Dig Liver Dis 2002 Jan;34(1):29-38
Treatment of severe Crohn's disease using antimycobacterial triple therapy--approaching a cure?
Borody TJ, Leis S, Warren EF, Surace R
Centre for Digestive Diseases, Sydney, Australia. tborody at zip.com.au
BACKGROUND: Mycobacterium avium subspecies paratuberculosis is probably the best candidate for a microbial cause of Crohn's disease although arguments to the contrary can be equally convincing. Growing evidence suggests that prolonged antimycobacterial combination therapy can improve Crohn's disease in some patients. AIM: To report long-term observations in patients with severe Crohn's disease treated with triple macrolide-based antimycobacterial therapy. PATIENTS: A series of 12 patients (7 male, 5 female; aged 15-42 years) with severe, obstructive or penetrating Crohn's disease were recruited. METHODS: Patients failing maximal therapy were commenced prospectively on a combination of rifabutin (450 mg/d), clarithromycin (750 mg/d) and clofazimine (2 mg/kg/d). Progress was monitored through colonoscopy, histology, clinical response and Harvey-Bradshaw activity index. RESULTS: Follow-up data were available for up to 54 months of therapy Six out of 12 patients experienced a full response to the antiMycobacterium avium subspecies paratuberculosis combination achieving complete clinical, colonoscopic and histologic remission of Crohn's disease. Four of these patients were able to cease treatment after 24-46 months, 3 of whom remained in total remission without treatment for up to 26 months and one patient relapsed after six months off treatment. A partial response to the anti-Mycobacterium avium subspecies paratuberculosis combination was seen in 2 patients showing complete clinical remission with mild histologic inflammation. Return to normal of terminal ileal strictures occurred in 5 patients. Harvey-Bradshaw activity index in patients showing a full or partial response to therapy fell from an initial 13.4 +/- 1. 91 to 0. 5 +/- 0. 47 (n = 8, p < 0. 001) after 52-54 months. CONCLUSIONS: Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-Mycobacterium avium subspecies paratuberculosis therapy alone. Three patients remain in long-term remission with no detectable Crohn's disease off all therapy These results support a causal role for Mycobacterium avium subspecies paratuberculosis in Crohn's disease while also suggesting that a cure may become possible.
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PARA's SUMMARY
ANTIBIOTICS ACTIVE AGAINST MAP REVERSE SEVERE CROHN'S DISEASE SYMPTOMS AND INDUCES REMISSION IN AT LEAST 50% of CD PATIENTS.
http://www.crohns.org/articles/2002_01_29-38_dld.htm
http://www.crohns.org/articles/index.htm
Nov 3, 2003
By: Kelly Dowhower Karpa, Ph.D., R. Ph.
Drug Topics
SPECIAL REPORT
CROHN'S: AN INFECTIOUS DISEASE?
Rather than an autoimmune disorder, inflammatory bowel disease is increasingly being viewed as bacterial in origin
When it comes to gastroenterology, we may not know as much as we think we do. Remember, for example, how we scoffed at the Australian physician in the early 1990s who asserted that the bacterium Helicobacter pylori caused peptic ulcer disease (PUD)? Now, the association between H. pylori and gastric ulcers is accepted as dogma, and antibiotics to eradicate this infectious microbe are commonly included in treating PUD.
Currently, the etiology underlying inflammatory bowel disease (IBD) is also being called into question. For years Crohn's disease and ulcerative colitis have been accepted as autoimmune disorders. Yet the tide may be about to turn. Last year, two prominent physicians at Harvard Medical School put forth four theories of IBD. Data exist to support all four theories, yet not one is based on the premise that IBD is autoimmune in nature. Instead, each theory relies upon the notion that IBD is a result of the immune system's response to bacteria in the gastrointestinal tract. If, in fact, IBD is an infectious disease, a microorganism should be identifiable in the gastrointestinal tract of Crohn's patients, and the illness should respond to antibiotics. According to some clinicians, these criteria have already been met.
In the laboratory of molecular research at the VA Medical Center in the Bronx, Robert Greenstein, M.D., director, and his researchers have consistently isolated RNA belonging to Mycobacterium avium paratuberculosis (MAP) from 100% of patients with Crohn's disease, but this microorganism is not isolated from patients used as negative controls. If MAP is indeed a causative agent in Crohn's disease, this changes the entire IBD paradigm. These findings, in Greenstein's words, "change the I in IBD from 'inflammatory' to 'infectious.'"
Antimycobacterials
Like other mycobacterial strains, MAP reproduces very slowly. For antibiotics to effectively eliminate MAP, a cocktail of antimycobacterial drugs must be used for extended periods of time. And that is just what the doctor orders for patients with Crohn's disease in Sydney, Australia. Thomas Borody, M.D., director of the Centre for Digestive Diseases, utilizes triple antimycobacterial therapy for his Crohn's patients.
Borody said he uses a combination of rifabutin (Mycobutin, Pharmacia), clarithromycin (Biaxin, Abbott), clofazimine (Lamprene, Novartis), and ethambutol for at least three years in his Crohn's disease patients. In his experience, "cures are achieved in 20%-25% of patients and the rest go into total remission." By cure, he means that when his patients are off all medications, they not only have no symptoms, but, endoscopically, they have no inflammation, no histologic evidence of Crohn's disease, and their blood work is negative for markers of inflammation. In contrast, those patients that "go into total remission" experience only minor symptoms, and there is still slight evidence of the disease in endoscopic examination.
The patients who come to Borody are the sickest patients—the ones who "have failed everything else." Although his practice is "down under," patients routinely travel to Sydney, even from the United States, to see him. "There has never been a spontaneous cure reported in the literature," Borody said, a fact that clearly indicates his patients are not getting better by chance. For patients to respond so dramatically to antimycobacterials, the etiology underlying their Crohn's disease must be infectious in nature.
While Borody is not the only physician approaching Crohn's disease in this fashion, he noted the skepticism that others in his profession have when existing paradigms are challenged. Borody likened the current situation to that of Helicobacter pylori in the 1990s: "No amount of double-blind trials will turn doctors' hearts," he said. Doctors are not convinced with proof. Slowly some will try this, and eventually they will come around in herds."
Other antimicrobial treatments
At the American College of Gastroenterology annual meeting in Baltimore last month, Salix Pharmaceuticals announced that its lead antimicrobial compound, Lumenax (rifaximin), a rifampin-like drug, may reach the U.S. market as early as spring 2004. Mechanistically, according to Dan Lundberg, a senior director with the marketing department at Salix, "rifaximin inhibits bacterial RNA synthesis."
However, the new compound is chemically larger than rifampin and is not systemically absorbed. Therefore, it is being termed a novel "gastrointestinal, site-specific antibiotic." In a small 16-week trial of rifaximin in Crohn's disease patients, the drug reduced the mean Crohn's Disease Activity Index (CDAI) 43% from baseline, and clinical remission was achieved by 59% of patients. If approved, the drug may become yet another agent in the cocktail of antibacterials used to treat patients with Crohn's disease.
Probiotics
Some other gastroenterologists who believe an infectious agent may underlie Crohn's disease have taken a different approach to treating the illness. Instead of using antibiotics to wipe out infectious microorganisms, they have instead opted to treat patients with therapeutic doses of "healthy bacteria," or probiotics. Rather than using antibiotics to kill bacteria, this novel approach lets bacteria kill bacteria.
Probiotics can be defined as "live microorganisms that have the potential to bring about beneficial effects on the host." Yogurt immediately comes to mind. In actuality, however, most yogurts contain relatively few "live and active cultures" by the time they reach our refrigerator shelves. Instead, numerous companies have begun to market probiotic products on a large scale, in the form of capsules or powders, for health purposes.
One company, Questcor Pharmaceuticals, manufactures a probiotic product called VSL#3, which is made up of eight different strains of bacteria, including Lactobacillus, Bifidobacteria, and Streptococcus. In clinical trials of IBD, VSL#3 has been beneficial in maintaining remission in patients with both Crohn's disease and ulcerative colitis. Likewise, another company, BioBalance Corp., markets an Escherichia coli product in many countries, called PROBACTRIX. This product has been shown to significantly reduce not only abdominal symptoms but also intestinal inflammation in patients with IBD.
John Azzarelli, R.Ph., CNC, supervising pharmacist/ manager of Nature's Apothecary, a health food store and pharmacy in Brooklyn, N.Y., frequently recommends a probiotic product called Healthy Trinity (two strains of Lactobacillus and one strain of Bifidobacterium), manufactured by Natren. He said, "Probiotics make me look like a genius to my patients. Patients think I know more than their GI doctors who have told them that they have IBD and there is no cure." Azzarelli told the story of one man with Crohn's disease who was having 60 bowel movements every day. Since beginning probiotic therapy, Azzarelli said, this man now passes only three stools a day.
While the exact beneficial mechanisms of probiotics in IBD are not clear, probiotics may be able to wipe out infectious agents in the gut simply by competing with pathogenic bacterial strains for essential nutrients or intestinal binding sites. Also, many strains of probiotics are known to secrete toxins or peroxides that are deleterious to pathogenic bacteria and may, in this way, combat infectious bacteria.
Although the therapeutic approaches to managing Crohn's disease will not change overnight, don't be surprised if someday you find yourself dispensing what you once considered to be antitubercular drugs to patients with Crohn's disease, and don't be horrified if other patients with IBD tell you that they had bacteria for breakfast!
Kelly Dowhower Karpa, Ph.D., R.Ph.
The AUTHOR is a medical writer based in the Philadelphia area and the author of a new book, Bacteria for Breakfast: Probiotics for Good Health.
Kelly Karpa. Special Report -- Crohn's: An infectious disease? Drug Topics Nov. 3, 2003;147:52.
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