- Email: [email protected]
Fecal Microbiota Transplant
F e c a l M i c ro b i o t a Tra n sp la n t Richard Vestal,
MD
a,b,
*
KEYWORDS Fecal microbiota transplant Stool therapy Clostridium difficile Recurrent Clostridium difficile Clostridium difficile–associated diarrhea Inflammatory bowel disease
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Clostridium difficile–associated diarrhea is a growing problem, and traditional antimicrobial therapy is associated with a high rate of recurrence. 2. Recurrent C difficile–associated diarrhea can be difficult to treat and repeat recurrences are common. 3. Fecal microbiota transplant can be administered by the use of several techniques and is associated with a high cure rate for recurrent and refractory C difficile–associated diarrhea. 4. Stool donors should undergo comprehensive testing to avoid the transmission of infectious agents during the transplant. 5. Adverse effects of fecal microbiota transplant are nonserious, well tolerated, and typically resolve within a few hours. 6. Patients whose recurrent C difficile–associated diarrhea fails to respond to fidaxomicin or a prolonged taper of oral vancomycin should be evaluated by a provider comfortable in performing fecal microbiota transplant. 7. More studies are needed to determine the role of fecal microbiota transplant in inflammatory bowel disease and other gastrointestinal and nongastrointestinal disorders.
Disclosure: Dr R. Vestal has no conflicts of interest or funding sources to disclose. a Presbyterian Hospital, 1100 Central Avenue SE, Albuquerque, NM 87106, USA; b Hospital Medicine Section, Division of General Internal Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Leprino Building, 4th Floor, Mailstop F-782, 12401 East 17th Avenue, Aurora, CO 80045, USA * Presbyterian Hospital, 1100 Central Avenue SE, Albuquerque, NM 87106. E-mail address: [email protected] Hosp Med Clin 5 (2016) 58–70 http://dx.doi.org/10.1016/j.ehmc.2015.08.006 2211-5943/16/$ – see front matter Ó 2016 Published by Elsevier Inc.
Fecal Microbiota Transplant
HISTORY IN MEDICINE
When was fecal microbiota transplant (FMT) first used? Although often considered an emerging therapy, the first known use of FMT dates to fourth century China, where Ge Hong, a practitioner with the Dong Jin dynasty, used ingested human fecal suspensions to treat ailments such as food poisoning and severe diarrhea.1 In sixteenth century China, Li Shizhen, a physician with the Ming dynasty, described the use of what he called yellow soup and other more palatablesounding names to treat several gastrointestinal illnesses.1 The first documented modern use of FMT in treating human disease was in 1958 at the University of Colorado, where donor stool was administered via a retention enema to successfully treat 4 patients with pseudomembranous enterocolitis caused by Micrococcus pyogenes.2 The first documented use of FMT to treat Clostridium difficile–associated diarrhea (CDAD) was in 1983, when a woman who experienced 5 relapses despite oral vancomycin was cured after undergoing the procedure.3 In more recent years, renewed use of FMT has led to the development of new preparation and delivery techniques as well as interest in its potential role in managing other gastrointestinal and nongastrointestinal disorders. What is the mechanism of action of FMT? The gut microbiome is composed primarily of 4 bacterial phyla; Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria, each with diverse genera.4 Normal healthy patients and patients with only 1 prior episode of CDAD tend to have a predominance of Bacteroidetes and Firmicutes.4 Patients with recurrent CDAD tend to have increased Proteobacteria and decreased Bacteroidetes with less abundant Firmicutes species in addition to an overall decreased richness and diversity of their microbiota.4 Regardless of route, FMT results an increased abundance of both Bacteroidetes and Firmicutes, a decrease in Proteobacteria, and an overall increased richness and diversity comparable with healthy people.5–10 These findings suggest that microbiome diversity creates colonization resistance and that the disturbance of the normal microbial flora, for instance by the use of antimicrobial therapy, may allow the overgrowth of harmful organisms that can contribute to disease. The aim of FMT is to restore the normal microbial flora in hopes of reversing or preventing the resultant disease processes, although the exact relationship between microbiota and the pathogenesis of disease has yet to be fully defined.
EPIDEMIOLOGY
What is driving the renewed interest in FMT? The increasing frequency of CDAD and its high recurrence rates with standard therapy for both initial (15%–30%) and recurrent (65%) disease is associated with increasing health care costs. As antimicrobial resistance to standard CDAD therapies increases, FMT may be a safe and effective intervention to improve patient outcomes and decrease the costs associated with recurrent CDAD. In addition, curiosity in the expanding role of FMT has been piqued with the growth of data showing gut microbiome disturbances in various disease processes.11
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INDICATIONS/CONTRAINDICATIONS
What are the indications and contraindications for FMT? There are currently no US Food and Drug Administration (FDA)–approved indications for FMT because it is considered an investigational new drug; however, according to an FDA statement in July 2013, health care providers may bypass the investigational new drug application process if informed consent is obtained and if FMT is used for the purpose of treating CDAD not responsive to standard therapies.12 As such, Box 1 outlines suggested indications by Bakken and colleagues. Note that although case reports have described success in treating toxic megacolon with FMT,13 this indication has not been well studied in randomized trials. Although not currently implemented, the FDA has drafted an updated statement that would require that transplanted product be obtained from a donor known either to the patient or to the health care provider.14 No absolute contraindications exist that would prohibit a patient from receiving FMT.
PATIENT AND DONOR PREPARATION
How are fecal donors selected? Family members or close contacts are often identified as donors for FMT.15 It is theorized that they share similar infectious risk factors with the patient and are thus less likely to transmit an infectious agent. This consideration may be important in patients with an urgent need for FMT whose clinical course does not facilitate the time needed to perform the necessary donor testing (described later).11 However, embarrassment in asking close contacts to donate stool, unwillingness of close contacts to donate, and lack of potential donors identified by patients may limit this approach. Study protocols have also described using healthy anonymous donors,16 which could potentially allow more rapid acquisition of stool for FMT because these patients would theoretically be able to undergo less frequent testing, although it remains unclear exactly how often these donor pools should undergo testing. As fecal microbiota preparation and storage techniques evolve, healthy donor pools may increase the availability and rapidity of this procedure. As with all tissue and organ donations, transmitting an infectious agent to the recipient is of high concern. Donors should be evaluated with a thorough history and physical to determine their infectious risk. A questionnaire for this purpose is available
Box 1 Suggested indications for FMT At least 3 episodes of mild to moderate CDAD and failure of a 6-week to 8-week taper with vancomycin with or without an alternative antibiotic At least 2 episodes of severe CDAD resulting in hospitalization and associated with significant morbidity Moderate CDAD not responding to standard therapy for at least a week Severe or fulminant CDAD with no response to standard therapy after 48 hours
Fecal Microbiota Transplant
online at http://apps.umchealthsystem.com/forphysicians/medicalorders/Fecal% 20Microbiota%20Transplant%20Donor%20Questionnaire.pdf. Although little evidence exists to support the practice, infectious disease testing of the donor is commonly performed. Boxes 2 and 3 represent a comprehensive list of infectious agents for which providers may test, although specific protocols may vary by institution.11,17–21 What preparations are necessary for the donor? Donors are instructed to notify the practitioner if any symptoms suggestive of an infection develop between the time of initial screening and that of donation, and they should avoid any food the recipient may have an allergy to for at least 5 days before the procedure.11 A mild osmotic laxative taken the evening before the procedure may assist in reliable bowel evacuation the following morning.19 What preparations are necessary for the recipient? When used in the management of recurrent CDAD, pretreatment antibiotics, typically oral vancomycin or metronidazole, are provided to the patient until symptoms are reduced.22 Antibiotics are held 24 to 72 hours before the procedure.15,23 Although not universally practiced for all upper gastrointestinal routes of FMT, it has been
Box 2 Serologic screening tests for donors Complete blood count Liver function tests Cytomegalovirus Immunoglobulin (Ig) M and IgG antibodies Epstein-Barr virus Viral capsid antigen (VCA) IgM VCA IgG Epstein-Barr virus nuclear antigen (EBNA) IgG Hepatitis A virus IgM antibody Hepatitis B virus Surface antigen and antibody Core IgM and IgG antibodies Human immunodeficiency virus (HIV) HIV1 and HIV2 antibodies Human T-lymphotropic virus Human T-lymphotropic virus I and II antibodies Treponema pallidum Rapid plasma reagin Entamoeba histolytica Latex agglutination test Dipstick assay Strongyloides stercoralis IgG antibody
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Box 3 Stool screening tests for donors Bacterial culture To include: Salmonella species Shigella species Escherichia coli O157:H7 Yersinia enterocolitica Campylobacter species Vibrio species Aeromonas species Plesiomonas Ova and parasites C difficile Toxin enzyme-linked immunosorbent assay Polymerase chain reaction Giardia lamblia antigen Cryptosporidium antigen Acid-fast staining Cyclospora species Isospora species Cryptosporidium species (if unable to test for antigen) Microsporidia species antigen Helicobacter pylori antigen Rotavirus antigen
recommended that all patients should receive a large bowel lavage, similar to that given before a colonoscopy, before the procedure.11 PREPROCEDURE PREPARATION
How is the fecal material prepared? Several techniques have described the preparation of donor stool.11,16,22–24 Although minor differences exist between the protocols, the general approaches are similar. Typically, at least 50 g of stool are placed in a liquid, which is typically sterile normal saline, although bottled water, tap water, milk, yogurt, and psyllium have all been described. This mixture is homogenized in a standard blender, ideally committed to this use (Fig. 1). The mixture is filtered through several filtering devices, most frequently gauze, to remove large particles. The filtered liquid is drawn into 60-mL syringes and is ready for immediate use (Fig. 2). Another commonly described technique involves manually stirring the stool and liquid into a mixture and using a syringe to obtain the supernatant, which is typically filtered and ready for available use. Fresh fecal transplant material that is not immediately used may be stored on ice.15 The preparation of frozen specimens has also been described in which the homogenized stool slurry is centrifuged to produce a pellet of fecal material that is resuspended in normal saline and glycerol to produce an odorless, tasteless liquid that can either be placed into capsules or may be frozen at 80 C and thawed when ready
Fecal Microbiota Transplant
Fig. 1. A fecal sample homogenized in normal saline.
to use.20,25,26 The preparation of capsules that are subsequently frozen has also been reported.27 Regardless of the technique used, it has been advised that the donor fecal preparation be prepared using a hood and universal precautions because stool is considered a biosafety level 2 substance.11
Fig. 2. A homogenized fecal sample that has been filtered and distributed into 60-mL syringes and is now ready for transplantation.
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APPROACH AND DELIVERY
How can FMT be delivered? Nasoenteric Tube
In this procedure, a nasoenteric tube is placed with location confirmed on radiography. Once confirmed in place, the liquid fecal suspension is delivered through the tube, which is often followed by a normal saline flush. After administration of the suspension, the nasoenteric tube may be removed immediately. To increase the viability of the donor bacterial flora in the upper gastrointestinal tract, patients commonly receive a proton-pump inhibitor (PPI) the evening before, and on the morning of, the procedure.11 This technique is inexpensive, widely available, and does not require specialty training. However, lower volumes of transplant material are delivered when using the upper gastrointestinal tract to decrease the incidence of adverse effects such as belching or vomiting of fecal material, which the patient may find disturbing. This risk may be increased in patients with impaired bowel motility, and other approaches may be more favorable in this population. In general, lower volumes of transplanted fecal material are associated with a lower efficacy.28 Studies regarding patient attitudes also suggest that this is the least preferred method.29 Upper Endoscopy
Patients undergoing endoscopy usually receive a PPI the evening before, and on the morning of, the procedure.30 The endoscope is advanced past the suspensory muscle of the duodenum, and the fecal material is passed through the endoscope. This procedure still carries a risk of belching, nausea, vomiting, and aspiration, so a smaller amount of transplanted material is used. Upper endoscopy is associated with a higher success rate than administration through a retention enema or nasoenteric tube, but a lower success rate than with use of colonoscopy.31 Retention Enema
In this procedure, the fecal preparation is delivered per the protocol of the specific enema being used, and the patient is instructed to retain the contents for as long as possible, preferably at least 6 hours. Antimotility agents such as loperamide may be given to help assist retention.11 This approach has the advantage of providing direct inoculation of the colon. In addition, the procedure is inexpensive and widely available, with home selfadministration protocols described. Disadvantages such as difficulty retaining stool and reduced efficacy compared with upper and lower endoscopic approaches may necessitate multiple attempts.31 Colonoscopy
To perform an FMT via colonoscopy, a colonoscope is advanced to either the cecum or terminal ileum, and the transplanted material is delivered through the colonoscope. This approach has shown the highest efficacy and allows visualization of the colon to assist in additional diagnosis and bowel preparation as needed.31 This procedure can only be performed by an appropriately trained provider, and is the mostly technically involved and costly delivery route. Patients with severe colitis or significant distension are at higher risk of perforation, and other approaches may be more favorable in this population.
Fecal Microbiota Transplant
Oral Capsules
Patients receiving FMT via oral capsules are instructed to fast for several hours before ingesting the pills and for 1 hour after. Protocols both with and without the use of pretreatment PPI have been described, as have protocols delivering the capsules over 1 or 2 days. The use of oral capsules is the simplest method of ingestion, although the number of pills required (20–30 capsules total) may prove challenging to patients with difficulty swallowing pills. Also, the equipment and capability needed to produce the capsules may exceed the capacity of many health care facilities.20,27 OUTCOMES AND EVIDENCE
How effective is FMT in the treatment of C difficile–associated colitis? Establishing the efficacy of FMT in treating recurrent CDAD is challenging, because there are few well-designed studies on the topic. Five systematic review articles dedicated to the efficacy of FMT in recurrent or refractory CDAD have been published,19,28,31–33 along with 2 randomized controlled trials.16,26 The original systematic review published by Gough and colleagues28 found a promising overall cure rate of 92%, with 89% cure after a single treatment. However, this review did not include any randomized controlled trials. A review by Cammarota and colleagues31 found the overall cure rate in recurrent CDAD to be 87%. Further analysis revealed that the highest cure rates were associated with delivery to the cecum/ascending colon (93%), followed by duodenum/ jejunum (86%), distal colon (84%), and stomach (81%).31 This review included results from a randomized controlled trial that was stopped early after markedly higher success rates were observed in treating recurrent CDAD with FMT (81%) versus oral vancomycin alone (31%) or oral vancomycin with a bowel lavage.16 The most recent systematic review by Drekonja and colleagues,33 including results from 2 randomized controlled trials, found an overall cure rate for recurrent CDAD of 85% and a cure rate for refractory CDAD of 55%. The investigators pointed out that direct comparison studies of FMT with newer antimicrobial dosing practices, such as tapered vancomycin, vancomycin followed by rifaximin, or fidaxomicin, are lacking, making the optimal role of FMT in the treatment of recurrent CDAD unclear.33 How effective is FMT in the treatment of inflammatory bowel disease? Three systematic reviews have evaluated the benefit of FMT in inflammatory bowel disease (IBD).34–36 The first systematic review was published in 2012 and did not contain data from any controlled trials. Limited by reliance on weak data with a risk of publication bias, the investigators found an improvement in symptoms in 76% of patients and also found 63% of patients with no evidence of active disease at follow-up (3–36 months).34 A second systematic review that evaluated outcomes in several digestive and nondigestive disorders, and thus did not specify details on outcomes, reported a 77.8% success rate following FMT. This review included only 1 placebo-controlled trial for pouchitis.35 A third systematic review, which included 9 cohort studies and 1 randomized controlled trial, reported an overall clinical remission of 45% of patients. Rates of mucosal healing were variable between the case studies (75%) and cohort studies (3%). A meta-analysis was also performed as a part of this review and found a
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more modest clinical remission rate of 36.2% with moderate effect heterogeneity. Studies specifically evaluating response in ulcerative colitis showed a clinical remission rate of 22%.36 Note that the randomized controlled trial used in this systematic review was terminated early for futility because the primary end point was unlikely to be achieved. The study found a statistically significant improvement in clinical remission (defined as a full Mayo score <3), but failed to show a significant difference in clinical response (defined as a reduction in Mayo score of at least 3 points), improvement in symptoms, quality of life, or mucosal healing.37 A more recent randomized controlled trial not included in the previous systematic reviews randomized patients with ulcerative colitis to undergo FMT via a healthy donor or autologous stool transplant. Results were evaluated on an intention-to-treat and per-protocol analysis. This trial was also stopped because of futility in reaching the clinical end point of clinical remission and mucosal healing.38 Although initial results regarding the use of FMT in the treatment of IBD were promising, more appropriately designed studies have not been as reassuring. As such, enthusiasm for this intervention should be tempered until more promising results from well-designed trials are seen. What other disorders may benefit from FMT? One systematic review evaluated the efficacy of FMT in several digestive and nondigestive diseases, and found high cure rates for FMT in chronic constipation (100%), irritable bowel syndrome/abdominal pain (93.8%), and metabolic syndrome (100%).35 These results were based on few, small, and uncontrolled studies with high risk of publication bias and should be interpreted with caution until stronger clinical data can more effectively drive clinical decision making. Growing interest is developing regarding the use of FMT in nongastrointestinal diseases. However, this interest is largely based on small numbers of case reports and anecdotal data. Stronger clinical evidence should be produced before the clinical application of FMT to treat nongastrointestinal disease can be appropriately discussed. REDUCING COMPLICATIONS
What are the adverse effects associated with FMT? FMT is well tolerated overall irrespective of the route of administration. Common symptoms following FMT include abdominal pain, bloating, flatulence, belching, gurgling bowel sounds, increased feelings of gaseousness, nausea, vomiting, and bowel abnormalities; however, these symptoms are self-limited and generally resolve within several hours.15,39 No serious adverse events have been directly attributable to the transplanted fecal material. A recent systematic review reported an all-cause mortality of 3.4% (n 5 35) for patients undergoing FMT, although most (n 5 29) seem to be of unknown cause or apparently unrelated to FMT.39 One death attributable to FMT occurred as a result of aspiration during sedation for a planned colonoscopic FMT.40 Another patient died 3 days following FMT from peritonitis that might have been related to FMT, although the patient was already severely ill and was undergoing peritoneal dialysis for endstage renal disease at the time of the procedure.41 In one long-term follow-up study, 4 patients out of 77 developed an autoimmune disease at some point following the FMT, although a relationship to the FMT was
Fecal Microbiota Transplant
not established, and autoimmune conditions as a result of FMT have not been observed in additional studies.15 Patients with IBD also had no reported serious adverse effects related to the transplanted fecal material, although fever, increased risk of disease flare, increased C-reactive protein level, and abdominal tenderness have been observed.36 One patient also developed pancreatitis of unclear cause during the follow-up period, although it is unclear whether this was related to his FMT.42 Immunosuppression has previously been used as an exclusion criterion in some studies.15 However, FMT has been performed in patients with human immunodeficiency virus/acquired immunodeficiency syndrome, end-stage chronic medical conditions, and solid organ transplants, as well as in patients on immunosuppressive medications or on antineoplastic agents for cancer.43 Transmission of infectious agents has never been documented in either immunosuppressed or immunocompetent patients, further supporting the safety of FMT.43 PERFORMANCE IMPROVEMENT
How can hospitalists use FMT in their practice? The Infectious Disease Society of America (IDSA) guidelines on recurrent CDAD advise that treatment of a first recurrence should be with the same antibiotic used to treat the first episode of CDAD (usually oral metronidazole or vancomycin), unless clinical severity dictates otherwise. In addition, tapered or pulsed courses of vancomycin are recommended for second recurrences.44 Because FMT has never been studied in a head-to-head trial against a prolonged vancomycin taper in patients with their first recurrence of CDAD, its appropriateness in this setting is poorly defined. However, patients who have completed a prolonged taper of vancomycin, or other standard therapy for recurrent CDAD as defined by the IDSA, and who experience an additional recurrence, or patients who fail to respond at all, should be evaluated by a provider comfortable in performing FMT because it has been shown to be safe, effective, and deliverable in a wide array of clinical settings, including the inpatient setting. Use of FMT for any other clinical scenario requires an investigational new drug application through the FDA, which is beyond the standard scope of practice of most providers. CLINICAL GUIDELINES
Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431–55. REFERENCES
1. Zhang F, Luo W, Shi Y, et al. Should we standardize the 1700-year-old-fecal microbiota transplantation? Am J Gastroenterol 2012;107:1755. 2. Eiseman B, Silen W, Bascom G, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854–9. 3. Schwan A, Sjolin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983;2:845. 4. Chang J, Antonopoulos D, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197(3):435–8.
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5. Fuentes S, van Nood E, Tims S, et al. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection. ISME J 2014;8(8):1621–33. 6. Seekatz A, Aas J, Gessert C, et al. Recovery of the gut microbiome following fecal microbiota transplantation. MBio 2014;5(3). e00893–14. 7. Hamilton M, Weingarden A, Unno T, et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013;4(2):125–35. 8. Shahinas D, Silverman M, Sittler T, et al. Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing. MBio 2012;3(5):e00338–12. 9. Weingarden A, Gonza´lez A, Va´zquez-Baeza Y, et al. Dynamic changes in shortand long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 2015;30(3):10. 10. Song Y, Garg S, Girotra M, et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One 2013;8(11):e81330. 11. Bakken J, Borody T, Brandt L, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9(12): 1044–9. 12. US 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. US Department of Health and Human Services; 2013. Availabe at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatory Information/Guidances/Vaccines/ucm361379.htm. 13. Gweon T, Lee K, Kang D, et al. A case of toxic megacolon caused by Clostridium difficile infection and treated with fecal microbiota transplantation. Gut Liver 2015; 9(2):247–50. 14. US 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. US Department of Health and Human Services; 2014. Available at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatory Information/Guidances/Vaccines/ucm387023.htm. 15. Brandt L, Aroniadis O, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplantation for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079–87. 16. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal Infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15. 17. van Nood E, Speelman P, Nieuwdorp M, et al. Fecal microbiota transplantation: facts and controversies. Curr Opin Gastroenterol 2014;30(1):34–9. 18. Brandt L, Aroniadis O. An overview of fecal microbiota transplantation: techniques, indications and outcomes. Gastrointest Endosc 2013;78(2):240–9. 19. Dodin M, Katz DE. Faecal microbiota transplantation for Clostridium difficile infection. Int J Clin Pract 2014;68(3):363–8. 20. Hirsch B, 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(1):191. 21. Lo Vecchio A, Cohen M. Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers. Curr Opin Gastroenterol 2014;30(1):47–53.
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22. Mattila E, Uusitalo-Seppa¨la¨ R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective for recurrent Clostridium difficile infection. Gastroenterology 2012;142(3):490–6. 23. Rao K, Young VB. Fecal microbiota transplantation for the management of Clostridium difficile infection. Infect Dis Clin North Am 2015;29(1):109–22. 24. Patel N, Griesbach C, DiBaise J, et al. Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona experience. Mayo Clin Proc 2013;88(8):799–805. 25. Hamilton M, Weingarden A, Sadowsky M, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107(5):761–7. 26. 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(11): 1515–22. 27. Youngster I, Russell G, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312(17): 1772–8. 28. Gough E, Shaikh H, Manges A. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53(10):994–1002. 29. Zipursky J, Sidorsky T, Freedman C, et al. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis 2012 Dec;55(12):1652–8. 30. Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol 2012;5(6):403–20. 31. Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48(8): 693–702. 32. Kassam Z, Lee C, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108(4):500–8. 33. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162(9):630–8. 34. Anderson J, Edney R, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharacol Ther 2012;36(6):503–16. 35. Sha S, Liang J, Chen M, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther 2014;39(10):1003–32. 36. Colman R, Rubin D. Fecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2014;8(12):1569–81. 37. Moayyedi P, Surete M, Kim P, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015;149(1):102–9. 38. Rossen N, Fuentes S, van der Spek M, et al. Findings from a randomized trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 2015; 149(1):110–8.e4. 39. Rossen N, MacDonald J, de Vries E, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: a systematic review. World J Gastroenterol 2015;21(17):5359–71.
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40. Kelly C, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109(7):1065–71. 41. Aas J, Gessert C, Bakken J. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with stool administered via nasogastric tube. Clin Infect Dis 2003;36(5):580–5. 42. Angelberger S, Reinish W, Lichtenberger C, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol 2013;108(10):1620–30. 43. Di Bella S, Gouliouris T, Petrosillo N. Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother 2015;21(4):230–7. 44. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431–55.
MD
a,b,
*
KEYWORDS Fecal microbiota transplant Stool therapy Clostridium difficile Recurrent Clostridium difficile Clostridium difficile–associated diarrhea Inflammatory bowel disease
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Clostridium difficile–associated diarrhea is a growing problem, and traditional antimicrobial therapy is associated with a high rate of recurrence. 2. Recurrent C difficile–associated diarrhea can be difficult to treat and repeat recurrences are common. 3. Fecal microbiota transplant can be administered by the use of several techniques and is associated with a high cure rate for recurrent and refractory C difficile–associated diarrhea. 4. Stool donors should undergo comprehensive testing to avoid the transmission of infectious agents during the transplant. 5. Adverse effects of fecal microbiota transplant are nonserious, well tolerated, and typically resolve within a few hours. 6. Patients whose recurrent C difficile–associated diarrhea fails to respond to fidaxomicin or a prolonged taper of oral vancomycin should be evaluated by a provider comfortable in performing fecal microbiota transplant. 7. More studies are needed to determine the role of fecal microbiota transplant in inflammatory bowel disease and other gastrointestinal and nongastrointestinal disorders.
Disclosure: Dr R. Vestal has no conflicts of interest or funding sources to disclose. a Presbyterian Hospital, 1100 Central Avenue SE, Albuquerque, NM 87106, USA; b Hospital Medicine Section, Division of General Internal Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Leprino Building, 4th Floor, Mailstop F-782, 12401 East 17th Avenue, Aurora, CO 80045, USA * Presbyterian Hospital, 1100 Central Avenue SE, Albuquerque, NM 87106. E-mail address: [email protected] Hosp Med Clin 5 (2016) 58–70 http://dx.doi.org/10.1016/j.ehmc.2015.08.006 2211-5943/16/$ – see front matter Ó 2016 Published by Elsevier Inc.
Fecal Microbiota Transplant
HISTORY IN MEDICINE
When was fecal microbiota transplant (FMT) first used? Although often considered an emerging therapy, the first known use of FMT dates to fourth century China, where Ge Hong, a practitioner with the Dong Jin dynasty, used ingested human fecal suspensions to treat ailments such as food poisoning and severe diarrhea.1 In sixteenth century China, Li Shizhen, a physician with the Ming dynasty, described the use of what he called yellow soup and other more palatablesounding names to treat several gastrointestinal illnesses.1 The first documented modern use of FMT in treating human disease was in 1958 at the University of Colorado, where donor stool was administered via a retention enema to successfully treat 4 patients with pseudomembranous enterocolitis caused by Micrococcus pyogenes.2 The first documented use of FMT to treat Clostridium difficile–associated diarrhea (CDAD) was in 1983, when a woman who experienced 5 relapses despite oral vancomycin was cured after undergoing the procedure.3 In more recent years, renewed use of FMT has led to the development of new preparation and delivery techniques as well as interest in its potential role in managing other gastrointestinal and nongastrointestinal disorders. What is the mechanism of action of FMT? The gut microbiome is composed primarily of 4 bacterial phyla; Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria, each with diverse genera.4 Normal healthy patients and patients with only 1 prior episode of CDAD tend to have a predominance of Bacteroidetes and Firmicutes.4 Patients with recurrent CDAD tend to have increased Proteobacteria and decreased Bacteroidetes with less abundant Firmicutes species in addition to an overall decreased richness and diversity of their microbiota.4 Regardless of route, FMT results an increased abundance of both Bacteroidetes and Firmicutes, a decrease in Proteobacteria, and an overall increased richness and diversity comparable with healthy people.5–10 These findings suggest that microbiome diversity creates colonization resistance and that the disturbance of the normal microbial flora, for instance by the use of antimicrobial therapy, may allow the overgrowth of harmful organisms that can contribute to disease. The aim of FMT is to restore the normal microbial flora in hopes of reversing or preventing the resultant disease processes, although the exact relationship between microbiota and the pathogenesis of disease has yet to be fully defined.
EPIDEMIOLOGY
What is driving the renewed interest in FMT? The increasing frequency of CDAD and its high recurrence rates with standard therapy for both initial (15%–30%) and recurrent (65%) disease is associated with increasing health care costs. As antimicrobial resistance to standard CDAD therapies increases, FMT may be a safe and effective intervention to improve patient outcomes and decrease the costs associated with recurrent CDAD. In addition, curiosity in the expanding role of FMT has been piqued with the growth of data showing gut microbiome disturbances in various disease processes.11
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INDICATIONS/CONTRAINDICATIONS
What are the indications and contraindications for FMT? There are currently no US Food and Drug Administration (FDA)–approved indications for FMT because it is considered an investigational new drug; however, according to an FDA statement in July 2013, health care providers may bypass the investigational new drug application process if informed consent is obtained and if FMT is used for the purpose of treating CDAD not responsive to standard therapies.12 As such, Box 1 outlines suggested indications by Bakken and colleagues. Note that although case reports have described success in treating toxic megacolon with FMT,13 this indication has not been well studied in randomized trials. Although not currently implemented, the FDA has drafted an updated statement that would require that transplanted product be obtained from a donor known either to the patient or to the health care provider.14 No absolute contraindications exist that would prohibit a patient from receiving FMT.
PATIENT AND DONOR PREPARATION
How are fecal donors selected? Family members or close contacts are often identified as donors for FMT.15 It is theorized that they share similar infectious risk factors with the patient and are thus less likely to transmit an infectious agent. This consideration may be important in patients with an urgent need for FMT whose clinical course does not facilitate the time needed to perform the necessary donor testing (described later).11 However, embarrassment in asking close contacts to donate stool, unwillingness of close contacts to donate, and lack of potential donors identified by patients may limit this approach. Study protocols have also described using healthy anonymous donors,16 which could potentially allow more rapid acquisition of stool for FMT because these patients would theoretically be able to undergo less frequent testing, although it remains unclear exactly how often these donor pools should undergo testing. As fecal microbiota preparation and storage techniques evolve, healthy donor pools may increase the availability and rapidity of this procedure. As with all tissue and organ donations, transmitting an infectious agent to the recipient is of high concern. Donors should be evaluated with a thorough history and physical to determine their infectious risk. A questionnaire for this purpose is available
Box 1 Suggested indications for FMT At least 3 episodes of mild to moderate CDAD and failure of a 6-week to 8-week taper with vancomycin with or without an alternative antibiotic At least 2 episodes of severe CDAD resulting in hospitalization and associated with significant morbidity Moderate CDAD not responding to standard therapy for at least a week Severe or fulminant CDAD with no response to standard therapy after 48 hours
Fecal Microbiota Transplant
online at http://apps.umchealthsystem.com/forphysicians/medicalorders/Fecal% 20Microbiota%20Transplant%20Donor%20Questionnaire.pdf. Although little evidence exists to support the practice, infectious disease testing of the donor is commonly performed. Boxes 2 and 3 represent a comprehensive list of infectious agents for which providers may test, although specific protocols may vary by institution.11,17–21 What preparations are necessary for the donor? Donors are instructed to notify the practitioner if any symptoms suggestive of an infection develop between the time of initial screening and that of donation, and they should avoid any food the recipient may have an allergy to for at least 5 days before the procedure.11 A mild osmotic laxative taken the evening before the procedure may assist in reliable bowel evacuation the following morning.19 What preparations are necessary for the recipient? When used in the management of recurrent CDAD, pretreatment antibiotics, typically oral vancomycin or metronidazole, are provided to the patient until symptoms are reduced.22 Antibiotics are held 24 to 72 hours before the procedure.15,23 Although not universally practiced for all upper gastrointestinal routes of FMT, it has been
Box 2 Serologic screening tests for donors Complete blood count Liver function tests Cytomegalovirus Immunoglobulin (Ig) M and IgG antibodies Epstein-Barr virus Viral capsid antigen (VCA) IgM VCA IgG Epstein-Barr virus nuclear antigen (EBNA) IgG Hepatitis A virus IgM antibody Hepatitis B virus Surface antigen and antibody Core IgM and IgG antibodies Human immunodeficiency virus (HIV) HIV1 and HIV2 antibodies Human T-lymphotropic virus Human T-lymphotropic virus I and II antibodies Treponema pallidum Rapid plasma reagin Entamoeba histolytica Latex agglutination test Dipstick assay Strongyloides stercoralis IgG antibody
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Box 3 Stool screening tests for donors Bacterial culture To include: Salmonella species Shigella species Escherichia coli O157:H7 Yersinia enterocolitica Campylobacter species Vibrio species Aeromonas species Plesiomonas Ova and parasites C difficile Toxin enzyme-linked immunosorbent assay Polymerase chain reaction Giardia lamblia antigen Cryptosporidium antigen Acid-fast staining Cyclospora species Isospora species Cryptosporidium species (if unable to test for antigen) Microsporidia species antigen Helicobacter pylori antigen Rotavirus antigen
recommended that all patients should receive a large bowel lavage, similar to that given before a colonoscopy, before the procedure.11 PREPROCEDURE PREPARATION
How is the fecal material prepared? Several techniques have described the preparation of donor stool.11,16,22–24 Although minor differences exist between the protocols, the general approaches are similar. Typically, at least 50 g of stool are placed in a liquid, which is typically sterile normal saline, although bottled water, tap water, milk, yogurt, and psyllium have all been described. This mixture is homogenized in a standard blender, ideally committed to this use (Fig. 1). The mixture is filtered through several filtering devices, most frequently gauze, to remove large particles. The filtered liquid is drawn into 60-mL syringes and is ready for immediate use (Fig. 2). Another commonly described technique involves manually stirring the stool and liquid into a mixture and using a syringe to obtain the supernatant, which is typically filtered and ready for available use. Fresh fecal transplant material that is not immediately used may be stored on ice.15 The preparation of frozen specimens has also been described in which the homogenized stool slurry is centrifuged to produce a pellet of fecal material that is resuspended in normal saline and glycerol to produce an odorless, tasteless liquid that can either be placed into capsules or may be frozen at 80 C and thawed when ready
Fecal Microbiota Transplant
Fig. 1. A fecal sample homogenized in normal saline.
to use.20,25,26 The preparation of capsules that are subsequently frozen has also been reported.27 Regardless of the technique used, it has been advised that the donor fecal preparation be prepared using a hood and universal precautions because stool is considered a biosafety level 2 substance.11
Fig. 2. A homogenized fecal sample that has been filtered and distributed into 60-mL syringes and is now ready for transplantation.
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APPROACH AND DELIVERY
How can FMT be delivered? Nasoenteric Tube
In this procedure, a nasoenteric tube is placed with location confirmed on radiography. Once confirmed in place, the liquid fecal suspension is delivered through the tube, which is often followed by a normal saline flush. After administration of the suspension, the nasoenteric tube may be removed immediately. To increase the viability of the donor bacterial flora in the upper gastrointestinal tract, patients commonly receive a proton-pump inhibitor (PPI) the evening before, and on the morning of, the procedure.11 This technique is inexpensive, widely available, and does not require specialty training. However, lower volumes of transplant material are delivered when using the upper gastrointestinal tract to decrease the incidence of adverse effects such as belching or vomiting of fecal material, which the patient may find disturbing. This risk may be increased in patients with impaired bowel motility, and other approaches may be more favorable in this population. In general, lower volumes of transplanted fecal material are associated with a lower efficacy.28 Studies regarding patient attitudes also suggest that this is the least preferred method.29 Upper Endoscopy
Patients undergoing endoscopy usually receive a PPI the evening before, and on the morning of, the procedure.30 The endoscope is advanced past the suspensory muscle of the duodenum, and the fecal material is passed through the endoscope. This procedure still carries a risk of belching, nausea, vomiting, and aspiration, so a smaller amount of transplanted material is used. Upper endoscopy is associated with a higher success rate than administration through a retention enema or nasoenteric tube, but a lower success rate than with use of colonoscopy.31 Retention Enema
In this procedure, the fecal preparation is delivered per the protocol of the specific enema being used, and the patient is instructed to retain the contents for as long as possible, preferably at least 6 hours. Antimotility agents such as loperamide may be given to help assist retention.11 This approach has the advantage of providing direct inoculation of the colon. In addition, the procedure is inexpensive and widely available, with home selfadministration protocols described. Disadvantages such as difficulty retaining stool and reduced efficacy compared with upper and lower endoscopic approaches may necessitate multiple attempts.31 Colonoscopy
To perform an FMT via colonoscopy, a colonoscope is advanced to either the cecum or terminal ileum, and the transplanted material is delivered through the colonoscope. This approach has shown the highest efficacy and allows visualization of the colon to assist in additional diagnosis and bowel preparation as needed.31 This procedure can only be performed by an appropriately trained provider, and is the mostly technically involved and costly delivery route. Patients with severe colitis or significant distension are at higher risk of perforation, and other approaches may be more favorable in this population.
Fecal Microbiota Transplant
Oral Capsules
Patients receiving FMT via oral capsules are instructed to fast for several hours before ingesting the pills and for 1 hour after. Protocols both with and without the use of pretreatment PPI have been described, as have protocols delivering the capsules over 1 or 2 days. The use of oral capsules is the simplest method of ingestion, although the number of pills required (20–30 capsules total) may prove challenging to patients with difficulty swallowing pills. Also, the equipment and capability needed to produce the capsules may exceed the capacity of many health care facilities.20,27 OUTCOMES AND EVIDENCE
How effective is FMT in the treatment of C difficile–associated colitis? Establishing the efficacy of FMT in treating recurrent CDAD is challenging, because there are few well-designed studies on the topic. Five systematic review articles dedicated to the efficacy of FMT in recurrent or refractory CDAD have been published,19,28,31–33 along with 2 randomized controlled trials.16,26 The original systematic review published by Gough and colleagues28 found a promising overall cure rate of 92%, with 89% cure after a single treatment. However, this review did not include any randomized controlled trials. A review by Cammarota and colleagues31 found the overall cure rate in recurrent CDAD to be 87%. Further analysis revealed that the highest cure rates were associated with delivery to the cecum/ascending colon (93%), followed by duodenum/ jejunum (86%), distal colon (84%), and stomach (81%).31 This review included results from a randomized controlled trial that was stopped early after markedly higher success rates were observed in treating recurrent CDAD with FMT (81%) versus oral vancomycin alone (31%) or oral vancomycin with a bowel lavage.16 The most recent systematic review by Drekonja and colleagues,33 including results from 2 randomized controlled trials, found an overall cure rate for recurrent CDAD of 85% and a cure rate for refractory CDAD of 55%. The investigators pointed out that direct comparison studies of FMT with newer antimicrobial dosing practices, such as tapered vancomycin, vancomycin followed by rifaximin, or fidaxomicin, are lacking, making the optimal role of FMT in the treatment of recurrent CDAD unclear.33 How effective is FMT in the treatment of inflammatory bowel disease? Three systematic reviews have evaluated the benefit of FMT in inflammatory bowel disease (IBD).34–36 The first systematic review was published in 2012 and did not contain data from any controlled trials. Limited by reliance on weak data with a risk of publication bias, the investigators found an improvement in symptoms in 76% of patients and also found 63% of patients with no evidence of active disease at follow-up (3–36 months).34 A second systematic review that evaluated outcomes in several digestive and nondigestive disorders, and thus did not specify details on outcomes, reported a 77.8% success rate following FMT. This review included only 1 placebo-controlled trial for pouchitis.35 A third systematic review, which included 9 cohort studies and 1 randomized controlled trial, reported an overall clinical remission of 45% of patients. Rates of mucosal healing were variable between the case studies (75%) and cohort studies (3%). A meta-analysis was also performed as a part of this review and found a
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more modest clinical remission rate of 36.2% with moderate effect heterogeneity. Studies specifically evaluating response in ulcerative colitis showed a clinical remission rate of 22%.36 Note that the randomized controlled trial used in this systematic review was terminated early for futility because the primary end point was unlikely to be achieved. The study found a statistically significant improvement in clinical remission (defined as a full Mayo score <3), but failed to show a significant difference in clinical response (defined as a reduction in Mayo score of at least 3 points), improvement in symptoms, quality of life, or mucosal healing.37 A more recent randomized controlled trial not included in the previous systematic reviews randomized patients with ulcerative colitis to undergo FMT via a healthy donor or autologous stool transplant. Results were evaluated on an intention-to-treat and per-protocol analysis. This trial was also stopped because of futility in reaching the clinical end point of clinical remission and mucosal healing.38 Although initial results regarding the use of FMT in the treatment of IBD were promising, more appropriately designed studies have not been as reassuring. As such, enthusiasm for this intervention should be tempered until more promising results from well-designed trials are seen. What other disorders may benefit from FMT? One systematic review evaluated the efficacy of FMT in several digestive and nondigestive diseases, and found high cure rates for FMT in chronic constipation (100%), irritable bowel syndrome/abdominal pain (93.8%), and metabolic syndrome (100%).35 These results were based on few, small, and uncontrolled studies with high risk of publication bias and should be interpreted with caution until stronger clinical data can more effectively drive clinical decision making. Growing interest is developing regarding the use of FMT in nongastrointestinal diseases. However, this interest is largely based on small numbers of case reports and anecdotal data. Stronger clinical evidence should be produced before the clinical application of FMT to treat nongastrointestinal disease can be appropriately discussed. REDUCING COMPLICATIONS
What are the adverse effects associated with FMT? FMT is well tolerated overall irrespective of the route of administration. Common symptoms following FMT include abdominal pain, bloating, flatulence, belching, gurgling bowel sounds, increased feelings of gaseousness, nausea, vomiting, and bowel abnormalities; however, these symptoms are self-limited and generally resolve within several hours.15,39 No serious adverse events have been directly attributable to the transplanted fecal material. A recent systematic review reported an all-cause mortality of 3.4% (n 5 35) for patients undergoing FMT, although most (n 5 29) seem to be of unknown cause or apparently unrelated to FMT.39 One death attributable to FMT occurred as a result of aspiration during sedation for a planned colonoscopic FMT.40 Another patient died 3 days following FMT from peritonitis that might have been related to FMT, although the patient was already severely ill and was undergoing peritoneal dialysis for endstage renal disease at the time of the procedure.41 In one long-term follow-up study, 4 patients out of 77 developed an autoimmune disease at some point following the FMT, although a relationship to the FMT was
Fecal Microbiota Transplant
not established, and autoimmune conditions as a result of FMT have not been observed in additional studies.15 Patients with IBD also had no reported serious adverse effects related to the transplanted fecal material, although fever, increased risk of disease flare, increased C-reactive protein level, and abdominal tenderness have been observed.36 One patient also developed pancreatitis of unclear cause during the follow-up period, although it is unclear whether this was related to his FMT.42 Immunosuppression has previously been used as an exclusion criterion in some studies.15 However, FMT has been performed in patients with human immunodeficiency virus/acquired immunodeficiency syndrome, end-stage chronic medical conditions, and solid organ transplants, as well as in patients on immunosuppressive medications or on antineoplastic agents for cancer.43 Transmission of infectious agents has never been documented in either immunosuppressed or immunocompetent patients, further supporting the safety of FMT.43 PERFORMANCE IMPROVEMENT
How can hospitalists use FMT in their practice? The Infectious Disease Society of America (IDSA) guidelines on recurrent CDAD advise that treatment of a first recurrence should be with the same antibiotic used to treat the first episode of CDAD (usually oral metronidazole or vancomycin), unless clinical severity dictates otherwise. In addition, tapered or pulsed courses of vancomycin are recommended for second recurrences.44 Because FMT has never been studied in a head-to-head trial against a prolonged vancomycin taper in patients with their first recurrence of CDAD, its appropriateness in this setting is poorly defined. However, patients who have completed a prolonged taper of vancomycin, or other standard therapy for recurrent CDAD as defined by the IDSA, and who experience an additional recurrence, or patients who fail to respond at all, should be evaluated by a provider comfortable in performing FMT because it has been shown to be safe, effective, and deliverable in a wide array of clinical settings, including the inpatient setting. Use of FMT for any other clinical scenario requires an investigational new drug application through the FDA, which is beyond the standard scope of practice of most providers. CLINICAL GUIDELINES
Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431–55. REFERENCES
1. Zhang F, Luo W, Shi Y, et al. Should we standardize the 1700-year-old-fecal microbiota transplantation? Am J Gastroenterol 2012;107:1755. 2. Eiseman B, Silen W, Bascom G, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854–9. 3. Schwan A, Sjolin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983;2:845. 4. Chang J, Antonopoulos D, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197(3):435–8.
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5. Fuentes S, van Nood E, Tims S, et al. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection. ISME J 2014;8(8):1621–33. 6. Seekatz A, Aas J, Gessert C, et al. Recovery of the gut microbiome following fecal microbiota transplantation. MBio 2014;5(3). e00893–14. 7. Hamilton M, Weingarden A, Unno T, et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013;4(2):125–35. 8. Shahinas D, Silverman M, Sittler T, et al. Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing. MBio 2012;3(5):e00338–12. 9. Weingarden A, Gonza´lez A, Va´zquez-Baeza Y, et al. Dynamic changes in shortand long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 2015;30(3):10. 10. Song Y, Garg S, Girotra M, et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One 2013;8(11):e81330. 11. Bakken J, Borody T, Brandt L, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9(12): 1044–9. 12. US 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. US Department of Health and Human Services; 2013. Availabe at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatory Information/Guidances/Vaccines/ucm361379.htm. 13. Gweon T, Lee K, Kang D, et al. A case of toxic megacolon caused by Clostridium difficile infection and treated with fecal microbiota transplantation. Gut Liver 2015; 9(2):247–50. 14. US 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. US Department of Health and Human Services; 2014. Available at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatory Information/Guidances/Vaccines/ucm387023.htm. 15. Brandt L, Aroniadis O, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplantation for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079–87. 16. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal Infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15. 17. van Nood E, Speelman P, Nieuwdorp M, et al. Fecal microbiota transplantation: facts and controversies. Curr Opin Gastroenterol 2014;30(1):34–9. 18. Brandt L, Aroniadis O. An overview of fecal microbiota transplantation: techniques, indications and outcomes. Gastrointest Endosc 2013;78(2):240–9. 19. Dodin M, Katz DE. Faecal microbiota transplantation for Clostridium difficile infection. Int J Clin Pract 2014;68(3):363–8. 20. Hirsch B, 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(1):191. 21. Lo Vecchio A, Cohen M. Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers. Curr Opin Gastroenterol 2014;30(1):47–53.
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22. Mattila E, Uusitalo-Seppa¨la¨ R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective for recurrent Clostridium difficile infection. Gastroenterology 2012;142(3):490–6. 23. Rao K, Young VB. Fecal microbiota transplantation for the management of Clostridium difficile infection. Infect Dis Clin North Am 2015;29(1):109–22. 24. Patel N, Griesbach C, DiBaise J, et al. Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona experience. Mayo Clin Proc 2013;88(8):799–805. 25. Hamilton M, Weingarden A, Sadowsky M, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107(5):761–7. 26. 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(11): 1515–22. 27. Youngster I, Russell G, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312(17): 1772–8. 28. Gough E, Shaikh H, Manges A. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53(10):994–1002. 29. Zipursky J, Sidorsky T, Freedman C, et al. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis 2012 Dec;55(12):1652–8. 30. Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol 2012;5(6):403–20. 31. Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48(8): 693–702. 32. Kassam Z, Lee C, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108(4):500–8. 33. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162(9):630–8. 34. Anderson J, Edney R, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharacol Ther 2012;36(6):503–16. 35. Sha S, Liang J, Chen M, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther 2014;39(10):1003–32. 36. Colman R, Rubin D. Fecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2014;8(12):1569–81. 37. Moayyedi P, Surete M, Kim P, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015;149(1):102–9. 38. Rossen N, Fuentes S, van der Spek M, et al. Findings from a randomized trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 2015; 149(1):110–8.e4. 39. Rossen N, MacDonald J, de Vries E, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: a systematic review. World J Gastroenterol 2015;21(17):5359–71.
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40. Kelly C, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109(7):1065–71. 41. Aas J, Gessert C, Bakken J. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with stool administered via nasogastric tube. Clin Infect Dis 2003;36(5):580–5. 42. Angelberger S, Reinish W, Lichtenberger C, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol 2013;108(10):1620–30. 43. Di Bella S, Gouliouris T, Petrosillo N. Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother 2015;21(4):230–7. 44. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431–55.