Ciprofloxacin reduced treatment failure in ulcerative colitis at 6 months but not at 12 months
ACP J Club. 1999 May-June;130:71. doi:10.7326/ACPJC-1999-130-3-071
Turunen UM, Färkkilä MA, Hakala K, et al. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology. 1998 Nov;115:1072-8.
Is ciprofloxacin effective for inducing and maintaining remission in patients with moderate to severe ulcerative colitis (UC) who are treated with prednisone and mesalamine?
Randomized, double-blind, placebo-controlled trial with 12-month follow-up.
A gastroenterology unit at the University of Helsinki, Finland.
83 patients who were 18 to 65 years of age (mean age 34 y, 70% men) and had histologically confirmed UC (mean duration 5.4 y) with moderate to severe endoscopic activity over ≥ 2 segments of the bowel. Exclusion criteria included ulcerative proctitis, need for antibiotic treatment, antibiotic treatment (except for metronidazole) in the previous 2 weeks, pregnancy, lactation, or severe concomitant medical or surgical disease. Follow-up was complete.
Patients were allocated to prednisone, mesalamine, and ciprofloxacin (n = 38) or prednisone, mesalamine, and placebo (n = 45). Prednisone was given at doses of 0.75 mg/kg of body weight for 4 weeks, 0.50 mg/kg for the next 4 weeks, and 0.25 mg/kg for up to 12 weeks. The dose was then tapered, if possible. If disease activity was limited to the rectum, corticosteroids and mesalamine were given rectally after steroids were tapered. Hospitalization and intravenous treatment were used at study entry, if necessary. Ciprofloxacin, 500 to 750 mg twice daily, was given for 6 months and mesalamine, 800 mg twice daily, was given for 12 months.
Main outcome measures
Treatment failure (colonoscopic finding of moderate to severe activity in ≥ 2 segments of the colon after no response to treatment) during 6 months of treatment.
At 6 months, treatment failed in fewer patients in the ciprofloxacin group than in the placebo group (P = 0.02) (Table). The difference was not statistically significant at 12 months (P = 0.07) (Table).
In patients with ulcerative colitis who were treated with prednisone and mesalamine, the addition of ciprofloxacin decreased treatment failure at 6 months but not at 12 months.
Source of funding: Bayer AG.
For correspondence: Dr. U.M. Turunen, Maria Hospital, Sisätautien poliklinikka, Lapinlahdenkatu 16, 00180 Helsinki, Finland. FAX 358-9-310-63249.
Table. Treatment failure rates for ciprofloxacin vs placebo in ulcerative colitis treated with mesalamine and prednisone*
|Length of follow-up||Ciprofloxacin||Placebo||RRR (95% CI)||NNT (CI)|
|6 mo||21%||44%||53% (9 to 77)||5 (3 to 35)|
|12 mo||45%||60%||25% (-13 to 52)||Not significant|
*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
In this study by Turunen and colleagues, patients were directly referred or had been treated at other hospitals and were refractory to treatment for UC. Many patients were already receiving steroids and 5-acetylsalicylic acid compounds at study entry. Presumably, many patients had remission in response to steroids during the first 3 months; patients with active disease at 6 months included those who had relapse after withdrawal of steroids and those who were refractory to further therapy. The statistically significant treatment effect is also clinically important. The finding of a 23% absolute increase in the proportion of patients who achieved remission with well-tolerated antibiotic therapy is useful, although no evidence exists of a steroid-sparing effect.
The primary outcome was the continuation of colonoscopic disease activity "after failure to respond," which was not defined. Nonresponders received increased doses of steroids or, in the case of distal disease, topical therapy. Colectomy was done by 6 months in a relatively high proportion of patients, which suggests that many patients had severe or refractory disease. In addition, an unstated number of patients were initially hospitalized for intravenous therapy and therefore had severe disease.
A potential confounder might have been an imbalance in the number of patients in each group with severe or refractory disease. Randomization was not stratified for refractoriness, severity, or previous steroid therapy. Post hoc subgroup analysis suggested that ciprofloxacin was more effective in patients who had received steroids before study entry. This finding suggests that the favorable outcome in the ciprofloxacin group did not result from random assignment to placebo of more patients who were severely ill, even though more patients in the placebo group than in the treatment group had received steroids. However, more patients in the placebo group may have had refractory disease.
Antibiotic therapy may be a simple and effective additional therapy for UC. Further studies are required before concluding that ciprofloxacin should be offered to patients. Such studies should involve a more homogeneous group of patients or include equal proportions of patients with refractory and severe disease in each group. An attempt should also be made to determine whether steroid sparing occurs.
John W.D. McDonald, MD
University of Western OntarioLondon, Ontario, Canada