Genomic diversity and topical antimicrobial resistance in Staphylococcus aureus from clinical and carriage populations in the New York-New Jersey region.

Staphylococcus aureus remains a major public health concern due to its capacity for colonization, transmission, and antimicrobial resistance. Both methicillin-resistant (MRSA) and methicillin-susceptible S. aureus (MSSA) serve as reservoirs for resistance determinants, including those conferring reduced susceptibility to topical decolonization agents. We analyzed 2,330 S. aureus isolates collected between 2022 and 2025 from hospitals and community clinics in New Jersey and New York City, including 962 MRSA infection isolates and 1,368 nasal carriage isolates (310 MRSA and 1,058 MSSA) obtained from patients upon admission to intensive care, neonatal intensive care, and transplant units. Whole-genome sequencing and PCR characterized clonal lineages, plasmid structures, and resistance determinants, with focus on mupA, which mediates high-level mupirocin resistance. MRSA infection isolates were dominated by clonal complexes CC8 (63%), CC5 (21%), and CC30 (10%), whereas MSSA carriage isolates were more diverse, with CC398 most prevalent (15%). The mupA gene was detected in 26% of MRSA infection isolates, 50% of MRSA carriage isolates, and 36% of MSSA carriage isolates. Pairwise single-nucleotide polymorphism (SNP) analysis revealed most mupA variants differed by 0-2 SNPs across diverse lineages, consistent with recent horizontal dissemination. Long-read sequencing identified three major mupA-carrying plasmid groups-conjugative, mobilizable, and non-mobilizable-frequently co-harboring qacC, aadD1, msr(A), and mph(C). Non-mobilizable plasmids were confined to CC8, while mobilizable and conjugative variants circulated across multiple lineages. The high prevalence of mupA-bearing plasmids co-associated with quaternary ammonium resistance genes raises concerns regarding empiric mupirocin- and chlorhexidine-based decolonization strategies. Genomic surveillance and rapid resistance screening may be critical to preserving topical agent efficacy.