Nationwide spread of multidrug resistant Klebsiella pneumoniae across US communities.

Traditionally viewed as a hospital pathogen, multidrug-resistant (MDR) Klebsiella pneumoniae is emerging in community settings, yet its population structure and spread are currently undefined. A nationwide genomic survey of 2006 ceftriaxone-nonsusceptible outpatient isolates from 42 US states reveals that the spread of resistance is primarily driven by the blaCTX-M-15 extended-spectrum-β-lactamase (ESBL) gene across diverse K. pneumoniae lineages. This gene, harbored by a family of IncFIB(Kpn3) plasmids, has spread to hundreds of lineages, coupling antibiotic resistance with stress- and metal-tolerance traits that may enhance survival beyond human hosts. Nearly half of isolates formed transmission clusters spanning multiple states, underscoring active community dissemination. The majority originated from elderly women with urinary tract infections, where oral treatment options are increasingly ineffective. Capsule and O-antigen profiling reveal broad antigenic diversity, yet a manageable subset of serotypes could offer wide coverage for vaccine development. Our findings expose a rapidly evolving, plasmid-driven epidemic of community-associated MDR K. pneumoniae across the United States.