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Background A healthy gut microbiome is associated with colonization resistance against C. difficile and other pathogens, including bacteria carrying antibiotic resistance genes (AbRG). Designed to facilitate microbiome restoration and reduce the risk of recurrent C. difficile infection (rCDI), SER-109, an investigational microbiome therapeutic, is an ecology of bacterial spores purified from stool from healthy screened donors. We evaluated the impact of engraftment of SER-109 dose species on the abundance of AbRG in rCDI subjects. Methods We generated whole metagenomic shotgun (WMS) data for a subset of study subjects with available stool samples receiving SER-109 (n = 66) or placebo (n = 25) from 2 clinical trials (a dose-ranging Phase 1b study and a fixed-dose Phase 2 trial). WMS data from stool was analyzed to (1) quantify the abundance of AbRG (Comprehensive Antibiotic Resistance Database CARD v.1.1.8) and (2) define subjects with significant engraftment of SER-109 dose species. For each subject and antibiotic drug class, we calculated the change in abundance of AbRG between samples collected at baseline (after antibiotic therapy for an episode of C. difficile infection) and following treatment with SER-109 or placebo. We evaluated the effect of SER-109 engraftment on AbRG abundance, independent of dose. Results In subjects with significant high-confidence engraftment of SER-109 organisms (n = 30) we observed significantly greater reduction in AbRG relative to placebo at week 1 post treatment. These AbRG were associated with multiple classes of antibiotics including, but not limited to, cephalosporins (P = 0.035), and fluoroquinolones (P = 0.035) (Figure 1). Furthermore, the reduction of AbRG was correlated with the increased abundance of SER-109 dose species, and with a reduction in Proteobacteria (e.g., Enterobactericeae) (Figure 2).Figure 1. (a) Cephalosporin antibiotics (b) Fluoroquinolone antibioticsFigure 2. Conclusion Restoration of the gut microbiome with SER-109 in subjects with a history of rCDI is associated with a reduction in abundance of antibiotic resistance genes. These observations suggest that microbiome therapeutics could play a role in more rapidly decolonizing drug-resistant bacteria. Disclosures C. Ford, Seres Therapeutics, Inc: Employee and Shareholder, Salary. M. Henn, Seres Therapeutics, Inc: Employee and Shareholder, Salary. J. Bryant, Seres Therapeutics, Inc: Employee and Shareholder, Salary. L. Diao, Seres Therapeutics, Inc: Employee and Shareholder, Salary. J. Wortman, Seres Therapeutics, Inc: Employee and Shareholder, Salary. A. Tomlinson, Seres Therapeutics, Inc: Employee and Shareholder, Salary. K. Litcofsky, Seres Therapeutics, Inc: Employee and Shareholder, Salary. P. Bernardo, Seres Therapeutics, Inc: Employee and Shareholder, Salary. B. McGovern, Seres Therapeutics, Inc: Employee and Shareholder, Salary. J. G. Aunins, Seres Therapeutics, Inc: Employee and Shareholder, Salary. D. N. Cook, Seres Therapeutics, Inc: Employee and Shareholder, Salary. M. Trucksis, Seres Therapeutics, Inc: Employee and Shareholder, Salary.

1641. Treatment of Recurrent Clostridium difficile Infection With SER-109 Reduces Gastrointestinal Carriage of Antimicrobial Resistance Genes