title: Healthcare-associated outbreak of meticillin-resistant Staphylococcus aureus bacteraemia: role of a cryptic variant of an epidemic clone.
abstract: BACKGROUND
  New strains of meticillin-resistant Staphylococcus aureus (MRSA) may be associated with changes in rates of disease or clinical presentation. Conventional typing techniques may not detect new clonal variants that underlie changes in epidemiology or clinical phenotype.
  
  
  OBJECTIVE
  To investigate the role of clonal variants of MRSA in an outbreak of MRSA bacteraemia at a hospital in England.
  
  
  METHODS
  Bacteraemia isolates of the major UK lineages (EMRSA-15 and -16) from before and after the outbreak were analysed by whole-genome sequencing in the context of epidemiological and clinical data. For comparison, EMRSA-15 and -16 isolates from another hospital in England were sequenced. A clonal variant of EMRSA-16 was identified at the outbreak hospital and a molecular signature test designed to distinguish variant isolates among further EMRSA-16 strains.
  
  
  RESULTS
  By whole-genome sequencing, EMRSA-16 isolates during the outbreak showed strikingly low genetic diversity (P < 1 × 10(-6), Monte Carlo test), compared with EMRSA-15 and EMRSA-16 isolates from before the outbreak or the comparator hospital, demonstrating the emergence of a clonal variant. The variant was indistinguishable from the ancestral strain by conventional typing. This clonal variant accounted for 64/72 (89%) of EMRSA-16 bacteraemia isolates at the outbreak hospital from 2006.
  
  
  CONCLUSIONS
  Evolutionary changes in epidemic MRSA strains not detected by conventional typing may be associated with changes in disease epidemiology. Rapid and affordable technologies for whole-genome sequencing are becoming available with the potential to identify and track the emergence of variants of highly clonal organisms.
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Miller
authors.affiliation: Department of Microbiology and Infectious Diseases, Brighton and Sussex University Hospital NHS Trust, Brighton, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Price
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Batty
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: X
authors.initials: X
authors.lastname: Didelot
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: D
authors.initials: D
authors.lastname: Wyllie
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: T
authors.initials: T
authors.lastname: Golubchik
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: D W
authors.initials: DW
authors.lastname: Crook
authors.affiliation: Public Health England, Royal Sussex County Hospital, Brighton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Paul
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: T E A
authors.initials: TE
authors.lastname: Peto
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Cule
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: C L C
authors.initials: CL
authors.lastname: Ip
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Rajthevee, Bangkok, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: N P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Collaborative Laboratory, Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: C E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; Department of Statistics, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Bowden
authors.affiliation: Department of Microbiology and Infectious Diseases, Brighton and Sussex University Hospital NHS Trust, Brighton, UK. Electronic address: m.j.llewelyn@bsms.ac.uk.
authors.forename: M J
authors.initials: MJ
authors.lastname: Llewelyn
mesh_terms: D016470:Bacteremia / Q000453:epidemiology* / Q000382:microbiology; D015373:Bacterial Typing Techniques; D016000:Cluster Analysis; D003428:Cross Infection / Q000453:epidemiology* / Q000382:microbiology; D004196:Disease Outbreaks; D004739:England; D014644:Genetic Variation; D016680:Genome, Bacterial; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006761:Hospitals; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D013203:Staphylococcal Infections / Q000453:epidemiology* / Q000382:microbiology; D006113:United Kingdom / Q000453:epidemiology
keywords: Bacteraemia; Meticillin-resistant Staphylococcus aureus; Outbreak; Whole-genome sequencing