Antimicrobial Efficacy Evaluations of Metronidazole against Clostridioides difficile Infection using Fecal Pharmacokinetic and Pharmacodynamic Analyses.

Objectives: The pharmacokinetics/pharmacodynamics (PK/PD) characteristics of metronidazole (MNZ) in Clostridioides difficile infection (CDI) remain unclear. We aimed to determine the PK/PD characteristics of MNZ using a fecal PK/PD analysis model.

Methods: Susceptibility testing, time-kill studies, and post-antibiotic effect (PAE) measurements were performed to evaluate in vitro PD profiles. MNZ was subcutaneously administered to mice infected with C. difficile ATCC 43255 to evaluate in vivo PK and PD profiles, followed by determining fecal PK/PD indices with target value.

Results: MNZ exerted concentration-dependent bactericidal activities with minimum inhibitory concentration (MIC) and PAE being 0.79 µg/mL and 4.8 h, respectively, against C. difficile ATCC 43255. The reduction in vegetative cells in feces and treatment outcomes were most closely correlated with the ratio of the area under the fecal drug concentration-time curve from 0 to 24 h to the MIC (fecal AUC/MIC). The target value of fecal AUC/MIC to achieve a 1 log reduction in vegetative cells was 188. Upon meeting the target value, high survival rates (94.5%) and low clinical sickness score grading (5.2) were achieved in the CDI mouse models.

Conclusions: The PK/PD index and its target value of MNZ for CDI treatment was fecal AUC/MIC ≥ 188. These findings may contribute to the effective clinical use of MNZ.