title: Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile infection in an in vitro human gut model.
abstract: BACKGROUND
  Fidaxomicin treatment reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. Extending duration of fidaxomicin therapy may further reduce recurrence. We compared the efficacy of four extended fidaxomicin regimens in an in vitro model of CDI.
  
  
  METHODS
  Four gut models were primed with human faeces, spiked with C. difficile spores (PCR ribotype 027) and clindamycin instilled (33.9 mg/L, four-times daily, 7 days) to induce simulated CDI. Four extended fidaxomicin treatment regimens were evaluated: model 1, 20 days, 200 mg/L twice daily; model 2, 5 days 200 mg/L twice daily, 5 days rest, 5 days 200 mg/L twice daily; model 3, 5 days 200 mg/L twice daily, 5 days rest, 10 days 200 mg/L once daily; and model 4, 5 days 200 mg/L twice daily, 20 days 200 mg/L once every other day. C. difficile populations, toxin, gut microbiota and antimicrobial levels were monitored daily.
  
  
  RESULTS
  All fidaxomicin regimens successfully resolved simulated CDI without recurrence. Five days of fidaxomicin instillation was barely sufficient to resolve CDI (models 2-4). A second pulse or tapered dosing further reduced C. difficile and toxin detection. All regimens were sparing of microbiota, affecting only enterococci and bifidobacteria. Pulsed or tapered regimens allowed greater bifidobacteria recovery than the extended (20 day) regimen. Bioactive fidaxomicin persisted throughout the experiment in all models at concentrations inhibitory to C. difficile.
  
  
  CONCLUSIONS
  Pulsed or tapered fidaxomicin regimens may enhance suppression of C. difficile whilst allowing microbiota recovery; clinical studies are required to ascertain the potential of this approach in further reducing recurrent CDI.
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds, UK c.h.chilton@leeds.ac.uk.
authors.forename: C H
authors.initials: CH
authors.lastname: Chilton
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
authors.forename: G S
authors.initials: GS
authors.lastname: Crowther
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Todhunter
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
authors.forename: H
authors.initials: H
authors.lastname: Ashwin
authors.affiliation: Astellas Pharma EMEA, 2000 Hillswood Drive, Chertsey, Surrey KT16 0RS, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Longshaw
authors.affiliation: Astellas Pharma EMEA, 2000 Hillswood Drive, Chertsey, Surrey KT16 0RS, UK.
authors.forename: A
authors.initials: A
authors.lastname: Karas
authors.affiliation: Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Leeds, UK Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Infirmary, Old Medical School, Leeds, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000008:administration & dosage*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D000077732:Fidaxomicin; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077732:Fidaxomicin