title: Efficacy of surotomycin in an in vitro gut model of Clostridium difficile infection.
abstract: OBJECTIVE
  We investigated the efficacy of the cyclic lipopeptide surotomycin in treating clindamycin-induced Clostridium difficile infection (CDI) using an in vitro gut model.
  
  
  METHODS
  Two three-stage chemostat gut models were inoculated with human faeces, spiked with C. difficile spores (∼10(7) cfu/mL, PCR ribotype 027 or 001). Clindamycin (33.9 mg/L, four times daily for 7 days) was dosed to induce CDI. Following high-level toxin production, surotomycin (250 mg/L, twice daily for 7 days) was instilled. Microflora populations, C. difficile vegetative cells and spores, cytotoxin titres and antimicrobial levels (LC-MS/MS and bioassay) were determined. The emergence of C. difficile and enterococci with reduced susceptibility to surotomycin was monitored on breakpoint agar (4 × MIC).
  
  
  RESULTS
  Counts of viable C. difficile were reduced to near the limit of detection on Days 1 and 3 of surotomycin instillation, and cytotoxin was undetectable on Days 3 and 4 of surotomycin instillation in the 027 and 001 models, respectively. Recurrence of vegetative growth and toxin production occurred 11 days (001 model) and 15 days (027 model) after surotomycin instillation had ceased, and remained for the duration of the experiment. Surotomycin instillation decreased populations of bifidobacteria, clostridia, enterococci and lactobacilli, but was sparing of Bacteroides fragilis group populations. All enumerated organisms had recovered to steady-state levels by 3 weeks post-surotomycin instillation. No evidence of the emergence of reduced susceptibility to surotomycin was observed.
  
  
  CONCLUSIONS
  Surotomycin successfully reduced C. difficile vegetative cell counts and toxin levels in the gut model and was sparing of B. fragilis group populations. There was no evidence of decreased susceptibility to surotomycin during exposure or post-exposure.
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Chilton
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: G S
authors.initials: GS
authors.lastname: Crowther
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Todhunter
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: S
authors.initials: S
authors.lastname: Nicholson
authors.affiliation: Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Old Medical School, Leeds, UK.
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chesnel
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Old Medical School, Leeds, UK mark.wilcox@leedsth.nhs.uk.
authors.forename: M H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D055666:Lipopeptides / Q000627:therapeutic use*; D008962:Models, Theoretical; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D010456:Peptides, Cyclic
keywords: chemostat; recurrence; ribotype 027