Primary Treatment of Crohn's Disease

Combined Antibiotics Taking Center Stage

William Chamberlin; Thomas J Borody; Jordana Campbell

Disclosures

Expert Rev Clin Immunol. 2011;7(6):751-760. 

In This Article

Anti-Mycobacterium Avium Paratuberculosis Therapy in CD

Given the poor activity of classic anti-tuberculous agents against Mycobacterium avium paratuberculosis (MAP), and their lack of intracellular access, where MAP is located, new antimycobacterial agents with intracellular activity against MAP, alone and in combination, were slowly introduced with improving results. Employing a combination of rifampicin, ethambutol, isoniazid and pyrazinamide or clofazimine for 9 months, Hampson et al. reported that 10 out of 20 CD patients (50%) achieved remission by 9 months.[35] Of the remaining ten, three had achieved remission by 6 months but had relapsed. Nine out of ten patients (90%) on steroids were weaned off by 9 months. Five patients required surgery for stricture formation, although no evidence of CD was noted at colonoscopy. Three patients with severe CD facing total colectomy were spared surgery. Similarly Prantera et al. compared a combination of ethambutol, clofazimine, dapsone and a 1 day dose of rifampicin versus placebo for 9 months in 40 patients with refractory, steroid dependent CD.[36] In the active group, 16 out of 19 patients (84.2%) achieved clinical remission versus six out of 17 (35.3%) in the placebo group. Additionally nine patients who relapsed on placebo were crossed over to anti-MAP therapy where five out of nine (55.5%) were then able to achieve sustained clinical remission.

Afdhal et al. employed either 100 mg/day clofazimine with corticosteroids or corticosteroids alone in 49 CD patients.[37] A total of 18 patients achieved remission (36.7%) with 12 out of 18 (66%) in the clofazimine group versus six out of 18 (33%) in the corticosteroid group. The modified disease activity score at the end of the trial was 1.4 ± 1.6 for clofazimine patients versus 4 ± 5.3 for placebo.

In 1995, Graham et al. trialed clarithromycin alone in 15 severe CD patients, achieving prolonged remission after 3 months of treatment in approximately 40% of patients.[38] Leiper et al. also used clarithromycin alone in 25 patients for a 4-week period, continuing to 12 weeks in responding patients.[39] In total, 11 of the 25 patients (44%) continued after 12 weeks for a median of 28 weeks (20–60 weeks). Two patients were withdrawn owing to nonserious side-effects. Inoue et al. also reported positive findings, treating 14 patients with active CD using clarithromycin for 4 weeks.[40] Patients who showed a clinical response within 4 weeks continued the therapy for up to 24 weeks. The mean CDAI score at entry was 343.5. Within 4 weeks, eight (57.1%) of the 14 patients showed clinical improvement, and five (35.7%) of the eight patients achieved remission. Each of the eight patients continued clarithromycin therapy after 4 weeks, and six (42.9%) were in clinical remission by 12 weeks. Out of the 14 total patients, four (28.6%) continued clarithromycin for more than 24 weeks and have remained in remission.

We now know that effective MAP treatment should consist of at least two different drugs, including a macrolide, and be administered for >6 months in a dosage similar to that used in Mycobacterium avium complex infection.[13,41–44] Monotherapy with a macrolide such as clarithromycin, while achieving good initial results in studies by Graham et al.[38] and the recent pilot study with Japanese CD patients,[40] is likely to result in the development of antibiotic resistance as is seen in tuberculosis therapy.[45–47] Combination regimens of three to four agents containing macrolides with known intracellular drug activity against MAP, such as rifabutin combined with the macrolide clarithromycin and/or clofazimine, have therefore been recommended for periods >6 months to minimize antibiotic resistance.[13] The favorable response of this treatment regimen, first evidenced in early studies by Hampson et al.[35] and Prantera et al.,[36] has since resulted in clinical remission in seven clinical trials with a success rate ranging from 44 to 89%, the results of which have been summarized (Table 2).[48–55]

Of the previously summarized studies, perhaps the most well-known and widely criticized study of anti-MAP therapy (AMAT) in CD was that conducted by Selby et al.[54] Touted as a 'landmark study',[56] the controversial trial used anti-mycobacterial drugs against atypical mycobacteria (rifabutin, clarithromycin, clofazimine) with prednisolone to induce remission followed by maintenance therapy with AMAT (n = 102). At 16 weeks, an unprecedented 66% of patients (n = 102) on AMAT were in remission without further benefit beyond this point by per-protocol analysis. However as surmised by Feller et al. the results of the Australian trial "were not based on an intention-to-treat analysis and may have underestimated the beneficial effects of the drug".[13] By an intention-to-treat (ITT) analysis the remission rate was significantly higher in the AMAT group compared with placebo (Table 2) with a p-value of <0.005 at 52 weeks and <0.008 at 104 weeks. As expected, after cessation of medication at 102 weeks the difference between treatment and placebo at 156 weeks was not significant (p = 0.19). Had the trial been based on an ITT analysis, as is the case with a number of other CD drugs on the market, the remission rate for AMAT would probably have been much higher.[13,55] The drop in efficacy over time is uncharacteristic compared with previous studies and may be attributed to two problems identified in the trial. First, the authors used "a suboptimal dose of clofazamine (50 mg/day) and other antibiotics",[57] and second, by the author's own admission, the clofazamine capsule "failed to rupture due to hardening of the outer gelatine capsule shell, resulting in a period of approximately 10 months where patients were likely not exposed to the correct dosage of clofazamine";[54] however, these patients were not replaced. Taken together, the results of the Selby trial were surprisingly good in spite of the shortcomings of the Australian Phase III trial. To demonstrate the superior efficacy of the treatment in CD it is essential to compare the results of the Selby trial with those of other CD treatments currently on the market, such as the anti-TNF therapy infliximab. AMAT remains a far more effective treatment than published results for infliximab, which reported remission rates of 39% at 12 weeks in the ACCENT I trial.[58,59] For example, on an ITT analysis, the AMAT remission rate at 16 weeks was 66% compared with 39% at 12 week for infliximab. Although no data is available for the trial of infliximab at 52 weeks, the ITT AMAT remission rate at 52 weeks was 41% compared with 26% at 26 weeks for the highest dose of infliximab used. The AMAT remission rate was also higher than that achieved with the recently US FDA-approved humanized anti-TNF antibody (adalimumab) in the CHARM trial, with the ITT remission rate of 24% for adalimumab at 52 weeks calculated for the highest dose.[60] The demonstrated superior results of anti-MAP therapy over other treatments currently on the market for CD support their use as a preferred primary treatment. This view was echoed by Feller et al. in their recent meta-analysis of antibiotic therapy in CD, who reported on the "potentially more favorable adverse effect profile and lower costs" of antibiotic therapy compared with infliximab.[13] With the serious, and at times fatal side effects encountered with anti-TNF therapy,[61,62] coupled with an efficacy below 39%,[57] it could readily be argued that failure to inform patients of this safe and effective antibiotic CD treatment may expose physicians to the question of 'duty of care' with its legal implications.

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