Oritavancin does not induce Clostridium difficile germination and toxin production in hamsters or a human gut model

• Published in: Journal of antimicrobial chemotherapy 2012-12, Vol.67 (12), p.2919-2926
• Main Authors: FREEMAN, Jane, MARQUIS, Miriam, CROWTHER, Grace S, TODHUNTER, Sharie L, FAWLEY, Warren N, CHILTON, Caroline H, MOECK, Gregory, LEHOUX, Dario, WILCOX, Mark H
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents - metabolism; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Load; Bacterial Toxins - biosynthesis; Biological and medical sciences; Cecum - chemistry; Cecum - microbiology; Clostridium difficile; Clostridium difficile - drug effects; Clostridium difficile - growth & development; Clostridium Infections - microbiology; Clostridium Infections - pathology; Cricetinae; Disease Models, Animal; Drug resistance; Feces - chemistry; Feces - microbiology; Gastroenterology. Liver. Pancreas. Abdomen; Glycopeptides - metabolism; Gram-positive bacteria; Humans; Laboratory animals; Medical sciences; Medical treatment; Other diseases. Semiology; Pharmacology. Drug treatments; Spores, Bacterial - drug effects; Spores, Bacterial - growth & development; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Vancomycin - metabolism
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dks309

To evaluate the relative propensities of oritavancin and vancomycin to induce Clostridium difficile infection (CDI) in hamster and in vitro human gut models. Hamsters received clindamycin (100 mg/kg orally or subcutaneously), oritavancin (50 mg/kg orally) or vancomycin (50 mg/kg orally). C. difficile spores were administered orally the next day. Control hamsters received vehicle only (polyethylene glycol 400) plus spores or clindamycin but no spores. Hamsters were monitored for clinical signs for 20 days. Caecal contents were analysed for C. difficile cells, spores and the presence of (cyto)toxin. Oritavancin and vancomycin were instilled over 7 days into separate in vitro gut models primed with pooled human faeces and inoculated with C. difficile ribotype 027 spores. Gut flora, C. difficile total viable and spore counts, toxin titres and antimicrobial concentrations were determined. All hamsters treated with oritavancin survived up to 20 days, with no evidence of C. difficile spores, vegetative cells or toxin in their caeca. No hamsters treated with clindamycin or vancomycin survived >6 days after spore administration. Death was associated with high C. difficile counts and toxin in caecal contents. In the gut model, oritavancin dosing elicited a rapid, marked decrease in total viable C. difficile and spore counts to below the limit of detection. Vancomycin did not elicit germination or toxin production in the gut model, but C. difficile remained present as spores throughout. Oritavancin exposure, unlike exposure to vancomycin or clindamycin, did not lead to CDI in hamsters. In both models, oritavancin reduced C. difficile total counts and spores to below detectable limits. The data indicate the potential of oritavancin for CDI treatment, since exposure did not induce C. difficile germination and toxin production, which are known to exacerbate the disease state.