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1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)

BACKGROUND: CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomy...

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Autores principales: Ford, Christopher, Litcofsky, Kevin, McGovern, Barbara, Pardi, Darrell, Nathan, Richard, Hansen, Val, Brennan, Robert, Pullman, John, Bernardo, Patricia, Tomlinson, Amelia, Horgan, Kevin, Bryant, Jessica, Walsh, Emily, Rodriguez, Michelle, Rogalin, Henry, Wang, Elaine, Henn, Matt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6809198/
http://dx.doi.org/10.1093/ofid/ofz360.1367
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author Ford, Christopher
Litcofsky, Kevin
McGovern, Barbara
Pardi, Darrell
Nathan, Richard
Hansen, Val
Brennan, Robert
Pullman, John
Bernardo, Patricia
Tomlinson, Amelia
Horgan, Kevin
Bryant, Jessica
Walsh, Emily
Rodriguez, Michelle
Rogalin, Henry
Wang, Elaine
Henn, Matt
author_facet Ford, Christopher
Litcofsky, Kevin
McGovern, Barbara
Pardi, Darrell
Nathan, Richard
Hansen, Val
Brennan, Robert
Pullman, John
Bernardo, Patricia
Tomlinson, Amelia
Horgan, Kevin
Bryant, Jessica
Walsh, Emily
Rodriguez, Michelle
Rogalin, Henry
Wang, Elaine
Henn, Matt
author_sort Ford, Christopher
collection PubMed
description BACKGROUND: CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance. METHODS: SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks. RESULTS: SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3). CONCLUSION: In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.
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spelling pubmed-68091982019-10-28 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI) Ford, Christopher Litcofsky, Kevin McGovern, Barbara Pardi, Darrell Nathan, Richard Hansen, Val Brennan, Robert Pullman, John Bernardo, Patricia Tomlinson, Amelia Horgan, Kevin Bryant, Jessica Walsh, Emily Rodriguez, Michelle Rogalin, Henry Wang, Elaine Henn, Matt Open Forum Infect Dis Abstracts BACKGROUND: CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance. METHODS: SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks. RESULTS: SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3). CONCLUSION: In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2019-10-23 /pmc/articles/PMC6809198/ http://dx.doi.org/10.1093/ofid/ofz360.1367 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Ford, Christopher
Litcofsky, Kevin
McGovern, Barbara
Pardi, Darrell
Nathan, Richard
Hansen, Val
Brennan, Robert
Pullman, John
Bernardo, Patricia
Tomlinson, Amelia
Horgan, Kevin
Bryant, Jessica
Walsh, Emily
Rodriguez, Michelle
Rogalin, Henry
Wang, Elaine
Henn, Matt
1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title_full 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title_fullStr 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title_full_unstemmed 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title_short 1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
title_sort 1503. engraftment of investigational microbiome drug, ser-262, in subjects receiving vancomycin is associated with reduced rates of recurrence after primary clostridium difficile infection (cdi)
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6809198/
http://dx.doi.org/10.1093/ofid/ofz360.1367
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