Integrated Genetic Characterization and Quantitative Risk Assessment of Cephalosporin- and Ciprofloxacin-Resistant <i>Salmonella</i> in Pork from Thailand

<b>Background/Objectives</b>: This study assessed the risk associated with third-generation cephalosporin- and fluoroquinolone-resistant <i>Salmonella</i> from pork consumption by integrating phenotypic resistance profiles with genetic data to characterize the risks and transmission pathways. <b>Methods</b>: <i>Salmonella</i> were isolated from raw pork meat samples (<i>n</i> = 793) collected from fresh markets and hypermarkets across Bangkok during 2021-2022, of which 150 were extended-spectrum β-lactamase (ESBL)-producing and 31 were fluoroquinolone-resistant isolates. Phenotypic and genotypic resistance profiles were characterized. Quantitative antimicrobial resistance risk assessment (AMR RA) was conducted using a dose-response model. <b>Results</b>: <i>Salmonella</i> spp. was detected in 42.75% of pork samples, with a higher prevalence in fresh markets (75.5%) than in hypermarket samples and with concentrations ranging from 1.3 to 180 MPN/g. Twenty-eight percent of isolates were ESBL producers, with ciprofloxacin and levofloxacin resistance observed in 5.3% and 3.0%, respectively. The <i>bla</i>_CTX-M55 genes were located on conjugative plasmids. Whole genome sequencing revealed both vertical and horizontal gene transfer. IncHI2/N and IncC plasmids shared conserved backbones and resistance gene architectures, indicating horizontal dissemination of resistance genes. Phylogenomics suggested possible clonal transmission among pigs, pork, and humans. AMR RA estimated 88,194 annual illness cases per 100,000 people from ESBL-producing <i>Salmonella</i> and 61,877 from ciprofloxacin-resistant strain, compared with 95,328 cases predicted by QMRA from <i>Salmonella</i> contamination. Cooking pork at ≥64 °C for 3 min eliminated the risk in all scenarios. Sensitivity analysis identified initial contamination level and cooking temperature as key determinants. <b>Conclusions</b>: Raw pork meat consumption represents the highest risk, which can be mitigated by thorough cooking (>64 °C, ≥3 min), while integrating genomic data enhances AMR hazard identification, source attribution, and exposure assessment. Therefore, promoting well-cooked meat consumption and safe cooking practices, alongside the use of AMR genetic data to inform targeted interventions, is recommended.