DR. CORDOVER: My name is Mitch Cordover. I am a practicing emergency physician at a large urban medical center where we are treating an ever-increasing number of patients who present with Community-associated methicillin-resistant Staphylococcal infections (CA-MRSA). We know from studies published in the Annals of Emergency Medicine and other professional journals that this increase in CA-MRSA cases in the ED is widespread, and continuing to expand. This CME course, MRSA: An Emerging Crisis in the ED, has been created to provide timely information and guidance on dealing with this fairly recent phenomenon.

We are fortunate to have as the principal faculty for this course Dr. Barry Fox, who is Clinical Associate Professor of Medicine at the University of Wisconsin School of Medicine, a member of the faculty in the Division of Infectious Diseases at the University Medical Foundation and University Hospitals, and Director of the Anti-Infective Program.

Dr. Fox, we have a number of questions that we’re going to ask about the pathogen of CA-MRSA. To begin, can you give us some background on this resistant organism?

DR. FOX: It’s interesting to trace the history of resistant Staphylococcal infections. In the 1940’s, when we first developed penicillin and sulfa-based medications, all Staphylococci were susceptible to plain penicillin. However, it did not take long for Staphylococcus to become resistant to penicillin. The mechanism of this resistance was the production of a simple beta-lactamase enzyme which cleaved the 5-member beta-lactam ring of penicillin and subsequently rendered penicillin ineffective in its prevention of cross-linking of the cell membrane.

In the 1960’s, when penicillin-resistance was prevalent, we needed antibiotics for the treatment of Staph aureus infections. Fortunately, we were able to modify or adapt the penicillin molecule to the class of antibiotics known as semi-synthetic penicillins. At the same time, the whole class of antibiotics known as cephalosporins was developed in order to treat Staph aureus infections that had this beta-lactamase mechanism of resistance.

However, Staph aureus is smarter than we are and microbes in general are smarter than we are, so it didn’t take long for Staph aureus to develop a new mechanism of resistance against the penicillinase-resistant penicillins and the cephalosporins. Staph aureus subsequently developed an altered penicillin binding protein, usually penicillin binding protein 2, and hence methicillin-resistant Staph aureus was born in the 1960’s and 1970’s.

We actually didn’t hear much about this until the 1980’s when the frequency of MRSA in hospitals and long-term care facilities started to increase to 5% or 10%. Even then, when we had patients outside the hospital, we virtually would never think of them having methicillin-resistant Staphylococcal infections. We were concerned also in the 1990’s that Staph aureus would take the resistance issues one step further. The only antibiotic we had that was effective for Staph aureus and MRSA at the time was vancomycin. We very much feared as infectious disease specialists in the early 1990’s that Staph aureus would become resistant to vancomycin and hence we would return to the pre-antibiotic era with no antibiotics at all effective against Staph aureus.

Since we know that Staph aureus is the most serious cause of endocarditis and osteomylitis, and that it is the most common cause of infections in diabetics and patients that are above the age of 65, infectious disease specialists were really fearing the day of the return to this pre-antibiotic era. We’ve been very fortunate so far that in the United States, there are only 6 or 7 isolates of Staph aureus that are truly resistant to vancomycin. There has however, on a more sophisticated basis, been a trend towards an increasing need for higher concentrations of vancomycin to treat Staphylococcal infections and there have been strains of Staph aureus that are known as vancomycin intermediate Staphylococcus, or VISA-based organisms.

What really has happened is that aside from the use of vancomycin, we are fortunate that there are several new anti-infective agents available for the treatment of MRSA including daptomycin, linezolid, tigecycline, and some other upcoming anti-infectives.

The frequency of methicillin-resistant Staph infections in hospital-associated institutions (HA-MRSA) has tremendously increased through the 1990’s and through the early 2000’s. In surveys of hospitalassociated organisms, the average rate of MRSA organisms in the institutions of the United States hovers around 50%. Now certainly those numbers are going to be different in one institution or another. We are blessed at the University of Wisconsin Hospital in Madison to have a prevalence rate that is relatively low, in the 30% to 35% range. However, as a visiting professor I have also visited other institutions where the rate of MRSA infections in the hospital is as high as 65% or 70%.

So the average is about 50% and again, these are local factors that need to be taken into account when assessing infections. We also expect that the rate of MRSA is going to be about 10 percentage points higher in the intensive care units of any hospital because of the severity of illness and the subpopulation of patients that would be in the intensive care unit. We also know that approximately 25% to 35% of all post-operative wound infections are going to be due to methicillin-resistant Staph, either community- or hospital-associated strains and hence, in most institutions, most post-operative wound infections need coverage with antibiotics for methicillin-resistant Staph, at least until culture information is available.

Infectious disease specialists are often faced with patients that have late-onset hospital-associated pneumonia, either on the general hospital ward or in the intensive care unit and virtually all of those Staphylococcal organisms are due to the hospital-associated strain of methicillin-resistant Staph.

The era of community-associated methicillin-resistant Staph had its beginnings in 1999 when the Center for Disease Control Morbidity and Mortality Weekly had an issue that was titled “Four Pediatric Deaths from Community-associated methicillin-resistant Staph aureus in Minnesota and North Dakota.” This was a report of four Native American children with no risk factors for resistant Staphylococcal infections dying of Staphylococcus that had methicillin resistance. And this isolated report was the harbinger of the community-associated MRSA era and got our attention for looking at this new strain of community-associated methicillin-resistant Staph.

Those of you in the emergency department may wonder, “How did this clone, or how did this organism really come to be?” There is still much speculation about how Staph aureus has acquired this MEC-A genetic component and the PVL-related toxin. In the references with this course you will find more detail, but one relatively highly regarded hypothesis is that the resistance plasmid, which harbored the MEC-A gene which encodes for the alteration in penicillin binding proteins, was transferred from Staphylococcus Epidermitis to Staph aureus. Subsequently when this Staph aureus also acquired the PVL genetic component, this made the community-associated MRSA an ideal candidate for causing skin and soft tissue infections and also being resistant to beta-lactam drugs.

I would encourage you as emergency department physicians to read the articles from the New England Journal of Medicine entitled “Methicillin-resistant Staph Disease in 3 Communities” and “Methicillinresistant Staph aureus Infections in Patients in the Emergency Department” for some first-hand experience of emergency department physicians managing community-associated MRSA infections. (Please see Appendix, References and Resources.)

These articles were based on experiences in major urban medical centers where there is a higher frequency of patients with community-associated MRSA and hence the proportion or percentage of patients that had MRSA in these emergency departments is likely higher than your local hospital. However, I do believe that there’s likely a higher proportion of community-associated MRSA patients that will present to the emergency room because these are possibly patients that are less likely to seek healthcare from primary care physicians given the demographic populations involved. So, while the general community may have a MRSA rate that is as low as 1% to 3%, it is still certainly possible that the percentage of patients that have community-associated MRSA presenting to the emergency department may be as high as 25% or 30%.

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DR. CORDOVER: How common is it for patients to be colonized with Staph aureus of the skin?

DR. FOX: I think you’re aware that the most common organism on the skin is Staphylococcus Epidermitis. In large population studies in the United States, about 30% of patients, at one point in time, will be colonized with methicillin-resistant Staph. If you bring the same group of 100 or 1,000 people back a month later, it might be slightly different patients that would be colonized with Staphylococcus Aureus. When we look more specifically at the concept of what’s called methicillinresistant Staphylococcal colonization, it’s actually closer to about 1% of the general population that is colonized with resistant Staphylococcus. However, there are certainly subgroups of individuals that are at higher risk for colonization with resistant Staphylococcus and we’ll go through this a little bit later. And certainly geographic location is also going to play a role in the percentage of patients that might have background colonization with methicillin-resistant Staphylococcus on their skin.

Another issue that arises in the epidemiology of transmission of community-associated MRSA is the long held dogma that the nose is a site of colonization for resistant Staphylococcus. This is not necessarily true for community-associated Staphylococcus. We know that for hospital-associated strains of methicillin-resistant Staph, the nose is a frequent site, and it is not uncommon for infection control or infectious disease specialists to do nasal swabs and even apply more rapid molecular-based technology to screen for patients that have methicillin-resistant Staph on admission to the hospital or admission to the intensive care units. However, when we look at the epidemiology of community MRSA, the nose is really not considered to be a reliable marker. It is postulated that community-associated MRSA is much more frequently transmitted by skin-to-skin contact and actually by fomites that would exist in the environment or by direct transfer from one patient to another and not the nose as a sequestered focus where you would constantly repopulate the skin by touching the nose.

So, a negative nose culture screen for MRSA is not necessarily predictive that the wound will not be a community-associated MRSA strain. In addition, the routine use of mupirocin-based products for the nose cannot routinely be recommended for patients with community-associated MRSA. This is a strategy that had been widely adopted for hospital-associated strains of MRSA to prevent transmission or to reduce the frequency of infection. It’s actually recommended from the Center for Disease Control for dialysis patients to consider using nasal mupirocin to reduce frequency of dialysis-related MRSA-based infections. But this cannot routinely be recommended. On the other hand mupirocin, which is generic now, can have other roles for the management of skin and soft tissue infections.

Rather than prescribe antibiotics, I think it is perfectly reasonable if you do not believe a patient needs systemic antibiotics, to send the patient home after incision-and-drainage with topical mupirocin to potentially provide some local-based antimicrobial therapy. However, to the best of my knowledge, there’s been no randomized trial that tells us that the addition of mupirocin to those particular boils or carbuncles that have been lanced will definitely speed resolution.

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DR. CORDOVER: Is the rise in resistant Staphylococcus in the community the epidemic that has been reported in the press recently?

DR. FOX: Yes, it is, and the epidemic that has been reported in the lay press recently is the community based (CA) strain of resistant Staphylococcus. This was prompted in the media by the report in JAMA that the percentage of invasive Staphylococcal infections in hospitalized patients has nearly doubled in the past 10 years. And again, the predominant organism of this is the community-associated strain of resistant Staphylococcus.