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Research Article

Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins

Elizabeth J. Klemm, Sadia Shakoor, Andrew J. Page, Farah Naz Qamar, Kim Judge, Dania K. Saeed, Vanessa K. Wong, Timothy J. Dallman, Satheesh Nair, Stephen Baker, Ghazala Shaheen, Shahida Qureshi, Mohammad Tahir Yousafzai, Muhammad Khalid Saleem, Zahra Hasan, Gordon Dougan, Rumina Hasan
Keith P. Klugman, Editor
Elizabeth J. Klemm
aWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Sadia Shakoor
bThe Aga Khan University, Karachi, Pakistan
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Andrew J. Page
aWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Farah Naz Qamar
bThe Aga Khan University, Karachi, Pakistan
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Kim Judge
aWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Dania K. Saeed
bThe Aga Khan University, Karachi, Pakistan
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Vanessa K. Wong
cUniversity of Cambridge Department of Medicine, Cambridge, United Kingdom
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Timothy J. Dallman
dGastrointestinal Bacteria Reference Unit, National Infection Service, Public Health England, London, United Kingdom
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Satheesh Nair
dGastrointestinal Bacteria Reference Unit, National Infection Service, Public Health England, London, United Kingdom
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Stephen Baker
eThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit-Vietnam, Ho Chi Minh City, Vietnam
fCentre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom
gFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
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Ghazala Shaheen
bThe Aga Khan University, Karachi, Pakistan
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Shahida Qureshi
bThe Aga Khan University, Karachi, Pakistan
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Mohammad Tahir Yousafzai
bThe Aga Khan University, Karachi, Pakistan
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Muhammad Khalid Saleem
bThe Aga Khan University, Karachi, Pakistan
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Zahra Hasan
bThe Aga Khan University, Karachi, Pakistan
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Gordon Dougan
aWellcome Trust Sanger Institute, Hinxton, United Kingdom
cUniversity of Cambridge Department of Medicine, Cambridge, United Kingdom
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Rumina Hasan
bThe Aga Khan University, Karachi, Pakistan
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Keith P. Klugman
Emory University
Roles: Editor
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Neil Fairweather
Imperial College London
Roles: Solicited external reviewer
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Brendan Wren
London School of Hygiene and Tropical Medicine
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Levine
University of Maryland School of Medicine
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DOI: 10.1128/mBio.00105-18
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ABSTRACT

Antibiotic resistance is a major problem in Salmonella enterica serovar Typhi, the causative agent of typhoid. Multidrug-resistant (MDR) isolates are prevalent in parts of Asia and Africa and are often associated with the dominant H58 haplotype. Reduced susceptibility to fluoroquinolones is also widespread, and sporadic cases of resistance to third-generation cephalosporins or azithromycin have also been reported. Here, we report the first large-scale emergence and spread of a novel S. Typhi clone harboring resistance to three first-line drugs (chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) as well as fluoroquinolones and third-generation cephalosporins in Sindh, Pakistan, which we classify as extensively drug resistant (XDR). Over 300 XDR typhoid cases have emerged in Sindh, Pakistan, since November 2016. Additionally, a single case of travel-associated XDR typhoid has recently been identified in the United Kingdom. Whole-genome sequencing of over 80 of the XDR isolates revealed remarkable genetic clonality and sequence conservation, identified a large number of resistance determinants, and showed that these isolates were of haplotype H58. The XDR S. Typhi clone encodes a chromosomally located resistance region and harbors a plasmid encoding additional resistance elements, including the blaCTX-M-15 extended-spectrum β-lactamase, and carrying the qnrS fluoroquinolone resistance gene. This antibiotic resistance-associated IncY plasmid exhibited high sequence identity to plasmids found in other enteric bacteria isolated from widely distributed geographic locations. This study highlights three concerning problems: the receding antibiotic arsenal for typhoid treatment, the ability of S. Typhi to transform from MDR to XDR in a single step by acquisition of a plasmid, and the ability of XDR clones to spread globally.

IMPORTANCE Typhoid fever is a severe disease caused by the Gram-negative bacterium Salmonella enterica serovar Typhi. Antibiotic-resistant S. Typhi strains have become increasingly common. Here, we report the first large-scale emergence and spread of a novel extensively drug-resistant (XDR) S. Typhi clone in Sindh, Pakistan. The XDR S. Typhi is resistant to the majority of drugs available for the treatment of typhoid fever. This study highlights the evolving threat of antibiotic resistance in S. Typhi and the value of antibiotic susceptibility testing and whole-genome sequencing in understanding emerging infectious diseases. We genetically characterized the XDR S. Typhi to investigate the phylogenetic relationship between these isolates and a global collection of S. Typhi isolates and to identify multiple genes linked to antibiotic resistance. This S. Typhi clone harbored a promiscuous antibiotic resistance plasmid previously identified in other enteric bacteria. The increasing antibiotic resistance in S. Typhi observed here adds urgency to the need for typhoid prevention measures.

FOOTNOTES

    • Received 17 January 2018
    • Accepted 19 January 2018
    • Published 20 February 2018
  • Copyright © 2018 Klemm et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins
Elizabeth J. Klemm, Sadia Shakoor, Andrew J. Page, Farah Naz Qamar, Kim Judge, Dania K. Saeed, Vanessa K. Wong, Timothy J. Dallman, Satheesh Nair, Stephen Baker, Ghazala Shaheen, Shahida Qureshi, Mohammad Tahir Yousafzai, Muhammad Khalid Saleem, Zahra Hasan, Gordon Dougan, Rumina Hasan
mBio Feb 2018, 9 (1) e00105-18; DOI: 10.1128/mBio.00105-18

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Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins
Elizabeth J. Klemm, Sadia Shakoor, Andrew J. Page, Farah Naz Qamar, Kim Judge, Dania K. Saeed, Vanessa K. Wong, Timothy J. Dallman, Satheesh Nair, Stephen Baker, Ghazala Shaheen, Shahida Qureshi, Mohammad Tahir Yousafzai, Muhammad Khalid Saleem, Zahra Hasan, Gordon Dougan, Rumina Hasan
mBio Feb 2018, 9 (1) e00105-18; DOI: 10.1128/mBio.00105-18
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KEYWORDS

antibiotic resistance
Salmonella
Typhi
typhoid

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