Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments

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

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

Original languageEnglish
Pages (from-to)1839-1846
Number of pages8
JournalPharmaceutical research
Volume38
Issue number11
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • Beta-lactamase
  • Cefmetazole
  • Escherichia coli
  • Murine thigh infection model
  • Pharmacokinetics/pharmacodynamics

ASJC Scopus subject areas

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

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