Revisiting Whether Cefepime Raises Mortality Risk

Antibiotics Deconstructed is a series where we examine newly approved, existing, and novel therapeutics.

There is a high probability that cefepime treatment increases risk of mortality relative to other ß-lactam antibiotics, albeit with effect that is small and potentially mitigable, according to interpretations of a new systematic review and bayesian meta-analysis.¹

That determination is congruent with a 2007 report of a relative increase in mortality, ² but contrasts with the FDA finding no increased mortality in its investigation of the data from that report and of unpublished, industry-sponsored trials.³

Although the question continues to be revisited in analyses, anecdotal reports, and commentaries, the Infectious Diseases Society of America (IDSA) recommends cefepime as first-line treatment of febrile neutropenia and infections from organisms with moderate risk of AmpC ß-lactamase production.⁴

"Interest in this question has recently intensified following a large observational study⁵ that suggested lower mortality with cefepime than with piperacillin-tazobactam," observe Zhara Sohani, MD, PhD,Division of Infectious Diseases and Medical Microbiology, Department of Medicine, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montreal, Quebec, Canada, and colleagues.

Sohani and colleagues conducted the present review and analysis of 30-day all-cause mortality, they indicate, "given ongoing uncertainty and the widespread use of cefepime in serious infections."

Their investigation included 110 trials comparing either monotherapies of cefepime vs another ß-lactam; or cefepime in combination with a second antimicrobial vs another ß-lactam in the same combination.The trials comprised 22,608 patients, with 11,726 receiving cefepime, and 10,882 a comparator ß-lactam.In addition to drawing on a larger evidence base than previous analyses, their review includes unpublished, industry-sponsored trials which had been considered, and were provided by the FDA (25 of 41 meeting inclusion criteria for the analysis).

Applying a bayesian random-effects model to the larger evidence base enabled the investigators to ascertain a probability of harm rather than a binary of statistical significance, which an accompanying commentary points out, "is closer to how clinicians reason."⁶

Despite that possible advantage, however, the commentators Daniel Usian, MD, MBA, and Ethan Smith, PharmD, David Geffen School of Medicine at UCLA, Los Angeles, CA. call for more direct analysis of the patient data."Twenty years of reanalyzing summary estimates is a poor substitute for access to the underlying patient-level data, and the case for releasing it is now overwhelming."⁶

Sohani and colleagues calculated a 94.4% posterior probability that the pooled odds ratio (OR) mortality exceeded 1 with cefepime use compared with other ß-lactams (778 [6.6%] vs 674 [6.2%]; OR, 1.10, 95% CI 0.98-1.24).Their meta-analysis of 73 published peer-reviewed trials comprising 15,411 patients associated cefepime with a 98.6% posterior probability of higher mortality compared with other ß-lactams (OR 1.17, 1.02-1.34).

In subgroup analyses, the investigators found the signal of increased mortality risk in adults but not children; that it was most pronounced in trials of febrile neutropenia and severe bacterial infections; and with higher doses.

"This systematic review and bayesian meta-analysis found that cefepime was associated with higher odds of all-cause mortality compared with other ß-lactams," the investigators conclude, adding "these findings support a nuanced discussion of cefepime's safety in guidance statements."

Usian and Smith concur that a "nuanced reading of its safety in future guidance" is more appropriate than a recommendation against its use.They note that the all-cause mortality outcome is a "blunt instrument" for discerning drug safety, particularly in a critically ill study population; and that mortality may stem from underexposure or overexposure dosing rather than to the drug molecule itself.

They point out that the margin of safety for cefepime is narrower than for other ß-lactams, and could warrant prospective therapeutic drug monitoring."Cefepime is not a dangerous drug in search of a replacement; it is a useful drug in search of a dose," they argue.

References

1. Sohani ZN, Zhong YJ, Afshar A, et al. Cefepime and mortlity. A systematic review and bayesian meta-analysis. JAMA Netw Open. 2026;9(9):e2633017. doi:10.1001/jamanetworkopen.2026.33017.

2. Yahav D, Paul M, Fraser A, et al. Efficacy and safety of cefepime: a systematic reviwe and meta-analysis. Lancet Infect Dis. 2007; 7(5):338-348.

3. Kim PW, Wu YT, Cooper C, et al. Meta-analysis of a possible signal of increased mortality associated with cefepime use. Clin Infect Dis. 2010; 51(4):381-389.

4. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011; 52(4):e56-e93. doi:10.1093/cid/cir073.

5. Chanderraj R, Admon AJ, He Y, et al. Mortality of patients with sepsis administered piperacillin-tazobactam vs cefepime. JAMA Intern Med. 2024; 184(7):769-777.

6. Uslan DZ, Smith EA. Cefepime and mortality—A dosing problem, not a drug problem. JAMA Netw Open. 2026;9(9):e2632904. doi:10.1001/jamanetworkopen.2026.32904.