SCIENCE LECTURE

MRSA Epidemiology & Evolution

Chaired by Andy Pepperdine

Dr Mark Enright

University of Bath

21 April 2005

Dr Enright is a senior researcher at the University of Bath and acknowledges the support given to him for research into MRSA from the Wellcome Trust and the Royal Society.

MRSA (methicillin resistant Staphylococcus aureus) has hit the headlines recently as the number rises of serious cases of infection in hospitals, which have been attributed to this bacterium. However, it is not only in hospitals that it can be found, and there is now evidence of resistance to antibiotics growing among the strains that are in the community.

It has been known for some time that bacteria can evolve to become resistant to the antibiotics that are commonly used in hospitals, for example, strains of Enterococci, Acinetobacter, Pseudomonas, Aeromonas as well as MRSA can be found, although MRSA is the most important from the point of view of infection and transmission rates. In the general population, there are other bacteria that are becoming resistant, like strains of Streptococcus, Haemophilus, Moraxella and again MRSA. We would like to know more about how these bacteria spread and acquire their resistance so that appropriate steps can be taken to control the occurrence and spread of the diseases they cause.

In the US, in 1989, about 20% of cases of S. aureus infections in hospitals were due to MRSA. By 2000, this figure had risen to about 50%. In the UK, the figures are slightly less and are about 47% now. In parts of Asia, especially Japan, the number is greater than 70%. In Europe, the picture is more mixed. In most of the countries bordering the Mediterranean, and in southeastern Europe, more than 25% of cases are due to MRSA, but in the Netherlands and Scandinavia, less than 1%. It is noticeable that these latter countries immediately put in place a strategy for controlling the pathogen on a national scale; whereas the others have tried to manage the situation as it develops without an overall plan.

S. aureus has always been with us. The first chemical attacks on it were with penicillin in 1944, but even by 1946 there were reports of some resistance to it. Another antibiotic that came into use, methicillin, is chemically similar to penicillin, and resistance to that was also rapidly acquired. A completely different type of antibiotic, vancomycin, was the last reliable defence against the bacterium until 2002 when the first reported resistant MRSA strain was found in the US, 40 years after the first use of the drug. And now there are strains that are resistant to even the most recently developed drugs. It is important for us to know how these bacteria acquire their resistance and so determine whether we can slow their progress or evolutionary development, since the prospect of even newer treatments is not good. The big drug companies are less willing to concentrate on antibiotics that are used infrequently and can cure a disease; their main commercial goals are for repeat business and drugs that are used frequently over long periods of time. The smaller companies are more prepared to take the risks, but cannot afford on their own to perform the necessary medical trials to ensure the safety and efficacy of the drug and its best mode of use.

In hospitals, there are a number of factors contributing to the prevalence of infection, for instance, patients are usually ill from some other disease, are usually older than average, and the use of catheters can produce the openings the bacteria need to cause infection. Resistance can arise in these circumstances as they are being more frequently challenged by antibiotics, as the infections are treated. In the UK, there are two strains that account for over 96% of all MRSA blood infections; these are known as EMRSA-15 and EMRSA-16. Infections have increased in line with the appearance of clones of these two strains. E-15 is resistant to methicillin, ciproflaxicin and erythromycin, is associated generally with women over 80 years old. Methicillin resistance is conferred on it by the small gene SCCmec class IV, only 24kilobases long. E-16 is resistant to some other drugs too, is associated with 60-80 year old men, and its resistance is given by SCCmec class II which is twice as long an element.

In order to study these strains, a typing method has been developed involving partial sequencing of seven genes to identify variants (alleles) of each. These allelic profiles provide an indication of how the various strains are related and how each may have evolved from other strains. In this way a number of strains have been found to have identical profiles and are called clones. The relationships established between a large number of strains show that there are five separate lineages of hospital-acquired MRSA, although this analysis does not show how or from where the resistance was acquired. But there is evidence that the strains that first acquire the resistance are weaker than their antecedents, but that over time they evolve to become fitter.

In 1997, in Japan and the US, the first reports were made of a strain of MRSA that had reduced susceptibility (VISA) to vancomycin. Then in 2002, in the US, 4 cases of resistant (VRSA) were found in patients that probably had vancomycin-resistant enterococci too. It is thus likely that the genes were transferred from one species to the other, an occurrence that is considered to be very rare. VISA however occur in 5 distantly related MRSA strains and show a high cost as they grow more slowly than their wild cousins and are unlikely to spread. They should be fairly easily controlled when found. However, VRSA shows no such cost and poses a greater danger to public health if it becomes common.

Away from hospitals and in the community, the position is different. Most of the strains of MRSA are resistant to all β-lactam antibiotics and also contain the Panton Valentine leukocidin (PVL) gene, which enables the bacterium to infect healthy children and young people, making it more virulent than hospital clones. Work is going on to establish how it might be related to a strain known as phage 80/81, which was first identified in the 1950s, but may have been around in 1927. All the 80/81 isolates examined have the PVL gene, which gives them the ability to cause local epidemics as has been documented over the decades,and around the world. So far these community-acquired forms are not so resistant to so many drugs, but they are much more virulent than the hospital forms, and we can expect resistant forms to evolve over time.

In the UK at the moment the bed occupancy approaches 100% in some hospitals. This makes it impossible to isolate infectious patients when they are found, when an occupancy rate of 80-85% would be preferable. By contrast, in the Netherlands, the occupancy is around 60%, making the separation of infected patients much easier. They, along with Scandinavia, have carried out a ‘search and destroy’ campaign against it from the early 1990s, with clear effect.

A vaccine is under test, but it would have to be given to everyone. However, we have an uneasy relationship with this bug. About one third of us carry it in our noses all the time, and it is not pathogenic unless it gets into a wound. Another third never carry it; the remainder carry it occasionally. Removing this bug may allow others to colonise the vacant spaces with unforeseen consequences.

Further reading