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Aminoglycoside and β-Lactam Combination Therapy for Pseudomonas aeruginosa Bacteremia in Pediatric Patients:

Is it a Match Made in Heaven or a Beautiful Disaster?

Brittany A. Rodriguez, Pharm.D. PGY-1 Pharmacy Resident

Children’s Hospital of San Antonio Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health Science Center at San Antonio

February 12, 2016

Learning Objectives: I. Define characteristics of Pseudomonas aeruginosa (P. aeruginosa) bacteremia II. Discuss the controversy of definitive combination antibiotic therapy for P. aeruginosa bacteremia in

pediatric patients III. Analyze and differentiate evidence for and against the use of combination antibiotic therapy for P.

aeruginosa bacteremia IV. Formulate an evidence-based recommendation for P. aeruginosa bacteremia in pediatric patients

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Introduction

I. P. aeruginosa a. Aerobic gram-negative rod-shaped bacterium1 b. Found in soil and water1 c. Frequently found on the skin or in the gastrointestinal tract of healthy people2 d. Important cause of community and hospital-acquired infections3

i. Community-acquired infections: 1. Ulcerative keratitis 2. Otitis externa 3. Skin and soft tissue infections

ii. Hospital-acquired infections: 1. Pneumonias 2. Surgical site infections 3. Skin infections due to burn injuries 4. Urinary tract infections 5. Bacteremia

P. aeruginosa Bacteremia

I. Epidemiology (pediatric population)

Table 14 Nosocomial bacteremia pathogens in pediatric patients among 49 hospitals throughout the United States

Organisms Total % of isolates Crude

Mortality* (%)

No. of isolates % of isolates Age < 1yr Age 1–5yr Age >5yr

CoNS 1658 43.3 46.3 39 31 10.6 Entercoccus species 357 9.4 9.1 7.1 12.6 11.8

Candida species 355 9.3 9.3 8.2 10.5 19.6 S. aureus 351 9.2 8.4 10.3 12.4 12

Klebsiella species 223 5.8 5.8 5.2 6.5 14.5 E. coli 190 5 5.4 3.2 3.4 17.4

Enterobacter species 190 5 5.1 4.1 5.1 14.6

P. aeruginosa 121 3.2 2.4 5.4 5.3 28.7

Streptococcus species 113 3 2.3 5.2 4.5 16.1 CoNS: coagulase negative staphylococci *Crude mortality of patients with monomicrobial bacteremia

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II. Pathophysiology  Stages of Infection2 a. Stage 1: Injury

i. Cellular injury mediates the adherence of P. aeruginosa ii. Examples: trauma, surgery, serious burns, indwelling devices, etc.

b. Stage 2: Colonization and attachment i. Pili: a hair-like appendage found on the surface of P. aeruginosa

ii. Glycocalyx: a glycoprotein-polysaccharide covering that surrounds the cell membrane of P. aeruginosa resulting in a sticky, fuzz-like coat

c. Stage 3: Invasion and local infection i. Multifactorial

ii. Extracellular virulence factors produced by P. aeruginosa 1. Proteases: destroy protein elastin which is a major part of human lung tissue

and blood vessels 2. Hemolysins: act synergistically to break down lipids and lecithin 3. Exotoxin A: responsible for local tissue damage, bacterial invasion, and

immunosuppression d. Stage 4: bloodstream dissemination and systemic disease

i. Infected host: immune defenses alone cannot clear P. aeruginosa ii. Extracellular virulence factors produced by P. aeruginosa

1. Exotoxin A: kills human macrophages 2. Lipopolysaccharide (endotoxin): activates the clotting, fibrinolytic, and

complement systems and stimulates the release of vasoactive peptides

Figure 1: Pathophysiology of P. aeruginosa Bacteremia30

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III. Risk Factors

Table 2.5

Table 3. 5-8

Antimicrobial Therapy: Antipseudomonal β-Lactam and Aminoglycoside Agents

I. Aminoglycosides8,9 a. Bactericidal  bacterial killing by antimicrobial agent b. Concentration-dependent killing

i. Provides optimal bactericidal effect with higher doses to maximize the concentration above the minimum inhibitory concentration (MIC) and is generally dosed less frequently

ii. These agents have an associated concentration-dependent PAE (post antibiotic effect) in which bactericidal action continues for a period of time after the antibiotic level falls below the MIC

c. Mechanism of action (MOA) i. Interferes with bacterial protein synthesis by binding to the 30S and 50S ribosomal

subunits resulting in a defective bacterial cell membrane d. Side effects  nephrotoxicity, ototoxicity, and neurotoxicity e. Monitoring

i. Serum creatinine (SCr) ii. Creatinine clearance (CrCl)

iii. Urine output, hearing tests iv. Serum drug levels

1. Extended interval dosing a. Random drug level

Risk Factors for P. aeruginosa Bacteremia • Previous exposure to antimicrobial agents • Ventilator use in previous month

• Long hospital stay (> 30 days) • Presence of indwelling vascular catheters, urinary

catheters, drainage tubes and endotracheal intubation devices

• Care in an ICU within previous month • Immunocompromised patients

Risk Factors for Poor Prognosis Underlying disease Complications at onset of treatment Severity

• Neutropenia • Diabetes • Renal failure • Congestive heart failure • Respiratory failure • Immunocompromised

patients

• Shock • Anuria • Abnormal coagulation

• Polymicrobial • Resistant organism

Antibiotic therapy Source of infection Interval to onset of therapy

• Previous antibiotic exposure • Pneumonia • Surgery

• Delay in appropriate antimicrobial therapy

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2. Conventional dosing a. Peak level

i. Correlates with efficacy ii. Draw 30 min after the infusion has completed

iii. Goal level: 8-10 mcg/mL b. Trough level

i. Correlates with toxicity ii. Draw immediately before the next dose

iii. Goal level: ≤ 2 mcg/mL f. Dosing

i. Extended interval dosing 1. Total daily dose is given as a single dose (usually every 24hrs) 2. Nomograms for monitoring serum drug levels have not been validated in

pediatrics ii. Conventional dosing

1. Total daily dose is given in 2-3 divided doses

Table 4.8,9 Aminoglycoside Agents & Dosing

Agents Pediatric Dosing

Gentamicin

Extended Interval Dosing IV: 4.5–7.5 mg/kg/dose every 24 hrs

Conventional Dosing

Infants: IV: 2.5 mg/kg/dose every 8 hrs

Children and Adolescents: IV: 2–2.5 mg/kg/dose every 8 hrs

Tobramycin Extended Interval Dosing IV: 4.5–7.5 mg/kg/dose every 24 hrs

Conventional Dosing IV: 2.5 mg/kg/dose every 8 hrs Amikacin Conventional Dosing IV: 5-7.5 mg/kg/dose every 8 hrs

Renal adjustment dosing: See Appendix A.

II. Antipseudomonal β-Lactams8 a. Bactericidal  bacterial killing by antimicrobial agent b. Time-dependent killing

i. Provides bactericidal effect with frequent dosing to optimize the time above the MIC c. MOA

i. Inhibits bacterial cell wall synthesis by binding to one or more penicillin-binding proteins (PBPs), which in turn prevents the final transpeptidation step of peptidoglycan synthesis in the bacterial cell walls

d. Side effects  stomach upset, diarrhea, and rash/anaphylaxis e. Monitor

i. SCr ii. CrCl

iii. Symptoms of anaphylaxis with first dose

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Table 5.8 Antipseudomonal β-Lactam Agents & Dosing

Agents Class Pediatric Dosing

Piperacillin/Tazobactam (Zosyn®) Ureidopenicillin

Infants 9 months, Children, and Adolescents: IV: 100 mg/kg/dose every 8 hrs

(max: 16 g piperacillin/day) Ceftazidime

(Fortaz®, Tazicef®) 3th generation cephalosporin

IV: 70–100 mg/kg/dose every 8 hrs (max: 6000 mg/day)

Cefepime (Maxipime®)

4th generation cephalosporin

IV: 50 mg/kg/dose every 8-12 hours (max: 6000 mg/day)

Imipenem/Cilastatin (Primaxin®) Carbapenem

IV: 15–25 mg/kg/dose every 6 hrs (max: 4,000 mg/day)

Meropenem (Merrem®) Carbapenem

IV: 20 mg/kg/dose every 8 hrs (max: 3,000 mg/day)

Renal adjustment dosing: See Appendix B.

Controversy

I. Empiric therapy3 a. Antimicrobial therapy administered before final susceptibility results are available b. Initial empiric therapy is made based on the knowledge of pathogens likely to cause a particular

infection, local pathogen profiles and various host risk factors for infection II. Definitive therapy3

a. After initial regimen is prescribed, modification of the antibacterial regimen should occur based on patient’s clinical response and on the final susceptibility results

b. Controversial in the pediatric population c. Combination therapy (antipseudomonal β-lactam + aminoglycoside) vs. monotherapy

(antipseudomonal β-lactam) i. Before October 2013, no studies had evaluated which therapy regimen was more

beneficial10 ii. However, there is some data that recommends combination therapy based on the idea

that “two drugs are better than one” and this therapy continues to be prescribed10-13

Table 6.11,14 Advantages of Combination Therapy