Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines

• DOI: 10.1016/j.ijantimicag.2021.106443
• Publication Date: 2021-09-20T21:42:41Z
• Authors: Cindy Lau; Deborah Marriott; Hayley B. Schultz; Michael Gould; David Andresen; Sebastian G. Wicha; Jan-Willem Alffenaar; Jonathan Penm; Stephanie E. Reuter
• Keywords: Adult; Male; 0303 health sciences; therapeutic drug monitoring; Microbial Sensitivity Tests; Middle Aged; toxicity threshold; Anti-Bacterial Agents; 3. Good health; 03 medical and health sciences; Risk Factors; neurotoxicity; Pseudomonas aeruginosa; cefepime; Humans; Female; Neurotoxicity Syndromes; Pseudomonas Infections; Renal Insufficiency; Drug Monitoring; Cefepime; Aged; Retrospective Studies

Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets.Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold.In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%).The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.