Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis

Background: Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have certain advantages over beta-lactam monotherapy. Objectives: We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE (1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted all corresponding authors. Selection criteria: We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis. Data collection and analysis: The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible. Main results: We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same beta-lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75 to 1.35) and clinical failure, RR 1.11 (95% CI 0.95 to 1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71 to 1.01), clinical failure RR 0.77 (95% CI 0.69 to 0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23 to 0.39). We found no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. Authors' conclusions: The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.