American Association for Clinical Chemistry
Better health through laboratory medicine
August 2007 Clinical Laboratory News: The Path to Better MRSA Control

August 2007: Volume 33, Number 8

The Path to Better MRSA Control
How Active Surveillance and Molecular Tests Can Reduce Infections and Transmission
By Deborah Levenson

Each year, almost 2 million patients acquire infections in U.S. hospitals. Most infections are resistant to at least one of the drugs commonly used to treat them, and lead to longer hospital stays and further treatment with second- or third-choice drugs that may be more costly and more toxic than other antibiotics. Meanwhile, the number of such infections caused specifically by methicillin-resistant Staphlycoccus aureus (MRSA) has skyrocketed in recent years. While these bacteria accounted for 22% of hospital staphylcoccus infections in 1995, by 2004 that number had risen to 63%, according to the Centers for Disease Control and Prevention (CDC). New data from a major national prevalence study conducted by the Association for Professionals in Infection Control & Epidemiology (APIC) shows that 46 of every 1,000 inpatients at more than 1,200 healthcare facilities were either colonized or infected with MRSA in October and November 2006. The Joint Commission and the Institute for Healthcare Improvement (Boston, Mass.) both have voluntary campaigns aimed at reducing hospital infection rates, several states have passed or are considering legislation that would mandate reports of hospital-acquired rates, and now the federal government is poised to take bolder action that will put labs at the forefront of identifying infected patients.

A new proposal by the Centers for Medicare & Medicaid Services aims to eliminate reimbursement for patient complications that stem from preventable nosocomial infections, beginning in October. Complicating matters are a growing number of patients who are admitted to hospitals colonized with MRSA acquired in the community or during previous healthcare admissions. Some institutions have begun more active surveillance aimed at reducing transmission by separating these incoming MRSA carriers from other patients. The goal is to quickly identify and separate carriers to prevent transmission, and molecular assays can speed up this process.

“No one is saying you have to use molecular methods, but they make it possible to identify colonized patients and have them in isolation within a few hours, whereas with a traditional culture, the patient with MRSA is usually sitting there with other patients a whole day or two,” noted Richard “Tom” Thomson, PhD, Professor of Pathology at Northwestern University and Director of Microbiology at Evanston Northwestern Healthcare (ENH), which has implemented a very successful MRSA control program at its three hospitals (See Sidebar, below). Thomson has received honoraria from Becton, Dickinson and Company (Franklin Lakes, N.J.), which markets one of two FDA-approved molecular assays that identify MRSA. Molecular assays, however, are just one part of an overall MRSA control strategy, and may not be an immediate, viable option for financially strapped institutions. Molecular testing is much more expensive than culture methods, and its role in preventing transmission ultimately depends on establishing systems of care that enable physicians to match the test’s quick results with prompt clinical action. But if a hospital can implement both molecular testing and effective systems, the combination can offset the huge costs associated with treating MRSA infections.

Reducing MRSA Infections
Two Success Stories

Comprehensive, active surveillance strategies that involve screening incoming patients can result in impressive reductions in rates of MRSA infection, as demonstrated by data from the Veterans Affairs (VA) Pittsburgh (Pa.) Medical Center and three hospitals in the Evanston (Ill.) Northwestern Healthcare (ENH) system.

ENH’s reduction of MRSA rates is widely touted as an example for other hospitals to follow, and for good reason. The ENH program drove a marked decrease in infections after the institution began universal testing by molecular methods in August 2005. According to a case study on ENH’s program in a guide to reducing MRSA published by the Association for Professionals in Infection Control & Epidemiology, in the project’s first 12 months, the three hospitals reduced bactermia cases from a range of 20 to 26 annually during the previous three years to 7. While respiratory cases of MRSA had totaled between 54 and 62 annually in the previous three years, that figure was 28 after 12 months of universal screening.

At the VA Pittsburgh, a sustained MRSA prevention program also brought success. In October 2001, the institution’s program began with a 36-bed unit, and expanded in October 2003 to an 11-bed surgical ICU unit. The third phase, begun in July 2005, extended the intervention to all remaining acute care units. At a recent meeting of the Society for Healthcare Epidemiology of America, VA researchers reported a 39% reduction in MRSA incidence during the final 2 years of the intervention. The proportion of incident methicillin-resistant S. aureus decreased from 63% in the pre-intervention year to 44% in the final intervention year.

After the Pittsburgh success, the VA has expanded the program to 17 other sites. Most local programs are targeting specific units, with the intention of incorporating all inpatient care areas. Some centers have received funding for PCR molecular testing, and VA has said it intends to eventually expand PCR to all inpatient areas. “PCR technology will likely be the future goal and planning should begin immediately,” according to a VA directive for the expanded program.

Part of a Comprehensive Plan

The choice of a molecular or culture screening test is just one part of a comprehensive strategy that stresses risk assessment, notes a March 2007 guide to eliminating MRSA, issued by APIC.

“There should be zero tolerance for hospital-acquired infections,” emphasized Kathy Aureden, MS, and Epidemiology Coordinator at Sherman Hospital, Elgin, Ill., and a member of the APIC Practice Guidance Committee that developed the MRSA guide. “The quicker the identification of an organism, especially if it’s drug-resistant, the quicker the implementation of both specific clinical management of the patient and implementation of infection control interventions. That’s vital for the patient next door.”

The APIC guide emphasizes the potential of active surveillance, versus the passive screening most hospitals perform. In passive screening, hospitals test patients with obvious signs of infection like a purulent wound, whereas active surveillance strategies generally involve screening patients entering areas of the hospital known to have higher rates of MRSA infections—such as the intensive care unit, the APIC guide notes.

Active surveillance programs can also target patients known to be carriers upon admission, suggested Kimberle C. Chapin, MD, Associate Professor of Pathology at Brown Medical School, Director of Microbiology for the Lifespan AMC Healthcare System in Providence, R.I. and recipient of research funding from several companies that have MRSA testing products. Patients at risk for colonization include those who have had recent hospitalizations, come from another healthcare setting such as a nursing home, and those who are on dialysis, in prison, or attend daycare. The ultimate active strategy involves universal screening of all patients upon admission, as performed at the ENH hospitals. But as Chapin points out, “It’s a question of how much screening you can afford. Not everyone has ENH’s resources. Most hospitals will have to decide what testing strategies will give them the biggest bang for the buck.”

Finding Resistant S. aureus: Screening Choices

MRSA screening choices should be made as part of an overall control plan developed in conjunction with infection control, pharmacy, and medical staff, noted Janet F. Hindler, MCLS, MT, Senior Specialist for Clinical Microbiology at UCLA Healthcare, Los Angeles and member of the Dade Behring Microscan (Deering, Ill.) speakers’ bureau.

“Labs and hospitals considering rapid testing by a molecular method must determine if rapid molecular testing for MRSA is worth the extra cost for their facilities, as compared to less expensive, slower culture methods. Numerous factors must be considered, including the speed at which infection control and physicians receive and act on results. If they can’t act soon after results become available, rapid testing may not be worth the added expense,” she said.

Current MRSA screening choices include several culture-based products, two FDA-approved molecular assays, and homebrew molecular tests. The traditional method involves culturing S. aureus and then performing phenotypic antimicrobial susceptibility tests to determine if the isolate is resistant to the methicillin group of drugs, which include oxycillin and nafcillin. Most culture methods yield results within 24 and 48 hours, but special MRSA-screening media now identify most MRSA within 24 hours, according to Hindler. Culture has fewer up-front costs, ranging from about $5 to $10 for negative tests and $10 to $25 for positive cultures, according to Thomson.

Molecular testing focuses on mecA, the gene that confers methicillin resistance. Located in a long sequence know as the mec cassette, it’s not actually detected by the two existing FDA-approved assays. These tests actually target gene sequences within the mec cassette and adjacent to it. If these sequences—which are unique to MRSA— are present, the assays give a positive result. Occasionally, the commercial assays give false-positive results due to a phenomenon known as mecA dropout. Dropout occurs when mutations within MRSA organisms cause mecA to fall out of the cassette, but the sequences detected by the assay remain.

One of the commercial tests is the BD GeneOhm MRSA Assay, marketed by BD (Becton Dickinson and Company) of Franklin Lakes, N.J., and originally sold as the IDI-MRSA assay before Becton Dickinson bought GeneOhm Sciences (San Diego, Calif.) last year. The other assay is the newer GeneXpert, marketed by Ceheid (Sunnyvale, Calif.). Both assays detect MRSA colonization directly from nasal swabs using real-time PCR within 60 to 75 minutes. The BD GeneOhm MRSA and GeneXpert tests offer comparable performance, according to a recently released FDA 501(k) summary for GeneXpert. In Cepheid’s seven-site clinical trial of the two assays in 1,077 patients, GeneXpert’s sensitivity and specificity were 86.3% and 94.9%, respectively, versus 83.3% and 94.4%, respectively, for the BD GeneOhm assay. A side-by-side comparison notes that lesser-trained lab staff can run GeneXpert, classified as moderate complexity under CLIA. (See Chart, below) In contrast, the BD Gene-Ohm assay is a high-complexity assay that requires more training such as that received by medical technologists.

Comparison of Commercial MRSA Assays
Feature Cepheid GeneXpert BD GeneOhm*
Instrumentation Cepheid GeneXpert Dx System PCR equipment
Fluidics Self-contained and automated after swab elution and 2 single-dose reagents Multiple manual steps
Lysis Sonication (automated single-use cartridge) Glass beads (manual)
DNA Target Sequences incorporating the Sequence insertion site (AttBssc) of SCCmec Sequence near the insertion site of SCCmec
Internal Controls Sample processing control and probe check control Internal control
Time to Result 75 minutes 60 to 75 minutes
Users Operators with little clinical lab experience to experienced lab technologists CLIA high complexity technologists

*Originally marketed as the IDI-MRSA.

Source: FDA 510(k) summary

The BD GeneOhm MRSA assay is particularly well-suited to medium to high volume testing situations, according to Andy Guhl, MS, Becton Dickinson’s Vice President for Healthcare-Associated Infections. Predicting that many hospitals will eventually adopt universal MRSA screening upon admission, as some Veteran Healthcare Administration hospitals have, he noted, “If you have more than 12 samples a day, it makes sense to batch process. All-admission screening could mean 50 to 100-plus patient samples a day. Our test is well-suited to batching, although it is designed to accommodate any workflow situation.” Hospitals pay roughly $25 for the BD GeneOhm test and about $30,000 for the necessary PCR equipment it’s designed to run on, according to Thomson and others.

In contrast, MRSA testing experts noted that GeneXpert offers much more convenience at much greater cost. At about $42, the test comes in a cartridge that’s designed to be inserted into Cepheid’s GeneXpert Dx System instrument after about two minutes of hands-on time, according to David Persing, MD, Chief Medical Officer for Cepheid, who added the instrument costs between $25,000 and $35,000. According to Persing, the fact that little training is needed to run his company’s test makes it especially useful during night and weekend shifts when trained personnel are often unavailable and to hospitals that do not have high-complexity labs “and the high priced technologists that go with those labs.” The Cepheid instrument can run as many as 16 samples at once, and each cartridge contains built-in internal process controls, he added. “Specimens can be run in periodic batches, but that only delays time to result. The GeneXpert is more like a current-generation chemistry analyzer, and is as well-suited for running batches as for stat testing on patients being admitted to the ER or those being transferred to the ICU from other areas of the hospital after evening rounds. It allows random-access, on-demand testing with no requirement for batching, and therefore provides deceptively high throughput, mainly because it can be run 24/7 by virtually any warm body in the lab.” Persing noted that the throughput of a GX-16 is over 300 samples per day, “which should be able to handle the comprehensive screening requirements of even the largest medical centers.”

The companies both have forthcoming products for better detection of MRSA. Cepheid is developing a combined MRSA/S. aureus test that will identify mecA and two additional genetic targets in less than one hour, Persing said, noting the targets will enable it to identify strains with empty mecA cassettes. “This matters especially in blood cultures from wound infections, because one can discriminate MRSA false positive results in cases of invasive infection that are most effectively treated with cephalosporins.” The forthcoming BD GeneOhm StaphSR assay from Becton Dickinson—now awaiting FDA approval—will distinguish methicillin-sensitive S. aureus from MRSA from positive blood cultures, nasal swabs, and wounds in two hours, according to Guhl.

Homebrews and Quick Cultures

Some institutions also use homebrew molecular tests to screen for MRSA, but Thomson does not recommend trying to develop them. CLIA requires labs to validate homebrew assays and document that validation, and while that’s often feasible with certain assays, “a molecular test for MRSA is technically very difficult,” Thomson noted. “MRSA from the nose is challenging. The gene we’re looking for, mecA, is in many other types of bacteria, so labs must prove that the mecA is from MRSA specifically. That requires a sophisticated assay,” he explained. “Evanston Northwestern Healthcare has a very extensive molecular lab that uses many homebrews, but they haven’t developed one for MRSA.”

Molecular methods are quick, but less expensive and fairly rapid culture methods also available in Europe, noted Hindler and Rajiv Jain, MD, Chief of Staff at the Veterans Affairs Pittsburgh (Pa.) Healthcare System, Professor of Medicine at University of Pittsburgh program director of a recently begun nationwide VA MRSA initiative that encourages molecular testing. Although a 4-year-long pilot program in Jain’s system used the BD GeneOhm MRSA assay in its last 6 months, Jain suggested that labs and hospitals choose testing strategies carefully and consider newer culture products that can give results in as little as 5 hours. “Clearly the testing technology is still evolving, and hopefully prices will come down. We got reductions in MRSA infections with standard culture. At the same time, there’s room for molecular methods where there’s lots of acute patients who have shorter lengths of stay. If your hospital’s average length of stay is three or four days, you probably can’t afford to wait for a standard culture.”

Molecular technology similar to that used to detect MRSA can identify other active infections and at the same time determine if they are drug-resistant or not, Thomson noted. “We have had molecular technology for a decade, but there are few commercially available tests,” he pointed out. ENH has developed its own homebrew version that detects MRSA in blood culture broths within 3 hours, according to Thomson, who noted that conventional technology needs 24 to 48 hours to yield the same information. “The homebrew test confers a large advantage as far as selecting and dosing antibiotics,” he explained. But he complained that until a commercially available, FDA-approved test—such as the forthcoming BD Gene-Ohm StaphSR assay—can do this, labs are divided into “‘haves’ and ‘have nots’,” creating two standards of care. “The BD test now at FDA is a good first step that applies this technology to MRSA and brings it to everyone. I hope it’s the first of several steps that make the technology apply to other organisms,” he commented.

Decisions about Molecular Testing

The first consideration for implementing molecular testing is a hospital’s MRSA rate and where the organisms are most prevalent, Thomson suggested. The best way to figure this out is a “point prevalence” survey that determines actual MRSA rates at a particular time. Three years ago, ENH surveyed each of its hospitals within a 3-day period, testing every patient in every bed, about 550 in all. The survey revealed that 7.5% of all patients had MRSA, as compared to the 2% “we already knew about,” Thomson recalled. “Point prevalence surveys are something hospitals generally haven’t done. Few know how much MRSA is really in the hospital. They’re usually only aware of active infections.”

But smaller and rural hospitals probably cannot afford this kind of study or even sustain a regular molecular testing program, he added. “But if these hospitals have MRSA, they can reduce its incidence and prevent it. The question is do you use a molecular test or culture? No one says you have to use a molecular test—although they are more sensitive and faster—but there’s no research that shows that they do a better job at reducing infection rates. But everyone generally agrees that they do.”

Noting that MRSA screening has become popular only in the last few years, and that some hospitals don’t screen at all, Thomson suggested that these institutions get started by determining their MRSA rate by either test after implementing a control plan, and then go back and check to see that infection rates are improving. “If you have data that says your plan and test are working, you can make a case to get the money for a more sophisticated test,” he offered.

Making a Case for Molecular Tests

In order to make the case for more money to implement molecular MRSA testing, Chapin suggested that laboratorians emphasize that MRSA testing is more than the cost of assays, plates, and instruments, and focus on the potential to offset huge costs associated with MRSA throughout the hospial. A systematic audit of published hospital-associated infections reports has estimated the mean cost of a MRSA infection at a hefty $35,367 (Am J Infect Control 2002; 30:145–152). “If you prevent a half dozen of these cases, that’s more than $150,000 right there. That money does a lot of tests,” Thomson said.

“If you can prevent one serious MRSA external wound infection with major complications, you can pay for the instrument. Almost every hospital has at least one of these cases every year,” Chapin added. “Unfortunately for labs, it’s hard to argue for the money to prevent something way down the line.” Some labs have implemented strategies to make the molecular tests more cost-effective. These include adapting the commercial assays to other instruments and equipment that can run larger batches of samples, explained Chapin, who added that it’s possible to adapt a microtiter plate format so it has 96 wells.

But it’s also possible to curb the spread of MRSA without molecular tests, Jain asserted. “We achieved success at Pittsburgh and reduced MRSA 50–60 percent by using standard culturing techniques,” he pointed out. “But we do believe there’s merit in promoting rapid testing because it identifies colonized patients earlier and can thus prevent patients from spreading infection before their results come back. There aren’t any data yet to show that rapid testing is cost effective, but it seems like the right thing to do.”