Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 66, Issue 5, Pages 1087-1095Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkr033
Keywords
CDI; sporulation; toxin; hamster infection
Funding
- Ranbaxy Research Laboratories, Gurgaon
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Objectives: RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile. Methods: The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition. Results: RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4xMIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis. Conclusions: RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection.
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