Fidaxomicin Inhibits Clostridium difficile Toxin A-Mediated Enteritis in the Mouse Ileum

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 8; pp. 4642 - 4650
• Main Authors: HON WAI KOON, SAMANTHA HO, HING, Tressia C, CHENG, Michelle, XINHUA CHEN, ICHIKAWA, Yoshi, KELLY, Ciarán P, POTHOULAKIS, Charalabos
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.08.2014
• Subjects: Aminoglycosides; Aminoglycosides - pharmacology; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Anti-Inflammatory Agents; Anti-Inflammatory Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Toxins; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - toxicity; Biological and medical sciences; Clostridium difficile; Clostridium difficile - chemistry; Clostridium difficile - pathogenicity; Edema - chemically induced; Edema - pathology; Edema - prevention & control; Enterocolitis, Pseudomembranous - drug therapy; Enterocolitis, Pseudomembranous - microbiology; Enterocolitis, Pseudomembranous - pathology; Enterotoxins; Enterotoxins - antagonists & inhibitors; Enterotoxins - toxicity; Epithelial Cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Experimental Therapeutics; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - drug effects; Ileum - drug effects; Ileum - metabolism; Ileum - pathology; Injections, Intralesional; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Medical sciences; Metronidazole - pharmacology; Mice; Mice, Inbred C57BL; Neutrophil Infiltration - drug effects; Other diseases. Semiology; Pharmacology. Drug treatments; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Vancomycin - pharmacology; Rodentia; Clostridium difficile; Clostridiales; Diarrhea; Fidaxomicin; Ileum; Toxin; Vertebrata; Antibiotic; Mammalia; Mouse; Animal; Clostridiaceae; Bacteria; Digestive diseases; Intestinal disease; Enteritis; Inhibitor
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02783-14

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.