EvidenceAlerts

IMPORTANCE: Cefepime is recommended for the treatment of febrile neutropenia and gram-negative infections at moderate risk of ampicillin resistance locus C ß-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 ß-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 ß-lactam monotherapy or (2) combination therapy of cefepime and a second drug vs ß-lactam and the same second drug. Studies of prophylactic cefepime or cefepime and ß-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 ß-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 ß-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 ß-lactams (OR, 1.17; 95% credible interval, 1.02-1.34). Posterior distributions generally favored higher odds of mortality across all comparator ß-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 ß-lactams. These findings support a nuanced discussion of cefepime's safety in guidance statements.

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