Pharmacokinetics/Pharmacodynamics Evaluation of Flomoxef against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli In Vitro and In Vivo in a Murine Thigh Infection Model

Sho Tashiro, Marina Hayashi, Wataru Takemura, Yuki Igarashi, Xiaoxi Liu, Yuki Mizukami, Nana Kojima, Yuki Enoki, Kazuaki Taguchi, Yuta Yokoyama, Tomonori Nakamura, Kazuaki Matsumoto

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC24/MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalPharmaceutical research
Volume38
Issue number1
DOIs
Publication statusPublished - 2021 Jan

Keywords

  • extended-spectrum beta-lactamase-producing Escherichia coli
  • flomoxef
  • murine thigh infection model
  • pharmacokinetics/pharmacodynamics
  • time–kill curves

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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