Incidence of Potentially Neurotoxic Cefepime Trough Concentrations Using Published Thresholds

Introduction: Higher cefepime trough concentrations increase the risk for cefepime-induced neurotoxicity (CIN). The relationship between cefepime dosing and resultant trough concentrations during critical illness is unknown. The objective of this study was to determine the proportion of cefepime trough concentrations that were higher than two recommended thresholds for CIN in critically ill patients despite receiving label- or clinical practice guideline-directed dosing.


Methods: This single-center retrospective cohort study was conducted at an academic medical center and included patients ≥18 years of age who were admitted to any ICU between April 2020 and January 2025, had a total cefepime trough concentration measured ( < 2 hours before next scheduled dose), and received label- or clinical practice guideline-directed dosing accounting for both estimated renal function and indication. Threshold trough concentrations for CIN were >20 mcg/mL, endorsed by Antimicrobial Therapeutic Drug Monitoring in Critically Ill Adult Patients (ATDM), and >16 mcg/mL, a concentration threshold associated with 50% risk of CIN (Boschung-Pasquier et al., 2019). Continuous data are reported as median (IQR) and frequency data is number (%).


Results: A total of 185 patients were screened and 77 (42%) were included in the analysis. Median age was 61 (46, 69) years, most patients were male (50/77; 65%), and had an estimated creatinine clearance of 104 (79, 183) mL/min. The most common indications for cefepime were lower respiratory tract infection (44/77; 57%) and meningitis (10/77; 13%), and the most common doses were 2 gm IV q12h (32/77; 42%) and 2 gm IV q8h (30/77; 39%). The median total cefepime trough concentration was 21 (12, 43) mcg/mL. Using the ATDM threshold of >20 mcg/mL for CIN, 41/77 (53%) patients had a potentially neurotoxic cefepime trough concentration, while using the Boschung-Pasquier threshold of >16 mcg/mL, 53/77 (69%) had a potentially neurotoxic cefepime trough concentration.


Conclusions: Cefepime trough concentrations were frequently above published CIN thresholds despite administering label- or clinical practice guideline-directed dosing. Future studies of cefepime dosing during critical illness should account for both safety and effectiveness.