Importance of the Australian Crohn’s Disease Antibiotic Study

Chamberlin, William

doi:10.1053/j.gastro.2007.09.013

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Volume 133, Issue 5 , Pages 1744-1745, November 2007

Importance of the Australian Crohn’s Disease Antibiotic Study

Texas Tech University Health Sciences Center, El Paso, Texas

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Dear Sir:

The article by Warwick Selby, “Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease”¹ and the accompanying commentary² are well written and worth reading carefully. They contain important data and commentary. Unfortunately, despite data supporting the positive impact of properly chosen antibiotics in treating Crohn’s disease (CD) patients, the authors emphasize the negative. The authors report the data accurately, but their interpretations need to be challenged. It is true that atypical mycobacterial antibiotic therapy (AMAT) did not provide a cure for CD, and thus this trial was technically a negative study, but the antibiotic limb did significantly better than the comparison limb as long as antibiotics were being administered. At 4 months, 66% of patients on AMAT were in complete clinical remission. This response rate is better than any other therapy (including infliximab) to date. The data support another interpretation: AMAT provides a more effective treatment regimen with a more favorable side effect profile than current conventional therapy. This is indisputably true for a subset of patients who need to be better defined. Certain points need to be made.

1.The control arm was not a placebo arm; patients continued to receive treatment with mesalamine drugs and 6-mercaptopurine (6-MP).

2.Unknown at the time, but recently published by Robert Greenstein and Sheldon Brown is the fact that mesalamine and 6-MP have an antibiotic effect against Mycobacterium avium paratuberculosis (MAP) in vitro. They opine that conventional therapeutic regimens may be effective because of their anti-MAP characteristics and not because of their immune suppressive characteristics.³, ⁴ Nevertheless, adding antibiotics to the treatment was associated with a significant improvement (66% vs 50%) in achieving complete clinical remission at 4 months, 42% versus 25% at 1 year, and 34% versus 18% at 2 years. The fact that the difference between the 2 groups no longer remained statistically significant at 3 years (1 year after the antibiotics were removed; 19% vs 12%) should not have been interpreted as showing that AMAT was not beneficial. The conclusion could have been that AMAT suppresses CD activity, but evidence for a cure in this group study was not achieved.

3.Important specific information on individuals was not reported. Clinical responses not achieving complete remission were considered to be failures. Physicians with experience with AMAT have all seen patients whose disease disappears and their bowels heal. The subset of patients for whom AMAT is a miracle therapy is completely unreported.

4.Conventional therapies do not provide a cure and are accompanied by predictable, serious side effects. Infliximab initially has a 60% response rate with only 20% achieving remission at 1 year.⁵, ⁶ In this study, 42% of patients receiving AMAT were in clinical remission at 1 year. It is inconsistent to extol the virtues of one form of therapy that improves symptoms but does not cure the disease and then dismiss AMAT because it does not cure the disease, although it is safer and does a better job at achieving remission.

We are all seeking additional options to treat this disease. Antibiotics have been, and still are, first-line therapy for CD. Most choose single agents such as metronidazole or ciprofloxacin. They both seem to work for a while. The triple antibiotic regimen used in this study is an improvement on the monotherapy usually given. This is truly a situation where the glass is half full or half empty. Presenting the positive data in a negative manner is not helpful. Perhaps if the authors were to reevaluate their conclusions they would realize the true value of their efforts.

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References

Selby W, Pavill P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132:2313–2319

Peyrin-Biroulet L, Neut C, Columbel JF. Antimycobacterial therapy in Crohn’s disease; game over?. Gastroenterology. 2007;132:2594–2598

Greenstein RJ, Liya S, Haroutunian V, et al. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis. PLos One. 2007;2:e161

Greenstein RJ, Su L, Shahidi A, et al. On the action of 5-amino-salicylic acid and sulfapyridine on M. avium subspecies paratuberculosis. PLos One. 2007;2:e516

Mannon P. Gain for loss: adalimubab for infliximab-refractory Crohn disease. Ann Intern Med. 2007;146:888–890
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Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the Accent/Randomised trial. Lancet. 2002;359:1541–1549