Treatment & diagnosis of Crohn's Disease



An Interview with Dr. T.J. Borody


Introduction


The following is the transcript of an interview with Dr. T.J. Borody, of the Center for Digestive Diseases, Sydney, Australia. Dr. Borody is a gastroenterologist with over 2 decades of clinical experience. He also conducts research, focusing mainly on the microbial ecology of the alimentary tract, and its role in development of a range of disease conditions in humans. Dr. Borody conducts both Phase 1 and Phase 2 clinical trials of novel treatments he derives from his own research, using both probiotics and antibiotics. He is well known for his work in the early days of H. pylori/Ulcers research, developing novel treatments that could eradicate this complex infection.

This interview was conducted on behalf of PARA by Alan Kennedy.

 


PARADr. Borody, you have been treating patients with Crohn's Disease using antibiotics effective against Mycobacterium avium subspecies paratuberculosis for over three years now. What results have you seen?
Dr. Borody

Well, this has been a very positive experience for my patients. Most of my patients, once commenced on anti-MAP antibiotics do very well - at least initially. Over 6-8 months they are able to abandon steroid usage and go off 5-ASA compounds: Azathioprine is ceased immediately on commencing the anti-MAP therapy. However, not all patients continue to do well over the 24 month treatment period. During treatment, about 30% of my patients have redeveloped symptoms while on continuous anti-MAP treatment. The majority however do well for up to two years in spite of the fact that endoscopically and histologically their disease may still be present in a proportion of the group. In other words, about 45% experienced complete disappearance - on our combination of drugs - of active Crohn's Disease whilst the rest have ongoing disease histologically and some clinically.

Overall, we had a percentage of patients - under 50% - who ended up experiencing complete remission, so that by 2 years we consider they have absence of Crohn's Disease. About 30% were clinically unwell on treatment and the other 30% are well as if they are taking standard maintenance therapy, but they nonetheless have active disease, although in much lesser severity on their biopsy.

 


PARAYou only treat patients with severe Crohn's Disease. Why?
Dr. Borody

Our study was a prospective trial which enrolled only special cases. These patients were those who were either failing or had failed high dose long term treatment which included combinations of steroids, 5-ASA compounds and immunosuppressants, including 6-MP and Azathioprine. They were also patients with ongoing severe Crohn's Disease with multiple pseudo polyps, obstructive and penetrating disease. In other words, they had active inflammatory strictures or had a history of active fistulae. We enrolled the worst and the most severe Crohn's patients in this trial. They had all been treated with conventional therapy first and had failed. Two of these patients were facing resection and this reflects the type of patients that we included in our study.

 


PARAWhy do you think there were some failures with this 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.

Many patients also have previous exposure to metronidazole (Flagyl). What is little known is that Metronidazole has activity against dormant forms of mycobacteria1,2. Many patients with Crohn's have been exposed previously to Flagyl, and there is a remote possibility that pre-treatment in the past with Metronidazole may make Mycobacterium avium subspecies paratuberculosis infections more difficult to eradicate. This is speculation, but needs to be kept in mind.

 


PARACan you describe your treatment protocol?
Dr. Borody

Our treatment consists of a combination of Clarithromycin, Rifabutin and Clofazimine. We commence treatment at a lower dose and raise to a higher dose after four weeks to try to avoid any profound side effects that can occur if we go to a high dose immediately. Following baseline studies of patients including blood workup, cross sectional ultrasound of small bowel (if small bowel is involved), inflammatory leucocyte bowel scan, colonoscopy with biopsies and photography, and small bowel X-ray if relevant - we then go on to commence the patient on the anti-MAP antibiotics. They are started with a dose of Rifabutin 150mg twice daily with food, combined with Clarithromycin 250mg twice daily and Clofazimine 50mg twice daily. Second weekly the patients undergo full blood count and liver function tests to monitor changes, especially in white cell count, neutrophil levels and liver function test elevations.

Generally speaking most patients have a minimal drop in white cell count, but many of these patients, being so ill, have highly elevated white cell count, so that this never reaches a leucopenia level. In three of twelve patients, when initially treated, we did reach leucopenia which was just below the level of normality, but we did not have to stop the medication in any of these because of our stepwise elevation of drugs. If this did occur, we planned to reduce the Rifabutin and Clarithromycin dosage down to 50% until the white cells recover. At four weeks the dose then goes up to 300mg of Rifabutin in the morning and 150mg at night and 250mg of Clarithromycin in the morning and 500mg at night. We use a high dose of Clarithromycin at night, to reduce the metallic taste which Clarithromycin can cause. For the next 24 months the patients are maintained on this treatment, progressively reducing and ceasing steroids and other Crohn's treatments.

 


PARAWhat side effects have you seen in your patients?
Dr. Borody

Globally, the anti-MAP therapy is better tolerated than the treatments patients were on for their severe disease. Most have some side effects, although there have been patients who have been totally without any side effects.

Leucopenia can occur if we start with too high a dose immediately - hence the ramping up dose. A flu-like syndrome can occur, again with high doses. We had one patient who had quite a severe flu like syndrome which was diagnosed as being encephalitis. He underwent lumbar puncture and an MRI. Nothing was found. He then re-commenced the treatment after it was ceased for a week and has continued on this for nearly two years without any recurrence.

Joint pains occur in more than 50% of patients and can be mild or severe. Only 1 out of our 6 patients who had arthralgias required non-steroidal anti inflammatory agents transiently and intermittently. However, the arthralgia can persist for many months.

Uveitis is a published side effect of this treatment3, but in our patients we have not experienced this. Perhaps because our patients were on high dose steroids, and because we use the ramping up dose of treatment, we did not see one case of uveitis. There is evidence which suggests that uveitis is not a direct drug toxicity but more of an immunological factor, because it does not occur in AIDS patients treated with the same protocol4. Hence, steroids and recent use of immunosuppressants may mask the uveitis. Indeed, arthralgia tends to occur weeks after the treatment has commenced, indicating that perhaps this only occurs after the steroid and Azathioprine withdrawal.

Antibiotic associated colitis is always a worry with use of antibiotics, especially Clarithromycin. We have seen diarrhoea in two patients, in one patient where Ciprofloxacin was substituted for Clofazimine, and the other with the current protocol. In these patients, standard investigations with stool examination for Clostridium difficile and its toxin at sigmoidoscopy were carried out. The protocol was continued without change, except for addition of Vancomycin followed then, longer term, by Metronidazole (Flagyl).

Although no patients suffered a rash it has been described with these medications, so we monitor for this. We had one patient with a transient elevation of liver function tests which disappeared on ongoing treatment. Patients did complain of a metallic taste, from Clarithromycin, but the complaint ceased and we suspect it was due to the fact that they became accustomed to the taste or perhaps it went away.

One possibly serious complication is the development of a benign stricture as the Crohn's Disease affected segment of bowel begins to heal. In our selected group of patients, none had this complication, although it is our understanding from other physicians experience3 that, as the inflamed bowel heals, a fibrous stricture can develop and, while the patient is actually improving, they may have the symptoms of partial obstruction. This is something that is to be expected in some patients. Such strictures would be diagnosed in the usual way, rather than ceasing therapy which is actually being successful.

 


PARAHow long did you treat your patients for?
Dr. Borody

Patients were treated for a minimum of 24 months. This decision was made by looking back over the history of treatment of mycobacterial infections. For example, Mycobacterium tuberculosis has historically been treated with three anti-tuberculous agents for 18 months. Although better agents have now been developed and this duration has been shortened, what we are dealing with is a very slowly dividing bacterium. Mycobacterium avium subspecies paratuberculosis divides much more slowly than Mycobacterium tuberculosis, and so its treatment should probably be double if not triple that of Mycobacterium tuberculosis. Other mycobacterial diseases, such as leprosy, also require prolonged treatment. Mycobacterium Avium Complex infection of the lung, in patients who are not immunocompromised, has been treated for between 15 months and five years5. Overall, therefore, when dealing with mycobacterial infections we are looking at very prolonged therapy. We settled on two years arbitrarily to make it longer than Mycobacterium tuberculosis but still within a manageable length of time.

 


PARAIn your opinion, is Clarithromycin + Rifabutin + Clofazimine the optimal treatment regime?
Dr. Borody

There is clearly no optimal treatment regime known to us at this time. This combination was more of an intelligent guess based on various publications of data for anti-MAP drugs in the literature.

The Mycobacterium Avium Complex (MAC) data has been of help. It has been demonstrated that a combination of Clarithromycin and Rifabutin was a highly active in-vitro and ex-vivo combination for treatment of MAC infection6,7. We are targeting here an intracellular, Cell Wall Deficient organism and our drugs need to address this. We have no real questions about the need for combining Clarithromycin and Rifabutin because from MAC data, there is clear direction for using these two agents in combination.

However, from previous mycobacterial therapy, we believe that we should not be using two drugs alone. Some would argue that we need to use at least three and perhaps up to seven drugs to eradicate a MAP infection. We didn't go to these lengths but added the next drug which appeared to be the optimal drug from available data at the time the treatment protocol was designed.

Clofazimine was chosen for the following reasons. It's an antimycobacterial which is active against spheroplasts, functions and accumulates intracellularly, and which localises and stains the lumen of the bowel. It has been used safely in long term treatment of leprosy. Hence, there is a track record of use of this drug.

Mycobacterium tuberculosis has been shown to be sensitive to Clofazimine in-vitro8 and Rifabutin combined with Clofazimine shows synergy9,10. Activity of Clofazimine has been shown to be present in animal models10,11,12,13, and it has been recommended in various combination treatments14,15,16,17,18. When used in a variety of drug combinations against MAC growing either intracellularly or in broth, the combination of Clarithromycin plus Rifabutin plus Clofazimine was the most active triple combination for intracellular MAC, being twice as effective in efficacy as the double Clarithromycin plus Rifabutin combination19.

Nonetheless, based on recent publications on treatment of MAC infection in patients with AIDS, the combination of Clarithromycin + Rifabutin + Ethambutol is considered to be more effective than Clarithromycin, Rifabutin and Clofazimine4. This is in agreement with study by Rastogi et al which shows synergy against Mycobacterium avium subspecies paratuberculosis between Clarithromycin and Ethambutol20. In fact, from intracellular and in-broth combinations the most effective was a 4 drug combination of Clarithromycin plus Rifabutin plus Clofazimine plus Ethambutol21.

However, data available to us at the commencement of our study pointed to Clarithromycin plus Rifabutin plus Clofazimine as the best available therapy.

We should bear in mind the fact that other agents could be available for this combination either to be added onto the current triple therapy or to replace Clofazimine. For example Ethambutol, as mentioned above, could be used. Quinolones have also been raised as possibilities22, although the data for sparfloxacin and levofloxacin is in-vitro data and has not been demonstrated to be active against spheroplasts.

 


PARAWhat are your opinions on the use of other antibiotics in Crohn's Disease?
Dr. Borody

A number of antimicrobial agents have been used to combat flare ups in Crohn's Disease. These have included Ciprofloxacin and metronidazole (Flagyl), used either alone or in combination. There is a perception that these two agents may be useful in short term treatment, through their effect on the enteric flora by reducing the antigenic load which can aggravate the underlying condition of Crohn's Disease.

When using such antibiotics, we need to remember that most molecules have more than one action. We may indeed be looking at effects of Ciprofloxacin and Flagyl which go beyond their action against the enteric flora. Both Ciprofloxacin and metronidazole have anti-mycobacterial activity. Although there is data which shows that Ciprofloxacin has little activity against MAP in-vitro23, ciprofloxacin does accumulate inside macrophages, raising its concentration to an inhibitory level against some members of the Mycobacterium Avium Complex24,25,26. Flagyl has been shown to be the only effective agent against dormant Mycobacterium tuberculosis, and other dormant mycobacteria, in an anaerobic environment1,2. In fact, one could make the case of adding Flagyl to our regime to provide activity against these potentially dormant organisms.

 


PARAWhat would you say to patients considering treatment with this regime?
Dr. Borody

It would be reasonable to wait until the trials of this regime have been completed before attempting treatment. We do not yet know the activity of available antibiotic regimes against Mycobacterium avium subspecies paratuberculosis. We have difficulty in diagnosing the infection and culturing the bacterium. The current regime does have potentially serious side effects. Thus, we cannot recommend this as a routine treatment for patients with Crohn's Disease.

 


PARADo you have any recommendations for patients with Crohn's Disease?
Dr. Borody

One recommendation would be to be careful in using drugs which may render MAP in the patient with Crohn's Disease resistant to future curative therapy. For example, use of the macrolides, Clarithromycin and Azithromycin, as short term monotherapy for other infections should be carefully considered. Clarithromycin is included in many combination therapies for H. pylori eradication, with treatment periods of less than one month. Patients with Crohn's Disease who have Helicobacter infection might consider using alternative antibiotic regimes when treating the H. pylori infection.

If the reason why Ciprofloxacin is beneficial to patients with Crohn's Disease is because of its anti-mycobacterial activity, then the use of Ciprofloxacin as monotherapy needs also to be carefully examined, since use of quinolones as monotherapy for the treatment of mycobacterial diseases is associated with increased risk of developing quinolone resistance27.

 


PARAAre there any lessons learned from the H. pylori experience that can be carried across to our understanding of Crohn's Disease treatment?
Dr. Borody

The H. pylori experience has taught us that the underlying cause of disease we are taught by our mentors may not turn out to be the real aetiology. I was taught that ulcers are caused by excess of acid and aggravated by stress. We now know that the majority of ulcers are caused by a simple but chronic infection, which is difficult to eradicate and requires Triple Therapy which still may not be completely successful.

Initially such concepts were met with total non-acceptance, but slowly, with accumulating evidence, eradication of H. pylori for cure of chronic duodenal ulcer has become the treatment of choice. Furthermore, we are now beginning to understand that H. pylori may be the cause of a number of other conditions which previously were not linked with ulcer disease. These include gastric carcinoma, low serum iron, short stature in children and a group of other yet-to-be-proven associations.

We should also remember that conditions with unknown aetiology in the past have turned out to be infectious diseases. These would include Lyme disease, Gullain-Barré syndrome, Reiter's syndrome, and most recently coronary artery disease - possibly caused by a strain of Chlamydia pneumoniae. The clear lesson is that we need to learn from the H. pylori experience, so that we can apply new paradigms to developing a cure for Crohn's Disease.


References

1Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis.
Wayne LG, Sramek HA.
Antimicrob Agents Chemother 1994 Sep;38(9):2054-8: [Abstract]
2Oxygen depletion induced dormancy in Mycobacterium smegmatis.
Dick T, Lee BH, Murugasu-Oei B.
FEMS Microbiol Lett 1998 Jun 15;163(2):159-64: [Abstract]
3Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics.
Gui GP, Thomas PR, Tizard ML, Lake J, Sanderson JD, Hermon-Taylor J.
J Antimicrob Chemother 1997 Mar;39(3):393-400: [Abstract] [Full Text]
4Clarithromycin, Rifabutin and Clofazimine for Treatment of Disseminated Mycobacterium avium Complex Disease in AIDS Patients
Haefner M, Funke-Kissling P, Pfyffer GE, Lüthy R, Opravil M.
Clin Drug Invest 17(3):171-178, 1999.: [Full Text]
5Antimicrobial agents and Crohn's disease: do they have a therapeutic role? [editorial; comment]
Chiodini RJ.
Ital J Gastroenterol Hepatol 1998 Dec;30(6):593-8: [Abstract] [Full Text]
6Effects of clarithromycin and rifabutin alone and in combination on intracellular and extracellular replication of Mycobacterium avium.
Mor N, Vanderkolk J, Mezo N, Heifets L.
Antimicrob Agents Chemother 1994 Dec;38(12):2738-42: [Abstract] [Full Text]
7Clarithromycin against Mycobacterium avium complex infections.
Heifets LB.
Tuber Lung Dis 1996 Feb;77(1):19-26: [Abstract] [Full Text]
8In vitro antimicrobial susceptibility of a Mycobacterium sp. isolated from patients with Crohn's disease.
Chiodini RJ, Van Kruiningen HJ, Thayer WR, Coutu JA, Merkal RS.
Antimicrob Agents Chemother 1984 Dec;26(6):930-2: [Abstract]
9Antimicrobial activity of rifabutin in combination with two and three other antimicrobial agents against strains of Mycobacterium paratuberculosis.
Chiodini RJ.
J Antimicrob Chemother 1991 Feb;27(2):171-6: [Abstract]
10Activity of rifabutin alone or in combination with clofazimine or ethambutol or both against acute and chronic experimental Mycobacterium intracellulare infections.
Gangadharam PR, Perumal VK, Jairam BT, Rao PN, Nguyen AK, Farhi DC, Iseman MD.
Am Rev Respir Dis 1987 Aug;136(2):329-33: [Abstract]
11Activity of rifabutin alone and in combination with clofazimine, kanamycin and ethambutol against Mycobacterium intracellulare infections in mice.
Saito H, Sato K.
Tubercle 1989 Sep;70(3):201-5: [Abstract]
12In vivo activity of amikacin alone or in combination with clofazimine or rifabutin or both against acute experimental Mycobacterium avium complex infections in beige mice.
Gangadharam PR, Perumal VK, Podapati NR, Kesavalu L, Iseman MD.
Antimicrob Agents Chemother 1988 Sep;32(9):1400-3: [Abstract]
13Mycobacterium avium complex infection in the acquired immunodeficiency syndrome.
Horsburgh CR Jr.
N Engl J Med 1991 May 9;324(19):1332-8: [Abstract]
14Mycobacterioses and the acquired immunodeficiency sundrome.
Snider DE, Hopwell PC, Mills J, Reichman LB.
Am Rev Respir Dis 1987 Feb;136:492-498:
15Individualized therapy versus standard regimens in the treatment of Mycobacterium avium infections [editorial; comment]
Heifets LB, Iseman MD.
Am Rev Respir Dis 1991 Jul;144(1):1-2: [Abstract]
16Diagnosis and treatment of disease caused by nontuberculous mycobacteria.
Wallace RJ, O'Brien R, Glassroth J, et al..
Am Rev Respir Dis 1990;142:940-953:
17[Mycobacterium avium intracellulare infections. Treatment with a clarithromycin-clofazimine combination. 18 cases]
Saint-Marc T, Marneff E, Touraine JL.
Presse Med 1993 Dec 4;22(38):1903-7: [Abstract]
18In vitro activities of rifabutin, azithromycin, ciprofloxacin, clarithromycin, clofazimine, ethambutol, and amikacin in combinations of two, three, and four drugs against Mycobacterium avium.
Yajko DM, Sanders CA, Madej JJ, Cawthon VL, Hadley WK.
Antimicrob Agents Chemother 1996 Mar;40(3):743-9: [Abstract]
19Effect of combined clofazimine and ansamycin therapy on Mycobacterium avium-Mycobacterium intracellulare bacteremia in patients with AIDS.
Masur H, Tuazon C, Gill V, Grimes G, Baird B, Fauci AS, Lane HC.
J Infect Dis 1987 Jan;155(1):127-9: [Abstract]
20Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement of its extracellular and intracellular activities by ethambutol.
Rastogi N, Goh KS, Labrousse V.
Antimicrob Agents Chemother 1992 Dec;36(12):2843-6: [Abstract]
21Clofazimine - Miscellaneous Infectives.
AHFS Drug Information 1997;639-644.:
22Development of a firefly luciferase-based assay for determining antimicrobial susceptibility of Mycobacterium avium subsp. paratuberculosis.
Williams SL, Harris NB, Barletta RG.
J Clin Microbiol 1999 Feb;37(2):304-9: [Abstract] [Full Text]
23Bactericidal activities of various antimicrobial agents against human and animal isolates of Mycobacterium paratuberculosis.
Chiodini RJ.
Antimicrob Agents Chemother 1990 Feb;34(2):366-7: [Abstract]
24Activity of ciprofloxacin and other fluorinated quinolones against mycobacteria.
Young LS, Berlin OG, Inderlied CB.
Am J Med 1987 Apr 27;82(4A):23-6: [Abstract]
25Activity of quinolones against mycobacteria.
Jacobs MR.
Drugs 1995;49 Suppl 2:67-75: [Abstract]
26Comparison of the activity of fluoroquinolones against Mycobacterium avium in cell-free systems and a human monocyte in-vitro infection model.
Shiratsuchi H, Jacobs MR, Pearson AJ, Venkataprasad N, Klopman G, Ellner JJ.
J Antimicrob Chemother 1996 Mar;37(3):491-500: [Abstract]
27The clinical use of fluoroquinolones for the treatment of mycobacterial diseases.
Alangaden GJ, Lerner SA.
Clin Infect Dis 1997 Nov;25(5):1213-21: [Abstract]

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