title: Efficacy of vancomycin extended-dosing regimens for treatment of simulated Clostridium difficile infection within an in vitro human gut model.
abstract: OBJECTIVE
  Effects of two vancomycin extended-dosing regimens on microbiota populations within an in vitro gut model of simulated Clostridium 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 (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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Grace S
authors.initials: GS
authors.lastname: Crowther
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK c.h.chilton@leeds.ac.uk.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Chilton
authors.affiliation: Astellas Pharma EMEA, Chertsey, Surrey, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Longshaw
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Sharie L
authors.initials: SL
authors.lastname: Todhunter
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Ewin
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vernon
authors.affiliation: Astellas Pharma EMEA, Chertsey, Surrey, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Karas
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Leeds, UK.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D058491:Bacterial Load; D001441:Bacteroides fragilis / Q000187:drug effects; D016360:Clostridioides difficile; D024881:Drug Resistance, Bacterial; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D064307:Microbiota; D008954:Models, Biological; D012008:Recurrence; D014640:Vancomycin / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin