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

Tashiro, Sho ; Taguchi, Kazuaki ; Enoki, Yuki ; Matsumoto, Kazuaki

Pharmaceutical research, 2023-07, Vol.40 (7), p.1799-1806 [Periódico revisado por pares]

New York: Springer US

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  • Título:
    Antimicrobial Efficacy Evaluations of Metronidazole against Clostridioides difficile Infection using Fecal Pharmacokinetic and Pharmacodynamic Analyses
  • Autor: Tashiro, Sho ; Taguchi, Kazuaki ; Enoki, Yuki ; Matsumoto, Kazuaki
  • Assuntos: Animal models ; Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Clostridioides difficile ; Feces ; Fidaxomicin ; Health aspects ; Infection ; Medical colleges ; Medical Law ; Metronidazole ; Minimum inhibitory concentration ; Original Research Article ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology/Toxicology ; Pharmacy ; Vegetative cells
  • É parte de: Pharmaceutical research, 2023-07, Vol.40 (7), p.1799-1806
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: 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 24 /MIC). The target value of fecal AUC 24 /MIC to achieve a 1 log 10 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 24 /MIC ≥ 188. These findings may contribute to the effective clinical use of MNZ.
  • Editor: New York: Springer US
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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