms and,

436tParamyxoviruses, zoonotic, 222-223Parapoxvirus infections, 178

513In

dex

Parasiteschronic pneumonia and, 31Legionella spp. as, 342noninflammatory gastroenteritis from, 100

Parenteral therapyfor cutaneous infections, 91for gonorrhea, 305, 306t

Paromomycinfor amebiasis, 413, 414tfor blastocystosis, 434tfor giardiasis, 427t

Parvovirus B19 (B19V), 202infection of, 202

Passive immunization, with immunoglobulin G, in measles, 221

Pasteurella species, 335-336, 336tPathogenic vibrios, 312-313Pathogens

causing foodborne illnesses, 105causing microbial keratitis, 124

Patient factors, in surgical site infections, 482, 483tPatient population, of burn, 486PCP. see Pneumocystis pneumonia (PCP).PCR. see Polymerase chain reaction (PCR).Pediarix, 201tPediatric epiglottitis, 15

clinical manifestations of, 15therapy for, 16

Pediculosis, 446-447Pediculosis capitis. see Head lice.Pediculosis corporis. see Body lice.Pediculus humanus corporis, 262Pediococcus, 287Pegylated interferon-α (PEG IFN-α), for chronic

hepatitis B, 200tPelvic inflammatory disease

from Chlamydia trachomatis, clinical characteristics of, 251t-252t

in female, 119Pelvis, female, infections of, 119Penetrating trauma, clostridial myonecrosis and, 92Penicillin, 76, 285

for Pasteurella species, 335for S. pyogenes infections, 278

Penicillin-allergic patients, antimicrobial therapy for group A streptococcal pharyngitis in, 9t

Penicillin/β-lactamase inhibitor, for Capnocytophaga, 345

Penicillin G, for syphilis, 352Penicillin V, for group A streptococcal pharyngitis, 9tPenicillin VK, for infections, in HSCT, 471Penicillium marneffei, 407Pentamidine, aerosolized, for infections, in cancer

patients, 465t-466tPeptic ulceration, 315Percutaneous intravascular devices, infections caused by,

456-457Pericarditis, 69-70

infectious causes of, 71tpurulent, 70tuberculous, 70

Perinatal human immunodeficiency virus infection, 147

Perinatal infections, chlamydial, 249-250Periocular infections, 129Periodontitis, antimicrobial regimens for, 18t-19tPeripheral blood films, positive, tropical diseases with, in

returning travelers, 493Peripheral blood stem cells, in HSCT, 470Peripheral leukocytosis, in epiglottitis, 15Peripheral nervous system, human immunodeficiency

virus and, 146Periprosthetic joint infection (PJI), 113

treatment algorithm for, 113, 114fPeritoneal dialysis, antibiotic dosage for peritonitis

during, 46tPeritonitis, 42

antibiotic dosage for, during peritoneal dialysis, 46tprimary, 42, 44-45, 45t

prophylaxis, 47secondary, 42-43

causes of, 43ttertiary, 42

Permethrin, for scabies, 448Persistent generalized lymphadenopathy, from human

immunodeficiency virus infection, 140Person-to-person transmission, of arenaviruses, 233Pertussis, 339Pertussis toxin (PT), 339Pfiesteria-associated syndrome, harmful algal blooms

and, 436tPhaeohyphomycosis, 405Pharmacologic therapies, for chronic fatigue syndrome,

172Pharyngitis, 6-7

acute, microbial causes of, 7tin herpes simplex virus, 179modified Centor score and culture management

approach for, 8tstreptococcal, 277

Phialophora verrucosa, 387Phlebotomus sand fly, 419Phthiriasis, 446Physical examination, for management of bite wounds,

488t-489tPicobirnaviruses, 246Picornaviridae, 243Pinworm, 437-438, 438tPIV. see Parainfluenza viruses (PIV).Plague, 337

pneumonic, treatment, 338tPlasmodium falciparum, 417Plasmodium knowlesi, 417Plasmodium malariae, 417Plasmodium ovale, 417Plasmodium species, 417-418Plasmodium vivax, 417Pleconaril, 238Pleural effusion, 28

transudative, features differentiating exudative from, 29t

Pleural fluid, Pasteurella in, 335Pleuropulmonary infections, from Clostridium, 362PML. see Progressive multifocal leukoencephalopathy

(PML).

514In

dex

Pneumococcal polysaccharide-protein conjugate vaccine (PCV13), 282

Pneumocystis jirovecii, 410prophylaxis against, 464-467

Pneumocystis jirovecii pneumonia (PCP), 142Pneumocystis pneumonia (PCP), 410

prophylaxis of, 168t-171ttreatment of, 156t-168t

Pneumocystis species, 410-411definition of, 410diagnosis of, 410epidemiology of, 410prevention of, 411treatment of, 410

Pneumolysin, 281Pneumonia

acute, 25-26atypical, 255bacterial, in human immunodeficiency virus infection,

142from Chlamydia pneumoniae, 254from Chlamydia trachomatis, clinical characteristics of,

251t-252tchronic, 31-32community-acquired, Legionnaires’ disease and, 342in elderly, 476fungal, in human immunodeficiency virus infection,

143in injection drug users, 480melioidosis and, 320methicillin-resistant Staphylococcus aureus, treatment

of, 156t-168tmycobacterial, in human immunodeficiency virus

infection, 142nosocomial, 458-459Pneumocystis

prophylaxis of, 168t-171ttreatment of, 156t-168t

Pneumocystis jirovecii, 142Pseudomonas, treatment of, 156t-168tpsittacosis causing, 253SCI and, 475Streptococcus pneumoniae in, 281tularemia, 333fviral, in human immunodeficiency virus infection, 143

Pneumonic plague, treatment, 338tPoliomyelitis, 237Poliovirus, 237Polymerase chain reaction amplification, of rickettsial

nucleic acids, 257Polymerase chain reaction assay

for Coxiella burnetii, 260for human T-lymphotropic virus, 234reverse-transcriptase, for astroviruses, 246for Rickettsia prowazekii, 262for scrub typhus, 265

Polymerase chain reaction (PCR)for adenovirus diagnosis, 192for herpes B virus diagnosis, 190for treponemes diagnosis, 351for VZV diagnosis, 183

Polymorphonuclear leukocytes, urethritis and, 117

Polyneuropathy, distal sensory, human immunodeficiency virus and, 146

Polysaccharide vaccine, 10423-valent, 282

Polysaccharides, capsular, of Staphylococcus aureus, 270t-271t

Pontiac fever, 342-343Porphyromonas species, 364

definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t

Posaconazolefor aspergillosis, 384tfor chromoblastomycosis, 387for infections

in cancer patients, 464, 465t-466tin HSCT, 471

Positive immunoglobulin G (IgG), toxoplasmosis and, 424

Post-cardiac surgery mediastinitis, 72Post-Giardia lactose intolerance, 426Post-traumatic endophthalmitis, 125Posterior reversible encephalopathy syndrome, in HSCT,

471Posterior uveitis, 127, 128tPostexposure prophylaxis

for hepatitis A virus, 242tfor herpes B virus, 191tfor rabies, 225

Postinjection endophthalmitis, 125Postnatal rubella, 209Postsurgical wound infections, initial empirical

antimicrobial regimens for, 20t-21tPotassium iodide, for Sporothrix schenckii, 386Powassan virus, 81t-83tPoxviruses, infecting humans, 178Praziquantel

for cestodes, 443for trematodes, 441, 441t-442t

Prednisone, for PCP, 410Preexposure prophylaxis, for rabies, 226Pregnancy

hepatitis E virus during, 247syphilis during, 351toxoplasmosis in, 424

Preseptal cellulitis, 129Pressure sores, infection of, SCI and, 475Prevotella species, 364

brain abscess and, 84definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t

Primary amebic meningoencephalitis (PAM), patients with, 415-416

Primary genital infections, in herpes simplex virus, 179Primary lung abscess, 30Primary peritonitis, 42, 45t

prophylaxis, 47

515In

dex

Primary varicella infection (chickenpox), treatment of, 156t-168t

Prion diseases, of central nervous system, 248Prion protein (PrP), 248Prions, 248Procedural factors, in surgical site infections, 482, 483tProceduralist factors, in surgical site infections, 482, 483tProctitis, from Chlamydia trachomatis, clinical

characteristics of, 251t-252tProgressive multifocal leukoencephalopathy (PML), 196

treatment of, 156t-168tProgressive outer retinal necrosis (PORN), treatment of,

156t-168tProguanil, for malaria prevention, in travelers, 491Prophylactic antibiotics, for infections, in asplenic

patients, 478Prophylaxis

for hepatitis A virus, 242tfor human immunodeficiency virus, 139of infection, in cancer patients, 464-467, 465t-466tfor Pasteurella species, 336for pertussis, 340for preventing first episode of opportunistic disease,

168t-171tPropionibacterium acnes, in periprosthetic joint infection,

113Proptosis, orbital infections and, 129Prostatitis, 120

classification of, 121tProsthetic valve endocarditis, 63-64

caused by staphylococci, therapy for, 64tindications for consideration of surgical intervention,

64tProsthetic vascular graft infections (PVGIS), 65-66Protease inhibitors, for human immunodeficiency virus

infection, 152t-153tProtein-synthesis inhibitors, for infections associated

with toxic shock syndrome, 91Proteins, sortase-mediated cell wall-associated,

Staphylococcus aureus MSCRAMMs belonging to, 271t-272t

Proteus spp., 316Prototheca spp., 408Protozoa, noninflammatory gastroenteritis from, 100Protozoan lymphadenitis, 95t-96tPseudallescheria boydii, 404Pseudocyst, acute, 50tPseudomonas aeruginosa, 12, 317

cystic fibrosis and, 33Pseudomonas pneumonia, treatment of, 156t-168tPseudomonas species, 317Psittacosis, 253Pubic lice, 446-447Pulmonary disease

in human immunodeficiency virus infection, 142-143, 143t

from Mycobacterium avium complex, 373from Sporothrix schenckii, 386

Pulmonary infectionsfrom herpes simplex virus, 180in injection drug users, 480

Pulmonary tuberculosis, in injection drug users, 480

Purulent pericarditis, 70PVGIS. see Prosthetic vascular graft infections (PVGIS).Pyogenic liver abscess, 48Pyomyositis, 92Pyrazinamide, for tuberculosis, 366, 369t-370tPyrimethamine, for toxoplasmosis, 425Pyrogenic exotoxin B, 277Pythium spp., 409

QQ fever, 59t, 260-261Quaternary ammonium formulations, hepatitis A virus

and, 240Quellung reaction, 281Quinacrine, for giardiasis, 427tQuinine, for Babesia microti, 429, 430tQuinolones, for genital mycoplasmas, 256Quinupristin-dalfopristin, 284

RRabies, 225-226Radiographs, for management of bite wounds, 488t-489tRaltegravir, for human immunodeficiency virus

infection, 154tRapid molecular tests, for Capnocytophaga, 344Rash

acutely ill patient with, 3-4from murine typhus, 264Neisseria meningitidis in, 301from Rocky Mountain spotted fever, 257

Rat-bite fever, 341Recombivax HB, 201tRed blood cell, exchange transfusion of, for babesiosis,

430, 430tReinfection

in human metapneumovirus, 219in respiratory syncytial virus, 218in rotaviruses, 205

Relapsing fever, due to Borrelia species, 356Renal disease, from human immunodeficiency virus

infection, 140Reoviruses, 203Replication

in Kaposi’s sarcoma-associated herpesvirus, 189of rotaviruses, 205

Reporting, in management of bite wounds, 488t-489tRespiratory diseases, bacterial, treatment of, 156t-168tRespiratory droplets, transmission of adenoviruses, 192Respiratory syncytial virus (RSV), 218

bronchiolitis and, 24Respiratory tract colonization, of Burkholderia

cenocepacia, 319Respiratory viruses, in solid-organ transplant recipients,

474Retinal necrosis, acute, 127Retinochoroiditis, toxoplasmosis and, 424Reverse-transcriptase polymerase chain reaction

(RT-PCR), in diagnosis of Filovirus infection, 227Rhabdoviruses, 225-226Rheumatic fever

nonsuppurative poststreptococcal sequelae of, 279-280from Streptococcus pyogenes, 277

516In

dex

Rhinocladiella aquaspersa, 387Rhinogenic infections, initial empirical antimicrobial

regimens for, 20t-21tRhinosporidium seeberi, 409Rhinovirus, 243Rhodococci, 292Rhodococcus equi, 292Ribavirin

for arenaviruses, 232for Bunyavirus infections, 231for hepatitis C virus, 135for human metapneumovirus, 219monotherapy, for chronic hepatitis E, 247for parainfluenza virus, 216

Rickettsia akari, 259Rickettsia felis, 257Rickettsia prowazekii, 262Rickettsia rickettsii, 257-258Rickettsia typhi, 264Rickettsiae, lymphadenitis and, 95t-96tRickettsialpox, 259

house mouse mites in, 452Rickettsiosis

mite-borne, 265in returning travelers, 493

Rifabutin, for tuberculosis, 369t-370tRifampin

for brucellosis, 329tfor coagulase-negative staphylococcal infections, 276for tuberculosis, 366, 369t-370t

Rifapentine, for tuberculosis, 369t-370tRift Valley fever virus, 81t-83tRilpivirine, for human immunodeficiency virus infection,

150t-152tRing worm, 400Ritonavir, for human immunodeficiency virus infection,

152t-153tRMSF. see Rocky Mountain spotted fever (RMSF).RNA tests, of hepatitis C virus, 212Rocio virus, 81t-83tRocky Mountain spotted fever (RMSF), 257-258Rodents, Francisella tularensis from, 330Rose-Bengal card agglutination test, for brucellosis, 328Rotaviruses, 205-206Rothia, 287Roundworms, 437-438, 438tRSV. see Respiratory syncytial virus (RSV).RT-PCR. see Reverse-transcriptase polymerase chain

reaction (RT-PCR).Rubella

congenital, 209postnatal, 209

Rubella vaccine, 209Rubella virus, 81t-83t, 209Rubeola, 220-221

SSalmonella flagellin, inflammatory enteritides from,

102Salmonella species, 324Salmonellosis, 324

treatment of, 156t-168t

San Joaquin Valley fever, 398Sapoviruses, 244-245Saquinavir, for human immunodeficiency virus infection,

152t-153tSarcocystis species, 432-433Sarcoptes scabiei var. hominis, 448SARS. see Severe acute respiratory syndrome (SARS).Scabies, 448-449Scabies mite, 448Scedosporium prolificans, 404Schistosoma guineensis, 441t-442tSchistosoma haematobium, 441t-442tSchistosoma intercalatum, 441t-442tSchistosoma japonicum, 441t-442tSchistosoma mansoni, 441t-442tSchistosoma mekongi, 441t-442tSchistosomes, 440-441

features of, 441t-442tSchistosomiasis, in returning travelers, 493Scratches

Pasteurella infection from, 335rat-bite fever from, 341

Screeningof blood and organ donors, for Chagas’ disease,

421for Chlamydia trachomatis, 250of donor, for transfusion- and transplantation-

transmitted infections, 463test, for human immunodeficiency virus, 138-139,

139tScrub typhus, 265

Asian scrub typhus chiggers in, 452Seadornaviruses, 204Secondary peritonitis, 42-43

causes of, 43tSelenium sulfide, for dermatophytosis, 400Sennetsu neorickettsiosis, 266Sepsis, 40

from Capnocytophaga, 344Septic bursitis, 110Septic shock, 40

empirical antibiotic options for, 41tSeptic thrombophlebitis, in injection drug users, 480Sequential urine cultures, for prostatitis, 121tSerologic assays

for enteric fever, 104in toxoplasmosis, 424

Serologic tests, in hepatitis B, 199tSerology, for Chlamydia pneumoniae, 254Severe acute pancreatitis, 50tSevere acute respiratory syndrome (SARS), 215Severe sepsis, 40

empirical antibiotic options for, 41tSexually transmitted diseases, in injection drug users,

481Shellfish, harmful algal blooms in, 435Shigella, 325

inflammatory enteritides from, 102Shigellosis, 325Shunt infections, of cerebrospinal fluid, 88-89Sialadenitis, antimicrobial regimens for, 18t-19tSinusitis, 14

517In

dex

Skingenital, lesions of, 116infections of, 90-91

in injection drug users, 479lesions, in acutely ill patients, 3

Skin biopsy, for leprosy, 371Skin slit smear, for leprosy, 371Sleeping sickness, 422-423Small intestine, disorders of, from human

immunodeficiency virus infection, 145Snowshoe hare virus, 81t-83tSofosbuvir, for hepatitis C virus, 135Soft tissue infections, 90-91

in injection drug users, 479Solid-organ transplant recipients, infections in, 474Solvents, hepatitis A virus and, 240South American hemorrhagic fevers, 232-233Spinal cord, human immunodeficiency virus and, 146Spinal cord injury (SCI), infections in, 475Spinal epidural abscess, in injection drug users, 481Spirillum minus, 341Spirometra mansonoides, 444tSplenectomy, for splenic abscess, 54Splenic abscess, 54

in injection drug users, 481Spondylodiskitis, 111Spore-forming bacilli, gram-positive, 298Sporothrix schenckii, 386Spotted fever group (SFG) rickettsiae, 257-258Sprue, tropical, 107Sputum, Pasteurella in, 335Squirrels, flying, Rickettsia prowazekii in, 262St. Louis encephalitis (SLE) virus, 210Staphylococcal species, in CSF shunt infections, 88Staphylococcal toxic shock syndrome, 268-269Staphylococci

coagulase-negative, 275-276prosthetic valve endocarditis caused by, therapy for,

64tStaphylococcus aureus, 58, 268-269

brain abscess and, 84CLABSIs, incidence of, 456cystic fibrosis and, 33definition of, 268diagnosis of, 268epidemiology of, 268epidural abscess and, 86infection with, in injection drug users, 479-480lymphadenitis from, 94methicillin-resistant, 268, 269f

decontaminating scheme for, 274trisk factors for, 458

methicillin-susceptible, 269fmicrobiology of, 268mobile genetic elements in, 273t-274tMSCRAMMs, 271t-272tpathogenesis of, extracellular factors involved in,

270t-271tprevention of, 269pyomyositis from, 92response to global regulatory elements during

bacterial growth, 270t-271t

sinusitis and, 14superficial cutaneous infection from, 90therapy for, 268-269

Staphylococcus epidermidis, 275-276Staphylococcus haemolyticus, 275Staphylococcus lugdunensis, 275Staphylococcus saprophyticus, 275Stavudine, for human immunodeficiency virus infection,

150t-151tStenotrophomonas maltophilia, 318-319Sterile pancreatic necrosis, 49Stomach, disorders of, from human immunodeficiency

virus infection, 144Streptobacillus moniliformis, 341Streptococcal pharyngitis, 277Streptococcal toxic shock syndrome, 277Streptococci

brain abscess and, 84group A, 279

myonecrosis from, 92group B, 285

Streptococcus agalactiae, 285Streptococcus anginosus group, 289Streptococcus bovis group, 283Streptococcus gallolyticus group, 283-284Streptococcus iniae, 287Streptococcus pneumoniae, 281-282

infection, prophylaxis of, 168t-171tsinusitis and, 14

Streptococcus pyogenes, 277-278Streptococcus suis, 287Streptolysin O, 277Streptolysin S, 277Streptomycin

doxycycline with, for brucellosis, 328, 329tfor plague, 337for tularemia, 331, 334t

Strongyloides, 437-438, 438tStye, 129Subacute faucial infection, 290Subcutaneous tissue, infections of, 90-91Subdural empyema, 86-87Superantigens, of Staphylococcus aureus, 270t-271tSupportive therapy, for noroviruses, 244Suppurative cavernous sinus thrombosis, initial empirical

antimicrobial regimens for, 20t-21tSuppurative cervical adenitis, initial empirical

antimicrobial regimens for, 20t-21tSuppurative intracranial thrombophlebitis, 86-87Suppurative jugular thrombophlebitis, initial empirical

antimicrobial regimens for, 20t-21tSuppurative lymphadenitis, 94Suppurative orofacial odontogenic infections, initial

empirical antimicrobial regimens for, 20t-21tSuppurative parotitis, antimicrobial regimens for, 18t-19tSuppurative thyroiditis, initial empirical antimicrobial

regimens for, 20t-21tSupragingival dental plaque, and dental caries

prevention, antimicrobial regimens for, 18t-19tSurface proteins, of Staphylococcus aureus, 270t-271tSurgical antimicrobial prophylaxis, 482, 484f-485f

Staphylococcus aureus (Continued)

518In

dex

Surgical site infections (SSIs)antimicrobial prophylaxis and, 482prevention of, 482, 483t-484trisk factors for, 482, 483tsurveillance of, 482

Sustained virologic response (SVR), 135-136Swimmer’s ear, 13Swine influenza, 228Syphilis, 351-352

ocular, uveitis and, 127prophylaxis of, 168t-171ttherapy for, 116

Systemic antibiotics, for empyema, 28Systemic exertion intolerance disease, 172

IOM diagnostic criteria for, 173t

TTachyzoites, of Toxoplasma, 424Taenia multiceps, 444tTaenia saginata, 443, 444tTaenia solium, 443, 444tTapeworms. see Cestodes.TaqMan Array Card, 103Tdap, for pertussis, 340Telaprevir, for hepatitis C virus, 135fTelbivudine, for chronic hepatitis B, 200tTenofovir

for chronic hepatitis B, 200tfor hepatitis B virus, 132for human immunodeficiency virus infection, 150t-151tfor infections, in HSCT, 471

Terbinafine, for chromoblastomycosis, 387Tertiary peritonitis, 42Tetanospasmin, 360Tetanus, 360Tetanus prophylaxis

for myiasis, 450for tungiasis, 451

Tetracyclinefor atypical pneumonia, 255for balantidiasis, 433tfor conjunctivitis, 123for enteropathy, 107for ureaplasmas, 256

Therapeutics, for orthopoxvirus infections, 176Thrombophlebitis, suppurative intracranial, 86-87Tick-borne encephalitis (TBE) virus, 81t-83t, 210Ticks, 204

Francisella tularensis from, 330including tick paralysis, 453Rocky Mountain spotted fever from, 257

Tinidazolefor amebiasis, 413, 414tfor giardiasis, 426, 427tfor Trichomonas vaginalis, 428

Tipranavir, for human immunodeficiency virus infection, 152t-153t

Tissue antibiotic concentration, over time, 484fTissue nematodes, 439Tobramycin, 34t-36t

for infective endocarditis, in injection drug users, 480Toscana virus, 81t-83t

Total body surface area (TBSA), burn size in, 486Toxic shock syndrome

staphylococcal, 268-269streptococcal, 277

Toxocara canis, 445Toxocara cati, 445Toxocariasis. see Visceral larva migrans.Toxoplasma gondii, 424-425Toxoplasma gondii encephalitis

prophylaxis of, 168t-171ttreatment of, 156t-168t

Toxoplasmosis, 424human immunodeficiency virus and, 146

Trachoma, 124, 249-250Transesophageal echocardiography (TEE), for prosthetic

valve endocarditis diagnosis, 63Transfusion-transmitted infections, 463Transmissible neurodegenerative diseases, 248Transplant recipients, solid-organ, infections in, 474Transplantation, incidence of aspergillosis in, 381, 382tTransplantation-transmitted infections, 463Transplanted organ, toxoplasmosis in, 424Transudative pleural effusion, features differentiating

exudative from, 29tTrauma

acute mediastinitis and, 73tocular, keratitis and, 124penetrating, clostridial myonecrosis and, 92

Travelersprotection of, 491-492returning, infections in, 493, 494t-495t

Trematodes, 440-441features of, 441t-442t

Trench fever, from Bartonella quintana, 346Treponema pallidum, 351-353Treponemal tests, for syphilis, 351Treponematoses, endemic, 353Trichinellosis, 439Trichomonas vaginalis, 428Trichomoniasis, 118Trichosporon spp., 405-406Trichuris, 437-438, 438tTriclabendazole, for trematodes, 441, 441t-442tTricuspid valve, infective endocarditis, in injection drug

users, 480Trimethoprim-sulfamethoxazole

for bites, 487for blastocystosis, 434tfor Cyclospora and Cystoisospora, 432, 433tfor infections

in cancer patients, 464-467, 465t-466tin HSCT, 471

for Nocardia infection, 379for paracoccidioidomycosis, 402, 403tfor PCP, 410-411for S. maltophilia, 319for toxoplasmosis, 425

Tropheryma whipplei, 59t, 300Tropical diseases, in returning travelers, 493Tropical sprue, 107Trypanosoma brucei gambiense, 422Trypanosoma brucei rhodesiense, 422

519In

dex

Trypanosoma cruzi, 420-421Trypanosoma species, 420-421Trypanosomiasis, 420-421Tsetse flies, in African trypanosomiasis, 422Tube agglutination test, for brucellosis, 328Tuberculin skin testing, 365-366Tuberculous pericarditis, 70Tularemia, 330-333

clinical manifestations of, 330-331, 332f-333fdefinition of, 330diagnosis of, 331epidemiology of, 330microbiology of, 330prevention of, 333therapy for, 331, 334t

Tularemia pneumonia, 333fTungiasis, 451Twinrix, 201tTyphlitis, 56-57Typhoid, in returning travelers, 493Typhoid conjugate vaccines, 104Typhoid vaccine, 104Typhoidal fever, 104Typhus

epidemic, 262, 263tlouse-borne, 262murine, 264scrub, 265

Tzanck smears, of lesion scrapings, 183

UUlceration, aphthous, esophagitis from, 99tUlceroglandular tularemia, 332f-333fUmbilical cord blood, in HSCT, 470Uncomplicated infections, 42United States, pediatric HIV infection in, 147Ureaplasma parvum, 256Ureaplasma species, 256Ureaplasma urealyticum, 256Urethritis, 117, 117t

nongonococcal, clinical characteristics of, 251t-252tTrichomonas vaginalis of, in men, 428

Urinary tract infection (UTI), 37-38in elderly, 476nosocomial, 460-461recommendations for initial therapy of, 39tSCI and, 475

Urine antigen testing, for Legionella spp., 342U.S.-licensed vaccines, for flaviviruses, 211UTI. see Urinary tract infection (UTI).Uveitis, 127

infectious etiologies of, 128t

VVaccination

for hepatitis, 462with hepatitis B vaccine, 199for human papillomavirus, 195measles, 220poliovirus, 237with smallpox vaccine, 177for travelers, 491

Vaccinefor H. influenzae, 327for hepatitis A virus, 241, 241tfor hepatitis E virus, 247for infections

in asplenic patients, 478in cancer patients, 465t-466t

for invasive pneumococcal disease, 282for noninflammatory gastroenteritis, 101for norovirus, 245polysaccharide-conjugate, for Neisseria meningitidis,

303, 304tfor zoonoses, 490

Vaccinia, 81t-83tVaccinia Immune Globulin Intravenous (VIGIV), 176Vaccinia virus (smallpox vaccine), 176Vaginitis, Trichomonas vaginalis of, in women, 428Vaginosis, bacterial, 118Valacyclovir, for infections, in cancer patients, 465t-466t,

467Valganciclovir

for cytomegalovirus infection, 185for infections, in HSCT, 471

Vancomycinfor Clostridium difficile infections, 358-359for coagulase-negative staphylococcal infections,

275-276for infections, in HSCT, 472for pneumonia, 458-459

VAP. see Ventilator-assisted pneumonia (VAP).Varicella-zoster immune globulin (VariZIG), 184Varicella-zoster virus (VZV), 183-184

vaccine for, 184Varicella-zoster virus (VZV) disease

prophylaxis of, 168t-171ttreatment of, 156t-168t

Variola (smallpox), 176VariZIG. see Varicella-zoster immune globulin

(VariZIG).Vascular infections, noncardiac, in injection drug users,

480Vascular insufficiency, osteomyelitis and, 112Venereal exposure, bacterial inflammatory enteritides

and, 102Veno-occlusive disease, in HSCT, 471Ventilator-assisted pneumonia (VAP), 458Ventriculoperitoneal (VP) shunt infections, 88Vermiform appendix, 55Verruga peruana, 346Vertebral osteomyelitis, 111Vesicular fever, with eschar, 259Vesicular stomatitis virus (VSV), 224Vesiculoviruses, 224Veterinary vaccines, for alphaviruses, 208Vibrio cholerae, 308-310

clinical manifestations of, 308diagnosis of, 308management of, 309-310, 309tmicrobiology and epidemiology of, 308prevention of, 310, 310t

Vibrio parahaemolyticus, inflammatory enteritides from, 102

520In

dex

Vibrio vulnificus, 312Vibrios, pathogenic, 312-313Video-assisted thoracoscopy, for empyema, 28VIGIV. see Vaccinia Immune Globulin Intravenous

(VIGIV).Vincent’s angina, antimicrobial regimens for, 18t-19tViral arthritis, 108Viral encephalitis, important and emerging causes of,

81t-83tViral hepatitis, 130-137

acute, 130chronic, 130diagnostic approach for, 131tHAV, 130HBV, 130-134HCV, 134-136, 135f-136f, 137tHDV, 134HEV, 136-137viruses causing, 130-137, 131t

Viral lymphadenitis, 95t-96tViral pneumonia, in human immunodeficiency virus

infection, 143Viral polyprotein, of hepatitis C virus, 213fViridans streptococci, 287-288Virulence factors, of Pseudomonas aeruginosa, 317Virus

see also specific viruscausing microbial keratitis, 124conjunctivitis from, 122mucous membrane lesions, 116noninflammatory gastroenteritis from, 100orchitis from, 120

Visceral larva migrans, 445Visceral leishmaniasis, 419Vision, decreased, in endophthalmitis, 125Vitamin A, administration of, in measles, 220Vitrectomy, for endophthalmitis, 126Vomiting, with nausea and noninflammatory diarrhea,

100-101Voriconazole

for aspergillosis, 381, 384tfor infections, in HSCT, 471for paracoccidioidomycosis, 403t

VSV. see Vesicular stomatitis virus (VSV).Vulvitis, 118Vulvovaginal candidiasis, 118

treatment of, 156t-168tVulvovaginitis, 118VZV. see Varicella-zoster virus (VZV); Varicella-zoster

virus (VZV) disease.

WWater

contaminated, 105hepatitis E virus in, 247noroviruses, 244-245

sanitation of, for noninflammatory gastroenteritis, 101Weil-Felix test, for scrub typhus, 265West Nile virus (WNV), 210Whipple’s disease, 59t, 300Whipworm, 437, 438tWild-type poliovirus type 2, 237Wound botulism, 361Wound closure, for management of bite wounds,

488t-489tWound management, and tetanus prevention, 360

YYatapoxvirus infections, 178Yaws, 353Yeasts, uncommon, 406-407Yellow fever (YF), 210Yersinia enterocolitica, 337Yersinia pestis, 337Yersinia pseudotuberculosis, 337Yersinia species, 337YF. see Yellow fever (YF).Youth, aging HIV-infected, therapy for, 147-148

ZZidovudine, for human immunodeficiency virus

infection, 150t-151tZika virus (ZIKV) infections, 210Zinc pyrithione, for dermatophytosis, 400Zoonoses, 490Zoonotic paramyxoviruses, 222-223

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