The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi: a genomic epidemiology study

Kesia Esther da Silva, Arif Mohammad Tanmoy, Agila Kumari Pragasam, Junaid Iqbal, Mohammad Saiful Islam Sajib, Ankur Mutreja, Balaji Veeraraghavan, Dipesh Tamrakar, Farah Naz Qamar, Gordon Dougan, Isaac Bogoch, Jessica C. Seidman, Jivan Shakya, Krista Vaidya, Megan E. Carey, Rajeev Shrestha, Seema Irfan, Stephen Baker, Steve P. Luby, Yanjia CaoZoe Anne Dyson, Denise O. Garrett, Jacob John, Gagandeep Kang, Yogesh Hooda, Samir K. Saha, Senjuti Saha, Jason R. Andrews*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

Background: The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies. Methods: In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers. Findings: Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades. Interpretation: Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions. Funding: Bill & Melinda Gates Foundation.

Original languageEnglish
Pages (from-to)e567-e577
JournalThe Lancet Microbe
Volume3
Issue number8
DOIs
Publication statusPublished - 1 Aug 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the Bill & Melinda Gates Foundation (grant number INV-008335).

Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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