Fidaxomicin inhibits Clostridium difficile toxin A-mediated enteritis in the mouse ileum.

Abstract

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.

• Authors: Hon Wai Koon, Samantha Ho, Tressia C Hing, Michelle Cheng, Xinhua Chen, Yoshi Ichikawa, Ciarán P Kelly, Charalabos Pothoulakis
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 8 Pg. 4642-50 (Aug 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24890583 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Aminoglycosides
• Anti-Bacterial Agents
• Anti-Inflammatory Agents
• Bacterial Toxins
• Enterotoxins
• Interleukin-1beta
• OP-1118
• RNA, Messenger
• tcdA protein, Clostridium difficile
• Metronidazole
• Vancomycin
• Fidaxomicin

Topics

• Aminoglycosides (pharmacology)
• Animals
• Anti-Bacterial Agents (pharmacology)
• Anti-Inflammatory Agents (pharmacology)
• Bacterial Toxins (antagonists & inhibitors, toxicity)
• Clostridioides difficile (chemistry, pathogenicity)
• Edema (chemically induced, pathology, prevention & control)
• Enterocolitis, Pseudomembranous (drug therapy, microbiology, pathology)
• Enterotoxins (antagonists & inhibitors, toxicity)
• Epithelial Cells (drug effects, metabolism, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Fidaxomicin
• Gene Expression (drug effects)
• Ileum (drug effects, metabolism, pathology)
• Injections, Intralesional
• Interleukin-1beta (antagonists & inhibitors, genetics, metabolism)
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Male
• Metronidazole (pharmacology)
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration (drug effects)
• RNA, Messenger (antagonists & inhibitors, genetics, metabolism)
• Vancomycin (pharmacology)