Experimental clindamycin-associated colitis in rabbits: Evidence for toxin-mediated mucosal damage

Abstract

Rabbits given clindamycin by nasogastric tube at a dosage of 15 mg per kg per day developed diarrhea within 48 to 72 hr which was uniformly fatal by 72 to 96 hr. Control rabbits given comparable doses of ampicillin, tetracycline, neomycin, vancomycin, or saline remained well. At autopsy the major gross pathological finding was limited to the cecum which was massively dilated with watery stool. The light microscopic findings in the cecum included necrosis of the surface epithelium and a prominent inflammatory infiltrate in the lamina propria. Fatal clindamycin colitis was prevented in 10 of 10 rabbits by co-administration of vancomycin, 30 mg per kg per day; coadministration of penicillin or neomycin prevented the ileocolitis in 3 of 5 and 1 of 5 animals, respectively. Cell proliferation, measured by radioautography after [3H]thymidine injection, was significantly increased in cecal mucosa but not more distal colonic or small intestinal mucosa during clindamycin administration. Protein synthesis, as determined by incorporation of [3H]leucine into intestinal slices, was significantly increased in both the ileum and cecum after 48 hr of clindamycin administration. Cell-free, sterile extracts of cecal contents of clindamycin-treated animals were injected into ileal loops of untreated rabbits. These fecal extracts produced a severe, hemorrhagic ileitis, although control filtrates from clindamycin-vancomycin-treated animals produced no histological changes. Using selective anaerobic culture media there was an increase in clostridial species from 105 organisms of cecal content per g in controls to 108 organisms per g after 48 hr of clindamycin treatment and a reduction to 104 organisms per g in clindamycin-vancomycin-treated animals. The pathogenesis of clindamycin-associated colitis in rabbits appears to be mediated by a bacterial toxin present in the cecal contents.