Nuts and Bolts of Fecal Microbiota Transplantation

Nuts and Bolts of Fecal Microbiota Transplantation

Clinical Gastroenterology and Hepatology 2018;-:-–- 1 2 3 4 5 6 7 Q10 8 Q1 9 Q2 10 11 12 13Q5 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 3...

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Nuts and Bolts of Fecal Microbiota Transplantation Edward Krajicek, Monika Fischer, Jessica R. Allegretti, and Colleen R. Kelly Alpert Medical School, Brown University, Providence, Rhode Island ---

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he gut microbiome has become a hot topic in both the scientific literature and the lay press. It has been postulated that the microbiome may have pathologic, diagnostic, and therapeutic implications in a spectrum of disorders from irritable bowel syndrome (IBS) to neuropsychiatric disease.1,2 Arguably the best example of harnessing the gut microbiota to cure disease is the use of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection (CDI), where robust evidence for use of FMT has shifted the treatment paradigm.3 The first report of FMT for the treatment of pseudomembranous colitis was published in 1958,4 though nearly 30 years passed before another case series described installation of donor stool by enema for treatment of CDI.5 Over the past decade, coinciding with the rising incidence in CDI and our growing understanding of the human gut microbiome, FMT has become a widely used and accepted therapy for recurrent and refractory infections. While CDI directed antimicrobials are first-line therapy, they are a double-edged sword, perpetuating the antibiotic-induced dysbiosis that promotes CDI. It is well described that commensal microbiota play an important role in inhibiting harmful pathogens via competition for niche and nutrients, production of bactericidal products and alteration of the bile acid milieu.6,7 Our current mechanistic understanding of FMT emphasizes restoration of diversity, function, and health of the commensal microbiota.8–11

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Efficacy and Safety Data Initial evidence, based on retrospective series, showed an efficacy rate of 89%.8 Randomized controlled trials have since confirmed the superior efficacy of FMT for CDI compared with both standard therapies and placebo.12–15 The most recent systematic review and meta-analysis looking at patients with recurrent and refractory CDI showed a clinical resolution rate of 92% with a relative risk of 0.23 when compared with vancomycin.3 FMT provides not only superior efficacy compared with other therapies for recurrent CDI but it is

also more cost-effective.16,17 Furthermore, FMT appears safe, with few reports of short-term serious adverse events, although potential long-term sequelae are yet unknown. The Fecal Microbiota Transplant National Registry, a venture led by the American Gastroenterology Association and funded by the National Institutes of Health, aims to follow 4000 FMT recipients for up to 10 years and will provide robust real world efficacy data as well as short- and long-term safety outcomes (grant number 1R24A118629-01A1).

Developing an FMT Toolbox FMT has been defined as the transfer of distal gut microbial communities from a healthy individual to a patient’s intestinal tract to cure a disease.18 The procedure is not complicated, but a recent survey showed that 80% of physicians have concerns around the logistics of stool preparation or delivery, while nearly half named complexity and cost of donor screening as the main barrier to providing FMT.19 The availability of screened donor material from stool banks has enabled centers to deliver FMT more efficiently and has increased the availability of the procedure to patients. However, it is important to implement current guidelines and best practices into FMT protocols and policies. To aid practitioners and hospitals in the development of safe FMT treatment protocols, we propose here a logical and practical “nuts and bolts” approach to FMT. We discuss various stool preparation and delivery methods, and their advantages and shortcomings. We also share the challenges we have faced and lessons we learned along the way at our FMT centers. The 5D FMT framework (a concept our group has published previously in Gastrointestinal Endoscopy)20 includes decision (selecting appropriate patient for FMT), donor (selection and screening), discussion (risk, benefits, alternatives), delivery (selecting appropriate modality for FMT administration), and discharge Abbreviations used in this paper: CDI, Clostridium difficile infection; FDA, Food and Drug Administration; FMT, fecal microbiota transplantation; GI, gastrointestinal; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IDSA, Infectious Disease Society of America; PCR, polymerase chain reaction. © 2018 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.09.029

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175 176 177 178 179 180 181 182 183 Figure 1. Fecal microbiota 184 transplantation (FMT) 185 toolbox. CPT, ; EGD, Q7 186 . 187 188 189 confirmatory test with enzyme immunoassay for toxin 190 A/B (high positive predictive value).31 The recently 191 published guidelines from the IDSA support this recom192 mendation, in particular, when institutional standard 193 procedure for stool testing is lacking.25 Positive PCR 194 tests in patients without the typical clinical picture may 195 suggest colonization rather than acute infection. In these 196 cases, symptom correlation with testing results and 197 response to previous anti-CDI therapies can help distin198 guish colonization from active infection. Historical fac199 tors which should alert to the possibility of an alternative 200 diagnosis include ongoing diarrhea despite negative stool 201 studies, intermittent or nonprogressive symptoms while 202 off anti-CDI therapy, and minimal or no response to 203 vancomycin or fidaxomicin.32 Younger patients are more 204 likely to have an alternative cause for diarrhea, most 205 commonly postinfectious IBS, and colonoscopic FMT 206 delivery is favored in patients who have not had recent 207 endoscopy to rule out underlying inflammatory bowel 208 disease (IBD).32,33 209 FMT appears safe in immunocompromised patients 210 including patients on biologic therapy, organ transplant 211 recipients, and those with decompensated cirrhosis and 212 end-stage kidney disease.34 However, there are a lack of 213 data on safety in patients with severe neutropenia 214 (absolute neutrophil cell count <500/mL); therefore, risk 215 vs benefit of FMT must be carefully considered in this 216 population. Finally, the procedure has not been 35 217 adequately studied in pregnancy and should be 218 delayed until the patient is postpartum. 219 220 Donor Selection 221 222 223 There are 2 approaches to donor selection, patient224 directed or universal donor. When a patient selects a 225 donor, usually a family member or friend donates to a 226 single recipient. A universal donor is typically unknown 227 to the patient and donates to multiple individuals. In the 228 stool bank model, the screening of universal donors and 229 stool processing are centralized and the stool is stored 230 for future use. 231 Both methods should employ an intensive screening 232 process, including donor informed consent.20 The donor print & web 4C=FPO

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(counseling at discharge and follow-up) (Figure 1). This so-called FMT Toolbox will provide a framework through which to review the nuts and bolts of performing FMT.

Decision: Selecting the Right Patient for FMT The indications for FMT were initially defined by a working group formed by gastroenterologists and infectious disease specialists. These included patients with >3 recurrences, 2 previous episodes requiring hospitalization, severe disease without response to antiCDI therapy at 48 hours, or moderate CDI without response by 5 days.21,22 In our experience, patients who do not respond to oral vancomycin or fidaxomicin therapy by day 5, either have severe CDI or an alternative cause of their diarrhea. American College of Gastroenterology C. difficile guidelines recommend FMT for the treatment of third recurrence,23 while the European FMT consensus makes a strong recommendation for treatment of all recurrent CDI based on efficacy and shortterm safety.24 The recently published Infectious Disease Society of America (IDSA) guidelines agree with consideration of FMT for recurrent infection.25 Additionally, while randomized trials are needed, the evidence for FMT in severe and fulminant CDI is compelling. Fischer et al and others have demonstrated high cure rates in severe and complicated CDI applying sequential FMT protocols.26–30 Before offering an FMT, the practitioner should confirm that the CDI diagnosis is correct and that the patient’s symptoms are indeed caused by CDI. Most institutions in the United States rely on a polymerase chain reaction (PCR)–based assay to diagnose CDI; a method with high negative predictive value but with only moderate positive predictive value when the disease prevalence is low. Molecular testing only confirms the presence of a toxigenic strain, but not necessarily active infection and toxin production. The 2016 European Society of Clinical Microbiology and Infectious Diseases Guidelines recommend a 2-step approach with either glutamate dehydrogenase, enzyme immunoassay, or PCR (high negative predictive value), followed by a

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291 292 Minimum Screening Additional Considerations Immunocompromised Recipient 293 294 HIV (EIA) Viral serology (adenovirus, norovirus, rotavirus) Cytomegalovirus 295 Hepatitis A (HAV IgM) Antibiotic resistant bacteria Epstein-Barr virus Hepatitis B (HBsAg) 296 Hepatitis C (Anti-HCV Ab) 297 Syphilis (FTA-ABS) 298 Stool (culture vs PCR) for common pathogen 299 Clostridium difficile toxin B PCR 300 Stool ova and parasites 301 302 36 Adapted from Allegretti et al. Ab, antibody; EIA, enzyme immunoassay; FTA-ABS, ; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human Q8 303 immunodeficiency virus; PCR, polymerase chain reaction. 304 305 306 307 inclusion and exclusion criteria are based on medical and Investigational New Drug is required.39 The banked 308 social history along with stool and serologic testing for frozen stool is shipped directly to the physician’s 309 which there are no standardized evidenced based pro- office and may be stored in a standard medical freezer 310 tocols across U.S. and European medical societies. An under –20 C for up to 6 months. Before the procedure, 311 approach to screening is outlined below and summarized material is thawed in a warm water bath or overnight in 312 in Table 1.1,24 the refrigerator. It should be used within 6 hours of 313 Donors should be healthy, without known gastroin- thawing. 314 Frozen stool and fresh stool are equally efficatestinal (GI) disease or recent (within 90 days) antibiotic 315 therapy. Donors should be excluded if they have a history cious.40,41 Furthermore, when FMT is used to treat CDI, it 316 of disease potentially associated with alterations in the does not matter whether the stool in handled under 317 gut microbiome including autoimmune disease, chronic aerobic or anaerobic circumstances.42 Donor diet and gut 318 pain syndromes, neurologic disease, certain neuropsy- microbiota characteristics, including diversity and 319 chiatric syndromes, metabolic syndrome, obesity (body metabolic profile, do not seem to affect outcomes.43–45 320 mass index >30 kg/m2), moderate or severe malnutri321 tion, malignancy, or ongoing oncologic therapy.21 Special Discussion (Informed Consent) 322 consideration should be taken in patients who are 323 severely immunocompromised. Donor screening for 324 these patients may need to include Epstein-Barr virus Practitioners are responsible for detailing potential 325 and cytomegalovirus given the high prevalence of risks of the procedure. A sample informed consent form 326 Epstein-Barr virus and cytomegalovirus exposure in the was previously published by Kelly et al.39 FMT has been 327 community.20 shown to be safe in both immunocompetent and immu328 The patient directed method may be preferable to nocompromised individuals, with minimal to no serious 329 some patients but can lead to delays in treatment, adverse events having been directly associated with the 34,46–48 330 increased cost, and questions about full disclosure or therapy. A systematic review of adverse events in 331 coercion given the relationships between donor and FMT showed an adverse event rate of 28.5%, the most 332 recipient.37 The complex and time-consuming nature of common of which was abdominal pain.49 However, 333 donor screening and stool preparation19 create a serious adverse events were noted in 2% and 6% for the 334 potential barrier to access. The universal donor strategy upper and lower GI administration routes, respectively, 335 allows scalability leading to reduced cost and delays in and only 2 of the 44 serious events were definitely 336 treatment,37 but runs the theoretical risk of a safety associated with FMT, both of which were procedural 337 event, such as infection transmission, affecting hundreds complications (aspiration, perforation). Serious events 338 of recipients. Significant preventative measures are taken included relapse or flare of IBD, GI viral infection, auto339 by some stool banks, including the quarantine of stool immune disease, bacterial infection, or death. 340 In general, patients should be counseled on the before shipping to allow for repeated donor testing and 341 possible risk of treatment failure, systemic bacterial or detection of latent infectious disease. 342 In general, the universal donor approach seems an viral infection, GI bacterial or viral infection, allergic 343 effective way to subvert the logistical hurdles of FMT and reaction (especially in those with food allergy), autoim344 to increase safety.19 Current guidance statements by the mune disease, and IBD flare. The risk of IBD flare has 345 Food and Drug Administration (FDA) allow physicians been well studied, with reported rates as high as 346 to obtain stool from stool banks without needing to 15%,50,51 though randomized controlled trials suggest 347 submit Investigational New Drug paperwork.38 However, much lower risk.33,52–54 Any standard procedure-related 348 for other indications or any research studies an risks should be included in the informed consent. Table 1. Serologic and Stool Screening Recommendations for FMT Donation

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Alternatives to FMT include continuation of anti-CDI therapy or colectomy depending on the clinical circumstance. Long-term suppressive vancomycin therapy (125 mg orally daily or every other day) is a viable option for patients with limited life expectancy or for patients requiring ongoing systemic antibiotic therapy. Finally, patients should be informed that FMT is considered an experimental procedure that is not yet approved by the FDA.

Delivery Method Initial evidence suggests that colonic delivery affords better success rates than upper-GI administration (91.4% vs 82.3%); however, well-designed head-to-head studies are lacking.8 In general, colonic delivery via retention enema, sigmoidoscopy, and colonoscopy has shown success rates from 84% to 93%.8 Endoscopic administration, while well tolerated and safe, does carry increased cost and risk due to the inherent invasive nature of the procedure. However, direct visualization of the mucosa can provide diagnostic data with regard to pseudomembranes, underlying IBD, or other competing etiologies of symptoms. Furthermore, therapy can be delivered directly to the site of infection, mitigating concerns around the ileus or anatomical factors that may inhibit delivery of microbiota to the colon. While lower GI tract administration does carry some inherent risks, it remains the most common delivery method given the wealth of data supporting its efficacy.8,18 Colonoscopic FMT, with care to avoid overinsufflation of air and looping, has been shown to be safe even in patients with severe and severe complicated CDI,27 though it has been suggested that sigmoidoscopy may be the modality of choice for these high risk patients to mitigate procedural risk as much as possible.34,55 Success rates with upper GI administration have been reported at 81%–86%.8 Nasoenteric tubes are often used in Europe and carry the benefit of not requiring sedation. However, patient discomfort and poor perception of this administration route can inhibit its utility.56 More concerning are the risks of regurgitation, vomiting, and aspiration. In 1 study, 13% of patients undergoing FMT via the nasoduodenal route experienced regurgitation, with 1 death due to pneumonia, in which an aspiration event could not be ruled out.57,58 When stool is administered via upper route, a more concentrated, lowvolume preparation (30 mL) should be used to minimize risk of aspiration. This route may be considered for use by nonendoscopists in patients with complex abdominal surgeries and increased endoscopic risks.20 Administration via upper endoscopy carries the same risk and efficacy as enteric tube administration,8 but with the additional need for sedation. Finally, FMT administered via capsules has generated great interest, given the benefits of lower cost, ease of administration, and lack of the procedural risks.56 This

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modality, while promising, is still undergoing investigation. Initial studies have shown efficacy rates of 70% after a first dose of therapy which increases to 90% after a second treatment.15,59 A study looking at dosing found the both standard dose and high dose (double the standard dose) had similar efficacy.60 A more recent study showed similar efficacy at 12 weeks when comparing oral capsule to colonoscopically administered FMT in 116 patients.41 Several oral preparations are in clinical trials, though a commercially available formulation may still be several years away. It recommended that patients with acute CDI receive pretreatment for a minimum of 4–10 days with vancomycin or fidaxomicin before FMT. New IDSA/Society for Healthcare Epidemiology of America guidelines published earlier this year no longer recommended oral metronidazole for therapy of CDI in adults.25 Anti-CDI therapy should be held 1–3 days before the procedure.8,14,46 However, clinical judgment should be used in the case of severe or severe complicated disease in which continuing antimicrobial therapy until the time of transplant seems to be beneficial. If the colonoscopic route of delivery is planned, a partial or full bowel preparation is helpful to permit adequate endoscopic visualization and evaluation of CDI severity and other underlying pathology. There are conflicting data about the association between the quality of bowel prep and cure rates.61,62 It is permissible to bill for FMT including procedural costs and preparation or installation of donor material with appropriate diagnoses including recurrent CDI, diarrhea, and abdominal pain. Prior authorization from the patient’s insurance company may be required. As FMT is considered investigational by the FDA, most insurers will not cover the cost of donor stool obtained from a bank. Practices may build this cost into the fee for FMT or hospitals may cover the donor stool as a matter of policy, understanding the value in reduction of length of stay and readmissions for CDI. At some sites, patients are billed for the cost of banked donor stool and pay out of pocket. Screening of directed donors can be expensive and may not be covered by the donor’s insurance. Billing codes as well as a link to FMT coding guidance maintained by the AGA are included in Figure 2.

Discharge, Counseling, and Postprocedure Follow-Up Patients should be instructed to retain the FMT material for as long as possible, for which a preprocedure dose of loperamide may be helpful. Patient may resume a regular diet, without restrictions. Adequate consumption of dietary fiber is encouraged to promote beneficial short-chain fatty acid production by gut flora.63 Antimicrobial therapy should be discontinued postprocedure; however, in cases of severe CDI, with visualization of pseudomembranes at colonoscopy, it is

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Figure 2. Fecal microbiota transplantation billing codes. CDI, Clostridium difficile infection; FDA, Food and Drug Administration.

prudent to continue anti-CDI therapy27 and repeat FMT again after a few days. Patients should be educated on anti-microbial stewardship as evidence shows significantly increased recurrence risk with antibiotic use within 8 weeks postFMT.64 Consider referring patients with ongoing need for frequent courses of antibiotics to an infectious disease specialist to determine whether antibiotics are indeed appropriate, such as in the case of bacteriuria in the elderly, and whether lower risk antibiotics can be used. In a survey of over 400 post-FMT patients, we found that neither concomitant prophylactic antibiotics (ie, metronidazole, vancomycin) nor probiotics were helpful in decreasing CDI recurrence.65 Some evidence suggests that probiotic therapy started with within 2 days of initiation of the antibiotic therapy can help prevent recurrent CDI.66 Another retrospective study showed promise for prophylactic vancomycin in preventing recurrent CDI in patients treated with systemic antimicrobials.67 These interventions require further validation in prospective controlled trials. Post-FMT patients should be followed closely with telephone contacts and/or office visits within 2–4 weeks of the procedure. FMT failure is often defined as diarrhea and a positive C. difficile stool test within 8 weeks postFMT. The majority of FMT failures occur within 4 weeks of FMT and repeat testing, preferably with the 2-step model described previously, is appropriate if the

patient experiences recurrent diarrhea. Overall, 10%– 30% fail a single FMT while 5% fail multiple FMTs.68 Options for patients who fail multiple FMTs include repeat FMT using fresh donor stool by colonoscopy, simultaneous multimodality FMT (upper and lower) or chronic low-dose suppressive therapy with oral vancomycin. Additionally, combining FMT with new CDI treatments may increase success rates and reduce recurrence rates even further. This may be seen with wider use of fidaxomicin or potentially even in combination with new toxin directed therapies such as the anti-toxin B monoclonal antibody such as bezlotoxumab.69 Of note, none of these strategies have been evaluated in clinical trials.

Conclusion: Additions to the Toolbox and Future Uses FMT has been shown to be a highly efficacious, safe, Q9 and cost-effective therapy. Tremendous success in treating CDI has led to a rapid explosion of research on manipulation of gut microbiota to treat disease and advancement in our understanding of mechanisms around the gut microbiome’s effect on health. Beyond CDI, FMT has been evaluated as a treatment option in a variety of gastrointestinal diseases, such as IBD,52–54

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IBS,70 and hepatic encephalopathy.71 Manipulation of gut microbiota through FMT is even being studied in conditions outside the GI tract, such as autism and the metabolic syndrome.72,73 The field continues to advance and new technologies, such as encapsulated full-spectrum microbiota and defined microbial consortia, are likely to make this therapeutic tool more accessible, safer, and potentially more effective. With better understanding of the risks and benefits around FMT that will come with large clinical trials, it is easy to imagine FMT being used earlier in the disease course, perhaps even after a first CDI. Furthermore, “microbial restoration therapy” may become standard of care after courses of systemic antibiotics and a new subspecialty of medicine, microbiome therapeutics, may need to evolve. As Hippocrates said, “all disease starts in the gut.” For now, we hope this nutsand-bolts approach provides a framework for implementation of FMT in any practice setting and facilitates better care of patients suffering with CDI.

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difficile infection: a randomized trial. Ann Intern Med 2016; 165:609–616. 14. van Nood E, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368:407–415. 15. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772–1778. 16. Arbel LT, Hsu E, McNally K. Cost-effectiveness of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection: a literature review. Cureus 2017; 9:e1599. 17. Merlo G, Graves N, Brain D, Connelly LB. Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia. J Gastroenterol Hepatol 2016;31:1927–1932. 18. 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. 19. Bakken JS, Polgreen PM, Beekmann SE, Riedo FX, Streit JA. Treatment approaches including fecal microbiota transplantation for recurrent Clostridium difficile infection (RCDI) among infectious disease physicians. Anaerobe 2013;24:20–24.

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20. Allegretti JR, Kassam Z, Osman M, Budree S, Fischer M, Kelly CR. The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection. Gastrointest Endosc 2018;87:18–29. 21. Kelly CR, Kahn S, Kashyap P, et al. Update on fecal microbiotatransplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology 2015;149:223–237. 22. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044–1049. 23. Hartmann KE, Jerome RN, Lindegren ML, et al. Primary care management of abnormal uterine bleeding. Rockville, MD: AHRQ, 2013. 24. Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017;66:569–580. 25. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66:987–994. 26. Fischer M, Sipe BW, Rogers NA, et al. Faecal microbiota transplantation plus selected use of vancomycin for severecomplicated Clostridium difficile infection: description of a protocol with high success rate. Aliment Pharmacol Ther 2015; 42:470–476. 27. Fischer M, Sipe B, Cheng YW, et al. Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: a promising treatment approach. Gut Microbes 2017; 8:289–302. 28. Aroniadis OC, Brandt LJ, 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. 29. Hocquart M, Lagier JC, Cassir N, et al. Early fecal microbiota transplantation improves survival in severe Clostridium difficile infections. Clin Infect Dis 2018;66:645–650.

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Reprint requests Address requests for reprints to: Colleen R. Kelly, Alpert Medical School of Brown University, Lifespan Physician Group Gastroenterology, 146 W River Street, Suite 11C, Providence, Rhode Island 02904. e-mail: [email protected] brown.edu; fax: (401) 793-7988. Conflicts of interest The author discloses no conflicts.

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