In a new study released today in New England Journal of Medicine, researchers demonstrate that whole genome sequencing can provide clinically relevant data on bacterial transmission within a timescale that can influence infection control and patient management.

Scientists from the Wellcome Trust Sanger Institute, University of Cambridge, and Illumina collaborated to use whole genome sequencing to identify which isolates of methicillin-resistant Staphylococcus aureus (MRSA) were part of a hospital outbreak.

Current laboratory techniques often cannot distinguish between MRSA isolates. This study indicates that whole genome sequencing can provide precise information in a fast turnaround time, and could make a clear distinction between MRSA isolates in a way that was not previously possible.

MRSA infection is a major public health problem. For example, in the United States, an estimated 89,785 invasive MRSA infections associated with 15,249 deaths occurred in 2008. Even when the disease is treated, MRSA infections double the average length of hospital stay and increase healthcare costs. Fast and accurate detection of bacterial transmission is crucial to better control of healthcare-associated infection.

"An important limitation of current infection control methodology is that the available bacterial typing methods cannot distinguish between different strains of MRSA," explains Professor Sharon Peacock, lead author from the University of Cambridge and clinical specialist at the Health Protection Agency. "The purpose of our study was to see if whole genome sequencing of MRSA could be used to distinguish between related strains at a genome level, and if this would inform and guide outbreak investigations."

The team focused on an outbreak in a neonatal intensive care unit that had already ended. They took the samples and sequenced them as if they had been working in real time. They found they could distinguish between strains that were part of the outbreak and strains that were not, and showed that they could have identified the outbreak earlier than current clinical testing, potentially shortening the outbreak.

"This study demonstrates how advances in whole genome sequencing can provide essential information to help combat hospital outbreaks in clinically relevant turnaround times," says Dr Geoffrey Smith, co-lead author and Senior Director of Research at Illumina. "As sequencing has become increasingly accurate and comprehensive, it can be used to answer a wide range of questions. Not only could we distinguish different MRSA strains in the hospital, we were also able to rapidly characterise antibiotic resistance and toxin genes present in the clinical isolates."

The team constructed a list of all the MRSA genes that cause antibiotic resistance. Rapidly identifying drug resistance in MRSA strains will guide healthcare professionals to give each infected patient the most appropriate treatment possible. This also provides a powerful tool for the discovery of new drug resistance mechanisms.

MRSA produces numerous unique toxins that can inflict severe clinical syndromes, including septic shock, pneumonia, and complicated skin and soft tissue infections. The team created a list of toxin genes to rapidly identify those present in the MRSA strains, which currently can only be identified with multiple assays in reference laboratories.

"Distinguishing between strains is important for infection control management," says Dr Julian Parkhill, lead author from the Wellcome Trust Sanger Institute. "Quick action is essential to control a suspected outbreak, but it is of equal importance to identify unrelated strains to prevent unnecessary ward closures and other disruptive control measures. Healthcare needs better, more efficient ways of identifying an outbreak and then processing the data."

"Current clinical methods to make links between related strains compare the pattern of bacterial susceptibility to a profile of antibiotics. We found this method to be inaccurate. We showed that two MRSA strains, which seemed by current methods to be identical, were genetically very different."

The use of whole genome sequencing will ultimately become part of routine health care. This study indicates that whole genome sequencing in real time will be valuable in controlling MRSA and other outbreaks in a hospital setting.

"The next stage is to develop interactive tools that provide automated interpretation of genome sequence and provide clinically meaningful information to healthcare workers, a necessary advance before this can be rolled out into clinical practice," adds Professor Peacock.

###

Notes to Editors

Publication Details

Köser CU, Holden MTG, Ellington MJ, Cartwright EJP et al. (2012) A neonatal MRSA outbreak investigation using rapid whole genome sequencing. New England Journal of Medicine doi: 10.1056/NEJMoa1109910

Funding

This research was funded by UKCRC Translational Infection Research (TIR) Initiative, the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research on behalf of the Department of Health, the Chief Scientist Office of the Scottish Government Health Directorate, the Health Protection Agency, the NIHR Cambridge Biomedical Research Centre, the Department of Health, the Wellcome Trust and Illumina, Inc.

Participating Centres

University of Cambridge

Wellcome Trust Sanger Institute

Health Protection Agency

Cambridge University Hospitals NHS Foundation Trust

Illumina, Inc.

Biocontrol Ltd

National University Health System, Singapore

Selected Websites

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. It admits the very best and brightest students, regardless of background, and offers one of the UK's most generous bursary schemes. The University of Cambridge's reputation for excellence is known internationally and reflects the scholastic achievements of its academics and students, as well as the world-class original research carried out by its staff. Some of the most significant scientific breakthroughs occurred at the University, including the splitting of the atom, invention of the jet engine and the discoveries of stem cells, plate tectonics, pulsars and the structure of DNA. From Isaac Newton to Stephen Hawking, the University has nurtured some of history's greatest minds and has produced more Nobel Prize winners than any other UK institution with over 80 laureates. http://www. cam. ac. uk

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www. sanger. ac. uk

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www. wellcome. ac. uk

Illumina is a leading developer, manufacturer, and marketer of life science tools and integrated systems for the analysis of genetic variation and function. We provide innovative sequencing and array-based solutions for genotyping, copy number variation analysis, methylation studies, gene expression profiling, and low-multiplex analysis of DNA, RNA, and protein. We also provide tools and services that are fueling advances in consumer genomics and diagnostics. Our technology and products accelerate genetic analysis research and its application, paving the way for molecular medicine and ultimately transforming healthcare. www.illumina.com

For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

Contact details

Don Powell Media Manager

Wellcome Trust Sanger Institute

Hinxton, Cambridge, CB10 1SA, UK

Tel +44 (0)1223 496 928

Mobile +44 (0)7753 7753 97

Email press.office@sanger.ac.uk