In vivo efficacy of fidaxomicin against rpoB mutant Clostridioides difficile infection

Abstract

Objectives

Clostridioides difficile infection (CDI) is a well-known healthcare-associated diarrheal disease. Fidaxomicin, a key antibiotic used to treat CDI, targets bacterial RNA polymerase. However, some clinical isolates have mutations in rpoB, which reduces their susceptibility to this antibiotic. In this study, the effects of rpoB mutations on the virulence of C. difficile and efficacy of fidaxomicin against CDI were evaluated in vivo.

Methods

An rpoB mutant strain (C. difficile G1073R-2024) with reduced fidaxomicin susceptibility was generated through spontaneous induction in a murine CDI model from the parental strain C. difficile VPI 10463. The virulence and therapeutic responses of the mutant strain were compared with those of the parental strain using a CDI model, including survival rate, body weight changes, clinical scores, and bacterial loads in feces.

Results

C. difficile G1073R-2024 had an amino acid alteration in Gln1073Arg and the minimum inhibitory concentration of fidaxomicin was 128 μg/mL. In vivo virulence was not significantly different between strains. Fidaxomicin treatment resulted in 100 % survival rates and a comparable reduction in the bacterial load for both strains.

Conclusions

Fidaxomicin was effective against CDI caused by the rpoB mutant strain. The emergence of such mutations highlights the need for ongoing surveillance of drug resistance trends in clinical settings.