Identification of Multiple Variant Extensively Drug-Resistant Typhoid Infections across Pakistan

Rashid Kamal Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan;

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Carly Ching Department of Biomedical Engineering, Boston University, Boston, Massachusetts;

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Muhammad H. Zaman Department of Biomedical Engineering, Boston University, Boston, Massachusetts;

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Faisal Sultan Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan;

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Salma Abbas Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan;

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Ezza Khan Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan

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Shaper Mirza Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan

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Summiya Nizamuddin Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan;

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ABSTRACT.

Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening bacterial infection. Recently, an outbreak of a new sublineage of extensively drug resistant (XDR) S. Typhi emerged in Pakistan in the province of Sindh. This sublineage had both a composite multidrug resistance transposon integrated on the chromosome and an acquired IncY plasmid carrying the extended spectrum beta-lactamase, blaCTX-M-15, which conferred resistance to third-generation cephalosporins. We observed previously that XDR typhoid had spread beyond the originating southern Sindh Province. Thus, we sought to determine the genetic diversity of 58 ceftriaxone-resistant S. Typhi clinical isolates by whole genome sequencing collected across Pakistan from November 2018 to December 2020 to provide insights into the molecular epidemiology of the evolving outbreak. We identify multiple novel genomic integrations of the extended spectrum beta-lactamase gene into the chromosome in S. Typhi, revealing the existence of various XDR typhoid variants circulating in the country. Notably, the integration of the IncY plasmid bearing antibiotic resistance genes may allow for subsequent plasmid acquisition by these variants, potentially leading to further plasmid-borne multidrug resistance. Our results can inform containment initiatives, help track associated outcomes and international spread, and help determine how widespread the risk is.

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Author Notes

Address correspondence to Carly Ching, Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215. E-mail: chingc@bu.edu

These authors contributed equally to this work.

Financial support: This work was funded by a research grant from the Shaukat Khanum Memorial Cancer Hospital and Research Centre.

Disclaimer: This study was granted exemption from the Shaukat Khanum Memorial Cancer Hospital and Research Centre’s Institutional Review Board.

Authors addresses: Rashid Kamal, Faisal Sultan, Salma Abbas, and Summiya Nizamuddin, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, E-mails: dr.rashidkamal@gmail.com, faisal@skm.org.pk, salmaabbas@skm.org.pk, and summiyan@skm.org.pk. Carly Ching and Muhammad H. Zaman, Department of Biomedical Engineering, Boston University, Boston, MA, E-mails: chingc@bu.edu and zaman@bu.edu. Ezza Khan and Shaper Mirza, Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan, E-mails: ezzakhan283@gmail.com and shaper.mirza@lums.edu.pk.

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