Efficacy of vancomycin extended-dosing regimens for treatment of simulated Clostridium difficile infection within an in vitro human gut model.

Abstract

Effects of two vancomycin extended-dosing regimens on microbiota populations within an in vitro gut model of simulated Clostridium difficile infection (CDI) were evaluated. Two chemostat gut models were inoculated with faecal emulsion and clindamycin instilled to induce CDI. Simulated CDI was treated with vancomycin (125 mg/L four times daily, 7 days) followed by different vancomycin dosing extensions totalling 7 g (lower dose) or 9.5 g (higher dose) over 6 weeks in Model A and Model B, respectively. Microbiota populations, C. difficile vegetative cells and spores, cytotoxin, antimicrobial concentrations and vancomycin-tolerant enterococci (VTE) were measured every 1-2 days. In both models, vancomycin instillation caused a rapid decline in vegetative cells and cytotoxin, and declines in the 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 vancomycin instillation and post-vancomycin instillation. 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 that 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.