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

Guohua An, C. Buddy Creech, Nan Wu, Roger L. Nation, Kenan Gu, Demet Nalbant, Natalia Jimenez-Truque, William Fissell, Pratish C. Patel, Nicholas Fishbane, Amy Watanabe, Stephanie Rolsma, Carl M.J. Kirkpatrick, Cornelia B. Landersdorfer, Patricia Winokur

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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.

Original languageEnglish
Pages (from-to)1460-1470
Number of pages11
JournalJournal of Antimicrobial Chemotherapy
Issue number6
Publication statusPublished - Jun 2023

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