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

OBJECTIVES: The pharmacokinetics/pharmacodynamics (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 for FDX and VCM against CDI.

METHODS: Antimicrobial susceptibility, time-kill curves, and post-antibiotic effects (PAEs) of FDX and VCM against C. difficile were determined in vitro. Optimal fecal PK/PD indices with target values were determined from the results of PK and PD studies involving five-week-old female C57BL/6J mice infected with C. difficile ATCC® 43255. Minimum inhibitory concentration (MIC) breakpoints for C. difficile were estimated based on clinical data concerning fecal antibiotic concentrations in CDI patients.

RESULTS: FDX and VCM inhibited C. difficile growth with time-dependent antibacterial activity and exerted PAEs. In CDI mouse model experiments, changes in C. difficile load and clinical cures (72 h-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 were 13,173 and 8,308, respectively. The MIC breakpoints of FDX and VCM for C. difficile were estimated to be 1.0 μg/mL 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 for FDX and VCM against CDI.