Australian Crohn’s Antibiotic Study Opens New Horizons
Article Outline
Dear Sir:
The recently reported trial by Selby et al, “Two year combination antibiotic therapy with Clarithromycin, Rifabutin and Clofazimine for Crohn’s Disease”1 and the accompanying editorial refer to the controversial topic of Crohn’s disease causation by an infectious agent. In this letter, we address 3 important aspects that may have given careful readers concern.
As correctly stated in the editorial, the trial suffered profoundly from the problem of treating a very slow-growing mycobacterium with drug dosages that were not only suboptimal, but where 1 drug was only partially bioavailable owing to faulty capsule design. According to recommended dosing for Mycobacterium avium infection rifabutin was underdosed by >30%, clarithromycin by approximately 50%, and clofazimine by >50%—and then in the crucial part of the trial, as admitted by the authors—clofazimine did not dissolve properly. Clofazimine has a half-life of 70 days and would begin to be active about halfway through the 16-week induction of remission period. Once capsules stopped dissolving, its anti-DNA effect on the cell wall free mycobacteria was lost. Given the low doses and nondissolution, it is highly likely that in the longer term the development of drug resistance—known to occur with mycobacteria—would have played a major role in the apparent increased relapse in the “active” group. According to Good Clinical Practice,2 patients whose treatment violated the protocol should have been replaced by new trial patients where the clofazimine dissolved properly and was bioavailable. This raises the serious question of this trial’s validity beyond 16 weeks when the issue with clofazimine bioavailability commenced.
In reexamining the study design, it is clear that the trial failed to follow the recent trend toward meaningful achievement of remission.3 Most Crohn’s disease trials are designed to show response and/or remission and possibly later measure maintenance of remission. Instead, this study focused on measuring “proportions of patients experiencing at least one relapse,” yet it downplayed remission induction. Looking at initial remission rates of other studies, the 66% remission at 16 weeks in this trial ranks among the highest remissions generally achieved, with or without steroids. By contrast, infliximab was approved by the US Food and Drug Administration with 39% remission at 12 weeks. One can only imagine how high the 66% anti-M avium paratuberculosis (MAP) remission rate would have raised had nonresponders not been removed at week 16 and treatment continued longer on anti-MAP drugs, given the known slow response of mycobacteria. Indeed, the editorial should have lauded Selby’s group for bringing to gastroenterologists a totally new therapy that can induce high rates of remission for their ill Crohn’s patients. This fact was correctly emphasized by the journal in the CME section.4
Finally, Selby et al conclude that the short-term improvement may have been “because of nonspecific antibacterial effects.” Such a conclusion cannot be drawn from their data in that nonspecific antibacterial effects were never studied in their trial. Furthermore, the literature does not support such a concept and is replete with antimycobacterial trials using broad-spectrum anti-tuberculosis antibiotics in Crohn’s disease5 that demonstrate no evidence of “nonspecific antibacterial effects.” Hence, the high remission rate is clearly a specific effect of the anti-MAP drugs on MAP. The Selby et al paper did intimate that metronidazole and ciprofloxacin may cause “nonspecific” effects but failed to mention that both drugs have known antimycobacterial activity and therefore their effect can be directly attributed to an anti-MAP effect rather than the nebulous “nonspecific antibacterial effect.”6
We, as physicians currently treating patients with Crohn’s disease using anti-MAP drugs and seeing results not achievable with established therapies,7, 8 are surprised that this Gastroenterology paper—describing an effective, new “breakthrough therapy” with a high remission rate—was cast in a negative light. Nevertheless, we congratulate the journal for publishing this novel treatment so needed in an area crying out for effective therapies.
References
- Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132:2313–2319
- ICH Harmonised Tripartite Guideline: General Considerations for Clinical Trials E8.
- A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002;122:512–530
- Continuing medical education exam 2. Gastroenterology. 2007;132:2578–2579
- . Is Crohn’s disease caused by a mycobacterium? (Comparisons with leprosy, tuberculosis, and Johne’s disease). Lancet. 2003;3:507–514
- . Severe recurrent Crohn’s disease of ileocolonic anastomosis and antimicrobial (anti-mycobacterial) therapy. Gut. 2006;55:1211
- Successful treatment of a Crohn’s disease patient infected with bacteremic Mycobacterium paratuberculosis. Am J Gastroenterol. 2006;102:689–691
- Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars. Dig Liver Dis. 2007;39:438–444
PII: S0016-5085(07)01655-1
doi:10.1053/j.gastro.2007.09.014
© 2007 AGA Institute. Published by Elsevier Inc. All rights reserved.