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Paratuberculosis and Crohn's Disease: Got Milk?
by Michael Greger, MD
http://www.veganMD.org
Updated January 2001

Antibiotics for Crohn's

The lesson researchers learned from stories like H. pylori90 was that their best bet at convincing the world that MAP causes Crohn's lay in trying to cure Crohn's -- a disease thought incurable -- with appropriate antibiotics.[74] Of course, there was no guarantee that even if the disease were caused by MAP that it would respond to treatment.[156] For example, we can cure most pulmonary TB with antibiotics, but when TB bacteria move from the lung to the intestine and cause intestinal TB, it cannot typically be cured by antibiotics alone.[23] Researchers, though, set out to try.

Before we knew that ulcers were treatable with simple antibiotics, people underwent repeated grueling surgeries -- some almost as risky and debilitating as Crohn's sufferers now undergo. Not only would a cure save Crohn's sufferers from the surgeon's knife, but it would also protect them from the toxic chemotherapy regimens currently used just for symptom relief, which can include immunosuppressants like steroids, cancer chemo agents,136 and even thalidomide.[50]

Researchers started trying antibiotics they thought might kill MAP in Crohn's. Early results were disappointing,156 leading to much of the deep-seated resistance among clinicians to accepting MAP as the cause of Crohn's.[14] Yet in hindsight, it turns out that doctors were using the wrong antibiotics, in the wrong combinations, for an inadequate period of time.

Perhaps because of the name similarity, many researchers assumed that antibiotics effective against M. tuberculosis should also be effective against M. paratuberculosis.189 They were wrong; when one actually tested antibiotics against MAP in a lab, researchers found that it was in general resistant to anti-tuberculous drugs.[22] They didn't work in cows;[23] they don't work in people.[120]

Another problem with some early studies was that they used monotherapy -- meaning that they only used a single agent -- which is rarely, if ever, effective in mycobacterial diseases because mycobacteria are so adept at developing resistance.[22] By giving multiple antibiotics at once, one decreases the chance that resistance will develop.

Adequate treatment duration had also been neglected. Mycobacterial infections in general are difficult to eradicate; prolonged treatment is required and relapses, either on treatment or off treatment, are common.[156] Tuberculosis takes months to treat; leprosy takes years -- sometimes a lifetime -- to treat. Our best estimate of how long it might take to rid the body of MAP can be made by studying pathogens in the same species. Infections caused by one of MAP's closest cousins (M. avium intracellulare) routinely require treatment for 3-4 years with 3 or 4 different antibiotics.[71] In some cases, it took five antibiotics all used in combination for 5 years before clinical improvement was achieved. We cannot expect trials using too few drugs, the wrong drugs, or even the right drugs for too short a time, to be successful.[21]

There are some factors which complicate any trial, even if the agents are chosen and used appropriately. Crohn's can be a cyclical disease, with periods of flare-ups and remissions, so approximately 20% of Crohn's patients during a treatment period will spontaneously improve on their own. The placebo effect is also expected to play a role in 30-40% of patients undergoing short-term therapy. And as mentioned previously, Crohn's is a poorly delineated disease -- 20% of people diagnosed with Crohn's may actually have something else.186 There is also clinical, epidemiological, and molecular evidence indicating that there are two distinct clinical manifestations of Crohn's disease, which each may respond differently to treatment. These factors make it difficult to evaluate any therapeutic intervention.[150]

Despite these hurdles, the latest results are quite promising.74 Instead of just blindly trying different antibiotics, scientists actually endured the laborious task of testing the antibiotics one by one on MAP in the lab. The breakthrough came in 1992 when the newly developed antibiotic clarithromycin was found to be the most effective known killer of Mycobacterium paratuberculosis. Many of the antibiotics used earlier worked by blocking cell wall synthesis. But Crohn's is thought to be caused by the spheroplast form of MAP which doesn't have a cell wall; it's therefore no wonder these earlier drugs didn't work. Clarithromycin, and an antibiotic called rifabutin, have a different mechanism of action, blocking protein synthesis.[157]

Another reason why drugs like clarithromycin (called macrolides) work against paraTB where others have failed is that MAP is an intracellular pathogen. They live inside our cells (another reason why they're so hard to see under a microscope). Only certain antibiotics, like macrolides, can penetrate inside human cells and still work effectively.[157] None of the previous MAP trials properly evaluated these newer macrolide antibiotics.[60] The time was ripe for a trial of these newer agents in Crohn's disease.

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