Clostridium difficile and inflammatory bowel disease

Ben-Horin S, Margalit M, Bossuyt P, et al.; European Crohn's and Colitis Organization (ECCO). Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and C. difficile infection. Clin Gastroenterol Hepatol. 2009;7:981–987. Clostridium difficile is increasingly recognized as an important pathogen in patients with inflammatory bowel disease (IBD), particularly among those requiring hospitalization. Ben-Horin et al, from 20 centers in Israel and Europe, retrospectively examined a cohort of 155 hospitalized patients with IBD who also developed C. difficile infection (CDI) between January 1, 2000, and March 1, 2008. Most of the patients (150) were admitted with symptoms suggestive of a disease flare. CDI was diagnosed by a positive enzyme-linked immunosorbent assay (ELISA) stool toxin assay in a majority of the patients with a mean time to diagnosis of 3 days. Among the 155 patients, 59% had ulcerative colitis and 102 were not on immunomodulators prior to a diagnosis of CDI. In their cohort, 104 patients (67%) were cotreated with antibiotics and immunomodulators (defined as prednisone >20 mg/day, azathioprine/6-mercaptopurine, methotrexate, biologics, cyclosporine, tacrolimus) (AB+IM) for their C. difficile-associated IBD exacerbation, while the remaining 51 patients (33%) were treated with AB alone. A majority of the patients (80%) were initially treated with metronidazole. The primary outcome of the study was death or colectomy, colon perforation or toxic megacolon, shock requiring vasopressors, or need for mechanical ventilation. In addition, they examined the duration of hospitalization, CDI-relapse within 3 months, and the need to substitute antibiotics due to CDI persistence. The adverse primary outcome occurred in 12 patients (12/104, 12%), all of whom were on combined AB+IM therapy, compared to 0/51 patients treated with AB only (P = 0.01). On multivariate analysis, AB+IM therapy showed a trend for independent association with the primary outcome (likelihood ratio: 11.9, 95% confidence interval [CI] 0.9–157, P = 0.06). Double or triple IM treatment was in particular associated with a significantly higher rate of the adverse primary outcome (odds ratio 17.1, 95% CI 3.2–91). Recent literature has supported the growing adverse consequence of CDI in patients with IBD.1,–6 In addition to the risk for relapse and recurrence, the long-term effect of a single episode of CDI may persist beyond the index hospitalization, with increased rates of adverse outcomes being reported as far as 1 year out from the initial episode.6,7 Being chronic immunologically mediated disorders, the mainstay of treatment for a significant cohort of patients with IBD is long-term immunosuppression. The study by Ben-Horin et al examines the impact of combined AB+IM therapy on the course of CDI. While their results of finding worse outcomes in patients on combined therapy compared to antibiotics alone are interesting and potentially important, they also highlight several possible methodological issues with such retrospective studies. One important limitation is confounding by indication. Were patients who received both AB+IM simply sicker, and thus more likely to require surgery, than patients who were deemed not to need IM therapy? That AB+IM patients were more likely to have severe diarrhea (>6/day), blood in stool, or abdominal tenderness than those with AB alone suggests that this may partly be the case. In the absence of randomized treatment allocation, it is difficult to shape practice solely according to the results of this study. While the odds ratios are striking (11.9), the small sample size also results in extremely large confidence intervals (0.9–157) for the outcomes of interest. Given the prevalence of CDI reported to be as high as 47% in patients hospitalized with a disease flare, it is also interesting that over an 8-year period from 20 centers only 155 patients with CDI-IBD were accrued in this retrospective study. There are also several key pieces of the puzzle missing from the present study. Were patients started on a few days of AB prior to adding corticosteroids/IM therapy due to presumed nonresponse from the disease flare? Were both started simultaneously? Was there a difference in the timing or dose of AB use between the two groups? What dose of steroids was used? Was IM use reserved for those who cleared C. difficile toxin with AB? With the superior efficacy of oral vancomycin in severe CDI, would a more widespread use of it upfront have resulted in different results? There are two separate situations that arise with regard to IM use in IBD patients with CDI. What do you do with the immunosuppressive therapy in IBD patients already on IM prior to acquiring CDI, and do you initiate IM therapy in combination with AB in IBD not previously on these agents? In answer to the first question, the authors do not directly provide the data. But on calculation, 4 patients among 44 patients already on IM therapy prior to CDI underwent colectomy, a rate not statistically different from the rate in the AB alone group (0/46), suggesting that the approach of continuing prior IM therapy during an episode of CDI may not be harmful. In response to the second question, as with other infections complicating patients on long-term immunosuppression, it makes intuitive sense in patients with mild underlying IBD to avoid initiation of new IM therapy or escalate ongoing IM therapy before the infection is under control. This approach, however, may not be always possible in those with acute severe colitis complicated by CDI who are at a high risk for colectomy. From this study and from the work published so far on this topic, we do not yet have the definitive answer to that question, but a sufficient trial of therapy against CDI (oral vancomycin ± intravenous metronidazole) may be warranted prior to moving on to the next line of immunosuppressive therapy (biologics, cyclosporine) or colectomy in such patients. The authors should also be congratulated on their ambitious multicenter effort to answer this important question. Such collaboration can form a platform for future studies as we go forward in examining the natural history of the disease and complications. But such studies also carry with them the potential confounding due to variation in treatment practices (timing and dosage of AB and IM) between centers. These limitations of the present study emphasize the urgent need for a gold standard of randomized controlled trials to define the appropriate management algorithm for CDI in patients with IBD.