What are the concepts related to methicillin resistant Staphylococcus aureus (MRSA) and the control and prevention of MRSA infections in healthcare facilities?
Background
S. aureus, the most virulent staphylococcal species, causes infections ranging from relatively minor superficial skin infections to severe conditions such as bacteremia. S. aureus is an opportunistic pathogen that often colonizes body surfaces such as the nares, skin, or perineum without causing symptoms of infection. Approximately 30 percent of the United States (US) population is colonized with S. aureus.
Previous studies have found that patients colonized with S. aureus were more likely to acquire healthcare-associated (HA) S. aureus infections, compared with patients who were not colonized. However, a study by Wertheim et al., demonstrated that all cause and bacteremia-related deaths were significantly higher among patients who were not colonized compared with those who were colonized before their bacteremias, even though colonization was a strong risk-factor for bacteremia. This finding was possibly due to up-regulated immune responses in colonized patients or to lower virulence of colonizing strains compared with infecting strains. Thus colonization, while increasing infection risk, may actually protect patients who become infected from dying.
Today, 39 to 60 percent of S. aureus clinical isolates in US hospitals are methicillin resistant. MRSA bacteremia is associated with higher mortality rates than is methicillin-susceptible S. aureus (MSSA) bacteremia. Several hypotheses may explain this association:
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1) Patients infected with MRSA may be more likely to receive inadequate or inappropriate antimicrobial therapy compared with patients infected with MSSA
2) Appropriate antimicrobial treatment for MRSA bacteremia, which until recently has been limited to vancomycin, may not be as effective as the β-lactam agents used to treat MSSA infections
3) MRSA-infected patients may be more likely to have comorbidities and more severe acute underlying illness compared with MSSA-infected patients or
4) MRSA may possess virulence genes that MSSA does not have.
Risk factors for acquisition of MRSA include: comorbidities such as HIV and renal failure, dialysis, severe illness, intensive care unit (ICU) admission, previous admission to a hospital, injection drug use, and residence in a long-term-care facility, incarceration, living in crowded conditions, and poor hygiene.
Currently, vancomycin is the most frequently prescribed antimicrobial therapy for MRSA bacteremia. However, rare cases of vancomycin resistance among S. aureus have made vancomycin a less appealing option. Since 1997, both vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA), and the fully resistant vancomycin-resistant S. aureus (VRSA) have emerged around the world.
VRSA is defined as an MRSA isolate that carries the VanA gene. VISA is defined as a S. aureus isolate with a vancomycin minimum inhibitory concentration greater than the Clinical and Laboratory Standards Institute (CLSI) break point of 4 μg/ml and hVISA is defined as a S. aureus isolate that has one subpopulation that is vancomycin susceptible according to current CLSI breakpoints and a subpopulation that grows in the presence of vancomycin. The molecular mechanism of intermediate vancomycin resistance is not fully understood. Some investigators have hypothesized that thick S. aureus cell walls trap vancomycin before it reaches the cytoplasmic membrane of S. aureus, thereby rendering the vancomycin inactive.
Prevention and control of methicillin resistant Staphylococcus aureus
Given this background information, what are the key concepts regarding prevention and control of MRSA transmission and infection? First, the reservoir for MRSA is primarily colonized or infected patients. In addition, colonized or infected healthcare workers (HCWs) and contaminated items in the environment can also serve as reservoirs for MRSA. Second, the fact that there are relatively few clones of MRSA worldwide suggests that person-to-person spread, not antimicrobial use, is the most important factor in the spread of MRSA. However, antimicrobial use may predispose patients to acquiring MRSA colonization or infection if they are exposed to the organism. Thus, breaking transmission from these reservoirs and appropriate use of antimicrobial agents are both essential steps in preventing MRSA colonization and infection among patients in healthcare facilities.
What are the conclusions of clinical trials and meta-analyses regarding infection control and Gram positive bacteria – Staphylococcus aureus?
Results of studies have conflicted and the quality of many studies about MRSA control has been poor. Thus, it is difficult to make definitive conclusions based on the results of clinical trials and systematic literature reviews. For example, a cluster randomized trial in 18 ICUs compared surveillance for MRSA and VRE colonization and expanded use of barrier precautions to existing practice and found no difference in the two arms with respect to mean ICU-level incidence of colonization or infection with MRSA or VRE. Investigators for the two meta-analyses of active detection and isolation (ADI) concluded that evidence may favor the use of ADI, but the evidence is of poor quality and the studies had major methodological weaknesses. Thus, they felt that they could not make definitive recommendations.
Three systematic literature reviews have assessed the effectiveness of antimicrobial agents for treating MRSA colonization. Investigators for two of the three reviews concluded that mupirocin might be effective at reducing nasal carriage. Investigators also disagree about the effectiveness of decolonization. The results of randomized controlled trials of decolonization agents (e.g., mupirocin, chlorhexidine gluconate) to reduce the number of MRSA healthcare-associated infections (HAIs) have varied. The investigators who conducted the only meta-analysis assessing these studies stated that the currently available evidence did not support routine use of topical intranasal mupirocin for infection prophylaxis.
Another meta-analysis found that perioperative mupirocin may prevent surgical site infections (SSI) among patients undergoing cardiothoracic surgery, orthopedic surgery or neurosurgery but not among patients undergoing general surgery because the former procedures were often complicated by Gram-positive surgical site infections but general surgical procedures could be complicated by Gram-negative or by Gram-positive SSIs.
What are the consequences of ignoring control of Gram positive bacteria – Staphylococcus aureus?
The consequences of ignoring the key principles and concepts of Gram positive bacteria-S. aureus control are the continued spread of MRSA within healthcare facilities and continued harm to patients who acquire healthcare-associated infections caused by MRSA. In addition, the cost of healthcare will be increased by the MRSA infections and some or all of these costs may not be reimbursed.
What information supports the research on Gram positive bacteria – Staphylococcus aureus, e.g., case-control studies and case series?
Multiple cohort studies have been performed in a variety of patient populations with the goal of establishing a rule to predict which patients are at high risk for MRSA colonization. A prediction rule would help infection prevention staff determine which patients are likely to carry MRSA and, thus, could transmit MRSA to other patients or could acquire an MRSA infection. Ideally, screening the patients identified as high risk of carrying MRSA would be more cost-effective and take less time than testing all patients for MRSA.
Many prediction rules include recent admission to the hospital and this variable has been a strong predictor of MRSA colonization, with sensitivities ranging from 50% to 70% and specificities ranging from 46% to 88%. Prediction rules have also included risk factors for colonization such as prior operation, antimicrobial use during the past year, and a current wound. These prediction rules had varying success. If these prediction rules were applied, the proportion of MRSA or VRE colonized patients who would be missed ranged from 15% to 43%.
Summary of current controversies regarding Gram positive bacteria – Staphylococcus aureus.
Active surveillance
One of the major controversies with respect to prevention and control of MRSA is whether active surveillance (detection) for patients who are colonized but not infected with MRSA is essential for preventing spread of this pathogen within hospitals. Both sides in this debate argue strongly for their position. Proponents of active surveillance for MRSA argue that active surveillance and isolation, which has prevented spread of other nosocomial pathogens such as smallpox and severe acute respiratory syndrome, can also be used to contain endemic MRSA.
Active surveillance for MRSA, which is a vertical approach because it focuses only on one organism, has been credited with the low rates of morbidity and mortality from MRSA in northern Europe and in Western Australia. Proponents of active surveillance acknowledge that a single-pathogen approach is not ideal; however, they argue that current horizontal approaches such as hand hygiene have not decreased MRSA HAI rates significantly. Proponents state that MRSA may have a selective advantage compared with MSSA, may be associated with higher mortality rates than MSSA, and be more virulent compared with other pathogens. Furthermore, ADI for asymptomatic MRSA carriers could prevent transmission of MRSA through multiple routes such as directly from one patient to another, via healthcare workers’ contaminated hands or clothing, and via the environment. Studies have also shown that ADI of MRSA-colonized patients are cost effective.
In contrast, proponents of a horizontal approach argue that hospitals should implement interventions that will decrease spread of any pathogens, including other antimicrobial-resistant pathogens such as enterococci resistant to vancomycin, Acinetobacter baumannii resistant to imipenem, and Pseudomonas aeruginosa resistant to imipenem, because these interventions (e.g., the central-line-associated bloodstream infection [CLABSI] prevention bundle, universal contact precautions, or improved hand hygiene), would decrease the overall rate of healthcare-associated infections more than ADI. (Proponents of a horizontal approach also argue that strategies focusing on active surveillance for patients colonized with MRSA and use of contact precautions for patients with MRSA will not prevent spread of MSSA, spread of other resistant organisms, or infections in patients colonized with MRSA.
Active surveillance also will not prevent MRSA transmission from colonized healthcare workers or from healthcare workers who transiently carry the organism on their hands to un-colonized patients. Additionally, active surveillance programs that only assess nasal carriage will miss colonization of the throat and perineum, which is quite common. Moreover, the isolation component of ADI has been associated with potential harms because contact precautions have been associated with fewer physician visits, (Saint) depression, and decreased patient satisfaction. Furthermore, the costs for active surveillance may decrease the funds available to implement other important infection prevention interventions.
Four large studies have assessed the effectiveness of active surveillance plus contact precautions for preventing spread of MRSA. Robicsek et al., performed a three-phase quasi-experimental study in three hospitals in which they compared baseline (phase 1) to ICU-based universal surveillance for MRSA and contact precautions for patients who carried MRSA (phase 2) and whole-hospital universal surveillance for MRSA, contact precautions for carriers, and decolonization of MRSA carriers (phase 3). These investigators found a significant decrease in MRSA infections over the course of the study.
Similarly, investigators in the Veterans Health Administration performed a quasi-experimental study to assess their nationwide MRSA Prevention Initiative, which included universal ADI. They found that the rates of HA MRSA infections declined by 45% in non-ICUs and by 62% in ICUs after the Initiative was implemented. In contrast, Harbarth et al., implemented ADI plus decolonization for MRSA carriers in half of the surgical wards while the remaining wards served as a control. After a washout period, the intervention and control wards were switched. This study did not find a significant decrease in MRSA infections. Finally, the STAR*ICU Trial was a cluster-randomized ICU trial comparing standard of care to a bundle that included universal surveillance for MRSA, contact precautions for MRSA positive patients, and universal gloving until surveillance culture results were reported to be negative for all other ICU patients. That study found no difference between the intervention and control groups in terms of mean ICU-level incidence of colonization or infection with MRSA.
Decolonizing patients colonized with methicillin resistant Staphylococcus aureus
Experts also disagree about the importance of decolonizing patients colonized with MRSA. Some studies have shown that nasal decolonization with the topical agent mupirocin decreases the incidence of MRSA healthcare-associated infections. Unlike other infection prevention and control interventions, such as ADI, the colonized patient can benefit from MRSA decolonization. Patients colonized with S. aureus have three times higher odds of acquiring a S. aureus infection (ventilator-associated pneumonia, catheter-related infection, bacteremia, urinary infection, wound infection or sinusitis) compared with uncolonized patients. Thus, decolonization may prevent infection with endogenous MRSA. However, mupirocin resistance, the cost of decolonization, the difficulty of decolonizing patients who carry MRSA at sites other than the nares, and recurrent colonization with the same MRSA strain have led some to argue against nasal decolonization.
What is the impact of controlling methicillin resistant Staphylococcus aureus colonization and the implications for infection control?
Infection prevention staff seeks to prevent spread of all pathogens, including MRSA, within healthcare settings. Thus, preventing spread of MRSA and preventing MRSA infections is a major function of all infection prevention programs. However, proponents of ADI (a vertical approach) and proponents of horizontal infection prevention approaches disagree about the extent to which infection prevention programs should focus their attention on MRSA specific interventions and on general prevention interventions. Regardless of which approach an infection prevention program takes, there are substantial adverse effects if MRSA spread in a healthcare setting and if patients acquire MRSA infections.
Klevens et al., estimated that overall in the US, about 18,650 people died during 2005 with invasive MRSA infections, which is greater than the number of persons who died due to HIV during the same time period. Noskin et al., used AHRQ National Inpatient Sample (NIS) data to determine that the marginal impact of S. aureus infection increased: 1) total charges per stay by US $28,526, 2) length of stay by 8.84 days, and 3) mortality per stay by 1.81%. Cosgrove et al., found that MRSA bacteremia was associated with significantly higher mortality rates, lengths of stay, and costs compared with MSSA bacteremia.
Numerous studies have documented that patients who carry MRSA are at increased risk of MRSA infection. For example, Garrouste-Orgeas et al., found that nasal carriage was associated with a three times higher odds of acquiring a S. aureus infection (ventilator-associated pneumonia, catheter-related infection, bacteremia, urinary tract infection, wound infection, or sinusitis) compared with uncolonized patients. Gupta et al., found that preoperative nasal carriage of MRSA was associated with a significantly increased risk of MRSA postoperative infection (relative risk [RR] =8.46; 95% confidence interval [CI]: 1.70, 42.04).
Overview of important clinical trials, meta-analyses, case control studies, case series, and case reports related to infection control and Gram positive bacteria – Staphylococcus aureus.
Most studies evaluating organization-level strategies to prevent MRSA colonization and infection are poorly-controlled quasi-experimental studies. These studies typically have very low internal validity due to selection bias, regression to the mean and temporal biases. Most quasi-experimental studies also have limited external validity because factors such as the prevalence of MRSA on admission and hospital characteristics (e.g., ICU size and ICU length of stay) vary among healthcare facilities and, thus, the effectiveness of many organization-level strategies may also vary among healthcare facilities.
See Table I, Table II and Table III for a summary of clinical work.
What national and international guidelines exist related to Gram positive bacteria – Staphylococcus aureus?
Table IV describes five guidelines, a Dutch guideline, a British guideline, an Australian guideline, and two guidelines written by organizations based in the US, the Society for Healthcare Epidemiology of America (SHEA) and the Centers for Disease Control and Prevention’s Healthcare Infection Control Practices Advisory Committee (CDC HICPAC), on prevention of MRSA transmission in healthcare facilities. All of these guidelines recommend similar control measures, however the recommendations for implementation of these measures varies from guideline to guideline. For instance, the SHEA, Dutch, and British guidelines recommend routinely screening high-risk patients for MRSA but the CDC HICPAC and Australian guidelines recommend active surveillance as a targeted measure to be implemented when the incidence or prevalence of MRSA is not decreasing despite other infection control strategies. None of these guidelines recommend active surveillance of all admitted patients.
The recommendations regarding MRSA decolonization strategies also differ. The Dutch guideline is the only guideline that recommends decolonization for all patients colonized with MRSA. The SHEA and Australian guidelines recommend decolonization as an adjunctive measure when the MRSA incidence or prevalence is not decreasing despite implementation of other strategies. CDC HICPAC recommends decolonization for patients who are epidemiologically linked to outbreaks, and the British guidelines recommend decolonization of patients in specific situations such as during outbreaks or before surgical procedures.
Additionally, the CDC HICPAC and Australian guidelines recommend that HCW be screened and decolonized only if they are linked epidemiologically to an MRSA outbreak. The British guidelines state that healthcare workers with skin lesions who were exposed to an MRSA carrier should be treated. The SHEA guideline recommends decolonizing HCWs only if other strategies do not reduce the incidence or prevalence of MRSA. In contrast, the Dutch guideline recommends the “Search and Destroy” approach for MRSA. Thus, the Dutch guideline defines situations in which HCWs should be screened for MRSA (e.g., treated in a foreign hospital) and recommends decolonization of all HCWs found to carry MRSAs.
Finally, all of the guidelines promote some form of contact or barrier precautions for patients colonized or infected with MRSA; however the recommendations for implementation of the precautions differ. Both the SHEA and Dutch guidelines recommend that HCWs wear a mask when treating MRSA carriers, while the British guideline recommends that HCWs wear masks only when they perform procedures that may generate staphylococcal aerosols (e.g., suctioning respiratory secretions).
The CDC HICPAC and Australian guidelines do not recommend that HCWs use masks when implementing contact precautions for MRSA. All of the guidelines recommend that HCWs wear gowns and gloves and that they do hand hygiene after removing the personal protective equipment. However, the Dutch and Australian guidelines state that gloves and gowns must be worn whenever HCWs enter the contact precaution patient-care area, while the SHEA, CDC HICPAC, and British guidelines make exceptions to this rule. For example, when HCWs enter a patient’s room but do touch the patient or the environmental surfaces.
See Table IV and Table V for the strategies and guidelines for controlling MRSA.
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Interventions to Reduce the Risk of Staphylococcus aureus Infections and Transmission of this Organism
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Controversy Regarding Control of Staphylococcus aureus, particularly MRSA
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Cost, Cost-Benefit, and Savings associated with Control Programs
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Contact Precautions and Possible Adverse Effects of Contact Precautions
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Quasi-Experimental Studies
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Community-Associated MRSA
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Guidelines for Controlling Resistant Staphylococcus aureus
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