Original Contribution | Published:

Functional GI

Meta-Analysis of Probiotics for the Prevention of Antibiotic Associated Diarrhea and the Treatment of Clostridium difficile Disease

The American Journal of Gastroenterology volume 101, pages 812822 (2006) | Download Citation

Subjects

Abstract

CONTEXT:

Antibiotic-associated diarrhea (AAD) is a common complication of most antibiotics and Clostridium difficile disease (CDD), which also is incited by antibiotics, is a leading cause of nosocomial outbreaks of diarrhea and colitis. The use of probiotics for these two related diseases remains controversial.

OBJECTIVE:

To compare the efficacy of probiotics for the prevention of AAD and the treatment of CDD based on the published randomized, controlled clinical trials.

DATA SOURCES:

PubMed, Medline, Google Scholar, NIH registry of clinical trials, metaRegister, and Cochrane Central Register of Controlled Trials were searched from 1977 to 2005, unrestricted by language. Secondary searches of reference lists, authors, reviews, commentaries, associated diseases, books, and meeting abstracts.

STUDY SELECTION:

Trials were included in which specific probiotics given to either prevent or treat the diseases of interest. Trials were required to be randomized, controlled, blinded efficacy trials in humans published in peer-reviewed journals. Trials that were excluded were pre-clinical, safety, Phase 1 studies in volunteers, reviews, duplicate reports, trials of unspecified probiotics, trials of prebiotics, not the disease being studied, or inconsistent outcome measures. Thirty-one of 180 screened studies (totally 3,164 subjects) met the inclusion and exclusion criteria.

DATA EXTRACTION:

One reviewer identified studies and abstracted data on sample size, population characteristics, treatments, and outcomes.

DATA SYNTHESIS:

From 25 randomized controlled trials (RCTs), probiotics significantly reduced the relative risk of AAD (RR = 0.43, 95% CI 0.31, 0.58, p < 0.001). From six randomized trials, probiotics had significant efficacy for CDD (RR = 0.59, 95% CI 0.41, 0.85, p= 0.005).

CONCLUSION:

A variety of different types of probiotics show promise as effective therapies for these two diseases. Using meta-analyses, three types of probiotics (Saccharomyces boulardii, Lactobacillus rhamnosus GG, and probiotic mixtures) significantly reduced the development of antibiotic-associated diarrhea. Only S. boulardii was effective for CDD.

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References

  1. 1.

    , , , et al. Antibiotics and Clostridium difficile diarrhea in the ambulatory care setting. Clin Ther 2000;22: 91–102.

  2. 2.

    . Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998;16: 292–307.

  3. 3.

    , , , et al. Beta-lactam antibiotic therapy in febrile granulocytopenic patients. A randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem alone. Ann Intern Med 1991;115: 849–859.

  4. 4.

    , , , et al. Prevalence and characteristics of bacteria and host factors in an outbreak situation of antibiotic-associated diarrhea. J Med Microbiol 2005;54(Pt 2):149–153.

  5. 5.

    . Normal flora: Diversity and functions. Microb Ecol Health Dis 2000;12: 193–207.

  6. 6.

    , , , et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: A changing pattern of disease severity. J Ayub Med Coll Abbottabad 2004;171: 466–472.

  7. 7.

    , , , et al. Clostridium difficile-associated diarrhoea in hospitalized patients. J Clin Pharm Ther 2000;25: 101–109.

  8. 8.

    , , , et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34: 346–353.

  9. 9.

    , , , et al. Recurrent Clostridium difficile disease: Epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999;20: 43–50.

  10. 10.

    , , , et al, Canadiam Hospital Epdemiology Committee. Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals. Infect Control Hosp Epidemiol 2002;23: 137–140.

  11. 11.

    . Clostridium difficile-associated diarrhea: Risk factors, diagnostic methods and treatment. Rev Gastroenterol Disord 2004;4(4):186–195.

  12. 12.

    . A review of the evidence of health claims for biotherapeutic agents. Microb Ecol Health Dis 2000;12: 65–76.

  13. 13.

    , , , et al. Saccharomyces boulardii stimulates intestinal immunoglobulin A immune response to Clostridium difficile toxin A in mice. Infect Immun 2001;69: 2762–2765.

  14. 14.

    . Probiotics: “Living drugs.Am J Health Syst Pharm 2001;58: 1101–1109.

  15. 15.

    . UK launches inquired into Clostridium difficile outbreak. J Ayub Med Coll Abbottabad 2005;173(2):138.

  16. 16.

    , , , et al. Probiotics in prevention of antibiotic associated diarrhoea: Meta-analysis. BMJ 2002;324: 1361.

  17. 17.

    , , , et al. Meta-analysis: The effect of probiotic administration on antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2002;16: 1461–1467.

  18. 18.

    , , , et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2005;25(1):CD004610.

  19. 19.

    , . Clostridium difficile disease: Diagnosis and treatment. In: McDonaldJ WD, Burroughs AK, FeaganBG, eds. Evidence based gastroenterology and hepatology, 2nd Ed. BMJ Books: London, 2004. Chapter 18: 285–301.

  20. 20.

    , , , et al. Finding qualitative research: An evaluation of search strategies. BMC Med Res Methodol 2004;4: 5–9.

  21. 21.

    , , . Meta-analysis: Principles and procedures. BMJ 1997;315: 1533–1537.

  22. 22.

    , , , et al. Improving the quality of reports of meta-analyses of randomized controlled trials: The QUOROM statement. QUOROM Group. Br J Surg 2000;87(11):1448–1454.

  23. 23.

    , , , et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. JAMA 2000;283: 2008–2012.

  24. 24.

    , . Properties of evidence-based probiotics for human health. In: Goklepe I, Juneja V eds. Probiotics in food safety and human health: New York Marcel Dekker, Inc, 2005: 109–137.

  25. 25.

    . Antibiotic-associated diarrhea and pseudomembranous colitis: Are they less common with poorly absorbed antimicrobials? Chemotherapy 2005;51(suppl 1):81–89.

  26. 26.

    , , , et al. Current methods of the U.S. Preventive Services Task Force: A review of the process. Am J Prev Med 2001;20(suppl 3):21–35.

  27. 27.

    , , . Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323: 42–46.

  28. 28.

    , . Meta-analysis in clinical trials. Control Clin Trials 1986;7(3):177–188.

  29. 29.

    , , , et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629–634.

  30. 30.

    , . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088–1101.

  31. 31.

    , , , et al. A randomized trial of yogurt for prevention of antibiotic-associated diarrhea. Dig Dis Sci 2003;48: 2077–2082.

  32. 32.

    , . Antibiotic associated diarrhea: A controlled study comparing plain antibiotic with those containing protected Lactobacilli. J Indian Med Assoc 2002;100(5):334–335.

  33. 33.

    , , , et al. Failure of dietary oligofructose to prevent antibiotic-associated diarrhea. Aliment Pharmacol Ther 2005;21: 469–477.

  34. 34.

    , , . Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: A randomized, controlled study. Clin Gastroenterol Hepatol 2005;3: 442–448.

  35. 35.

    , , , et al. Controlled double-blind clinical trials of Ultra-Levure: Multicentre study by 25 physicians in 388 cases. Gaz Med Fr 1977;84: 2072–2078.

  36. 36.

    , , , et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii—A prospective-study. Gastroenterology 1989;96: 981–988.

  37. 37.

    , , , et al. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995;90: 439–448.

  38. 38.

    , , . Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther 2005;21: 583–590.

  39. 39.

    , , . The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. J Infect 1998;36: 171–174.

  40. 40.

    , , , et al. Effect of different probiotic preparations on anti-Helicobacter pylori therapy-related side effects: A parallel group, triple blind, placebo-controlled study. Am J Gastroenterol 2002;97(11):2744–2749.

  41. 41.

    , , , et al. Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: A randomized study. Pediatrics 1999;104: e64.

  42. 42.

    , , , et al. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr 1999;135: 564–568.

  43. 43.

    , , , et al. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138: 361–365.

  44. 44.

    , , , et al. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: A randomized, placebo-controlled trial. Mayo Clin Proc 2001;76: 883–889.

  45. 45.

    , , , et al. Effect of Lactobacillus GG supplementation on antibiotic-associated gastrointestinal side effects during Helicobacter pylori eradication therapy: A pilot study. Digestion 2001;63: 1–7.

  46. 46.

    , , , et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: Randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther 2004;20: 1181–1188.

  47. 47.

    , , . Effects of supplements of Bifidobacterium longum and Lactobacillus acidophilus on the intestinal microbiota during administration of clindamycin. Microb Ecol Health Dis 1994;7: 17–25.

  48. 48.

    , , , et al. Prevention of antibiotic-associated diarrhea in children by Clostridium butyricum MIYAIRI. Pediatr Int 2003;45: 86–90.

  49. 49.

    , , , et al. Double-blind report on the efficacy of lactic acid-producing Enterococcus SF68 in the prevention of antibiotic-associated diarrhoea and in the treatment of acute diarrhoea. J Int Med Res 1989;17: 333–338.

  50. 50.

    , , , et al. A controlled clinical study on Streptococcus faecium preparation for the prevention of side reactions during long term antibiotic treatments. Curr Ther Res 1982;31: 265–271.

  51. 51.

    , , , et al. Effect of Lactobacillus acidophilus on antibiotic-associated gastrointestinal morbidity: A prospective randomized trial. J Otolarynogol 1995;24: 231–233.

  52. 52.

    , , , et al. Prophylaxis against ampicillin-associated diarrhea with a Lactobacillus preparation. Am J Hosp Pharm 1979;36: 754–757.

  53. 53.

    , , , et al. A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea. DICP 1990;24: 382–384.

  54. 54.

    , , , et al. A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for prevention of antibiotic-associated diarrhea in infants. J Clin Gastroenterol 2005;39: 385–389.

  55. 55.

    , , , et al. Prevention of antibiotic-associated diarrhea with Lactobacillus sporogens and fructo-oligosaccarides in children. A multicentric double-blind vs placebo study. Minerva Pediatr 2003;55(5):447–452.

  56. 56.

    , , , et al. Prevention of antibiotic-associated diarrhea in infants by probiotics. J Med Assoc Thai 2002;85(suppl 2):S739–42.

  57. 57.

    , , , et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271: 1913–1918.

  58. 58.

    , , , et al. The search for a better treatment for recurrent Clostridium difficile disease: Use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31: 1012–1017.

  59. 59.

    . The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95: S11–S13.

  60. 60.

    , , . Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: A double-blind, placebo-controlled trial. Scand J Infect Dis 2003;35: 365–367.

  61. 61.

    , , . Probiotics for recurrent Clostridium difficile disease. J Med Microbiol 2005;54(Pt 9):905–906.

  62. 62.

    , , , et al. Clostridium difficile pilot study: Effects of probiotoic supplementation on the incidence of Clostridium difficile diarrhoea. Int Microbiol 2004;7: 59–62.

  63. 63.

    , , , et al. Impact of statewide program to promote appropriate antimicrobial drug use. Emerg Infect Dis 2005;11(6):912–920.

  64. 64.

    , , . Appropriate antibiotic administration in elective surgical procedures: Still missing the message. Asian J Surg 2005;28(2):104–108.

  65. 65.

    , , , et al. Clostridium difficile infections related to antibiotic use and infection control facilities in two university hospitals. J Hosp Infect 2003;54(3):202–206.

  66. 66.

    , . Meta-analysis: Non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea. Aliment Pharmacol Ther 2005;22: 365–372.

  67. 67.

    , , , et al. Assessment of a new synbiotic preparation in health volunteers: Survival, persistence of probiotic strains and its effect on the indigenous flora. Nutr J 2003;2: 11–16.

  68. 68.

    , , , et al. In vitro selection criteria for probiotic bacteria of human origin: Correlation with in vivo findings. Am J Clin Nutr 2001;73: 386S–92S.

  69. 69.

    , , , et al. Empirical assessment of effect of publication bias on meta-analysis. BMJ 2000;320: 1574–1577.

  70. 70.

    , , , et al. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediar Infect Dis J 2005;24(3):278–280.

  71. 71.

    , . Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004;39(4):436–437.

  72. 72.

    , , , et al. Possible role of catheters in Saccharomyces boulardii fungemia. Eur J Clin Microbiol Infect Dis 2000;19: 16–20.

  73. 73.

    , , , et al. Liver abscess due to a Lactobacillus rhamnosus strain indistinguishable from L. rhamnosus strain GG. Clin Infect Dis 1999;28: 1159–1160.

  74. 74.

    , , . Safety of Lactobacillus strains used as probiotic agents. Clin Infect Dis 2002;34: 1283–1284.

  75. 75.

    , , , et al. Saccharomyces cerevisiae fungemia: An emerging infectious disease. Clin Infect Dis 2005;40: 1625–1634.

  76. 76.

    , , , et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004;38: 62–69.

  77. 77.

    , , , et al. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005;115(1):178–181.

  78. 78.

    , . Risks of biotherapeutic agents. In: Elmer GW, McFarland LV, Surawicz CM, eds. Biotherapeutic agents and infectious diseases. Humana Press: Totowa, NJ, 1999: 263–268.

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Acknowledgements

The author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The author also would like to acknowledge the participants in these trials; without their willingness to volunteer, scientific discoveries would not be made.

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Affiliations

  1. Department of Health Services Research and Development, Veterans Administration Puget Sound Health Care System, Seattle, Washington

    • Lynne V McFarland
  2. Department of Medicinal Chemistry, University of Washington, Seattle, Washington

    • Lynne V McFarland

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Correspondence to Lynne V McFarland.

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DOI

https://doi.org/10.1111/j.1572-0241.2006.00465.x

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