Zahra Sohani reported that cefepime was associated with higher odds of all-cause mortality than other beta-lactams in a systematic review and meta-analysis published in JAMA Network Open. The analysis pooled 110 randomized trials with over 22,000 patients and found a 94.4% probability of increased mortality with cefepime.
The 110-trial analysis put mortality at 6.6% with cefepime and 6.2% with other beta-lactams. It reported OR 1.10 with a 95% credible interval of 0.98-1.24, and an approximate number needed to harm of 227.
Zahra Sohani and the 110 trials
Sohani said, "This analysis does not imply that cefepime should no longer be used." She and the study authors said the result should prompt "a cautious and nuanced interpretation of cefepime's role in a given patient's therapy, stimulate prospective investigation into optimized dosing for both efficacy and safety, and be considered in the creation of future guidance statements".
The pooled data matter because the comparison was not limited to one infection or one hospital setting. It drew on randomized trials of cefepime against other beta-lactams across more than 22,000 patients, which makes the mortality signal large enough to shape dosing questions rather than just trial-by-trial interpretation.
Daniel Uslan on cefepime
Daniel Uslan wrote in the accompanying editorial, "This is a signal, not a verdict," and argued that cefepime is often given empirically, sometimes with other drugs, before clinicians narrow therapy once the infective organism is identified. He said the proper response is not to strike cefepime from febrile neutropenia guidelines or to avoid it for susceptible Pseudomonas aeruginosa.
Uslan also pointed to recent findings that cut against a simple drug-wide explanation. The ACORN trial comparing cefepime with piperacillin-tazobactam in adults hospitalized for acute infections showed no significant difference in 14-day mortality, and another contemporary trial in patients hospitalized with suspected sepsis linked cefepime to a lower mortality rate versus piperacillin-tazobactam.
Earlier cefepime reviews
The newer 110-trial analysis also sits alongside an earlier peer-reviewed review of 73 randomized trials with 15,411 patients. That review found a 98.6% posterior probability of higher mortality with cefepime, with OR 1.17 and a 95% credible interval of 1.02-1.34, plus an approximate number needed to harm of 111.
Those two pooled estimates do not point in the same direction with equal force, but they both leave cefepime under a stronger mortality spotlight than comparators. The authors said the pattern may reflect an inherent safety concern with cefepime or an issue with pharmacologic exposure, and they said the issue could potentially be mitigated by considering the organism's minimum inhibitory concentration, optimized dosing, and therapeutic drug monitoring for exposure-related toxic effects.
The practical take-away is narrow but immediate: cefepime is not being pulled from use, but its dose and exposure deserve closer attention in high-risk infections. Whether the mortality signal reflects the drug itself, pharmacologic exposure, or trial conditions remains the open question left by the analysis.
