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The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection

      Clostridium difficile infection is the most common health care–associated infection in the United States. Recently, fecal microbiota transplantation (FMT) has emerged as an effective and safe therapy for recurrent C difficile infection; however, despite rapid adoption there is no standardized clinical approach. Given the rapid adoption of FMT, in part because of stool banks, there is a need for a practical primer for clinicians to safely perform FMT. Accordingly, we aim to provide a simple approach entitled the 5D FMT framework to guide physicians. The 5D FMT framework includes: decision (selecting appropriate patient for FMT), donor (selection and screening), discussion (risk, benefits, alternatives), delivery (selecting appropriate modality for FMT administration), and discharge (counseling at discharge and follow-up). We aim to help clinicians take a simple but evidence-based approach to FMT to optimize efficacy and safety. This primer navigates how to decide whether a patient with C difficile infection is appropriate for FMT and how to select and screen stool donors, identify the ideal delivery modality, and provide follow-up care after FMT.

      Abbreviations:

      CMV (cytomegalovirus), EBV (Epstein-Barr virus), EIA (enzyme immunoassay), FDA (U.S. Food and Drug Administration), FMT (fecal microbiota transplantation), IBD (inflammatory bowel disease), IND (investigational new drug), NAAT (nucleic acid amplification test), PCR (polymerase chain reaction)
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      References

        • Lessa F.C.
        • Winston L.G.
        • McDonald L.C.
        Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States.
        N Engl J Med. 2015; 372: 2369-2370
        • Lessa F.C.
        • Mu Y.
        • Bamberg W.M.
        • et al.
        Burden of Clostridium difficile infection in the United States.
        N Engl J Med. 2015; 372: 825-834
        • Shaughnessy M.K.
        • Amundson W.H.
        • Kuskowski M.A.
        • et al.
        Unnecessary antimicrobial use in patients with current or recent Clostridium difficile infection.
        Infect Control Hosp Epidemiol. 2013; 34: 109-116
        • Gould C.V.
        • Edwards J.R.
        • Cohen J.
        • et al.
        Effect of nucleic acid amplification testing on population-based incidence rates of Clostridium difficile infection.
        Clin Infect Dis. 2013; 57: 1304-1307
        • Longtin Y.
        • Trottier S.
        • Brochu G.
        • et al.
        Impact of the type of diagnostic assay on Clostridium difficile infection and complication rates in a mandatory reporting program.
        Clin Infect Dis. 2013; 56: 67-73
        • Persson S.
        • Jensen J.N.
        • Olsen K.E.
        Multiplex PCR method for detection of Clostridium difficile tcdA, tcdB, cdtA, and cdtB and internal in-frame deletion of tcdC.
        J Clin Microbiol. 2011; 49: 4299-4300
        • Surawicz C.M.
        • Brandt L.J.
        • Binion D.G.
        • et al.
        Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
        Am J Gastroenterol. 2013; 108 (98; quiz 499): 478
        • Surawicz C.M.
        • McFarland L.V.
        • Greenberg R.N.
        • et al.
        The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii.
        Clin Infect Dis. 2000; 31: 1012-1017
        • Gerding D.N.
        Metronidazole for Clostridium difficile–associated disease: Is it okay for mom?.
        Clin Infect Dis. 2005; 40: 1598-1600
        • Wenisch C.
        • Parschalk B.
        • Hasenhundl M.
        • et al.
        Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile–associated diarrhea.
        Clin Infect Dis. 1996; 22: 813-818
        • Sadowsky M.J.
        • Khoruts A.
        Faecal microbiota transplantation is promising but not a panacea.
        Nat Microbiol. 2016; 1: 16015
        • Weingarden A.R.
        • Chen C.
        • Bobr A.
        • et al.
        Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G310-G319
      1. Mullish B, McDonald J, Kao D, et al. Understanding the mechanisms of efficacy of fecal microbiota transplantation in the treatment of Clostridium difficile infection: the potential role of bile-metabolising enzymes. Gastroenterology 2017;152(Suppl 1):S47.

        • Allegretti J.R.
        • Kearney S.
        • Li N.
        • et al.
        Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles.
        Aliment Pharmacol Ther. 2016; 43: 1142-1153
        • Khoruts A.
        • Sadowsky M.J.
        Understanding the mechanisms of faecal microbiota transplantation.
        Nat Rev Gastroenterol Hepatol. 2016; 13: 508-516
        • Cammarota G.
        • Ianiro G.
        • Gasbarrini A.
        Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review.
        J Clin Gastroenterol. 2014; 48: 693-702
        • Kelly C.R.
        • Khoruts A.
        • Staley C.
        • et al.
        Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial.
        Ann Intern Med. 2016; 165: 609-616
        • 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
        • 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
        • Kassam Z.
        • Lee C.H.
        • Hunt R.H.
        Review of the emerging treatment of Clostridium difficile infection with fecal microbiota transplantation and insights into future challenges.
        Clin Lab Med. 2014; 34: 787-798
        • 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
        • Kassam Z.
        • Lee C.H.
        • Yuan Y.
        • et al.
        Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
        Am J Gastroenterol. 2013; 108: 500-508
        • Wang S.
        • Xu M.
        • Wang W.
        • et al.
        Systematic review: adverse events of fecal microbiota transplantation.
        PLoS One. 2016; 11: e0161174
        • Smith M.B.
        • Kelly C.
        • Alm E.J.
        Policy: how to regulate faecal transplants.
        Nature. 2014; 506: 290-291
      2. U.S. Food and Drug Administration. Guidance for industry: enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. Available at: https://Www.fda.gov/downloads/biologicsblood vaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/UCM488223.pdf. Accessed May 2017.

        • Kelly C.R.
        • Kunde S.S.
        • Khoruts A.
        Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies.
        Clin Gastroenterol Hepatol. 2014; 12: 283-288
      3. Lieberman A, Munoz R, Edelstein C, et al. The impact of stool banks on access to fecal microbiota transplantation for recurrent Clostridium difficile infection in the United States: a geospatial analysis. Poster presented at: American College of Gastroenterology Meeting; October 14-19, 2016; Las Vegas, NV.

        • Kelly C.R.
        • Kahn S.
        • Kashyap P.
        • et al.
        Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook.
        Gastroenterology. 2015; 149: 223-237
        • Bakken J.S.
        • Borody T.
        • Brandt L.J.
        • et al.
        Treating Clostridium difficile infection with fecal microbiota transplantation.
        Clin Gastroenterol Hepatol. 2011; 9: 1044-1049
      4. Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. Epub 2017 Jan 13.

        • Fischer M.
        • Sipe B.W.
        • Rogers N.A.
        • et al.
        Faecal microbiota transplantation plus selected use of vancomycin for severe-complicated Clostridium difficile infection: description of a protocol with high success rate.
        Aliment Pharmacol Ther. 2015; 42: 470-476
        • Aroniadis O.C.
        • Brandt L.J.
        • Greenberg A.
        • et al.
        Long-term follow-up study of fecal microbiota transplantation for severe and/or complicated Clostridium difficile infection: a multicenter experience.
        J Clin Gastroenterol. 2016; 50: 398-402
        • Fischer M.
        • Rex D.K.
        • Sipe B.W.
        Letter: Faecal microbiota transplantation in combination with fidaxomicin to treat severe complicated recurrent Clostridium difficile infection—authors' reply.
        Aliment Pharmacol Ther. 2015; 42: 1031
      5. Fischer M, Sipe B, Cheng YW, et al. Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: a promising treatment approach. Gut Microbes. Epub 2016 Dec 21.

        • Crobach M.J.
        • Planche T.
        • Eckert C.
        • et al.
        European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection.
        Clin Microbiol Infect. 2016; 22: S63-S81
        • Jackson M.
        • Olefson S.
        • Machan J.T.
        • et al.
        A high rate of alternative diagnoses in patients referred for presumed Clostridium difficile infection.
        J Clin Gastroenterol. 2016; 50: 742-746
        • Saeedi B.J.
        • Morison D.G.
        • Kraft C.S.
        • et al.
        Fecal microbiota transplant for Clostridium difficile infection in a pregnant patient.
        Obstet Gynecol. 2017; 129: 507-509
        • Kelly C.R.
        • Ihunnah C.
        • Fischer M.
        • et al.
        Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.
        Am J Gastroenterol. 2014; 109: 1065-1071
      6. Infectious Disease Society of America. Available at: https://www.gastro.org/research/Joint_Society_FMT_Guidance.pdf. Accessed May, 2017.

        • Edelstein C.
        • Daw J.R.
        • Kassam Z.
        Seeking safe stool: Canada needs a universal donor model.
        CMAJ. 2016; 188: E431-E432
        • Bakken J.S.
        • Polgreen P.M.
        • Beekmann S.E.
        • et al.
        Treatment approaches including fecal microbiota transplantation for recurrent Clostridium difficile infection (RCDI) among infectious disease physicians.
        Anaerobe. 2013; 24: 20-24
        • Hamilton M.J.
        • Weingarden A.R.
        • Sadowsky M.J.
        • et al.
        Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection.
        Am J Gastroenterol. 2012; 107: 761-767
        • Lee C.H.
        • Steiner T.
        • Petrof E.O.
        • 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
        • Smith M.
        • Kassam Z.
        • Edelstein C.
        • et al.
        OpenBiome remains open to serve the medical community.
        Nat Biotechnol. 2014; 32: 867
        • Smith M.
        • Kassam Z.
        • Burgess J.
        • et al.
        The international public stool bank: a scalable model for standardized screening and processing of donor stool for fecal microbiota transplantation.
        Gastroenterology. 2015; 148 (S-211)
        • Dubois N.
        • Ling K.
        • Osman M.
        • et al.
        Prospective assessment of donor eligibility for fecal microbiota transplantation at a public stool bank: Results from the evaluation of 1387 candidate donors.
        Open Forum Infect Dis. 2016; 2: 962
        • Osman M.
        • O’Brien K.
        • Stoltzner Z.
        • et al.
        Safety and efficacy of fecal microbiota transplantation for recurrent Clostridium difficile infection from an international public stool bank: results from a 2050-patient multicenter cohort.
        Open Forum Infect Dis. 2016; 3: S599
        • Bate S.L.
        • Dollard S.C.
        • Cannon M.J.
        Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004.
        Clin Infect Dis. 2010; 50: 1439-1447
        • Rossen N.G.
        • Fuentes S.
        • van der Spek M.J.
        • et al.
        Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis.
        Gastroenterology. 2015; 149: 110-118.e4
        • Hohmann E.L.
        • Ananthakrishnan A.N.
        • Deshpande V.
        Case records of the Massachusetts General Hospital. Case 25-2014. A 37-year-old man with ulcerative colitis and bloody diarrhea.
        N Engl J Med. 2014; 371: 668-675
        • Baxter M.
        • Colville A.
        Adverse events in faecal microbiota transplant: a review of the literature.
        J Hosp Infect. 2016; 92: 117-127
        • Quera R.
        • Espinoza R.
        • Estay C.
        • et al.
        Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection.
        J Crohns Colitis. 2014; 8: 252-253
        • Aas J.
        • Gessert C.E.
        • Bakken J.S.
        Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube.
        Clin Infect Dis. 2003; 36: 580-585
        • De Leon L.M.
        • Watson J.B.
        • Kelly C.R.
        Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection.
        Clin Gastroenterol Hepatol. 2013; 11: 1036-1038
        • Kunde S.
        • Pham A.
        • Bonczyk S.
        • et al.
        Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis.
        J Pediatr Gastroenterol Nutr. 2013; 56: 597-601
        • Mandalia A.
        • Kraft C.S.
        • Dhere T.
        Diverticulitis after fecal microbiota transplant for C. difficile infection.
        Am J Gastroenterol. 2014; 109: 1956-1957
        • van Nood E.
        • Speelman P.
        • Kuijper E.J.
        • et al.
        Struggling with recurrent Clostridium difficile infections: Is donor faeces the solution?.
        Euro Surveill. 2009; 14: 19316
        • Brandt L.J.
        • Aroniadis O.C.
        • Mellow M.
        • et al.
        Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection.
        Am J Gastroenterol. 2012; 107: 1079-1087
        • Newman K.M.
        • Rank K.M.
        • Vaughn B.P.
        • et al.
        Treatment of recurrent Clostridium difficile infection using fecal microbiota transplantation in patients with inflammatory bowel disease.
        Gut Microbes. 2017; 8: 303-309
        • Khoruts A.
        • Rank K.M.
        • Newman K.M.
        • et al.
        Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection.
        Clin Gastroenterol Hepatol. 2016; 14: 1433-1438
        • Moayyedi P.
        • Surette M.G.
        • Kim P.T.
        • et al.
        Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial.
        Gastroenterology. 2015; 149: 102-109.e6
      7. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. Epub 2017 Feb 14.

        • Fischer M.
        • Kao D.
        • Mehta S.R.
        • et al.
        Predictors of early failure after fecal microbiota transplantation for the therapy of Clostridium difficile infection: a multicenter study.
        Am J Gastroenterol. 2016; 111: 1024-1031
        • Obi O.
        • Hampton D.
        • Anderson T.
        • et al.
        Fecal microbiota transplant for treatment of resistant C. difficile infection using a standardized protocol: a community hospital experience.
        Am J Gastroenterol. 2014; 109: S629
        • Baxter M.
        • Ahmad T.
        • Colville A.
        • et al.
        Fatal aspiration pneumonia as a complication of fecal microbiota transplant.
        Clin Infect Dis. 2015; 61: 136-137
      8. Environmental Protection Agency. Available at: https://www.epa.gov/sites/production/files/2017-01/documents/20172701.listk_.pdf.

        • Zipursky J.S.
        • Sidorsky T.I.
        • Freedman C.A.
        • et al.
        Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection.
        Clin Infect Dis. 2012; 55: 1652-1658
        • Lee C.H.
        • Belanger J.E.
        • Kassam Z.
        • et al.
        The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema.
        Eur J Clin Microbiol Infect Dis. 2014; 33: 1425-1428
        • Varier R.U.
        • Biltaji E.
        • Smith K.J.
        • et al.
        Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection.
        Clin Microbiol Infect. 2014; 20: 1343-1351
        • Varier R.U.
        • Biltaji E.
        • Smith K.J.
        • et al.
        Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection.
        Infect Control Hosp Epidemiol. 2015; 36: 438-444
        • van Beurden Y.H.
        • van Gils T.
        • van Gils N.A.
        • et al.
        Serendipity in refractory celiac disease: full recovery of duodenal villi and clinical symptoms after fecal microbiota transfer.
        J Gastrointest Liver Dis. 2016; 25: 385-388
        • Youngster I.
        • Russell G.H.
        • Pindar C.
        • et al.
        Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection.
        JAMA. 2014; 312: 1772-1778
        • Youngster I.
        • Mahabamunuge J.
        • Systrom H.K.
        • et al.
        Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection.
        BMC Med. 2016; 14 (134,016-0680-9)
        • Hirsch B.E.
        • Saraiya N.
        • Poeth K.
        • et al.
        Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection.
        BMC Infect Dis. 2015; 15 (191,015-0930-z)
      9. Allegretti J, 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. Gastroenterology 2016;150(Suppl 1):S540.

        • Jalanka J.
        • Salonen A.
        • Salojarvi J.
        • et al.
        Effects of bowel cleansing on the intestinal microbiota.
        Gut. 2015; 64: 1562-1568
        • O'Brien C.L.
        • Allison G.E.
        • Grimpen F.
        • et al.
        Impact of colonoscopy bowel preparation on intestinal microbiota.
        PLoS One. 2013; 8: e62815
      10. Fischer M, Phelps E, Bolla R, et al. Long term risk of Clostridium difficile infection recurrence with or without antibiotics exposure following successful fecal microbiota transplant. Presented at Digestive Disease Week; May 21-24, 2016; San Diego, CA.

        • Wadhwa A.
        • Al Nahhas M.F.
        • Dierkhising R.A.
        • et al.
        High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.
        Aliment Pharmacol Ther. 2016; 44: 576-582