Cefepime Tied to Higher All-Cause Mortality Than Other Beta-Lactams in 110-Trial Bayesian Meta-Analysis
核心洞察
A systematic review and Bayesian meta-analysis of 110 randomized trials found cefepime was associated with higher odds of all-cause mortality than comparator beta-lactam antibiotics.
Mortality occurred in 6.6% of cefepime-treated patients versus 6.2% of comparator patients, a pooled odds ratio of 1.10 (95% credible interval 0.98-1.24).
The posterior probability that cefepime was associated with greater mortality reached 94.4% overall and 98.6% in the 73 published peer-reviewed trials.
Cefepime, a widely used intravenous cephalosporin, was associated with higher odds of all-cause mortality than other beta-lactam antibiotics in a systematic review and Bayesian meta-analysis of 110 randomized clinical trials published Sept. 10 in JAMA Network Open (搜索). The analysis, led by Zahra N. Sohani of the Division of Infectious Diseases and Medical Microbiology at Hôpital Maisonneuve-Rosemont (搜索), CIUSSS de l'Est-de-l'Île-de-Montréal, in Montreal, found a 94.4% posterior probability that cefepime was associated with greater mortality than comparator beta-lactams.
The pooled analysis included 22,608 patients, of whom 11,726 received cefepime and 10,882 received a comparator beta-lactam. Mortality occurred in 778 patients (6.6%) in the cefepime group compared with 674 patients (6.2%) in comparator groups, a difference of roughly four additional deaths per 1,000 patients studied. The pooled odds ratio was 1.10 (95% credible interval, 0.98-1.24), and the estimated number needed to harm ranged from 111 to 227.
Signal Strengthens in Published Peer-Reviewed Trials
When the analysis was restricted to the 73 published peer-reviewed trials involving 15,411 patients, the probability of higher mortality with cefepime rose to 98.6% (OR, 1.17; 95% credible interval, 1.02-1.34). The trend toward higher mortality was generally observed across different comparator beta-lactams, clinical indications and cefepime doses of 2 g or more every 12 hours.
The investigators searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov and LILACS from inception through May 25, 2026. Eligible studies compared cefepime with another beta-lactam in children or adults and reported all-cause mortality.
Dosing Window Cited as Possible Mechanism
The authors suggested the mortality signal may relate to both underexposure and overexposure, given cefepime's relatively narrow therapeutic window. Cefepime is cleared from the body through the kidneys, so doses must be adjusted for patients with reduced kidney function. FDA prescribing information already warns that the drug can cause neurologic side effects, including confusion, seizures and reduced consciousness, particularly when patients with kidney problems receive doses that are too high.
Cefepime is widely used for conditions including febrile neutropenia (搜索) and infections caused by Gram-negative organisms with potential AmpC beta-lactamase (搜索) production, as well as pneumonia (搜索) and certain urinary tract infections (搜索). It is also used in patients whose immune systems are weakened.
Adults Show Clearer Signal Than Children
The finding was clearer in adults than in children; the study did not find a clear difference in deaths among children who received cefepime. The researchers noted that the patients across the included trials had very different illnesses, received different doses and were compared against different antibiotics, and that some unpublished trials included in the analysis found results pointing in the other direction.
The authors also flagged methodological limitations. Many included studies were open-label, potentially allowing treatment modifications after randomization, and limited information from unpublished trials restricted assessment of their methodology. All-cause mortality is a broad outcome that may reflect underlying illness, particularly among patients with cancer, rather than a specific drug-related mechanism.
Authors Stop Short of Calling for Withdrawal
The researchers emphasized that the findings do not mean cefepime should be abandoned, and they did not call for the drug to be pulled from use. Instead, they said the observed mortality signal supports careful consideration of cefepime's role in individual patients and highlights the need for prospective studies examining dosing strategies that balance antimicrobial effectiveness with safety. Further research is warranted to determine whether optimized dosing can reduce potential harm and to inform future clinical guidelines.
For clinicians, the authors' stated implications center on when cefepime is the best choice, how it is dosed, and whether some patients may benefit from another antibiotic. Patients with questions about the drug are advised to ask their care team why it was chosen, whether the dose is adjusted for kidney function, and whether other treatment options exist for their specific infection, and not to stop an antibiotic without consulting the medical team treating the infection.