Principles of Infectious Diseases S.A. ZIAI Pharm D., PhD. Associate Professor at Pharmacology Dept

Principles of Infectious DiseasesS.A. ZIAI

Pharm D., PhD.

Associate Professor at Pharmacology Dept.

Case

R.G., a 63-year-old, 70-kg man in the intensive care unit, underwent

emergency resection of his large bowel. He has been mechanically

ventilated throughout his postoperative course. On day 20 of his

hospital stay, R.G. suddenly becomes confused; his blood pressure

(BP) drops to 70/30 mm Hg, with a heart rate of 130 beats/minute.

His extremities are cold to the touch, and he presents with

circumoral pallor. His temperature increases to 40◦C (axillary), and

his respiratory rate is 24 breaths/minute. Copious amounts of

yellow-green secretions are suctioned from his endotracheal tube.

…

Physical examination reveals sinus tachycardia with no rubs or

murmurs. Rhonchi with decreased breath sounds are observed on

auscultation. The abdomen is distended, and R.G. complains of new

abdominal pain. No bowel sounds can be heard, and the stool is guaiac

positive. Urine output from the Foley catheter has been 10 mL/hour for

the past 2 hours. Erythema is noted around the central venous catheter.

A chest radiograph demonstrates bilateral lower lobe infiltrates, and

urinalysis reveals >50 white blood cells/highpower field (WBC/HPF), few

casts, and a specific gravity of 1.015. Blood, endotracheal aspirate, and

urine cultures are pending.

Laboratory values

Sodium (Na), 131 mEq/L (normal, 135 to 147) Hemoglobin (Hgb), 10.3 g/dL

Potassium (K), 4.1 mEq/L (normal, 3.5 to 5) Hematocrit (Hct), 33% (normal, 39%–49% [male patients])

Chloride (Cl), 110 mEq/L (normal, 95–105) WBC count, 15,600/μL with bands present (normal, 4,500–10,000 μL)

CO2, 16 mEq/L (normal, 20–29 mEq/L) Platelets, 40,000/μL (normal, 130,000–400,000)

Blood urea nitrogen (BUN), 58 mg/dL (normal, 8–18)

Prothrombin time (PT), 18 seconds (normal, 10–12)

Serum creatinine (SCr), 3.8 mg/dL (increased from 0.9 mg/dL at admission; normal, 0.6–1.2)

Erythrocyte sedimentation rate (ESR), 65 mm/hour (normal, 0–20)

Glucose, 320 mg/dL (normal, 70–110) Procalcitonin, 1 mcg/L (normal <0.25mcg/L)

Serum albumin, 2.1 g/dL (normal, 4–6)

What signs and symptoms manifested by R.G. are consistent with a serious systemic infection?

Hemodynamic Changes

Critically ill patients often have central intravenous (IV) lines in place for measuring cardiac output and systemic vascular resistance (SVR).

Normal SVR of 800 to 1,200 dyne ・ s ・ cm–5 may fall to 500 to 600 dyne ・ s ・ cm–5 in septic shock

The heart reflexively increases cardiac output from a normal 4 to 6 L/minute to up to 11 to 12 L/minute

The combination of decreased cardiac output and decreased SVR results in hypotension often unresponsive to pressors and IV fluids.

R.G. has hemodynamic evidence of septic shock. He is hypotensive (BP, 70/30 mm Hg) and tachycardic (130 beats/minute)

Hemodynamic Changes

In sepsis, blood generally is shunted away from the kidneys, mesentery, and extremities.

Normal urine output of approximately 0.5 to 1.0 mL/kg/hour (30–70 mL/hour for a 70-kg patient) can decrease to less than 20 mL/hour in sepsis (R.G’s urine output is 10 mL/hour)

Decreased blood flow to the kidney as well as mediator induced microvascular failure can cause acute-tubular necrosis (ATN)

R.G.’s uremia (BUN, 58 mg/dL) and increased serum creatinine concentration (3.8 mg/dL) are consistent with decreased renal perfusion secondary to sepsis.

Hemodynamic Changes

Decreased blood flow to the liver may result in “shock liver,” in which liver function tests, including ALT, AST, ALP, become elevated.

R.G. serum albumin concentration is low (2.1 g/dL) and his PT of 18 seconds is prolonged.

R.G. is confused, his extremities are cold, and the area around his mouth appears pale.

All these signs and symptoms provide strong evidence that he is in septic shock.

Cellular Changes

Glucose intolerance commonly is observed in sepsis (RG’s 320 mg/dL)

ESR, C-reactive protein, and procalcitonin, nonspecific tests that are commonly elevated in various inflammatory states, including infection (R.G.’s ESR is 65 mm/hour).

Procalcitonin is a marker that is a more specific indicator for infection than ESR or C-reactive protein (R.G.’s procalcitonin is 1.0 mcg/L).

Respiratory Changes

Production of organic acids (lactate), glycolysis , fractional extraction of oxygen, and abnormal delivery-dependent oxygen consumption are observed in sepsis

R.G.’s acid-base status is consistent with sepsis-associated metabolic acidosis (chloride 110 meq/L) and compensatory respiratory alkalosis (CO2, 16 mEq/L) (respiratory rate, 24 breaths/minute).

The chronic phase of ARDS (10–14 days after development of the syndrome) is associated with significant lung destruction.

Severe ARDS is associated with ratios of arterial oxygen level to fraction of inspired oxygen (Pao2/Fio2) of less than 100, low lung compliance, a need for high positive end-expiratory pressure (PEEP), and other respiratory maneuvers.

Although R.G. currently does not have ARDS, the severity of his sepsis strongly suggests he may develop this complication.

Hematologic Changes

Disseminated intravascular coagulation (DIC) is a well recognized sequel of sepsis.

Huge quantities of clotting factors and platelets are consumed in DIC

Decreased fibrinogen levels and increased fibrin split products generally are diagnostic for DIC.

The PT of 18 seconds and the decreased platelet count of 40,000/μL in R.G. are consistent with sepsis-induced DIC.

Neurologic Changes

Central nervous system (CNS) changes, including lethargy, disorientation, confusion, and psychosis, are commonly observed in septic patients.

R.G.’s confused state is consistent with that expected with septic shock.

PROBLEMS IN THE DIAGNOSIS OFAN INFECTION

R.G.’s medical history includes temporal arteritis and seizures chronically treated with corticosteroids and phenytoin. Perioperative “stress doses” of hydrocortisone recently were administered because of his surgical procedure. What medications or disease states confuse the diagnosis of infection?

Confabulating Variables

Various factors, including major surgery, acute myocardial infarction, and initiation of corticosteroid therapy, are associated with an increased WBC count.

Unlike infection, however, a shift to the left does not occur with these disease states or drugs.

Drug Effects

Corticosteroids are associated with an increased WBC count and glucose intolerance with the initiation of therapy or when doses are increased.

Furthermore, some patients experience corticosteroid-induced mental status changes that may mimic those associated with sepsis.

Corticosteroids can reduce and sometimes ablate the febrile response.

When the dexamethasone dose is decreased after neurosurgery, the patient subsequently may experience classic meningismus, including stiff neck, photophobia, and headache.

The lumbar puncture may demonstrate cloudy cerebrospinal fluid (CSF), an elevated WBC count, high CSF protein, and low CSF glucose.

Certain drugs may cause aseptic meningitis, including OKT3, NSAIDs, sulfonamides, and certain antiepileptics.

Fever

Fever also is a common finding with autoimmune diseases, such as systemic lupus erythematosus and temporal arteritis.

25% incidence of FUO caused by cancer

Other diseases associated with fever include sarcoidosis, chronic liver disease, and familial Mediterranean fever

Acute myocardial infarction, pulmonary embolism, and postoperative pulmonary atelectasis also are commonly associated with fever

After infection, autoimmune disease, and malignancy have been ruled out, drug fever should be considered.

Drug fever generally occurs after 7 to10 days of therapy and resolves within 48 hours of the drug’s discontinuation

A rechallenge with the offending agent usually results in recurrence of fever within hours of administration

In summary

R.G. has an autoimmune disease, temporal arteritis, which is known to be associated with fever.

Similarly, his corticosteroid administration and phenytoin use may confound the diagnosis of infection.

His other signs and symptoms, however, strongly suggest that R.G.’s problems are of an infectious origin.

ESTABLISHING THE SITE OF THEINFECTION

What are the most likely sources of R.G.’s infection?

After blood culture sampling, a thorough physical examination often documents the source of infection.

Urosepsis, the most common cause of nosocomial infection, may be associated with dysuria, flank pain, and abnormal urinalysis

Tachypnea, increased sputum production, altered chest radiograph, and hypoxemia may direct the clinician toward a pulmonary source

Evidence for an infected IV line might include pain, erythema, and purulent discharge around the IV catheter

Other potential sites of infection include the peritoneum, pelvis, bone, and CNS

R.G. has several possible sites of infection

The copious production of yellow-green sputum, tachypnea, and the altered chest radiograph suggest the presence of pneumonia.

The abdominal pain, absent bowel sounds, and recent surgical procedure, however, suggest an intra-abdominal source.

Lastly, the abnormal urinalysis (>50 WBC/HPF) and the erythema around the central venous catheter suggest urinary tract and catheter infections, respectively.

DETERMINING LIKELY PATHOGENS

What are the most likely pathogens associated with R.G.’s infection(s)?

Site of Infection: Suspected OrganismsSuspected Organisms Site/Type of Infection

1 .Respiratory

Viral, group A streptococci Pharyngitis

Viral, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis

Bronchitis, otitis

Viral, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis

Acute sinusitis

Anaerobes, Staphylococcus aureus (as well as suspected organisms associated with acute sinusitis)

Chronic sinusitis

Viral, Haemophilus influenzae Epiglottitis


1 .Respiratory

Pneumonia

Community -acquired

Streptococcus pneumoniae, viral, mycoplasma Normal host

Normal aerobic and anaerobic mouth flora Aspiration

Streptococcus pneumoniae, Haemophilus influenzae Pediatrics

Streptococcus pneumoniae, Haemophilus influenzae, Legionella, Chlamydia, Mycoplasma

COPD

Streptococcus pneumoniae, Klebsiella Alcoholic

Hospital-acquired

Mouth anaerobes, aerobic gram-negative rods, Staphylococcus aureus

Aspiration

Fungi, aerobic gram-negative rods, Staphylococcus aureus Neutropenic

Fungi, Pneumocystis, Legionella, Nocardia, Streptococcus pneumoniae, Pseudomonas

HIV

Site of Infection: Suspected Organisms

Suspected Organisms Site/Type of Infection

2 .Urinary Tract

Escherichia coli, other gram-negative rods, Staphylococcus aureus, Staphylococcus epidermidis,enterococci

Community-acquired

Resistant aerobic gram-negative rods, enterococci Hospital-acquired

3 .Skin and Soft Tissue

Group A streptococci, Staphylococcus aureus Cellulitis

Staphylococcus aureus, Staphylococcus epidermidis IV catheter infection

Staphylococcus aureus, gram-negative rods Surgical wound

Staphylococcus aureus, gram-negative aerobic rods, anaerobes Diabetic ulcer

Staphylococcus aureus Furuncle


Bacteroides fragilis, Escherichia coli, other aerobic gram-negative rods, enterococci

4. Intra-Abdominal

Salmonella, Shigella, Helicobacter, Campylobacter, Clostridium difficile, amoeba, Giardia, viral,enterotoxigenic-hemorrhagic Escherichia coli

5 .Gastroenteritis

6 .Endocarditis

Viridans streptococci Pre-existing valvular disease

Staphylococcus aureus, aerobic gram-negative rods, enterococci, fungi

IV drug user

Staphylococcus epidermidis, Staphylocccus aureus Prosthetic valve

Staphylococcus aureus, aerobic gram-negative rods 7 .Osteomyelitis and Septic Arthritis


8 .Meningitis

Escherichia coli, group B streptococci, Listeria <2 months

Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae

2 months–12 years

Streptococcus pneumoniae, Neisseria meningitidis Adults

Streptococcus pneumoniae, Neisseria meningitidis, aerobic gram-negative rods

Hospital-acquired

Staphylococcus aureus, aerobic gram-negative rods Postneurosurgery

In R.G.

Intra-abdominal infection is likely caused by aerobic gram-negative enteric bacteria, Bacteroides fragilis, and possibly enterococcus

Nosocomial urinary tract infection is usually caused by aerobic gram-negative bacteria.

Pneumonia could be attributable to gram-negative bacilli and staphylococci, as well as other organisms.

His long-term use of corticosteroids may predispose him to infection caused by more opportunistic organisms, including Legionella, P. jiroveci, and fungi

His IV catheter infection suggests infection caused by staphylococci, including Staphylococcus epidermidis and S. aureus.

MICROBIOLOGIC TESTS ANDSUSCEPTIBILITY OF ORGANISMS

If the Gram stain of the tracheal aspirate demonstrates gram-positive cocci in clusters, empirical anti staphylococcal therapy is indicated

The India ink and potassium hydroxide (KOH) stains are helpful in the identification of certain fungi.

The acid-fast bacilli (AFB) stain is critical in the diagnosis of infection caused by Mycobacterium tuberculosis or atypical mycobacteria.

In R.G.’s case, the Gram stain suggests that antimicrobials active against gram-negative bacilli should be used

Culture and Susceptibility Testing

Although these tests provide more information than the Gram stain, they generally require 18 to 24 hours to complete.

DISK DIFFUSION Based on guidelines provided by the Clinical and Laboratory

Standards Institute (CLSI), the diameter of inhibition is reported as susceptible, intermediate, or resistant

BROTH DILUTION As an example, if bacterial growth is observed with S. aureus at 0.5

mcg/mL of nafcillin but not at 1.0 mcg/mL, then 1.0 mcg/mL would be considered the minimum inhibitory concentration (MIC) for nafcillin against S. aureus.

…

Similar to the disk diffusion method, the CLSI provides guidelines that also take into account the pharmacokinetic characteristics of an antimicrobial

For example, ciprofloxacin achieves serum concentrations of only 1 to 4 mcg/mL, whereas the fourth-generation cephalosporin, cefepime, achieves peak serum concentrations of 75 to mcg/mL; consequently an MIC of 4.0 mcg/mL for E. coli would be interpreted by CLSI as resistant to ciprofloxacin, but susceptible to cefepime.

…

E test, which uses an antibiotic-laden plastic strip with increasing concentrations of a specific antimicrobial from one end to the other.

Several automated antimicrobial susceptibility systems are available

In some disease states (e.g., endocarditis), bactericidal therapy is necessary. The minimum bactericidal concentration (MBC) is the test that can be used to determine the killing activity associated with an antimicrobial.

The MBC is determined by taking an aliquot from each clear MIC tube for subculture onto agar plates. The concentration at which no significant bacterial growth (i.e., 99.9% of the original inoculum) is observed on these plates is considered the MBC.

Gram-positive cocciOrganism Drug of

choiceAlternatives Comments

Streptococcus pyogenes (group A streptococci)

Penicillin Clindamycin, macrolide, cephalosporin

Clindamycin is the most reliable alternative for penicillin-allergic patients.

Streptococcus pneumoniae

Ceftriaxone, ampicillin, oralamoxicillin

Macrolide, cephalosporin, doxycycline

• Although the incidence of penicillin-nonsusceptible pneumococci is 20%–30%, high-dose penicillin or amoxicillin is active against most of these isolates.

• Penicillin-resistant pneumococci commonly demonstrate resistance to other agents, including erythromycin, tetracyclines, and cephalosporins.

• Antipneumococcal quinolones (gemifloxacin, levofloxacin, moxifloxacin), ceftriaxone, and cefotaxime are options for treatment of high-level penicillin-resistant isolates.



Enterococcus faecalis Ampicillin ± gentamicin

Piperacillin-tazobactam; vancomycin ± gentamicin; daptomycin,linezolid, tigecycline

Most commonly isolated enterococcus (80%–85%).

Most reliable antienterococcal agents are ampicillin (penicillin, piperacillin-tazobactam), vancomycin, and linezolid.

Monotherapy generally inhibits but does not kill the enterococcus.

Daptomycin is unique in its bactericidal activity against enterococci.

Aminoglycosides must be added to ampicillin or vancomycin to provide bactericidal activity.

High-level aminoglycoside resistance should be determined for endocarditis.

Gram-positive cocci

Organism Drug of choice

Alternatives Comments

Enterococcus faecium Vancomycin ± gentamicin

Linezolid, daptomycin, dalfopristin/quinupristin (D/Q), tigecycline

Second most common enterococcal organism (10%–20%) and is more likely than E. faecalis to be resistant to multiple antimicrobials.

Most reliable agents are daptomycin, D/Q, and linezolid.

Monotherapy generally inhibits but does not kill the enterococcus.

Aminoglycosides must be added to cell wall–active agents to provide bactericidal activity.

Ampicillin and vancomycin resistance is common.

Daptomycin, D/Q, and linezolid are drugs of choice for vancomycin-resistant isolates.



Staphylococcus aureus Nafcillin Cefazolin, vancomycin, clindamycin, trimethoprimsulfamethoxazolelinezolid,

10%–15% of isolates inhibited by penicillin.

Most isolates susceptible to nafcillin, cephalosporins, trimethoprim-sulfamethoxazole, and clindamycin.

First-generation cephalosporins are equal to nafcillin.

Most second- and third-generation cephalosporins adequate in the treatment of infection (exceptions include ceftazidime and cefonicid)

(nafcillin-resistant) Vancomycin Trimethoprim-sulfamethoxazole, minocycline, daptomycin,tigecycline, televancin

Methicillin-resistant S. aureus mustbe treated with vancomycin; however, trimethoprim-sulfamethoxazole,daptomycin, D/Q, linezolid, or minocycline can be used.

Organism Drug of choice

Alternatives Comments

Staphylococcus epidermidis

Nafcillin Cefazolin, vancomycin, clindamycin

Most isolates are β-lactam-, clindamycin-, and trimethoprim-sulfamethoxazole–resistant.

Most reliable agents are vancomycin, daptomycin, D/Q, and linezolid.

Rifampin is active and can be used in conjunction with other agents; however, monotherapy with rifampin is associated with development of resistance.

(nafcillin-resistant) Vancomycin Daptomycin, linezolid, D/Q

Gram-positive cocci

Gram-positive Bacilli

Organism Drug of choice Alternatives Comments

Diphtheroids Penicillin Cephalosporin

Listeria monocytogenes Penicillin,ampicillin

Trimethoprim-sulfamethoxazole

Corynebacterium jeikeium Vancomycin Erythromycin, quinolone

Gram-negative Cocci


Moraxella catarrhalis Trimethoprim-sulfamethoxazole

Amoxicillin-clavulanic acid, erythromycin, doxycycline, second- or third-generation cephalosporin

Neisseria gonorrhoeae

Cefixime Ceftriaxone

Neisseria meningitidis

Penicillin Third-generation cephalosporin

Gram-negative bacilliOrganism Drug of choice Alternatives Comments

Campylobacter jejuni Quinolone, erythromycin

A tetracycline, amoxicillin-clavulanic acid

Enterobacter Trimethoprim-sulfamethoxazole

Quinolone, carbapenem, aminoglycoside

Not predictably inhibited by third-generation cephalosporins.

Carbapenems, quinolones, trimethoprim-sulfamethoxazole, cefepime, and aminoglycosides are

most active agents.

Escherichia coli Third-generation cephalosporin

First- or second-generation cephalosporin, gentamicin

Extended-spectrum β-lactamase (ESBL) –producers should be treated with acarbapenem

Gram-negative bacilli


Haemophilus influenzae

Third-generation cephalosporin

β-Lactamase inhibitor combinations, second-generation cephalosporin, trimethoprim-sulfamethoxazole

Helicobacter pylori Amoxicillin + clarithromycin +omeprazole

Tetracycline + metronidazole + bismuth subsalicylate

Klebsiella pneumoniae Third-generation cephalosporin

First- or second-generation cephalosporin, gentamicin,trimethoprim-sulfamethoxazole

Extended-spectrum β-lactamase (ESBL) –producers should be treated with acarbapenem.

Legionella Fluoroquinolone Erythromycin ± rifampin, doxycycline

Gram-negative bacilliOrganism Drug of choice Alternatives Comments

Proteus mirabilis Ampicillin First-generation cephalosporin, trimethoprim-sulfamethoxazole

Other Proteus Third-generation cephalosporin

β-Lactamase inhibitor combination, aminoglycoside,trimethoprim-sulfamethoxazole

Pseudomonas aeruginosa

Antipseudomonal penicillin (orceftazidime)± aminoglycoside(or quinolone)

Quinolone or imipenem ± aminoglycoside

Most active agents include aminoglycosides, doripenem, imipenem, meropenem, ceftazidime, cefepime, aztreonam and the extended-spectrum penicillins.

Monotherapy is adequate for most pseudomonal infections.

Salmonella typhi Quinolone Ceftriaxone

Gram-negative bacilli


Serratia marcescens Third-generation cephalosporin Trimethoprim-sulfamethoxazole, aminoglycoside

Shigella Quinolone Trimethoprim-sulfamethoxazole, ampicillin

Stenotrophomonasmaltophilia

Trimethoprim-sulfamethoxazole

Ceftazidime, minocycline, β-lactamase inhibitor combination(Timentin)

AnaerobesOrganism Drug of


Bacteroides fragilis

Metronidazole β-Lactamase inhibitor combinations, penems

Most active agents (95%–100%) include metronidazole, the β-lactamase inhibitor combinations (ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanic acid), and penems.

Clindamycin, cefoxitin, cefotetan, cefmetazole, ceftizoxime have good activity but not to the degree of metronidazole.

Aminoglycosides and aztreonam are inactive.

Clostridia difficile Metronidazole Vancomycin Oral vancomycin is the drug of choice for severe infection.

Fusobacterium Penicillin Metronidazole, clindamycin

Other Oropharyngeal


Prevotella β-Lactamase inhibitor combination

Metronidazole, clindamycin

Peptostreptococcus Penicillin Clindamycin, cephalosporin

Most β-lactams active (exceptions include aztreonam, nafcillin, ceftazidime).

Other


Actinomyces israelii Penicillin Tetracyclines

Nocardia Trimethoprim-sulfamethoxazole

Amikacin, minocycline, imipenem

Chlamydia trachomatis Doxycycline Azithromycin

Chlamydia pneumoniae Doxycycline Azithromycin, clarithromycin

Mycoplasma pneumoniae

Doxycycline Azithromycin, clarithromycin

Borrelia burgdorferi Doxycycline Ampicillin, second- or third-generation cephalosporin

Treponema pallidum Penicillin Doxycycline

DETERMINATION OF ISOLATEPATHOGENICITY

Serratia marcescens grows from a culture of R.G.’s endotracheal aspirate. How can it be determined whether an isolate represents a true bacterial infection versus colonization or contamination?

Colonization indicates that bacteria are present at the site; however, they are not actively causing infection.

Poor sampling techniques or inappropriate handling of specimens can result in contamination

If a suction catheter was used to sample R.G.’s endotracheal aspirate, the infecting organism likely would be cultured; however, other nonpathogenic flora would also appear in the culture medium (colonization)

…

In summary, culture results do not solely identify true pathogens. In R.G., the Serratia may be a pathogen, contaminant, or colonizer. Nevertheless, considering the severity of R.G.’s illness and his associated respiratory symptoms, treatment directed against this pathogen is necessary.

ANTIMICROBIAL TOXICITIES

In light of the positive culture for Serratia, his increased respiratory secretions, and a worsening chest radiograph, ventilator-associated pneumonia (VAP) is likely. Pending susceptibility results, R.G. is empirically started on imipenem and gentamicin. In review of his patient records, R.G. has no known allergies. Are there equally effective, less toxic options for this patient?

Adverse Effects and Toxicities

Before antimicrobial therapy is started, it is important to elicit an accurate drug and allergy history.

When “allergy” has been reported by the patient, it is necessary to determine whether the reaction was intolerance, toxicity, or true allergy

β-Lactams, (penicillin, cephalosporins, monobactams, penems)

Allergic: anaphylaxis, urticaria, serumsickness, rash, fever

• Many patients will have “ampicillin rash” or “β-lactam rash” with no cross-reactivity with any other penicillins/β-lactams. Most commonly observed in patients with concomitant EBV disease.

• Likelihood of IgE-mediated cross-reactivity between penicillins and cephalosporins approximately 5%–10%.

• Most recent data strongly suggest minimal IgE cross-reactivity between penicillins and imipenem/meropenem.

• No IgE cross-reactivity between aztreonam and penicillins.

Diarrhea Particularly common with ampicillin, augmentin, ceftriaxone, and cefoperazone. Antibiotic-associated colitis can occur with most antimicrobials.

β-Lactams, (penicillin, cephalosporins, monobactams, penems)

Hematologic: anemia, thrombocytopenia,antiplatelet activity, hypothrombinemia

• Hemolytic anemia more common with higher doses. • Antiplatelet activity (inhibition of platelet aggregation) most common

with the antipseudomonal penicillins and high serum levels of other β-lactams.

• Hypothrombinemia more often associated with those cephalosporins with the methyltetrazolethiol side chain (cefamandole, cefotetan). Reaction preventable and reversible with vitamin K.

Hepatitis or biliary sludging

Hepatitis most common with oxacillin. Biliary sludging and stones reported with ceftriaxone

Phlebitis

Seizure activity Associated with high levels of β-lactams, particularly penicillins and imipenem.

Potassium load Penicillin G (K+).

Nephritis

Neutropenia Nafcillin

Disulfiram reaction Associated with cephalosporins with methyltetrazolethiol side chain (cefamandole, cefotetan).

Hypotension, nausea Associated with fast infusion of imipenem

Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin)

Nephrotoxicity Averages 10%–15% incidence. Generally reversible, usually occurs after 5–7 days of therapy. Risk factors: dehydration, age, dose, duration, concurrent nephrotoxins, liver disease.

Ototoxicity 1%–5% incidence, often irreversible. Both cochlear and vestibular toxicity occur.

Neuromuscular paralysis Rare, most common with large doses administered via intraperitoneal instillation or in patients with myasthenia gravis.

Macrolides (erythromycin, azithromycin, clarithromycin)

Nausea, vomiting, “burning” stomach

Oral administration. Azithromycin and clarithromycin associated with less nausea than erythromycin.

Cholestatic jaundice Reported for all erythromycin salts, most common with estolate.

Ototoxicity Most common with high doses in patients with renal or hepatic failure.

Clindamycin

Diarrhea Most common adverse effect. High association with antibiotic-associated colitis.

Tetracyclines (including tigecycline)

Allergic

Photosensitivity

Teeth and bone deposition and discoloration

Avoid in pediatrics (<8 years old), pregnancy, and breast-feeding

GI Upper GI predominates

Hepatitis Primarily in pregnancy or the elderly.

Renal (azotemia) Tetracyclines have antianabolic effect and should be avoided in patients with ↓ renal function. Less problematic with doxycycline.

Vestibular Associated with minocycline, particularly high doses.

Vancomycin

Ototoxicity Only with receipt of concomitant ototoxins such as aminoglycosides or macrolides.

Nephrotoxicity Nephrotoxic only with high doses or in combination with other nephrotoxins.

Hypotension, flushing Associated with rapid infusion of vancomycin. More common with increased doses.

Phlebitis Needs large volume dilution.

Linezolid

Thrombocytopenia, neutropenia, anemia, MAO inhibition, tongue discoloration

Sulfonamides

GI Nausea, diarrhea.

Hepatic Cholestatic hepatitis, ↑ incidence in HIV

Rash Exfoliative dermatitis, Stevens-Johnson syndrome. More common in HIV.

Hyperkalemia Only with trimethoprim (as a component of trimethoprim-sulfamethoxazole).

Bone marrow Neutropenia, thrombocytopenia. More common in HIV.

Kernicterus Caused by unbound drug in the neonate. Premature liver cannot conjugate bilirubin. Sulfonamide displaces bilirubin from protein, resulting in excessive free bilirubin and kernicterus.

Chloramphenicol

Anemia Idiosyncratic irreversible aplastic anemia (rare). Reversible dose-related anemia.

Gray syndrome Caused by inability of neonates to conjugate chloramphenicol.

Quinolones

GI Nausea, vomiting, diarrhea.

Prolonged QT Moxifloxacin; possibly all quinolones as a class.

Drug interactions ↓ Oral bioavailability with multivalent cations.

CNS Altered mental status, confusion, seizures.

Cartilage toxicity Toxic in animal model. Despite this toxicity, appears safe in children including patients with cystic fibrosis.

Tendonitis or tendon rupture

Common in elderly, renal failure, concomitant glucocorticoids.

…

Imipenem is associated with seizures, particularly in patients with renal failure and in doses in excess of 50 mg/kg/day.

Considering R.G.’s acute onset of renal failure and his history of seizures, other carbapenems, such as meropenem or doripenem, or alternative classes of antibacterials would be preferable.

Gentamicin similarly may not be a good choice in R.G. His increased age and declining renal function predispose him to aminoglycoside nephrotoxicity and ototoxicity (cochlear and vestibular).

A reasonable recommendation pending susceptibility results would be to discontinue imipenem and gentamicin and treat with meropenem or doripenem with or without a fluoroquinolone.

ROUTE OF ADMINISTRATION

The Serratia was determined to be susceptible to ciprofloxacin. Oral ciprofloxacin was considered for the treatment of R.G.’s presumed Serratia pneumonia, but the IV route was prescribed. Why is the oral administration of ciprofloxacin reasonable (or unreasonable) in R.G.?

The proper route of antibiotic administration depends on many factors, including the severity of infection, antimicrobial oral bioavailability, and other patient factors

…

In patients who appear “septic,” blood flow often is shunted away from the mesentery and extremities, resulting in unreliable bioavailability from the gastrointestinal (GI) tract or muscles

Some drug interactions with oral agents (e.g., reduced bioavailability associated with concomitant quinolone and antacid administration and the decreased absorption of itraconazole with concurrent proton-pump inhibitor [PPI] therapy).

ANTIMICROBIAL DOSING

What dose of IV ciprofloxacin should be given to R.G.? What factors must be taken into account in determining a proper antimicrobial dose?

Selection of the appropriate dosage should be based on evidence confirming the efficacy of the dosage in the treatment of a specific infection

Patient-specific factors, including weight, site of infection, and route of elimination, also must be considered in dosage selection

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The patient’s weight is important, particularly for agents with a low therapeutic index (e.g., aminoglycosides, imipenem, flucytosine); these drugs should be dosed on a milligram per kilogram per day basis

Site of Infection An uncomplicated urinary tract infection requires lower doses

considering the high urinary drug concentrations that are achieved with most renally cleared agents

Anatomic and Physiologic Barriers For example, penetration into cerebrospinal fluid, Vitreous humor,

and the prostate gland

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Route of Elimination Renal function can be estimated via 24-hour urine collection or with

equations, such as the Cockcroft and Gault equation

Aminoglycosides, vancomycin, acyclovir, and ganciclovir are cleared primarily by the kidney. Thus, dosage adjustment is recommended for these drugs in patients with renal failure

Azithromycin, clindamycin, and metronidazole are primarily eliminated by the liver

Most β-lactams are eliminated by the kidney. In contrast, ceftriaxone and most antistaphylococcal penicillins (e.g., nafcillin, oxacillin, dicloxacillin) are eliminated both renally and nonrenally

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R.G.’s age (63 years),weight (70 kg) and current serum creatinine (3.8 mg/dL) results in a calculated creatinine clearance of 14 mL/minute. R.G. normally would be given an IV dosage of ciprofloxacin at 400 mg every 12 hours.

His increasing creatinine, however, suggests that his dosage should be decreased to 200 to 300 mg every 12 hours.

No standard liver function test (AST, ALT, alkaline phosphatase) has been demonstrated to correlate well with hepatic drug clearance

Patient Age

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Fever and Inoculum Effect Fever increases and decreases blood flow to mesenteric, hepatic, and

renal organ systems and can either increase or decrease drug clearance

As an example, piperacillin may demonstrate an MIC of 8.0 mcg/mL against P. aeruginosa at a concentration of 105 colony-forming units/mL (CFU/mL); however, at 109 CFU/mL, the MIC may increase to 32 to 64 mcg/mL.

This phenomenon is well recognized, particularly with β-lactamase–producing bacteria treated with β-lactam antimicrobials

Aminoglycosides, quinolones, and imipenem appear to be less affected by the inoculum effect than β-lactams.

PHARMACOKINETICS ANDPHARMACODYNAMICS

R.G.’s respiratory status remains unchanged; thus, the ciprofloxacin is discontinued and cefotaxime and gentamicin are started empirically. The use of a constant IV infusion of cefotaxime is being considered in R.G. In addition, the use of single daily dosing of gentamicin is being discussed. What is the rationale for these approaches, and would either be advantageous for R.G.?

Concentration dependent vs Time dependent Killing

The animal model suggests that β-lactam antimicrobials should be dosed such that their serum levels exceed the MIC of the pathogen as long as possible

This observation appears to be most important in the neutropenic model, in which the use of a constant infusion more reliably inhibits bacterial growth compared with traditional intermittent dosing

An additional benefit of the use of constant infusions of β-lactams is that smaller daily doses appear to be as effective as higher doses administered intermittently

The efficacy of quinolone antimicrobials appears to correlate with the peak plasma concentration to MIC ratio or area under the curve (AUC) to MIC ratio

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Aminoglycosides traditionally have been administered every 8 to 12 hours to achieve peak serum gentamicin levels of 5 to 8 mcg/mL to ensure efficacy in the treatment of serious gram-negative infection

Gentamicin troughs of greater than 2mcg/mL have been associated with an increased risk for nephrotoxicity

Vancomycin troughs of 5 to 10 mcg/mL have been traditionally recommended; however, more recent recommendations suggest higher troughs (10 to 20 mcg/mL) depending on the site of infection and severity of illness

Post Antibiotic Effect

Several antimicrobials (e.g., aminoglycosides) have been associated with a pharmacodynamic phenomenon known as a post antibiotic effect (PAE)

PAE is delayed regrowth of bacteria after exposure to an antibiotic (i.e., continued suppression of normal growth in the absence of antibiotic levels above the MIC of the organism)

As an example, if P. aeruginosa is cultured in broth, it will multiply to a concentration of 109 CFU/mL. If piperacillin is added in a concentration above the MIC for the organism, a reduction in the bacterial concentration is observed. When piperacillin is removed from the broth, immediate bacterial growth takes place.

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If the above experiment is repeated with gentamicinif the gentamicin is removed from the system, a lag period of 2 to 6 hours takes place before characteristic bacterial growth occurs. This lag period is defined as the PAE

A PAE also has been observed with quinolones and imipenem against gram-negative organisms.

Although most β-lactam antibiotics, such as antipseudomonal penicillins or cephalosporins, do not exhibit PAE with gram-negative organisms, PAE has been demonstrated with β-lactam with gram-positive pathogens such as S. aureus.

Once-Daily Dosing of Aminoglycosides

Single daily dosing of aminoglycosides has been investigated primarily in patients with normal renal function

Thus, patients in septic shock are less clear candidates for once-daily dosing.

In summary, the use of a constant IV infusion of cefotaxime is possible in R.G., but the benefit of this mode of administration is not clear. Considering the severity of R.G.’s infection and his elevated serum creatinine level, he is not a candidate for single daily dosing of aminoglycosides (i.e., 5 to 6 mg/kg every 24 hours).

ANTIMICROBIAL FAILURE

Despite “appropriate” treatment, R.G. is unresponsive to antimicrobial therapy. What antibiotic-specific factors may contribute to “antimicrobial failure”?

Antimicrobials may fail for various reasons, including patient specific host factors, drug or dosage selection, and concomitant disease states

One of the most common reasons is drug resistance Organisms that produce extended-spectrum (ESBL) or

amp C β-lactamases may be unresponsive to β-lactam therapy despite associated in vitro susceptibility

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Superinfection also may play a role in the unsuccessful treatment of infection

If R.G.’s ceftriaxone-treated Serratia pneumonia subsequently worsens and a tracheal aspirate returns positive for P. aeruginosa, then supercolonization and, perhaps, superinfection have occurred.

Combination Therapy

Most infections can be treated with monotherapy (e.g., an E. coli wound infection is treatable with a cephalosporin).

Some infections, however, require two-drug therapy, including most cases of enterococcal endocarditis and perhaps certain P. aeruginosa infections

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Hilf et al. studied 200 consecutive patients with P. aeruginosa bacteremia and demonstrated a 47% mortality in those receiving monotherapy (antipseudomonal β-lactam or aminoglycoside) versus 27% in those in whom two-drug therapy was used

In contrast to the findings of the previous trial, more current investigations do not support the use of two drugs over monotherapy in the treatment of serious gram-negative infection, including P. aeruginosa

An exception to this rule is bacteremia caused by P. aeruginosa in neutropenic patients

Indifference, synergism, or antagonism

An example of antagonism is the combination of imipenem with a less β-lactamase–stable β-lactam, such as piperacillin. If P. aeruginosa is exposed to imipenem and piperacillin, the imipenem induces the organism to produce increased β-lactamase

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Pharmacologic Factors Subtherapeutic dosing regimens are commonplace,

particularly for agents with a low therapeutic index, such as the aminoglycosides.

For example, a serious gram-negative pneumonia may not respond to aminoglycoside therapy if the achievable peak gentamicin serum levels are only 3 to 4 mcg/mL. Considering that only 20% to 30% of the aminoglycoside penetrates from serum into bronchial secretions, only 0.5 to 1.0 mcg/mL may exist at the site of infection level that may be inadequate to treat pneumonia

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Another example of dosing contributing to antimicrobial failure centers on the use of loading doses.

Aminoglycosides or vancomycin should be initiated with a loading dose, particularly in patients with renal failure. If the clinician neglects to use a loading dose, it may take several days before a therapeutic level is achieved.

Retrospective analyses have, however, demonstrated a high failure rate associated with vancomycin in the treatment of MRSA isolates with an MIC of 2 mcg/mL

By CLSI standards, an isolate of MRSA with an MIC of 2 mcg/mL is considered susceptible

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The pharmacodynamic parameter that serves as the best predictor of vancomycin activity against S. aureus is the AUC to MIC ratio, with a value greater than 350 independently associated with success. The probability of attaining this value with isolates with an MIC of 2 mcg/mL is 0%, even when achieving vancomycin trough concentrations of 15 mcg/mL

The infection site also potentially contributes to antimicrobial failure

Another potential reason for antimicrobial failure is inadequate therapy duration

Host Factors Infection of prosthetic material (e.g., IV catheters, orthopaedic

prostheses, mechanical cardiac valves, and vascular grafts) is difficult to eradicate without removal of the hardware.

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Similar to removal of prostheses, large undrained abscesses are difficult, if not impossible, to treat with antimicrobial therapy.

Diabetic foot ulcer cellulitis may not respond adequately to antimicrobial therapy.

Immune status, particularly neutropenia or lymphocytopenia, also affects the outcome in the treatment of infection

Profoundly neutropenic patients with disseminated Aspergillus infections are unlikely to respond to even the most appropriate antifungal therapy.

Similarly, patients with AIDS who have low CD4 lymphocyte counts cannot eradicate various infections, including those caused by cytomegalovirus, atypical mycobacteria, and cryptococci.

Other than initiation of adequate antimicrobial therapy, what adjunct measures can be considered in this patient with septic shock?

Key recommended

adjuncts include administration of broad-spectrum antibiotics within 1 hour of diagnosis of septic shock, administration of either crystalloid or colloid fluid resuscitation, and norepinephrine or dopamine to maintain mean arterial pressure of at least 65 mm Hg.

Stress-dose steroid therapy can be given to those patients whose blood pressure is poorly responsive to fluid resuscitation and vasopressors

Other adjuncts include targeting lower blood glucose levels, stress ulcer prophylaxis, and prevention of deep vein thrombosis in septic patients.

Documents

Principles of Infectious Diseases S.A. ZIAI Pharm D., PhD. Associate Professor at Pharmacology Dept