Population pharmacokinetics of cefepime in febrile neutropenia: implications for dose-dependent susceptibility and contemporary dosing regimens

Nathaniel J. Rhodes, Meagan E. Grove, Patrick J. Kiel, J. Nicholas O'Donnell, Laura K. Whited, Dusten T. Rose, David R. Jones, Marc H. Scheetz

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4–8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3–8 g/day infused over 0.5–24 h, replaced every 6–24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3–4 g/day administered as continuous infusions and doses of 2 g administered q6h (0–5 h infusion) to q8h (4-h infusion) achieved ≥90% PTA at MICs up to 8 µg/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5-h infusion) achieved ≥90% PTA only against MICs up to 4 µg/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs.

Original languageEnglish (US)
Pages (from-to)482-486
Number of pages5
JournalInternational Journal of Antimicrobial Agents
Volume50
Issue number3
DOIs
StatePublished - Sep 2017

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Keywords

  • Cefepime
  • Febrile neutropenia
  • Pharmacology
  • Population pharmacokinetics
  • β-Lactams

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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