Review
Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis

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Summary

The use of combination antimicrobial therapy for bacteraemia caused by Gram-negative bacilli is controversial. We did a meta-analysis of published studies to determine whether a combination of two or more antimicrobials reduces mortality in patients with Gram-negative bacteraemia. Criteria for inclusion were: analytic studies of patients with documented Gramnegative bacteraemia that included patients receiving a single antibiotic (monotherapy) and patients receiving two or more antibiotics (combination therapy). Data on mortality (outcome) had to be provided. A pooled odds ratio was calculated with the random effects model of DerSimonian and Laird. Assessment of heterogeneity was done with the Breslow-Day test and reasons for heterogeneity were explored. 17 studies met the inclusion criteria, five prospective cohort studies, two prospective randomised trials, and ten retrospective cohort studies. Most studies used beta-lactams or aminoglycosides alone and in combination. The summary odds ratio was 0·96 (95% CI 0·70–1·32), indicating no mortality benefit with combination therapy. Subgroup analyses adjusting for year of publication, study design, and severity of illness did not change the results. Considerable heterogeneity was present in the main analyses. Analysis of only Pseudomonas aeruginosa bacteraemias showed a significant mortality benefit (OR 0·50, 95% CI 0·30–0·79). Our analysis does not support the routine use of combination antimicrobial therapy for Gram-negative bacteraemia, beyond settings where infection by P aeruginosa is strongly suspected or more than one drug would be desirable to assure in-vitro efficacy.

Section snippets

Search strategy and selection criteria

We searched the following databases: Medline (Jan 1 1966–2003), Current Contents (Jan 1 1993–Aug 1 2003), Pubmed (Jan 1 1966–Aug 1, 2003), CancerLit, and the Cochrane Network. The following MeSH keywords were used alone and in combination: “Gram-negative bacteraemia”, “combination antibiotic”, “antibiotic”, “antimicrobial”, “mortality”, “Pseudomonas aeruginosa”, “Serratia”, “Klebsiella”, “Escherichia coli”, “bloodstream infection”, and “neutropenic fever”. The term Gram-negative bacteraemia was

Results

Of the 471 studies identified by the initial search strategy, 17 met the inclusion criteria, encompassing 3077 patients.19, 20, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 The remainder were excluded because they did not adequately compare combination and single antimicrobial therapy (326), were not studies of bacteraemia (76), did not use mortality as an outcome measure (50), did not provide sufficient data to calculate an odds ratio for mortality (1),48 or had no fatal outcomes

Adverse events of monotherapy and combination therapy

Only one study44 reported the adverse effects of combination or monotherapy among the 17 included studies. In a randomised trial, de Pauw et al44 found that, overall, adverse events were 2·9 times more frequent in patients treated with the combination of piperacillin with tobramycin than in patients treated only with ceftazidime. The adverse effects consisted of renal toxicity, skin rash, and ototoxicity.

Discussion

Gram-negative bacilli cause serious, life-threatening infections, especially in neutropenic or critically ill patients. Several studies have convincingly shown that appropriate antimicrobial therapy, defined as the use of at least one antibiotic active in vitro against the causative organism, leads to lower mortality rates in Gram-negative bacteraemia. A landmark study by McCabe and Jackson50 in the early 1960s reported a reduction in mortality associated with Gram-negative bacteraemia in 173

Search strategy and selection criteria

These are described in detail in the Methods section on page 519.

References (75)

  • DM Shlaes et al.

    Combination antimicrobial therapy

    Pediatr Clin North Am

    (1983)
  • P Furno et al.

    Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis

    Lancet Infect Dis

    (2002)
  • BE Kreger et al.

    Gramnegative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients

    Am J Med

    (1980)
  • E Bouza et al.

    Serratia bacteremia

    Diagn Microbiol Infect Dis

    (1987)
  • Y Siegman-Igra et al.

    Pseudomonas aeruginosa bacteremia: an analysis of 123 episodes, with particular emphasis on the effect of antibiotic therapy

    Int J Infect Dis

    (1998)
  • H Giamarellou

    Aminoglycosides plus beta-lactams against gram-negative organisms. Evaluation of in vitro synergy and chemical interactions

    Am J Med

    (1986)
  • JK Pohlman et al.

    Timed killing kinetic studies of the interaction between ciprofloxacin and beta-lactams against gram-negative bacilli

    Diagn Microbiol Infect Dis

    (1996)
  • DG Maki

    Risk factors for nosocomial infection in intensive care. Devices vs nature and goals for the next decade

    Arch Intern Med

    (1989)
  • HS Gold et al.

    Antimicrobial-drug resistance

    N Engl J Med

    (1996)
  • GS Itokazu et al.

    Antimicrobial resistance rates among aerobic gram-negative bacilli recovered from patients in intensive care units: evaluation of a national postmarketing surveillance program

    Clin Infect Dis

    (1996)
  • L Archibald et al.

    Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit

    Clin Infect Dis

    (1997)
  • SandersWE et al.

    Enterobacter spp: pathogens poised to flourish at the turn of the century

    Clin Microbiol Rev

    (1997)
  • GW Waterer et al.

    Increasing threat of Gram-negative bacteria

    Crit Care Med

    (2001)
  • National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1992 to June 2002

    Am J Infect Control

    (2002)
  • DM Livermore

    Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare?

    Clin Infect Dis

    (2002)
  • SE Cosgrove et al.

    Health and economic outcomes of the emergence of third-generation cephalosporin resistance in Enterobacter species

    Arch Intern Med

    (2002)
  • DM Shlaes

    The clinical relevance of enterobacter infections

    Clin Ther

    (1993)
  • MS Niederman

    Impact of antibiotic resistance on clinical outcomes and the cost of care

    Crit Care Med

    (2001)
  • A Harris et al.

    Epidemiology and clinical outcomes of patients with multiresistant Pseudomonas aeruginosa

    Clin Infect Dis

    (1999)
  • Y Carmeli et al.

    Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa

    Arch Intern Med

    (1999)
  • M Barza et al.

    Excess infections due to antimicrobial resistance: the “attributable fraction”

    Clin Infect Dis

    (2002)
  • KS Kaye et al.

    Multidrug-resistant pathogens: mechanisms of resistance and epidemiology

    Curr Infect Dis Rep

    (2000)
  • MJ Rybak et al.

    Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician

    Drugs

    (1996)
  • M Paul et al.

    Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis

    BMJ

    (2003)
  • R DerSimonian

    Meta-analysis in the design and monitoring of clinical trials

    Stat Med

    (1996)
  • NE Breslow et al.

    Statistical methods in cancer research

  • M Egger et al.

    Bias in meta-analysis detected by a simple, graphical test

    BMJ

    (1997)
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