Comparison of cefepime versus piperacillin-tazobactam or meropenem for risk for delirium and neurotoxicity among patients hospitalized for acute infection: two target trial emulation studies

Cefepime, piperacillin–tazobactam, and meropenem are commonly used broad-spectrum β-lactam antibiotics for hospitalized patients with acute infection. Concerns persist regarding cefepime-associated neurotoxicity, but comparative real-world evidence is limited. The objective of the target trial emulations is to compare the risk of hospital-onset delirium and other neurotoxicity events among adults treated initially with cefepime versus piperacillin–tazobactam or meropenem. Retrospective observational cohort study emulating 2 target trials using propensity score–matched analyses of electronic health record data (January 1, 2023 to December 31, 2024) from patients admitted to a fourteen-hospital integrated health system including academic, community, suburban, and rural hospitals. Adults (≥ 18 years) hospitalized with suspected or confirmed acute infection who received initial treatment with cefepime, piperacillin–tazobactam or meropenem in the emergency department or within 12 h of ICU admission were included. The primary outcome was incident hospital-onset delirium or other neurotoxicity events identified using ICD-CM-10 codes with a “not present on admission” indicator. After matching, 4,447 patient pairs (cefepime versus piperacillin-tazobactam) and 1,262 pairs (cefepime versus meropenem) were analyzed. Cefepime was not associated with a higher risk of combined delirium or neurotoxicity versus piperacillin-tazobactam (relative risk, 0.99; 95% CI, 0.80–1.22; incidence rate difference [IRD] per 100 patient days, 0.00; 95% CI, − 0.13 to 0.13) or meropenem (relative risk, 1.09; 95% CI, 0.75–1.59; IRD per 100 patient days, 0.07; 95% CI, − 0.16 to 0.30). No difference between groups in either study was observed in mortality at 30 days or hospital length of stay. Secondary outcomes findings were consistent with the primary outcome result and robust across subgroup and sensitivity analyses. Cefepime was not associated with higher risk of delirium or neurotoxicity compared with piperacillin–tazobactam or meropenem, suggesting neurotoxicity risk alone should not guide empiric antibiotic selection.