̽��ֱ�� of Cambridge - superbug

March of the superbugs

admin — Wed, 13 Feb 2013 09:38:50 +0000

Every so often, research laboratories and hospitals testing patients for the superbug methicillin-resistant Staphylococcus aureus (MRSA) have come across an oddity: a strain that appeared to be MRSA because it was resistant to antibiotics but one that tested negative with the ‘gold standard’ molecular test. ̽��ֱ��quirky cases were so infrequent that they were usually filed away for future analysis or disregarded. Until, that is, PhD student Laura Garcia-Alvarez from Cambridge’s Department of Veterinary Medicine had the tenacity to look a little further at a bacterial strain she had spotted in cows’ milk.

MRSA first appeared in 1961 and epidemic strains of this difficult-to-treat bacterium have since spread worldwide in hospitals and the community. In the farming world, MRSA causes bovine mastitis – an infection of cows’ udders – affecting both animal welfare and milk yields.

Garcia-Alvarez was working with Dr Mark Holmes on bovine mastitis when she came across one of the ‘curious anomalies’. ̽��ֱ��strain was resistant to antibiotics but in the standard molecular test was negative for the presence of mecA – the gene responsible for methicillin resistance. She had the isolates retested and then sequenced at the Wellcome Trust Sanger Institute.

It turned out that she had discovered a new strain of MRSA. Its antibiotic resistance is carried not by mecA but by mecC, a gene that is so genetically dissimilar to mecA that it can’t be picked up by the standard molecular test used to define MRSA but only by DNA sequencing.

As Holmes and Garcia-Alvarez began to spread the information to colleagues around Europe, it soon became clear that this phenomenon was not confined to cows: others had found the unusual samples in humans. “We started to get calls from hospitals and research groups who had come across a small number of human MRSA strains that behaved differently,” said Holmes. “Within a few weeks, we had a further 50 isolates. This meant that what we were looking at was a human problem too.”

Garcia-Alvarez, who at the time was a student on the Department’s postgraduate training in infectious disease dynamics programme, described how finding the same new strain in both humans and cows was worrying, although no cause for immediate alarm: “Pasteurisation of milk will prevent any risk of infection via the food chain. In the wider UK community, less than 3% of individuals carry MRSA – typically in their noses – without becoming ill.”

“Nonetheless,” added Holmes, “MRSA presents a major challenge to the control of infectious diseases. Finding a new strain – studying its prevalence, how it confers antibiotic resistance and how it’s transmitted – can tell us enormous amounts about the origins and evolution of antibiotic resistance.”

New understanding

Since the discovery, Holmes’ team has been investigating the prevalence of the strain in human and animal populations – and the potential for passing the strain between species – in partnership with Cambridge’s Department of Medicine, the Sanger Institute and the Moredun Research Institute (Scotland), and funded by the Medical Research Council.

One of their first steps was to develop a better genetic test, one that also detected the new strain. ̽��ֱ��timing was fortuitous. Moves to help hospitals identify MRSA more quickly have resulted in the development of automated systems based on genetic testing. Because the standard genetic test does not detect the new strain, the scientists have now developed a protocol that will pick up both strains.

Moreover, their recent research has shown that additional MRSA strains have emerged that possess other mechanisms of antibiotic resistance: “We’ve found about 40 human MRSA isolates that don’t have a mecA or a mecC gene, and we are trying to establish why these are resistant to methicillin-family antibiotics. In retrospect, it was incredibly lucky that the original isolate we investigated happened to have a genetic variation in a known gene that could be picked up by whole genome sequencing.”

To identify how mecC confers antibiotic resistance, Holmes collaborated with Professor Alexander Tomasz at Rockefeller ̽��ֱ��, New York. They discovered that the gene is more resistant than mecA to cefoxitin (one of the newer classes of antibiotics): “Inappropriate use of antibiotics in human and veterinary medicine has favoured the selection and growth of antibiotic-resistant microorganisms,” explained Holmes. “Our finding suggests that an increased use of this drug may have driven emergence of the new strain.”

“We also now know that the new strain is found in almost every species that we’ve studied, including domestic cats and dogs, wild rats, deer, a rabbit, a common seal, sheep and a chaffinch. ̽��ֱ��bacterium may have lost factors that restricted it to certain species, or gained pan-host virulence factors that make it better able to colonise multiple species. We need to know how and why this has happened to understand the emergence of bacterial pathogens from animals and their dissemination into human populations.”

Now, their latest research has tracked transmission of the superbug, providing the first direct evidence of transmission of the new strain between livestock and humans.

̽��ֱ��researchers capitalised on a growing trend to use increasingly rapid and affordable DNA sequencing for tracking the transmission of pathogens. This technique is helping scientists to look for differences at the level of single letters in the genetic code as a means to map the direction of infection – from patient to patient, and from one animal species to another. ̽��ֱ��team investigated two cases of mecC MRSA in Danish farmers. ̽��ֱ��strains circulating in the farmers’ livestock and those isolated from the patients only differed by a small number of letters – strong evidence that the farmers had acquired their infections from their animals, in one case a sheep and in another a cow.

“ ̽��ֱ��ability to confirm animal-to-human transmission in virtual real time using this technology can’t be underestimated,” said Holmes. “High-throughput DNA sequencing is going to revolutionise clinical microbiology by enabling targeted epidemiological follow-up and infection control.”

Nearing the precipice

Mastitis is the most common infectious disease of dairy cattle, affecting the welfare of cows and, according to one estimate, costs the UK dairy industry around £170 million per year. Its control and treatment relies on the use of millions of doses of therapeutic and prophylactic antibiotics every year. “Our research on MRSA is pointing to the fact that although we are not on the precipice of having the whole system collapse through selection of bugs that are even more resistant or having husbandry systems that make it impossible to eliminate them, we are closer to the precipice than we would like to be,” said Holmes. “As it is, S. aureus is considered impossible to eliminate in dairy herds – you have to live with it once you’ve got it. “Farmers and veterinarians are in a constant battle to improve the health of dairy cows, yet farming cannot be sustained at these levels if it is generating these types of resistance. Moreover, we can’t predict how these bacterial strains will evolve – they could become more resistant, more virulent or better able to jump between species.”
Holmes views the interface between veterinary medicine and human medicine as crucial to understanding infectious diseases such as MRSA: “There is very little research on S. aureus mastitis in cows in comparison to research into it as a human pathogen, and yet now we’re beginning to see exactly the same organism being found in people and in cows. This means that we should be thinking about the epidemiology of disease control and the development of antibiotic resistance in both species. Understanding how new strains emerge will help us to understand the growing public health problem of antibiotic resistance.”

For more information, please contact Louise Walsh at the ̽��ֱ�� of Cambridge Office of External Affairs and Communications.

Scientists who recently discovered a new strain of superbug have now tracked its transmission between animals and humans.

We can’t predict how these bacterial strains will evolve – they could become more resistant, more virulent or better able to jump between species

Mark Holmes

JelleS on flickr

Cow

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Stopping superbugs in their tracks

bjb42 — Mon, 01 Nov 2010 14:10:52 +0000

Hundreds of millions of patients around the world are affected by healthcare-associated infections each year, although the true scale of their global burden and impact on health remains unknown because of the difficulty in gathering reliable data. In developing countries, the problem of such infections is compounded by the fact that the pathogens involved are frequently resistant to the antibiotics available.

Reducing mortality and morbidity from healthcare-associated infections depends on effective prescribing policies based on information provided by diagnostic microbiology, as well as prevention through improved hygiene such as frequent hand washing. ‘One of the major difficulties in resource-poor countries,’ says Professor Sharon Peacock, from the Departments of Medicine and Pathology, ‘is the lack of even simple diagnostic microbiology in many hospitals. As a result, many pathogens go unrecognised.’

Having spent most of the past decade working in resource-restricted areas of south-east Asia, Professor Peacock believes that researchers can help tackle this problem using technology at two ends of the spectrum. ‘By supporting the development of low-cost, sustainable diagnostic microbiology laboratories to identify pathogens, information is generated to guide prescribing and highlight the need for infection control. This also provides bacterial strain collections that can then be examined using cutting-edge tools to define transmission pathways of important pathogens at local, national and global levels.’

Detective work

̽��ֱ��antibiotic-resistant MRSA ‘superbug’ has a deservedly high profile across the developed world but is barely on the radar in developing countries. For example, until recently, there had been no documented report of MRSA in Cambodia. This isn’t because the country has remained completely free of the pathogen but simply because there were no facilities to detect its presence. Now, the Angkor Hospital for Children in Western Cambodia has such a laboratory, the development of which was supported by a team led by Professor Peacock while working at the Wellcome Trust-Mahidol ̽��ֱ��-Oxford Tropical Medicine Research Unit in Thailand, where she continues to support research following her move to Cambridge in 2009.

Within a month of opening, the first child with MRSA infection was identified. And, with continued support from Cambridge- and Thailand-based researchers, the laboratory has recently reported that MRSA causes infection in both the hospital and the community, and is being carried by a proportion of the population.

̽��ֱ��impact of detecting these and other multi-resistant pathogens is potentially huge, explains Professor Peacock: ‘Such information alerts healthcarers and policy makers of the possibility of infection with these organisms and the risk of treatment failure using the readily available antimicrobial drugs, as well as supporting the need for hand washing to reduce spread among hospital patients’.

Tracking the global spread of multi-resistant pathogens

As highlighted by a study published this year in Science magazine, cutting-edge technology also has an important role to play. In this study, Professor Peacock was part of a team led by the Wellcome Trust Sanger Institute at Hinxton, Cambridge, which developed high-throughput genome sequencing to study the transmission of a single clone of MRSA that has become disseminated across much of the world.

Existing techniques were unable to discriminate between individual strains, but genome sequencing showed that no two strains were genetically identical. ̽��ֱ��beauty of the technique is that it allows healthcare officials to see how MRSA, or any other pathogen, can evolve and spread – from person to person, from hospital to hospital, and from country to country.

Professor Peacock’s research is continuing to use this sophisticated technology to inform better infection control of MRSA, and other pathogens, in hospital settings. ‘Being able to feed this information back to hospitals,’ she explains, ‘is key for interventions to be targeted with precision and according to need.’

For more information, please contact Professor Sharon Peacock (sjp97@cam.ac.uk) at the Departments of Medicine and Pathology. Professor Peacock chairs the Cambridge Infectious Disease Initiative, one aim of which is the development and translation of research in developing countries.

Work in resource-restricted healthcare settings in south-east Asia is defining the transmission of hospital ‘superbugs’ using low-tech diagnostics and high-tech tools.

One of the major difficulties in resource-poor countries is the lack of even simple diagnostic microbiology in many hospitals. As a result, many pathogens go unrecognised.

Professor Sharon Peacock

Matt Holden, WT Sanger Institute

MRSA

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Superbug detective

bjb42 — Sat, 01 May 2010 00:00:00 +0000

On returning to the UK after seven years in Thailand researching infectious diseases, Cambridge's new Professor of Clinical Microbiology, Sharon Peacock, has taken up with an 'old friend', as she resumes her long-standing research interest in the bacterium Staphylococcus aureus, particularly the MRSA strains that have become resistant to the antibiotic drug methicillin. ̽��ֱ��increasing incidence of antibiotic resistance in such bacteria is a global health threat. Her expertise is helping to drive a programme of research that will track and block routes of transmission for these 'superbugs'.

Based within the Departments of Medicine and Pathology, and working closely with the Health Protection Agency and the Wellcome Trust Sanger Institute, Professor Peacock has recently returned from the Mahidol-Oxford Tropical Medicine Research Unit in Thailand. There, she directed a wide-ranging programme of bacterial disease research focused on prevalent diseases in South-East Asia. This included clinical treatment trials, diagnostic test development and the molecular epidemiology of several bacteria.

Professor Peacock has also had a long-term interest in MRSA, which over the past four decades has spread around the world and is resistant to many of the antibiotics commonly used in hospitals. ‘Tracking how MRSA spreads can be likened to playing detective since it’s all about trying to identify and follow specific strains of bacteria as they move globally, between countries and between individuals,’ she explained. ‘It’s important that we can do this because measures can then be introduced to further reduce transmission in settings where the bacteria pose the greatest problem such as hospitals.’

Through a collaboration with the Wellcome Trust Sanger Institute, her research has already had a dramatic impact on moving forward the detective story: in 2004, the genome of the MRSA strain that is a common cause of hospital-based infection in the UK was sequenced; and in January 2010, a new method for tracking transmission routes based on the rapid sequencing of genetic differences between strains was published in Science. Her focus now is to translate these research tools from the laboratory into the clinical setting, so that preventive interventions can then be targeted with precision and according to need

What’s the best piece of advice you’ve ever been given?

‘Make it hard, but make it look easy’; in other words, challenge yourself, but don’t let on that it’s so difficult. I’ve always tried not to settle into a comfort zone for very long before I’m looking for the next challenge, and the one after that.

Have you ever had a Eureka moment?

Yes – when I realised that what I really wanted to be was a doctor. But, at the time, I was six months into student nurse training, and having left school at 16 almost empty handed and without the O-levels I needed to study medicine. It was only when I saw how enthralling the whole diagnostic process was – taking a history, examining the patient, carrying out investigations, and reaching a diagnosis – that I knew that’s what I wanted to do. I had a very long way to go to achieve it. I did my O-levels at night school, then my A-levels part-time while working as a nurse to fund myself. It was quite difficult to get into ̽��ֱ�� to study medicine because of this unusual background, but Southampton ̽��ֱ�� gave me the opportunity. I haven’t really had a Eureka moment since – I’ve just been trying to achieve what I set out to do all those years ago!

If you could wake up tomorrow with a new skill, what would it be?

Wouldn’t it be good to wake up and realise you could run a marathon? I’m a very keen spinner – it’s a fitness regimen using a specially designed stationary bike – and I’d love to have the fitness of a marathon runner.

What is your favourite research tool?

There’s no doubt that access to information on the scale the internet provides has revolutionised the way we do our work. It’s hard to imagine that, when I was a medical student, finding scientific articles involved a trip to the library and locating the right volume of Index Medicus on a bookshelf, all to provide what PubMed does at the touch of a button. ̽��ֱ��other major research tool for me is the advent of high-throughput sequencing technology, and the speed with which we can now sequence genomes and tell individual strains of bacterial pathogens apart, some of which may only differ at a few bases of DNA. It’s an incredibly powerful tool in the battle against the spread of bacteria.

What will the future look like in 2050?

Antibiotic resistance in bacteria is a result of the widespread use of antibiotics over recent decades. Unless we embark on a better global vision for conserving the efficacy of current drugs by limiting their use, this will be a major problem in the future. However, we’ll have a better genetic understanding of bacterial pathogens and based on this I hope that we’ll be able to identify weaknesses that can be targeted with a new generation of antibiotics. And, crucially, many of the technologies that are now becoming available for diagnosing and tracking disease will be translated into cost-effective clinical tools. Even in the face of rising antibiotic resistance, we’ll have the front-line measures to understand and reduce bacterial transmission and limit the spread of infection.

̽��ֱ��expertise of Cambridge's new Professor of Clinical Microbiology, Sharon Peacock, is helping to drive a programme of research that will track and block routes of transmission for superbugs.

Tracking how MRSA spreads can be likened to playing detective since it’s all about trying to identify and follow specific strains of bacteria as they move globally, between countries and between individuals."

Sharon Peacock

̽��ֱ�� of Cambridge

Sharon Peacock

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Yes