Steroid Therapy Exacerbates Clostridium difficile Infection in a Mouse Model

Abstract

Purpose: The importance of IClostridium difficile infection (CDI) amongst patients with inflammatory bowel disease (IBD) is increasingly recognized. CDI is now the leading recognized cause of infectious colitis in IBD patients. Recent studies indicate increased morbidity, mortality, and health costs in IBD patients with CDI, and guidelines now promote testing for C. difficile in IBD patients experiencing a relapse. Similar to colitis in IBD, CDI is associated with acute inflammatory injury to the colon, leading us to hypothesize that colitis in CDI might respond to anti-inflammatory agents used as adjuncts to antibiotic treatment. The objective of this study is to determine whether adjunct treatment with mesalamine (5-ASA) or corticosteroids (systemic hydrocortisone or enteric budesonide) changes outcomes in CDI-induced colitis, in comparison to fidaxomicin treatment alone. Methods: We used a mouse model of antibiotic-associated CDI, as previously reported. Twenty-four hours after C. difficile challenge (0.5x10E5 cfu), mice received oral fidaxomcin (20 mg/kg) either alone or in combination with 5-ASA (200 or 400 mg/kg) or budesonide (0.2, 1, or 10 mg/kg) for 5 days. For systemic steroid experiments, mice were given a single dose of hydrocortisone (50mg/kg) 48 hours prior to C. difficile challenge. Mice survival and weight were recorded. Colonic and cecal tissues were harvested for histologic scoring of colitis severity. Results: Fidaxomicin completely protected against CDI for all parameters (weight, survival, and histopathology). Adjunctive administration of 5-ASA (200 or 400 mg/kg) did not significantly alter any of the study parameters. Budesonide, given with fidaxomicin, worsened disease outcomes in terms of weight loss, colitis severity, and survival. Similarly, hydrocortisone administration prior to C. difficile challenge significantly increased CDI-related mortality. Conclusion: Fidaxomicin prevented the effects of CDI in mice. No additional benefit was evident using 5-ASA as an adjuvant, but this negative finding is limited by the fact that fidaxomicin alone was completely protective. Conversely, corticosteroid therapy, either enteric budesonide or systemic hydrocortisone, exacerbated CDI and lead to more severe disease outcomes. These studies may have important clinical implications in terms of limiting steroid therapy in patients with IBD, until acute CDI is brought under control using antibiotic therapy. Disclosure - Xinhua Chen: No conflict of interest Lei Lu: No conflict of interest Hua Xu: No conflict of interst Pam Sears - Employee, Optimer Pharmaceuticals, Inc. Ciaran P Kelly: No conflict of interst. This research was supported by an industry grant from This project was partially sponsored by Optimer Pharmaceuticals, Inc.