title: SMT19969 as a treatment for Clostridium difficile infection: an assessment of antimicrobial activity using conventional susceptibility testing and an in vitro gut model.
abstract: OBJECTIVE
  We investigated the efficacy of the novel antimicrobial agent SMT19969 in treating simulated Clostridium difficile infection using an in vitro human gut model.
  
  
  METHODS
  Concentrations of the predominant cultivable members of the indigenous gut microfloras and C. difficile (total and spore counts) were determined by viable counting. Cytotoxin titres were determined using cell cytotoxicity and expressed as log10 relative units (RU). Clindamycin was used to induce simulated C. difficile PCR ribotype 027 infection. Once high-level cytotoxin titres (≥ 4 RU) were observed, SMT19969 was instilled for 7 days. Two SMT19969 dosing regimens (31.25 and 62.5 mg/L four times daily) were evaluated simultaneously in separate experiments. MICs of SMT19969 were determined against 30 genotypically distinct C. difficile ribotypes.
  
  
  RESULTS
  SMT19969 was 7- and 17-fold more active against C. difficile than metronidazole and vancomycin, respectively, against a panel of genotypically distinct isolates (P < 0.05). Both SMT19969 dosing regimens demonstrated little antimicrobial activity against indigenous gut microflora groups except clostridia. SMT19969 inhibited C. difficile growth and repressed C. difficile cytotoxin titres in the gut model.
  
  
  CONCLUSIONS
  These data suggest that SMT19969 is a narrow-spectrum and potent antimicrobial agent against C. difficile. Additional studies evaluating SMT19969 in other models of C. difficile infection are warranted, with human studies to place these gut model observations in context.
authors.affiliation: Department of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK s.baines2@herts.ac.uk.
authors.forename: S D
authors.initials: SD
authors.lastname: Baines
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: G S
authors.initials: GS
authors.lastname: Crowther
authors.affiliation: Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Old Medical School, Leeds LS1 3EX, UK.
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: S
authors.initials: S
authors.lastname: Todhunter
authors.affiliation: Summit plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
authors.forename: R
authors.initials: R
authors.lastname: Vickers
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds LS2 9JT, UK Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Old Medical School, Leeds LS1 3EX, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods*; D008954:Models, Biological
chemical_list: D000900:Anti-Bacterial Agents
keywords: Clostridium difficile; NAP1/027; antibiotics; cytotoxin; gut model; microflora