Objective To conduct an exploratory comparison of the differences in neurotoxicity characteristics and onset patterns between cefepime and third-generation cephalosporins using the FDA Adverse Event Reporting System (FAERS) database and propensity score matching (PSM).

Methods Reports were extracted from the FAERS database from the first quarter of 2004 to the first quarter of 2026, cases with concomitant use of antiepileptic drugs were excluded, and reports identifying target cephalosporins as the primary suspect drug were included. Signal detection was performed using the reporting odds ratio (ROR) method and the Bayesian confidence propagation neural network (BCPNN) approach. A 1∶1 propensity score matching (PSM) was conducted adjusted for age, gender and report year, followed by exploratory sensitivity analysis. A neurotoxicity fingerprint was established, and the Weibull model was applied to characterize the distribution of time-to-onset (TTO). All statistical analyses were implemented with Python 3.11.7.

Results A total of 1,056 relevant neurotoxicity ADE reports were included, including 339 reports related to cefepime and 717 reports associated with third-generation cephalosporins. After 1:1 PSM, 313 matched cases were obtained in the cefepime group. Patients in the cefepime group were predominantly elderly (64.3% aged ≥ 65 years), with males accounting for 57.52%. The neurotoxicity signal intensity of cefepime (ROR = 9.82, 95%CI [8.67, 11.11]) was significantly higher than that of third-generation cephalosporins after PSM (ROR = 10.86, 95%CI [7.70, 15.34]). Cefepime exhibited a specific neurotoxicity fingerprint centered on encephalopathy, status epilepticus and myoclonus, whereas the neurotoxicity spectrum of third-generation cephalosporins was relatively mild and scattered. The median TTO of cefepime-induced neurotoxicity was 6.0 days, and relevant signals could be continuously detected throughout the medication period.

Conclusion Cefepime's neurotoxicity surveillance signals are significantly stronger than those of third-generation cephalosporins, with reported events concentrated within the first week of therapy, consistent with the drug accumulation hypothesis. Enhanced neurological monitoring throughout the treatment course is warranted when prescribing cefepime, particularly for elderly patients and those receiving prolonged therapy.

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