title: Rifalazil treats and prevents relapse of clostridium difficile-associated diarrhea in hamsters.
abstract: Although vancomycin and metronidazole effectively treat Clostridium difficile-associated diarrhea and colitis (CDAD), their use is associated with a high incidence of relapsing C. difficile infection. Rifalazil is a new benzoxazinorifamycin that possesses activity against Mycobacterium tuberculosis and gram-positive bacteria. Here we compared rifalazil and vancomycin for effectiveness in preventing or treating clindamycin-induced cecitis in a hamster model of CDAD. Golden Syrian hamsters were injected subcutaneously with clindamycin phosphate (10 mg/kg), followed 24 h later by C. difficile gavage. Hamsters received by gavage for 5 days vehicle, vancomycin (50 mg/kg), or rifalazil (20 mg/kg) either simultaneously with (prophylactic protocol) or 24 h after C. difficile administration (treatment protocol). While all vehicle-administered animals became moribund within 48 h of C. difficile administration, no rifalazil- or vancomycin-treated animals in either protocol showed signs of morbidity after 7 days. Ceca of rifalazil-treated animals showed absence of epithelial cell damage, significantly reduced congestion and edema, and less, but not statistically significantly less, neutrophil infiltration compared to those of vehicle-treated animals. In contrast, vancomycin-treated animals demonstrated severe epithelial cell damage and mildly reduced congestion and edema. Moreover, hamsters relapsed and tested C. difficile toxin positive (by enzyme-linked immunosorbent assay) 10 to 15 days after discontinuation of vancomycin treatment. None of the rifalazil-treated hamsters showed signs of disease or presence of toxins in their feces 30 days after discontinuation of treatment. Our results indicate that once daily rifalazil may be superior to vancomycin for curative treatment of CDAD.
authors.affiliation: Beth Israel Deaconess Medical Center, Division of Gastroenterology, Dana 601, 330 Brookline Ave., Boston, MA 02215, USA. cpothoul@bidmc.harvard.edu
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Anton
authors.forename: Michael
authors.initials: M
authors.lastname: O'Brien
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
authors.forename: Barry
authors.initials: B
authors.lastname: Eisenstein
authors.forename: Arthur
authors.initials: A
authors.lastname: Michaelis
authors.forename: David
authors.initials: D
authors.lastname: Rothstein
authors.forename: Sophia
authors.initials: S
authors.lastname: Paraschos
authors.forename: Ciáran P
authors.initials: CP
authors.lastname: Kelly
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002432:Cecum / Q000187:drug effects / Q000382:microbiology; D016360:Clostridioides difficile / Q000187:drug effects*; D006224:Cricetinae; D003967:Diarrhea / Q000188:drug therapy* / Q000382:microbiology; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D008647:Mesocricetus; D008826:Microbial Sensitivity Tests; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use*; D055502:Secondary Prevention; D016019:Survival Analysis; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; C068980:KRM 1648; D014640:Vancomycin