title: South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study.
abstract: Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei.
  
  
  
  We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei.
  
  
  
  This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Hao
authors.identifier: 0000-0002-4028-4074
authors.initials: H
authors.lastname: Chung The
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Maia A
authors.identifier: 0000-0003-0529-2228
authors.initials: MA
authors.lastname: Rabaa
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Duy
authors.initials: D
authors.lastname: Pham Thanh
authors.affiliation: National Salmonella, Shigella, and Listeria monocytogenes Reference Laboratory, University Hospital Galway, Galway, Ireland.
authors.forename: Niall
authors.initials: N
authors.lastname: De Lappe
authors.affiliation: School of Medicine, National University of Ireland Galway, Galway, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Cormican
authors.affiliation: Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.
authors.forename: Mary
authors.identifier: 0000-0002-1004-3210
authors.initials: M
authors.lastname: Valcanis
authors.affiliation: Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Howden
authors.affiliation: Public Health Laboratory, Department of Public Health, Ministry of Health, Royal Government of Bhutan, Thimphu, Bhutan.
authors.forename: Sonam
authors.initials: S
authors.lastname: Wangchuk
authors.affiliation: Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Ladaporn
authors.initials: L
authors.lastname: Bodhidatta
authors.affiliation: Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Carl J
authors.identifier: 0000-0002-3676-2811
authors.initials: CJ
authors.lastname: Mason
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: To
authors.initials: T
authors.lastname: Nguyen Thi Nguyen
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Duong
authors.identifier: 0000-0003-2507-4893
authors.initials: D
authors.lastname: Vu Thuy
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Corinne N
authors.initials: CN
authors.lastname: Thompson
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Phu Huong Lan
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Phat
authors.initials: P
authors.lastname: Voong Vinh
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Tuyen
authors.initials: T
authors.lastname: Ha Thanh
authors.affiliation: Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.|Cambodia-Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.affiliation: Cambodia-Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: Poda
authors.initials: P
authors.lastname: Sar
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
authors.affiliation: The London School of Hygiene and Tropical Medicine, London, United Kingdom.|The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Thomson
authors.affiliation: Centre for Systems Genomics, The University of Melbourne, Melbourne, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Holt
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.|The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001315:Australia / Q000453:epidemiology; D001631:Bhutan / Q000453:epidemiology; D002160:Cambodia / Q000453:epidemiology; D002675:Child, Preschool; D002939:Ciprofloxacin / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D016680:Genome, Bacterial / Q000235:genetics; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D010802:Phylogeny; D012764:Shigella sonnei / Q000187:drug effects* / Q000235:genetics; D013785:Thailand / Q000453:epidemiology; D014744:Vietnam / Q000453:epidemiology
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin