Objectives: Faecal microbiota transplantation (FMT) has emerged as a useful approach for treating Clostridium difficile-associated diarrhoea (CDAD). Randomised controlled trials (RCTs) have recently evaluated its effectiveness, but systematic reviews have focused on evidence from case series. We therefore conducted a systematic review and meta-analysis of RCTs evaluating the effectiveness of FMT for treating CDAD.
Study design: We included RCTs that primarily recruited adults with CDAD and compared the effectiveness of FMT with that of placebo, antibiotic therapy, or autologous stool transplantation, or compared different preparations or modes of delivery of FMT. Dichotomous symptom data were pooled to calculate a relative risk (RR) of CDAD persisting after therapy, and the number needed to treat (NNT).
Data sources: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched to 6 February 2017.
Data synthesis: We identified ten RCTs that evaluated the treatment of a total of 657 patients with CDAD. Five RCTs compared FMT with placebo (including autologous FMT) or vancomycin treatment (total of 284 patients); FMT was statistically significantly more effective (RR, 0.41; 95% CI, 0.22–0.74; NNT, 3; 95% CI, 2–7). Heterogeneity across studies was significant (I2 = 61%); this heterogeneity was attributable to the mode of delivery of FMT, and to the therapy being more successful in European than in North American trials. The other five RCTs evaluated different approaches to FMT therapy. Frozen FMT preparations were as efficacious as fresh material in one RCT, but the numbers of patients in the remaining RCTs were too small to allow definitive conclusions.
Conclusions: Moderate quality evidence from RCT trials indicates that FMT is more effective in patients with CDAD than vancomycin or placebo. Further investigations are needed to determine the best route of administration and FMT preparation.
- 1. Hall I, O’Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935; 49: 390.
- 2. Heinlen L, Ballard JD. Clostridium difficile infection. Am J Med Sci 2010; 340: 247-252.
- 3. Bartlett JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis. 1994; 18 (Suppl 4): S265-S272.
- 4. Reveles KR, Lee GC, Boyd NK, Frei CR. The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001–2010. Am J Infect Control 2014; 42: 1028-1032.
- 5. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372: 1539-1548.
- 6. Slimings C, Armstrong P, Beckingham WD, et al. Increasing incidence of Clostridium difficile infection, Australia, 2011–2012. Med J Aust 2014; 200: 272-276. <MJA full text>
- 7. O'Connor JR, Johnson S, Gerding DN. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology 2009; 136: 1913-1924.
- 8. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile in the United States. N Engl J Med 2015; 372: 825-834.
- 9. Zhang F, Luo W, Shi Y, et al. Should we standardize the 1700-year old fecal microbiota transplantation? Am J Gastroenterol 2012; 107: 1755.
- 10. Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol 2014; 30: 97-105.
- 11. Debast SB, Bauer MP, Kuipers EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbial Infect 2014; 20 (Suppl 2): 1-26.
- 12. Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017; 66: 569-580.
- 13. Moayyedi P, Marshall JK, Yuan Y, Hunt R. Canadian Association of Gastroenterology position statement: fecal microbiota transplant therapy. Can J Gastroenterol Hepatol 2014; 28: 66-68.
- 14. Cheng AC, Ferguson JK, Richards MJ, et al. Australasian Society for Infectious Diseases guidelines for the diagnosis and treatment of Clostridium difficile infection. Med J Aust 2011; 194: 353-358. <MJA full text>
- 15. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection. a systematic review. Ann Intern Med 2015; 162: 630-638.
- 16. Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors). Cochrane handbook for systematic reviews of interventions; version 5.2 (updated Feb 2017), Cochrane, 2017. http://training.cochrane.org/ (accessed June 2017).
- 17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188.
- 18. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557-560.
- 19. Moayyedi P. Meta-analysis: can we mix apples and oranges? Am J Gastroenterol 2004; 99: 2297-2301.
- 20. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002.
- 21. Egger M, Davey-Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634.
- 22. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368: 407-415.
- 23. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015; 41: 835-843.
- 24. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection. Ann Intern Med 2016; 165: 609-616.
- 25. Orenstein R, Dubberke E, Lee CH, et al. RBX2660, a microbiota-based drug for the prevention of recurrent Clostridium difficile infection, is safe and effective: results from a randomised, double-blinded, placebo-controlled trial (abstract LB08). 24th UEG Week 2016; Vienna (Austria), 17–19 Oct 2016. United European Gastroenterol J 2016; 4: 802.
- 26. Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: an open-label, randomized controlled trial. Clin Infect Dis 2017; 64: 265-271.
- 27. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014; 58: 1515-1522.
- 28. Allegretti JR, Fischer M, Papa E, et al. Fecal microbiota transplantation delivered via oral capsules achieves microbial engraftment similar to traditional delivery modalities: safety efficacy and engraftment results from a multi-center cluster randomized dose-finding study (abstract Su1738). Digestive Disease Week (DDW) 2016; San Diego (USA), 21–24 May 2016. Gastroenterology 2016; 150 (Suppl 1): S540.
- 29. Kao D, Roach B, Hotte N, et al. A prospective dual center, randomized trial comparing colonoscopy versus capsule delivered fecal microbiota transplantation (FMT) in the management of recurrent Clostridium difficile infection (RCDAD) (poster A117). Canadian Digestive Diseases Week 2016; Montreal (Canada), 26–29 Feb 2016. Can J Gastroenterol Hepatol 2016: article 4792898, p. 71.
- 30. Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection a randomized clinical trial. JAMA 2016; 315: 142-149.
- 31. Jiang ZD, Ajami NJ, Petrosino JF, et al. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difﬁcile infection — fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther 2017; 45: 899-908.
- 32. Guyatt GH, Oxman AD, Vist G, et al; for the GRADE Working Group. Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-926.
- 33. Rossen NG, MacDonald JK, de Vries EM, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: a systematic review. World J Gastroenterol 2015; 21: 5359-5371.
- 34. Chapman BC, Moore HB, Overby DM, et al. Fecal microbiota transplant in patients with Clostridium difficile infection: a systematic review. Acute Care Surg 2016; 81: 756-764.
- 35. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108: 500-508.
- 36. Borody TJ, George L, Andrews P, et al. Bowel-flora alteration: a potential cure for inflammatory bowel disease and irritable bowel syndrome? Med J Aust 1989; 150: 604.
- 37. Costello SP, Conlon MA, Vuaran MS, et al. Faecal microbiota transplant for recurrent Clostridium difficile infection using long-term frozen stool is effective: clinical efficacy and bacterial viability data. Aliment Pharmacol Ther 2015; 42: 1011-1018.
- 38. Borody TJ, Fischer M, Mitchell S, Campbell J. Fecal microbiota transplantation in gastrointestinal disease: 2015 update and the road ahead. Expert Rev Gastroenterol Hepatol 2015; 9: 1379-1391.
- 39. University of Texas Health Science Center, Houston. Fecal microbiota transplantation to treat recurrent C. difficile associated diarrhea via retention enema or oral route. https://clinicaltrials.gov/ct2/show/NCT02449174 (accessed June 2017).
- 40. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364: 422-431.
- 41. Baxter M, Ahmad T, Colville A, Sheridan R. Fatal aspiration pneumonia as a complication of fecal microbiota transplantation. Clin Inf Dis 2015; 61: 136-137.
Publication of your online response is subject to the Medical Journal of Australia's editorial discretion. You will be notified by email within five working days should your response be accepted.