Cefepime and Mortality

Importance Cefepime is recommended for the treatment of febrile neutropenia and gram-negative infections at moderate risk of ampicillin resistance locus C β-lactamase production. Concerns regarding cefepime’s safety have been raised in the literature without firm conclusions. Objective To conduct a systematic review and bayesian random-effects meta-analysis of all randomized clinical trials (RCTs) comparing cefepime with other β-lactams for all-cause mortality. Data Sources Cochrane Central Register of Controlled Trials, Medline, Embase, Web of Science, World Health Organization–International Clinical Trials Registry Platform, ClinicalTrials.gov, and LILACS were searched from inception to May 25, 2026. Study Selection Randomized clinical trials of children and adults comparing either (1) cefepime monotherapy vs any β-lactam monotherapy or (2) combination therapy of cefepime and a second drug vs β-lactam and the same second drug. Studies of prophylactic cefepime or cefepime and β-lactamase inhibitor combinations were excluded. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Two independent reviewers extracted data and assessed the risk of bias using the Cochrane risk-of-bias tool, version 2.0. Main Outcomes and Measures The main outcome was all-cause mortality (30-day or closest reported). Odds of mortality were synthesized using a hierarchical bayesian random-effects model on the log-odds scale. The posterior probabilities of increased mortality (odds ratio [OR] >1) with cefepime for the overall analysis and relevant subgroups were examined. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Results Synthesis of 110 trials including 22 608 patients (cefepime: 11 726 patients [approximately 56% male]; comparator β-lactam: 10 882 patients [approximately 56% male]) showed a 94.4% posterior probability that the pooled OR mortality exceeded 1 with cefepime use compared with other β-lactams (778 [6.6%] vs 674 [6.2%]; OR, 1.10, 95% credible interval, 0.98-1.24). Meta-analysis of published peer-reviewed RCTs (73 trials, 15 411 patients) showed that cefepime was associated with a 98.6% posterior probability of higher mortality compared with other β-lactams (OR, 1.17; 95% credible interval, 1.02-1.34). Posterior distributions generally favored higher odds of mortality across all comparator β-lactams, across all clinical indications, and with doses of 2 g or more every 12 hours. Conclusions and Relevance This systematic review and bayesian meta-analysis found that cefepime was associated with higher odds of all-cause mortality compared with other β-lactams. These findings support a nuanced discussion of cefepime’s safety in guidance statements.