Review
β-Lactam plus aminoglycoside or fluoroquinolone combination versus β-lactam monotherapy for Pseudomonas aeruginosa infections: A meta-analysis

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Abstract

The objective of this review was to compare the effectiveness and safety of β-lactam combined with aminoglycoside or fluoroquinolone with that of β-lactam monotherapy for the treatment of Pseudomonas aeruginosa infections. We searched Scopus and PubMed databases and synthesised the outcomes of the individual studies in a meta-analysis. Both non-randomised studies and randomised controlled trials (RCTs) that evaluated outcomes of patients with P. aeruginosa infections receiving treatment with β-lactams alone or in combination with an aminoglycoside or a fluoroquinolone were included. Studies including patients with cystic fibrosis were excluded. Nineteen articles (eight RCTs) were included (1721 patients with P. aeruginosa infections). Patients receiving combination therapy had no difference in mortality compared with patients receiving β-lactam monotherapy either as definitive (risk ratio = 0.97, 95% confidence interval 0.77–1.22) or as empirical treatment (1.02, 0.78–1.34). In the definitive treatment group, no difference in mortality was found between combination therapy and monotherapy for patients with bacteraemia (0.95, 0.67–1.34) or severe infections (0.96, 0.75–1.24). Patients receiving definitive combination therapy had non-significantly higher clinical cure compared with patients receiving β-lactam monotherapy (1.36, 0.99–1.86). A higher clinical cure rate was observed for patients receiving empirical treatment with combination therapy (1.23, 1.05–1.43). There was no difference in clinical cure either for RCTs (1.29, 0.91–1.83) or for non-randomised studies (1.18, 0.97–1.45). In conclusion, no benefit in mortality was observed in patients receiving combination therapy for P. aeruginosa infections. A well-designed multicentre RCT is warranted to address this important issue.

Introduction

Pseudomonas aeruginosa is among the leading causes of infections in hospitalised and immunocompromised patients and is associated with significant morbidity and mortality [1], [2]. It has been suggested that a combination of antibiotics might be more effective than monotherapy at least for severe infections, and combination therapy with a β-lactam plus an aminoglycoside or a fluoroquinolone has been proposed in the guidelines of several medical associations [3]. Findings of in vitro studies suggested that synergism was accomplished against P. aeruginosa strains when two drugs that target a different or even the same bacterial mechanism are combined [4], [5]. Similar studies suggested that development of resistance is prevented by combination antibiotic regimens [6], [7]. Furthermore, in an era of increasing antibiotic resistance, adequate empirical treatment is more likely with the use of a combination of antibiotics.

Several efforts have been made through meta-analyses of randomised controlled trials (RCTs) to investigate whether combination antibiotic therapy was associated with better clinical outcomes than monotherapy. However, these meta-analyses either included a small number of patients with P. aeruginosa infections, or a variety of antibiotic classes were compared in the treatment arms of the included studies [8], [9], [10], [11]. We aimed to review systematically and to synthesise the published evidence with the methodology of meta-analysis in order to examine whether combination antibiotic therapy of β-lactam with either aminoglycoside or fluoroquinolone was associated with more favourable clinical outcomes compared with β-lactam monotherapy in patients with P. aeruginosa infections.

Section snippets

Literature search

A systematic search was performed in the PubMed and Scopus databases until April 2012. The following search term was applied: ‘(pseudomonas OR aeruginosa) AND (combination OR monotherapy) AND (mortality OR outcome)’. The bibliographies of relevant studies were also hand-searched to identify additional potentially eligible studies. Articles published in languages other than English, German, French, Spanish, Italian or Greek were not evaluated. Unpublished studies presented at scientific

Results

Fig. 1 shows the process used for article selection. Nineteen articles from those retrieved from the literature search were included [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. A total of 8675 patients were enrolled, of whom 1721 had P. aeruginosa infections. Table 1 shows the reason for exclusion of RCTs from the meta-analysis.

Table 2 shows the characteristics of the 19 selected studies and their outcomes. Eight studies

Discussion

The published available evidence suggests that the combination of a β-lactam with an aminoglycoside or fluoroquinolone does not result in a survival benefit in patients with P. aeruginosa infections compared with β-lactam monotherapy. Most of the studies reported on mortality of patients receiving definitive treatment. Fewer data regarding empirical treatment were available. In addition, all but one of the studies that provided data on mortality were non-randomised, and none of those that

References (46)

  • American Thoracic Society

    Infectious Diseases Society of America, Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia

    Am J Respir Crit Care Med

    (2005)
  • H. Giamarellou et al.

    In vitro synergistic activities of aminoglycosides and new β-lactams against multiresistant Pseudomonas aeruginosa

    Antimicrob Agents Chemother

    (1984)
  • D.E. Johnson et al.

    Efficacy of single-agent therapy with azlocillin, ticarcillin, and amikacin and β-lactam/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia in granulocytopenic rats

    Am J Med

    (1986)
  • J.C. Pechère et al.

    Emergence of resistance after therapy with antibiotics used alone or combined in a murine model

    J Antimicrob Chemother

    (1986)
  • M. Paul et al.

    β Lactam monotherapy versus β lactam–aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials

    BMJ

    (2004)
  • M. Paul et al.

    β Lactam monotherapy versus β lactam–aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis

    BMJ

    (2003)
  • I.A. Bliziotis et al.

    Impact of definitive therapy with β-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia

    PLoS One

    (2011)
  • G.P. Bodey et al.

    Pseudomonas bacteremia. Retrospective analysis of 410 episodes

    Arch Intern Med

    (1985)
  • I. Chatzinikolaou et al.

    Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: retrospective analysis of 245 episodes

    Arch Intern Med

    (2000)
  • M. Chaudhary et al.

    Efficacy and safety evaluation of fixed dose combination of cefepime and amikacin in comparison with cefepime alone in treatment of nosocomial pneumonia patients

    Curr Clin Pharmacol

    (2008)
  • A. Cometta et al.

    Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients

    Antimicrob Agents Chemother

    (1994)
  • A. Del Favero et al.

    A multicenter, double-blind, placebo-controlled trial comparing piperacillin–tazobactam with and without amikacin as empiric therapy for febrile neutropenia

    Clin Infect Dis

    (2001)
  • A. Endimiani et al.

    Pseudomonas aeruginosa bloodstream infections: risk factors and treatment outcome related to expression of the PER-1 extended-spectrum β-lactamase

    BMC Infect Dis

    (2006)
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