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Elliott et al. (Gut 2005; 54: 1818-19) present an interesting
and clinically useful finding of successful treatment of a patient with
severe Crohn’s disease and circumferential narrowing of the ileo-colonic
anastomosis treated with 750 mg ciprofloxacin plus 400mg metronidazole
daily for almost three years, resulting in complete healing and opening up of
the stenosed anastomosis.
The authors list a number of bacterial species known to be
susceptible to these antibiotics. However, they have omitted perhaps the
most important potential pathogen, Mycobacterium avium ss paratuberculosis
(MAP), the leading candidate causal agent of Crohn’s disease[1,2]. It is
well known that ciprofloxacin exhibits marked activity against
Mycobacterium avium. It is also known that metronidazole can be
bactericidal against dormant M. tuberculosis in anaerobic conditions.
Although no such data are yet available concerning other mycobacteria, the
role of metronidazole in affecting M. avium ss. paratuberculosis cannot be
excluded, when these bacteria persisted in anaerobic conditions. It is
indeed very unlikely that the success of metronidazole/ciprofloxacin
combination had much to do with luminal flora bacteria, but more likely,
it treated indolent tissue MAP, which may explain the need for prolonged
therapy. We can be even more certain that luminal flora was not the only
target of these antibiotics, especially ciprofloxacin, because more than
10 prolonged trials of various combinations of anti-tuberculosis
antibiotics were inactive against MAP, were active against luminal flora
bacteria, yet still failed to improve the outcome of Crohn’s disease. On
the other hand, in our experience with specific anti-MAP treatment, we
have reported five patients whose terminal ileal strictures returned to
normal, an indication that prolonged, targeted anti-microbial therapy is
necessary to inhibit tissue MAP and its consequent inflammation and
In retrospect it was difficult to accept that a chronic infection
with a previously poorly-known organism could cause such widespread gastro
-duodenal disease. In the pre-Helicobacter era bismuth was thought to
“chelate with protein at an acid pH...may stimulate release of mucus”[7,8]
when actually it was acting via a completely different mechanism,
inhibiting growth of Helicobacter pylori. Similarly, in this case report
one could initially postulate that metronidazole+ciprofloxacin exerts its
effect by inhibiting local bowel flora. On closer examination it becomes
more plausible that data presented in this case report supports
involvement of MAP in causation of inflammation, oedema and stenosis in
Crohn’s disease and that prolonged anti-MAP treatment can progressively
1. Bull TJ, McMinn EJ, Sidi-Boumedine K, et al. Detection and verification
of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic
mucosal biopsy specimens from individuals with and without Crohn’s
disease. J Clin Microbiol 2003; 41: 2915-23.
2. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium
avium subspecies paratuberculosis from the blood of patients with Crohn’s
disease. Lancet 2004; 364: 1039-44.
3. Heifets LB, Lindholm-Levy PJ. Bacteriostatic and bactericidal activity
of ciprofloxacin and ofloxacin against Mycobacterium tuberculosis and
Mycobacterium avium complex. Tubercle 1987; 68: 267-76.
4. Wayne LG, Sramek HA. Metronidazole is bactericidal to dormant cells of
Mycobacterium tuberculosis. Antimicrob Agents Chemother 1994; 38: 2054-8.
5. Greenstein RJ. Is Crohn’s disease caused by a mycobacterium?
Comparisons with leprosy, tuberculosis and Johne’s disease. Lancet Infect
Dis 2003; 3: 507-14.
6. Borody TJ, Leis S, Warren EF, Surace R. Treatment of severe Crohn’s
disease using antimycobacterial triple therapy – approaching a cure? Dig
Liver Dis 2002; 34: 9-12.
7. Salmon P, Brown P, Williams R, Read A. Evaluation of colloidal bismuth
(TDB) in treatment of duodenal ulcers employing endoscopic selection and
followup. Gut 1974; 15: 189-93
8. Jagu J. Bismuth in medicine. Bull Bismuth Inst 1971; 2:1.