The bacterial-mediated diarrheal diseases include cholera, typhoid fever, traveller's diarrhea, and diarrheal illness in infants. The diseases are basically of two types, invasive and non-invasive gastroenteritis. Typhoid fever is representative of the invasive type of disease, which is characterized by invasion of the intestinal mucosa by the pathogen. In the non-invasive type of gastroenteritis, the symptoms are effected by bacterial toxins which stimulate an enormous increase in the secretory activity of the cells lining the small intestine causing an acute loss of body fluid. Although mild diarrhea is a common side effect of antibiotics, sometimes the diarrhea is severe or protracted andthe patient is found to have colitis, often with nodular pseudomembraneous plaques.
A major recognized cause of antibiotic-associated diarrhea and pseudomembraneous colitis is Clostridium difficile which produces toxins that cause intestinal cell damage and fluid secretion. (Bartlett Rev. Infect. Dis. 1,539 (1979)). Two toxins produced by pathogenic C. difficile have been identified from patients with antibiotic-associated colitis. Toxin A causes hemorrhagic fluid secretion and intestinal damage. Libby et al. Infec. Immun. 35, 374 (1982). Toxin B is a potent cause of cell damage in tissue culture cells. Both toxins appear to play separate immunological roles in causing antibiotic-assiciated diarrhea and pseudomembraneous colitis.
The detection of an identifiable microbial pathogen provided a rationale for prior forms of therapy. Prior therapy includes antibiotics directed against Clostridium difficile, or anion exchange resins that bind the toxin of Clostridium difficile. An example of antibiotic which has been directed against Clostridium difficile is vancomycin. (Fekdety, Microbiology, 1979, 276-279). Diarrhea, fever and toxicity were reported as markedly reduced 2 to 3 days after beginning vancomycin therapy. Oral cholestyramine, an anion-binding resin that may bind the toxin in the colon, has also been used to treat C. difficile diarrhea. (Fekety, supra).
A need exists for a direct, antitoxic treatment for Clostridium difficile pseudomembraneous colitis and antibiotic-associated diarrhea.