JAC Advance Access originally published online on September 5, 2005
Journal of Antimicrobial Chemotherapy 2005 56(4):717-725; doi:10.1093/jac/dki321
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Comparison of the efficacy of ramoplanin and vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection
1 Department of Microbiology, University of Leeds and The General Infirmary, Old Medical School, Leeds, LS1 3EX, UK; 2 NEeD Pharma, Via Ariberto, 17, 20123, Milano, Italy
Received 11 April 2005; returned 15 June 2005; revised 22 June 2005; accepted 15 August 2005
* Corresponding author. Tel: +44-113-392-6818; Fax: +44-113-233-5649; E-mail: mark.wilcox{at}leedsth.nhs.uk
Objectives: Treatment of Clostridium difficile infection (CDI) is limited primarily to either metronidazole or vancomycin. We compared vancomycin and a novel glycolipodepsipeptide, ramoplanin, in both hamster and in vitro gut models of clindamycin-induced CDI.
Methods: We used an in vitro triple-stage chemostat model that simulates the human gut, and an in vivo hamster model, both primed with clindamycin.
Results: Clindamycin exposure elicited symptomatic disease in the hamster model, and promoted C. difficile germination and toxin production in the gut model. C. difficile germination and toxin production were not associated with depletion of gut microflora in the gut model, but were temporarily associated with subinhibitory concentrations of clindamycin. Both ramoplanin and vancomycin were associated with rapid symptom resolution in the hamster model, and rapid toxin titre decrease in the in vitro gut model. In both models of CDI, vancomycin was associated with greater persistence of C. difficile spores. C. difficile spores were recovered significantly more often from the caecal contents of vancomycin-treated (n = 19/23) compared with ramoplanin-treated (n = 6/23) hamsters (P < 0.05).
Conclusions: Results from the in vitro gut and hamster models were concordant. Ramoplanin and vancomycin were similarly effective at reducing cytotoxin production in the gut CDI model and in resolving symptoms in the hamster model. Ramoplanin may be more effective than vancomycin at killing spores and preventing spore recrudescence. These findings suggest a potential therapeutic role for ramoplanin in CDI that requires further clinical investigation.
Keywords: antibiotic-associated diarrhoea , chemostat , hamster
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