Evolving Etiology and Management Of Infections in the Hematologic Malignancy Patient

8/4/2019 Evolving Etiology and Management Of Infections in the Hematologic Malignancy Patient

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Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or

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Management o f In fec t ions

in the Hemat o logic

Mal ignancy Pat ient

Lindsey R. Baden, MD

Dana-Farber/Brigham and Womens Cancer Center

Educational Objectives

(including antibiotic-resistant pathogens) currently

affecting patients with hematologic malignancies

Select appropriate antimicrobial regimens for the

treatment of patients with hematologic

mali nancies that minimize the contribution to the

rise of drug-resistant pathogens


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Fundamental Principles

Pathogen exposure

Reservoir, vector, mode of transmission

Candida: person to person with acquisition likely via

ingestion (GI tract reservoir) or via catheters

Aspergillus: air, ?water with acquisition via the respiratory

tract

Host susceptibility

Net state of immunosuppression

Critical Factors in Assessing theRisk for Infection I Net State of Immunosuppression

ose, urat on, sequence o mmunosuppress ve

medications (e.g., pulse steroids, OKT3)

Rejection

Leukopenia

Breakdown of barriers, devitalized tissue

Metabolic factors malnutrition, uremia

Infection w/ immunomodulating viruses (CMV, HIV)

Consequence of invasive procedures

Supportive (lines, Foley, ET tube)

Technical aspect of the surgery


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Critical Factors in Assessing theRisk for Infection II

Nosocomial

MRSA, VRE, C difficile, Aspergillus, Legionella,

Pseudomonas

Community

Respiratory viruses, Legionella, Mycobacteria, Cryptococcus

, , ,

carinii, Listeria, Salmonella, Strongyloides

Geographic

Histoplasma, Coccidioides, Blastomyces


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Transplant ID Principles

Immediate transplant period (100 days)

Typically at risk for community acquired processes

Ner do well patient

GVHD, increased immunosuppression, protein-caloriemalnutrition

At risk for all of the above

normal

host

Intensity of

signs and

symptoms

compromised

ost

Time


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Micro ial

burdencompromised

host

Time

host

Antibiotic Strategies Therapeutic

Treat established clinical infection

Diagnostic dilemma vs. therapeutic emergency

Prophylactic

Given to all members of a population to prevent theoccurrence of clinical infection

Preemptive

infection based on a laboratory or epidemiologicmarker

Empiric

Given to individuals with signs of a possible infection


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Key Factors to Consider for

Prophylaxis/Preemption Pathogen

Pathogenesis e.g., Candida (GI/GU) vs. Aspergillus (environmental)

Cause significant morbidity/mortality

How difficult is it to treat established disease

Therapy

Effective

Safe adverse effects, drug-drug interactions, evolutionary stress

Dose Affordable

Kinetics

What is the risk period (beginning and end)

Effect of Antimicrobial Prophylaxis on the Rate of and Time to Infection

Baden L. N Engl J Med 2005;353:1052-1054


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Which patient group(s), during what specific time

frame have a high enough attach rate for the

patient to benefit from prophylaxis (?vs. pre-

emption)?

Organisms of Interest for Prophylaxis,Preemption, or Empiric Therapy

Bacteria

Gram-negative rods

MTb

Fungae

Candida, Aspergillus, PCP, Cocci

HSV, CMV

Parasites

Strongyloides


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Neutropenia as a Risk Factor for

Infection

45

50

10

15

20

25

30

35

40

fectionsper1000Days

0

5

< 100 100-500 500-1000 1000-1500 > 1500

Neutrophil Count (cells/L)

I

Bodey et al. (1966) Ann Intern Med 64:328-40.


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Nature of the Host Defects

Disruption of mucosal integrity

Devices compromising mechanical defenses

(central lines, urinary catheters)

Approach to Empiric Antibiotics

When Fever Develops Flora of concern

Established regimens

Ceftazidime, Piperacillin/gentamicin, Cefipime, Imipenem

Approx 65% patients will respond to Abx

B-lactam allergic patient

Aztreonam/gentamicin (no streptococcal coverage),

quinolone/gentamicin

Alter regimen if significant prior antimicrobialtreatment or local antimicrobial resistance patterns ofconcern

NCCN Guidelines at www.NCCN.org

IDSA Guidelines CID 2011;52(4):e56-93


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Approach to Empiric Antibiotics

When Fever Develops -

Only when a likely Gram-positive source is identifiedsuch as an infected catheter

Role for anaerobic coverage

When evidence for oral, abdominal or perianal infection

Duration of empiric antibiotics

Until ANC > 500

If BM failure then re-assess goals of antibiotics after 14days of afebrility. If Abx stopped and patient remainsneutropenia approximately 30% will become febrileagain

NCCN Guidelines at www.NCCN.org

IDSA Guidelines CID 2011;52(4):e56-93

High vs. Low Risk Patients

Underlying disease, therapy, severity of neutropenia,

concomitant factors (e.g., mucositis, catheters)

Typically low risk patients with


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Kaplan-Meier Estimates of Survival Free from Fever among All Patients (Panel A), Patients withAcute Leukemia (Panel B), and Patients with Solid Tumors or Lymphoma (Panel C)

Bucaneve G et al. N Engl J Med 2005;353:977-987

Characteristics of Bacterial Isolates and Number with Resistance to Levofloxacin



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Mortality Rates in the Treated Population



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Case 3

induction chemotherapy

for AML. 4weeks into

therapy develops fevers

and elevated AlkPhos. Abd

CT demonstrates multiple

abscesses in the liver and

spleen. Biopsy

demonstrate C albicans.

General Risk Factors for IFI

Immunosuppression

Prolonged neutropenia, allograft issues, rejection

Host

Renal failure, DM, malnutrition

Large inoculum

Environmental exposure (even remote), colonization w/

, Permissive co-infections

CMV, ?HHV-6


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Prevention Strategies for IFI:

Key Concepts Prophylaxis Fluconazole diminishes invasive Candida infections

, ,

Empiric

F+N for > 96h of appropriate antimicrobials for GNRs

?Dose: 0.3, 0.5, 0.7, 1.0 mg/kg ampho all used by differentmajor centers. ? Role for lipid formulations

Itraconazole (IV), caspofungin, ?voriconazole

reempt on

Colonized with a pathogenic species (Aspergillus)

Radiologic or molecular evidence of infection

Molecular markers

Caillot J Clin Onc 1997;15:139 Boogaerts Ann Intern Med 2001;135:412 Caillot CID 2001;33

Maertens ICAAC 2000;40:371 abstr 1103

IFI Prophylaxis: Oncology - BMT

When is the risk period?

Neutropenia, GVHD (acute/chronic)

Who is at highest risk?

Allogeneic BMT, likely relapsed leukemia

Limited benefit for Auto-BMT, induction chemo

Evolving risk factors

Novel chemo (targeted therapies), mini-allos

mmune-mo u ators - Pathogens of greatest interest

Candida, Aspergillus

Drugs studied

Fluc, Itra, Ampho (Inh, PO, IV), NYS, Vori, Micafungin


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Prevention of IFI in Allo-BMT

Fluconazole use decreases invasive yeast infectionsduring transplant period

Dose 400m d

Day 0 until engraftment/d75

Associated with the emergence of resistant yeastspecies (C krusei and glabrata)

7 fold increase risk for C krusei infection but less C albicans andtropicalis

40% vs 17% rate of colonization with C krusei

One study w/ increased mold infections associated

w/Flu prophylaxis 18 vs 29% of autopsied patients (RR 0.4, p=.009)

Slavin JID 1995:171;1545, Marr Blood 2000:96;2055 and van Burik Medicine 1998;77:246-54

Goodman NEJM 1992:326;845 and Wingard NEJM 1991;325:1274

Candida Species Before andAfter Fluconazole Prophylaxis

585 patients undergoing

BMT, 1994-97.

Fluc 400 mg for 75 days.

Colonization during azole

prophylaxis: 44% overall,

38.4% C. krusei, 37% C.

glabrata. 20

30

40

50

60

70

No. patients

1980-86

1994-97

Marr et.al. JID 181:309-16, 2000

34 episodes of Candidemia:

C. glabrata (47%), C.

parapsilosis (23%), C. krusei

(20%)Blood isolates

0

10

C albi C trop C glab C krus C para


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Randomized Studies of

Fluconazole ProphylaxisYear N Disease Proven IFI (%) Mortality (%)

Goodman 1992 BMT

FLU 400mg 179 3 31

Placebo 177 16 26

Slavin 1995 BMT

FLU 400mg 152 7 28

Placebo 148 18 55

Winston 1993 Leukemia

FLU 400mg 123 4 1

Placebo 132 8 3

Rotstein 1999 Leuk/Auto

FLU 400mg 141 3 11

Placebo 133 17 11

Schaffner 1995 AML/NHL

FLU 400mg 75 8 5

Placebo 76 9 7

Cornely Blood 2003;101:3365-3372

Micafungin Prophylaxis in HSCT

micafungin (50)

n= 882

PIII, randomized, double

blind

Medication iven durin

neutropenic period

Success 73.5 vs 80%

van Burik CID 2004;39:1407


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Time to Proven or Probable Invasive Fungal Infection

Ullmann A et al. N Engl J Med 2007;356:335-347


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Proven or Probable Invasive Fungal Infection during the Treatment Phase

Cornely O et al. N Engl J Med 2007;356:348-359

Clinical Response and Reasons for Failure during the Treatment Phase

Cornely O et al. N Engl J Med 2007;356:348-359


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Case 5

63 ear female develo s facial

pain and fever on d+10 of an

allo-BMT for M2 AML. Her

antimicrobial therapy included:

ceftazidime and amphotericin B

(0.5 mg/kg/day empirically

begun 2 days earlier). An

emergent head CT revealed the

o ow ng:


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Bodey et al. (1966) Ann Intern Med 64:328-40.

1/20/07 1/26/07 2/05/07 2/23/07 4/04/07


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Empiric Anti-Fungal Therapy

CAB Pizzo Am J of Med 1982;72:101-11 50 F+N pts

Walsh NEJM 1999;340:764-71

CAB vs AmB inc cr (34 vs 19%) 787 F+N pts

Voriconazole

Walsh NEJM 2002;346:225-34 837 F+N pts.

Boogarts Ann Intern Med 2001;135:412-422 384 F+N pts.

Caspofungin

Walsh NEJM 2004;351:1391-1402 1000 F+N pts

GalactomannanProspective serial GM measurement in 362 consecutive high-risk

treatment episodes in 191 patients (BMT and leukemic). Time

period: 1/97-2/00. EORTC/MSG definitions of IFI with autopsy

confirmation. Based on 2 or more positive GM samples.

Sensitivity Specificity PPV NPV

Proven IA 100 98.1 85.7 100

Probable IA 55.5 98.1 50 98.4

Maertens Blood 2001:97;1604

Proven + probable IA 89.7 98.1 87.5 98.4

Possible IFI 7.4 98.1 44.4 83.8


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Important Fungal Syndromes

Hepatosplenic Candidiasis

Invasive Pulmonary Aspergillosis

Disseminated Aspergillosis

Issues to Consider withNew Diagnostics for IFI How many pathogenic species can be identified by a

IsAspergillus detection enough?

What is the gold standard for diagnosis?

Diagnostic vs. therapeutic use?

Does earlier diagnosis of an IFI matter?

Is it the NPV or PPV that we are after?

Are the performance characteristics equal across body

sites of infection?

Is the diagnostic technique exportable?


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HSV

will reactivate HSV with neutropenia

Typically oropharynx

Acyclovir 400 mg po/iv bid is highly effective


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Typical Infectious Sources of

Fever in the Setting of Neutropenia

Respiratory tract

GI tract

Typhlitis, peri-rectal abscess, C diff

v

History, physical exam, CBC, SMA-7, LFTs, urine

analysis, blood/sputum/urine cultures, CXR +/- CT Source identified in approximately 50% cases

Conclusion Prophylaxis is a blunt hammer and should be

supplanted by pre-emption

Identification of high risk groups, during high risk

Molecular markers hold great promise

Geographic and local organism burden are important

Development of safe, effective, convenientantimicrobial agents will alter the equation

Emer ence of resistant or anisms and medication

toxicity remain significant concerns

Novel therapies for the underlying condition leadingto transplantation may shift the spectrum of theinfectious complications - dynamic environment

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Evolving Etiology and Management Of Infections in the Hematologic Malignancy Patient