GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis

• Published in: Antimicrobial agents and chemotherapy Vol. 45; no. 8; pp. 2340 - 2347
• Main Authors: KURTZ, Caroline B, CANNON, E. Pat, PAPOULIS, Andrew T, GODDARD, Philip J, BARKER, Robert H, PALACE, Gerard P, KLINGER, Jeffrey D, BREZZANI, Alex, PITRUZZELLO, Mary, DINARDO, Carol, RINARD, Emilie, ACHESON, David W. K, FITZPATRICK, Richard, KELLY, Pamela, SHACKETT, Keith
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01-08-2001
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins - antagonists & inhibitors; Bacterial Toxins - metabolism; Biological and medical sciences; Cercopithecus aethiops; Cholestyramine resin; Cholestyramine Resin - therapeutic use; Clostridium difficile; Clostridium difficile - physiology; Clostridium Infections - drug therapy; Clostridium Infections - metabolism; Clostridium Infections - microbiology; Colitis - drug therapy; Colitis - metabolism; Colitis - microbiology; Cricetinae; Enterotoxins - metabolism; Experimental Therapeutics; Humans; In Vitro Techniques; Ions - metabolism; Ions - pharmacology; Ions - therapeutic use; Lactams - pharmacology; Male; Medical sciences; Metronidazole - therapeutic use; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Polymers - metabolism; Polymers - pharmacology; Polymers - therapeutic use; Rats; Rats, Wistar; Sulfonic Acids; Survival Rate; Vero Cells - microbiology; Nitro compound; Imidazole derivatives; Rat; Clindamycin; Clostridiales; Bacteria; Intestinal disease; Subcutaneous administration; Drug interaction; Drug combination; Rodentia; Clostridium difficile; Oral administration; Polymer; In vitro; Biological activity; In vivo; Toxin; Vertebrata; Antibiotic; Mammalia; Animal; Clostridiaceae; Digestive diseases; Colitis; Metronidazole; Antibacterial agent; Hamster
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.45.8.2340-2347.2001

GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246 neutralized fluid accumulation caused by 5 microg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete neutralization of fluid accumulation caused by 5 microg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment, 80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial treatment of C. difficile disease in humans.