title: In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection.
abstract: OBJECTIVE
  We investigated the in vitro activity of cadazolid against 100 Clostridium difficile isolates and its efficacy in a simulated human gut model of C. difficile infection (CDI).
  
  
  METHODS
  MICs of cadazolid, metronidazole, vancomycin, moxifloxacin and linezolid were determined using agar incorporation for 100 C. difficile isolates, including 30 epidemic strains (ribotypes 027, 106 and 001) with reduced metronidazole susceptibility, 2 linezolid-resistant isolates and 2 moxifloxacin-resistant isolates. We evaluated the efficacy of two cadazolid dosing regimens (250 versus 750 mg/L twice daily for 7 days) to treat simulated CDI. Microflora populations, C. difficile total viable counts and spores, cytotoxin titres, possible emergence of cadazolid, linezolid or quinolone resistance, and antimicrobial concentrations were monitored throughout.
  
  
  RESULTS
  Cadazolid was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The cadazolid geometric mean MIC was 152-fold, 16-fold, 9-fold and 7-fold lower than those of moxifloxacin, linezolid, metronidazole and vancomycin, respectively. Both cadazolid dosing regimens rapidly reduced C. difficile viable counts and cytotoxin with no evidence of recurrence. Cadazolid levels persisted at 50-100-fold supra-MIC for 14 days post-dosing. Cadazolid inhibition of enumerated gut microflora was limited, with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus spp. counts were unaffected. There was no evidence for selection of strains resistant to cadazolid, quinolones or linezolid.
  
  
  CONCLUSIONS
  Cadazolid activity was greater than other tested antimicrobials against 100 C. difficile strains. Cadazolid effectively treated simulated CDI in a gut model, with limited impact on the enumerated gut microflora and no signs of recurrence or emergence of resistance within the experimental timeframe.
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Chilton
authors.forename: G S
authors.initials: GS
authors.lastname: Crowther
authors.forename: S D
authors.initials: SD
authors.lastname: Baines
authors.forename: S L
authors.initials: SL
authors.lastname: Todhunter
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.forename: H H
authors.initials: HH
authors.lastname: Locher
authors.forename: A
authors.initials: A
authors.lastname: Athanasiou
authors.forename: M H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D058491:Bacterial Load; D016360:Clostridioides difficile / Q000187:drug effects* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008962:Models, Theoretical; D023303:Oxazolidinones / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D023303:Oxazolidinones; C000591679:cadazolid
keywords: MICs; antimicrobial persistence; chemostat