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Original Research
23 August 2016

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial

Authors: 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, MDAuthor, Article, & Disclosure Information
Publication: Annals of Internal Medicine
Volume 165, Number 9
https://doi.org/10.7326/M16-0271
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Abstract

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.

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Supplement. Supplemental Information

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 165 • Number 9 • 1 November 2016
Pages: 609 - 616

History

Published online: 23 August 2016
Published in issue: 1 November 2016

Keywords

  1. Antibiotics
  2. Antimicrobials
  3. Bacterial diseases
  4. Clostridium infections
  5. Diarrhea
  6. Drugs
  7. Endoscopy
  8. Gastroenterology and hepatology
  9. Gram positive bacterial infections
  10. Hospital medicine
  11. Infectious diseases
  12. Medical conditions
  13. Nephrology
  14. Pharmacology
  15. Prevention, policy, and public health
  16. Safety
  17. Salts
  18. Surgery
  19. Transplantation

Copyright

© 2016 American College of Physicians.

Authors

Affiliations

Colleen R. Kelly, MD
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.
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Alexander Khoruts, MD
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.
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Christopher Staley, PhD
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.
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Michael J. Sadowsky, PhD
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.
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Mortadha Abd, MD
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.
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Mustafa Alani, MD
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.
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Brianna Bakow, BA
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.
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Patrizia Curran, MD
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.
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Joyce McKenney, MS
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.
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Allison Tisch, NP
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.
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Steven E. Reinert, MS
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.
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Jason T. Machan, PhD
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.
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Lawrence J. Brandt, MD
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.
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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, [email protected]).
Corresponding Author: Colleen R. Kelly, MD, Women's Medicine Collaborative, The Miriam Hospital, 146 West River Street, Suite 11C, Providence, RI 02904; e-mail, [email protected].
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.
This article was published at www.annals.org on 23 August 2016.

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Colleen R. Kelly, Alexander Khoruts, Christopher Staley, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med.2016;165:609-616. [Epub 23 August 2016]. doi:10.7326/M16-0271

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