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Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S. Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S. Typhi isolates from India to predict their potential dissemination. Five ceftriaxone resistant S. Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S. Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with bla CTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (bla SHV-12) or IncN (bla T EM-1B + bla DHA-1). Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally. • S. Typhi to develop cephalosporin resistance by acquiring diverse plasmids from other Enterobacteriaceae. • Independent acquisition of drug-resistant plasmids such as IncX3 and IncN with genes encoding beta-lactamases in H58 lineage II of S. Typhi. • A short-term persistence of drug-resistant plasmids in H58 lineage II can be the reason for the sporadic cases cephalosporin resistant S. Typhi in India. • Plasmid acquisition and maintenance of cephalosporin resistant S. Typhi appears to be specific to the phylogenetic lineage. • Critical strategies in monitoring and control of cephalosporin resistant S. Typhi is needed to tackle further public health crisis. [ABSTRACT FROM AUTHOR]