{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:27:11Z","timestamp":1793114831060,"version":"4.5.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2018,2,20]],"date-time":"2018-02-20T00:00:00Z","timestamp":1519084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T00:00:00Z","timestamp":1520380800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2018,3,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Antibiotic resistance is a major problem in\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    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\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi 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\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi clone encodes a chromosomally located resistance region and harbors a plasmid encoding additional resistance elements, including the\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-15<\/jats:sub>\n                    extended-spectrum \u03b2-lactamase, and carrying the\n                    <jats:italic>qnrS<\/jats:italic>\n                    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\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi to transform from MDR to XDR in a single step by acquisition of a plasmid, and the ability of XDR clones to spread globally.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Typhoid fever is a severe disease caused by the Gram-negative bacterium\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    serovar Typhi. Antibiotic-resistant\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi strains have become increasingly common. Here, we report the first large-scale emergence and spread of a novel extensively drug-resistant (XDR)\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi clone in Sindh, Pakistan. The XDR\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi is resistant to the majority of drugs available for the treatment of typhoid fever. This study highlights the evolving threat of antibiotic resistance in\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi and the value of antibiotic susceptibility testing and whole-genome sequencing in understanding emerging infectious diseases. We genetically characterized the XDR\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi to investigate the phylogenetic relationship between these isolates and a global collection of\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi isolates and to identify multiple genes linked to antibiotic resistance. This\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi clone harbored a promiscuous antibiotic resistance plasmid previously identified in other enteric bacteria. The increasing antibiotic resistance in\n                    <jats:italic>S<\/jats:italic>\n                    .\u00a0Typhi observed here adds urgency to the need for typhoid prevention measures.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00105-18","type":"journal-article","created":{"date-parts":[[2018,2,19]],"date-time":"2018-02-19T09:32:23Z","timestamp":1519032743000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":564,"title":["Emergence of an Extensively Drug-Resistant\n                    <i>Salmonella enterica<\/i>\n                    Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins"],"prefix":"10.1128","volume":"9","author":[{"given":"Elizabeth J.","family":"Klemm","sequence":"first","affiliation":[{"name":"Wellcome Trust Sanger Institute, Hinxton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadia","family":"Shakoor","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Page","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, Hinxton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah Naz","family":"Qamar","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Judge","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, Hinxton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dania K.","family":"Saeed","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa K.","family":"Wong","sequence":"additional","affiliation":[{"name":"University of Cambridge Department of Medicine, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Dallman","sequence":"additional","affiliation":[{"name":"Gastrointestinal Bacteria Reference Unit, National Infection Service, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satheesh","family":"Nair","sequence":"additional","affiliation":[{"name":"Gastrointestinal Bacteria Reference Unit, National Infection Service, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Baker","sequence":"additional","affiliation":[{"name":"The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit-Vietnam, Ho Chi Minh City, Vietnam"},{"name":"Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom"},{"name":"Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghazala","family":"Shaheen","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahida","family":"Qureshi","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Tahir","family":"Yousafzai","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Khalid","family":"Saleem","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Hasan","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Dougan","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, Hinxton, United Kingdom"},{"name":"University of Cambridge Department of Medicine, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rumina","family":"Hasan","sequence":"additional","affiliation":[{"name":"The Aga Khan University, Karachi, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"346","article-title":"The global burden of typhoid fever","volume":"82","author":"Crump JA","year":"2004","unstructured":"Crump JA, Luby SP, Mintz ED. 2004. 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Extended spectrum beta lactamase producing cephalosporin resistant Salmonella typhi, reported from Rawalpindi, Pakistan. J Pak Med Assoc 66:1035\u20131036.","journal-title":"J Pak Med Assoc"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1509.090567"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.044065-0"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix652"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/genomeA.00850-17"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005595"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112963"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0849-0"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-421"},{"key":"e_1_3_3_26_2","unstructured":"Ponstingl H. 2015. SMALT. 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