title: Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.
abstract: 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.
  
  
  OBJECTIVE
  We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis.
  
  
  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.
  
  
  METHODS
  We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis.
  
  
  METHODS
  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.
  
  
  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 0.75-1.35) and clinical failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). 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 0.23-0.39). 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.
  
  
  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.
authors.affiliation: Internal Medicine E, Rabin Medical Center, Beilinson Campus, Petah-Tikva, Israel, 49100. pil1pel@zahav.net.il
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: I
authors.initials: I
authors.lastname: Silbiger
authors.forename: S
authors.initials: S
authors.lastname: Grozinsky
authors.forename: K
authors.initials: K
authors.lastname: Soares-Weiser
authors.forename: L
authors.initials: L
authors.lastname: Leibovici
mesh_terms: D000617:Aminoglycosides / Q000627:therapeutic use*; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D002423:Cause of Death; D004359:Drug Therapy, Combination; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D047090:beta-Lactams / Q000627:therapeutic use*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D047090:beta-Lactams