November 2009
Feature Story

Anne Ford

Call it the equal-opportunity infection. Whereas methicillin-resistant Staphylococcus aureus once affected mostly people who had been exposed to the health care system or crowded conditions such as prison, it now has the potential to pop up in just about anyone, anywhere, anytime. “In 2009, if someone comes in with a skin infection, I don’t care who they are—they could be the Pope, the Dalai Lama—they have MRSA until proven otherwise,” says Loren Miller, MD, director of the Infection Control Program in the Division of Infectious Diseases at Harbor-UCLA Medical Center. “You don’t have to have been in the hospital. You don’t have to have been in jail. If you have skin, you can get MRSA.”

As anyone who’s read a newspaper in the past few years knows, the prevalence of MRSA, combined with its disconcerting ability to cause illness in otherwise healthy people, has led to a virtual public health crusade against it. Several states now mandate that hospitals perform active MRSA surveillance for at least some patient populations, and a Chicago-based group called the MRSA Survivors Network recently declared October MRSA Awareness Month. “MRSA has gotten a lot of media play,” says Michael B. Edmond, MD. “It’s an organism that the average person can talk about. Five years ago, if you said the word ‘MRSA,’ they wouldn’t have a clue.” Dr. Edmond is professor of internal medicine, epidemiology, and community health as well as chair of the Division of Infectious Diseases and associate chair for education in the Department of Internal Medicine at Virginia Commonwealth University, Richmond, and hospital epidemiologist for the university’s health system.

But is MRSA receiving all this attention at the expense of other multidrug-resistant organisms? How should the screening and treatment of MRSA infections vary by setting? And what are the latest tests and treatments? Those were some of the questions that Dr. Edmond, Dr. Miller, and others addressed in interviews with CAP TODAY and in a session titled “MRSA Everywhere: Implications for Prevention” at the American Society for Microbiology’s general meeting in Philadelphia earlier this year.

In his portion of the ASM talk, Dr. Miller addressed community-acquired MRSA, or CA-MRSA, which, he noted, can colonize or contaminate almost anything, from plastic, metal, and cloth to salt- and freshwater. Despite the attention it often receives in the media, some physicians remain unaware of CA-MRSA’s ability to infect otherwise healthy people, he now adds. “I can tell you anecdotally that even in 2009, there are still many health care workers who are not aware of this,” though “I think that knowledge is increasing.”

It doesn’t help that, in his view, MRSA protocols for health care facilities are few. “The Infectious Diseases Society of America has guidelines for treating skin infection, but they were developed before the rise of CA-MRSA, so those haven’t been updated yet, for example,” he says. “I don’t know too many hospitals that have policies about how to treat skin infection, but my sense is that they aren’t many. My concern is that there are many policies and procedures out there that haven’t been updated since MRSA became so common.”

That dearth of protocols may stem from a dearth of data. “The question I always get is: How can we control CA-MRSA?” Dr. Miller says. “The short answer is ‘We still don’t know.’ It would be quite difficult, because staph colonizes humans asymptomatically very commonly. At least one-third of humans are colonized.” Not only that, but sites of potential colonization are still being discovered: “Older studies suggest that the nose is the part of the body where people are colonized, but there are mounting studies suggesting that people are colonized in the pharynx and various places on the skin, such as the inguinal fold.”

It’s especially frustrating when CA-MRSA infection recurs several times in the same person. “They come and see a physician, and they say, ‘I’ve had three or four MRSA infections. How can I control it?’” Dr. Miller says. “The surprising thing is, we have really no good data on that. There’s a lot of doctors who recommend things, but there’s really poor evidence to support specific treatments. For example, decolonizing patients with a nasal topical antibiotic in combination with a body wash that’s a potent antimicrobial, such as chlorhexidine or hexachlorophene. A lot of people recommend those to decolonize patients, but how well they work is not well understood.” That said, he’s quick to add, “It doesn’t mean they don’t work.” He’s helping to conduct a clinical trial now that aims to discover whether eradicating CA-MRSA on household surfaces (such as with bleach wipes and sprayable alcohol) or decolonizing patients, or both, can prevent infection. He also recently presented a small, separate pilot study of 30 CA-MRSA patients who have been treated with topical and systemic antibiotics. This latter study was presented recently as a poster at the Infectious Diseases Society of America’s 2009 meeting. “I don’t know of any other studies that have looked at this,” he says. “People say ‘I use it and it seems to work,’ and that’s about as good as the data we have right now gets.”

In the meantime, Dr. Miller offers suggestions for addressing CA-MRSA. “As there is more community-acquired MRSA, the use of older, generic antibiotics for the treatment of less serious MRSA has gone up, so there’s a lot more use of trimethoprim-sulfamethoxazole and an increased use of clindamycin,” he says. “And there is a type of resistance to clindamycin that’s inducible and not detected by standard microbiological tests. It is detected by the so-called D test.” Most experts in MRSA don’t recommend the use of clindamycin for serious MRSA infection that has a positive D test, he says. “You might have some clinicians, especially infectious disease physicians, recommending the D test for community-acquired MRSA. So laboratories should be familiar with how to do it.” He describes it as simple: “You place a clindamycin disk and an erythromycin disk on an agar plate that has the MRSA on it, and if inducible resistance is there, there’s a characteristic letter D shape that is seen on the plate around the clindamycin disk rather than a circle.”

He’d also like hospitals to be aware of potential limitations with the use of vancomycin to treat MRSA infection, whether community-acquired or nosocomial. “Some strains of vancomycin-resistant staph are not detected with standard microbiologic methods,” he points out. “For example, there have been at least eight cases of vancomycin-resistant S. aureus, and some of those were misidentified initially as susceptible to vancomycin, because susceptibility testing was done using an automated method.” He refers to the Vitek and MicroScan systems and says, “Those sometimes incorrectly quantify vancomycin susceptibility and misread resis­tant or intermediately resistant strains as susceptible. But when older, more accurate tests are done, such as broth dilution, they are found to be vancomycin-resistant, or vancomycin intermediately susceptible. One should consider, if a patient isn’t responding, doing a more accurate test to quantify vancomycin susceptibility.”

In addition, he cautions physicians that vancomycin use may induce resistance to a newer antibiotic, daptomycin, that seems to work well for skin and bloodstream MRSA infections. “If, for example, a patient has a bloodstream infection that’s difficult to control and the cultures are repeatedly positive on vancomycin, and the physician wants to switch to daptomycin, they should get susceptibility to daptomycin as well,” he says. “This is uncommon, but it’s been reported several times, so it’s something to look out for.”

There’s another way that microbiology laboratories can use susceptibility testing to help clinicians, too. “Some strains that are resistant to tetracycline are actually susceptible to doxycycline and minocycline,” Dr. Miller says. “So if a clinician wants to use doxycycline or minocycline for a skin infection, even if it’s tetracycline-resistant, you can still test it for those other drugs, and it might be susceptible. There’s a pretty reasonable chance.”

In the acute-care setting, the MRSA debate continues to center largely on the question of whether or not to implement active surveillance cultures with contact precautions, or ASC-CP. Sometimes referred to as “search and destroy,” ASC-CP entails testing all hospital patients for MRSA upon admission and imposing contact precautions on anyone found to be colonized—meaning the patient is either isolated in a private room or shares a room with another MRSA patient, and that anyone entering that room must wear a gown and gloves. The colonized patient may be treated with mupirocin ointment in the nares twice a day for five days and asked to shower with chlorhexidine on days one, three, and five after admission. Critics say the strategy is expensive, impractical, unproven, and even potentially harmful to the patient. Advocates say that ASC-CP can drastically reduce a hospital’s MRSA infection rates, and that it yields a high return on investment by saving the hospital dollars that would otherwise be spent on treatment.

One of those advocates is Lance Peterson, MD, director of microbiology and infectious disease research at NorthShore University HealthSystem, Evanston, Ill., and clinical professor in the Department of Pathology, University of Chicago Pritzker School of Medicine. In 2005, NorthShore (then Evanston Northwestern Healthcare) became the first health care system in North America to implement universal MRSA surveillance and decolonization, as reported in CAP TODAY (“Mitigating MRSA, steps ahead of the law,” May 2008). The results, Dr. Peterson says, have been phenomenal. “We’ve been able to show a dramatic reduction in disease—70 percent reduction of MRSA infection in the first year,” he says. “This is at a time when most hospitals in Illinois are still seeing an increase.” As for expense, “we published our cost-effectiveness data in the Joint Commission Journal on Quality and Patient Safety in December 2007, and showed that our return on investment was easily $3 for each dollar spent.”

Sensitive, accurate, and fast MRSA testing is crucial to good surveillance, Dr. Peterson says. NorthShore uses the BD Gene Ohm MRSA PCR-based test, which yields about 98 percent sensitivity. “If you’re using a traditional agar-based test, where you just put a swab onto agar, the sensitivity drops to 80 percent,” he cautions. “It’s important for laboratories to really pay attention to how they’re testing, because they become a key component as to whether the program’s going to be successful or unsuccessful. You can certainly spend a lot of money doing MRSA surveillance, and if you have an unsuccessful program, then you basically just wasted all of those resources.”

To hear critics of ASC-CP tell it, the entire approach may be a waste of resources. Says Virginia Commonwealth’s Dr. Edmond, “The [ASC-CP] programs have high opportunity costs, because unless your hospital is going to add lots of resources to offset your diversion, you’re going to have a negative impact on your overall infection control program” if you fund a MRSA active surveillance program at the expense of other infection control activities. He frowns on the vertical approach to infection control that MRSA-specific infection control programs represent, citing CDC findings that less than 10 percent of infections in the ICU are due to MRSA. “What we ought to be doing is not designing programs that are vertically based: a specific program for MRSA, a specific program for C. diff, a specific program for K. pneumoniae carbapenemases, whatever organism you want to name. The patient doesn’t come to the hospital saying ‘I don’t want to get a MRSA infection.’ If you’re the person who gets an infection from C. diff, you’re not going to be happy that you didn’t get a MRSA infection.” MRSA active surveillance programs, he says, divert energy, time, and thinking from the bigger picture: “Where we ought to really put our time and energy and effort is into activities that have the capacity to reduce” infections across the board, Dr. Edmond says.

Mary-Claire Roghmann, MD, associate professor of epidemiology and preventive medicine at the University of Maryland School of Medicine, agrees, saying, “I think what we have to do is balance the interventions we put in place so they serve double duty. For instance, in the long-term care facility, I’m just as worried about flu as I am about MRSA, and so I want to make sure that the infection control precautions I have in place are going to reduce the risk of flu being transmitted in the same way they reduce the risk of MRSA. Less than 10 percent of hospital-acquired infections are due to MRSA. We should not ignore the other 90 percent.”

MRSA-specific active surveillance programs, Dr. Edmond adds, also pose the danger of diverting attention from other infectious organisms that may represent even greater threats. The organisms that concern Dr. Edmond now are the multidrug-resistant gram-negative rods. He says: “We have several drugs we can use to treat MRSA infections. For some of the gram-negative rods we’re seeing now, there are no treatment options. And yet, do you hear anybody on television talking about that, or are there any expert advocates for these organisms? And these organisms are occurring less frequently, meaning we’re much earlier in the progression of their epidemiology, and we could likely have a greater impact on controlling them.”

Dr. Miller’s perspective on active surveillance cultures with contact precautions for MRSA: “I’m underwhelmed. If it were cheap and safe, I’d say, ‘Well, the data aren’t in, but it may be reasonable to do it now.’ But it is not cheap to do, and there are some data that being under contact precautions may worsen patients’ outcomes.” In addition, he says, “I have bigger battles to fight than to ask my administrators to pay a lot of money for a rapid test that costs about $200 apiece. But I may be wrong. I’ll be the first to admit, five or 10 years from now, maybe it’ll be shown that MRSA screening is a good thing for patients. But right now, the jury is still out.”

What does the literature say? “You can find papers to support either argument—that it works or it doesn’t work,” Dr. Edmond says. “There are many, many papers in the literature in which a benefit has been demonstrated, but those are papers that have relatively weak methodologies. They are before-and-after type studies in which it is very difficult to control for other interventions. On the other hand, the studies that have the strongest methodologies have tended to show that active surveillance does not work.”

Rather than pour resources into ASC-CP implementation, he recommends interventions such as daily chlorhexidine baths for ICU patients, elevating the heads of beds in the ICU to prevent ventilator-associated pneumonia, and steps to reduce central line infections that can stem from the insertion process. “These are the types of things that have impacts on all organisms,” he says. Perhaps most important, however, is “putting tons of energy into the improvement of hand hygiene.”

“Good hand washing trumps any other thing that you do,” agrees Henry F. Chambers, MD, professor of medicine and chief of the Division of Infectious Diseases at San Francisco General Hospital and director of the University of California San Francisco’s infectious disease fellowship training program. “A lot of what other measures—isolating patients, attempts at decolonization, gowns and gloves—are designed to do is to make up for deficiencies in good hand washing.” And, of course, improving hand hygiene has the potential to decrease all rates of infection from many pathogens, not just MRSA.

Dr. Peterson doesn’t disagree that it’s important for a hospital to address all health-care-associated infections. “You need to know for your own facility what your top three infection risks are, and whether they’re going up or down,” he says. “I would clearly agree that if somebody has more of a problem with infection and deaths from C. diff than they do from MRSA, then that should be their No. 1 issue. Each facility needs to look at its numbers.” At the same time, he takes issue with any argument that downplays the dangers of MRSA: “The CDC has estimated that the number of MRSA-related deaths in 2005 across the United States was greater than the number of AIDS deaths. It’s clearly the No. 1 cause of health-care-associated mortality.”

Several large, well-done studies have been conducted in the past few years on the effectiveness of ASC-CP and the role of rapid testing. “What is fascinating,” Dr. Peterson says, “is that we are now starting to understand why some programs work and others do not.” For each of these reports one can calculate the approximate percentage of potential MRSA isolation days that patients are actually in contact precautions based on who is tested, the test sensitivity, time to reporting, and length of hospital stay. “It appears that if a relatively short period—less than one year—is used to assess an intervention when evaluating a MRSA control program, then more than 70 percent of potential MRSA isolation days need to be captured with patients actually in contact precautions,” he says. To achieve this, in his view, only a rapid test with high sensitivity provides a satisfactory result, rapidly detecting more than 90 percent of possible MRSA-colonized patients. “Thus, the main reason that ASC-CP fails, based on the current literature, is that either not enough of the patient population is tested combined with the test being used lacking sensitivity or taking too long for a result to be reported,” Dr. Peterson explains.

Infection control is “not a zero-sum game,” he says, in which control of one infection necessarily leads to less funds for the control of another. In NorthShore’s case, hospital administration is more willing to support the MRSA and other infection control efforts because of the success with MRSA and the cost savings that resulted.

As more hospitals implement active MRSA surveillance—and more states consider requiring them to do so—manufacturers of tests that detect the organism find their products in greater demand. One of those manufacturers is Cepheid, which introduced its rapid genetic Xpert MRSA test last year for use on the company’s GeneXpert instrument. The test’s main advantages, says chief medical and technology officer David Persing, MD, PhD, are its ease of use and short turnaround time, which allows hospitals to avoid isolating patients unnecessarily and to prevent MRSA-colonized patients from spreading the organism to others.

“I like to say that until the GeneXpert came along, the term ‘real-time PCR’ was a bit of an oxymoron because of the high complexity and batch dependence of most PCR protocols, which led to patient results that were anything but real-time,” he says. Every GeneXpert test is designed to inform a specific patient treatment or management decision, he notes. “And in this setting, we think maximum medical value is preserved by minimizing time to result.” In development at Cepheid, he says, is a product intended to detect both MRSA and methicillin-sensitive S. aureus in nasal swabs “as part of a development of a presurgical screening test to inform clinicians about the potential for decolonization prior to an elected surgical procedure.” Dr. Persing is also consulting professor of pathology at Stanford University School of Medicine.

Another dominant test on the market is the one used at NorthShore, the BD GeneOhm MRSA assay, which can provide results in two hours but is complex enough that it is generally performed in batches. Roche introduced in the European Union earlier this year its LightCycler MRSA Advanced test for rapid detection of MRSA nasal colonization. Its sensitivity appears to be similar to that of the GeneOhm test (95.2 percent compared with GeneOhm’s 95.7 percent). Its specificity, however, may be greater (96.4 percent instead of GeneOhm’s 91.7 percent), according to a multicenter clinical trial conducted in part by Dr. Peterson, who says that the possibly higher specificity can be a major step forward but needs to be confirmed. The test is awaiting FDA clearance.

The Abbott Plex-ID system was introduced at this year’s AACC Clinical Lab Expo. Now available for research use only, the system uses a technology that marries PCR with electrospray ionization time-of-flight mass spectrometry, or PCR/ESI-MS. Broad-range and target-specific primers are designed to amplify multiple PCR products, and electrospray ionization is used to determine the nucleic base composition—the number of adenosine (A), cytosine (C), guanine (G), and thymidine (T) bases—of the PCR amplicons. The base composition signature is then compared with a database of the base composition signatures of known MRSA strains. Unlike PCR assays that incorporate nucleic acid probes or microarrays, mass spectrometry detection does not require complete and prior knowledge of products analyzed. Unique genetic sequences can be identified and added to the database if new strains arise.

Donna Wolk, PhD, D(ABMM), took part in a research study, published in October, that examined the performance of a precursor to the Plex-ID system—the T5000 instrument. In the study, bacterial profiling of staphylococcal isolates was performed using PCR/ESI-MS (J Clin Microbiol. 2009;47:3129–3137). Dr. Wolk is division chief for clinical and molecular microbiology, Department of Pathology, Arizona Health Science Center and University Medical Center, Tucson, and associate research professor at the university’s BIO5 Institute.

“The study was conducted to assess the performance of a single test method, the PCR/ESI-MS, in comparison with a battery of standard phenotypic tests for MRSA identification and antimicrobial susceptibility testing as well as genetic testing by single-target PCR, pulsed-field gel electrophoresis, multilocus sequence typing, and repetitive sequence-based identification,” Dr. Wolk says. A diverse group of MRSA strains was used. Three centers contributed MRSA isolates and provided reference testing—the University of Arizona, Johns Hopkins University, and the Centers for Disease Control and Prevention.

“The new technology is important because traditional methods for bacterial strain characterization for health-care-associated infections are labor-intensive, time-consuming, and often costly,” Dr. Wolk says, adding that they may require subjective interpretation and comparison of genotype fingerprint images. In contrast, the PCR/ESI-MS method uses digital data, based on genetic sequences, and should provide a more objective tool, she says, for characterizing drug-resistant microbes. “We hope the method will be adaptable to clinical settings and provide a rapid and comprehensive tool for monitoring drug-resistant microbes.”

The study’s results impressed Dr. Wolk, who says the technology made it possible to combine MRSA identification and genotyping in one rapid and accurate testing platform and that it has the potential to streamline outbreak investigation and public health surveillance. But while the research results are extremely promising, the clinical performance now has to be evaluated in medical microbiology settings. “The broader utility of the methods remains to be assessed in real-time outbreak situations for MRSA and other microbes,” Dr. Wolk says.

“The PCR/ESI-MS method provides an unparalleled breadth of information from one assay—information that crosses boundaries, covering territory of traditional culture, antimicrobial susceptibility testing, and historic genotyping methods.” In less than one day, she says, the method can yield all the information now expected to take several days to compile. “Properly priced and used, it could change the way clinical and public health microbiology labs define their role in controlling and preventing MRSA and other infections.”

Related Links

• The long-term care challenge