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

Abstract

Objective: To compare beta lactam monotherapy with beta lactam-aminoglycoside combination therapy for severe infections.

Data sources: Medline, Embase, Lilacs, Cochrane Library, and conference proceedings, to 2003; references of included studies; contact with all authors. No restrictions, such as language, year of publication, or publication status.

Study selection: All randomised trials of beta lactam monotherapy compared with beta lactam-aminoglycoside combination therapy for patients without neutropenia who fulfilled criteria for sepsis.

Data selection: Two reviewers independently applied selection criteria, performed quality assessment, and extracted the data. The primary outcome assessed was all cause fatality by intention to treat. Relative risks were pooled with the random effect model (relative risk < 1 favours monotherapy).

Results: 64 trials with 7586 patients were included. There was no difference in all cause fatality (relative risk 0.90, 95% confidence interval 0.77 to 1.06). 12 studies compared the same beta lactam (1.02, 0.76 to 1.38), and 31 studies compared different beta lactams (0.85, 0.69 to 1.05). Clinical failure was more common with combination treatment overall (0.87, 0.78 to 0.97) and among studies comparing different beta lactams (0.76, 0.68 to 0.86). There was no advantage to combination therapy among patients with Gram negative infections (1835 patients) or Pseudomonas aeruginosa infections (426 patients). There was no difference in the rate of development of resistance. Nephrotoxicity was significantly more common with combination therapy (0.36, 0.28 to 0.47). Heterogeneity was not significant for these comparisons.

Conclusions: In the treatment of sepsis the addition of an aminoglycoside to beta lactams should be discouraged. Fatality remains unchanged, while the risk for adverse events is increased.

Fig 1

Detail of trial selection. The list of excluded references (w1-w80) can be found on bmj.com

Fig 2

All cause fatality in comparison of β lactam monotherapy v β lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight

Fig 3

Clinical failure in comparison of β lactam monotherapy v β lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight

Fig 4

Bacteriological failure in comparison of β lactam monotherapy v β lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight

Fig 5

Summary relative risks for outcome relating to resistance development in comparison of β lactam monotherapy v β lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight

Fig 6

Adverse events: nephrotoxicity in comparison of β lactam monotherapy v β lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight

Fig 7

Sensitivity analyses Randomisation methods were classified as A=adequate; B=unknown; C=inadequate. Central randomisation, inaccessible computer randomisation, and sealed opaque envelopes were considered adequate for allocation concealment. Table of random numbers, computer generated lists, and consecutive selection were considered adequate for allocation generation. ^*Fatality comparison includes studies that reported results for all randomised patients (ITT=intention to treat) v studies reporting results for evaluable patients only (PP=per protocol). Studies that did not state method of analysis and did not refer to drop outs are not included. Failure comparison includes studies that reported results or drop outs for all randomised patients (drop outs counted as failures, ITT) v studies performed per protocol that did not state number of drop outs per study arm (PP). Results with all studies combined in this graph differ from those attained in main comparison because drop outs are counted as failures (relative risk 0.92, 0.82 to 1.03). †Comparison for studies comparing same β lactam was not performed as only one study used blinding