Genomic census of invasive nontyphoidal Salmonella infections reveals global and local human-to-human transmission.

Extraintestinal infections caused by Enterobacteriaceae represent a global concern, further exacerbated by the growing prevalence of antimicrobial resistance (AMR). Among these, invasive nontyphoidal Salmonella (iNTS) infections have become increasingly challenging to manage, and their global spread remains poorly understood. Here we compiled 1,115 patient records and generated a comprehensive genomic dataset on iNTS. Age and sex emerged as significant risk factors, with Salmonella Enteritidis identified as a major cause. We observed serovar-specific AMR patterns, with notable resistance to fluoroquinolones and third-generation cephalosporins. A global phylogenomic analysis of Enteritidis revealed three distinct clades, highlighting the accumulation of AMR determinants during its international spread. Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways. Collectively, our newly generated cohort and iNTS genomic dataset provide a framework for precise local iNTS burden and underscore emerging transmission trends.