Skip to main content
×
×
Home

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 (a1), Lyubov Lytvyn (a2), Calvin Ka-Fung Lo (a3), Stephen J. Allen (a4), Duolao Wang (a4), Hania Szajewska (a5), Mark Miller (a6), Stephan Ehrhardt (a7), John Sampalis (a6), Deniz G. Duman (a8), Pietro Pozzoni (a9), Agostino Colli (a9), Elisabet Lönnermark (a10), Christian P. Selinger (a11), Samford Wong (a12), Susan Plummer (a13), Mary Hickson (a14), Ruzha Pancheva (a15), Sandra Hirsch (a16), Bengt Klarin (a17), Joshua Z Goldenberg (a18), Li Wang (a19) (a20), Lawrence Mbuagbaw (a2), Gary Foster (a21), Anna Maw (a22), Behnam Sadeghirad (a2), Lehana Thabane (a2) and Dominik Mertz (a2) (a23)...
  • Please note a correction has been issued for this article.
Abstract
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;771–781

Copyright
Corresponding author
Address correspondence to Bradley C. Johnston, PhD, Department of Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Centre for Clinical Research, Room 404, 5790 University Avenue, Halifax, Nova Scotia, Canada, B3H 1V7 (bjohnston@dal.ca).
References
Hide All
1. Dubberke, ER, Olsen, MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55(Suppl 2):S88S92.
2. Freeman, J, Bauer, MP, Baines, SD, et al. The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 2010;23:529549.
3. Dubberke, ER, Butler, AM, Reske, KA, et al. Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients. Emerg Infect Dis 2008;14:10311038.
4. Johnson, S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect 2009;58:403410.
5. Lessa, FC, Mu, Y, Bamberg, WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372:825834.
6. Slimings, C, Riley, TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother 2014;69:881891.
7. Bauer, MP, Notermans, DW, Van Benthem, BH, et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2011;377(9759):6373.
8. Lessa, FC, Gould, CV, McDonald, LC. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 2012;55(Suppl 2):S65S70.
9. Louie, TJ, Miller, MA, Crook, DW, et al. Effect of age on treatment outcomes in Clostridium difficile infection. J Am Geriatr Soc 2013;61:222230.
10. Vesteinsdottir, I, Gudlaugsdottir, S, Einarsdottir, R, Kalaitzakis, E, Sigurdardottir, O, Bjornsson, ES. Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case-control study. Eur J Clin Microbiol Infect Dis 2012;31:26012610.
11. Hill, C, Guarner, F, Reid, G, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506514.
12. 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. doi: 10.1002/14651858.CD006095.pub3.
13. Goldenberg, JZ, Yap, C, Lytvyn, L, Lo, CK, Beardsley, J, Mertz, D, Johnston, BC. Probiotics for the prevention of Clostridium difficile associated diarrhea in adults and children. Cochrane Database Syst Rev 2017:12:CD006095.
14. Lytvyn, L, Mertz, D, Sadeghirad, B, Alaklobi, F, Selva, A, Alonso-Coello, P, Johnston, BC. Prevention of Clostridium difficile infection: a systematic survey of clinical practice guidelines. Infect Control Hosp Epidemiol 2016;37:901908.
15. Carrico, R, Bryant, K, Lessa, F, et al. Guide to preventing Clostridium difficile infections. Association for Professionals in Infection Control and Epidemiology website. http://apic.org/Resource_/EliminationGuideForm/e3a85b7e-7ad8-4ab6-9892- 54aef516cf10/File/2013CDiffFinal.pdf. Published 2013. Accessed August 14, 2017.
16. Dubberke, ER, Carling, P, Carrico, R, et al. Strategies to prevent Clostridium difficile infections in acute-care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:628645.
17. Surawicz, CM, Brandt, LJ, Binion, DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478498.
18. Vonberg, RP, Kuijper, E, Wilcox, M, et al. Infection control measures to limit the spread of Clostridium difficile . Clin Microbiol Infect 2008;14(s5):220.
19. Hawkey, P, Bain, L, Borriello, P, et al. Clostridium difficile infection: how to deal with the problem. London: Public Health England and Department of Health; 2008.
20. Debast, S, Bauer, M, Kuijper, E. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20(s2):126.
21. Lytvyn, L, Mertz, D, Thabane, L, et al. Probiotics for the prevention of Clostridium difficile infection in adults and children: an individual patient data meta-analysis. PROSPERO: International prospective register of systematic reviews. Master’s thesis, McMaster University. 2015. doi: 10.15124/CRD42015015701.
22. Bartlett, JG, Gerding, DN. Clinical recognition and diagnosis of Clostridium difficile Infection. Clin Infect Dis 2008;46(Suppl 1):S12S18.
23. Higgins, J, Altman, DG, Gøtzsche, PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011:343.
24. Guyatt, GH, Oxman, AD, Vist, GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924926.
25. Egger, M, Smith, GD, Schneider, M, Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629634.
26. Deeks, JJ, Higgins, J, Altman, DG. Analysing data and undertaking meta‐analyses. In: The Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series. Chichester, UK: Wiley & Sons; 2008. Pp. 243296.
27. Johnston, BC, Goldenberg, JZ, Vandvik, PO, Sun, X, Guyatt, GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev 2011;9(11).
28. Gerding, DN, Olson, MM, Peterson, LR, et al. Clostridium difficile—associated diarrhea and colitis in adults: a prospective case-controlled epidemiologic study. Arch Intern Med 1986;146:95100.
29. Gao, XW, Mubasher, M, Fang, CY, Reifer, C, Miller, LE. 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;105:16361641.
30. Duman, DG, Bor, S, Özütemiz, Ö, et al. Efficacy and safety of Saccharomyces boulardii in prevention of antibiotic-associated diarrhoea due to Helicobacter pylori eradication. Eur J Gastroenterol Hepatol 2005;17:13571361.
31. Bravo, MV, Bunout, D, Leiva, L, et al. Effect of probiotic Saccharomyces boulardii on prevention of antibiotic-associated diarrhea in adult outpatients with amoxicillin treatment. [In Spanish.] Revista Medica de Chile 2008;136:981988.
32. 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;21:583590.
33. 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;107:922931.
34. 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(7610):80.
35. Klarin, B, Wullt, M, Palmquist, I, Molin, G, Larsson, A, Jeppsson, B. Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol Scand 2008;52:10961102.
36. Miller, M. Results of 2 prospective randomized studies of Lactobacillus GG to prevent C. difficile infection in hospitalized adults receiving antibiotics; 2008a.
37. Miller, M. Results of 2 prospective randomized studies of Lactobacillus GG to prevent C. difficile infection in hospitalized adults receiving antibiotics; 2008b.
38. Plummer, S, Weaver, MA, Harris, JC, Dee, P, Hunter, J. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea. Int Microbiol 2010;7:5962.
39. Psaradellis, E, Sampalis, J, Rampakakis, E. Efficacy of BIO K+ CL1285® in the reduction of antibiotic associated diarrhea–a placebo controlled double-blind randomized, multi-center study. Arch Med Sci 2010;6:5664.
40. Selinger, C, Bell, A, Cairns, A, Lockett, M, Sebastian, S, Haslam, N. Probiotic VSL# 3 prevents antibiotic-associated diarrhoea in a double-blind, randomized, placebo-controlled clinical trial. J Hosp Infect 2013;84:159165.
41. 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(9900):12491257.
42. Wong, S, Jamous, A, O’Driscoll, J, et al. A Lactobacillus casei Shirota probiotic drink reduces antibiotic-associated diarrhoea in patients with spinal cord injuries: a randomised controlled trial. Brit J Nutr 2013;111:672678.
43. Georgieva, M, Pancheva, R, Rasheva, N, Usheva, N, Ivanova, L, Koleva, K. Use of the probiotic Lactobacillus reuteri DSM 17938 in the prevention of antibiotic-associated infections in hospitalized Bulgarian children: a randomized controlled trial. J IMAB Annual Proceeding (Scientific Papers) 2015;21(4):895900.
44. Ehrhardt, S, Guo, N, Hinz, R, et al. Saccharomyces boulardii to prevent antibiotic-associated diarrhea: randomized, double-masked, placebo-controlled trial. Open Forum Infect Dis 2016;3(1):ofw011.
45. Lönnermark, E, Friman, V, Lappas, G, Sandberg, T, Berggren, A, Adlerberth, I. Intake of Lactobacillus plantarum reduces certain gastrointestinal symptoms during treatment with antibiotics. J Clin Gastroenterol 2010;44:106112.
46. Ruszczyński, M, Radzikowski, A, Szajewska, H. Clinical trial: effectiveness of Lactobacillus rhamnosus (strains E/N, Oxy and Pen) in the prevention of antibiotic‐associated diarrhoea in children. Aliment Pharmacol Ther 2008;28:154161.
47. Hempel, S, Newberry, S, Ruelaz, A, et al. Safety of probiotics to reduce risk and prevent or treat disease. Evid Rep Technol Assess (Full Rep). 2011:1645.
48. Colli, A, Pozzoni, P, Conte, D, Casazza, G. Response to Kolber et al. Am J Gastroenterol 2014;109:10821083.
49. Brown, KA, Fisman, DN, Moineddin, R, Daneman, N. The magnitude and duration of Clostridium difficile infection risk associated with antibiotic therapy: a hospital cohort study. PLoS One 2014;9:e105454.
50. Szajewska, H. Pooling data on different probiotics is not appropriate to assess the efficacy of probiotics. Eur J Pediatr 2014;173:975.
51. Zawistowska-Rojek, A, Zareba, T, Mrówka, A, Tyski, S. Assessment of the microbiological status of probiotic products. Pol J Microbiol 2016;65:97104.
52. Thomas, D, Radji, S, Benedetti, A. Systematic review of methods for individual patient data meta-analysis with binary outcomes. BMC Med Res Method 2014;14:79.
53. Brown, K, Valenta, K, Fisman, D, Simor, A, Daneman, N. Hospital ward antibiotic prescribing and the risks of Clostridium difficile infection. JAMA Intern Med 2015;175:626633.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Infection Control & Hospital Epidemiology
  • ISSN: 0899-823X
  • EISSN: 1559-6834
  • URL: /core/journals/infection-control-and-hospital-epidemiology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×
Type Description Title
WORD
Supplementary materials

Johnston et al. supplementary material 1
Johnston et al. supplementary material

 Word (4.3 MB)
4.3 MB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed