Superbugs meet their match in rapid genome sequencing

It was the first sign of trouble. Three babies on the special care ward at Rosie Hospital in Cambridge tested positive for the MRSA superbug. Fearing an outbreak of the dangerous organism, managers ordered a deep clean. Staff duly disinfected the ward and went back to work as normal. Four days later the bug struck again.

The cases, in 2011, prompted an investigation by the local infection control team. Through no fault of the staff, it left many questions dangling. Was it a new strain of MRSA (methicillin-resistant Staphylococcus aureus) or merely a cluster of unrelated MRSA infections? Had MRSA spread beyond the baby ward? And how had it come back?

What happened next was a remarkable feat of genetic sleuthing. A team of researchers, led by Sharon Peacock, a clinical microbiologist at the nearby Wellcome Trust Sanger Institute took up the investigation and sequenced the whole genomes of MRSA bugs taken from the babies. Standard genetic tests inspect only a handful of genes and are fine for confirming what strain is causing an infection. But with whole genome sequencing, scientists had the power to reconstruct the history of each pathogen they found.

The work took time and effort, but it made clear what had happened. First the team confirmed that it was an outbreak caused by a new strain of MRSA. They then linked the outbreak to earlier infections on the ward and showed how it had spread to parents, including a mother whose child was on another ward. For their finale, they tracked down a health worker who unwittingly carried the bug and had reinfected the baby unit. The worker was treated for the infection and the outbreak was finally over.

As a demonstration of the power of genetics, the intervention was dramatic. It was the first time rapid genetic sequencing had been used to track and halt an outbreak. But the technology has since moved on. Scientists at the newly formed Centre for Genomic Pathogen Surveillance at the Sanger Institute are developing systems to track outbreaks of all sorts in close to real-time. It is not an overstatement to call it a medical revolution.

“The outbreak in Cambridge, from the first few babies being treated, to the identification of the health worker, took months of hard work. The challenge now is to provide real-time interpretation tools for hospital staff to spot outbreaks much faster,” said David Aanensen, who is developing the tools at the Sanger Institute. Using the new system, the hospital could have been on top of the outbreak in three days.

It will surely save lives. The Cambridge outbreak did not kill anyone, but even as deaths from MRSA continue to fall, the infection still claims hundreds of lives each year in England and Wales. Another common infection, Clostridium difficile, killed 1,646 people in the region in 2012. Other drug-resistant bugs are on the rise.

In a demonstration at his Cambridge office, Aanensen showed how the system works. If a hospital suspects an outbreak, doctors swab the patients and send the samples for whole-genome sequencing. The business was once time-consuming and expensive, but Peacock’s investigation showed that the whole genome of a bacterium could be read in eight hours for less than £100. This price is set to fall much further.

Aanensen’s demo system takes the genetic sequences and compares them with each other and to DNA sequences held on a database. The computer first searches a library of common mutations that make bugs resistant to drugs. It then compiles a list of antibiotics that will kill the strain in question and those drugs that will have no effect.

Next, the computer builds up a family tree that shows how the bugs taken from each patient are related to one another and to others reported elsewhere. When the analysis is done, the information is beamed back to the hospital.

Armed with the results, doctors could go straight to the most effective drugs to treat their patients. That, at least, is the hope.

The family tree is useful too. It reveals when a string of infections belong to an outbreak caused by a single strain that needs to be brought under control. It can also help doctors trace the source of an infection and warn them of any problems. For example, a bug’s DNA might show that the strain is new to the UK, but caused deaths in a hospital in Spain. A patient who visited the hospital on holiday may have carried the infection home with them.

Aanensen and his colleagues are demonstrating their system to researchers in the UK and Europe, where rapid genome sequencing is gradually becoming available. Addenbrookes Hospital in Cambridge is due to be the first in the UK to adopt the system next year. The hospital’s infection control team will trial its use alongside tools that follow the movement of patients to track infections even more closely.

Ultimately, the scientists want to do real-time, or close to real-time, tracking of diseases on a global scale. But that will mean high-tech sequencing machines and infrastructure in other countries. “The idea is that this could be used by any laboratory anywhere in the world,” said Aanensen. “We need to be looking at South East Asia, South America and Africa. We need to enable labs to do their own sequencing,” he said.

By gathering information on the latest outbreaks as they happen, the system should pick up trends in drug resistance, for example by revealing the spread of known drug-resistant bugs, or the rise of bugs with new kinds of resistance.

One of the most serious emerging threats comes from carbapenemase-producing Enterobacteriaceae (CPE), a growing family of drug-resistant bugs that infected only a handful of patients in England in 2006, but more than 600 in 2013.

Ross Fitzgerald at Edinburgh University’s Centre for Infectious Diseases said real-time whole-genome sequencing of pathogens offers “enormous benefits” to hospital staff and patients, because it can accurately predict which drugs will be effective at containing outbreaks, but also reveal transmission routes within a hospital, the UK, and even on a global scale. “This is a big deal. It is going to become routine and there are clearly major benefits for infection control in hospitals,” he said.