title: Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model.
abstract: OBJECTIVE
  Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI.
  
  
  METHODS
  MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations.
  
  
  RESULTS
  Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing.
  
  
  CONCLUSIONS
  Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.
authors.affiliation: Microbiology, University of Leeds and Leeds Teaching Hospitals, Leeds General Infirmary, Old Medical School, Leeds LS1 3EX, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Baines
authors.forename: Alan R
authors.initials: AR
authors.lastname: Noel
authors.forename: Grace S
authors.initials: GS
authors.lastname: Huscroft
authors.forename: Sharie L
authors.initials: SL
authors.lastname: Todhunter
authors.forename: Rachael
authors.initials: R
authors.lastname: O'Connor
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Hobbs
authors.forename: Jane
authors.initials: J
authors.lastname: Freeman
authors.forename: Andy M
authors.initials: AM
authors.lastname: Lovering
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wilcox
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D016360:Clostridioides difficile / Q000187:drug effects* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D066298:In Vitro Techniques; D000069349:Linezolid; D008795:Metronidazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D008795:Metronidazole; D000069349:Linezolid