infection control & hospital epidemiology july 2018, vol. 39, no. 7 original article Microbial Preparations (Probiotics) for the Prevention of
Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants
Bradley C. Johnston, PhD;1 Lyubov Lytvyn, MSc;2 Calvin Ka-Fung Lo, BHSc;3 Stephen J. Allen, MD;4 Duolao Wang, PhD;4 Hania Szajewska, MD;5 Mark Miller, MD;6 Stephan Ehrhardt, MD;7 John Sampalis, MD;6 Deniz G. Duman, MD;8 Pietro Pozzoni, MD;9 Agostino Colli, MD;9 Elisabet Lönnermark, MD;10 Christian P. Selinger, MD;11
Samford Wong, PhD;12 Susan Plummer, MD;13 Mary Hickson, PhD;14 Ruzha Pancheva, MD, PhD;15 Sandra Hirsch, MD;16 Bengt Klarin, MD;17 Joshua Z Goldenberg, ND;18 Li Wang, MD;19,20 Lawrence Mbuagbaw, PhD;2,* Gary Foster, PhD;21 Anna Maw, MD;22 Behnam Sadeghirad, MPH;2 Lehana Thabane, PhD;2 Dominik Mertz, MD2,23
objective. To determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children. design. Individual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.
methods. We searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.
results. Probiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25–0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23–0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11–4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is ≥5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89–1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89–1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.
conclusions. Moderate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%.
trial registration. PROSPERO 2015 identifier: CRD42015015701 Infect Control Hosp Epidemiol 2018;39:771–781
Clostridium difficile infection (CDI) is the leading cause of hospital-associated infectious diarrhea.1 Diarrhea is the most
common presentation; however, CDI may result in more serious sequelae including pseudomembranous colitis, toxic
Affiliations: 1. Department of Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada;
2. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 3. McMaster University, Hamilton, Ontario, Canada; 4. Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; 5. Department of Pediatrics, The Medical University of Warsaw, Warsaw, Poland; 6. McGill University, Montreal, Québec, Canada; 7. Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States; 8. Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey; 9. Department of Internal Medicine, A Manzoni Hospital AO Provincia di Lecco, Lecco, Italy; 10. Department of Infectious Diseases, Gothenburg University, Göteborg, Sweden; 11. Department of Gastroenterology, St James University Hospital, Leeds, United Kingdom; 12. National Spinal Injuries Center, Stoke Mandeville Hospital, Aylesbury, United Kingdom; 13. Research and Development Department, Cultech Ltd, Port Talbot, United Kingdom; 14. Nutrition and Dietetic Research Group, Plymouth University, United Kingdom; 15. Department of Hygiene, Medical University, Varna, Bulgaria; 16. Instituto de Nutrición y Tecnología de los Alimentos, University of Chile, Santiago, Chile; 17. Department of Anesthesiology and Intensive Care, Lund University Hospital, Lund, Sweden; 18. Bastyr University Research Institute, Kenmore, Washington, United States; 19. Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada; 20. Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; 21. St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada; 22. Division of Hospital Medicine, Department of Medicine, University of Colorado, Denver, Colorado, United States; 23. Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
*Author name has been corrected since original publication. A corrigendum notice detailing this change was also published (DOI: 10.1017/ice.2018.120). © 2018 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2018/3907-0002. DOI: 10.1017/ice.2018.84
Received August 29, 2017; accepted March 13, 2018; electronically published April 26, 2018
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