A genomic portrait of the emergence, evolution and global spread of a methicillin resistant Staphylococcus aureus pandemic
- Matthew T. G. Holden1,
- Li-Yang Hsu2,
- Kevin Kurt3,
- Lucy A. Weinert4,
- Alison E. Mather5,
- Simon R. Harris5,
- Birgit Strommenger3,
- Franziska Layer3,
- Wolfgang Witte3,
- Herminia de Lencastre6,
- Robert Skov7,
- Henrik Westh8,
- Helena Zemlickova9,
- Geoffrey Coombs10,
- Angela M. Kearns11,
- Robert L. R. Hill11,
- Jonathan Edgeworth12,
- Ian Gould13,
- Vanya Gant14,
- Jonathan Cooke4,
- Giles F. Edwards15,
- Paul R. McAdam16,
- Kate E. Templeton17,
- Angela McCann18,
- Zhemin Zhou18,
- Santiago Castillo-Ramirez19,
- Edward J. Feil19,
- Lyndsey O. Hudson4,
- Mark C. Enright4,
- Francois Balloux4,
- David M. Aanensen4,
- Brian G. Spratt4,
- J. Ross Fitzgerald20,
- Julian Parkhill21,
- Mark Achtman18,
- Stephen D. Bentley21 and
- Ulrich Nübel22,23
- 1 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK;
- 2 National University Health System, Singapore;
- 3 Robert Koch Institute, Wernigerode, Germany;
- 4 Imperial College London, UK;
- 5 Wellcome Trust Sanger Institute, UK;
- 6 Universidade Nova de Lisboa, Portugal;
- 7 Statens Serum Institut, Copenhagen, Denmark;
- 8 Hvidovre Hospital, Copenhagen, Denmark;
- 9 National Institute of Public Health, Prague, Czech Republic;
- 10 Royal Perth Hospital, Perth, Australia;
- 11 Health Protection Agency, London, UK;
- 12 King's College London, UK;
- 13 Aberdeen Royal Infirmary, UK;
- 14 University College London Hospital, London, UK;
- 15 Scottish MRSA Reference Laboratory, Glasgow, UK;
- 16 The Roslin Institute, University of Edinburgh, UK;
- 17 Royal Infirmary of Edinburgh, UK;
- 18 Environmental Research Institute, Cork, Ireland;
- 19 University of Bath, UK;
- 20 Roslin Institute, University of Edinburgh, UK;
- 21 Sanger Institute;
- 22 Robert Koch Institute
- ↵* Corresponding author; email: nuebelu{at}rki.de
Abstract
The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalised patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with healthcare. The most rapidly spreading and tenacious healthcare-associated clone in Europe currently is EMRSA-15, a lineage that was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. To understand the genetic events that have accompanied the emergence of the EMRSA-15 pandemic, we obtained genome sequences for 193 isolates that were chosen for their geographical and temporal diversity, and belong to the same multilocus sequence type as EMRSA-15. Using phylogenomic methods, we were able to show that the current pandemic population of EMRSA-15 descends from a healthcare-associated MRSA epidemic that spread through England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 sub-clone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this sub-clone over the last twenty years has grown four times faster than its progenitor. Using comparative genomic analysis we were able to identify the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens.
- Received August 11, 2012.
- Accepted January 7, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
