Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis

Care of the Elderly Section, Faculty of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN

Contributed by

Contributors: CJB had the original plan for the meta-analysis, researched individual papers, offered statistical advice, and edited the final paper. AD'S conducted the online and other searches, researched individual papers, extracted output data from individual trials, and wrote the paper. JC was responsible for the statistical analysis, calculated final output data and odds ratios, drew the final graph, and conducted tests of publication bias. CR researched individual papers and assisted in the preparation of the article.

Correspondence to: A L D'Souza ku.ca.ci@azuosd.suisyola

Accepted 2001 Nov 7.

Abstract

Objective

To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics.

Design

Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups.

Identification

Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library.

Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics.

Results

Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P<0.001) for the yeast and 0.34 (0.19 to 0.61; P<0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P<0.001) in favour of active treatment over placebo.

Conclusions

The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.

What is already known on this topic

Probiotics are well known for their microbiological properties and have been used to treat gastrointestinal and vaginal mucosal infections

Conflicting results have prevented probiotics from being accepted as viable alternatives to conventional treatments for antibiotic associated diarrhoea

The commercial availability of probiotics is increasing

What this study adds

Probiotics may prevent antibiotic associated diarrhoea

The potential of specific probiotics to prevent Clostridium difficile infection secondary to the use of antibiotics should be re-examined

A large trial looking at the efficacy of probiotics in preventing antibiotic associated diarrhoea, particularly in elderly patients, with an emphasis on the optimal dose and cost benefits is needed

Abstract

Footnotes

Editorial by Barbut and Meynard

Funding: No funding was sought or obtained for the conduct of this study.

Competing interests: None declared.

Footnotes

References

1. Fuller RBProbiotics in human medicine. Gut. 1991;32:439–442.[Google Scholar]
2. McFarland LV, Elmer GWBiotherapeutic agents: past, present and future. Microecol Ther. 1995;23:46–73.[PubMed][Google Scholar]
3. Kollaritsch H, Holst H, Grobara P, Wiederman GProphylaxe der Reisediarrhöe mit Saccharomyces boulardii. Fortschr Med. 1993;111:153–156.[PubMed][Google Scholar]
4. Chicoine L, Joncas JHEmploi des ferments lactiques dans la gastro-entérite non bactérienne. Union Med Canada. 1973;102:1114–1115.[PubMed][Google Scholar]
5. Chapoy PTraitement des diarrhées aiguës infantiles: essai contrôlé de Saccharomyces boulardii. Ann Pédiatr. 1985;32:561–563.[PubMed][Google Scholar]
6. Saint-Marc T, Rossello-Prats L, Touraine JLEfficacité de Saccharomyces boulardii dans le traitement des diarrhées du SIDA. Ann Med Intern. 1991;142:64–65.[PubMed][Google Scholar]
7. Colombel JF, Cortot A, Neut C, Romond CYoghurt with Bifidobacterium longum reduces erythromycin induced gastrointestinal effects. Lancet. 1987;ii:43.[PubMed][Google Scholar]
8. Siitonen S, Vapaatalo H, Salminen S, Gordin A, Saxelin M, Wikberg R, et al Effect of Lactobacillus GG yoghurt in the prevention of antibiotic-associated diarrhoea. Ann Med. 1990;22:57–59.[PubMed][Google Scholar]
9. Isolauri E, Juntunen M, Rautanen T, Silanaukee P, Koivula TA human Lactobacillus strain (L casei GG) promotes recovery from acute diarrhoea in children. Pediatrics. 1991;88:90–97.[PubMed][Google Scholar]
10. Gorbach SL, Chang TW, Goldin BSuccessful treatment of relapsing C difficile colitis with Lactobacillus GG. Lancet. 1987;ii:1519.[PubMed][Google Scholar]
11. Schellenberg D, Bonington A, Champion CM, Lancaster R, Webb S, Main JTreatment of C difficile diarrhoea with Brewer's yeast. Lancet. 1994;343:171–172.[PubMed][Google Scholar]
12. Buts JP, Corthier G, Delmee MSaccharomyces boulardii for Clostridium difficile-associated enteropathies in infants. J Pediatr Gastroenterol Nutr. 1993;16:419–425.[PubMed][Google Scholar]
13. Biller JA, Katz AJ, Flores AF, Buie TM, Gorbach SLTreatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr. 1995;21:224–227.[PubMed][Google Scholar]
14. Levy JExperience with live Lactobacillus plantarum strain 299v in immune-deficient infants [abstract] Gastroenterology. 1997;112:A397.[PubMed][Google Scholar]
15. Borgia M, Sepe N, Brancaro V, Simone P, Borgia REffect of lactic acid-producing bacteria Streptococcus SF68 strain on body weight in man: a double-blind controlled study. Current Ther Res. 1983;33:214–218.[PubMed][Google Scholar]
16. Reid G, Bruce AW, Taylor MInfluence of three day anti-microbial therapy and Lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clin Ther. 1992;14:11–16.[PubMed][Google Scholar]
17. Bleichner G, Blehaut H, Mentec H, Moyse D. Saccharomyces boulardii prevents diarrhoea in critically ill tube-fed patients. A multi-centre, randomized, double blind, placebo-controlled trial. Intensive Care Med. 1997;23:517–523.[PubMed]
18. Pozo-Olano JD, Warram JH, Gómez RG, Cavazos MGEffect of a Lactobacillus preparation on traveller's diarrhoea. Gastroenterology. 1978;74:829–830.[PubMed][Google Scholar]
19. Black FT, Anderson PL, Orskov J, Gaarslev K, Laulund SProphylactic efficacy of Lactobacilli on traveller's diarrhoea. Travel Med. 1989;7:333–335.[PubMed][Google Scholar]
20. Oksanen PJ, Salminen S, Saxelin M, Hamalainen P, Ihantola-Vormisto A, Muurasniemi-Isoviita L, et al Prevention of traveller's diarrhoea by Lactobacillus GG. Ann Med. 1990;22:53–56.[PubMed][Google Scholar]
21. Katelaris PH, Salam ILactobacilli to prevent traveller's diarrhoea. N Engl J Med. 1995;333:1360–1361.[PubMed][Google Scholar]
22. Pearce JL, Hamilton JRControlled trial of orally administered Lactobacilli in acute infantile diarrhoea. J Pediatrics. 1974;84:261–262.[PubMed][Google Scholar]
23. Bellomo G, Mangiagle A, Nicastro L, Frigerio GA controlled double-blind study of SF68 strain as a new biological preparation for the treatment of diarrhoea in pediatrics. Curr Ther Res. 1980;28:927–936.[PubMed][Google Scholar]
24. Clements ML, Levine MM, Black RE, Robins-Browne RM, Cisneros LA, Drusano GL, et al. Lactobacillus prophylaxis for diarrhoea due to enterotoxigenic E. coli. Antimicrob Agents Chemother. 1981;20:104–108.
25. Tojo M, Oikawa T, Morikawa Y, Yamashita N, Iwata S, Satoh Y, et al The effects of Bifidobacterium breve administration on campylobacter enteritis. Acta Ped Jap. 1987;29:160–167.[PubMed][Google Scholar]
26. Mitra AK, Rabbani GH. A double blind controlled trial of Streptococcus SF68 in adults with acute diarrhoea due to Vibrio cholerae and enterotoxigenic E. coli. Gastroenterology. 1990;99:1149–1152.[PubMed]
27. Guandalini S, Pensabene L, Zikri MA, Dias JA, Casali LG, Hoekstra H, et al Lactobacillus GG administered in oral rehydration solution to children with acute diarrhoea: a multicenter European trial. J Pediatr Gastroenterol Nutr. 2000;30:54–60.[PubMed][Google Scholar]
28. Isolauri E, Kaila M, Mykkänen H, Ling WH, Salminen SOral bacteriotherapy for viral gastro-enteritis. Dig Dis Sci. 1994;39:2595–2600.[PubMed][Google Scholar]
29. Saavadra JM, Bauman NA, Oung I, Perman JA, Yolken RHFeeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet. 1994;344:1046–1049.[PubMed][Google Scholar]
30. Oberhelman RA, Gilman RH, Sheen P, Taylor DN, Black RE, Cabrera L, et al A placebo-controlled trial of Lactobacillus GG to prevent diarrhoea in undernourished Peruvian children. J Pediatrics. 1999;134:15–20.[PubMed][Google Scholar]
31. Adam J, Barret A, Barret-Bellet CEssais cliniques contrôlés en double insu de l'ultra-levure lyophilisée: étude multicentrique par 25 médicins de 388 cas. Gaz Med Fr. 1977;84:2072–2078.[PubMed][Google Scholar]
32. Gotz V, Romankiewicz JA, Moss J, Murray HWProphylaxis against ampicillin associated diarrhoea with Lactobacillus preparation. Am J Hosp Pharm. 1979;36:754–757.[PubMed][Google Scholar]
33. Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, Van Belle GPrevention of antibiotic associated diarrhoea by Saccharomyces boulardii. Gastroenterology. 1989;96:981–988.[PubMed][Google Scholar]
34. Wunderlich PF, Braun L, Fumagalli I, D'Apuzzo V, Heim F, Karly M, 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.[PubMed][Google Scholar]
35. Tankanow RM, Ross MB, Ertel IJ, Dickinson DG, McCormick LS, Garfinkel JFDouble blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhoea. DICP, Ann Pharm. 1990;24:382–384.[PubMed][Google Scholar]
36. Orrhage K, Brismar B, Nord CEEffects of supplements of Bifidobacterium longum and Lactobacillus acidophilus on intestinal microbiota during administration of clindamycin. Microb Ecol Health Dis. 1994;7:17–25.[PubMed][Google Scholar]
37. McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, et al Prevention of β-lactam-associated diarrhoea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol. 1995;90:439–448.[PubMed][Google Scholar]
38. Lewis SJ, Potts LF, Barry REThe lack of therapeutic effect of S boulardii in the prevention of antibiotic related diarrhoea in elderly patients. J Infect. 1998;36:171–174.[PubMed][Google Scholar]
39. Vanderhoof JA, Whitney DB, Antonson DL, Hanner TL, Lupo JV, Young RJLactobacillus GG in the prevention of antibiotic-associated diarrhoea in children. J Pediatrics. 1999;135:564–568.[PubMed][Google Scholar]
40. McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, et al A randomized placebo-controlled trial of S boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:1913–1918.[PubMed][Google Scholar]
41. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF.for the QUOROM Group. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement Lancet 19993541896–1900. [[PubMed]
42. Egger M, Davey-Smith G, Schneider M, Minder CEBias in meta-analysis detected by a simple graphical test. BMJ. 1997;315:629–634.[Google Scholar]
43. Elmer GW, Surawicz CM, McFarland LVBiotherapeutic agents: a neglected modality for treatment and prevention of selected intestinal and vaginal infections. JAMA. 1996;275:870–876.[PubMed][Google Scholar]
44. Blehaut H, Massot J, Elmer GW, Levy RHDisposition kinetics of S boulardii in man and rat. Biopharm Drug Dispos. 1989;10:353–364.[PubMed][Google Scholar]
45. McFarland LVS boulardii is not S cerevisiae. Clin Infect Dis. 1996;22:200–201.[PubMed][Google Scholar]
46. McCullough MJ, Clemons KV, McCusker JH, Stevens DASpecies identification and virulence attributes of Saccharomyces boulardii. J Clin Microbiol. 1998;36:2613–2617.[Google Scholar]
47. Castagliulo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. S. boulardii protease inhibits effects of C. difficile toxins A and B in human colonic mucosa. Infect Immun. 1999;67:302–307.
48. Benno Y, He F, Hosada M, Hashimoto H, Kojima T, Yamazaki K, et al Effects of Lactobacillus GG yoghurt on human intestinal micro-ecology in Japanese subjects. Nutr Today. 1996;31(6 suppl):9–11S.[PubMed][Google Scholar]
49. Gorbach SLThe discovery of Lactobacillus GG. Nutr Today. 1996;31(6 suppl):2–4S.[PubMed][Google Scholar]
50. Spanhaak S, Havenaar R, Schaafsma GEffect of consumption of milk fermented by Lactobacillus casei shirota on intestinal microflora and immune parameters in humans. Eur J Clin Nutr. 1998;52:899–907.[PubMed][Google Scholar]
51. Yuki N, Watanabe K, Mike A, Tagami Y, Tanaka R, Ohwaki M, et al Survival of probiotic Lactobacillus casei shirota in the GI tract-selective isolation using monoclonal antibodies. Int J Food Microbiol. 1999;48:51–57.[PubMed][Google Scholar]
52. Niault M, Thomas F, Prost J, Ansari FH, Kalfon PFungaemia due to Saccharomyces species in a patient treated with enteral S boulardii. Clin Infect Dis. 1999;28:930.[PubMed][Google Scholar]
53. Harty DWS, Oakey HJ, Knox KWPathogenic potential of lactobacilli. Int J Food Microbiol. 1994;24:179–189.[PubMed][Google Scholar]
54. Schlegel L, Lemerle S, Geslin PLactobacillus species as opportunistic pathogens in immune-compromised patients. Eur J Clin Microbiol Infect Dis. 1998;17:887–888.[PubMed][Google Scholar]
55. Kelly CP, Pothoulakis C, Lamont JTClostridium difficile colitis. N Engl J Med. 1994;330:257–262.[PubMed][Google Scholar]
56. Walters BAJ, Roberts R, Stafford R, Seneviratne ERecurrence of antibiotic-associated colitis: endogenous persistence of C difficile during vancomycin therapy. Gut. 1983;24:206–212.[Google Scholar]
57. Berg RDProbiotics, prebiotics or ‘conbiotics’ Trends Microbiol. 1998;6:89–92.[PubMed][Google Scholar]
58. Begg CB, Mazumdar MOperating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101.[PubMed][Google Scholar]