MRSA Put to the Test

30 March 2009 (Last Updated March 30th, 2009 18:30)

Could new screening methods be the key to prevention of those infected by the modern world's most common "superbug"? Mark Enright of Imperial College London and Freddie Poole of the US FDA discuss with Lorrie Kelly why "miracle cures" may not be what they claim, and what's on the horizon for detection and treatment.

MRSA Put to the Test

According to the US Centers for Disease Control (CDC) more than 60% of hospitalised patients with a healthcare-associated staphylococcus infection run the risk of contracting Methicillin-resistant Staphylococcus aureus (MRSA).

A solution to the problem clearly must be found, but those in the healthcare industry are skeptical of companies claiming to have already discovered this and giving patients false information. With recent UK headlines proclaiming a cure for MRSA by way of a nasal gel, it's easy to understand why many researchers despair over the misuse of media channels.

"My colleagues and I think it's pretty disgraceful for newspapers to publish what is little more than PR from a company producing an antimicrobial gel," says Mark Enright, Professor of Molecular Epidemiology in the Department of Infectious Disease Epidemiology at Imperial College, London. "It is very similar in properties to any number of compounds that can be used topically and there is not even toxicity data available for this drug.

Prevalence of MRSA

"For MRSA we are desperate for antibiotics that can be used systemically," Enright explains. "In the UK, about one in nine hospital patients have an MRSA infection that has nothing to do with their reason for being in hospital. The healthcare agency in the UK reports there have been around 5,000 deaths from MRSA but it's probably closer to double that."

According to Freddie Poole, Associate Director of the Division of Microbiology Devices of the US FDA, a 2007 Surveillance report from the CDC estimates that 32% of the US population were colonised with S. aureus during 2007 and of those, 0.8% had MRSA.

"On average, treatment of an MRSA infection in the US can cost as much as $21,000 per patient."

Nearly one in three of us carry S. aureus on our skin or in our nose without ever becoming infected. With such a high prevalence of the bacterium, the CDC recommends that prevention and management of patients, in addition to testing for MRSA, would be the wisest way forward.

"The proportion of healthcare-associated staphylococcal infections that is due to MRSA has been increasing," the CDC says. "There are an estimated 292,000 hospitalisations with a diagnosis of S. aureus infection annually in US hospitals. Of these, approximately 126,000 hospitalisations are related to MRSA."

The vast majority (86%) are contracted within a healthcare setting such as hospitals, nursing homes and clinics.

On average, treatment of an MRSA infection in the US can cost as much as $21,000 per patient: that's more than $2.5bn annually. "Once laboratory susceptibility and resistance tests are completed, physicians may treat based on the patient's clinical presentation," says Poole. "However, basic infection control practices are essential to the prevention and control of MRSA in healthcare settings. The CDC and the Infectious Disease Society of America have guidelines and recommendations that are readily available to healthcare personnel for preventing the spread of infection and managing infected MRSA patients."

Treatment and testing

There are many challenges within the clinical setting to treating and containing these superbugs. "The frontline treatment for MRSA is intravenous Vancomycin for ten to 12 days," says Enright. "So patients must be hospitalised during treatment in order to monitor the IV. The antibiotic is fairly toxic and is quite a big molecule that doesn't penetrate very well."

Though there are alternatives available such as Zyvox from Pfizer which can be given over a shorter course or administered orally, most patients with MRSA blood infection are in poor health, making intravenous infusion the method of choice.

Prior to new-generation rapid results blood tests, it would typically take 24–48 hours for positive identification of MRSA to be grown by culture. "Today, most available technology is based on amplifying DNA," explains Enright. "The problem has been that you can look at the genes for MRSA, and there is one in particular which has been used widely, but you can find the same gene in other types of staph which are not MRSA. They are normal skin flora, especially common in hospitalised patients; so you have to be careful.

"You have to identify the genes for the species and for the MRSA. That's what these new tests do, compared to the old tests which are basically growing the strain and then testing its antibiotic resistance.

"There are some tests that can detect the protein on the outside of the bacterium but again there are problems with specificity. You don't want to have a positive test where you detect the normal bacteria on the surface. You want something that is very specific for MRSA and very sensitive. Polymerase chain reaction (PCR) gives the specificity and sensitivity needed for a good test."

"Ideally, what you would like to do is to test people coming into hospital with the new swabs."

"Tests such as Cepheid Xpert MRSA are walk-away tests," says Enright. "Basically you can just put the blood in it and walk away from it. You don't need to do any further analysis."

The recently FDA-approved BD GeneOhm StaphSR, the first ever rapid-result qualitative in vitro molecular assay, was adapted from existing technology used to detect biological agents such as anthrax in the US postal service.

BD GeneOhm's blood test has proven to be not only 100% accurate in detecting S.aureus from positive blood cultures, but is also 98% accurate in detecting MRSA with lab turnaround times of less than two hours.

In 2007, the British Journal of Surgery published results from a study on rapid screening of MRSA and its effect on overall hospital infection rates. Researchers at the University College London Hospital NHS Foundation Trust conducted trials on 19,000 surgical patients with BD GeneOhm StaphSR assays and concluded that using these two-hour tests to screen patients reduced MRSA infections by as much as 40%.

"Ideally, what you would like to do is to test people coming into hospital with the new swabs," says Enright. "You could find out very quickly whether they had MRSA or not – the quicker the better. However, the problem of where to put MRSA-positive patients requiring hospitalisation is an ever-present worry in the NHS, where high bed occupancy rates frequently preclude effective isolation or cohorting of such patients."

Halting the spread

Since MRSA is an opportunistic bacterium capable of spreading rapidly within the clinical environment, timelines are crucial for early containment of outbreaks. But hospitals and institutions are not the only places where MRSA has been able to thrive. MRSA infections that are acquired in absence of hospitalisation or medical procedure are known as community-acquired (CA-MRSA).

These infections usually manifest as skin infections such as pimples and boils and affect healthy individuals.

In California, rising rates of CA-MRSA have spawned intense interest within the healthcare industry and subsequent mandatory reporting of all MRSA infections occurring outside of hospital and clinical settings is currently being enforced by the Department of Public Health.

"The new types of MRSA which we are seeing are quickly spread between people," says Enright. "But they spread faster in hospitals because people are more sensitive or susceptible to infection. Hospital patients are generally on antibiotics post-surgery for a number of different reasons. Everything that isn't antibiotic resistant is killed off, leaving things like MRSA. This bacterium does very well in that type of environment because there is no competition.

"What we would like to see in the future is not just tests that tell us someone has MRSA but to give an idea of the antibiotics you can use to treat. Having a diagnostic would be fantastic – something cheap, fast and accurate. There are companies working on projects where, hopefully, we can determine the antibiotic profile and MRSA type. Currently, when you have an MRSA infection, you are given antibiotics without knowing if it is even an MRSA infection because traditional tests take so long. You always treat it in advance of really knowing what you've got.

"When someone is in the hospital with a fever and suspected sepsis, the clinician will have to work out from their experience what it is likely to be and, in some cases, you would assume it was an MRSA strain and give them vancomycin. It would only be later that you find out that you could have used other more effective antibiotics. But clinicians have to err on the side of caution.

"Broad-spectrum antibiotics are used in these cases to hit as many targets as possible, and that's the problem; because you are using antibiotics that aren't targeting the cause of the infection. We do know that when patients are treated with the wrong antibiotics, they always do badly compared with people who are treated with the correct antibiotic from the beginning. That's a problem we can't solve quickly enough to begin therapy, so the clinician has to use his judgement in those cases."

"There are a couple of developments coming along that might make things a bit better but, again, we won't be using them the same way and I don't think we can expect to see a new penicillin or anything along those lines in the near future," he concludes.

"The new rapid results tests were cleared for use only in cases where MRSA is suspected."

Further research

Though the new MRSA blood tests will likely improve early intervention timelines, it is too early to tell how much of an impact they will make. However, BD GeneOhm StaphSR has already been used on over 2 million patients worldwide and preliminary studies carried out at Pitt County Memorial Hospital in North Carolina have shown significant reductions in the rate of ventilator-associated pneumonia (VAP) due to MRSA.

During their 12-month study, MRSA VAP rates in the surgical intensive care unit decreased by 68% by implementing a combination of comprehensive infection control protocols and active surveillance using the BD GeneOhm MRSA real-time PCR diagnostic test.

Similar results were found by researchers at Evanston Northwestern Healthcare (ENH) in Evanston, Illinois, who conducted the first and largest study in the US to show the impact of implementing a universal, active surveillance programme to reduce MRSA infections. ENH reported a 70% decrease in MRSA infection rates in less than two years. Interestingly, the ENH study also concluded that screening of post-operative patients did not make a significant difference. The reductions were only achieved when screening all patients prior to hospital admission.

BD intends to follow up its StaphSR assay with a nasal swab and is currently developing a test to identify the vanA and vanB genes associated with vancomycin-resistant enterococci. Poole stated that the new rapid results tests were cleared for use only in cases where MRSA is suspected and may not help monitor treatment, because negative results cannot be used as the sole basis for diagnosis.

"Nucleic acid amplification tests cannot tell the difference between patients with good response to treatment and patients with no response, that is, the test cannot tell if staphylococcus bacteria detected is viable – or treated and dying or dead," says Poole. "Fortunately, the clinical history as well as signs and symptoms the patient presents with, and other medical evaluations can be used to monitor for treatment response.

"Test should not be used as the sole basis for diagnosis because a) it may detect staphylococcus in the absence of active infection (in previously treated patients) and b) it may not rule out the presence of complicating disorders."

Whether the rate of MRSA infections can be slowed remains to be seen. Overuse of common antibiotics has already been shown to increase the spread, and a new type of antibiotic is unlikely to be discovered any time soon. So, is standardised testing of all patients prior to hospital admission the way forward? With this idea still in development, it could be a long time before the superbug-related headlines die down.