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Background Antimicrobial resistance (AMR) poses an increasing challenge to the treatment of the nosocomial pathogen Pseudomonas aeruginosa, with the majority of highly resistant infections caused by relatively few high-risk clones. We investigated the role of clonal complex 298 (CC298: ST298 and ST446) in multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections at Northwestern Memorial Hospital (NMH). Methods We determined the AMR of 40 whole-genome sequenced CC298 isolates, including 30 from patients at NMH in Chicago (2000–2017), 7 from hospital environments (e.g., sinks) in Chicago (2017–2018), and 3 from patients at Brigham and Women’s Hospital (BWH) in Boston (2015–2016). We used phylogenetics to assess the population structure of these isolates and 38 additional publicly available CC298 genomes. We interrogated the genomes of NMH CC298 isolates to uncover drivers of AMR. Results NMH CC298 isolates showed high rates of AMR, with 76.7% (23/30) MDR and 46.7% (14/30) XDR. Phylogenetic analysis revealed that 21/23 MDR (13/14 XDR) isolates from NMH formed a subclade of ST298, termed ST298*, as of yet not seen elsewhere. A time-scaled phylogeny of ST298* indicates a last common ancestor in 1980 (mean 1980.8, 95% HPD interval 1973.3–1987.4), with XDR ST298* isolates seen between 2001 and 2017. Many ST298* isolates, including all XDR isolates, harbored a large plasmid with an AMR class 1 integron. This plasmid is part of a family of large Pseudomonas genus plasmids. By comparing a plasmid-cured strain to its parent, we show that the plasmid imparts resistance to gentamicin and piperacillin–tazobactam. In the parental strain we detect T83I GyrA and S87L ParC substitutions known to cause fluoroquinolone resistance, showing that mutational resistance also contributes to the high AMR of ST298*. Publicly available genomes and previous reports indicate that CC298 has caused infections worldwide with multiple instances of significant AMR. Conclusion The repeated isolation of XDR ST298* P. aeruginosa at NMH over 16 years raises concern for the ability of this strain to persist in the healthcare environment. With this local epidemic and additional reports of MDR CC298 isolates around the world, we argue that CC298 should be considered a high-risk clone. Disclosures All authors: No reported disclosures.

2453. Prolonged Local Epidemic of an XDR P. aeruginosa Subclade of High-Risk Clonal Complex 298