Universal decolonization study slashes BSI rates, but will mupirocin resistance be the Achilles heel?
Active surveillance proponents question findings
By Gary Evans, Executive Editor
A controversial MRSA study that showed universal decolonization of patients with mupirocin and chlorhexidine was much more effective than active detection and isolation (ADI) has been both commended and criticized, revealing a sharp divide in the infection control community between advocates of so-called "horizontal" and "vertical" interventions.1
The overriding concern among many epidemiologists and infection preventionists is that widespread adoption of the decolonization approach will create mupirocin-resistant MRSA staph strains.
"I expect that if we start using mupirocin like vaseline and chlorhexidene like water — bugs being bugs — this is only going to last a little while," said Martin Evans, MD, associate director of the MRSA Prevention Program in the Veterans Health Administration (VHA) hospital system. "That is not just my concern, but a concern of a lot of other people as well."
A key weapon against methicillin-resistant Staphylococcus aureus, mupirocin is often applied in the patient’s nares to eliminate a common MRSA reservoir. However, past research shows the topical invariably starts selecting out resistant bacteria if use becomes indiscriminate.2 With its much publicized findings of a 44% reduction in bloodstream infections, the new study has prompted calls for widespread adoption of the protocol in hospital ICUs. If so, Evans expects mupirocin resistance to follow.
An increase in mupirocin-resistant MRSA staph strains could undermine efforts to decolonize patients prior to surgery, a common approach to stave off post-operative infection, says Evans, an infectious disease physician at the University of Kentucky in Lexington.
"We might get to a situation where you have a patient who is colonized nasally or elsewhere with MRSA who needs a prosthetic hip or knee, a prosthetic valve," he says. "You would really like to get them cleaned up and decolonized. Typically today, we would use chlorhexidine and mupirocin to try to get rid of the MRSA and even drug sensitive bacteria. But if we have lost those drugs because we universally decolonize people, that option is not going to be available anymore."
Evans certainly comes from the ADI perspective, leading one of the most successful examples of the approach at VHA hospitals across the country. Since 2007 the use of ADI in more than 150 VHA hospitals has resulted in a 70% drop in MRSA infections, he says. (See related story, p. 113.) The direct relationship between mupirocin use and bacterial resistance is well documented, he emphasizes, citing a study that found that 31% of MRSA isolates developed high-level resistance after widespread use of the topical antibiotic in a long term facility. As stringent controls over mupirocin use were applied, the high-level resistant MRSA isolates fell to 4%.3"Over a number of years they developed huge numbers of high-level mupirocin resistance — they had to back off that entirely," Evans said.
But is benefit worth the risk?
As first reported in Hospital Infection Control & Prevention prior to publication, the decolonization study followed three research arms in a cluster-randomized trial of MRSA prevention strategies.4(See HIC Nov. 2012, cover.) Hospitals were randomly assigned to one of the three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; Group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and Group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or the screening and isolation approach. The widely hailed findings raised the possibility of a new standard of care in ICUs, but the issue of antibiotic resistance was only peripherally addressed in the paper.
Mupirocin resistance is an important issue and is the subject of ongoing research by the same team, says lead author Susan Huang, MD, MPH, FIDSA, medical director of epidemiology and infection prevention at University of California Irvine Healthcare in Orange, CA. While emerging resistance will have to be monitored at facilities that adopt the decolonization protocol, there is no reason to sideline an approach that demonstrated such efficacy against life-threatening bloodstream infections, she adds. "The reduction in bloodstream infections was large and hard to achieve by other means," Huang says. "In fact, the reduction was rather remarkable after what the nation has already achieved in preventing ICU-associated infections. If the impact of universal decolonization over the other arms were small, you could imagine that hospitals might choose from a range of interventions to achieve that reduction. In this study, universal decolonization was significantly better than the current proactive gold standard of screening and isolation."
In addition, accumulating evidence suggests that use of chlorhexidine alone without addressing the nasal reservoir of MRSA with mupirocin would be less effective in preventing serious infections, she notes.
"In fact failing to clear the main reservoir could potentially lead to an increased risk of resistance during use of [other] decolonization products," Huang says. "This may also be the case for targeted decolonization since nares screening has been consistently shown to only capture 65% to 75% of MRSA carriers."
As noted earlier, decolonization with mupirocin and chlorhexidine are currently being broadly used in patients who may be undergoing elective cardiac and orthopedic surgery.
"[Our] trial proposes the use of these topical products in our most critically ill patients," Huang says. "For whom else would we be saving these products? There are alternative products that are effective on mupirocin-resistant strains that can be used if mupirocin resistance rises. Finally, and fortunately, if resistance emerges, we will lose a topical agent — not one used to treat disease."
Something must be working
The intense focus on MRSA prevention in the last few years, whether by ADI or horizontal interventions, is paying considerable benefits. Though MRSA is still a formidable threat to patient safety, a new prevalence study reveals some statistics worthy of celebration. An estimated 30,800 fewer invasive MRSA infections occurred in the United States in 2011 compared with 2005. Hospital-onset infections dropped a dramatic 54%.5However, the same study found that MRSA is holding strong in the community (5% drop), assuring hospital introductions of infected and colonized patients will remain a critical issue. The ongoing challenge has been how to prevent MRSA spread to vulnerable patient populations via the unwashed hands of health care workers, environmental contamination and fomites. An aggressive "seek and destroy" approach first popularized in Europe, ADI has been advocated for years as the best strategy to prevent MRSA infections. It typically involves screening patients upon admission and placing those colonized with MRSA in contact isolation. The argument is that by identifying and isolating the MRSA reservoir, other patients are protected from spread of the infection. Not surprisingly, ADI proponents some of them who no doubt feel their efforts have certainly contributed to the aforementioned decline in MRSA are taking a critical look at the Huang study, questioning the methodology, perceiving possible bias and citing other variables that could have confounded the results. (See related story)
On the other hand, the classic vertical approach of ADI to infection prevention has been rejected by other epidemiologists who favor horizontal strategies that do not focus efforts on a single pathogen. Proponents of horizontal interventions see the decolonization study as a vindication of their approach, with two epidemiologists going as far as concluding "case closed" on the whole debate in an editorial that accompanied the decolonization study.6
Asked how such a definitive conclusion could be drawn from one study, one of the authors of the editorial says the new study actually caps a strong foundation of prior research.
"There has been a continuing building of evidence for this," says Richard Wenzel, MD, professor and chairman of the department of internal medicine at the Medical College of Virginia in Richmond. "There are many reasons to stress basic horizontal programs like hand washing and chlorhexidine baths. It’s a simple basic change that you do to everybody. It’s not only effective against the organisms you know about but also the ones that you don’t know about — that are emerging."
Indeed, the study has implications beyond MRSA, with the editorial noting that recent emergence of carbapenem-resistant Enterobacteriaceae has led to calls to implement ADI for those organisms in addition to MRSA. The thought of screening programs for an expanding array of pathogens reinforces the utility of horizontal interventions to prevent infections of any etiology. However, Wenzel makes a critical distinction between using ADI for epidemic versus endemic pathogens.
"We are not arguing against ADI approaches during MRSA outbreaks," he says. "What we are really talking about is controlling an agent that is infectious day to day, in and out. "When you have an epidemic you put all stops in place, and we are not arguing against that."
Overall, Wenzel and colleague Michael Edmond, MD, have steadily lowered infection rates at VCU without using ADI. "Over a decade we have seen a 90% reduction in all infections all infections without using a vertical program for MRSA," Wenzel says. "There are minor exceptions for people who are at unusually high risk, who are going to have implants and also for high-risk surgery such as cardiac surgery. But otherwise we have no broad screening program for MRSA."7
While there is intellectual vigor in this whole scientific debate, there is also the contrasting folly of trying to legislate clinical care. Exhibit A: At least nine states have adopted laws mandating some version of MRSA screening. Even if the superiority of the universal decolonization strategy is underscored in future studies, it will be hard to repeal the state laws, Wenzel says.
"One of the problems is that when people have long-held ideas — even if the evidence starts to argue the other way — it’s still hard to give them up," he says. "People will continue to push for this legislation because they have been spending a decade or more advocating for it. It’s probably difficult and complicated for them to change their minds. I think that’s human nature."
MRSA group pushes ADI, CDC praises new study
As this article went to press the MRSA Survivors Network was preparing to observe Sept 28th as World MRSA Day in Chicago, drawing attention to the plight of victims of the infection and continuing to call for the CDC and state legislators to respectively recommend and mandate ADI in the nation’s hospitals. The powerful narratives told by survivors and family members of those killed by MRSA infections are not to be underestimated. And whether by logic or emotion, these advocates have attached themselves to the notion that ADI is at least part of the answer because it shows the true prevalence of MRSA in patient populations. In light of the new decolonization study, the group posted rebuttals and criticism by prominent proponents of ADI on their website, holding fast to their call for widespread adoption of ADI.
"It continues to be unclear why the CDC has not adapted and strongly recommended this evidence-based [ADI] approach decades ago considering the incredible success of the VHA system nationwide MRSA screening program along with many other hospitals and healthcare systems proving ADI is effective in reducing MRSA infections," says Jeanine Thomas founder of the MRSA Survivors Network.
The CDC has indeed been reluctant to make such a broad recommendation, citing concerns about targeting a single pathogen with broad interventions. However, ADI is cited as an option in CDC guidelines for facilities experiencing MRSA outbreaks or ongoing transmission. Perhaps because it was in part supported by the CDC, the new decolonization study has received a somewhat warmer embrace. The study was done through a collaborative partnership within the CDC Prevention Epicenters Program, a group of CDC-funded researchers who work with the agency to explore novel approaches to prevent health care-associated infections.
"This study one of the largest to date on this subject, including over 74,000 patients — shows that using antimicrobial soap and ointment on all ICU patients can reduce bloodstream infections caused by MRSA and other germs by 44%," John Jernigan, MD, director of the CDC’s Prevention Epicenters Program, said in a blog post.8"The result is a major advance in science, good news for patients, and potentially a model for how to advance the science of patient safety even further."
The question of mupirocin resistance, which Jernigan did not address in the post, was raised in a comment on the blog by Katherine Stauffer, RN, CIC, infection control coordinator at Shands AGH in Gainesville, FL: "There have been concerns expressed among our ID physicians and others about mupirocin resistance, and whether we are setting ourselves up’ for increasing resistance should the decolonization of ICU patients be adopted on a widespread basis," she commented.
The CDC will carefully consider such unintended consequences, Jerigan reponded in a blog post. "As the authors state in the paper itself, it is possible that widespread use of chlorhexidine and mupirocin could engender resistance, thereby limiting the effectiveness of these agents in the long term," he said. "It will therefore be important for surveillance programs to monitor for the emergence of mupirocin and chlorhexidine resistance if this approach is used widely. CDC will carefully weigh these potential concerns against the benefits in the process of determining how the findings of the study might inform CDC infection prevention recommendations."
MRSA screening a great success as data 'flatten out'
Similar trend reflected in decolonization study?
An active detection and isolation (ADI) program adopted at all Veterans Health Administration (VHA) hospitals in 2007 has resulted in a 70% reduction in MRSA infections as of June 2012, says Martin Evans, MD, associate director of the VHA MRSA Prevention Program.1,2However, the reductions are becoming more incremental over time, as a flattening out "asymptotic" effect appears to be in evidence, says Evans, an infectious disease physician at the University of Kentucky in Lexington.
"Everything is going in the same direction. It's still going down, but like with many things you get a decline and then things flatten out over time," he says. "The slope is much less than it was originally. I expect if we follow this for 10 years, 20 years there will no longer be a significant change from year to year. It will start approaching zero, hopefully."
In light of the VHA trend, Evans raised an intriguing question about a recently published MRSA study that showed a universal decolonization approach was superior to ADI in reducing infections.3Another recently published study reveals that an MRSA ADI program had been in place in many of the same hospitals for several years before the decolonization study began.4Using ADI and a bundle similar to the VHA's, the authors of that study reported that infections decreased markedly over the period.
"They had a fairly significant decline in their MRSA HAI rates in their ICUs — anywhere from 39% to 70%-75%," Evans says. "Our question is if you do a study like [the decolonization study] — and one of your arms has had a screening and isolation effect going on for about three years — are you already close to that asymptotic phase of that intervention?
If the ADI effect had already peaked and was flattening out, could that explain why the universal decolonization approach seemed comparatively superior? "We could be totally off-base in our supposition, but we are asking the question whether essentially that [ADI] effect had already taken place and hence they didn't see a significant decrease in HAI rates with that intervention," Evans says.
Evans has sent a letter raising the issue to the New England Journal of Medicine and lead author of the decolonization study Susan Huang, MD, MPH, FIDSA, medical director of epidemiology and infection prevention at University of California Irvine Healthcare, is expected to respond in the journal.
In the interim, we asked her to address the question and she replied via email: "The REDUCE MRSA Trial showed that universal decolonization is superior to routine screening and isolation and selective decolonization for the important outcome of all-cause bacteremia. Our estimates of benefit are provided as what can be gained over and above these other two interventions. As we say in our discussion, it is possible, even likely, that hospitals who haven't implemented screening and isolation may derive an even greater benefit. Nevertheless, it does not affect the finding that universal decolonization is better than screening and isolation in reducing serious bloodstream infections."
References
- Jain R, Kralovic SM, Evans ME, et al. Veterans Affairs Initiative to Prevent Methicillin-Resistant Staphylococcus aureus Infections N Engl J Med 2011;364:1419-1430.
- Evans M, Kralovic S, Simbartl L, et al. Veterans Affairs (VA) Methicillin-Resistant Staphylococcus aureus (MRSA) Bundle Associated with a Sustained Effect on Transmissions and Healthcare-Associated Infections (HAIs). IDWeek 2012, San Diego, Oct 17-21.
- Huang SS, Septimus E, Kleinman K, et al. For the CDC Prevention Epicenters Program and the AHRQ DECIDE Network and Healthcare-Associated Infections Program. Targeted versus Universal Decolonization to Prevent ICU Infection N Engl J Med 2013; 368:2255-2265
- Perlin JB, Hickok JD, Septimus EJ, et al. A Bundled Approach to Reduce Methicillin-Resistant Staphylococcus aureus Infections in a System of Community Hospitals. Jrl Healthcare Qual 2013;35:5769.
References
- Huang SS, Septimus E, Kleinman K, et al. For the CDC Prevention Epicenters Program and the AHRQ DECIDE Network and Healthcare-Associated Infections Program. Targeted versus Universal Decolonization to Prevent ICU Infection N Engl J Med 2013;368:2255-2265.
- Patel JB, Gorwitz RJ, Jernigan JA. Mupirocin Resistance. Clin Infect Dis 2009;49:935-941
- Walker ES, Levy F, Shorman M, et al. A Decline in Mupirocin Resistance in Methicillin-Resistant Staphylococcus aureus Accompanied Administrative Control of Prescriptions J Clin Microbiol 2004 June;42(6):27922795.
- Huang SS, Septimus E, Kleinman K, et al. Randomized Evaluation of Decolonization vs. Universal Clearance to Eliminate Methicillin-Resistant Staphylococcus aureus in ICUs (REDUCE MRSA Trial). IDWeek 2012. San Diego, CA. Oct 17-21 2012.
- Dantes R, Mu Y, Belflower R, et al. National Burden of Invasive Methicillin-Resistant Staphylococcus aureus Infections, United States, 2011 JAMA Intern Med Published online September 16, 2013. doi:10.1001/jamainternmed.2013.10423
- Edmond MB, Wenzel RP. Screening Inpatients for MRSA — Case Closed. Editorial. N Engl J Med 2013;368:2314-2315
- Edmond M, Stevens M, Ober J, et al. Impact of a Horizontal Infection Prevention Strategy on MRSA Infections at an Academic Medical Center. IDWeek 2012, San Diego, Oct 17-21.
- Jerigan, J. REDUCE MRSA: From Novel Idea to 74,000 Patients. CDC Safe Healthcare blog: http://1.usa.gov/1a4M7Et
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