title: Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure.
abstract: OBJECTIVE
  Fidaxomicin reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. We investigated fidaxomicin primary or secondary treatment efficacy using a gut model.
  
  
  METHODS
  Four triple-stage chemostat gut models were inoculated with faeces. After clindamycin induction of CDI, fidaxomicin (200 mg/L twice daily), vancomycin (125 mg/L four times daily) or metronidazole (9.3 mg/L three times daily) was administered for 7 days. Following failure/CDI recurrence, fidaxomicin (200 mg/L twice daily, 7 days) was instilled. C. difficile (CD) total viable counts (TVC), spore counts (SP), toxin titres (CYT), gut bacteria counts and antimicrobial concentrations were measured throughout.
  
  
  RESULTS
  Fidaxomicin instillation reduced CD TVC/SP and CYT below the limit of detection (LOD) after 2 and 4 days, respectively, with no CDI recurrence. Metronidazole instillation failed to decrease CD TVC or CYT. Vancomycin instillation reduced CD TVC and CYT to LOD by day 4, but SP persisted. Recurrence occurred 13 days after vancomycin instillation; subsequent fidaxomicin instillation reduced CD TVC/SP/CYT below the LOD from day 2. CD was isolated sporadically, with no evidence of spore recrudescence or toxin production. Fidaxomicin had a minimal effect on the microflora, except for bifidobacteria. Fidaxomicin was detected for at least 21 days post-instillation, whereas other antimicrobials were undetectable beyond ∼4 days.
  
  
  CONCLUSIONS
  Fidaxomicin successfully treated simulated primary and recurrent CDI. Fidaxomicin was superior to metronidazole in reducing CD TVC and SP, and superior to vancomycin in reducing SP without recurrence of vegetative cell growth. Fidaxomicin, but not vancomycin or metronidazole, persisted in the gut model for >20 days after instillation.
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Chilton
authors.forename: G S
authors.initials: GS
authors.lastname: Crowther
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.forename: S L
authors.initials: SL
authors.lastname: Todhunter
authors.forename: S
authors.initials: S
authors.lastname: Nicholson
authors.forename: C M
authors.initials: CM
authors.lastname: Longshaw
authors.forename: M H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D016360:Clostridioides difficile / Q000187:drug effects* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D004359:Drug Therapy, Combination; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000382:microbiology*; D006801:Humans; D008795:Metronidazole / Q000008:administration & dosage*; D008826:Microbial Sensitivity Tests / Q000379:methods; D008954:Models, Biological; D017211:Treatment Failure; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D008795:Metronidazole; D014640:Vancomycin
keywords: antimicrobial persistence; recurrence; spores