Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial

Stephan Ehrhardt, Nan Guo, Rebecca Hinz, Stefanie Schoppen, Jürgen May, Markus Reiser, Maximilian Philipp Schroeder, Stefan Schmiedel, Martin Keuchel, Emil C Reisinger, Andreas Langeheinecke, Andreas de Weerth, Marcus Schuchmann, Tom Schaberg, Sandra Ligges, Maria Eveslage, Ralf M Hagen, Gerd D Burchard, Ansgar W Lohse, Stephan Ehrhardt, Nan Guo, Rebecca Hinz, Stefanie Schoppen, Jürgen May, Markus Reiser, Maximilian Philipp Schroeder, Stefan Schmiedel, Martin Keuchel, Emil C Reisinger, Andreas Langeheinecke, Andreas de Weerth, Marcus Schuchmann, Tom Schaberg, Sandra Ligges, Maria Eveslage, Ralf M Hagen, Gerd D Burchard, Ansgar W Lohse

Abstract

Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 ± 16.5 years and 231 patients aged 56.5 ± 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier. NCT01143272.

Keywords: Clostridium difficile-associated diarrhea; Saccharomyces boulardii; antibiotic-associated diarrhea; probiotic; randomized controlled trial.

Figures

Figure 1.
Figure 1.
Study flow. Abbreviation: Sac., Saccharomyces.
Figure 2.
Figure 2.
Enrollment, randomization, and follow-up. Abbreviations: Sac., Saccharomyces.

References

    1. Bartlett JG, Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346:334–9.
    1. McFarland LV. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998; 16:292–307.
    1. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med 2012; 157:878–88.
    1. Bergogne-Berezin E. Treatment and prevention of antibiotic associated diarrhea. Int J Antimicrob Agents 2000; 16:521–6.
    1. Kyne L, Hamel MB, Polavaram R, Kelly CP et al. . Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile . Clin Infect Dis 2002; 34:346–53.
    1. McFarland LV. From yaks to yogurt: the history, development, and current use of probiotics. Clin Infect Dis 2015; 60:S85–90.
    1. Elmer GW. Probiotics: “living drugs”. Am J Health Syst Pharm 2001; 58:1101–9.
    1. Antunes LC, Han J, Ferreira RB et al. . Effect of antibiotic treatment on the intestinal metabolome. Antimicrob Agents Chemother 2011; 55:1494–503.
    1. Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr 2010; 91:687–703.
    1. 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.
    1. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101:812–22.
    1. Lynen Jansen P, Stallmach A, Lohse AW, Lerch MM et al. . [Development of gastrointestinal infectious diseases between 2000 and 2012]. Z Gastroenterol 2014; 52:549–57.
    1. Lessa FC, Mu Y, Bamberg WM et al. . Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372:825–34.
    1. Sullivan A, Nord CE. Probiotics and gastrointestinal diseases. J Intern Med 2005; 257:78–92.
    1. Müller HH, Schäfer H. A general statistical principle for changing a design any time during the course of a trial. Stat Med 2004; 23:2497–508.
    1. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika 1981; 68:373–9.
    1. Pozzoni P, Riva A, Bellatorre AG et al. . Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2012; 107:922–31.
    1. Hickson M, D'Souza AL, Muthu N et al. . Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007; 335:80.
    1. Gao XW, Mubasher M, Fang CY et al. . Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol 2010; 105:1636–41.
    1. Allen SJ, Wareham K, Wang D et al. . Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382:1249–57.
    1. Hempel S, Newberry SJ, Maher AR et al. . Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012; 307:1959–69.
    1. Sazawal S, Hiremath G, Dhingra U et al. . Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis 2006; 6:374–82.
    1. Guandalini S. Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol 2011; 45:S149–53.
    1. Goldenberg JZ, Ma SS, Saxton JD et al. . Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2013; 5:CD006095.
    1. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2012; 35:1355–69.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere