Cefepime was linked to higher odds of all-cause mortality than other beta-lactams in a systematic review and meta-analysis that pooled 110 randomized trials and more than 22,000 patients. The comparison found death rates of 6.6% with cefepime and 6.2% with other beta-lactams, with an odds ratio of 1.10 and a 94.4% probability of increased mortality.
The finding lands where cefepime is still widely used, including as first-line treatment for febrile neutropenia and for gram-negative infections at moderate risk of ampicillin resistance locus C beta-lactamase production. That makes the new signal hard to ignore today, not because it proves harm, but because it raises a question clinicians cannot brush aside: whether the drug’s effect on outcomes depends on how it is given.
Zahra Sohani and colleagues, who led the analysis, also reported a narrower review of 73 published peer-reviewed randomized trials involving 15,411 patients. That review pointed the same way, with a 98.6% posterior probability of higher mortality, an odds ratio of 1.17 and a 95% credible interval of 1.02 to 1.34. It translated to an approximate number needed to harm of 111, compared with 227 in the larger analysis.
But the numbers do not read as a simple verdict against the drug. Sohani wrote that the analysis does not imply cefepime should no longer be used, and Daniel Uslan and Ethan Smith said the result is a signal, not a verdict. They also noted that the trials behind the signal bear limited resemblance to contemporary practice, where cefepime is often used empirically, paired with other drugs and then narrowed after the cause of infection is known.
That gap matters because newer randomized evidence has not matched the older mortality signal. The ACORN trial, which compared cefepime with piperacillin-tazobactam in adults hospitalized for acute infections, found no significant difference in 14-day mortality. In another contemporary trial of patients hospitalized with suspected sepsis, cefepime was linked to a lower mortality rate versus piperacillin-tazobactam. A meta-analysis in 2010 also found cefepime had a lower 30-day all-cause mortality rate than comparators.
The tension now is less about whether cefepime should disappear from practice than about what is driving the signal. The authors said the mortality pattern may reflect both underexposure and overexposure, not an inherent safety problem alone. Their response is not to drop cefepime from use, but to dose it adequately, at 2 g every 8 hours, and to treat the finding as a reason for more careful pharmacologic study rather than a reason for immediate abandonment.
