[Background, Purpose] Metronidazole (MNZ), vancomycin (VCM), and fidaxomicin (FDX) are standard therapeutic drugs against Clostridioides difficile infection (CDI). MNZ resulted in lower clinical cure rate compared with VCM. Detail information about antibacterial activities of the drugs and reasons for MNZ inferiority are not clear. Therefore, we evaluated the in vitro antibacterial activities, and measured fecal concentrations in CDI mouse models.
[Method] Minimum inhibitory concentration (MIC) against seven strains of C. difficile were determined. Time-kill curves and post-antibiotic effect (PAE) were determined against C. difficile ATCC^®43255. In addition, fecal concentrations in CDI mouse models were measured.
[Results] MNZ, VCM, and FDX geometric mean MIC were 0.91, 1.81, and 0.34 µg/mL, respectively. MNZ exhibited concentration-dependent and rapid antibacterial activities at low concentrations ranged from 0.5 to 2.0 µg/mL. On the other hands, VCM and FDX exhibited time-dependent and slow antibacterial activities at high concentrations ranged from 0.5 to 32 µg/mL. MNZ showed the shortest PAE (1.9 h). In addition, maximal fecal concentration of MNZ (21.7 µg/g) was significantly lower than that of VCM (222.7 µg/g) at the dose of 40 mg/kg.
[Conclusion] MNZ exhibited noteworthy antibacterial activities against C. difficile. However, MNZ PAE was short, and the fecal exposure was significantly small. We think the two characteristics are responsibility for the MNZ inferiority in clinical cure rate.