Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis - A systematic review with meta-analysis and trial sequential analysis

Objectives: To assess benefits and harms of empirical mono- vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (ICU).

Methods: We performed a systematic review according to the Cochrane Collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (TSA). We included randomised clinical trials (RCT) assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult ICU patients with severe sepsis. We exclusively assessed patient-important outcomes, including mortality. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated and the risk of random errors was assessed by TSA.

Results: Thirteen RCTs (n = 2633) were included; all were judged as having high risk of bias. Carbapenems were the most frequently used mono-antibiotic (8 of 13 trials). There was no difference in mortality (RR 1.11, 95% CI 0.95-1.29; p = 0.19) or in any other patient-important outcomes between mono- vs. combination therapy. In TSA of mortality, the Z-curve reached the futility area, indicating that a 20% relative risk difference in mortality may be excluded between the two groups. For the other outcomes, TSA indicated lack of data and high risk of random errors.

Conclusions: This systematic review of RCTs with meta-analysis and TSA demonstrated no differences in mortality or other patient-important outcomes between empirical mono- vs. combination antibiotic therapy in adult ICU patients with severe sepsis. The quantity and quality of data was low without firm evidence for benefit or harm of combination therapy.