title: Evolutionary History of the Global Emergence of the Escherichia coli Epidemic Clone ST131.
abstract: Escherichia colisequence type 131 (ST131) has emerged globally as the most predominant extraintestinal pathogenic lineage within this clinically important species, and its association with fluoroquinolone and extended-spectrum cephalosporin resistance impacts significantly on treatment. The evolutionary histories of this lineage, and of important antimicrobial resistance elements within it, remain unclearly defined. This study of the largest worldwide collection (n= 215) of sequenced ST131E. coliisolates to date demonstrates that the clonal expansion of two previously recognized antimicrobial-resistant clades, C1/H30R and C2/H30Rx, started around 25 years ago, consistent with the widespread introduction of fluoroquinolones and extended-spectrum cephalosporins in clinical medicine. These two clades appear to have emerged in the United States, with the expansion of the C2/H30Rx clade driven by the acquisition of ablaCTX-M-15-containing IncFII-like plasmid that has subsequently undergone extensive rearrangement. Several other evolutionary processes influencing the trajectory of this drug-resistant lineage are described, including sporadic acquisitions of CTX-M resistance plasmids and chromosomal integration ofblaCTX-Mwithin subclusters followed by vertical evolution. These processes are also occurring for another family of CTX-M gene variants more recently observed among ST131, theblaCTX-M-14/14-likegroup. The complexity of the evolutionary history of ST131 has important implications for antimicrobial resistance surveillance, epidemiological analysis, and control of emerging clinical lineages ofE. coli These data also highlight the global imperative to reduce specific antibiotic selection pressures and demonstrate the important and varied roles played by plasmids and other mobile genetic elements in the perpetuation of antimicrobial resistance within lineages.
  
  
  OBJECTIVE
  Escherichia coli, perennially a major bacterial pathogen, is becoming increasingly difficult to manage due to emerging resistance to all preferred antimicrobials. Resistance is concentrated within specificE. colilineages, such as sequence type 131 (ST131). Clarification of the genetic basis for clonally associated resistance is key to devising intervention strategies. We used high-resolution genomic analysis of a large global collection of ST131 isolates to define the evolutionary history of extended-spectrum beta-lactamase production in ST131. We documented diverse contributory genetic processes, including stable chromosomal integrations of resistance genes, persistence and evolution of mobile resistance elements within sublineages, and sporadic acquisition of different resistance elements. Both global distribution and regional segregation were evident. The diversity of resistance element acquisition and propagation within ST131 indicates a need for control and surveillance strategies that target both bacterial strains and mobile genetic elements.
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom nicole.stoesser@ndm.ox.ac.uk.
authors.forename: Nicole
authors.identifier: http://orcid.org/0000-0002-4508-7969
authors.initials: N
authors.lastname: Stoesser
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Sheppard
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Pankhurst
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Maio
authors.affiliation: Cambodia-Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: Catrin E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Icahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sebra
authors.affiliation: Cambodia-Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Anson
authors.affiliation: Icahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kasarskis
authors.affiliation: Wellcome Trust Center for Human Genetics, Oxford, United Kingdom.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Batty
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Kos
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao People's Democratic Republic (Laos).
authors.forename: Rattanaphone
authors.initials: R
authors.lastname: Phetsouvanh
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Wyllie
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Evgeni
authors.initials: E
authors.lastname: Sokurenko
authors.affiliation: University of British Columbia, School of Population and Public Health, Vancouver, British Columbia, Canada.
authors.forename: Amee R
authors.initials: AR
authors.lastname: Manges
authors.affiliation: College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Johnson
authors.affiliation: Translational Genomics Research Institute (TGen) North, Flagstaff, Arizona, USA.
authors.forename: Lance B
authors.initials: LB
authors.lastname: Price
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Timothy E A
authors.initials: TE
authors.lastname: Peto
authors.affiliation: Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota, USA Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Didelot
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Modernizing Medical Microbiology Consortium, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
mesh_terms: D002876:Chromosomes, Bacterial; D024881:Drug Resistance, Bacterial; D058872:Epidemics; D004926:Escherichia coli / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000453:epidemiology* / Q000382:microbiology*; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D005838:Genotype; D014943:Global Health; D006801:Humans; D017720:Molecular Epidemiology; D010957:Plasmids; D017422:Sequence Analysis, DNA