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Antimicrobial Agents and Chemotherapy, October 2004, p. 3975-3979, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3975-3979.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rifalazil Treats and Prevents Relapse of Clostridium difficile-Associated Diarrhea in Hamsters

Pauline M. Anton,¹ Michael O'Brien,² Efi Kokkotou,¹ Barry Eisenstein,^3,4, Arthur Michaelis,³ David Rothstein,³ Sophia Paraschos,¹ Ciáran P. Kelly,¹ and Charalabos Pothoulakis^1*

Divisions of Gastroenterology,¹ Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School,⁴ Department of Pathology, Boston University School of Medicine, Boston,² ActivBiotics Inc., Lexington, Massachusetts³

Received 5 February 2004/ Returned for modification 14 April 1004/ Accepted 16 June 2004

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.

Present address: Cubist Pharmaceutical, Inc., Lexington, MA 02421.

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