Abstract: Objectives: The United States Centers for Disease Control and Prevention (CDC) conducts active surveillance for typhoid fever cases caused by Salmonella enterica serovar Typhi (Typhi). Here we describe the characteristics of the first two cases of mph(A)-positive azithromycin-resistant Typhi identified through US surveillance. Methods: Isolates were submitted to public health laboratories, sequenced, and screened for antimicrobial resistance determinants and plasmids, as part of CDC PulseNet's routine genomic surveillance. Antimicrobial susceptibility testing and long-read sequencing were also performed. Basic case information (age, sex, travel, outcome) was collected through routine questionnaires; additional epidemiological data was requested through follow-up patient interviews. Results: The patients are related and both reported travel to India (overlapping travel dates) before illness onset. Both Typhi genomes belong to the GenoTyphi lineage 4.3.1.1 and carry the azithromycin-resistance gene mph(A) on a PTU-FE (IncFIA/FIB/FII) plasmid. These strains differ genetically from mph(A)-positive Typhi genomes recently reported from Pakistan, suggesting independent emergence of azithromycin resistance in India. Conclusions: Cases of typhoid fever caused by Typhi strains resistant to all available oral treatment options are cause for concern and support the need for vaccination of travellers to Typhi endemic regions. US genomic surveillance serves as an important global sentinel for detection of strains with known and emerging antimicrobial resistance profiles, including strains from areas where routine surveillance is not conducted.

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