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Managing methicillin-resistant staphylococci: A paradigm for preventing nosocomial transmission of resistant organisms
Managing methicillin-resistant staphylococci: A paradigm for preventing nosocomial transmission of resistant organisms David K. Henderson, MD Silver Spring, Maryland
Multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are endemic in healthcare settings in the United States and many other countries of the world. Nosocomial transmission of MRSA serves as a source of hospital outbreaks, and recent reports of vancomycin-resistant S aureus strains in the United States emphasize the need for better control of MRSA and other resistant bacteria within healthcare settings. Colonization with S aureus or MRSA is relatively common in both healthy and hospitalized individuals, most often involves the anterior nares, and is frequently asymptomatic. Colonization increases risk of infection. Patient-to-patient transmission of MRSA within healthcare settings primarily occurs via carriage on the hands of healthcare workers. The Society for Healthcare Epidemiology of America (SHEA) has developed guidelines for the prevention of transmission of MRSA and vancomycin-resistant enterococci within healthcare settings, and chief among the recommendations is an emphasis on adherence to hand hygiene guidelines. Other measures that may prevent the nosocomial transmission of MRSA include improved antibiotic stewardship, staff cohorting, maintenance of appropriate staffing ratios, reductions in length of hospital stays, contact isolation, active microbiologic surveillance, and better staff education. Currently, the efficacy of many of these individual infection control interventions remain in doubt. Many studies reporting improvement in infection control outcomes (eg, reduced transmission, decreasing prevalence) involve simultaneous institution of several of these measures, making it impossible to tease out the effects of any of the individual components. Nonetheless, the best approach in the current environment probably involves hand hygiene plus a careful assessment of an institution’s particular circumstances, applying more aggressive procedures such as patient isolation, staff cohorting, and active surveillance cultures, as indicated. (Am J Infect Control 2006;34:S46-54.)
Certain multidrug-resistant bacteria have become endemic in the hospital environment, particularly in intensive care units (ICUs).1-3 Chief among these are methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Guidelines have been developed for preventing the spread of these organisms within the hospital and other healthcare environments.4,5 The recent emergence of MRSA that are also resistant to vancomycin, through a mechanism involving horizontal transfer of genetic material from VRE,6-9 has made controlling the spread of MRSA and VRE even more important. Society for Healthcare Epidemiology of America (SHEA) guidelines focus on preventing nosocomial transmission of both MRSA and VRE.4 Guidelines published by the Hospital Infection Control Practices Advisory Committee (HICPAC) from the Centers for Disease Control and
Reprint requests: David K. Henderson, MD, 2815 Regina Drive, Silver Spring, Maryland 20106. E-mail: [email protected]. 0196-6553/$32.00 Copyright ª 2006 by the Association for Professionals in Infection Control and Epidemiology, Inc. and Elsevier, Inc. doi:10.1016/j.ajic.2006.05.228
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Prevention (CDC) specifically address preventing the spread of VRE.5 Recommendations for infection control interventions from these and other organizations are likely useful in controlling hospital spread of other resistant bacterial pathogens as well, although speciesspecific differences may necessitate modifications of the guidelines for some pathogens.10 This article examines strategies for managing MRSA as a paradigm for how the healthcare community might approach management of all resistant pathogens.
STAPHYLOCOCCUS AUREUS COLONIZATION AND TRANSMISSION Staphylococcal organisms are ‘‘people pathogens’’ that may be recovered from numerous sites on both patients and staff. They may colonize the face, hands, axilla, or groin, but their primary habitat is the epithelium of the anterior nares.11 Inpatients colonized or infected with MRSA probably serve as the major reservoir for MRSA spread within hospitals.12 From 30% to 60% of healthy adults are colonized with S aureus and 10% to 20% are chronically colonized, primarily in the nares.13,14 In a recent study of pediatric subjects in the community, 36% exhibited nasal carriage of S aureus, including carriage of MRSA in 9% of
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subjects.15 The MRSA carriage rate represented a significant increase compared with rates in recent years (P 5 .001) and has been associated with unique, community-based isolates. At the time of hospital admission, many patients in the United States have been identified as nasal carriers of S aureus, including MRSA.16,17 The rate of S aureus carriage among healthcare workers or hospital staff is also striking,18-20 with approximately 6% exhibiting nasal carriage of MRSA in some studies.19,20 High carriage rates are important because S aureus and MRSA colonizing the nares or other areas may be transferred or spread from patient to healthcare worker, patient to patient, or healthcare worker to patient. The primary route of MRSA transmission within the hospital appears to be from patient to patient, carried on the hands of hospital personnel.12 Further, MRSA can also exist on objects in the environment and be spread from these objects to patients, often via healthcare workers’ hands.21-23 Environmental or fomite spread may be substantially underestimated as a route of nosocomial transmission of MRSA.
GENERAL STRATEGIES TO PREVENT RESISTANCE IN HOSPITALS Mathematical models have been used to understand and predict nosocomial cross-transmission, and to provide a theoretical basis for interventions to control infection and resistance.24 Based on mathematical modeling, effective strategies that might be expected to prevent transmission or reduce the prevalence of resistant bacteria in hospitals include reducing antibiotic use, using antibiotics for which there is no resistance, decreasing length of hospital stays (ie, increasing the patient turnover rate), and instituting infection control measures to disrupt the spread of bacteria, including restricting contacts between patients and healthcare workers carrying resistant bacteria.25,26 Mathematical models further suggest that nonspecific interventions that reduce transmission of all bacteria within a hospital will disproportionately reduce the prevalence of colonization with resistant bacteria.26 These interventional strategies based on mathematical models need to be subjected to empirical testing to confirm their efficacy and utility in clinical settings. At a more pragmatic level, educating the hospital staff about the epidemiology, pathogenesis, and general routes of transmission of resistant bacteria within the hospital environment, as well as about the roles that antibiotic use plays in the emergence and spread of bacterial resistance, is extremely important. Education is required both to disseminate basic information and to encourage compliance with infection-control measures that are subsequently implemented.
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FACTORS INFLUENCING HOSPITAL SPREAD OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS A number of factors are known, or have been hypothesized, to influence risks for acquisition or transmission of MRSA in the healthcare setting.4,27 Factors known to decrease acquisition and/or nosocomial transmission of MRSA include appropriate antibiotic use/stewardship, proper hand hygiene, cohorting care of infected or colonized patients, decreasing unnecessary patient contacts, and decreasing length of stay for hospitalized patients. Factors hypothesized to influence risks for nosocomial transmission of MRSA include use of gowns and gloves by staff, isolation of infected or colonized patients, improved staffing ratios, antibiotic recycling, decolonization of colonized staff or patients, and disinfection of equipment or other objects in the environment. Microbiologic surveillance cultures of high-risk patients and staff have been postulated to be important in identifying patients harboring MRSA that may serve as reservoirs for transmission, and hence, may require heightened infectioncontrol measures. Interestingly, a recent investigation that performed cultures and did not notify staff of the results failed to identify transmission.28 Marshall and colleagues27 group transmission risk factors into 4 categories that represent critical points at which MRSA may be potentially controlled within the healthcare setting. The 4 critical points are prevention of selection of methicillin-resistant isolates in a population of S aureus (antibiotic stewardship), reduction in the pool of colonized patients or staff (discharge of colonized/infected patients/decolonization of carriers), prevention of patient-to-patient transmission (screening and alerts, hand hygiene, cohorting, patient isolation, use of gowns and gloves), and prevention of infection in a colonized patient (nasal decolonization). The remainder of this article examines evidence supporting the various infection-control measures that have been recommended or proposed, dividing them into factors for which strong evidence supports efficacy and those for which the support is less robust. Reasons for the remaining controversies are discussed, along with a personal view on how best to proceed in the current environment given these uncertainties.
INFECTION-CONTROL MEASURES WITH RELATIVELY STRONG SUPPORT Antibiotic stewardship An extensive discussion of the issue of antimicrobial stewardship is presented by Fishman elsewhere in this
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supplement.29 Over time, bacteria naturally acquire chromosomal mutations or acquire genetic material from other organisms in their environment that confer resistance to antibacterial drugs. Whether these resistant bacteria survive and replicate depends on a number of factors, including environmental conditions that are influenced by antibiotic use. Heavy use of antibiotics, particularly broad-spectrum agents, can create conditions that select for bacteria that have mechanisms for resistance.30,31 In other words, antibiotic use establishes conditions in which bacteria with mechanisms for resistance experience a competitive advantage and prosper compared with susceptible bacteria that are rapidly eradicated by an antibiotic therapy. In this way, prolonged administration of antibiotic therapy or inadequate dosing of antibiotics may select for methicillin-resistant isolates in an overall population of S aureus. These MRSA strains may colonize and subsequently cause infection and/or serve as a reservoir for transmission to other patients in the hospital setting. As reviewed in the SHEA guidelines for prevention of nosocomial transmission of MRSA and VRE, use of antimicrobial agents in US hospitals is often excessive and/or unnecessary, and contributes to the emergence and spread of resistant microorganisms such as MRSA.4 As a means to prevent selection of resistant bacteria, the SHEA guidelines underscore recommendations made in the past against inappropriate or excessive use of antibiotics. The relation between antibiotic usage and rates of nosocomial MRSA has been described in a number of reviews.4,27,32 Various studies have reported a positive association between antimicrobial use and incidence of MRSA colonization or infection within the hospital setting, including the use of broad-spectrum cephalosporins and fluoroquinolones.33-39 In some studies, other infection control procedures were instituted at the same time as restriction of antibiotic use,4,40 complicating interpretation of the data. To date, $1 study examining the relation between risk factors and nosocomial colonization and infection failed to identify antibiotic therapy as an independent risk factor.41 Nonetheless, the bulk of the evidence seems to identify antibiotic therapy as a potential risk factor for MRSA colonization and infection in the hospital setting, suggesting that better antibiotic stewardship should result in decreased rates of nosocomial transmission of MRSA.
Hand hygiene The rationale underlying careful adherence to hand hygiene guidelines is that most nosocomial patientto-patient transmission of MRSA occurs via the hands of healthcare workers. Proper hand hygiene clearly
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works in terms of reducing nosocomial transmission of MRSA. HICPAC and the HICPAC/SHEA/APIC (Association for Professionals in Infection Control)/IDSA (Infectious Diseases Society of America) Hand Hygiene Task Force reviewed the available evidence and concluded that adherence to hand hygiene recommendations is associated with a reduced risk for healthcare cross-contamination.42 Failure to perform appropriate hand hygiene is generally considered to be the leading cause of healthcare-associated infections and spread of multiresistant organisms such as MRSA. According to the Task Force, visibly dirty or contaminated hands should be washed with soap and water, and hands that are not visibly soiled should be decontaminated (preferably with an alcohol-based hand rub or, alternatively, with an antimicrobial soap and water) before contact with patients or engaging in clinical procedures. Hand decontamination should also occur after contact with patients’ intact or nonintact skin, bodily fluids, excretions, or mucous membranes; after contact with inanimate objects or medical equipment in the vicinity of patients; and after removing gloves. In the last several years, alcohol-based hand hygiene products have been introduced and shown to be superior to soap and water for hand hygiene.43 They are rapidly active, and they have a broad antimicrobial spectrum. Moreover, they are substantially more convenient, are easier to use, do not require a sink, and are less irritating to the skin than is hand washing with soap and water.44 The hands must be free from visible soiling before the use of an alcohol hand rub. Whereas the development and implementation of these new waterless hand hygiene products represent substantial progress, not all the news relating to hand hygiene in healthcare settings is good. Adherence to hand hygiene recommendations in the healthcare setting remains less than optimal. Adherence to hand hygiene recommendations rarely exceeds 50% in acute care institutions, and physicians seem to be the worst offenders.45-48 A number of studies have demonstrated that nurses adhere to hand hygiene guidelines much more frequently than do physicians, but still far less frequently than is warranted by the needs of patient care.45-47 Other factors adversely affecting adherence to hand hygiene recommendations include working in intensive care, compared with internal medicine wards, male sex, high intensity of patient care, clinical activities associated with high risk of cross-contamination, and high requirements for hand hygiene per hour of patient care.42 Perceived barriers to adherence to hand hygiene include skin irritation or inaccessible hand hygiene supplies, increased workload, and understaffing or overcrowding, among others.42 Ironically, adherence often decreases at times when increased adherence is most important. Some studies
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have suggested increased adherence rates when staff are using the new alcohol-based products, and that is an encouraging sign as well.44 Educational programs may also improve adherence to hand hygiene.49-51
Cohorting patients and decreasing unnecessary patient contacts Cohorting care means having staff provide care for either only those patients already infected or colonized with MRSA or for those known not to be colonized or infected. Staff thus do not cross-cover infected/ colonized and noncolonized patients. Although not systematically studied, cohorting care of infected and colonized patients should intuitively have a substantial impact on nosocomial transmission of MRSA. In an outbreak setting, keeping infected and colonized patients separate from noninfected and noncolonized patients provides a powerful tool to prevent transmission. When financially feasible, assigning staff to cover only patients who are infected may be a key mechanism for preventing transmission in the healthcare setting.
Maintenance of appropriate staffing ratios The rising prevalence of MRSA in healthcare settings is associated with greater hospital or ICU utilization and relative understaffing, particularly during MRSA outbreaks. The findings from 3 studies suggest that understaffing contributes to the spread of microorganisms such as MRSA in healthcare settings. A cohort study combining a comprehensive analysis of risk factors for MRSA transmission with mathematical modeling of the effectiveness of infection control measures identified exposure to a relative staff deficit as the only factor significantly associated with potential transmission (P 5 .001).52 The mathematical model showed that adherence to good hand-washing practice is difficult to attain during periods of understaffing and high workload, and the authors suggested that this probably accounted for the association between understaffing and hospital spread of MRSA. A study from the CDC reported a significant increase in patient-to-nurse ratio during an outbreak of central venous catheter– associated bloodstream infections compared with ratios in the preoutbreak period (P , .01).53 An association among understaffing, patient overcrowding, and spread of infectious diseases was also demonstrated in a neonatal nursery in which the incidence rates of staphylococcal infection substantially increased after periods of increased infant-to-nurse ratios, increasing 16-fold when the infant-to-nurse ratio was .7.54 Unfortunately, very few studies have actually quantified the relation between staffing levels and control of nosocomial infection under endemic hospital conditions. Nonetheless, the available data strongly point
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to understaffing and increased workload as being directly associated with increased transmission, probably as a result of diminished adherence to hand hygiene and subsequent patient-to-staff-to-patient transfer of pathogens.
Decreasing hospital stays Decreasing the length and/or frequency of hospital stays has been hypothesized to decrease the risk for nosocomial MRSA transmission, and results from a number of studies provide support for this concept. For example, a study evaluating acquisition of MRSA in the ICU found length of ICU stay to be a significant independent risk factor for MRSA acquisition (P # .0001).55 Another study similarly reported that both an ICU stay of .2 days as well as being a trauma patient were significant independent risk factors for MRSA acquisition in the ICU (P , .05).56 One case–control study identified previous hospitalization and $3 weeks of hospitalization as independent risk factors for MRSA colonization and infection in hospitalized patients in Spain.41 Similar findings were reported among hospitalized patients with acquired immunodeficiency syndrome.57 These studies suggest that rates of nosocomial MRSA transmission may be decreased by shortening hospital or ICU stays, where possible.
INFECTION-CONTROL MEASURES WITH LESS EVIDENCE-BASED SUPPORT Microbiologic surveillance A controversial issue in the healthcare epidemiology community right now is the use of active microbiologic surveillance as an intervention to minimize transmission of MRSA and other resistant pathogens. The intent of this strategy is to screen all patients admitted to a healthcare setting for MRSA or other multidrugresistant pathogens in order to identify colonized or infected patients who can then be managed with intensive infection-control procedures, such as isolation. Active surveillance is more labor intensive and costly than is passive surveillance, whereby problems are identified using data generated in the routine course of patient care. On the other hand, active surveillance is likely to identify problematic pathogens sooner and thus enable measures to be taken to prevent their spread within the healthcare environment. Many centers use an active surveillance strategy, but many do not. The data are somewhat conflicting with respect to the efficacy of this strategy as an intervention, but based on the available data, many experts believe that tight control, including use of active microbiologic surveillance, is important to prevent crosscontamination with MRSA.4,58 The use of this strategy
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is both labor and resource intensive, and to date, no studies definitively demonstrate the efficacy of this strategy as an independent intervention. Recent studies have demonstrated benefit of prospective surveillance cultures, but because virtually all of these studies introduced interventions simultaneously with active microbiologic surveillance, determining which of the interventions (either independently or in concert) actually induced the observed benefits is essentially impossible.4 The lack of wellcontrolled studies on the issue of active microbiologic surveillance has been the source of ongoing criticism of this intervention. Nonetheless, the published SHEA guidelines encourage an aggressive approach to surveillance, culturing, isolation, and cohort nursing of patients carrying MRSA.4 The potential limitations of current study designs evaluating effectiveness of active surveillance were highlighted by a recent study completed at the ICU of Cook County Hospital in Chicago.28 The study was designed to assess the effect of daily microbiologic surveillance alone, that is, without report of culture results versus isolating colonized patients. During the 10-week period of the study, the staff at this large county hospital was never informed of the surveillance results and colonized patients were never isolated. At the end of this period, the investigators were unable to identify a single instance of cross-transmission among patients in the ICU. Because the staff did not know the results of the surveillance cultures, the investigators concluded that microbiologic surveillance added no benefit. Ironically, however, it should be noted that if the staff had been made aware of the culture results and the same results were obtained, the investigators might have concluded that microbiologic surveillance cultures actually did have an impact. Studies such as this question the necessity of active screening and isolating patients colonized with MRSA. The Netherlands’ experience with nosocomial MRSA is often mentioned when discussing the potential benefits of active surveillance programs. The Netherlands is among the few countries where nosocomial and community levels of MRSA are very low, and the low prevalence has been attributed to the country’s ‘‘search and destroy’’ policy for the prevention of MRSA transmission, as well as a policy of restrictive antibiotic use.59,60 Strict barrier precautions are required for patients who carry the organisms, temporary furloughs are provided to colonized healthcare workers, and authorities even close hospital wards when the prevalence starts to rise in some situations. This strategy has been remarkably effective in limiting the spread in the Netherlands, such that currently the prevalence of staphylococcal isolates resistant to methicillin and causing infection in the hospital environment is ,2%.59
Curiously, countries surrounding the Netherlands have much higher prevalences, some of which approach or exceed rates found in the United States. For example, among countries participating in the European Antimicrobial Resistance Surveillance System (EARSS), MRSA prevalence in 2002 was reported to be #49% in Greece, 45% in Ireland and the United Kingdom, and 39% in Portugal.61 Thus, both patients transferred to the Netherlands from hospitals in surrounding countries as well as repatriates have high rates of methicillin resistance and are thus easily identified.62 In such a controlled setting, at-risk populations are readily identified and appropriate precautions can be rapidly implemented.
Contact isolation Most major infection control guidelines for MRSA recommend some kind of isolation for patients who harbor the bacteria, and the category of isolation most frequently recommended is contact isolation. The SHEA guidelines recommend contact (or cohort) isolation for all patients known to be colonized or infected with MRSA, including hand hygiene and the use of gloves and gowns before interacting with infected/colonized patients or entering their environments.4 In studies in which contact isolation has been implemented as a part of an infection-control program designed to limit the spread of MRSA, isolation has generally been effective in controlling further spread within the hospital.27 However, as previously discussed, contact isolation has typically been implemented concurrently with (usually several) other infection-control measures. Therefore, attributing the observed benefits of reduced spread of MRSA to any single intervention, including isolation, is not possible. A recent systematic literature review of isolation measures in the management of nosocomial MRSA concluded that, due to methodology weaknesses and inadequate reporting, assessing the contribution of isolation as a single measure to reduce spread is not possible.63 Another consideration is the potentially adverse impact of contact isolation on patient care. A 2003 report by Stelfox and coworkers64 illustrated the potential pros and cons of isolating patients who have infectious diseases. This study examined quality-of-care measures in adult patients who were isolated for MRSA colonization or infection at 2 North American teaching hospitals and found that isolated patients were twice as likely as were controls to experience adverse events during their hospitalization (31 vs. 15 per 1,000 days; P , .001). Isolated patients were also more likely to have incomplete records of vital signs (14% vs. 9%, P , .001; 5% vs. 1% with no vital sign recordings,
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P 5 .02) and were less likely to have nursing narratives (14% vs. 10%; P , .001) or physicians’ progress notes (26% vs. 13%, P , .001).64 Additionally, isolated patients in this study were 8 times more likely than were controls to experience failures of supportive care, including falls, pressure ulcers, and fluid and electrolyte imbalances. A second study, from the surgical literature, also highlighted the significant adverse impact of isolation on quality of care. This latter study reported that isolated patients were visited by staff fewer times than were nonisolated controls (5.3 vs. 10.9 visits per hour; P , .0001) and had less contact time overall—on the general floor and in the ICU—despite the fact that the isolated patients had higher APACHE II scores (10.1 6 1.0 vs. 7.6 6 0.8; P 5 .05) and, ostensibly, would have required more care.65 Therefore, the potential benefits associated with contact isolation need to be weighed against the potential costs in terms of patient care quality.
Decolonization with mupirocin Colonization with S aureus or MRSA is often asymptomatic, but colonization also increases the risk of infection due to these organisms and may serve as a reservoir for transmission to other patients. Therefore, a possible approach to preventing MRSA infection or nosocomial transmission of MRSA involves decolonizing patients or healthcare workers identified as carriers. Intranasal mupirocin has been most commonly used to decolonize S aureus in the anterior nares,27 although mupirocin in combination with chlorhexidine or other agents may also be used for whole-body decolonization of MRSA.66,67 Intranasal mupirocin has been shown to prevent endogenous acquisition of MRSA infections in the ICU.68 A recent review of randomized, controlled trials of the efficacy of intranasal mupirocin for eradication of S aureus in nasal carriage and prevention of infection concluded that mupirocin is highly effective, both in eradicating nasal carriage and in preventing infection over the short term; however, its longterm eradication efficacy is less impressive.69,70 The short-term effectiveness of decolonization with mupirocin has best been documented in epidemic settings, but its efficacy in settings of high MRSA endemicity is also less clear. In addition, mupirocin resistance may develop relatively quickly and is increasingly reported as a clinical concern.70
Antibiotic cycling Antibiotic cycling refers to the strategy of reducing antimicrobial resistance through the rotation or cycling of different antimicrobials over time. Fishman29 discusses this topic in much greater detail elsewhere in this supplement; suffice it to say that current data are inconsistent and are insufficient to evaluate the
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effectiveness of cycling in the prevention of resistance. Mathematical modeling has even suggested that cycling of 1 drug may have far worse effects on resistance than would using a combination of 2 drugs.71
PRACTICAL MANAGEMENT STRATEGIES FOR PRESENT TIMES At present we have inadequate scientific data to identify ideal infection-control strategies for the definitive prevention of nosocomial transmission of MRSA. Part of the reason that controversy still exists is that transmission of healthcare-associated infections is complex and multifactorial. Numerous independent and confounding or interacting factors influence the risk for spread. Studies of the topic are clinically difficult and labor intensive. Unfortunately, these infections often occur in settings in which a clear urgency to fix the problem exists. If a hospital is having an epidemic, the first concern of the healthcare workers is to terminate the epidemic—at all costs. In an epidemic, institutions are not likely to try just 1 intervention. Rather, they are likely to try several different interventions simultaneously in the hope that a single factor or a combination of factors will reduce the spread. From a clinical perspective, the multiple-intervention strategy is entirely understandable, but from ascientific perspective, this approach makes identifying independent infection-control measures difficult, if not impossible. Given the current state of affairs, then, how are healthcare professionals to decide what is the best and most cost-effective approach to preventing transmission of MRSA and other resistant pathogens within healthcare settings? As noted above, the literature base is inadequate at this time for identifying definitively efficacious strategies. In my opinion, an aggressive approach to control—including the use of aggressive patient isolation, and, when appropriate, cohorting of staff, and perhaps even microbiologic surveillance cultures—makes implicit sense in settings in which the prevalence of MRSA infection is low. The case for the tight-control approach is somewhat more difficult to make in settings in which the prevalence of methicillin resistance is high. Nonetheless, I favor a conservative approach to management of these patients, being mindful of the unique aspects of the individual healthcare environment being assessed, as well as being particularly aware of the barriers to patient care that have been associated with the implementation of some of the most conservative strategies. Even investigators who have questioned the quasi-experimental methodology in virtually all of the published studies evaluating interventions for MRSA have ultimately concluded that, ‘‘current isolation measures recommended in national
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guidelines should continue to be applied until further research establishes otherwise.’’63
SUMMARY Multidrug-resistant bacteria such as MRSA are endemic to the healthcare environment and serve as a potential source for outbreaks in these settings. Various protocols and guidelines have been developed to try and prevent the development of resistant species of S aureus and to slow the transmission of nosocomial MRSA. If healthcare professionals are to be successful in preventing transmission of MRSA in the healthcare setting, then understanding the epidemiology, pathogenesis, and routes of transmission of S aureus in these settings becomes critically important. First and foremost, all staff must understand the important role hand carriage plays in nosocomial transmission of these pathogens. For this reason, healthcare workers must attend to proper hand hygiene rigorously, as recommended by SHEA and other organizations. Other infection-control procedures that may be important in preventing nosocomial transmission of MRSA include contact isolation, cohorting care, maintaining appropriate staffing ratios, use of active microbiologic surveillance, and decreasing hospital stays. Antibiotic stewardship may also play a key role in reducing the development of MRSA and other multidrug-resistant pathogens in the first place. Depending on a variety of each individual institution’s specific circumstances, (eg, available resources, endemic rates of infection), and given the current state of knowledge in the field, SHEA has argued for an aggressive approach to infection control—emphasizing hand hygiene, aggressive patient isolation, microbiologic surveillance cultures, and staff cohorting—at least until subsequent research studies suggest alternative approaches.
References 1. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis 2001;1:314-25. 2. National Nosocomial Infections Surveillance (NNIS) System Report. Data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470-85. 3. Haddadin AS, Fappiano SA, Lipsett PA. Methicillin resistant Staphylococcus aureus (MRSA) in the intensive care unit. Postgrad Med J 2002; 78:385-92. 4. Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus. Infect Control Hosp Epidemiol 2003;24:362-86. 5. Centers for Disease Control and Prevention (CDC). Recommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 1995;44:1-13.
Henderson 6. Tenover FC, Weigel LM, Appelbaum PC, et al. Vancomycin-resistant Staphylococcus aureus isolate from a patient in Pennsylvania. Antimicrob Agents Chemother 2004;48:275-80. 7. Chang S, Sievert DM, Hageman JC, et al. Infection with vancomycinresistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med 2003;348:1342-7. 8. Centers for Disease Control and Prevention (CDC). Vancomycinresistant Staphylococcus aureus—New York, 2004. MMWR Morb Mortal Wkly Rep 2004;53:322-3. 9. Weigel LM, Clewell DB, Gill SR, et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 2003; 302:1569-71. 10. McGowan JE Jr, Tenover FC. Control of antimicrobial resistance in the health care system. Infect Dis Clin North Am 1997;11: 297-311. 11. Williams RE. Healthy carriage of Staphylococcus aureus: its prevalence and importance. Bacteriol Rev 1963;27:56-71. 12. Thompson RL, Cabezudo I, Wenzel RP. Epidemiology of nosocomial infections caused by methicillin-resistant Staphylococcus aureus. Ann Intern Med 1982;97:309-17. 13. Foster TJ. The Staphylococcus aureus ‘‘superbug.’’ J Clin Invest 2004; 114:1693-6. 14. Sista RR, Oda G, Barr J. Methicillin-resistant Staphylococcus aureus infections in ICU patients. Anesthesiol Clin North Am 2004;22: 405-35, vi. 15. Creech CB II, Kernodle DS, Alsentzer A, Wilson C, Edwards KM. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr Infect Dis J 2005;24: 617-21. 16. Hidron AI, Kourbatova EV, Halvosa JS, et al. Risk factors for colonization with methicillin-resistant Staphylococcus aureus (MRSA) in patients admitted to an urban hospital: emergence of community-associated MRSA nasal carriage. Clin Infect Dis 2005;41:159-66. 17. Troillet N, Carmeli Y, Samore MH, et al. Carriage of methicillin-resistant Staphylococcus aureus at hospital admission. Infect Control Hosp Epidemiol 1998;19:181-5. 18. Nulens E, Gould I, MacKenzie F, et al. Staphylococcus aureus carriage among participants at the 13th European Congress of Clinical Microbiology and Infectious Diseases. Eur J Clin Microbiol Infect Dis 2005; 24:145-8. 19. Eveillard M, Martin Y, Hidri N, Boussougant Y, Joly-Guillou ML. Carriage of methicillin-resistant Staphylococcus aureus among hospital employees: prevalence, duration, and transmission to households. Infect Control Hosp Epidemiol 2004;25:114-20. 20. Cesur S, Cokca F. Nasal carriage of methicillin-resistant Staphylococcus aureus among hospital staff and outpatients. Infect Control Hosp Epidemiol 2004;25:169-71. 21. Devine J, Cooke RP, Wright EP. Is methicillin-resistant Staphylococcus aureus (MRSA) contamination of ward-based computer terminals a surrogate marker for nosocomial MRSA transmission and handwashing compliance? J Hosp Infect 2001;48:72-5. 22. Oie S, Kamiya A. Survival of methicillin-resistant Staphylococcus aureus (MRSA) on naturally contaminated dry mops. J Hosp Infect 1996;34: 145-9. 23. Rutala WA, Katz EB, Sherertz RJ, Sarubbi FA Jr. Environmental study of a methicillin-resistant Staphylococcus aureus epidemic in a burn unit. J Clin Microbiol 1983;18:683-8. 24. Bonten MJ, Austin DJ, Lipsitch M. Understanding the spread of antibiotic resistant pathogens in hospitals: mathematical models as tools for control. Clin Infect Dis 2001;33:1739-46. 25. Levin BR, Bonten MJ. Cycling antibiotics may not be good for your health. Proc Natl Acad Sci U S A 2004;101:13101-2. 26. Lipsitch M, Bergstrom CT, Levin BR. The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc Natl Acad Sci U S A 2000;97:1938-43.
Henderson 27. Marshall C, Wesselingh S, McDonald M, Spelman D. Control of endemic MRSA—what is the evidence? A personal view. J Hosp Infect 2004;56:253-68. 28. Nijssen S, Bonten MJ, Weinstein RA. Are active microbiological surveillance and subsequent isolation needed to prevent the spread of methicillin-resistant Staphylococcus aureus? Clin Infect Dis 2005;40: 405-9. 29. Fishman N. Antimicrobial stewardship. Am J Med 2006;119(suppl 6A): S53-61. 30. Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med 2006;119(suppl 6A):S3-10. 31. Tenover FC, McGowan JE Jr. Reasons for the emergence of antibiotic resistance. Am J Med Sci 1996;311:9-16. 32. Monnet DL. Methicillin-resistant Staphylococcus aureus and its relationship to antimicrobial use: possible implications for control. Infect Control Hosp Epidemiol 1998;19:552-9. 33. Muller AA, Mauny F, Bertin M, et al. Relationship between spread of methicillin-resistant Staphylococcus aureus and antimicrobial use in a French university hospital. Clin Infect Dis 2003;36:971-8. 34. Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother 2002;49: 999-1005. 35. Hori S, Sunley R, Tami A, Grundmann H. The Nottingham Staphylococcus aureus population study: prevalence of MRSA among the elderly in a university hospital. J Hosp Infect 2002;50:25-9. 36. Dziekan G, Hahn A, Thune K, et al. Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study. J Hosp Infect 2000;46:263-70. 37. Gruson D, Hilbert G, Vargas F, et al. Rotation and restricted use of antibiotics in a medical intensive care unit. Impact on the incidence of ventilator-associated pneumonia caused by antibiotic-resistant gram-negative bacteria. Am J Respir Crit Care Med 2000;162:837-43. 38. Landman D, Chockalingam M, Quale JM. Reduction in the incidence of methicillin-resistant Staphylococcus aureus and ceftazidime-resistant Klebsiella pneumoniae following changes in a hospital antibiotic formulary. Clin Infect Dis 1999;28:1062-6. 39. Fukatsu K, Saito H, Matsuda T, Ikeda S, Furukawa S, Muto T. Influences of type and duration of antimicrobial prophylaxis on an outbreak of methicillin-resistant Staphylococcus aureus and on the incidence of wound infection. Arch Surg 1997;132:1320-5. 40. Stone SP, Beric V, Quick A, Balestrini AA, Kibbler CC. The effect of an enhanced infection-control policy on the incidence of Clostridium difficile infection and methicillin-resistant Staphyloccocus aureus colonization in acute elderly medical patients. Age Ageing 1998;27:561-8. 41. Asensio A, Guerrero A, Quereda C, Lizan M, Martinez-Ferrer M. Colonization and infection with methicillin-resistant Staphylococcus aureus: associated factors and eradication. Infect Control Hosp Epidemiol 1996;17:20-8. 42. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol 2002;23(suppl): S3-40. 43. Girou E, Loyeau S, Legrand P, Oppein F, Brun-Buisson C. Efficacy of handrubbing with alcohol based solution versus standard handwashing with antiseptic soap: randomised clinical trial. BMJ 2002;325:362-6. 44. Picheansathian W. A systematic review on the effectiveness of alcoholbased solutions for hand hygiene. Int J Nurs Pract 2004;10:3-9. 45. Pittet D, Mourouga P, Perneger TV, and members of the Infection Control Program Compliance with handwashing in a teaching hospital [brief communication]. Ann Intern Med 1999;130:126-30. 46. Meengs MR, Giles BK, Chisholm CD, Cordell WH, Nelson DR. Hand washing frequency in an emergency department. J Emerg Nurs 1994; 20:183-8.
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47. Albert RK, Condie F. Hand-washing patterns in medical intensive-care units. N Engl J Med 1981;304:1465-6. 48. Graham M. Frequency and duration of handwashing in an intensive care unit. Am J Infect Control 1990;18:77-81. 49. Pittet D, Hugonnet S, Harbarth S, et almembers of the Infection Control Programme. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene [published correction appears in Lancet. 2000;356:2196]. Lancet 2000;356:1307-12. 50. Larson EL, Early E, Cloonan P, Sugrue S, Parides M. An organizational climate intervention associated with increased handwashing and decreased nosocomial infections. Behav Med 2000;26:14-22. 51. Dubbert PM, Dolce J, Richter W, Miller M, Chapman SW. Increasing ICU staff handwashing: effects of education and group feedback. Infect Control Hosp Epidemiol 1990;11:191-3. 52. Grundmann H, Hori S, Winter B, Tami A, Austin DJ. Risk factors for the transmission of methicillin-resistant Staphylococcus aureus in an adult intensive care unit: fitting a model to the data. J Infect Dis 2002;185:481-8. 53. Fridkin SK, Pear SM, Williamson TH, Galgiani JN, Jarvis WR. The role of understaffing in central venous catheter-associated bloodstream infections. Infect Control Hosp Epidemiol 1996;17:150-8. 54. Haley RW, Bregman DA. The role of understaffing and overcrowding in recurrent outbreaks of staphylococcal infection in a neonatal special-care unit. J Infect Dis 1982;145:875-85. 55. Lucet JC, Paoletti X, Lolom I, et al. Successful long-term program for controlling methicillin-resistant Staphylococcus aureus in intensive care units. Intensive Care Med 2005;31:1051-7. 56. Marshall C, Harrington G, Wolfe R, Fairley CK, Wesselingh S, Spelman D. Acquisition of methicillin-resistant Staphylococcus aureus in a large intensive care unit. Infect Control Hosp Epidemiol 2003;24:322-6. 57. Onorato M, Borucki MJ, Baillargeon G, et al. Risk factors for colonization or infection due to methicillin-resistant Staphylococcus aureus in HIV-positive patients: a retrospective case-control study. Infect Control Hosp Epidemiol 1999;20:26-30. 58. Boyce JM, Havill NL, Kohan C, Dumigan DG, Ligi CE. Do infection control measures work for methicillin-resistant Staphylococcus aureus? Infect Control Hosp Epidemiol 2004;25:395-401. 59. Wertheim HF, Vos MC, Boelens HA, et al. Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission in the Netherlands: the value of search and destroy and restrictive antibiotic use. J Hosp Infect 2004;56:321-5. 60. Vandenbroucke-Grauls CM. Methicillin-resistant Staphylococcus aureus control in hospitals: the Dutch experience. Infect Control Hosp Epidemiol 1996;17:512-3. 61. Tiemersma EW, Bronzwaer SL, Lyytikainen O, et al. Methicillin-resistant Staphylococcus aureus in Europe, 1999–2002. Emerg Infect Dis 2004;10:1627-34. 62. Kaiser AM, Schultsz C, Kruithof GJ, Debets-Ossenkopp Y, Vandenbroucke-Grauls C. Carriage of resistant microorganisms in repatriates from foreign hospitals to the Netherlands. Clin Microbiol Infect 2004; 10:972-9. 63. Cooper BS, Stone SP, Kibbler CC, et al. Isolation measures in the hospital management of methicillin resistant Staphylococcus aureus (MRSA): systematic review of the literature. BMJ 2004;329:533-40. 64. Stelfox HT, Bates DW, Redelmeier DA. Safety of patients isolated for infection control. JAMA 2003;290:1899-905. 65. Evans HL, Shaffer MM, Hughes MG, et al. Contact isolation in surgical patients: a barrier to care? Surgery 2003;134:180-8. 66. Rohr U, Mueller C, Wilhelm M, Muhr G, Gatermann S. Methicillin-resistant Staphylococcus aureus whole-body decolonization among hospitalized patients with variable site colonization by using mupirocin in combination with octenidine dihydrochloride. J Hosp Infect 2003;54:305-9. 67. Watanakunakorn C, Axelson C, Bota B, Stahl C. Mupirocin ointment with and without chlorhexidine baths in the eradication of Staphylococcus aureus nasal carriage in nursing home residents. Am J Infect Control 1995;23:306-9.
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68. Muller A, Talon D, Potier A, Belle E, Cappelier G, Bertrand X. Use of intranasal mupirocin to prevent methicillin-resistant Staphylococcus aureus infection in intensive care units. Crit Care 2005;9:R246-50. 69. Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. Clin Infect Dis 2003;37:933-8.
Henderson 70. Kluytmans JA, Wertheim HF. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection 2005;33: 3-8. 71. Bergstrom CT, Lo M, Lipsitch M. Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc Natl Acad Sci U S A 2004;101:13285-90.
Multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are endemic in healthcare settings in the United States and many other countries of the world. Nosocomial transmission of MRSA serves as a source of hospital outbreaks, and recent reports of vancomycin-resistant S aureus strains in the United States emphasize the need for better control of MRSA and other resistant bacteria within healthcare settings. Colonization with S aureus or MRSA is relatively common in both healthy and hospitalized individuals, most often involves the anterior nares, and is frequently asymptomatic. Colonization increases risk of infection. Patient-to-patient transmission of MRSA within healthcare settings primarily occurs via carriage on the hands of healthcare workers. The Society for Healthcare Epidemiology of America (SHEA) has developed guidelines for the prevention of transmission of MRSA and vancomycin-resistant enterococci within healthcare settings, and chief among the recommendations is an emphasis on adherence to hand hygiene guidelines. Other measures that may prevent the nosocomial transmission of MRSA include improved antibiotic stewardship, staff cohorting, maintenance of appropriate staffing ratios, reductions in length of hospital stays, contact isolation, active microbiologic surveillance, and better staff education. Currently, the efficacy of many of these individual infection control interventions remain in doubt. Many studies reporting improvement in infection control outcomes (eg, reduced transmission, decreasing prevalence) involve simultaneous institution of several of these measures, making it impossible to tease out the effects of any of the individual components. Nonetheless, the best approach in the current environment probably involves hand hygiene plus a careful assessment of an institution’s particular circumstances, applying more aggressive procedures such as patient isolation, staff cohorting, and active surveillance cultures, as indicated. (Am J Infect Control 2006;34:S46-54.)
Certain multidrug-resistant bacteria have become endemic in the hospital environment, particularly in intensive care units (ICUs).1-3 Chief among these are methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Guidelines have been developed for preventing the spread of these organisms within the hospital and other healthcare environments.4,5 The recent emergence of MRSA that are also resistant to vancomycin, through a mechanism involving horizontal transfer of genetic material from VRE,6-9 has made controlling the spread of MRSA and VRE even more important. Society for Healthcare Epidemiology of America (SHEA) guidelines focus on preventing nosocomial transmission of both MRSA and VRE.4 Guidelines published by the Hospital Infection Control Practices Advisory Committee (HICPAC) from the Centers for Disease Control and
Reprint requests: David K. Henderson, MD, 2815 Regina Drive, Silver Spring, Maryland 20106. E-mail: [email protected]. 0196-6553/$32.00 Copyright ª 2006 by the Association for Professionals in Infection Control and Epidemiology, Inc. and Elsevier, Inc. doi:10.1016/j.ajic.2006.05.228
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Prevention (CDC) specifically address preventing the spread of VRE.5 Recommendations for infection control interventions from these and other organizations are likely useful in controlling hospital spread of other resistant bacterial pathogens as well, although speciesspecific differences may necessitate modifications of the guidelines for some pathogens.10 This article examines strategies for managing MRSA as a paradigm for how the healthcare community might approach management of all resistant pathogens.
STAPHYLOCOCCUS AUREUS COLONIZATION AND TRANSMISSION Staphylococcal organisms are ‘‘people pathogens’’ that may be recovered from numerous sites on both patients and staff. They may colonize the face, hands, axilla, or groin, but their primary habitat is the epithelium of the anterior nares.11 Inpatients colonized or infected with MRSA probably serve as the major reservoir for MRSA spread within hospitals.12 From 30% to 60% of healthy adults are colonized with S aureus and 10% to 20% are chronically colonized, primarily in the nares.13,14 In a recent study of pediatric subjects in the community, 36% exhibited nasal carriage of S aureus, including carriage of MRSA in 9% of
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subjects.15 The MRSA carriage rate represented a significant increase compared with rates in recent years (P 5 .001) and has been associated with unique, community-based isolates. At the time of hospital admission, many patients in the United States have been identified as nasal carriers of S aureus, including MRSA.16,17 The rate of S aureus carriage among healthcare workers or hospital staff is also striking,18-20 with approximately 6% exhibiting nasal carriage of MRSA in some studies.19,20 High carriage rates are important because S aureus and MRSA colonizing the nares or other areas may be transferred or spread from patient to healthcare worker, patient to patient, or healthcare worker to patient. The primary route of MRSA transmission within the hospital appears to be from patient to patient, carried on the hands of hospital personnel.12 Further, MRSA can also exist on objects in the environment and be spread from these objects to patients, often via healthcare workers’ hands.21-23 Environmental or fomite spread may be substantially underestimated as a route of nosocomial transmission of MRSA.
GENERAL STRATEGIES TO PREVENT RESISTANCE IN HOSPITALS Mathematical models have been used to understand and predict nosocomial cross-transmission, and to provide a theoretical basis for interventions to control infection and resistance.24 Based on mathematical modeling, effective strategies that might be expected to prevent transmission or reduce the prevalence of resistant bacteria in hospitals include reducing antibiotic use, using antibiotics for which there is no resistance, decreasing length of hospital stays (ie, increasing the patient turnover rate), and instituting infection control measures to disrupt the spread of bacteria, including restricting contacts between patients and healthcare workers carrying resistant bacteria.25,26 Mathematical models further suggest that nonspecific interventions that reduce transmission of all bacteria within a hospital will disproportionately reduce the prevalence of colonization with resistant bacteria.26 These interventional strategies based on mathematical models need to be subjected to empirical testing to confirm their efficacy and utility in clinical settings. At a more pragmatic level, educating the hospital staff about the epidemiology, pathogenesis, and general routes of transmission of resistant bacteria within the hospital environment, as well as about the roles that antibiotic use plays in the emergence and spread of bacterial resistance, is extremely important. Education is required both to disseminate basic information and to encourage compliance with infection-control measures that are subsequently implemented.
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FACTORS INFLUENCING HOSPITAL SPREAD OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS A number of factors are known, or have been hypothesized, to influence risks for acquisition or transmission of MRSA in the healthcare setting.4,27 Factors known to decrease acquisition and/or nosocomial transmission of MRSA include appropriate antibiotic use/stewardship, proper hand hygiene, cohorting care of infected or colonized patients, decreasing unnecessary patient contacts, and decreasing length of stay for hospitalized patients. Factors hypothesized to influence risks for nosocomial transmission of MRSA include use of gowns and gloves by staff, isolation of infected or colonized patients, improved staffing ratios, antibiotic recycling, decolonization of colonized staff or patients, and disinfection of equipment or other objects in the environment. Microbiologic surveillance cultures of high-risk patients and staff have been postulated to be important in identifying patients harboring MRSA that may serve as reservoirs for transmission, and hence, may require heightened infectioncontrol measures. Interestingly, a recent investigation that performed cultures and did not notify staff of the results failed to identify transmission.28 Marshall and colleagues27 group transmission risk factors into 4 categories that represent critical points at which MRSA may be potentially controlled within the healthcare setting. The 4 critical points are prevention of selection of methicillin-resistant isolates in a population of S aureus (antibiotic stewardship), reduction in the pool of colonized patients or staff (discharge of colonized/infected patients/decolonization of carriers), prevention of patient-to-patient transmission (screening and alerts, hand hygiene, cohorting, patient isolation, use of gowns and gloves), and prevention of infection in a colonized patient (nasal decolonization). The remainder of this article examines evidence supporting the various infection-control measures that have been recommended or proposed, dividing them into factors for which strong evidence supports efficacy and those for which the support is less robust. Reasons for the remaining controversies are discussed, along with a personal view on how best to proceed in the current environment given these uncertainties.
INFECTION-CONTROL MEASURES WITH RELATIVELY STRONG SUPPORT Antibiotic stewardship An extensive discussion of the issue of antimicrobial stewardship is presented by Fishman elsewhere in this
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supplement.29 Over time, bacteria naturally acquire chromosomal mutations or acquire genetic material from other organisms in their environment that confer resistance to antibacterial drugs. Whether these resistant bacteria survive and replicate depends on a number of factors, including environmental conditions that are influenced by antibiotic use. Heavy use of antibiotics, particularly broad-spectrum agents, can create conditions that select for bacteria that have mechanisms for resistance.30,31 In other words, antibiotic use establishes conditions in which bacteria with mechanisms for resistance experience a competitive advantage and prosper compared with susceptible bacteria that are rapidly eradicated by an antibiotic therapy. In this way, prolonged administration of antibiotic therapy or inadequate dosing of antibiotics may select for methicillin-resistant isolates in an overall population of S aureus. These MRSA strains may colonize and subsequently cause infection and/or serve as a reservoir for transmission to other patients in the hospital setting. As reviewed in the SHEA guidelines for prevention of nosocomial transmission of MRSA and VRE, use of antimicrobial agents in US hospitals is often excessive and/or unnecessary, and contributes to the emergence and spread of resistant microorganisms such as MRSA.4 As a means to prevent selection of resistant bacteria, the SHEA guidelines underscore recommendations made in the past against inappropriate or excessive use of antibiotics. The relation between antibiotic usage and rates of nosocomial MRSA has been described in a number of reviews.4,27,32 Various studies have reported a positive association between antimicrobial use and incidence of MRSA colonization or infection within the hospital setting, including the use of broad-spectrum cephalosporins and fluoroquinolones.33-39 In some studies, other infection control procedures were instituted at the same time as restriction of antibiotic use,4,40 complicating interpretation of the data. To date, $1 study examining the relation between risk factors and nosocomial colonization and infection failed to identify antibiotic therapy as an independent risk factor.41 Nonetheless, the bulk of the evidence seems to identify antibiotic therapy as a potential risk factor for MRSA colonization and infection in the hospital setting, suggesting that better antibiotic stewardship should result in decreased rates of nosocomial transmission of MRSA.
Hand hygiene The rationale underlying careful adherence to hand hygiene guidelines is that most nosocomial patientto-patient transmission of MRSA occurs via the hands of healthcare workers. Proper hand hygiene clearly
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works in terms of reducing nosocomial transmission of MRSA. HICPAC and the HICPAC/SHEA/APIC (Association for Professionals in Infection Control)/IDSA (Infectious Diseases Society of America) Hand Hygiene Task Force reviewed the available evidence and concluded that adherence to hand hygiene recommendations is associated with a reduced risk for healthcare cross-contamination.42 Failure to perform appropriate hand hygiene is generally considered to be the leading cause of healthcare-associated infections and spread of multiresistant organisms such as MRSA. According to the Task Force, visibly dirty or contaminated hands should be washed with soap and water, and hands that are not visibly soiled should be decontaminated (preferably with an alcohol-based hand rub or, alternatively, with an antimicrobial soap and water) before contact with patients or engaging in clinical procedures. Hand decontamination should also occur after contact with patients’ intact or nonintact skin, bodily fluids, excretions, or mucous membranes; after contact with inanimate objects or medical equipment in the vicinity of patients; and after removing gloves. In the last several years, alcohol-based hand hygiene products have been introduced and shown to be superior to soap and water for hand hygiene.43 They are rapidly active, and they have a broad antimicrobial spectrum. Moreover, they are substantially more convenient, are easier to use, do not require a sink, and are less irritating to the skin than is hand washing with soap and water.44 The hands must be free from visible soiling before the use of an alcohol hand rub. Whereas the development and implementation of these new waterless hand hygiene products represent substantial progress, not all the news relating to hand hygiene in healthcare settings is good. Adherence to hand hygiene recommendations in the healthcare setting remains less than optimal. Adherence to hand hygiene recommendations rarely exceeds 50% in acute care institutions, and physicians seem to be the worst offenders.45-48 A number of studies have demonstrated that nurses adhere to hand hygiene guidelines much more frequently than do physicians, but still far less frequently than is warranted by the needs of patient care.45-47 Other factors adversely affecting adherence to hand hygiene recommendations include working in intensive care, compared with internal medicine wards, male sex, high intensity of patient care, clinical activities associated with high risk of cross-contamination, and high requirements for hand hygiene per hour of patient care.42 Perceived barriers to adherence to hand hygiene include skin irritation or inaccessible hand hygiene supplies, increased workload, and understaffing or overcrowding, among others.42 Ironically, adherence often decreases at times when increased adherence is most important. Some studies
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have suggested increased adherence rates when staff are using the new alcohol-based products, and that is an encouraging sign as well.44 Educational programs may also improve adherence to hand hygiene.49-51
Cohorting patients and decreasing unnecessary patient contacts Cohorting care means having staff provide care for either only those patients already infected or colonized with MRSA or for those known not to be colonized or infected. Staff thus do not cross-cover infected/ colonized and noncolonized patients. Although not systematically studied, cohorting care of infected and colonized patients should intuitively have a substantial impact on nosocomial transmission of MRSA. In an outbreak setting, keeping infected and colonized patients separate from noninfected and noncolonized patients provides a powerful tool to prevent transmission. When financially feasible, assigning staff to cover only patients who are infected may be a key mechanism for preventing transmission in the healthcare setting.
Maintenance of appropriate staffing ratios The rising prevalence of MRSA in healthcare settings is associated with greater hospital or ICU utilization and relative understaffing, particularly during MRSA outbreaks. The findings from 3 studies suggest that understaffing contributes to the spread of microorganisms such as MRSA in healthcare settings. A cohort study combining a comprehensive analysis of risk factors for MRSA transmission with mathematical modeling of the effectiveness of infection control measures identified exposure to a relative staff deficit as the only factor significantly associated with potential transmission (P 5 .001).52 The mathematical model showed that adherence to good hand-washing practice is difficult to attain during periods of understaffing and high workload, and the authors suggested that this probably accounted for the association between understaffing and hospital spread of MRSA. A study from the CDC reported a significant increase in patient-to-nurse ratio during an outbreak of central venous catheter– associated bloodstream infections compared with ratios in the preoutbreak period (P , .01).53 An association among understaffing, patient overcrowding, and spread of infectious diseases was also demonstrated in a neonatal nursery in which the incidence rates of staphylococcal infection substantially increased after periods of increased infant-to-nurse ratios, increasing 16-fold when the infant-to-nurse ratio was .7.54 Unfortunately, very few studies have actually quantified the relation between staffing levels and control of nosocomial infection under endemic hospital conditions. Nonetheless, the available data strongly point
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to understaffing and increased workload as being directly associated with increased transmission, probably as a result of diminished adherence to hand hygiene and subsequent patient-to-staff-to-patient transfer of pathogens.
Decreasing hospital stays Decreasing the length and/or frequency of hospital stays has been hypothesized to decrease the risk for nosocomial MRSA transmission, and results from a number of studies provide support for this concept. For example, a study evaluating acquisition of MRSA in the ICU found length of ICU stay to be a significant independent risk factor for MRSA acquisition (P # .0001).55 Another study similarly reported that both an ICU stay of .2 days as well as being a trauma patient were significant independent risk factors for MRSA acquisition in the ICU (P , .05).56 One case–control study identified previous hospitalization and $3 weeks of hospitalization as independent risk factors for MRSA colonization and infection in hospitalized patients in Spain.41 Similar findings were reported among hospitalized patients with acquired immunodeficiency syndrome.57 These studies suggest that rates of nosocomial MRSA transmission may be decreased by shortening hospital or ICU stays, where possible.
INFECTION-CONTROL MEASURES WITH LESS EVIDENCE-BASED SUPPORT Microbiologic surveillance A controversial issue in the healthcare epidemiology community right now is the use of active microbiologic surveillance as an intervention to minimize transmission of MRSA and other resistant pathogens. The intent of this strategy is to screen all patients admitted to a healthcare setting for MRSA or other multidrugresistant pathogens in order to identify colonized or infected patients who can then be managed with intensive infection-control procedures, such as isolation. Active surveillance is more labor intensive and costly than is passive surveillance, whereby problems are identified using data generated in the routine course of patient care. On the other hand, active surveillance is likely to identify problematic pathogens sooner and thus enable measures to be taken to prevent their spread within the healthcare environment. Many centers use an active surveillance strategy, but many do not. The data are somewhat conflicting with respect to the efficacy of this strategy as an intervention, but based on the available data, many experts believe that tight control, including use of active microbiologic surveillance, is important to prevent crosscontamination with MRSA.4,58 The use of this strategy
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is both labor and resource intensive, and to date, no studies definitively demonstrate the efficacy of this strategy as an independent intervention. Recent studies have demonstrated benefit of prospective surveillance cultures, but because virtually all of these studies introduced interventions simultaneously with active microbiologic surveillance, determining which of the interventions (either independently or in concert) actually induced the observed benefits is essentially impossible.4 The lack of wellcontrolled studies on the issue of active microbiologic surveillance has been the source of ongoing criticism of this intervention. Nonetheless, the published SHEA guidelines encourage an aggressive approach to surveillance, culturing, isolation, and cohort nursing of patients carrying MRSA.4 The potential limitations of current study designs evaluating effectiveness of active surveillance were highlighted by a recent study completed at the ICU of Cook County Hospital in Chicago.28 The study was designed to assess the effect of daily microbiologic surveillance alone, that is, without report of culture results versus isolating colonized patients. During the 10-week period of the study, the staff at this large county hospital was never informed of the surveillance results and colonized patients were never isolated. At the end of this period, the investigators were unable to identify a single instance of cross-transmission among patients in the ICU. Because the staff did not know the results of the surveillance cultures, the investigators concluded that microbiologic surveillance added no benefit. Ironically, however, it should be noted that if the staff had been made aware of the culture results and the same results were obtained, the investigators might have concluded that microbiologic surveillance cultures actually did have an impact. Studies such as this question the necessity of active screening and isolating patients colonized with MRSA. The Netherlands’ experience with nosocomial MRSA is often mentioned when discussing the potential benefits of active surveillance programs. The Netherlands is among the few countries where nosocomial and community levels of MRSA are very low, and the low prevalence has been attributed to the country’s ‘‘search and destroy’’ policy for the prevention of MRSA transmission, as well as a policy of restrictive antibiotic use.59,60 Strict barrier precautions are required for patients who carry the organisms, temporary furloughs are provided to colonized healthcare workers, and authorities even close hospital wards when the prevalence starts to rise in some situations. This strategy has been remarkably effective in limiting the spread in the Netherlands, such that currently the prevalence of staphylococcal isolates resistant to methicillin and causing infection in the hospital environment is ,2%.59
Curiously, countries surrounding the Netherlands have much higher prevalences, some of which approach or exceed rates found in the United States. For example, among countries participating in the European Antimicrobial Resistance Surveillance System (EARSS), MRSA prevalence in 2002 was reported to be #49% in Greece, 45% in Ireland and the United Kingdom, and 39% in Portugal.61 Thus, both patients transferred to the Netherlands from hospitals in surrounding countries as well as repatriates have high rates of methicillin resistance and are thus easily identified.62 In such a controlled setting, at-risk populations are readily identified and appropriate precautions can be rapidly implemented.
Contact isolation Most major infection control guidelines for MRSA recommend some kind of isolation for patients who harbor the bacteria, and the category of isolation most frequently recommended is contact isolation. The SHEA guidelines recommend contact (or cohort) isolation for all patients known to be colonized or infected with MRSA, including hand hygiene and the use of gloves and gowns before interacting with infected/colonized patients or entering their environments.4 In studies in which contact isolation has been implemented as a part of an infection-control program designed to limit the spread of MRSA, isolation has generally been effective in controlling further spread within the hospital.27 However, as previously discussed, contact isolation has typically been implemented concurrently with (usually several) other infection-control measures. Therefore, attributing the observed benefits of reduced spread of MRSA to any single intervention, including isolation, is not possible. A recent systematic literature review of isolation measures in the management of nosocomial MRSA concluded that, due to methodology weaknesses and inadequate reporting, assessing the contribution of isolation as a single measure to reduce spread is not possible.63 Another consideration is the potentially adverse impact of contact isolation on patient care. A 2003 report by Stelfox and coworkers64 illustrated the potential pros and cons of isolating patients who have infectious diseases. This study examined quality-of-care measures in adult patients who were isolated for MRSA colonization or infection at 2 North American teaching hospitals and found that isolated patients were twice as likely as were controls to experience adverse events during their hospitalization (31 vs. 15 per 1,000 days; P , .001). Isolated patients were also more likely to have incomplete records of vital signs (14% vs. 9%, P , .001; 5% vs. 1% with no vital sign recordings,
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P 5 .02) and were less likely to have nursing narratives (14% vs. 10%; P , .001) or physicians’ progress notes (26% vs. 13%, P , .001).64 Additionally, isolated patients in this study were 8 times more likely than were controls to experience failures of supportive care, including falls, pressure ulcers, and fluid and electrolyte imbalances. A second study, from the surgical literature, also highlighted the significant adverse impact of isolation on quality of care. This latter study reported that isolated patients were visited by staff fewer times than were nonisolated controls (5.3 vs. 10.9 visits per hour; P , .0001) and had less contact time overall—on the general floor and in the ICU—despite the fact that the isolated patients had higher APACHE II scores (10.1 6 1.0 vs. 7.6 6 0.8; P 5 .05) and, ostensibly, would have required more care.65 Therefore, the potential benefits associated with contact isolation need to be weighed against the potential costs in terms of patient care quality.
Decolonization with mupirocin Colonization with S aureus or MRSA is often asymptomatic, but colonization also increases the risk of infection due to these organisms and may serve as a reservoir for transmission to other patients. Therefore, a possible approach to preventing MRSA infection or nosocomial transmission of MRSA involves decolonizing patients or healthcare workers identified as carriers. Intranasal mupirocin has been most commonly used to decolonize S aureus in the anterior nares,27 although mupirocin in combination with chlorhexidine or other agents may also be used for whole-body decolonization of MRSA.66,67 Intranasal mupirocin has been shown to prevent endogenous acquisition of MRSA infections in the ICU.68 A recent review of randomized, controlled trials of the efficacy of intranasal mupirocin for eradication of S aureus in nasal carriage and prevention of infection concluded that mupirocin is highly effective, both in eradicating nasal carriage and in preventing infection over the short term; however, its longterm eradication efficacy is less impressive.69,70 The short-term effectiveness of decolonization with mupirocin has best been documented in epidemic settings, but its efficacy in settings of high MRSA endemicity is also less clear. In addition, mupirocin resistance may develop relatively quickly and is increasingly reported as a clinical concern.70
Antibiotic cycling Antibiotic cycling refers to the strategy of reducing antimicrobial resistance through the rotation or cycling of different antimicrobials over time. Fishman29 discusses this topic in much greater detail elsewhere in this supplement; suffice it to say that current data are inconsistent and are insufficient to evaluate the
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effectiveness of cycling in the prevention of resistance. Mathematical modeling has even suggested that cycling of 1 drug may have far worse effects on resistance than would using a combination of 2 drugs.71
PRACTICAL MANAGEMENT STRATEGIES FOR PRESENT TIMES At present we have inadequate scientific data to identify ideal infection-control strategies for the definitive prevention of nosocomial transmission of MRSA. Part of the reason that controversy still exists is that transmission of healthcare-associated infections is complex and multifactorial. Numerous independent and confounding or interacting factors influence the risk for spread. Studies of the topic are clinically difficult and labor intensive. Unfortunately, these infections often occur in settings in which a clear urgency to fix the problem exists. If a hospital is having an epidemic, the first concern of the healthcare workers is to terminate the epidemic—at all costs. In an epidemic, institutions are not likely to try just 1 intervention. Rather, they are likely to try several different interventions simultaneously in the hope that a single factor or a combination of factors will reduce the spread. From a clinical perspective, the multiple-intervention strategy is entirely understandable, but from ascientific perspective, this approach makes identifying independent infection-control measures difficult, if not impossible. Given the current state of affairs, then, how are healthcare professionals to decide what is the best and most cost-effective approach to preventing transmission of MRSA and other resistant pathogens within healthcare settings? As noted above, the literature base is inadequate at this time for identifying definitively efficacious strategies. In my opinion, an aggressive approach to control—including the use of aggressive patient isolation, and, when appropriate, cohorting of staff, and perhaps even microbiologic surveillance cultures—makes implicit sense in settings in which the prevalence of MRSA infection is low. The case for the tight-control approach is somewhat more difficult to make in settings in which the prevalence of methicillin resistance is high. Nonetheless, I favor a conservative approach to management of these patients, being mindful of the unique aspects of the individual healthcare environment being assessed, as well as being particularly aware of the barriers to patient care that have been associated with the implementation of some of the most conservative strategies. Even investigators who have questioned the quasi-experimental methodology in virtually all of the published studies evaluating interventions for MRSA have ultimately concluded that, ‘‘current isolation measures recommended in national
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guidelines should continue to be applied until further research establishes otherwise.’’63
SUMMARY Multidrug-resistant bacteria such as MRSA are endemic to the healthcare environment and serve as a potential source for outbreaks in these settings. Various protocols and guidelines have been developed to try and prevent the development of resistant species of S aureus and to slow the transmission of nosocomial MRSA. If healthcare professionals are to be successful in preventing transmission of MRSA in the healthcare setting, then understanding the epidemiology, pathogenesis, and routes of transmission of S aureus in these settings becomes critically important. First and foremost, all staff must understand the important role hand carriage plays in nosocomial transmission of these pathogens. For this reason, healthcare workers must attend to proper hand hygiene rigorously, as recommended by SHEA and other organizations. Other infection-control procedures that may be important in preventing nosocomial transmission of MRSA include contact isolation, cohorting care, maintaining appropriate staffing ratios, use of active microbiologic surveillance, and decreasing hospital stays. Antibiotic stewardship may also play a key role in reducing the development of MRSA and other multidrug-resistant pathogens in the first place. Depending on a variety of each individual institution’s specific circumstances, (eg, available resources, endemic rates of infection), and given the current state of knowledge in the field, SHEA has argued for an aggressive approach to infection control—emphasizing hand hygiene, aggressive patient isolation, microbiologic surveillance cultures, and staff cohorting—at least until subsequent research studies suggest alternative approaches.
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