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Tracking a Superbug with Whole-Genome Sequencing

Analysis of MRSA starts to reveal its journey around the globe–and within a hospital.
January 22, 2010

By sequencing the entire genome of numerous samples of the notorious MRSA (Methicillin-resistant Staphylococcus aureus) bacteria–a drug-resistant strain of staph responsible for thousands of deaths in the United States each year–researchers at the Wellcome Trust Sanger Institute in the United Kingdom have gained clues as to how the superbug travels both around the globe and in local hospitals. Scientists say the approach will shed light on the epidemiology of the troublesome bacteria and help public health programs target their prevention efforts most effectively.

Bug decoding: By sequencing the genomes of numerous samples of the drug-resistant bacterium MRSA (shown here in yellow), scientists have confirmed where and when the superbug emerged.

The research, which would have been impossible just two years ago, was enabled by fast and inexpensive sequencing technology from Illumina, a genomics company based in San Diego. “The work demonstrates the value of applying high-resolution sequencing technology to public health problems,” said Caroline Ash, a senior editor at the journal Science, where the research was published, at a press conference on Wednesday. “Potentially the technology could pinpoint the origin of the outbreak and the origin of its spread.”

About 30 percent of people carry Staphylococcus aureus bacteria on their skin, often harmlessly. But for some people, the microbes can cause severe problems, including serious skin infections, sepsis, and death. Antibiotic-resistant strains of the virus emerged in the 1960s, and these now account for more than half of all hospital-acquired infections in the U.S.

In the current study, researchers sequenced 63 MRSA samples, some collected from across the globe during a 20-year period, and some from a single hospital in Thailand over 20 months. While standard analysis methods, which analyze only a small portion of the microbes’ DNA, classified each isolate as being of the same subtype, sequencing the whole genome allowed scientists to identify very small genetic differences between the microbes.

The researchers constructed an evolutionary tree for the microbes and confirmed that MRSA likely first emerged in Europe in the 1960s, coinciding with the growing use of antibiotics to treat staph infections. The tree also showed that the superbugs evolved drug resistance multiple times over the past 40 years. “That demonstrates there is immense selective pressure caused by antibiotic use worldwide,” said Simon Harris, the lead author on the study, at the press conference.

The researchers also analyzed minor genetic differences in MRSA samples collected in a much more localized setting–a single hospital in Thailand–and discovered greater than expected diversity among the microbes. That suggests that patients were infected by new strains coming into the hospital, rather than patient-to-patient transmissions, says Harris. That finding might affect control measures. “If you institute infection control settings in this hospital, it will only have limited success because, in this case, it looks like patients appear to be getting the infection from other sources,” said Sharon Peacock, a clinical microbiologist at the University of Cambridge who also participated in the research, at the press conference.

(The analysis will not affect how individual patients are treated, because all variants of MRSA are treated the same. Tests that classify subtypes of the bacteria are used to track the spread of infection, rather than to make treatment decisions.)

It’s not yet clear how the technology might be incorporated into standard public health efforts to track and control MRSA infections. “I believe this approach will expand our understanding of the evolution of MRSA, but I don’t think it will catch on right now in hospitals,” says Dan Diekema, a physician and epidemiologist at the University of Iowa, who was not involved in the study. “I think most hospitals find our current typing methods to be adequate in helping to guide prevention efforts. It’s not exactly clear to me how having a finer-grained look would impact prevention efforts.”

Peacock aims to address that question with ongoing studies. “We hope to clearly define through prospective studies of this tool what its value is and how to incorporate it into a hospital setting,” she said. The technology would need to undergo some major changes to transform from research tool to standard surveillance measure. “Before being adopted in standard clinical practice, the technology needs to be adapted so that it can be used in any major laboratory,” said Peacock. “We want the readout not in terms of sequencing but in what potential virulence it carries, and what its origins might be.”

Currently, sequencing a MRSA genome takes four to six weeks and costs about $300. “Even though turnaround time has been dramatically reduced from years to weeks, it’s still not a practical timescale for use in clinical settings,” said Stephen Bentley, senior author on the study. “But I expect that with third-generation sequencing technology, the turnaround time could be reduced to hours and the per sample cost might be reduced to the £20 mark [about $30].”

The project is part of a growing trend that capitalizes on increasingly affordable sequencing technologies to track the origins, evolution, and migration of human pathogens. “It’s going to require scientists to do some real innovative thinking to fully explore the potential of this technology,” said Bentley. Researchers at the Sanger Institute have already applied it to a number of other infectious organisms, including those responsible for tuberculosis, pneumonia, and meningitis.

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