Ehrhardt and colleagues randomized adults who were prescribed systemic antibiotics while hospitalized at 15 hospitals in Germany to receive either placebo or Saccharomyces boulardii administered as a commercial preparation (Perenterol) containing at least 1.8 x 1010 live cells/gram of lyophilisate. The test preparation was started a mean of 0.5 days after the administration of the first dose of antibiotic and was to be continued for 7 days after antibiotic(s) discontinuation. If antibiotic therapy was resumed during this period (phase II), there was a return to phase I.
The incidence of antibiotic-associated diarrhea (AAD), defined as first appearing ≥ 3 days after antibiotic initiation, was analyzed according to two definitions of diarrhea: the World Health Organization (WHO) definition requiring three or more loose or liquid stools within 24 hours; and a modified WHO definition requiring at least 2 days of diarrhea. A third definition with the WHO criteria and diarrhea for 5 days occurred in only one patient.
Of the 2444 patients screened, only 477 were randomized (1:1). While a power calculation had indicated that 686 patients would be needed in each group to achieve an 80% power to detect a 5% difference in the between-treatment group incidence of AAD, the study was stopped early because of futility — i.e., further enrollment would not be likely to alter the overall results. The mean age of the participants was 58.4 years, and 56.4% were male. The mean duration of antibiotic administration was 7.6 ± 6.5 days. Approximately four-fifths received a beta-lactam and the majority received combination antibiotic therapy. A nitroimidazole (presumably metronidazole) was administered to 15.5% and 13.0% in the S. boulardii and placebo arms, respectively. A total of 40 cases of AAD occurred in the 425 subjects whose total time at risk was 19,165 days. Of the total, 21 and 19 AAD episodes occurred in the S. boulardii and placebo recipients, respectively. The hazard ratio of AAD in the S. boulardii group compared with the placebo group was 1.02 (95% confidence interval [CI], 0.55–1.90; P = 0.94). There were 2 cases of Clostridium difficile infection in each arm of the study.
COMMENTARY
The authors cite data indicating that sales of probiotics are predicted to be $48 billion by 2017. There is a remarkably broad array of microorganisms that have been suggested to have favorable effects when administered to subjects. S. boulardii is very closely related both metabolically and genetically to common brewer’s yeast, Saccharomyces cerevisiae, to the extent that some have suggested they are basically the same organism. In fact, it should probably be formally referred to as Saccharomyces cerevisiae var boulardii (S. boulardii).
A recent meta-analysis of 21 randomized clinical trials with a comparison to placebo or no treatment concluded that S. boulardii administration was associated with a reduction in the incidence of AAD from 18.7% to 8.5% (risk ratio [RR], 0.47; 95% CI, 0.38-0.57) with a number needed to treat of 10 (95% CI, 9-13).2 It also appeared to significantly reduce the risk of C. difficile infection (CDI) in children, but not in adults.
In contrast, quasi-experimental experience at a large hospital, also recently reported, also argues against the usefulness of S. boulardii in the prevention of CDI. The hospital discontinued the use of an automatic order linking the administration of this organism to the prescription of selected broad-spectrum antibiotics and, at the same time, the preparation was removed from the hospital formulary.2 During a 13-month period while the protocol was active, the incidence of hospital-onset CDI for all inpatients was 0.99 per 1000 patients, compared to 1.04 per 1000 patient days (P = 0.10) after the removal of S. boulardii from the formulary. Limiting the analysis to those patients receiving the linked broad-spectrum antibiotics, the occurrence of CDI was 1.25% while the protocol was active and 1.51% (P = 0.70) after its abolition.
Once again, the role of probiotics remains unclear. In the study by Earhardt and colleagues, the incidence of AAP and of CDI was lower than that usually reported and than that anticipated by the investigators. This was likely due, at least in part, to the exclusion criteria, which resulted in a healthier, younger group of hospital inpatients than those at greatest risk of complications of antibiotic therapy. Thus, e.g., immunocompromised patients were excluded because of admonitions against the use of probiotics in this group.
The argument goes on, but right now I am on the “con” side.
REFERENCES
- Szajewska H, Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2015;42:793-801.
- Flatley EA, Wilde AM, Nailor MD. Saccharomyces boulardii for the prevention of hospital onset Clostridium difficile infection. J Gastrointestin Liver Dis 2015;24:21-24.
Saccharomyces boulardii administration failed to prevent antibiotic-associated diarrhea in a large randomized trial.
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