Population pharmacokinetics and target attainment analyses to identify a rational empirical dosing strategy for cefepime in critically ill patients.

Publication Type
Journal Article
Year of Publication
An, Guohua; Creech, C Buddy; Wu, Nan; Nation, Roger L; Gu, Kenan; Nalbant, Demet; Jimenez-Truque, Natalia; Fissell, William; Patel, Pratish C; Fishbane, Nicholas; Watanabe, Amy; Rolsma, Stephanie; Kirkpatrick, Carl M J; Landersdorfer, Cornelia B; Winokur, Patricia
J Antimicrob Chemother
Date Published
2023 Jun 01
Anti-Bacterial Agents; Cefepime; Chromatography, Liquid; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Prospective Studies; Tandem Mass Spectrometry

OBJECTIVES: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis.

PATIENTS AND METHODS: A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions.

RESULTS: The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion.

CONCLUSIONS: Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions.