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Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized TrialFecal Microbiota Transplantation and Recurrent C difficile Infection ONLINE FIRST

Colleen R. Kelly, MD; Alexander Khoruts, MD; Christopher Staley, PhD; Michael J. Sadowsky, PhD; Mortadha Abd, MD; Mustafa Alani, MD; Brianna Bakow, BA; Patrizia Curran, MD; Joyce McKenney, MS; Allison Tisch, NP; Steven E. Reinert, MS; Jason T. Machan, PhD; and Lawrence J. Brandt, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 23 August 2016.


From Warren Alpert Medical School of Brown University, Miriam Hospital, and Lifespan Hospital System, Providence, Rhode Island; University of Minnesota, Minneapolis/St. Paul, Minnesota; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and University of Rhode Island, Kingston, Rhode Island.

Acknowledgment: The authors thank all of the patients who participated in this study; Drs. Christina Surawicz and Pierre Gholam, who served on the data and safety monitoring board; the staff of the Women's Medicine Collaborative; and Beth Hott for her help with the manuscript submission.

Grant Support: Drs. Kelly and Brandt received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (1R21DK0939839). Drs. Khoruts and Sadowsky received grant support from the National Institutes of Health (R21AI114722-01).

Disclosures: Dr. Kelly reports a grant from Assembly Biosciences and other support from Seres Health outside the submitted work. Dr. Khoruts reports a grant from CIPAC outside the submitted work and a patent pending for compositions and methods for transplantation of colon microbiota. Dr. Sadowsky reports grants and personal fees from CIPAC during the conduct of the study and outside the submitted work and patents with royalties paid to CIPAC. Dr. Brandt reports a grant from the National Institutes of Health during the conduct of the study and nonfinancial support from OpenBiome and personal fees from CIPAC/Crestovo outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0271.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study protocol: See the Supplement. Statistical code and data set: The authors are willing to share the statistical code used to generate results and the data set from which the results were derived with the public after written agreement. Requests should be directed to Dr. Kelly (e-mail, colleen_r_kelly@brown.edu).

Requests for Single Reprints: Colleen R. Kelly, MD, Women's Medicine Collaborative, The Miriam Hospital, 146 West River Street, Suite 11C, Providence, RI 02904; e-mail, colleen_r_kelly@brown.edu.

Current Author Addresses: Drs. Kelly and Curran and Ms. McKenney: Women's Medicine Collaborative, The Miriam Hospital, 146 West River Street, Providence, RI 02904.

Dr. Khoruts: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Minnesota, 420 Delaware Street SE, MMC 36, Minneapolis, MN 55455.

Drs. Staley and Sadowsky: BioTechnology Institute, 1479 Gortner Avenue, Suite 140, St. Paul, MN 55108-6106.

Drs. Abd and Brandt: Albert Einstein College of Medicine, 625 Ullmann Building, 1300 Morris Park Avenue, Bronx, NY 10461.

Dr. Alani: Department of Medicine, Division of Gastroenterology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Ms. Bakow: The Warren Alpert Medical School of Brown University, Box G-A1, Providence, RI 02912.

Ms. Tisch: Optum Care Plus, 475 Kilvert Street, Suite 310, Warwick, RI 02886.

Mr. Reinert: Lifespan Information Services, The Coro Building, 167 Point Street, Providence, RI 02903.

Dr. Machan: Lifespan Biostatistics Core, 593 Eddy Street, Rhode Island Hospital, Grads Dorm 206a, Providence, RI 02903.

Author Contributions: Conception and design: C.R. Kelly, M.J. Sadowsky, J.T. Machan, L.J. Brandt.

Analysis and interpretation of the data: C.R. Kelly, A. Khoruts, C. Staley, M.J. Sadowsky, S.E. Reinert, J.T. Machan, L.J. Brandt.

Drafting of the article: C.R. Kelly, A. Khoruts, C. Staley, M.J. Sadowsky, S.E. Reinert, J.T. Machan, L.J. Brandt.

Critical revision of the article for important intellectual content: C.R. Kelly, A. Khoruts, C. Staley, M.J. Sadowsky, J.T. Machan, L.J. Brandt.

Final approval of the article: C.R. Kelly, A. Khoruts, C. Staley, M.J. Sadowsky, M. Abd, M. Alani, B. Bakow, P. Curran, J. McKenney, A. Tisch, S.E. Reinert, J.T. Machan, L.J. Brandt.

Provision of study materials or patients: M.J. Sadowsky, M. Abd, L.J. Brandt.

Statistical expertise: S.E. Reinert, J.T. Machan.

Obtaining of funding: J. McKenney.

Administrative, technical, or logistic support: M. Abd, M. Alani, B. Bakow.

Collection and assembly of data: C.R. Kelly, C. Staley, M. Abd, M. Alani, B. Bakow, P. Curran, J. McKenney, A. Tisch, L.J. Brandt.


Ann Intern Med. Published online 23 August 2016 doi:10.7326/M16-0271
© 2016 American College of Physicians
Text Size: A A A

Background: To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials.

Objective: To determine the efficacy and safety of FMT for treatment of recurrent CDI.

Design: Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494)

Setting: Two academic medical centers.

Patients: 46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode.

Intervention: Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy.

Measurements: The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool.

Results: In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors.

Limitation: The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older.

Conclusion: Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes.

Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.

Figures

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Figure 1.

Enrollment and outcomes.

Two patients at the Rhode Island site withdrew from the study before randomization. One reported that his CDI had resolved, and the other withdrew after the donor was unable to produce stool on the day of the planned FMT. Three patients in New York were determined to no longer have CDI after further evaluation by the investigator at that site and were withdrawn from the study before randomization. One patient in New York was found to have colon cancer (an exclusion criterion) at the time of the FMT colonoscopy and was withdrawn from the study. CDI = Clostridium difficile infection; FMT = fecal microbiota transplantation; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome.

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Figure 2.

Rates of clinical cure in the intention-to-treat population, overall and by site.

Error bars represent 95% CIs. FMT = fecal microbiota transplantation.

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Figure 3.

Distribution of phyla in samples from patients initially undergoing donor FMT (top), those initially under-going autologous FMT (middle), and those undergoing donor FMT after relapse (bottom) at both sites.

Less abundant phyla were present at a mean abundance <1.0% among all samples. FMT = fecal microbiota transplantation.

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Autologous FMT: Too strong to be a placebo?
Posted on September 7, 2016
Gianluca Ianiro, Antonio Gasbarrini, Giovanni Cammarota
Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
Conflict of Interest: None Declared
TO THE EDITOR
In their randomized controlled trial (RCT), Kelly and colleagues showed that fecal microbiota transplantation (FMT) from healthy donors is more effective than autologous FMT against multiply recurrent Clostridium difficile infection (CDI) (1). Their results (91% clinical cure in the donor FMT group) confirm the outstanding efficacy rates of FMT by recurrent CDI already achieved in previous RCTs (2-3). The most surprising finding of this study is actually the high (63%) overall resolution rate achieved in the autologous FMT group. This result is even more unexpected if we consider the significant difference of cure rates for sham FMT between the two study sites (90% in New York and 42.9% in Rhode Island). Authors considered this finding not unexpected overall, and gave possible explanation to the discrepancy between sites, including differences in microbiota composition and in previous use of vancomycin and fidaxomicin, and possible cure of recurrent CDI before enrollment. Bowel preparation has not been considered as a likely explanation for this finding in the related editorial by Hohmann (4).
A possible explanation of these results could lie in the collection process of autologous stools for fecal infusion. Patient feces were collected after bowel preparation with polyethylene glycol (PEG), which is a mechanical, isosmotic laxative agent. Through its “cascade” effect, PEG could have delivered the intraluminal content of the small bowel, including gut microbiota, biliary salts, and immune cells, downstream, to be collected for FMT. The transplanted autologous material, therefore, contained not only feces colonized by Clostridium difficile, but also commensal microbiota and other healthy components from the small bowel, which could have contributed to the resolution of recurrent CDI. The greater abundance of non-C. difficile Clostridia in the autologous fecal material at the New York site, probably due to the higher mean duration of oral vancomycin therapy in those patients, at least for some species (5), could therefore explain, at least partially, the difference in efficacy rates of autologous FMT between the two study sites. This hypothesis could undermine the use of sham fecal infusion as placebo in FMT trials.  

REFERENCES

1) Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016. [Epub ahead of print]doi: 10.7326/M16-0271.
2) van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407-15. [PMID: 23323867]. doi: 10.1056/NEJMoa1205037.
3) Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835-43. [PMID: 25728808] doi: 10.1111/apt.13144.
4) Hohmann EL. Are Microbial Politics Local? Ann Intern Med. 2016. [Epub ahead of print] doi: 10.7326/M16-1784.
5) Vrieze A, Out C, Fuentes S, Jonker L, Reuling I, Kootte RS, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60:824-31. [PMID: 24316517]. doi: 10.1016/j.jhep.2013.11.034.
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