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Multidrug-Resistant Organisms (MDROs)

Lauren Robertson, MPT

Wild Iris Medical Education is an approved provider (#PA-54) of continuing nursing education by the Washington State Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. Our courses fulfill continuing nursing education requirements in all 50 states.
Wild Iris Medical Education (CBRN Provider #12300) is approved as a provider of continuing education for RNs, LVNs, and respiratory therapists by the California Board of Registered Nursing.
Nurse practitioners may apply these contact hours to pharmacy continuing education and prescriptive authorization.

The material in this course is from the Centers for Disease Control and Prevention, National Center for Infectious Diseases. See http://www.cdc.gov/ncidod/dhqp/ for a complete list of references.

A list of acronyms used in this text is included at end of the course.

Multidrug-resistant organisms (MDROs), including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and certain Gram-negative bacilli (GNB), have important infection control implications that either have not been addressed or have received only limited consideration in earlier isolation guidelines. Increasing experience with these organisms is improving understanding of the routes of transmission and of effective preventive measures.

Although transmission of MDROs is most frequently documented in acute care facilities, all healthcare settings are affected by the emergence and transmission of organisms resistant to antimicrobials. The severity and extent of disease caused by these pathogens varies by the populations affected and by the institutions in which they are found.

Institutions, in turn, vary widely in physical and functional characteristics, ranging from long-term care facilities to specialty units such as intensive care units, burn units, and neonatal ICUs. Because of this, the approaches to prevention and control of these pathogens need to be tailored to the specific needs of each population and individual institution.

This is a national priority—one that requires all healthcare facilities and agencies to assume responsibility. The following discussion and recommendations are provided to guide implementation of strategies to prevent the transmission of MRSA, VRE, and other multidrug-resistant organisms. Healthcare facilities need to ensure that appropriate strategies are fully implemented, regularly evaluated for effectiveness, and adjusted to produce a consistent decrease in the incidence of targeted MDROs.

Successful prevention and control of MDROs requires both administrative and scientific leadership and a financial and human-resource commitment. Resources that must be made available for infection prevention and control include expert consultation, laboratory support, adherence monitoring, and data analysis.

Infection prevention and control professionals have found that healthcare personnel are more receptive and adherent to the recommended control measures when their facility's leaders participate in efforts to reduce transmission of MDROs.

CLINICAL IMPORTANCE OF MDROs

[Note: Multidrug-resistant strains of M. tuberculosis are not addressed in this course because of the markedly different patterns of transmission and spread of the pathogen and the very different control interventions that are needed. Recommendations for prevention and control of tuberculosis can be found at http://www.cdc.gov/mmwr/pdf/rr/rr5417.pdf.]

Multidrug-resistant organisms (MDROs) are defined as microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents. Although the names of certain MDROs describe resistance to only one agent (eg, MRSA or VRE), these pathogens are frequently resistant to most available antimicrobial agents.

These highly resistant organisms deserve special attention in healthcare facilities. In addition to MRSA and VRE, certain Gram-negative bacilli (GNB)—including those producing extended spectrum beta-lactamases (ESBLs) and others that are resistant to multiple classes of antimicrobial agents—are of particular concern. These include:

• Escherichia coli
• Klebsiella pneumoniae
• Strains of Acinetobacter baumannii resistant to all antimicrobial agents—or all except imipenem
• Organisms such as Stenotrophomonas maltophilia, Burkholderia cepacia, and Ralstonia pickettii that are intrinsically resistant* to the broadest-spectrum antimicrobial agents.

*Intrinsically resistant means that all bacteria of a particular species are resistant to a given antibiotic. For example, all Gram negative bacteria are intrinsically resistant to vancomycin.

In some residential settings, such as long-term care facilities, it is important to control multidrug-resistant S. pneumoniae (MDRSP) that are resistant to penicillin and other broad-spectrum agents such as the macrolides and fluoroquinolones.

Strains of S. aureus that have intermediate susceptibility or are resistant to vancomycin—such as vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA)—have affected specific populations including hemodialysis patients.

In most instances, MDRO infections have clinical manifestations that are similar to those caused by susceptible pathogens. However, options for treating patients with these infections are often extremely limited. For example, until recently only vancomycin provided effective therapy for potentially life-threatening MRSA infections, and during the 1990s there were virtually no antimicrobial agents to treat infections caused by VRE. Although antimicrobials are now available for treatment of MRSA and VRE infections, resistance to each new agent has already emerged in clinical isolates.

Similarly, therapeutic options are limited for ESBL-producing isolates of Gram-negative bacilli, strains of A. baumannii resistant to all antimicrobial agents except imipenem, and intrinsically resistant Stenotrophomonas sp. These limitations may influence antibiotic usage patterns in ways that suppress normal flora and create a favorable environment for colonization when exposed to potential multidrug-resistant pathogens (due to selective advantage, a genetic advantage of one organism over its competitors that causes it to be favored in survival and reproduction rates over time).

Increased lengths of stay, costs, and mortality also have been linked to MDROs. Two studies documented increased mortality as well as longer hospital stays and higher hospital charges associated with multidrug-resistant Gram-negative bacilli (MDR-GNBs), including a neonatal ICU outbreak of ESBL-producing Klebsiella pneumoniae and the emergence of third-generation cephalosporin resistance in Enterobacter spp. in hospitalized adults.

Vancomycin resistance has been reported to be an independent predictor of death from enterococcal bacteremia. Furthermore, VRE was associated with increased mortality, length of hospital stay, admission to the ICU, surgical procedures, and costs when VRE patients were compared with a matched hospital population.

However, MRSA may behave differently from other multidrug-resistant organisms. When patients with MRSA were compared to patients with methicillin-susceptible S. aureus (MSSA), MRSA-colonized patients more frequently developed symptomatic infections. Furthermore, higher fatality rates have been observed for certain MRSA infections, including bacteremia, post sternotomy mediastinitis, and surgical site infections.

These outcomes may be a result of delays in the administration of vancomycin, the relative decrease in the bactericidal activity of vancomycin, or persistent bacteremia associated with intrinsic characteristics of certain MRSA strains.

Mortality may be increased further by S. aureus with reduced vancomycin susceptibility. Some studies have reported an association between MRSA infections and increased length of stay and healthcare costs, while others have not.

Finally, some hospitals have observed an increase in the overall occurrence of staphylococcal infections following the introduction of MRSA into a hospital or special-care unit.

EPIDEMIOLOGY

Trends

Prevalence of multidrug-resistant organisms varies over time, geographically, and by healthcare setting. For example, VRE emerged in the eastern United States in the early 1990s, but did not appear in the western United States until several years later, and MDRSP varies in prevalence by state.

The type and level of care also influence the prevalence of MDROs. Intensive care units, especially those at tertiary facilities, may have a higher prevalence of MDRO infections than non-ICU settings. Antimicrobial resistance rates are also strongly correlated with hospital size, tertiary-level care, and facility type. For example, the frequency of clinical infection caused by these pathogens is low in long-term care facilities.

Nonetheless, MDRO infections in long-term care facilities can cause serious disease and mortality, and colonized or infected long-term residents may serve as reservoirs and vehicles for introducing MDRO into acute care facilities.

Pediatric populations also differ in their prevalence of multidrug-resistant organisms. Prevalence surveys conducted by the Pediatric Prevention Network (PPN) in eight American pediatric ICUs (PICUs) and seven neonatal ICUs (NICUs) found (2000):

• Less than 4% of pediatric patients were colonized with MRSA or VRE, compared with 10% to 24% colonized with ceftazidime- or aminoglycoside-resistant Gram-negative bacilli;
• Less than 3% were colonized with ESBL-producing Gram-negative bacilli.

Despite some evidence that the MDRO burden is greatest in adult hospital patients, MDRO still require similar control efforts in pediatric populations.

During the last several decades, the prevalence of multidrug-resistant organisms in U.S. hospitals and medical centers has increased steadily. MRSA was first isolated in the United States in 1968. By the early 1990s, MRSA accounted for 20% to 25% of Staphylococcus aureus isolates from hospitalized patients.

In 1999 MRSA accounted for more than 50% of S. aureus isolates from patients in ICUs in the National Nosocomial Infection Surveillance (NNIS) system; in 2003, 59.5% of S. aureus isolates in NNIS ICUs were MRSA.

A similar rise in prevalence has occurred with VRE. From 1990 to 1997, the prevalence of VRE in enterococcal isolates from hospitalized patients increased from less than 1% to approximately 15%. VRE accounted for almost 25% of enterococcus isolates in NNIS ICUs in 1999, and 28.5% in 2003.

Gram-negative bacilli resistant to ESBLs, fluoroquinolones, carbapenems, and aminoglycosides also have increased in prevalence. For example, in 1997 an antimicrobial surveillance program found that, among K. pneumoniae strains isolated in the United States, resistance rates to ceftazidime and other third-generation cephalosporins were between 3% and 10% for bloodstream, pneumonia, wound, and urinary tract infections. In 2003 one-fifth of all K. pneumoniae isolates from NNIS ICUs were resistant to these drugs.

Similarly, between 1999 and 2003, Pseudomonas aeruginosa resistance to fluoroquinolone antibiotics increased from 23% to 29.5% in NNIS ICUs. Also, a three-month survey of fifteen Brooklyn hospitals in 1999 found that 53% of A. baumannii strains exhibited resistance to carbapenems and 24% of P. aeruginosa strains were resistant to imipenem.

During 1994–2000, a national review of ICU patients in 43 states found that the overall susceptibility to ciprofloxacin decreased from 86% to 76% and was temporally associated with increased use of fluoroquinolones in the United States.

Finally, an analysis of trends of antimicrobial resistance in non-ICU patients in twenty-three U.S. hospitals during 1996–1997 and 1998–1999 found significant increases in the prevalence of resistant isolates including MRSA, ciprofloxacin-resistant P. aeruginosa, and ciprofloxacin- or ofloxacin-resistant E. coli. Factors that may have contributed to these increases include:

• Selective pressure (any phenomena that alter the behavior of fitness of living organisms and thus influence their survival) exerted by exposure to antimicrobial agents, particularly fluoroquinolones, outside of the ICU and/or in the community
• Increasing rates of community-associated MRSA colonization and infection
• Inadequate adherence to infection control practices
• A combination of these factors

Important Concepts in Transmission

Once multidrug-resistant organisms are introduced into a healthcare setting, transmission and persistence of the resistant strain is determined by:

• The availability of vulnerable patients
• Selective pressure exerted by antimicrobial use
• Increased potential for transmission from larger numbers of colonized or infected patients (colonization pressure, or the proportion of other patients colonized)
• The impact of implementation and adherence to prevention efforts

Patients vulnerable to colonization and infection include those with:

• Severe disease, especially those with compromised host defenses from underlying medical conditions
• Recent surgery
• In-dwelling medical devices such as urinary catheters or endotracheal tubes

Hospitalized patients, especially ICU patients, tend to have more risk factors than nonhospitalized patients and they have the highest infection rates. For example, the risk that an ICU patient will acquire VRE increases significantly once the proportion of ICU patients colonized with VRE exceeds 50% or the number days of exposure to a VRE-infected patient exceeds 15 days.

A similar effect of colonization pressure has been demonstrated for MRSA in a medical ICU. Increasing numbers of infections with multidrug-resistant organisms have also been reported in non-ICU areas of hospitals. There is ample evidence to suggest that MDROs are carried from one person to another via the hands of healthcare personal.

Hands are easily contaminated during the process of caregiving or from contact with environmental surfaces in close proximity to the patient. The latter is especially important when patients have diarrhea and the reservoir of the MDRO is the gastrointestinal tract.

Without adherence to published recommendations for hand hygiene and glove use, healthcare personnel are more likely to transmit MDROs to patients. Thus, strategies to increase and monitor adherence are important components of control programs.

Opportunities for transmission of MDROs beyond the acute care hospital results from patients receiving care at multiple healthcare facilities and moving between acute care, ambulatory and/or chronic care, and long-term care environments. System-wide surveillance at a hospital in Salt Lake City, Utah, monitored patients identified as being infected or colonized with MRSA or VRE, and found that those patients subsequently received inpatient or outpatient care at as many as sixty-two different healthcare facilities in that system during a five-year span.

Role of Healthcare Personnel in MDRO Transmission

It is rare for healthcare personnel to introduce a multidrug-resistant organism into a patient care unit. Occasionally, they can become persistently colonized with an MDRO, but these workers have a limited role in transmission unless other factors are present. Additional factors that can facilitate transmission include workers' chronic sinusitis, upper respiratory infection, and dermatitis.

Implications of Community-Associated MRSA (CA-MRSA)

The emergence of new epidemic strains of MRSA in the community among patients without established MRSA risk factors, may present new challenges for MRSA control in healthcare settings. Genetic analyses of MRSA isolated from patients in hospitals worldwide revealed that a small number of strains have unique qualities that facilitate their transmission from patient to patient within healthcare facilities over wide geographic areas; this could explain the dramatic increases in hospital-acquired infections caused by MRSA in the 1980s and early 1990s.

To date, most MRSA strains isolated from patients with community-acquired infections have been distinct from those commonly found in healthcare settings, suggesting that some of these strains may have arisen de novo within the community via acquisition of methicillin-resistant genes by established methicillin-susceptible S. aureus (MSSA) strains. Two identified types have accounted for the majority of CA-MRSA infections in the United States, whereas two different types predominate in healthcare settings.

CA-MRSA presents most commonly as relatively minor skin and soft-tissue infections, but severe invasive disease, including necrotizing pneumonia, necrotizing fasciitis, severe osteomyelitis, and asepsis syndrome with increased mortality have also been described in both children and adults.

Transmission within hospitals of MRSA strains is being reported with increasing frequency. Changing resistance patterns of MRSA in ICUs in the NNIS system from 1992 to 2003 provide additional evidence that the new epidemic MRSA strains are becoming established as healthcare-associated as well as community pathogens.

Infections with these strains have most commonly presented as skin disease in community settings. However, intrinsic virulence of the organisms can result in clinical manifestations similar to or potentially more severe than traditional healthcare-associated MRSA infections among hospitalized patients. The prevalence of MRSA colonization and infection in the surrounding community may therefore affect the selection of strategies for MRSA control in healthcare settings.

MDRO PREVENTION AND CONTROL

Preventing infections will reduce the burden of multidrug-resistant organisms in healthcare settings. Prevention of antimicrobial resistance depends on appropriate clinical practices that must be incorporated into all routine patient care. These include:

• Optimal management of vascular and urinary catheters
• Prevention of lower respiratory tract infection in intubated patients
• Accurate diagnosis of infectious etiologies
• Judicious antimicrobial selection and utilization

Guidance for these preventive practices includes the CDC's Campaign to Reduce Antimicrobial Resistance in Healthcare Settings, a multifaceted, evidence-based approach with four parallel strategies:

• Infection prevention
• Accurate and prompt diagnosis and treatment
• Prudent use of antimicrobials
• Prevention of transmission

Campaign materials are available for acute care hospitals, surgical settings, dialysis units, long-term care facilities, and pediatric acute care units online at http://www.cdc.gov/drugresistance/healthcare/.

To reduce rates of central venous line–associated bloodstream infections (CVL-BSIs) and ventilator-associated pneumonia (VAP), a bundle of evidence-based clinical practices has been implemented in many U.S. healthcare facilities. One report demonstrated a sustained effect on the reduction in CVL-BSI rates with this approach.

Although the specific effect on MDRO infection and colonization rates has not been reported, it is logical that decreasing these and other healthcare-associated infections will in turn reduce antimicrobial use and decrease opportunities for emergence and transmission of MDROs.

Successful control of MDROs has been documented in the United States and abroad using a variety of combined interventions. These include improvements in hand hygiene, use of Contact Precautions until patients are culture-negative for a target MDRO, active surveillance cultures, education, enhanced environmental cleaning, and improvements in communication about patients with MDROs within and between healthcare facilities. Active surveillance cultures (ASC) refers to routine culturing used to identify the reservoir for spread and isolation of colonized patients—usually combined with immediate contact precautions. The frequency of cultures is based on the prevalence of the pathogen and the risk factors for colonization.

Representative studies include:

• Reduced rates of MRSA transmission in The Netherlands, Belgium, Denmark, and other Scandinavian countries after the implementation of aggressive and sustained infection control interventions (ie, ASC; pre-emptive use of Contact Precautions upon admission until proven culture negative; and, in some instances, closure of units to new admissions). MRSA generally accounts for a very small proportion of S. aureus clinical isolates in these countries.
• Reduced rates of VRE transmission in healthcare facilities in the three-state Siouxland region (Iowa, Nebraska, and South Dakota) following formation of a coalition and development of an effective region-wide infection control intervention that included ASC and isolation of infected patients. The overall prevalence rate of VRE in the thirty participating facilities decreased from 2.2% in 1997 to 0.5% in 1999.
• Eradication of endemic MRSA infections from two NICUs. The first NICU included implementation of ASC, Contact Precautions, use of triple dye on the umbilical cord, and systems changes to improve surveillance and adherence to recommended practices and to reduce overcrowding. The second NICU used ASC and Contact Precautions; surgical masks were included in the barriers used for Contact Precautions.
• Control of an outbreak and eventual eradication of VRE from a burn unit over a 13- month period with implementation of aggressive culturing, environmental cleaning, and barrier isolation.
• Control of an outbreak of VRE in a NICU over a three-year period with implementation of ASC, other infection control measures such as use of a waterless hand disinfectant, and mandatory in-service education.
• Eradication of multidrug-resistant strains of A. baumannii from a burn unit over a 16-month period with implementation of strategies to improve adherence to hand hygiene, isolation, environmental cleaning, and temporary unit closure.
• In addition, more than 100 reports published during 1982–2005 support the efficacy of combinations of various control interventions to reduce the burden of MRSA, VRE, and MDR-GNBs. Case-rate reduction or pathogen eradication was reported in a majority of studies.
• VRE was eradicated in seven special-care units, two hospitals, and one long-term care facility.
• MRSA was eradicated from nine special-care units, two hospitals, one long-term care facility, and one Finnish district. Furthermore, four MRSA reports described continuing success in sustaining low endemic MDRO rates for over 5 years.
• An MDR-GNB was eradicated from thirteen special-care units and two hospitals.

These success stories testify to the importance of having dedicated and knowledgeable teams of healthcare professionals who are willing to persist for years, if necessary, to control MDROs. Eradication and control frequently required periodic reassessment and the addition of new and more stringent interventions over time (a tiered strategy).

For example, interventions were added in a stepwise fashion during a three-year effort that eventually eradicated MRSA from an NICU. A series of interventions was adopted over the course of a year to eradicate VRE from a burn unit. Eradication of carbapenem-resistant strains of A. baumannii from a hospital required multiple and progressively more intense interventions over several years.

Nearly all studies reporting successful MDRO control employed 7 to 8 different interventions concurrently or sequentially. These figures may underestimate the actual number of control measures used, because authors of these reports may have considered their earliest efforts routine (eg, added emphasis on handwashing), and did not include them as interventions; and some "single measures" are, in fact, a complex combination of several interventions. The use of multiple concurrent control measures in these reports underscores the need for a comprehensive approach to controlling MDROs.

It has not yet been possible to determine the effectiveness of individual interventions, or a specific combination of interventions, that would be appropriate for all healthcare facilities to implement. Randomized controlled trials are necessary to acquire this level of evidence. A National Institutes of Health–sponsored, randomized controlled trial on the prevention of MRSA and VRE transmission in adult ICUs is ongoing and may provide further insight into optimal control measures. This trial compares the use of education (to improve adherence to hand hygiene) and Standard Precautions to the use of ASC and Contact Precautions.

Control Interventions

The various types of interventions used to control or eradicate multidrug-resistant organisms may be grouped into seven categories. These interventions provide the basis for the recommendations for control of MDROs in healthcare settings. They include:

• Administrative support
• Judicious use of antimicrobials
• Surveillance (routine and enhanced)
• Standard and Contact Precautions
• Environmental measures
• Education
• Decolonization

In the studies reviewed, these interventions were applied in various combinations and degrees of intensity, with differences in outcome.

ADMINISTRATIVE SUPPORT

In several reports, administrative support and involvement were important for the successful control of the target MDRO, and authorities in infection control have strongly recommended such support. There are several examples of MDRO control interventions that require administrative commitment of fiscal and human resources. One is the use of ASC. Other interventions that require administrative support include:

• Implementing system changes to ensure prompt and effective communications such as computer alerts to identify patients previously known to be colonized/infected with MDROs
• Providing the necessary number and appropriate placement of hand washing sinks and alcohol-containing hand rub dispensers in the facility
• Maintaining staffing levels appropriate to the intensity of care required
• Enforcing adherence to recommended infection control practices such as hand hygiene and Standard and Contact Precautions for MDRO control

Other measures that require administrative support and have been associated with a positive impact on prevention efforts are direct observation of adherence to precautions with feedback to healthcare personnel and keeping staff informed about changes in transmission rates. When designing interventions, a how-to guide for implementing change in ICUs—including analysis of structure, process, and outcomes—can assist in identifying needed administrative interventions.

Finally, participation in existing (or the creation of new) city-wide, state-wide, regional or national coalitions to combat emerging or growing MDRO problems is an effective strategy that requires administrative support.

EDUCATION

Facility-wide, unit-targeted, and informal educational interventions were included in several successful studies. The focus was to encourage a behavior change through improved understanding of the problem MDRO the facility was trying to control. Whether the desired change involved hand hygiene, antimicrobial prescribing patterns, or something else, enhancing understanding and creating a culture that supported the desired behavior were viewed as essential to success.

Educational campaigns to enhance adherence to hand hygiene practices in conjunction with other control measures have been associated across time with decreases in MDRO transmission in various healthcare settings.

WISE USE OF ANTIMICROBIAL AGENTS

Recommendations for control of MDROs must include attention to judicious antimicrobial use. An association between formulary changes and decreased occurrence of a target MDRO was found in several studies, especially in those that focused on MDR-GNBs. Occurrence of C. difficile–associated disease has also been associated with changes in antimicrobial use.

Although some MRSA and VRE control efforts have attempted to limit antimicrobial use, the relative importance of this measure for controlling these multidrug-resistant organisms remains unclear. Limiting antimicrobial use alone may fail to control resistance due to a combination of factors, including:

• The relative effect of antimicrobials on providing initial selective pressure, compared to perpetuating resistance once it has emerged
• Inadequate limits on usage
• Insufficient time to observe the impact of this intervention

Addressing the second and third items above, one study demonstrated a decrease in the prevalence of VRE with a switch from ticarcillin-clavulanate to piperacillin-tazobactam.

The CDC Campaign to Prevent Antimicrobial Resistance that was launched in 2002 provides evidence-based principles for judicious use of antimicrobials and tools for implementation (http://www.cdc.gov/drugresistance/healthcare). This effort targets all healthcare settings and focuses on:

• Effective antimicrobial treatment of infections
• Use of narrow spectrum agents
• Treatment of infections and not contaminants
• Avoiding excessive duration of therapy
• Restricting use of broad-spectrum or more potent antimicrobials to treatment of serious infections when the pathogen is not known or when other effective agents are unavailable

Achieving these objectives would likely diminish the selective pressure that favors proliferation of MDROs. Strategies for influencing antimicrobial prescribing patterns within healthcare facilities include:

• Education
• Formulary restriction
• Prior-approval programs, including pre-approved indications
• Automatic stop orders
• Academic interventions to counteract pharmaceutical influences on prescribing patterns
• Antimicrobial cycling
• Computer-assisted management programs
• Active efforts to remove redundant antimicrobial combinations

A systematic review of controlled studies identified several successful practices. These include:

• Social marketing (consumer education)
• Practice guidelines
• Authorization systems
• Formulary restriction
• Mandatory consultation
• Peer review and feedback

It further suggested that online systems that provide clinical information, structured order entry, and decision support are promising strategies. These changes are best accomplished through an organizational, multidisciplinary, antimicrobial management program.

MDRO SURVEILLANCE

Surveillance is a critically important component of any MDRO control program, allowing detection of newly emerging pathogens, monitoring epidemiologic trends, and measuring the effectiveness of interventions. Multiple MDRO surveillance strategies have been employed, ranging from surveillance of clinical microbiology laboratory results obtained as part of routine clinical care to use of ASC to detect asymptomatic colonization.

Antibiograms

The simplest form of MDRO surveillance is monitoring of microbiologic isolates showing up in tests ordered as part of routine clinical care. This method is particularly useful to detect emergence of new MDROs not previously detected, either within an individual healthcare facility or community-wide.

In addition, this information can be used to prepare facility- or unit-specific antimicrobial susceptibility reports that describe pathogen-specific prevalence of resistance among clinical isolates. Such reports may be useful to monitor for changes in known resistance patterns that might signal emergence or transmission of MDROs and also to provide clinicians with information to guide antimicrobial prescribing practices.

Incidence Based on Clinical Culture

Some investigators have used clinical microbiology results to calculate incidence of MDRO isolates in specific populations or patient care locations (eg, new MDRO isolates/1,000 patient days, new MDRO isolates per month). Such measures may be useful for monitoring MDRO trends and assessing the impact of prevention programs, although they have limitations.

Because they are based solely on positive culture results without accompanying clinical information, they do not distinguish colonization from infection, and may not fully demonstrate the burden of MDRO-associated disease. Furthermore, these measures do not precisely measure acquisition of MDRO colonization in a given population or location.

Isolating an MDRO from a clinical culture obtained from a patient several days after admission to a given unit or facility does not establish that the patient acquired colonization in that unit. On the other hand, patients who acquire MDRO colonization may remain undetected by clinical culture.

Despite these limitations, incidence measures based on clinical culture results may be highly correlated with actual MDRO transmission rates derived from information using ASC, as demonstrated in a recent multicenter study. These results suggest that incidence measures based on clinical cultures alone might be useful surrogates for monitoring changes in MDRO transmission rates.

Infection Rates

Clinical cultures can also be used to identify targeted MDRO infections in certain patient populations or units. This strategy requires investigation of clinical circumstances surrounding a positive culture to distinguish colonization from infection, but it can be particularly helpful in defining the clinical impact of MDROs within a facility.

Molecular Typing of MDRO Isolates

Many investigators have used molecular typing of selected isolates to confirm clonal transmission in order to enhance understanding of MDRO transmission and the effect of interventions within their facility.

DETECTING ASYMPTOMATIC COLONIZATION

Another form of MDRO surveillance is the use of active surveillance cultures to identify patients who are colonized with a targeted MDRO. This approach is based upon the observation that, for some MDROs, detection of colonization may be delayed or missed completely if culture results obtained in the course of routine clinical care are the primary means of identifying colonized patients.

As stated earlier, active surveillance cultures refers to routine culturing used to identify the reservoir for spread and isolation of colonized patients—usually combined with immediate contact precautions. The frequency of cultures is based on the prevalence of the pathogen and the risk factors for colonization.

Several authors report having used ASC when new pathogens emerge in order to define the epidemiology of the particular agent. In addition, the authors of several reports have concluded that ASC, in combination with use of Contact Precautions for colonized patients, contributed directly to the decline or eradication of the target MDRO. However, not all studies have reached the same conclusion.

A recent study failed to identify cross-transmission of MRSA or MSSA in an MICU during a 10-week period when ASC were obtained, despite the fact that culture results were not reported to the staff. The investigators suggest that the degree of cohorting and adherence to Standard Precautions might have been the important determinants of transmission prevention, rather than the use of ASC and Contact Precautions for MRSA-colonized patients.

The authors of a systematic review of the literature on the use of isolation measures to control healthcare-associated MRSA concluded that there is evidence that concerted efforts that include ASC and isolation can reduce MRSA even in endemic settings. However, the authors also noted that methodological weaknesses and inadequate reporting in published research make it difficult to rule out plausible alternative explanations for reductions in MRSA acquisition associated with these interventions, and therefore concluded that the precise contribution of active surveillance and isolation alone is difficult to assess.

Mathematical modeling has been used to estimate the impact of ASC in controlling MDROs. One such study evaluating interventions to decrease VRE transmission indicated that use of ASC (versus no cultures) could potentially decrease transmission 39%, and that with pre-emptive isolation plus ASC transmission could be decreased 65%.

Another mathematical model examining the use of ASC plus isolation for control of MRSA predicted that isolating colonized or infected patients on the basis of clinical culture results is unlikely to be successful at controlling MRSA; conversely, use of active surveillance and isolation can lead to successful control, even in settings where MRSA is highly endemic. There is less literature on the use of ASC in controlling MDR-GNBs.

Active surveillance cultures have been used as part of efforts to control MDR-GNBs in outbreak settings. The experience with ASC as part of successful control efforts in endemic settings is mixed. One study reported successful reduction of ESBL–producing Enterobacteriaceae over a six-year period using a multifaceted control program that included use of ASC. Other reports suggest that use of ASC is not necessary to control endemic MDR-GNBs.

More research is needed to determine the circumstances under which active surveillance cultures are most beneficial, but their use should be considered in some settings, especially if other control measures have been ineffective. When use of ASC is incorporated into MDRO prevention programs, the following should be considered:

• The decision to use ASC as part of an infection prevention and control program requires additional support for successful implementation, including: (1) personnel to obtain the appropriate cultures, (2) microbiology laboratory personnel to process the cultures, (3) mechanism for communicating results to caregivers, (4) concurrent decisions about use of additional isolation measures triggered by a positive culture, eg, Contact Precautions, and (5) mechanism for assuring adherence to the additional isolation measures.
• The populations targeted for ASC are not well defined and vary among published reports. Some investigators have chosen to target specific patient populations considered at high risk for MDRO colonization based on factors such as location (eg, ICU with high MDRO rates), antibiotic exposure history, presence of underlying diseases, prolonged duration of stay, exposure to other MDRO-colonized patients, patients transferred from other facilities known to have a high prevalence of MDRO carriage, or having a history of recent hospital or nursing home stays.
  
  A more commonly employed strategy involves obtaining surveillance cultures from all patients admitted to units experiencing high rates of colonization/infection with the MDROs of interest, unless they are already known to be MDRO carriers. In an effort to better define target populations for active surveillance, investigators have attempted to create prediction rules to identify subpopulations of patients at high risk for colonization on hospital admission. Decisions about which populations should be targeted for active surveillance should be made in the context of local determinations of the incidence and prevalence of MDRO colonization within the intervention facility as well as other facilities with whom patients are frequently exchanged.
• Optimal timing and interval of ASC are not well defined. In many reports, cultures were obtained at the time of admission to the hospital or intervention unit or at the time of transfer to or from designated units. In addition, some hospitals have chosen to obtain cultures on a periodic basis to detect silent transmission. Others have based follow-up cultures on the presence of certain risk factors for MDRO colonization, such as antibiotic exposure, exposure to other MDRO–colonized patients, or prolonged duration of stay in a high risk unit.
• Methods for obtaining ASC must be carefully considered, and may vary depending upon the MDRO of interest.
• MRSA: Studies suggest that cultures of the nares identify most patients with MRSA and perirectal and wound cultures can identify additional carriers.
• VRE: Stool, rectal, or perirectal swabs are generally considered a sensitive method for detection of VRE. While one study suggested that rectal swabs may identify only 60% of individuals harboring VRE, and may be affected by VRE stool density, this observation has not been reported elsewhere in the literature.
• MDR-GNBs: Several methods for detection of MDR-GNBs have been employed, including use of perirectal or rectal swabs alone or in combination with oropharyngeal, endotracheal, inguinal, or wound cultures. The absence of standardized screening media for many Gram-negative bacilli can make the process of isolating a specific MDR-GNB a relatively labor-intensive process.
• Rapid detection methods: Using conventional culture methods for active surveillance can result in a delay of 2 to 3 days before results are available. If the infection control precautions (eg, Contact Precautions) are withheld until the results are available, the desired infection control measures could be delayed. If empiric precautions are used pending negative surveillance culture results, precautions may be unnecessarily implemented for many, if not most, patients. For this reason, investigators have sought methods for decreasing the time necessary to obtain a result from ASC.
  
  Commercially available media containing chromogenic enzyme substrates (CHROMagarMRSA has been shown to have high sensitivity and specificity for identification of MRSA and facilitate detection of MRSA colonies in screening cultures as early as 16 hours after inoculation. In addition, realtime PCR-based tests for rapid detection of MRSA directly from culture swabs (<1–2 hours) are now commercially available, as well as PCR-based tests for detection of vanA and van B genes from rectal swabs.
  
  The impact of rapid testing on the effectiveness of active surveillance as a prevention strategy, however, has not been fully determined. Rapid identification of MRSA in one study was associated with a significant reduction in MRSA infections acquired in the medical ICU, but not the surgical ICU.
  
  A mathematical model characterizing MRSA transmission dynamics predicted that, in comparison to conventional culture methods, the use of rapid detection tests may decrease isolation needs in settings of low-endemicity and result in more rapid reduction in prevalence in highly-endemic settings.
• Some MDRO control reports described surveillance cultures of healthcare personnel during outbreaks, but colonized or infected healthcare personnel are rarely the source of ongoing transmission, and this strategy should be reserved for settings in which specific healthcare personnel have been implicated in the transmission of MDROs.

INFECTION CONTROL PRECAUTIONS

Since 1996 CDC has recommended the use of Standard and Contact Precautions for MDROs "judged by an infection control program…to be of special clinical and epidemiologic significance." This recommendation was a general consensus and was not necessarily evidence-based. No studies have directly compared the efficacy of Standard Precautions alone versus Standard Precautions and Contact Precautions, with or without active surveillance cultures, for control of MDROs. Some reports mention the use of one or both sets of precautions as part of successful MDRO control efforts; however, the precautions were not the primary focus of the study intervention.

Standard Precautions have an essential role in preventing transmission of MDROs, even in facilities that use Contact Precautions for patients with an identified MDRO. Colonization with MDROs is frequently undetected; even surveillance cultures may fail to identify colonized persons due to lack of sensitivity, laboratory deficiencies, or intermittent colonization due to antimicrobial therapy. Therefore, Standard Precautions must be used in order to prevent transmission from potentially colonized patients.

Hand hygiene is an important component of Standard Precautions. The authors of the Guideline for Hand Hygiene in Healthcare Settings cited nine studies that demonstrated a relationship between improved adherence to hand hygiene practices and control of MDROs. It is noteworthy that in one report the frequency of hand hygiene did not improve with use of Contact Precautions—but did improve when gloves were used for contact with MDRO patients.

Studies of MDRO control efforts frequently involved changes in isolation practices, especially during outbreaks. In the majority of reports, Contact Precautions were implemented for all patients found to be colonized or infected with the target MDRO.

Some facilities also preemptively used Contact Precautions, in conjunction with ASC, for all new admissions or for all patients admitted to a specific unit until a negative screening culture for the target MDRO was reported.

Contact Precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, that are transmitted by direct or indirect contact with the patient or the patient's environment. A single-patient room is preferred for patients who require Contact Precautions. When a single-patient room is not available, consultation with infection control is necessary to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate).

Healthcare personnel caring for patients on Contact Precautions should wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. Donning gown and gloves upon room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination such as VRE, C. difficile, noroviruses, and other intestinal tract agents.

Cohorting and Other MDRO Control Strategies

In several reports, cohorting of patients, cohorting of staff, use of designated beds or units, and even unit closure were necessary to control transmission. Some authors indicated that implementation of the latter two strategies were the turning points in their control efforts; however, these measures usually followed many other actions to prevent transmission.

In one two-center study, moving MRSA-positive patients into single rooms or cohorting these patients in designated bays failed to reduce transmission in ICUs. However, in this study adherence to recommendations for hand hygiene between patient contacts was only 21%. Other published studies, including one commissioned by the American Institute of Architects and the Facility Guidelines Institute, have documented a beneficial relationship between private rooms and reduction in risk of acquiring MDROs.

Additional studies are needed to define the specific contribution of using single-patient rooms and/or cohorting on preventing transmission of MDROs.

Duration of Contact Precautions

The necessary duration of Contact Precautions for patients treated for infection with an MDRO, but who may continue to be colonized with the organism at one or more body sites, remains an unresolved issue. Patients may remain colonized with MDROs for prolonged periods; shedding of these organisms may be intermittent, and surveillance cultures may fail to detect their presence.

The 1995 HICPAC guideline for preventing the transmission of VRE suggested that three negative stool/perianal cultures obtained at weekly intervals be the criterion for discontinuation of Contact Precautions. One study found these criteria generally reliable. However, this and other studies have noted a recurrence of VRE-positive cultures in persons who subsequently receive antimicrobial therapy and persistent or intermittent carriage of VRE for more than 1 year has been reported.

Similarly, colonization with MRSA can be prolonged. Studies demonstrating initial clearance of MRSA following decolonization therapy have reported a high frequency of subsequent recolonization. There is little information in the literature on when to discontinue Contact Precautions for patients colonized with an MDR-GNB, possibly because infection and colonization with these MDROs are often associated with outbreaks.

Despite the uncertainty about when to discontinue Contact Precautions, the studies offer some guidance. In the context of an outbreak, it would be prudent to use Contact Precautions indefinitely for all previously infected and known colonized patients.

Likewise, if ASC are used to detect and isolate patients colonized with MRSA or VRE, and there is no decolonization of these patients, it is logical to assume that Contact Precautions would be used for the duration of stay in the setting where they were first implemented.

In general, it seems reasonable to discontinue Contact Precautions when three or more surveillance cultures for the target MDRO are repeatedly negative over the course of a week or two in a patient who has not received antimicrobial therapy for several weeks—especially in the absence of a draining wound, profuse respiratory secretions, or evidence implicating the specific patient in ongoing transmission of the MDRO within the facility.

Use of Barriers with Infected Patients

Three studies evaluated the use of gloves with or without gowns for all patient contacts to prevent VRE acquisition in ICU settings. Two of the studies showed that use of both gloves and gowns reduced VRE transmission while the third showed no difference in transmission based on the barriers used.

One study in a long-term care facility compared the use of gloves-only with gloves plus contact isolation, for patients with four MDROs, including VRE and MRSA, and found no difference. However, patients on contact isolation were more likely to acquire MDR-K. pneumoniae strains that were prevalent in the facility; reasons for this were not specifically known.

In addition to differences in outcome, differing methodologies make comparisons difficult. Specifically, healthcare professional adherence to the recommended protocol, the influence of added precautions on the number of patient interactions, and colonization pressure were not consistently assessed.

Impact of Contact Precautions on Patients

There are limited data regarding the impact of Contact Precautions on patients. Two studies found that healthcare professionals, including attending physicians, were half as likely to enter the rooms of, or examine, patients on Contact Precautions.

Other investigators have reported similar observations on surgical wards. Two studies reported that patients in private rooms and on barrier precautions for an MDRO had increased anxiety and depression scores.

Another study found that patients placed on Contact Precautions for MRSA had significantly more preventable adverse events, expressed greater dissatisfaction with their treatment, and had less documented care than control patients who were not in isolation.

Therefore, when patients are placed on Contact Precautions, efforts must be made by the healthcare team to counteract these potential adverse effects.

ENVIRONMENTAL MEASURES

The potential role of such things as surfaces and medical equipment (environmental reservoirs), in the transmission of VRE and other MDROs has been the subject of several reports. While environmental cultures are not routinely recommended, they were used in several studies to document contamination and led to interventions that included the use of dedicated noncritical medical equipment, assignment of dedicated cleaning personnel to the affected patient care unit, and increased cleaning and disinfection of frequently touched surfaces such as bedrails, charts, bedside commodes, and doorknobs.

A common reason given for finding environmental contamination with an MDRO was the lack of adherence to facility procedures for cleaning and disinfection. In an intervention that targeted a defined group of housekeeping personnel, there was a persistent decrease in the acquisition of VRE in one medical ICU. Therefore, monitoring environmental cleaning practices is an important factor for success in controlling transmission of MDROs and other pathogens in the environment.

In the MDRO reports reviewed, enhanced environmental cleaning was frequently undertaken when there was evidence of contamination and ongoing transmission. Rarely, control of the target MDRO required vacating a patient care unit for complete environmental cleaning and assessment.

DECOLONIZATION

Decolonization involves treatment of individuals colonized with a specific MDRO (usually MRSA) to eradicate carriage of that organism. Although some investigators have attempted to decolonize patients harboring VRE, few have achieved success.

However, decolonization of patients carrying MRSA in their nares has proved possible with several regimens that include topical mupirocin alone or in combination with orally administered antibiotics (eg, rifampin combined with trimethoprim-sulfamethoxazole or ciprofloxacin) plus the use of an antimicrobial soap for bathing.

In one report, a three-day regimen of baths with povidone-iodine and nasal therapy with mupirocin resulted in eradication of nasal MRSA colonization.

Decolonization regimens are not sufficiently effective to warrant routine use. Therefore, most healthcare facilities have limited the use of decolonization to MRSA outbreaks, or other high-prevalence situations, especially those affecting special-care units. Several factors limit the utility of this control measure on a widespread basis:

• Identification of candidates for decolonization requires surveillance cultures.
• Candidates receiving decolonization treatment must receive follow-up cultures to ensure eradication.
• Re-colonization with the same strain, initial colonization with a mupirocin-resistant strain, and emergence of resistance to mupirocin during treatment can occur.

Healthcare personnel implicated in transmission of MRSA are candidates for decolonization; they should be treated and found culture-negative before returning to direct patient care. In contrast, healthcare personnel who are colonized with MRSA, but are asymptomatic and have not been linked epidemiologically to transmission, do not require decolonization.

DISCUSSION

This review demonstrates the depth of published science on the prevention and control of multidrug-resistant organisms. Using a combination of interventions, MDROs in endemic, outbreak, and nonendemic settings have been brought under control. However, despite the volume of literature, an appropriate set of evidence-based control measures that can be universally applied in all healthcare settings has not been definitively established.

This is due in part to differences in study methodology and outcome measures, including an absence of randomized, controlled trials comparing one MDRO control measure or strategy with another. Additionally, the data are largely descriptive and quasi-experimental in design.

Few reports described pre-emptive efforts or prospective studies to control MDROs before they had reached high levels within a unit or facility. Furthermore, small hospitals and long-term care facilities are infrequently represented in the literature. A number of questions remain, as discussed below.

Impact of Targeted Interventions on Other MDROS

Only one report described control efforts directed at more than one MDRO (ie, MDR-GNB and MRSA. Several reports have shown either decreases or increases in other pathogens with targeted efforts to control one MDRO.

For example, two reports on VRE control efforts demonstrated an increase in MRSA following the prioritization of VRE patients to private rooms and cohort beds. Similarly an outbreak of Serratia marcescens was temporally associated with a concurrent but unrelated outbreak of MRSA in an NICU. In contrast, a decrease in MRSA and VRE acquisition was reported in an ICU during and after their successful effort to eradicate an MDR-strain of A. baumannii from the unit.

Colonization with multiple MDROs appears to be common. One study found that nearly 50% of residents in a skilled-care unit in a long-term care facility were colonized with a target MDRO and that 26% were co-colonized with more than one MDRO; a detailed analysis showed that risk factors for colonization varied by pathogen.

One review of the literature reported that patient risk factors associated with colonization with MRSA, VRE, MDR-GNB, C. difficile, and Candida sp, were the same. This review concluded that control programs that focus on only one organism or one antimicrobial drug are unlikely to succeed because vulnerable patients will continue to serve as a magnet for other MDROs.

COSTS

Several authors have provided evidence for the cost effectiveness of approaches that use ASC. However, the supportive evidence often relied on assumptions, projections, and estimated attributable costs of MDRO infections. Similar limitations apply to a study suggesting that gown use yields a cost benefit in controlling transmission of VRE in ICUs. To date, no studies have directly compared the benefits and costs associated with different MDRO control strategies.

FEASIBILITY

The subject of feasibility has not been addressed. For example, smaller hospitals and long-term care facilities may lack the on-site laboratory services needed to obtain ASC in a timely manner. This factor could limit the applicability of an aggressive program based on obtaining ASC and pre-emptive placement of patients on Contact Precautions in these settings.

However, with the growing problem of antimicrobial resistance, and the recognized role of all healthcare settings for control of this problem, it is imperative that appropriate human and fiscal resources be invested to increase the feasibility of recommended control strategies in every setting.

Factors that Influence Selection of Control Measures

Although some common principles apply, the preceding literature review indicates that no single approach to the control of MDROs is appropriate for all healthcare facilities. Many factors influence the choice of interventions to be applied within an institution, including:

• Type and significance of problem MDROs within the institution. Many facilities have an MRSA problem while others have ESBL-producing K. pneumoniae. Some facilities have no VRE colonization or disease; others have high rates of VRE colonization without disease; and still others have ongoing VRE outbreaks. The magnitude of the problem also varies. Healthcare facilities may have very low numbers of cases (eg, with a newly introduced strain), or may have prolonged, extensive outbreaks or colonization in the population. Between these extremes, facilities may have low or high levels of endemic colonization and variable levels of infection.
• Population and healthcare-settings. The presence of high-risk patients such as organ transplant and hematopoietic stem-cell transplant patients and special-care units will influence surveillance needs and could limit the areas of a facility targeted for MDRO control interventions. Although it appears that MDRO transmission seldom occurs in ambulatory and outpatient settings, some patient populations (eg, hemodialysis, cystic fibrosis) and patients receiving chemotherapeutic agents are at risk for colonization and infection with MDROs. Furthermore, the emergence of VRSA within the outpatient setting demonstrates that even these settings need to make MDRO prevention a priority.

Differences on the Optimal Strategy to Control MDROs

Published guidance on the control of MDROs reflects areas of ongoing debate on optimal control strategies. A key issue is the use of ASC in control efforts and pre-emptive use of Contact Precautions pending negative surveillance culture results.

The various guidelines currently available exhibit a spectrum of approaches, which their authors deem to be evidence-based. One guideline for control of MRSA and VRE, the Society for Healthcare Epidemiology of America (SHEA) guideline from 2003, emphasizes routine use of ASC and Contact Precautions. That position paper does not address control of MDR-GNBs. The salient features of SHEA recommendations for MRSA and VRE control and the recommendations in this guideline for control of MDROs, including MRSA and VRE, have been compared; recommended interventions are similar.

Other guidelines for VRE and MRSA (eg, those proffered by the Michigan Society for Infection Control) emphasize consistent practice of Standard Precautions and tailoring the use of ASC and Contact Precautions to local conditions, the specific MDROs that are prevalent and being transmitted, and the presence of risk factors for transmission.

A variety of approaches have reduced MDRO rates. Therefore, selection of interventions for controlling MDRO transmission should be based on assessments of the local problem, the prevalence of various MDROs, and feasibility. Individual facilities should seek appropriate guidance and adopt effective measures that fit their circumstances and needs. Most studies have been in acute care settings; for non-acute care settings (eg, long-term care facilities, small rural hospitals), the optimal approach is not well defined.

Two-Tiered Approach for Control of MDROs

Reports describing successful control of MDRO transmission in healthcare facilities have included seven categories of interventions. As a rule, these reports indicate that facilities confronted with an MDRO problem selected a combination of control measures, implemented them, and reassessed their impact. In some cases, new measures were added serially to further enhance control efforts. This evidence indicates that the control of MDROs is a dynamic process that requires a systematic approach tailored to the problem and healthcare setting.

The nature of this evidence gave rise to the two-tiered approach to MDRO control referred to earlier. This approach provides the flexibility needed to prevent and control MDRO transmission in every kind of facility.

SUMMARY

Healthcare facilities must not accept ongoing multidrug-resistant organism outbreaks or high endemic rates as the status quo. With selection of infection control measures appropriate to their situation, all facilities can achieve the desired goal and reduce the MDRO burden substantially.

Posted May 20, 2008

Expires May 3, 2010

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