TY - JOUR
T1 - Microbiota restoration reduces antibiotic-resistant bacteria gut colonization in patients with recurrent Clostridioides difficile infection from the open-label PUNCH CD study
AU - for the CDC Prevention Epicenter Program
AU - Langdon, Amy
AU - Schwartz, Drew J.
AU - Bulow, Christopher
AU - Sun, Xiaoqing
AU - Hink, Tiffany
AU - Reske, Kimberly A.
AU - Jones, Courtney
AU - Burnham, Carey Ann D.
AU - Dubberke, Erik R.
AU - Dantas, Gautam
N1 - Funding Information:
The authors would like to thank the staff at the Edison Family Center for Genome Sciences and Systems Biology at Washington University School of Medicine: Bonnie Dee, Kathleen Matheny, and Keith Page for administrative support; Jessica Hoisington-Lopez and MariaLynn Crosby for managing the high-throughput sequencing core; and Eric Martin and Brian Koebbe for computational cluster support. We would additionally like to thank members of the Dantas laboratory for helpful suggestions and critical appraisal of the manuscript.
Funding Information:
This work was supported by awards to the authors from the Centers for Disease Control and Prevention Epicenter Prevention Program Grant (1U1CI000033 301) and by Rebiotix, Inc. This work was also supported in part by awards to GD through the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (NIH) under award numbers R01AI123394 and R01HD092414, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Individual authors were supported by the following sources: NIH (TL1 TR000449) to AL, PIDS St. Jude Fellowship in Basic Research to DJS, and the National Human Genome Research Institute (T32 HG000045) to CB.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non-C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI. Methods: An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one (N = 16) or two doses of RBX2660 (N = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms. Results: Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted. Conclusions: Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others. Trial registration: ClinicalTrials.gov, NCT01925417; registered on August 19, 2013.
AB - Background: Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non-C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI. Methods: An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one (N = 16) or two doses of RBX2660 (N = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms. Results: Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted. Conclusions: Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others. Trial registration: ClinicalTrials.gov, NCT01925417; registered on August 19, 2013.
KW - Antibiotic resistance
KW - Clostridioides difficile
KW - Fecal microbiota transplantation
KW - Metagenomics
KW - Microbiome
KW - Multidrug resistance
UR - http://www.scopus.com/inward/record.url?scp=85100929943&partnerID=8YFLogxK
U2 - 10.1186/s13073-021-00843-9
DO - 10.1186/s13073-021-00843-9
M3 - Article
C2 - 33593430
AN - SCOPUS:85100929943
VL - 13
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 28
ER -