Mortality signal prompts closer look at cefepime use

Clinical Takeaway: Continue to use cefepime when it is the best choice for the suspected or confirmed infection, but tailor dosing to kidney function, monitor for neurotoxicity, and reassess therapy when culture and susceptibility results become available.

Cefepime is widely used for febrile neutropenia and serious gram-negative infections, including those caused by organisms at risk for AmpC β-lactamase production. A new analysis suggests its benefits should be weighed against a possible small increase in mortality relative to other β-lactam antibiotics.

The systematic review included 110 randomized trials involving 22,608 children and adults. Death occurred in 6.6% of patients treated with cefepime and 6.2% treated with another β-lactam—a difference of 0.4 percentage points, or approximately one additional death for every 227 patients treated. Researchers estimated a 94.4% probability that mortality was higher with cefepime, although the findings did not rule out no difference between treatments.

The signal was stronger when the analysis was limited to 73 peer-reviewed trials. In those studies, researchers estimated a 98.6% probability of higher mortality with cefepime, with approximately one additional death for every 111 patients treated.

The association appeared most pronounced in adults, patients with febrile neutropenia or severe bacterial infections, and those receiving at least 2 g of cefepime every 12 hours. No mortality signal was identified in children.

Interpretation is complicated by unpublished trials, most of which were industry-sponsored studies previously provided to the FDA. These trials favored cefepime and reduced the apparent mortality difference. Because methodological details were limited, researchers could not determine whether the discrepancy reflected publication bias or differences in patients, dosing, comparators, or outcome assessment. Overall confidence in the evidence was rated moderate, and the analysis could not establish that cefepime directly causes death.

The mortality difference could reflect challenges at both ends of cefepime exposure. Excess exposure can cause neurotoxicity, especially in older adults, critically ill patients, and those with impaired kidney function. Conversely, inadequate exposure may lead to treatment failure when an organism has reduced susceptibility. The findings reinforce the importance of kidney-adjusted dosing, attention to minimum inhibitory concentrations when available, monitoring for new neurologic symptoms, and timely de-escalation based on microbiology results.

“This analysis does not imply that cefepime should no longer be used,” the investigators emphasized. Instead, the findings support more deliberate, patient-specific use and further study of dosing strategies that balance effectiveness and safety.

Source: Sohani ZN, et al. (2026 Sep 10) JAMA Netw Open. Cefepime and mortality: A systematic review and Bayesian meta-analysis