Efficacy of vancomycin extended dosing regimens for treatment of simulated Clostridium difficile infection (CDI) within an in vitro human gut model

Abstract Objectives: Effects of two vancomycin extended-dosing regimens on microbiota populations within an in-vitro gut model of simulated C. difficile infection (CDI) were evaluated. Methods: Two chemostat gut models were inoculated with faecal emulsion, and clindamycin instilled to induce CDI. Simulated CDI was treated with vancomycin (125mg/L four-times daily, 7 days) followed by different vancomycin dosing extensions totalling 7g (lower dose) or 9.5g (higher dose) over 6 weeks in models A and B respectively. Microbiota populations, CD vegetative cells (VC) and spores (SP), cytotoxin (CYT), antimicrobial concentrations, and vancomycin-tolerant enterococci (VTE) were measured every 1-2 days. Results: In both models, vancomycin instillation caused a rapid decline in VC and CYT, and declines in Bacteroides fragilis group, Bifidobacteria, and Clostridia populations to the lower limit of detection. Bifidobacteria failed to recover for the remainder of the experiment. B .fragilis group populations recovered to pre-dosing levels during the dosing extension in model A and after dosing ceased in model B. Recurrent CDI was observed on the penultimate day of model B, but not model A. VTE were observed throughout the experiment in both models, but populations increased during- and post-vancomycin instillation. Conclusion: The two vancomycin extended-dosing regimens were efficacious in initial treatment of simulated CDI. Both had a prolonged deleterious effect on the indigenous gut microbiota, a factor which may contribute to recurrence; recurrence was observed only in model B, although the potential for vegetative regrowth within model A cannot be excluded. Vancomycin exposure appeared to select for VTE populations