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REVIEW: Antibacterial Therapy for Crohn's Disease: A Review Emphasizing Therapy Directed Against Mycobacteria

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Abstract

The most commonly used antibiotics in Crohn's disease are nitroimidazoles and macrolides often combined with corticosteroids or sulfasalazine. There has been interest in a mycobacterial involvement in Crohn's disease since its earliest description. It is not recognized that Mycobacterium avium subspecies paratuberculosis, a proven but uncommon cause of human disease, is widespread in the human food chain especially in dairy products and beef. M. paratuberculosis has been identified in tissues from a higher proportion of Crohn's disease patients than controls, suggesting that it may be one of the causes of Crohn's disease. We review the large number of antibiotic trials in Crohn's disease. Although studies have been performed with many different protocols and variations in the definition of success, preliminary reports of multiple drug therapies are encouraging. Nevertheless, large-well designed preferably placebo-controlled studies are needed before one could recommend such therapy.

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REFERENCES

  1. Gitnik G: Inflammatory Bowel Disease. Diagnosis and Treatment. New York, Igaku-Shoin Medical Publishers, 1991

    Google Scholar 

  2. Ekbom A, Blomqvist P: Cost to society in Crohn's disease. Res Clin Forum 20:33-39, 1998

    Google Scholar 

  3. Shivanada S, Lennard-Jones J, Logan R, Fear N, Prie A, Carpenter L, van Blankenstein M: Incidence of inflammatory bowel disease across Europe: Is there a difference between north and south? Results of the European collaborative study on inflammatory bowel disease (EC-IBD). Gut 39:690-697, 1996

    Google Scholar 

  4. Calkins BM, Lilienfield AM, Garland F, Mendeloff AI: Trends in incidence rates of ulcerative colitis and Crohn's disease. Dig Dis Sci 299:913-920, 1984

    Google Scholar 

  5. Cella Lanau J, Lopez Zaborras J, Gomollon Garcia F, Sainz Samitier R: Inflammatory bowel disease in Aragon: A more frequent diagnosis. Rev Esp Enferm Dig 87:363-367, 1995

    Google Scholar 

  6. Nunes GC, Ahlquist RE Jr: Increasing incidence of Crohn's disease. Am J Surg 145:578-581, 1983

    Google Scholar 

  7. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR: Crohn's disease in Olmsted County, Minnesota, 1940-1993: Incidence, prevalence, and survival. Gastroenterology 114:1161-1168, 1998

    Google Scholar 

  8. Crohn B, Ginzburg L, Oppenheimer G: Regional ileitis, a pathological and clinical entity. JAMA 99:1323-1329, 1932

    Google Scholar 

  9. Hodgson HJF: Pathogenesis of Crohn's disease. Bailliere's Clin Gastroenterol 12:1-17, 1998

    Google Scholar 

  10. Hanauer SB: Inflammatory bowel disease. N Engl J Med 334:841-848, 1996

    Google Scholar 

  11. van Deventer SJH, Camoglio L, te Velde AA: Crohn's disease: Current medical treatment possibilities. Res Clin Forums 20(3):11-18, 1998

    Google Scholar 

  12. Järnerot G, Sandberg-Gertzen H, Tysk C: Medical therapy of active Crohn's disease. Bailliere's Clin Gastroenterol 12:73-91, 1998

    Google Scholar 

  13. Shield MJ: The importance of immunologically effective contact with environmental mycobacteria. In The Biology of the Mycobacteria, Vol 2. C Ratledge, J Stanford (eds). New York, Academic Press, 1983, pp 343-415

    Google Scholar 

  14. Chiodini RJ: Crohn's disease and the mycobacterioses: A review and comparison of two disease entities. Clin Microbiol Rev 2:90-117, 1989

    Google Scholar 

  15. Markesich DC, Graham DY, Yoshimura HH: Progress in culture and subculture of spheroplasts and fastidious acid-fast bacilli isolated from intestinal tissue. J Clin Microbiol 26:1600-1603, 1988

    Google Scholar 

  16. Greig A, Stevenson K, Henderson D, Perez V, Hughes V, Pavlik I, Hines ME, II, McKendrick I, Sharp JM: Epidemiological study of paratuberculosis in wild rabbits in Scotland. J Clin Microbiol 37:1746-1751, 1999

    Google Scholar 

  17. Chiodini RJ, Van Kruiningen HJ, Merkal RS: Ruminant paratuberculosis (Johne's disease): The current status and future prospects. Cornell Vet 74:218-262, 1984

    Google Scholar 

  18. Collins MT: Mycobacterium paratuberculosis: A potential foodborne pathogen? J Dairy Sci 80:3445-3448, 1997

    Google Scholar 

  19. Moss MT, Sanderson JD, Tizard MLV, Hermon-Taylor J, El-Zaatari FAK, Markesich DC, Graham DY: Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp silvaticum in long term cultures from Crohn's disease and control tissues. Gut 33:1209-1213, 1992

    Google Scholar 

  20. Dalzeil TK: Chronic intestinal enteritis. BMJ 2:1068-1070, 1913

    Google Scholar 

  21. Mitchell DN, Rees RJW: Some diseases of possible mycobacterial etiology. In The Biology of the Mycobacteria, Vol 2. C Ratledge, J Stanford (eds). New York, Academic Press, 1983, pp. 525-526

    Google Scholar 

  22. Chiodini RJ, Van Kruiningen HJ, Thayer WR, Coutu JA: Spheroplastic phase of mycobacteria isolated from patients with Crohn's disease. J Clin Microbiol 27:357-363, 1986

    Google Scholar 

  23. Dell'Isola B, Poyart C, Goulet O, et al: Detection of Mycobacterium paratuberculosis by polymerase chain reaction in children with Crohn's disease. J Infect Dis 169:449-451, 1994

    Google Scholar 

  24. Dumonceau JM, Van Gossum A, Adler M, Fonteyne PA, Van Vooren JP, Deviere J, Portaels F: No Mycobacterium paratuberculosis found in Crohn's disease using polymerase chain reaction. Dig Dis Sci 4:421-426, 1996

    Google Scholar 

  25. Gitnick G, Collins J, Beaman B: Preliminary report on isolation of mycobacteria from patients with Crohn's disease. Dig Dis Sci 34:925-932, 1989

    Google Scholar 

  26. Kobayashi K, Blaser MJ, Brown WR: Immunohistochemical examination for mycobacteria in intestinal tissue from patients with Crohn's disease. Gastroenterology 96:1009-1015, 1989

    Google Scholar 

  27. Rowbotham DS, Mapstone NP, Trejdosiewicz LK, Howdle PD, Quirke P: Mycobacterium paratuberculosis DNA not detected in Crohn's disease tissue by fluorescent polymerase chain reaction. Gut 37:60-67, 1995

    Google Scholar 

  28. Suenaga K, Yokoyasma Y, Okazaki K, Yamamoto Y: Mycobacteria in the intestine of Japanese patients with inflammatory bowel disease. Am J Gastroenterol 90:76-80, 1995

    Google Scholar 

  29. El-Zaatari FAK, Naser SA, Graham DY: Characterization and seroreactivity of a specific Mycobacterium paratuberculosis recombinant clone expressing 35K antigen with clinical and subclinical johne's disease. J Clin Microbiol 35:1794-1799, 1997

    Google Scholar 

  30. Hulten K, El-Zimaity HMT, Almashhrawi A, Karttunen TJ, Graham DY, El-Zaatari FAK: In situ hybridization technique for the detection of mycobacterial spheroplasts in paraffin embedded tissue sections [abstract no. U-31]. In American Society for Microbiology General Meeting 1999, abstract book. Washington, DC, American Society for Microbiology, 1999, p 640

    Google Scholar 

  31. Naser S, Shafran I, El-Zaatari FAK. Mycobacterium avium subspecies paratuberculosis in Crohn's disease is serologically positive. Clin Diag Lab Immunol 6:282, 1999

    Google Scholar 

  32. Hermon-Taylor J, Barnes N, Clarke C, Finlayson C: Mycobacterium paratuberculosis cervical lymphadenitis, followed five years later by terminal ileitis similar to Crohn's disease. BMJ 316:449-453, 1998

    Google Scholar 

  33. Markesich DC, El-Zaatari FAK, Graham DY: Activity of clarithromycin against intracellular Mycobacterium paratuberculosis-putative agent of Crohn's disease. Eur J Gastroenterol Hepatol 5:613-615, 1993

    Google Scholar 

  34. Williams SL, Harris NB, Barletta RG: Development of a firefly luciferase-based assay for determining antimicrobial susceptibility of Mycobacterium avium subsp paratuberculosis. J Clin Microbiol 37:304-309, 1999

    Google Scholar 

  35. Gordin FM, Sullam PM, Shafran SD, Cohn DL, Wynne B, Paxton L, Perry K, Horsburgh CR Jr: A randomized placebocontrolled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis 28:1080-1085, 1999

    Google Scholar 

  36. Chiodini RJ, Van Kruiningen HJ, Thayer WR, Merkal RS, Coutu JA: In vitro antimicrobial susceptibility of a Mycobacterium sp. isolated from patients with Crohn's disease. Antimicrob Agents Chemother 26:930-932, 1984

    Google Scholar 

  37. Rastogi N, Goh KS, Labrousse V: Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement of its extracellular and intracellular activities by ethambutol. Antimicrob Agents Chemother 36:2843-2846, 1992

    Google Scholar 

  38. Gladue RP, Bright GM, Isaason RE, Newborg MF: In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: Possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother 33:277-282, 1989

    Google Scholar 

  39. Scaglione F, Demartini G, Dugnani S, Fraschini F: A new model examining intracellular and extracellular activity of amoxicillin, azithromycin and clarithromycin in infected cells. Chemotherapy 39:416-423, 1993

    Google Scholar 

  40. Peppercorn MA: Is there a role for antibiotics as primary therapy in Crohn's ileitis? J Clin Gastroenterol 17:235-237, 1993

    Google Scholar 

  41. Wright J: Current strategies for the prevention and treatment of disseminated Mycobacterium avium complex infection in patients with AIDS. Pharmacotherapy 18:738-747, 1998

    Google Scholar 

  42. Langholz E, Brynskov J, Bendtzen K, Vilien M, Binder V: Treatment of Crohn's disease with fusidic acid: An antibiotic with immunosuppressive properties similar to cyclosporin. Aliment Pharmacol Ther 6:495-502, 1992

    Google Scholar 

  43. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, 5th ed. New York, Macmillian, 1975, pp 1086-1089

    Google Scholar 

  44. Grove DI, Mahmond AAF, Warren KS: Suppression of cellmediated immunity by metronidazole. Clin Res Suppl 24:285, 1976 (abstract)

    Google Scholar 

  45. Borden E, Sammartano RJ, Dembe C, Boley SJ: Effect of metronidazole on wound healing in rats. Surgery 97:331-336, 1985

    Google Scholar 

  46. Triantafillidis JK, Niolakis D, Emmanoullidis A, Antoniou A, Papatheodorou K, Cheracakis P: Ornidazole in the treatment of active Crohn's disease: Short-term results. Ital J Gastroenterol 28:10-14, 1996

    Google Scholar 

  47. Kahara LM: Ethambutol in tuberculosis. Biomed Pharmacother 44:21-23, 1990

    Google Scholar 

  48. Bernstein LH, Frank MS, Brandt LJ, Boley SJ: Healing of perineal Crohn's disease with Metronidazole. Gastroenterology 79:357-365, 1980

    Google Scholar 

  49. Brandt LJ, Bernstein LH, Boley SJ, Frank MS: Metronidazole therapy for perineal Crohn's disease: A follow-up study. Gastroenterology 83:383-387, 1982

    Google Scholar 

  50. Jakobovits J, Schuster MM: Metronidazole therapy for Crohn's disease and associated fistulae. Am J Gastroenterol 79:533-540, 1984

    Google Scholar 

  51. Gugler R, Jensen JC, Schulte H, Fogel R: The course of Crohn's disease and side effect profile with long-term treatment using metronidazole. Z Gastroenterol 27:676-682, 1989

    Google Scholar 

  52. Ursing B, Alm T, Barany F, Bergelin I, Ganrot-Norlin K, Hoevels J, Huitfeldt B, Järnerot G, Krause U, Krook A, Lindström B, Nordle Ö, Rose? A: A comparative study of metronidazole and sulfasalazine for active Crohn's disease: The cooperative Crohn's disease study in Sweden. II Result. Gastroenterology 83:550-562, 1982

    Google Scholar 

  53. Blichfeldt P, Blomhoff JP, Myhre E, Gjone E: Metronidazole in Crohn's disease. A double blind cross-over clinical trial. Scand J Gastroenterol 13:123-127, 1978

    Google Scholar 

  54. Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M, Levine J, Thomson A, Alpert E, Prokipchuk E: Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 32:1071-1075, 1991

    Google Scholar 

  55. Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, Kerremans R: Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology 108:1617-1621, 1995

    Google Scholar 

  56. Nygaard K, Bergan T, Bjorneklett A, Hoverstad T, Lassen J, Aase S: Topical metronidazole treatment in pouchitis. Scand J Gastroenterol 29:462-467, 1994

    Google Scholar 

  57. Madden MV, Mintyre AS, Niholls RJ: Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci 39:1193-1196, 1994

    Google Scholar 

  58. Greenbloom SL, Steinhart AH, Greenberg GR: Combination ciprofloxacin and metronidazole for active Crohn's disease. Can J Gastroenterol 12:53-56, 1998

    Google Scholar 

  59. Prantera C, Zannoni F, Scribano ML, et al: An antibiotic regimen for the treatment of active Crohn's disease: A randomized, controlled clinical trial of metronidazole plus cipro-floxacin. Am J Gastroenterol 91:328-332, 1996

    Google Scholar 

  60. Prantera C, Berto E, Scribano ML, Falasco G: Use of antibiotics in the treatment of active Crohn's disease: experience with metronidazole and ciprofloxacin. Ital J Gastroenterol Hepatol 30:602-606, 1998

    Google Scholar 

  61. Warren JB, Rees HC, Cox TM: Remission of Crohn's disease with tuberculosis chemotherapy. N Engl J Med 314:182, 1986

    Google Scholar 

  62. Schultz MG, Rieder HL, Hersh T, Riepe S: Remission of Crohn's disease with antimycobacterial chemotherapy. Lancet 102:1391-1392, 1987

    Google Scholar 

  63. Picciotto A, Gesu GP, Schito GC, Testa R, Varagona G, Celle G: Anti-mycobacterial chemotherapy in two cases of inflammatory bowel disease. Biomed Pharmaother 43:141-143, 1989

    Google Scholar 

  64. Hampson SJ, Parker MC, Saverymuttu SH, Joseph AE, Mc-Fadden JJ, Hermon-Taylor J: Quadruple anti-mycobacterial chemotherapy in Crohn's disease: Results at 9 months of pilot study in 20 patients. Aliment Pharmacol Ther 3:343-352, 1989

    Google Scholar 

  65. Shaffer JL, Hughes S, Linaker BD, Baker RD, Turnberg LA: Controlled trial of rifampicin and ethambutol in Crohn's disease. Gut 25:203-205, 1984

    Google Scholar 

  66. Jörnerot G, Rolny P, Wickbom G, Alemayehy G: Antimycobacterial therapy ineffective in Crohn's disease after a year. Lancet 1:164-165, 1989

    Google Scholar 

  67. Swift GL, Srivastava ED, Stone R, Pullan RD, Newcombe RG, Rhodes J, Wilkinson S, Rhodes P, Roberts G, Lawrie BW, Evans KT, Jenkins PA, Williams GT, Strohmeyer G, Kreuzpaintner G, Thomas GAO, Calcraft B, Davies PS, Morris TJ, Morris J: Controlled trial of anti-tuberculosis chemotherapy for two years in Crohn's disease. Gut 35:363-368, 1994

    Google Scholar 

  68. Rutgeerts P, Geboes K, Vantrappen G, Van Isveldt J, Peeters M, Penninckx F, Hiele M: Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum. J Clin Gastroenterol 15:24-28, 1992

    Google Scholar 

  69. Afdhal NH, Long A, Lennon J, Crowe J, O'Donoghue DP: Controlled trial of antimycobacterial therapy in Crohn's disease: Clofazimine versus placebo. Dig Dis Sci 36:449-453, 1991

    Google Scholar 

  70. Ward M, McManus JP: Dapsone in Crohn's disease. Lancet 1:1236-1237, 1975 (letter)

    Google Scholar 

  71. Prantera C, Argentieri R, Mangiarotti R, Levenstein S: Dapsone and remission of Crohn's disease. Lancet 1:536, 1988 (letter)

    Google Scholar 

  72. Prantera C, Bothamley G, Levenstein S, Mangiarotti R, Argentieri R: Crohn's disease and mycobacteria: Two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy. Biomed Pharmacother 43:295-299, 1989

    Google Scholar 

  73. Prantera C, Kohn A, Mangiarotti R, Andreoli A, Luzi C: Antimycobacterial therapy in Crohn's disease: Results of a controlled, double-blind trial with a multiple antibiotic regimen. Am J Gastroenterol 89:513-518, 1994

    Google Scholar 

  74. Graham DY, Al-Assi MT, Robinson M: Prolonged remission in Crohn's disease following therapy for Mycobacterium paratuberculosis infection. Gastroenterology 108:A826, 1995

    Google Scholar 

  75. Goodgame RW, Kimball K, Akram, Graham DY, Ou Ching-Nan: Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease. Gastroenterology 116(suppl):A725, 1999 (abstract G3515)

    Google Scholar 

  76. Borody TJ, Pearce L, Bampton PA, Leis S: Treatment of severe Crohn's disease using rifabutin-macrolide-clofazimine combination: interim report. Gastroenterology 114:A938, 1998 (abstract G3842)

    Google Scholar 

  77. Shafran I, Campbell D, Romero C, Swartz D, Naser S: In vivo evaluation of antituberculosis drugs for treatment of Crohn's disease patients. In American Society for Microbiology General Meeting 1999, abstract book. Washington, DC, American Society for Microbiology, 1999, p 644 (abstract U-53)

    Google Scholar 

  78. Gui GPH, Thomas PRS, Tizard MLV, Lake J, Sanderson JD, Hermon-Taylor J: Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother 39:393-400, 1997

    Google Scholar 

  79. Panaccione R, Sandborn WJ, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR: Phenotypic classification of Crohn's disease patients in Olmsted County, Minnesota: Application of the Vienna classification. Gastroenterology 116:A810, 1999 (abstract G3150)

    Google Scholar 

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Hultén, K., Almashhrawi, A., El-Zaatari, F.A. et al. REVIEW: Antibacterial Therapy for Crohn's Disease: A Review Emphasizing Therapy Directed Against Mycobacteria. Dig Dis Sci 45, 445–456 (2000). https://doi.org/10.1023/A:1005453409445

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