http://www.paratuberculosis.org/pubs/proc9/abst182f_o6.htm

As noted by the authors, “These data may partially explain the paradoxical response of Crohn’s disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs i.e. they do not worsen with anti-inflammatory treatment as would be expected with a microbial etiologic pathogen.”
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The in vitro susceptibility of human and bovine-origin Mycobacterium paratuberculosis to the thiopurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) were established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn’s disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP even at high concentrations (>=64.0 microg/mL). Among rapidly growing mycobacteria, M. phlei was susceptible to 6-MP and AZA whereas M. smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-amino- salycilic acid (mesalamine)) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin (CPX) used as control drugs were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6- MP and CPX resulted in significantly higher CFUs as compared to use of CPX alone. These data may partially explain the paradoxical response of Crohn’s disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs i.e. they do not worsen with anti-inflammatory treatment as would be expected with a microbial etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn’s disease: azathioprine drugs may confound interpretation of data on therapeutic responses both antibiotic-treated and control groups.

http://www.ncbi.nlm.nih.gov/pubmed/17252054

Full Text

Abstract

BACKGROUND: Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP. METHODOLOGY: The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTEC detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (% -DeltacGI). PRINCIPAL FINDINGS: The positive control antibiotic (clarithromycin) has >or=85% -DeltacGI at a concentration of 0.5 microg/ml. The negative control (ampicillin) has minimal inhibition at 64 microg/ml. MAP ATCC 19698 shows >or=80% -DeltacGI for both agents by 4 microg/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate. CONCLUSIONS: We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % -DeltacGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups.

http://www.ncbi.nlm.nih.gov/pubmed/18575598

Full Text

Abstract

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the “immuno-modulators” methotrexate, azathioprine and 6-MP and the “anti-inflammatory” 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The “immunosuppressants” Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of “autoimmune” and “inflammatory” diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth. METHODOLOGY: The effect on radiometric MAP (14)CO(2) growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as “percent decrease in cumulative GI” (%-DeltacGI.) PRINCIPAL FINDINGS: The positive control clofazimine has 99%-DeltacGI at 0.5 microg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-DeltacGI by 32 microg/ml (Dominic), Rapamycin has 74%-DeltacGI by 64 microg/ml (UCF 4) and Tacrolimus 43%-DeltacGI by 64 microg/ml (UCF 4) CONCLUSIONS: We show heretofore-undescribed inhibition of MAP growth in vitro by “immunosuppressants;” the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some “autoimmune” and “inflammatory” diseases.

I expect to see results that show that RMATC (the Pharmacia trial is using RMAT + Clofazimine) is equally or more effective than existing treatments for Crohn’s Disease, and in a minority subgroup of patients, induces significantly longer clinical remission periods than existing treatments.

However, even when the results are published, we will still be in the following dissatisfactory position

1. We will not know in advance who will benefit from anti-MAP treatment and who will not.

2. If the treatment achieves a successful clinical outcome in any given patient, we will not know why.

3. If the treatment fails to achieve a successful clinical outcome, we will not know why. Which means that we will be unable to tell if the same treatment can be used again in the same patient, or if an alternative antibiotic treatment is required (e.g. due to antibiotic resistance).

4. We will not know the parameters which will define a successful end of the treatment period, e.g. organism clearance, antibody reduction, etc, etc. The currently proposed 2-year treatment period is essentially a guesstimate, based on experience with the treatment of related mycobacterial infections such as M avium subsp. avium. Since these antibiotics are expensive, and can be toxic, we need to be able to much more clearly define clinical outcome parameters. If 2 years is too short, then we risk antibiotic resistance. If 2 years is too long, then we need to reduce it. But we have little data to base conclusions upon.

5. We will not know if the treatment is microbiologically working in a patient with physical stricturing symptoms. RMAT treatment can accelerate stricture formation in a (hard to identify) subgroup of patients, due to fibrotic tissue formation, just as with other mycobacterial diseases. Physicians inexperienced with the protocol can misread the consequent temporary disimprovement in the patient’s clinical status as a treatment failure and take the patient off treatment, thus risking antibiotic resistance. We will have no tools, other than physician experience and intuition, to differentiate success from failure.

Or as Chiodini puts it, we will still be “at the whim of the individual physician”.

I believe that the bottom line is that most Gastroenterologists simply don’t know enough about infectious diseases, are not taught enough about infectious diseases: it’s not a large enough part of their educational, medical, or clinical culture. For example, some of the research published by gastroenterologists about anti-MAP antibiotic treatment for Crohn’s Disease displays fundamentally flawed reasoning and lack of microbiology experience.

I don’t find it at all strange that RMAT treatment was pioneered by a surgeon, John Hermon-Taylor. Fortunately, there are many excellent, open-minded and energetic gastroenterologists who are at the forefront of a fundamental rethink of Crohn’s Disease: Ira Shafran(Florida), Tom Borody(Sydney), Will Chamberlin(US Army), etc, etc. I’ve had the great fortune to work with all three: three things stand out about all of them: 1. They concern themselves deeply with the health of their patients, 2. they are not afraid to admit that they don’t know everything and are willing to learn, and 3. they are not driven by money.

Actually no, no way has yet been found of shortening the duration of RMAT.

Prof John Hermon-Taylor, as reported in his “Two year outcomes analysis…” treated patients for between 6 and 35 months, with a median of around 18 months. It is only a small percentage of patients that are treated for as little as six months.

Dr. T.J. Borody in Australia treats *all* of his patients for a minimum of 24 months, and adds Clofazimine (Lamprene) to the basic regime. This is the protocol upon which the Australian clinical trial is based.

Dr. Shafran is attempting to lower both the dosages and the duration of treatment, with good reason, because these drugs can be difficult to tolerate, especially for such long periods of time, not to mention the expense (approx US$500/month), a vital consideration if you have very little/very poor medical insurance. However, one must be very careful when treating bacterial infections with antibiotics at too low a dosage, because resistance can develop. Dr. Shafran is also adding probiotics to his regime, I believe to improve tolerance and assist in the reduction of inflammation.

There are other conceivable ways to reduce the duration of treatment.

1. By vaccination with a harmless mycobacterium, e.g. M. phlei or M. vaccae. Such a vaccination would assist in antigen uptake by the immune system, which would hopefully increase the efficacy of any antibiotic treatment. More on this interesting approach at

http://crohn.ie/archive/research/vaccine/m_vaccae.htm

Prof. JHT is also pursuing the possibility of a subunit vaccine, using raw DNA vaccination.

2. Hyperbaric Oxygen Therapy. Although no one is following up this possibility, I firmly believe that it could be of enormous benefit. If I ever hear of any work in this area, I’ll report on it.

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Question: Why do you think there were some failures with this treatment [anti-paratuberculosis antibiotic treatment]?

Dr Borody: We could probably spend a long time in this area. Firstly, let us reflect on Crohn’s Disease, which has a wide variety of manifestations, the symptoms of which are different in every patient. It is quite possible, and there is growing support for this view, that Crohn’s Disease may have more than one underlying cause, with MAP infection as one of those causes. If Crohn’s Disease is a collection of disorders, a proportion of which is caused by Mycobacterium avium subspecies paratuberculosis, then we aren’t going to be successful in 100% of patients by treating them with anti-MAP treatment.

Secondly, Mycobacterium avium subspecies paratuberculosis is a difficult infection to eradicate. Experience in Mycobacterium Avium Complex disease in patients with AIDS, where multiple drugs have to be used simultaneously and for a very long period of time, has shown that the success rate for clearance of infection is disappointingly low. Even with culturable Mycobacterium tuberculosis, we do not always achieve cure with multiple antibiotics given for a long time. In fact, there is a known increase in resistance of Mycobacterium tuberculosis to antibiotics. Hence we can expect that with the even more slowly growing and more antibiotic-resistant Mycobacterium avium subspecies paratuberculosis, we are going to get treatment failures.

Furthermore, we believe that pre-treatment with drugs used in these combinations, in particular the macrolide antibiotics Clarithromycin and Azithromycin, may increase the likelihood of ending up with antibiotic resistant Mycobacterium avium subspecies paratuberculosis in the patient. If we had the capability to culture Mycobacterium avium subspecies paratuberculosis and do sensitivity studies beforehand, we would be more likely to overcome treatment failure due to resistance. Unfortunately, reliable isolation of Mycobacterium avium subspecies paratuberculosis from Crohn’s Disease, and thus susceptibility testing of isolates, is not widely available.

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Dr Tom Borody (Center for Digestive Diseases, Sydney, Australia) is a Gastroenterologist of over two decades experience, who has been treating Crohn’s patients with anti-paratuberculosis antibiotics for the last three years.

Full text of this interview available at

http://www.crohns.org/treatment/borody.htm

http://crohn.ie/archive/htout.htm

The treatment was conducted based on the theory that Crohn’s disease is caused by the bacterium mycobacterium paratuberculosis. Reams of info from

http://crohn.ie/archive/welcome.htm

http://crohn.ie/archive/htout.htm

I have created a web page that contains a large amount of information about this topic. Follow this link for a summary of that information.

http://crohn.ie/archive/summary.htm

Follow this link to the main page:

http://crohn.ie/archive/welcome.htm

Please feel free to visit the site.