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Background Multidrug-resistant Enterococci are a major cause of nosocomial infections, yet our understanding of how resistance emerges during antibiotic treatment remains incomplete. We performed whole- and complete-genome sequencing of all paired isolates from 11 Enterococcus faecium and 10 Enterococcus faecalis cases that acquired resistance during hospitalization at Mount Sinai Hospital. Comparative and phylogenetic genomic analyses identified novel mechanisms of resistance and heteroresistance. Methods 2.5 years of electronic health records were analyzed to identify cases of bacteremia that acquired resistance to at least 1 of the 8 antibiotics. Core genome phylogenetic analyses of paired susceptible and resistant isolates was performed to confirm persistent single clone infections. Long read sequencing data, with Illumina error correction, were used to assemble and align complete genomes. Population analysis profile (PAP) assays were performed to assess the prevalence of heteroresistance. Results Among the 102 persistent enterococcal bacteremia cases, 57 isolates from 21 cases (20.6%) cases experienced a gain in resistance. Phylogenetic analyses confirmed that 80% of cases had single clone blood infections, with maximum of 138 days separating paired isolates. Known genetic determinants were responsible for emerging linezolid (LIN), vancomycin (VAN), and gentamicin synergy resistance in almost all cases. In 2 instances, emerging daptomycin (DAP) resistance was not accounted for by known resistance determinants. Notably, PAP assays revealed that LIN-, VAN-, and DAP-resistant subclones were present in only a subset of bacteria in clinical isolates. Longitudinal pairwise analyses of complete genomes revealed novel candidate SNPs for DAP resistance, both located in genes involving cell wall metabolism and maintenance, as well as multiplasmid recombination events that led to VAN heteroresistance. Conclusion Our study demonstrates the high prevalence of emerging antibiotic resistance during treatment. We find previously unreported single and structural genomic events that contribute rapid adaptation to antibiotic treatment. Disclosures All authors: No reported disclosures.

open forum infectious diseases

2561. Using Whole Genome Sequencing to Assess the Emergence of Antibiotic Resistance During Treatment of Enterococcus faecium and Enterococcus faecalis Bacteremia at Mount Sinai Hospital