Antibiotic therapy for ulcerative colitis: Time for reevaluation?

Ohkusa T, Kato K, Terao S, et al. Newly developed antibiotic combination therapy for ulcerative colitis: a double-blind placebo-controlled multicenter trial. Am J Gastroenterol 2010;105:1820–1829. Fusiobacterium varium has been identified in the colonic mucosa of ulcerative colitis (UC) patients1 and a product of this organism, butyric acid, causes UC-like lesions in mice.2 These observations provided the rationale for a double-blind, placebo-controlled trial by Ohkusa et al3 to evaluate combination antibiotic therapy targeting F. varium eradication for induction and maintenance of remission in active UC. Patients with chronic relapsing mild-to-severe relapsing UC were randomly assigned to oral amoxicillin 1500 mg/day, tetracycline 1500 mg/day, and metronidazole 750 mg/day (ATM, n = 105) versus placebo (n = 101) for 2 weeks. These antibiotics were chosen on the basis of F. varium susceptibility testing. The primary study endpoint was clinical response (decrease from baseline Mayo score at 3 months after treatment completion); secondary endpoints included clinical and endoscopic score improvements at 12 months. Concomitant oral or rectal medications for UC were not discontinued except for corticosteroids, which were tapered after week 8 until discontinuation. Corticosteroid discontinuation for ≥3 months in steroid-dependent patients was considered steroid withdrawal. The baseline characteristics were similar between the groups and 48% of patients were corticosteroid-dependent. The median Mayo score for each group was 6 (range: 2–12); 51 placebo and 65 ATM patients had moderately active UC (Mayo score ≥6). The rate of response at 3 months after treatment was greater with ATM than with placebo (44.8% versus 22.8%, P = 0.0011) and correlated with improvement in endoscopic scores (P = 0.002). However, at 3 months rates of remission were similar after ATM and placebo (19.0% versus 15.8%, P = 0.59). At 12 months the clinical response remained higher with ATM compared with placebo (49.5% versus 21.8%, P < 0.0001) and remission rates increased to 26.7% with ATM compared with 14.9% for placebo (P = 0.041). Endoscopic scores also were improved after ATM treatment compared with placebo (P = 0.002). At 12 months, 50 ATM and 61 placebo patients had withdrawn, predominately due to disease relapse. For patients completing the trial the rate of clinical remission with discontinuation of steroids was higher in the ATM group than placebo (34.7% versus 13.7%; P = 0.019). Subset analyses of patients with active UC (Mayo scores of 6–12) showed a higher rate of response and mucosal healing at 3 and 12 months with ATM than placebo; no differences were identified for patients with inactive UC (Mayo score <6). No serious drug-related toxicities were observed, including the absence of enteric pathogens. Before treatment, baseline titers of immunoglobulins to F. varium were similar in the two groups. Among patients positive for F. varium antibodies, clinical response rates were higher in the ATM than in the placebo group at 3 months (45.5% versus 21.1%, P = 0.0023) and at 12 months (48.5% versus 18.4%, P < 0.0001). F. varium antibody titers decreased in responders but not in nonresponders. The authors concluded that for patients with active UC 2-week triple antibiotic therapy achieved clinical improvement, remission, and steroid withdrawal more effectively than placebo.

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