Fecal pharmacokinetics/pharmacodynamics characteristics of fidaxomicin and vancomycin against Clostridioides difficile infection elucidated by in vivo feces-based infectious evaluation models

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Abstract

Objectives: The pharmacokinetics (PK)/pharmacodynamics (PD; PK/PD) characteristics of fidaxomicin (FDX) and vancomycin (VCM) against Clostridioides difficile infection (CDI) are yet to be elucidated because of the lack of an established PK/PD analysis method for intestinal infections and unabsorbed oral drugs. Here, we developed a feces-based PK/PD analysis method and determined the fecal PK/PD index, with target values of FDX and VCM against CDI. Methods: The antimicrobial susceptibility, time-kill curves, and post-antibiotic effects (PAEs) of FDX and VCM against C. difficile were determined in vitro. The optimal fecal PK/PD indices, with target values, were determined from the results of PK and PD studies involving 5-week-old female C57BL/6J mice infected with C. difficile ATCC® 43255. The minimum inhibitory concentration (MIC) breakpoints for C. difficile were estimated based on clinical data concerning fecal antibiotic concentrations in patients with CDI. Results: FDX and VCM inhibited C. difficile growth via time-dependent antibacterial activity and exerted PAEs. In the CDI mouse model experiments, the changes in C. difficile load and clinical cures (72-hour survival rates and clinical sickness score grading) were most highly correlated with the ratio of area under the fecal drug concentration-time curve to MIC (AUC0/MIC). The target AUC0→∞/MIC values of FDX and VCM for 3 log10 reduction in C. difficile load was 13,173 and 8,308, respectively. The MIC breakpoints of FDX and VCM for C. difficile was estimated to be 1.0 and 2.0 μg/mL, respectively. Conclusions: The developed in vivo feces-based PK/PD analysis method elucidated the optimal fecal PK/PD index, with target values of FDX and VCM against CDI.

Original languageEnglish
Pages (from-to)616-622
Number of pages7
JournalClinical Microbiology and Infection
Volume29
Issue number5
DOIs
Publication statusPublished - 2023 May

Keywords

  • Clostridioides difficile
  • Fidaxomicin
  • MIC breakpoint
  • Pharmacokinetics/pharmacodynamics
  • Vancomycin

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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