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We collected <jats:italic>S.<\/jats:italic> Typhi and <jats:italic>S.<\/jats:italic> Paratyphi isolates from blood or bone marrow culture-confirmed enteric fever cases at eight sites in seven cities across India between 2021 and 2024. We tested the antibiotic susceptibility of 1150 <jats:italic>S.<\/jats:italic> Typhi isolates and 265 <jats:italic>S.<\/jats:italic> Paratyphi isolates via disc diffusion and determined their minimum inhibitory concentrations (MICs) of ceftriaxone and azithromycin via broth dilution. We identified 18 <jats:italic>S.<\/jats:italic> Typhi isolates from Ahmedabad that were resistant to ceftriaxone, indicating a larger emergence of third-generation cephalosporin-resistant <jats:italic>S.<\/jats:italic> Typhi in Western India with a novel plasmid profile. Furthermore, we observed yearly increases in the mean, median and 90th percentile of azithromycin MICs for <jats:italic>S.<\/jats:italic> Typhi and <jats:italic>S.<\/jats:italic> Paratyphi isolates throughout India between 2021 and 2023. Finally, we found that only 0.70% of <jats:italic>S.<\/jats:italic> Typhi isolates and 1.13% of <jats:italic>S.<\/jats:italic> Paratyphi isolates exhibited susceptibility to ciprofloxacin. Our results indicate the necessity for a shift from ciprofloxacin in the treatment of enteric fever, and the importance of implementing long-term monitoring of resistance to alternative antibiotics such as azithromycin and ceftriaxone.<\/jats:p>","DOI":"10.1038\/s41598-025-93170-7","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T15:39:57Z","timestamp":1745249997000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antimicrobial susceptibility trends of S. Typhi and S. 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