Aminoglycoside and β-Lactam Combination Therapy for...

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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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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 <2 months: IV: 100 mg/kg/dose every 6 hrs

Infants 2 to 9 months: IV: 80 mg/kg/dose every 8 hrs

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

Synergistic Interaction

• Definition: effect of 2 or more agents combined to produce a greater effect than the sum of their individual effects

• Traditionally been seen with β-lactam–aminoglycoside combinations • Combination therapy allows for different mechanisms of bacterial killing • β-Lactam-mediated disturbance of the cell walls of gram-negative bacilli facilitates

passage of aminoglycosides into the periplasmic space Dosage Reduction

with Decreased Toxicity

• Combination therapy may permit the dosage of one or both agents to be reduced, which may result in a decrease in the frequency of dose-related toxicity

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Table 7.10,14,15 Disadvantages of Combination Therapy

Risk of Fungal & Bacterial

Superinfection

• Isolation of a pathogen responsible for a subsequent infection and of a species different from the initially isolated pathogen

• Superinfecting pathogens are often significantly more resistant than the pathogen initially isolated

Risk for Adverse Drug Effects

Nephrotoxicity • MOA: aminoglycosides accumulate in the kidney, with approximately 85% of the

drug found in the renal cortex. They bind to glycoproteins on the brush borders of renal tubular cells, which is necessary for internalization of the drug. When there is significant accumulation of the drug in the cytosol, aminoglycosides activate apoptosis, causing cell death

Ototoxicity • MOA: aminoglycosides penetrate into the vestibular and cochlear tissue,

damaging the sensory air cells in the cochlea and labyrinth

Higher Cost • Therapeutic monitoring of drug levels • Additional drug acquisition, preparation, and administration

P. aeruginosa Bacteremia in the Adult Population

I. Majority of the literature favors monotherapy once susceptibilities are available because studies have not found a difference in mortality when compared to combination therapy and there is less risk of adverse drug effects16

II. Several meta-analyses of randomized clinical trials with Pseudomonas bacteremia have included subgroup analyses evaluating risks vs. benefits of combination therapy, and all but one meta-analysis (Safdar et al.) found an advantage to combination therapy–survival benefit.17-21

Table 8. Summary of Meta-Analysis by Safdar et al.14,22 Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia? A meta-analysis. Lancet Infect. Dis. 2004;4:519–527.

Summary of Meta-Analysis Trials Included 17 studies (10 retrospective, 5 prospective cohort, 2 RCTs); 3,077 patients

Clinical Outcome Mortality Acquired Setting 53% were nosocomially-acquired

Most Common Source Respiratory tract or urinary tract Overall OR, 0.96; 95% CI, 0.70-1.32

P. aeruginosa (Subgroup Analysis) OR, 0.50; 95% CI, 0.32-0.79

Conclusion Monotherapy is effective as combination therapy; combination therapy beneficial for Pseudomonas bacteremia

CI: confidence interval; OR: odds ratio; For complete summary of trials: See Appendix C.

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Table 9. Summary of Subgroup Analysis from Safdar et al. 22 Subgroup Analysis of P. aeruginosa Bacteremia

Author Type of Study (n) Patient Population Setting Intervention

Tapper et al.23 1974 Retrospective 50 Malignancy Nosocomial Mono: ESBL, AG

Combo: ESBL + AG Hilf et al.24

1989 Prospective 200 General inpatients Nosocomial Mono: ESBL, AG

Combo: ESBL + AG Mendelson et al.25 1994 Retrospective 21 HIV/AIDS Community Mono: ESBL, AG

Combo: ESBL + AG Igra et al.26

1998 Retrospective 57 General inpatients Nosocomial Mono: ESBL, FQ

Combo: ESBL or FQ + AG Kuikka et al.27 1998 Retrospective 132 General

inpatients Nosocomial Mono: ESBL, AG, FQ Combo: AG or FQ + ESBL

AG: aminoglycoside; Combo: combination therapy; ESBL: extended spectrum beta-lactam; FQ: fluoroquinolone; Mono: monotherapy; (n): number of patients

III. Limitations of Meta-Analysis

a. Small subgroup analysis b. Dosing regimens and duration of therapy were not provided Safdar et al. could not correlate

these factors with survival c. Retrospective, observational studies unidentified confounding factors could not be ruled out d. Patients’ background underlying disease and severity of illness may have had a role in

determining the outcome of bacteremia, despite the antimicrobial treatment used

Literature Review Table 10.24

Hilf M, Yu VL, Sharp J, et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med. 1989;87:540-546.

Objective To analyze in vitro susceptibility and synergistic testing of antibiotics the patients received and clinical parameters to assess their relationship to survival

Study Design Prospective, multihospital clinical study at 8 Pittsburgh area hospitals from June 1982-June 1986

Population Inclusion Exclusion

Patients from whom P. aeruginosa was isolated in blood culture

Patients with polymicrobial episodes of infection

Intervention

• Definitive therapy: Combination (antipseudomonal β-lactam + aminoglycoside) vs. monotherapy (antipseudomonal β-lactam or aminoglycoside)

In Vitro Antibiotic Susceptibility Testing In Vitro Synergistic Testing

• Performed without knowledge of clinical outcome

• Antipseudomonal agent(s) selected for in vitro testing was the same agent the patient received for the bacteremia

• Performed by microdilution techniques

• Performed on isolates taken from patients who received combination therapy

• Performed by checkerboard technique and time-kill curves

Outcomes • Survival: defined as surviving 10 days after the onset of bacteremia • Mortality: defined as death within 10 days after the onset of bacteremia

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• Clinical parameters, in vitro susceptibility and synergistic test results for antibiotics the patient received, were assessed in their relationship to patient survival

Statistics

• Fisher’s exact test or χ2 test • Mann-Whitney rank sum test • Logistic regression model • Kaplan-Meier estimate • Mantel-Cox log rank and the Gehan-Breslow test

Results

• Baseline characteristics: the patient population that received combination therapy was comparable to those receiving monotherapy; See Appendix D.

Clinical Parameters • Association between increased mortality and presence of

neutropenia in patients receiving combination therapy p Value <0.05

• Patients whose portal of entry was the urinary tract had an improved survival rate vs. patients with non-urinary tract portals

p Value = 0.001

• Patients with pneumonia had a higher mortality rate p Value < 0.05 • Patients who were critically ill had a lower survival rate p Value < 0.01

Microbiologic Parameters • Improved outcome could not be demonstrated for patients

receiving antibiotic combinations that were synergistic in vitro vs. those combinations that were not

p Value = 0.10

Antibiotics • The 142 patients that received combination therapy had a 27%

mortality rate vs. patients receiving monotherapy who had a 47% mortality rate

p Value = 0.023

• Improved survival in patients given combination therapy was seen in these patient subgroups: nosocomial origin, pneumonia, and critically ill

p Values = 0.04, 0.033, and 0.016

respectively • Probability of survival during the 30-day period following a

positive blood culture result was better for patients receiving combination therapy

p Value = 0.041

Multivariate Analysis • Combination antibiotic therapy, urinary tract portal, and

absence of neutropenia were found to be associated with survival

p Values = 0.004, 0.052, and 0.03,

respectively

Author’s Conclusion

Despite failing to demonstrate any significant correlation between in vitro susceptibility and synergistic testing vs. outcome, this study strongly supported the use of combination therapy for Pseudomonas bacteremia. There were less mortalities in the combination therapy group and there was improved survival among a subgroup of patients who were severely ill.

Critique

Advantages Disadvantages • Large sample size • Controlled for severity of illness at the

time of bacteremia • Logistic regression model

• Limited inclusion and exclusion criteria • Allocation of patients • 22% received monotherapy (majority

with aminoglycoside) • Therapeutic drug concentration of

aminoglycosides were not reported

Take-Home Even though less mortalities were seen in the combination group, including those in the subgroup analysis, the validity of the results may be compromised by the fact that the majority (84%) of monotherapy patients received inadequate monotherapy with an

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aminoglycoside. Several studies have shown poor clinical outcomes when aminoglycosides are used as monotherapy.28,29

Table 11.29 Leibovici L, Paul M, Poznanski O, et al. Monotherapy versus β-lactam–aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. J Virol. 1997;41(5):1127-1133.

Objective To test whether the combination of a β-lactam drug plus an aminoglycoside has advantage over monotherapy for severe gram-negative infections

Study Design A prospective, observational study at Beilinson Medical Center, Petah-Tiqva, Israel, from 1988 to 1995

Population Inclusion Exclusion

Patients with a single gram-negative microorganism in the blood with evidence of infection

Patients with polymicrobial episodes of infection

Intervention • Empirical and definitive treatment:

− Combination therapy (β-lactam + aminoglycoside) vs. monotherapy (β-lactam) − Monotherapy (β-lactam) vs. monotherapy (aminoglycoside)

Outcomes

• Mortality or discharge • Duration of hospitalization • Duration of fever • Persistent positive blood cultures during follow-up

Statistics

• χ 2 test: contingency tables • Cochran-Mantell-Haenzel test • Breslow-Day test • Wilcoxon and Kruskal-Wallis tests • Stratified analysis and logistic regression analysis

Results

• Baseline characteristics: 2,165 patients; the patient population that received combination therapy was comparable to those receiving monotherapy; See Appendix E.

Empirical Treatment • See Appendix F.

Definitive Treatment • Of 1,878 patients given definitive treatment, 11% were given

inappropriate antibiotic treatment; mortality rate was 25% vs. 17% for patients given appropriate treatment

p Value < 0.0001

Definitive Treatment: combination vs. β-lactam monotherapy • Mortality rate for patients given combination therapy was 15% (67 of 442 patients) vs.

13% (109 of 816 patients) for patients given a single β-lactam drug • Patients were stratified according to risk factors for mortality and therapies were

compared; no advantage could be shown • Duration of hospital stay and fever, and the percentages of patients with persistent

positive blood cultures were similar • For patients infected with P. aeruginosa, the mortality rates were

32% (13 of 41) with single therapy and 21% (7 of 34) with combination therapy

OR, 0.6; 95% CI, 0.2 to 1.6

Definitive Treatment: aminoglycoside vs. β-lactam monotherapy • Of 193 patients given an aminoglycoside, 23% died p Value < 0.01 • Median hospital stay was 10 days (aminoglycoside) vs. 8 days (β-

lactam drug) p Value = 0.0001

• Duration of fever and the percentages of patients with persistent positive blood cultures were similar

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Author’s Conclusion

Combination therapy should be used only for neutropenic patients and patients at high risk for Pseudomonal infections. Other patients with gram-negative bloodstream infections are served best by treatment with a single appropriate β-lactam antibiotic.

Critique

Advantages Disadvantages • Pathogens were susceptible in vitro to the

antibiotics • Patients were stratified according to risk

factors for mortality • Used logistic regression analysis for a

multivariate analysis of risk factors for mortality

• Other endpoints besides mortality were analyzed

• Minimal data on P. aeruginosa bacteremia

• Did not mention side effects or adverse drug reactions

• Endpoints were not well-defined

Take-Home

Combination therapy with an aminoglycoside plus an antipseudomonal β-lactam should not be used as definitive therapy for P. aeruginosa bacteremia because no advantage has been seen with this regimen over monotherapy with an antipseudomonal β-lactam. Additionally, this study has shown an increase in mortality rates and a longer duration of hospital stay when aminoglycosides are used as monotherapy.

Table 12.10

Tamma PD, Turnbull AE, Harris AD, et al. Less is more: combination antibiotic therapy for the treatment of gram-negative bacteremia in pediatric patients. JAMA Pediatrics. 2013;167(10):903-910.

Objective To determine whether definitive combination antibiotic therapy affects mortality and nephrotoxicity in pediatric patients with gram-negative bacteremia

Study Design Retrospective cohort study at Johns Hopkins Children’s Center in Baltimore, Maryland, from January 1, 2002 – December 31, 2011

Population

Inclusion Exclusion • ≤ 18 years of age • Gram-negative bacteremia • Clinical signs and symptoms of

infection

• Polymicrobial bacteremia • Did not receive appropriate gram-negative

therapy within 24 hours after obtaining first positive blood culture result

• Received an antibiotic regimen other than a β-lactam with or without the addition of an aminoglycoside as definitive therapy

• Died within 48 hours after obtaining their first positive blood culture result

Interventions • Definitive treatment: combination therapy (aminoglycoside + β-lactam) vs. monotherapy (β-lactam)

Outcomes

• 30-day mortality from any cause from the first positive blood culture result • Nephrotoxicity (±RIFLE criteria) limited to risk, injury, and failure

− Risk: ↑in SCr to 1.5x baseline and/or urine output < 0.5 mL/kg/h for at least 6 hours

− Injury: ↑ in SCr to at least 2x baseline and/or urine output < 0.5 mL/kg/h for at least 12 hours

− Failure: ↑ in SCr to at least 3x baseline and/or urine output < 0.3 mL/kg/h for at least 24 hours or anuria for at least 12 hours

Statistics • Percentages for categorical variables, and means and standard deviations for

continuous variables • Propensity scores

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• Multivariable logistic regression • Unadjusted odds ratios (ORs) • All covariates with P < 0.20 in the unadjusted model were entered into a doubly robust,

adjusted model incorporating weights and potential confounders

Results

Baseline characteristics: 879 patients; See Appendix G. • Combination therapy: 537 patients (61.1%); Monotherapy: 342 (38.9%) • P. aeruginosa (257 pts; 22%): second most common organism identified • Zosyn: most commonly prescribed β-lactam (37.3%) • After patients receiving monotherapy were weighted, baseline demographic and

clinical characteristics between the groups were well balanced • Exception: patients with Pseudomonas bacteremia remained more likely to receive

combination therapy (p Value = 0.01) Mortality

• 41 deaths (7.6%) in combination therapy and 23 (6.7%) in monotherapy group p Value = 0.61

• No association between combination therapy and mortality in the weighted multivariable regression model

OR, 0.98; 95% CI, 0.93-1.02

• Failure to remove central venous lines; > 6x the odds of mortality in an unadjusted model

OR, 6.46; 95% CI, 3.04-13.71

• Failure to remove central venous lines; significant after controlling for relevant confounders

OR, 2.11; 95% CI, 2.07-2.15

• No difference in Pseudomonas bacteremia–associated mortality between the combination therapy and monotherapy groups in an adjusted model

p Value not available

Nephrotoxicity • Acute renal toxicity developed in 135 (25.1%) of those receiving combination therapy

vs. 35 (10.2%) of those receiving monotherapy

• Patients receiving combination therapy had > 2x the odds of nephrotoxicity and this persisted after adjustment for the receipt of additional nephrotoxic agents, *PRISM III score, and age

OR, 2.95; 95% CI, 1.97-4.41; OR, 2.15; 95% CI, 2.09-2.21, and OR, 2.15;

95% CI, 2.09-2.21, respectively

• Patients receiving aminoglycoside therapy: 68.8%, 27.4%, and 3.7% were in the risk, injury, and failure categories, respectively

Author’s Conclusion

The use of β-lactam monotherapy for definitive treatment in pediatric patients with gram-negative bacteremia is favored over combination therapy because it decreases the development of nephrotoxicity without affecting mortality.

Critique

Advantages Disadvantages • Calculated propensity scores for

each patient and achieved balance of measured demographic and clinical variables

• Removal of central lines within 72 hours after obtaining the first positive blood culture result

• Study definitions were well laid out

• Cannot conclude whether aminoglycoside-related nephrotoxicity in childhood contributes to chronic renal failure later in life

• Did not monitor serum drug levels of aminoglycosides

Take-Home De-escalation of therapy should occur once Pseudomonas has been identified in the bloodstream and when susceptibilities have returned. Monotherapy with an

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antipseudomonal β-lactam agent should be initiated for definitive treatment because no difference has been seen in mortality when comparing the two regimens. Additionally, monotherapy may decrease the risk of developing nephrotoxicity.

± RIFLE: risk for renal dysfunction, injury to kidney, failure of kidney function, loss of kidney function, and end-stage renal disease; *PRISM III score: Pediatric Risk of Mortality

Summary of Evidence Limited studies in the pediatric population evaluating combination therapy (antipseudomonal β-lactam plus aminoglycoside) vs. monotherapy (antipseudomonal β-lactam) as definitive treatment for P. aeruginosa bacteremia

• Evaluated adult studies in order to extrapolate data for the pediatric population • Evaluated the first pediatric study to discuss this treatment controversy

Table 13.10,24,29

Summary of Literature Literature Treatment Regimens Outcomes

Hilf et al.

• Combination (antipseudomonal β-lactam + aminoglycoside) vs. monotherapy (antipseudomonal β-lactam or aminoglycoside)

Survival and/or Mortality • There is no difference in mortality when

using combination therapy (antipseudomonal β-lactam + aminoglycoside) vs. monotherapy (antipseudomonal β-lactam)

• Aminoglycosides should not be used as monotherapy to treat Pseudomonas bacteremia because results of previous studies show poor clinical outcomes

Leibovici et al.

• Combination (antipseudomonal β-lactam + aminoglycoside) vs. monotherapy (antipseudomonal β-lactam)

• Monotherapy (antipseudomonal β-lactam) vs. monotherapy (aminoglycoside)

Tamma et al.

• Combination (β-lactam + aminoglycoside) vs. monotherapy (β-lactam)

Survival and/or Mortality • There is no difference in mortality when

using combination therapy vs. monotherapy

Adverse Effects • Monotherapy decreases development of

nephrotoxicity

Recommendation

I. P. aeruginosa bacteremia in pediatric patients de-escalation to monotherapy with an antipseudomonal β-lactam will provide optimal therapy and limit unnecessary antibiotic exposure

Conclusion

I. P. aeruginosa is a major cause of nosocomial infection, particularly in critically ill, immunocompromised patients and is associated with greatly prolonged hospitalization, increased costs and has a high rate of morbidity and mortality.

II. De-escalation of therapy must occur when susceptibilities are available. III. In the literature, antipseudomonal β-lactam monotherapy is favored because there is less risk of

nephrotoxicity and there is no difference in clinical outcomes when compared to combination therapy.

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Appendices Appendix A.8

Renal Adjustment for Aminoglycoside Agents Agents Renal Adjustment Dosing

Gentamicin

GFR >50 mL/minute/1.73 m2: No adjustment required GFR 30–50 mL/minute/1.73 m2: Administer every 12–18 hrs GFR 10–29 mL/minute/1.73 m2: Administer every 18–24 hrs GFR <10 mL/minute/1.73 m2: Administer every 48–72 hrs

Tobramycin

GFR >50 mL/minute/1.73 m2: No adjustment required GFR 30–50 mL/minute/1.73 m2: Administer every 12–18 hrs GFR 10–29 mL/minute/1.73 m2: Administer every 18–24 hrs GFR <10 mL/minute/1.73 m2: Administer every 48–72 hrs

Amikacin

GFR >50 mL/minute/1.73 m2: No adjustment required GFR 30-50 mL/minute/1.73 m2: Administer every 12-18 hrs GFR 10-29 mL/minute/1.73 m2: Administer every 18-24 hrs GFR <10 mL/minute/1.73 m2: Administer every 48-72 hrs

Appendix B.8

Renal Adjustment for Antipseudomonal β-Lactam Agents Agents Renal Adjustment Dosing

Piperacillin/Tazobactam (Zosyn®)

GFR >50 mL/minute/1.73 m2: No adjustment required GFR 30–50 mL/minute/1.73 m2: 35–50 mg/kg/dose every 6 hrs GFR <30 mL/minute/1.73 m2: 35–50 mg/kg/dose every 8 hrs

Ceftazidime (Fortaz®, Tazicef®)

GFR >50 mL/minute: No adjustment required GFR 30-50 mL/minute: 50 mg/kg/dose every 12 hrs GFR 10-29 mL/minute: 50 mg/kg/dose every 24 hrs GFR ≤10 mL/minute: 50 mg/kg/dose every 48 hrs

Cefepime (Maxipime®)

GFR >50 mL/minute/1.73 m2: No adjustment needed GFR 10-50 mL/minute/1.73 m2: 50 mg/kg/dose every 24 hrs GFR <10 mL/minute/1.73 m2: 50 mg/kg/dose every 48 hrs

Imipenem/Cilastatin (Primaxin®)

GFR 30–50 mL/minute/1.73 m2: 7–13 mg/kg/dose every 8 hrs GFR 10–29 mL/minute/1.73 m2: 7.5–12.5 mg/kg/dose every 12 hrs GFR <10 mL/minute/1.73 m2: 7.5–12.5 mg/kg/dose every 24 hrs

Meropenem (Merrem®)

GFR >50 mL/minute/1.73 m2: No adjustment required GFR 30–50 mL/minute/1.73 m2: 20–40 mg/kg/dose every 12 hrs GFR 10–29 mL/minute/1.73 m2: 10–20 mg/kg/dose every 12 hrs GFR <10 mL/minute/1.73 m2: 10–20 mg/kg/dose every 24 hrs

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Appendix C.22

Safdar et al. Meta-Analysis Summary of Trials

Author Type of Study Organisms Studied (n) Patient

Population Intervention Underlying Diseases

Tapper et al. 1974 Retrospective P. aeruginosa 50 Malignancy ESBL, AG Neutropenia

Kreger et al. 1980 Retrospective Multiple 612 General

outpatients ESBL, AG CHF,

diabetes, malignancy

Piccart et al. 1984 Prospective, RCT Multiple 23 Malignancy ESBL, AG Neutropenia

McCue et al. 1985 Retrospective

E. coli (51%), P. aeruginosa

(11%) 319 General

outpatients ESBL, AG Malignancy,

diabetes, neutropenia

de la Torre et al. 1985 Retrospective Klebsiella spp 100 General

inpatients Not reported Malignancy, heart disease

McCue. 1987 Retrospective E. coli (54%) 315 General outpatients ESBL, AG Not reported

Bouza et al. 1987 Retrospective Serratia spp 50 General

outpatients ESBL, AG COPD, cancer

Hilf et al. 1989 Prospective P. aeruginosa 200 General inpatients ESBL, AG

Malignancy, critically ill,

neutropenia

Feldman et al. 1990 Prospective Klebsiella spp 47 General

inpatients ESBL, AG, FQ Alcoholism, neoplastic

disease

Chow et al. 1991 Prospective Enterobacter

spp 129 General inpatients ESBL, AG, FQ

Malignancy, trans-

plantation

Leibovici et al. 1997 Prospective

Multiple, P. aeruginosa

(16%) 2,165 General

outpatients ESBL, AG Malignancy, CHF, renal

failure Korvick et al.

1992 Prospective Klebsiella spp 230 General inpatients ESBL, AG Malignancy,

diabetes Mendelson et

al. 1994 Retrospective P. aeruginosa 21 HIV/AIDS ESBL, AG PCP

De Pauw et al. 1994 Prospective, RCT Multiple 23 Not reported ESBL, AG Malignancy

Igra et al. 1998 Retrospective P. aeruginosa 57 General

inpatients ESBL, AG, FQ Malignancy

Kuikka et al. 1998 Retrospective P. aeruginosa 132 General

inpatients ESBL, AG, FQ Surgical, renal disease

Kim et al. 2002 Retrospective Klebsiella

oxytoca (34%) 125 General oupatients ESBL, AG, FQ Malignancy

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RCTs: randomized control trials; ESBL: extended spectrum beta-lactam; AG: aminoglycoside; FQ: fluoroquinolone; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; PCP: Pneumocystis carinii pneumonia

Appendix D.24 Hilf et al. Baseline Characteristics

Age Mean: 59 yo Community-acquired bacteremia 23% (46 of 200) Nosocomial-acquired bacteremia 77% (154 of 200)

Were in intensive-care units when bacteremia developed 34% (67 of 200) Immunosuppressed 58% (115 of 200)

Undergone invasive procedures within 7 days before onset of bacteremia 84% (168 of 200) Placement of intravascular catheters 86% (144 of 168)

Urinary tract catheters 55% (110 of 168) Required mechanical ventilator assistance 45% (76 of 168)

Undergone surgery within 7 days prior to the positive blood culture 34% (57 of 168) Appendix E.29

Leibovici et al. Baseline Characteristics Men 51% (1,106 of 2,165) Age Mean: 70 yo

Hospital-acquired bacteremia 38% (821 of 2,165)

Most common pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

39% (844 of 2,165), 17% (368 of 2,165), and

16% (346 of 2,165), respectively

Most common sources of bacteremia: urinary tract and unknown source 44% (952 of 2,165), and 21% (455 of 2,165), respectively

Median duration of hospital stay from the day of the first positive blood culture 8 days (range: 1–320 days)

Median duration of fever 2 days (range: 0–70 days) Median interval from the first to the last positive blood culture 5 days

Incomplete details on antibiotic treatment 1.9% (41 of 2,165) Appendix F.29

Leibovici et al. Empirical Treatment • Of 670 patients given inappropriate empirical antibiotic treatment, 228 died (34%) vs.

1,454 patients given appropriate empirical antibiotic where 268 patients died (18%) p Value = 0.0001

Empirical Treatment: combination vs. β-lactam monotherapy • Fatality rate for patients given appropriate empirical combination therapy (19%) was not different from

that of patients given an appropriate β-lactam drug (17%) • When patients were stratified according to risk factors for mortality; no advantage could be shown • On multivariable logistic regression analysis including all risk factors for mortality; no advantage could be

shown • The percentages of positive cultures during antibiotic treatment were 2% for patients

treated with a β-lactam and 1% for patients given combination therapy OR, 0.4;

95% CI, 0.1 to 1.4 • Duration of hospital stay and fever were similar

Empirical Treatment: aminoglycoside monotherapy vs. β-lactam monotherapy

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• Of 249 patients given only an appropriate aminoglycoside, 24% died p Value < 0.01 • Median hospital stay for patients treated with an aminoglycoside was 9.5 days vs. 8

days for patients given a β-lactam p Value = 0.001

• Duration of fever and the percentages of patients with persistent positive blood cultures were similar Appendix G.10

Tamma et al. Baseline Characteristics

Characteristic Combination

Therapy (n = 537)

Monotherapy, Unweighted

(n = 342)

P Value, Combination vs.

Unweighted

Mono- therapy,

Weighted

P Value, Combination vs. Weighted

Age, mean (SD), y 5.7 (6.4) 6.4 (7) 0.09 5.7 (6.5) 0.99 Female sex 39.9 43.6 0.28 44.8 0.18 Prematurity

(≤ 33 wk gestation) 16.2 12 0.08 12.3 0.14

Hematological 3.9 8.5 0.01 11.3 .07 Neuromuscular 6.1 9.4 0.09 10 0.08 Cardiovascular 8.2 5.8 0.18 7 .55

Respiratory 6.7 5.6 0.49 8 0.66 Gastrointestinal 30.5 18.1 <0.001 21 0.01

Renal 8.4 9.4 0.62 10 .58 Immuno-

compromised 16 22.2 0.02 20.3 0.16

Cancer 21.8 38.9 <0.001 26.3 0.20 Genetic or metabolic 10.4 7 0.08 9 0.56

Second- or third-degree burns 1 1 0.74 1.4 0.58

No. of pre-existing conditions, mean

(SD) 1.3 (0.6) 1.2 (0.6) 0.06 1.3 (0.6) 0.19

Highest PRISM III score, mean (SD) 7.6 (8.8) 7.1 (7.6) 0.37 7.7 (8.4) 0.99

ICU admission 46.7 35.7 0.001 45 0.57 Vasopressors 18.8 13.7 0.04 19.2 0.96 Mechanical ventilation 29.1 15.5 <0.001 24.6 0.19

Time at risk, mean (SD) 17.9 (33.4) 16.8 (35.2) 0.09 19.4 (39.5) 0.65

Absolute neutrophil count ≤100 cells/μL 13.1 10.2 0.01 12.2 0.35

Central line in place 72h after first positive blood culture result

58.1 49.1 0.01 54.6 0.45

Pseudomonas bacteremia 29.1 16.1 <0.001 19.3 0.01

Urine 12.7 7.3 0.01 6.5 0.003

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Pleural or broncho-alveolar lavage fluid 4.5 5.3 0.60 2.5 0.27

Bone/joint specimens 1 2 0.13 3.5 0.08

Intra-abdominal fluid 1 1.8 0.32 1.6 0.61

Cerebrospinal fluid 1.7 1 0.12 1.3 .60 Abbreviations: ICU, intensive care unit; PRISM, Pediatric Risk of Mortality; combination therapy: a β-lactam and an aminoglycoside; monotherapy: only a β-lactam; data represent percentages unless otherwise indicated

References

1. Grisaru-Soen G, Lerner-Geva L, Keller N, et al. Pseudomonas aeruginosa bacteremia in children: analysis of trends in prevalence, antibiotic resistance and prognostic factors. Pediatr Infect Dis J. 2000;19(10):959–963.

2. Pollack M. The virulence of pseudomonas aeruginosa. Rev Infect Dis. 1984;6(3):617-626. 3. Driscoll J, Brody S, Kollef M. The epidemiology, pathogenesis and treatment of pseudomonas aeruginosa

infections. Drugs. 2007;67(3):351-368. 4. Wisplinghoff H, Bischoff T, Tallent S, et al. Nosocomial bloodstream infections in US hospitals: analysis of

24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2003;39:309-317. 5. Yang M, Lee J, Choi E, et al. Pseudomonas aeruginosa bacteremia in children over ten consecutive years:

Analysis of clinical characteristics, risk factors of multi-drug resistance and clinical outcomes. J Korean Med Sci. 2011;26:612-618.

6. Jacobson M, Young L. New developments in the treatment of gram-negative bacteremia. West J Med. 1986;144:185-194.

7. Delden C. Pseudomonas aeruginosa bloodstream infections: how should we treat them. Int J Antimicrob Agents. 2007;30:71-75.

8. Taketomo C, Hodding J, Kraus D. Pediatric & neonatal dosage handbook. 20th ed. Hudson, Ohio: Lexicomp; 2013.

9. Kothari U, Krilov L. Aminoglycosides. Pediatr Rev. 2012;33(11):531-533. 10. Tamma P, Turnbull A, Harris A, et al. Less is more: combination antibiotic therapy for the treatment of

gram-negative bacteremia in pediatric patients. JAMA Pediatrics. 2013;167(10):903-910. 11. Chadwick E, Yogev R, Shulman S. Combination antibiotic therapy in pediatrics. Am J Med. 1986;80(6):166-

171. 12. Congeni B. Antibiotic susceptibility. Pediatr Rev. 2009;30(12):499-501. 13. Pai S, Enoch D, Aliyu S. Bacteremia in children: epidemiology, clinical diagnosis and antibiotic treatment.

Expert Rev Anti Infect Ther. 2015;13(9):1073-1088. 14. Tamma P, Cosgrove S, Maragakis L. Combination therapy for treatment of infections with gram-negative

bacteria. Clin Microbiol Rev. 2012;25(3):450–470. 15. Bliziotis I, Samonis G, Vardakas K, et al. Effect of aminoglycoside and beta-lactam combination therapy

versus beta-lactam monotherapy on the emergence of antimicrobial resistance: A meta-analysis of randomized, controlled trials . Clin Infect Dis. 2005;41:149-158.

16. Klibanov O, Raasch R, Rublein J. Single versus combined antibiotic therapy for gram-negative infections. Ann Pharmacother. 2004;38:332–337.

17. Paul M, Soares-Weiser K, Grozinsky S, et al. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia . Cochrane Database Syst Rev. 2003;3:CD003038.

18. Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: Systematic review and meta-analysis. 2003. BMJ;326:1111.

19. Marcus R, Paul M, Elphick H. Clinical implications of beta-lactam-aminoglycoside synergism: Systematic review of randomized trials. Int J Antimicrob Agents. 2011;37:491–503.

20. Elphick H, Tan A. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis. Cochrane Database Syst. 2005;CD002007.

Page 19: Aminoglycoside and β-Lactam Combination Therapy for ...sites.utexas.edu/pharmacotherapy-rounds/files/2016/02/rodriguez-12feb2016.pdfAminoglycoside and β-Lactam Combination Therapy

Rodriguez | 19

21. Paul M, Benuri-Silbiger I, Soares-Weiser K, et al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: Systematic review and meta-analysis of randomised trials . BMJ. 2004;328:668.

22. Safdar N, Handelsman J, Maki D. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004;4:519-527.

23. Tapper M, Armstrong D. Bacteremia due to pseudomonas aeruginosa complicating neoplastic disease: A progress report S14–23. J Infect Dis. 1974;130:S14–23.

24. Hilf M, Yu V, Sharp J, et al. Antibiotic therapy for pseudomonas aeruginosa bacteremia: Outcome correlations in a prospective study of 200 patients. Am J Med. 1989;87:540-546.

25. Mendelson M, Gurtman A, Szabo S, et al. Pseudomonas aeruginosa bacteremia in patients with AIDS. Clin Infect Dis. 1994;18:886–895.

26. Siegman-Igra Y, Ravona R, Primerman H, et al. Pseudomonas aeruginosa bacteremia: An analysis of 123 episodes, with particular emphasis on the effect of antibiotic therapy . Int J Infect Dis. 1998;2:211–215.

27. Kuikka A, Valtonen V. Factors associated with improved outcome of pseudomonas aeruginosa bacteremia in a finnish university hospital. Eur J Clin Microbiol Infect Dis. 1998;17:701–708.

28. Chatzinikolaou I, Abi-Said D, Bodey G, et al. Recent experience with pseudomonas aeruginosa bacteremia in patients with cancer: Retrospective analysis of 245 episodes. Arch Intern Med. 2000;160:501-509.

29. Leibovici L, Paul M, Poznanski O, et al. Monotherapy versus β-lactam–aminoglycoside combination treatment for gram-negative bacteremia: A prospective, observational study. J Virol. 1997;41(5):1127-1133.

30. Delden C, Iglewski B. Cell-to-cell signaling and pseudomonas aeruginosa Infections. http://wwwnc.cdc.gov/eid/article/4/4/98-0405_article. Accessed 1/28, 2016.