title: Vancomycin treatment's association with delayed intestinal tissue injury, clostridial overgrowth, and recurrence of Clostridium difficile infection in mice.
abstract: Antibiotic treatment, including vancomycin, for Clostridium difficile infection (CDI) has been associated with recurrence of disease in up to 25% of infected persons. This study investigated the effects of vancomycin on the clinical outcomes, intestinal histopathology, and anaerobic community during and after treatment in a murine model of CDI. C57BL/6 mice were challenged with C. difficile strain VPI 10463 after pretreatment with an antibiotic cocktail. Twenty-four hours after infection, mice were treated daily with vancomycin, nitazoxanide, fidaxomicin, or metronidazaole for 5 days. Mice were monitored for either 6 or 12 days postinfection. Clinical, diarrhea, and histopathology scores were measured. Cecal contents or stool samples were assayed for clostridial or Bacteroides DNA and C. difficile toxins A and B. Vancomycin treatment of infected mice was associated with improved clinical, diarrhea, and histopathology scores and survival during treatment. However, after discontinuation of the drug, clinical scores and histopathology were worse in treated mice than in untreated infected controls. At the end of the study, 62% of the vancomycin-treated mice succumbed to recurrence, with an overall mortality rate equivalent to that of the untreated infected control group. Fidaxomicin-treated mice had outcomes similar to those of vancomycin-treated mice. C. difficile predominated over Bacteroides in cecal contents of vancomycin-treated mice, similar to findings for untreated infected mice. Decreasing the duration of vancomycin treatment from 5 days to 1 day decreased recurrence and deaths. In conclusion, vancomycin improved clinical scores and histopathology acutely but was associated with poor outcome posttreatment in C. difficile-infected mice. Decreasing vancomycin exposure may decrease relapse and improve survival in CDI.
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Cirle A
authors.initials: CA
authors.lastname: Warren
authors.forename: Edward J
authors.initials: EJ
authors.lastname: van Opstal
authors.forename: Mary S
authors.initials: MS
authors.lastname: Riggins
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.forename: John H
authors.initials: JH
authors.lastname: Moore
authors.forename: Glynis L
authors.initials: GL
authors.lastname: Kolling
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hoffman
mesh_terms: D000617:Aminoglycosides / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001439:Bacteroides / Q000235:genetics; D002432:Cecum / Q000382:microbiology; D016360:Clostridioides difficile / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000188:drug therapy; D004269:DNA, Bacterial / Q000302:isolation & purification; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000401:mortality*; D005243:Feces / Q000382:microbiology; D000077732:Fidaxomicin; D007422:Intestines / Q000187:drug effects / Q000293:injuries / Q000382:microbiology; D008297:Male; D008795:Metronidazole / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds; D012008:Recurrence; D013844:Thiazoles / Q000627:therapeutic use; D016896:Treatment Outcome; D014640:Vancomycin / Q000627:therapeutic use*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D009574:Nitro Compounds; D013844:Thiazoles; D008795:Metronidazole; D014640:Vancomycin; C041747:nitazoxanide; D000077732:Fidaxomicin