A new study shows that whole genome sequencing can rapidly and accurately differentiate among strains of methicillin-resistant Staphylococcus aureus (MRSA) in a way that current lab methods can’t. Speeding up the turnaround of such vital information can help control hospital outbreaks of the superbug, said the researchers.

The researchers sequenced genomes of MRSA samples from a real hospital outbreak and found they could precisely distinguish strains that were part of the outbreak from strains that were not, faster than conventional clinical testing methods. They suggest had this been done, it could have helped infection control and patient management and shortened the duration of the outbreak, which occurred in a neonatal intensive care unit.

Scientists from the Wellcome Trust Sanger Institute, University of Cambridge in the UK, and Illumina, a global company that markets DNA sequencers, write about their findings in a 14 June online issue of the New England Journal of Medicine, NEJM.

The lead authors are Dr Sharon Peacock, a professor in the Departments of Medicine and Pathology at the University of Cambridge, Dr Geoffrey Smith, Senior Director of Research at Illumina, and Dr Julian Parkhill, from the Wellcome Trust Sanger Institute.

Parkhill told the press:

“Distinguishing between [MRSA] strains is important for infection control management.”

“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 need better, more efficient ways of identifying a outbreak and then processes the data,” he explained.

Peacock said “an important limitation of current infection control methodology is that the available bacterial typing methods cannot distinguish between different strains of MRSA.”

She said the team wanted to find out if whole genome sequencing of MRSA could tell the different strains apart at the genome level, and if this information could be helpful in guiding the investigation into an outbreak.

The team chose to study a recent outbreak that had already been brought to an end, and work at a pace that would have been like working in “real time” during the outbreak, which had occurred in the neonatal unit of a hospital.

“By using rapid high-throughput sequencing technology with a clinically relevant turnaround time, we retrospectively sequenced the DNA from seven isolates associated with the outbreak and another seven MRSA isolates associated with carriage of MRSA or bacteremia in the same hospital,” they write.

By comparing DNA sequences (single-nucleotide polymorphisms, SNPs) in the core genome to a reference genome, they produced an evolutionary tree that revealed a “distinct cluster of outbreak isolates and clear separation between these and the nonoutbreak isolates“.

The team also compiled a “resistome”, essentially a list of all the MRSA genes that cause antibiotic resistance. Such a tool should help health professionals quickly identify drug resistance in MRSA strains, so individual patients can receive the most appropriate treatment. It can also help discover new drug resistance mechanisms.

They also created a “toxome” of toxin genes that can rapidly identify those present in MRSA strains. At present these can only be found with multiple assays in reference labs. MRSA produces unique toxins that can cause severe illnesses like septic shock, pneumonia, and complicated skin and soft tissue infections.

In their conclusion, the team writes:

“Whole-genome sequencing can provide clinically relevant data within a time frame that can influence patient care. The need for automated data interpretation and the provision of clinically meaningful reports represent hurdles to clinical implementation.”

Smith said the study shows “how advances in whole genome sequencing can provide essential information to help combat hospital outbreaks in clinically relevant turnaround times.”

Sequencing techniques have advanced so rapidly, and become so accurate and comprehensive, they can answer a range of questions that are important for control of hospital infections.

“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,” said Smith.

Parkhill added:

“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 identified two MRSA strains, that seemed to be identical using current methods, were genetically very different.”

The researchers propose that whole genome sequencing will one day be a routine feature of healthcare, and this study shows how using it in real time could make a significant difference to the control of MRSA and other outbreaks in hospital settings.

Peacock said the next step is to make interactive tools that allow health workers to interpret genome sequences automatically. Only then can the method be rolled out for use in clinics.

MRSA infection is a major public health problem. Even when it is successfully treated, it can double the average time patients stay in hospital, which increases the costs of healthcare.

In the United States, estimates for 2008 suggest there were over 89,500 invasive MRSA infections that year, and over 15,200 deaths were linked to the superbug.

Written by Catharine Paddock PhD