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Revista médica de Chile

versión impresa ISSN 0034-9887

Rev. méd. Chile v.137 n.5 Santiago mayo 2009 

Rev Méd Chile 2009; 137: 719-720



Unraveling the causes of negative studies: a case of S boulardii for the prevention of antibiotic-associated diarrhea


Dirección para correspondencia

To the Editor: Bravo et al. published their study testing Saccharomyces boulardii for the preven-tion of antibiotic-associated diarrhea (AAD) in adults1. They enrolled 86 outpatients receiving amoxicillin for various acute infections and rando-mlzed patients to either S boulardii or placebo. They did not flnd a significant difference in AAD in the group (7.3%) compared to the placebo (11.1%). However, this result conflicts with earlier studies that did find a significant protective effect of S boulardii in adults receiving antibiotics2. Negative studies (or studies that do not find a significant efficacy of an investigational treatment) may result from several factors not related to the efficacy of the treatment itself. Bravo's study suffers from several of these factors.

The first limitation was a lack of power. Unfortunately, many clinical trials testing probiotics enroll insufficient numbers of patients, resul-ting in a negative study result. Because of the small study size, it is impossible to determine if the treatment was truly ineffective or if the negative result is due to low power. In the study of Bravo et al, although the rate of AAD was lower in the S boulardii group (3/41, 7.3%) compared to the placebo group (5/45, 11.1%), there was only a 4% power to detect a significant difference. A larger study may have detected a significant protective effect. Previous clinical trials finding a significant protective effect of S boulardii for AAD have typically had larger study sizes (151-389 enrolled subjects)3-7.

The second limitation in their paper is in the study design. This study gave the probiotic or placebo for 12 days and then followed subjects for only an additional nine days. Insufficient follow-up time after the antibiotic has been discontinued does not allow the detection of delayed onset AAD. Delayed onset AAD, which may occur 2-8 weeks after antibiotics have been stopped , has been cited previously in trials of other types of probiotics finding no significant efficacy for AAD9-10 and for one study testing S boulardii11. Clinical trials finding a significant efficacy for probiotics in preventing AAD followed subjects for a longer time than Bravo et al's study. Beausoleil et al followed subjects 21 days post-antibiotics12 and Cremonini et al followed subjects for four weeks13. McFarland et al followed patients for seven weeks and found cases of delayed onset AAD up to 46 days post-antibiotics. All three of these studies with longer follow-up periods found significant efficacy of probiotics for the prevention of AAD.

A third limitation is an uncertainty about the strain of S boulardii used in the trial. As not all probiotic strains or strains of Saccharomyces are effective as probiotics and many probiotics that are commercially available do not contain the probiotic strain Usted on their label14, it is impor-tant that clinical trials document not only the strain of probiotic used, but the source of manufacturer. Neither of these two were done in the study by Bravo et al. Perhaps the strain of S boulardii used was not the same strain that was found to be significantly protective for AAD in other trials.

In addition to the limitations listed above, there are other concerning errors and inconsistencies in the study by Bravo et al. The frequency of AAD for the S boulardii group is reported in the abstract as 4/ 41, but in the text, it is reported as 3/41. In the discussion section, the authors state that the study of McFarland et al. did not find efficacy for S boulardii and AAD. This is incorrect, as AAD was significantly less frequent in the S boulardii group (7.2%) compared to the placebo group (14.6%, P <0.05)4. The authors also incorrectly quote that a meta-analysis by D'Souza et al found 3 or 4 trials of S boulardii did not show clinical benefits for preventing AAD. This is incorrect, as this meta-analysis found that 3 of 4 trials did have significant benefits, and only one trial did not find any benefit15. Other meta-analyses have confirmed this finding. Szajewska et al pooled flve randomized clinical trials of S boulardii and found a significantly protective effect for AAD [pooled Odds Ratio (OR) =0.43, 95% CI 0.23, 0.78]16. I also found this protective effect in the pooled odds ratios from six trials of S boulardii and AAD [pooled OR =0.37, 95% CI 0.26, 0.52]2. Overall, there are seven randomized controlled trials that found significant protective efficacy of S boulardii for the prevention of AAD3-7,13,17 and one that failed to find efficacy11.

In conclusión, the publication of clinical trials with negative findings adds valué to our body of scientific knowledge; however, trials may be prone to factors that may mask true efficacy of investigational treatments. It is important that authors address these other variables in their studies. It is imperative that studies have sufficient power to detect a significant efficacy if it is present, use proper study design, and thoroughly evalúate other reasons for a lack of an effect before concluding that a treatment has no efficacy.

Lynne V. McFarland, Ph.D.

Affiliate Associate Professor, Department of Medicinal Chemistry, University of Washington, Seattle, WA. USA.



1. Bravo MV, Bunout D, Leiva L, de la Maza MP, Barrera G, de la Maza J, Hirsch S. Effect of probiotic Saccharomyces boulardii on prevention of AAD in adult outpatients with amoxicillin treatment. Rev Méd Chile 2008; 136: 981-8.        [ Links ]

2. McFarland LV. Meta-analysis of probiotics for prevention of antibiotic associated diarrhea and treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101: 812-22.        [ Links ]

3. Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, van Belle G. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology 1989; 96: 981-8.        [ Links ]

4. McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA et al. Prevention of ß-lactam-associated diarrhea by Saccharomyces boulardii compared to placebo. Am J Gastroenterol 1995; 90: 439-48.        [ Links ]

5. Duman DG, Bor S, Ozütemiz O, Sáhin T, Qguz D, Istan F et al. Efficacy and safety of Saccharomyces boulardii in prevention of antibiotic-associated diarrhoea due to Helicobacterpylori eradication. Am J Eur J Gastroenterol Hepatol 2005; 17: 1357-61.        [ Links ]

6. Can M, Besirbellioglu BA, Avci IY, Beker CM, Pahsa A. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit 2006; 12: PI19-22.        [ Links ]

7. Adam J, Barret C, Barret-Bellet A, Benedetti E, Calendini A, Darchen P et al. Controlled double-blind clinical trials of Ultra-Levure: multicentre study by 25 physicians in 388 cases. Gazette Medicale de France 1977; 84: 2072-8.        [ Links ]

8. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol 2008; 3: 563-78.        [ Links ]

9. Conway S, Hart A, Clark A, Harvey I. Does eating yogurt prevent antibiotic-associated diarrhoea? A placebo-controlled randomised controlled trial in general practice. Br J Gen Pract 2007; 57: 953-9.        [ Links ]

10. Tankanow RM, Ross MB, Ertel IJ, Dickinson DG, McCormick LS, Garfinkel JF. A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea. DICP 1990; 24: 382-4.        [ Links ]

11. Lewis SJ, Potts LF, Barry RE. The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. J Infect 1998; 36: 171-4.        [ Links ]

12. Beausoleil M, Fortier N, Guénette S, L'ecuyer A, Savoie M, Franco M et al. Effect of a fermented milk combining Lactobacillus acidophilus C11285 and Lactobacillus casei in the prevention of antibiotic-associated diarrhea: a randomized, double-blind, placebo-controlled trial. Can J Gastroenterol 2007; 21: 732-6.        [ Links ]

13. Cremonini F, Di Caro S, Nista EC, Bartolozzi F, Capelli G, Gasbarrini G, Gasbarrini A. Meta-analysis: the effect of probiotic administration on antibiotic-associated diarrhea. Aliment Pharmacol Ther 2002; 16: 1461-7.        [ Links ]

14. Marcobal A, Underwood MA, Mills DA. Rapid determination of the bacterial composition of commercial probiotic products by terminal restriction fragment length polymorphism analysis. J Pediatr Gastroenterol Nutr 2008; 46: 608-11.        [ Links ]

15. D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002; 324: 1361-7.        [ Links ]

16. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2005; 22: 365-72.        [ Links ]

17. Kotowska M, Albrecht P, Szajewska H. Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther 2005; 21: 583-90.        [ Links ]


Correspondence to: Lynne V. McFarland, Ph.D. 1100 Olive Way #1400, Seattle WA 98101. (206) 277-1095, Fax: (206) 764-5343. E mail:,

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