Prevention and control of methicillin-resistant Staphylococcus aureus
John M Boyce, MD
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INTRODUCTION — Shortly after the introduction of methicillin in 1959, outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) infections were reported in the early 1960s [1]. Since that time, MRSA has increased in prevalence worldwide as both a healthcare-associated (nosocomial) and a community-associated pathogen. Both the microbiology laboratory and the infection control departments play crucial roles in control of the spread of MRSA within an institution [2].
The prevention and control of MRSA infection will be reviewed here. The epidemiology and clinical manifestations and the treatment of MRSA infections in adults are discussed separately. (See "Epidemiology and clinical manifestations of methicillin-resistant Staphylococcus aureus infection in adults" and see "Treatment of methicillin-resistant or vancomycin resistant Staphylococcus aureus infection in adults").
ROLE OF MICROBIOLOGY LABORATORY — Clinical microbiology laboratories provide several services that are important in controlling transmission of MRSA in healthcare facilities. MRSA must be differentiated from other strains of S. aureus because special infection control precautions are recommended for patients with MRSA, but are not necessary for patients with low-level oxacillin-resistant (so-called "borderline-resistant") S. aureus that do not contain the mecA gene characteristic of MRSA.
The most accurate methods of detecting MRSA are polymerase chain reaction (PCR) methods for detection of the mecA gene and latex agglutination tests for PBP-2a. In microbiology laboratories where these methods are not available, other acceptable methods for routine testing of S. aureus isolates for their susceptibility to beta-lactams are [3,4]: Cefoxitin disk diffusion tests Oxacillin/salt screening plates containing 6 microgram/mL oxacillin and four percent NaCl Broth microdilution tests with two percent sodium chloride Agar dilution tests with two percent sodium chloride
Disk diffusion susceptibility tests identify most MRSA, but they may not identify some heterogeneous class 1 or 2 strains. Present versions of systems such as MicroScan, Vitek, BBL Crystal MRSA ID system, Alamar tests, and Rapid ATB Staph system appear to detect a majority of MRSA strains. However, occasional strains of methicillin-susceptible S. aureus may be misclassified as MRSA by the Vitek system when certain GPS cards are used. Unlike most MRSA, such strains usually are susceptible to clindamycin, gentamicin, and other non-beta-lactam antibiotics.
Most healthcare-associated MRSA (HA-MRSA) strains are multidrug resistant. Isolates that appear resistant to oxacillin but are susceptible to most non-beta-lactam agents (eg, clindamycin, gentamicin, and ciprofloxacin) may be community-associated MRSA (CA-MRSA), or may not represent MRSA. Such strains should be tested using a confirmatory test such as a mecA probe, PCR assay for mecA, oxacillin-salt agar screening plates, or cefoxitin disk diffusion tests.
Typing of MRSA isolates — When clusters or outbreaks of MRSA occur in hospitals, or when the organism becomes highly endemic, it is important to determine if the phenomenon represents healthcare-associated transmission of a single strain, or a cluster of cases caused by multiple unrelated strains. For most hospitals, analysis of antibiotic susceptibility patterns (antibiograms) of isolates represents the most practical initial approach to typing. Comparing the MICs or inhibitory zone diameters of isolates, rather than qualitative results, results in better differentiation of strains [5].
However, genotypic methods have superior discriminatory power and should be used whenever possible. PFGE is an excellent method for typing MRSA [6]. Arbitrary-primed PCR typing methods also differentiate MRSA strains adequately in many situations and are more rapid and less labor-intensive [5]. Although sequencing of protein A (spa) gene polymorphisms requires less time, is easier to interpret than PFGE, and has adequate discriminatory power for outbreak investigations, this method requires the availability of both PCR and DNA sequencing technologies, which are not currently available in many clinical laboratories.
No single typing method has been established to be ideal [3]. A combination of typing methods is likely to give the most accurate information about the relatedness of MRSA isolates [7,8].
ROLE OF INFECTION CONTROL
Nosocomial — HA-MRSA is most commonly transmitted on the hands of HCWs; as a result, good hand hygiene is considered an essential measure for reducing the spread of this pathogen. The potential efficacy of hand hygiene was illustrated in a report in which a hospital-wide hand hygiene program was implemented that emphasized bedside hand disinfection with an alcohol-based solution as well as handwashing with soap and water [9]. Compliance with hand hygiene increased progressively from 48 to 66 percent over a three-year period. At the same time, there were significant reductions in the prevalence of overall nosocomial infection (16.9 to 9.9 percent) and in MRSA transmission rates (2.16 to 0.93 episodes per 10,000 patient-days).
**Guideline recommendations — In 1996, the Hospital Infection Control Practices Advisory Committee (HICPAC) recommended a number of isolation and barrier precaution practices for use when caring for patients with MRSA [10]. The Centers for Disease Control and Prevention (CDC) published a guideline in 2002, recommending a number of new strategies for improving hand hygiene among HCWs [11]. The Society for Healthcare Epidemiology of America (SHEA) published a guideline in 2003 to prevent transmission of multidrug resistant strains of S. aureus and enterococci [12]. The guidelines provide useful strategies for reducing the transmission of MRSA in healthcare facilities.
The guideline recommendations are grouped by the strength of the recommendation based on available study data.
The following measures are strongly recommended and supported by well-designed experimental, clinical, or epidemiologic studies: Implement a program of active surveillance cultures to identify patients colonized or infected with MRSA. Early detection of colonized patients facilitates more timely institution of appropriate contact precautions (eg, use of gloves and gowns), which have been shown to control the spread of MRSA more effectively than standard precautions. Surveillance cultures of the anterior nares and open wounds are recommended for patients at high risk of MRSA colonization or infection. Wear clean, non-sterile gloves when entering the patient's room; remove the gloves when leaving the patient's room. Wear a gown when entering the room if substantial contact with the patient or environmental surfaces in the room is anticipated, or if the patient has wound drainage not contained by a dressing. Remove the gown before leaving the patient's room. Upon removing gloves and gown, clean hands with an alcohol-based hand rub. However, if hands are visibly contaminated with blood or other proteinaceous materials, wash hands with an antimicrobial soap and water.
The following measures are strongly recommended and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale: Place the patient in a private room whenever possible. If a private room is not available, then place two or more patients with MRSA in the same room. Limit transport of the patient from the room to essential purposes only. When possible, dedicate the use of non-critical equipment to a single patient or cohort of patients. If use for another patient is unavoidable, adequately clean and disinfect the item before use.
The following measure is suggested and supported by suggestive clinical or epidemiologic studies or a theoretical rationale: Wearing a mask when caring for MRSA patients may reduce nasal acquisition of MRSA by HCWs.
**Active surveillance — Since screening all patients upon hospital admission would require very substantial laboratory resources, a number of strategies for performing targeted screening have been evaluated. In one study, culturing the anterior nares of patients with a self-reported history of previous admission within one year identified 76 percent of those colonized with MRSA [13]. Another study found that screening individuals with one or more of the following risk factors would have detected 89 percent of those colonized with MRSA on hospital admission: antibiotic use within the past three months, hospitalization within the previous 12 months, diagnosis of skin or soft-tissue infection at admission, and HIV infection [14]. In facilities where admission screening is not performed, screening patients upon admission to intensive care units (ICUs) has been successful.
The impact of active surveillance programs are illustrated in the following studies: In a report from a German hospital from May 2001 through November 2002, 539 patients at high risk for MRSA carriage were screened and isolated until test results were available [15]. Patients that were culture positive (21 percent) were placed in private rooms under barrier precautions. As compared to a retrospective control period (1999 to 2001), the incidence of hospital-acquired MRSA infections was significantly reduced and saved about 110,000 Euros annually. In a hospital in Israel, active surveillance of patients admitted to the hospital who were at high-risk for MRSA carriage was instituted between July 2003 and December 2004 [16]. Patients identified as MRSA-positive were placed in contact isolation in single rooms and were given eradication treatment with intranasal mupirocin and 4 percent chlorhexidine baths. The mean number of MRSA bacteremia cases per month significantly decreased from 3.6 cases before surveillance (between January 2002 and February 2003) to 1.8 cases after the intervention. In an ICU setting with a high level of endemic MRSA, control measures including isolation and barrier precautions, skin decolonization with chlorhexidine for patients colonized with MRSA or mupirocin treatment for nasal carriers significantly decreased the incidence rate of newly acquired infections and colonization (5.8 and 5.6 percent to 2.6 and 1.4 percent, infection and colonization respectively, following implementation of control measures) [17].
Traditional methods used to process surveillance cultures take 48 to 72 hours after samples are obtained to yield results. However, newly available techniques shorten the amount of time required to detect MRSA in surveillance cultures. A selective agar containing cefoxitin (BBL CHROMagar MRSA) detects a majority of MRSA isolates within 24 hours. Commercially available real-time PCR tests for mecA can detect MRSA within two hours [18].
The utility of rapid diagnostic tests (eg, PCR) for early identification of MRSA carriers was evaluated in an ICU setting [19]. Patients were screened on admission for MRSA using a PCR-based test during an intervention period (November 2003 to March 2004) and the time interval from admission to notification of test results was calculated and compared to a historical control period (April 2003 to October 2003). The prevalence of MRSA on ICU admission was 71 of 1053 patients (6.7 percent) during the intervention period. The median time from admission to notification of test results significantly decreased (87 compared to 21 hours in the surgical ICU and 106 compared to 23 hours in the medical ICU). Without admission screening, 55 previously unknown MRSA carriers would have been missed. The combination of rapid diagnostic testing with preemptive contact isolation was associated with a reduction in medical ICU acquired MRSA infections (relative risk [RR] 0.3; 95% CI, 0.1-0.7) but had no effect in the surgical ICU (RR 1.0; 95% CI, 0.6-1.7).
**Further measures to control HA-MRSA — A number of other measures appear to have been useful in limiting healthcare-associated spread of MRSA and should be considered for use by hospitals. Line listing — Maintain a list (preferably computerized) of patients known to be positive for MRSA. Identify known cases on readmission — Develop a system for promptly identifying and isolating known MRSA carriers who are readmitted. Screen the patient to see if he or she is still colonized. The potential importance of this approach was demonstrated in a prospective study from France of MRSA colonization status in previously colonized patients readmitted to the same facility three or more months later [20]. Thirty-one of 78 such patients (40 percent) continued to be colonized with the organism (median time to clearing of 8.5 months). A break in the skin was the only risk factor for persistent colonization in a multivariate analysis. Prevalence surveys of patients — Culture roommates of newly identified MRSA cases. Consider culturing other patients on the ward if a clustering of new MRSA cases occurs on a nursing unit.
In ICUs where MRSA is not already endemic, perform prevalence culture survey of all other patients in the unit whenever a single, new MRSA case is identified. Culture specimens should be obtained from the anterior nares and from any wounds that may be present [21]. Consider culturing inguinal region if no wound is present. Use of a selective medium will reduce the workload for the microbiology laboratory. Monitor compliance with control measures — Because many studies have shown that compliance with barrier precautions and handwashing is often suboptimal, facilities with ongoing transmission of HA-MRSA should consider developing systems for monitoring compliance by HCWs and providing feedback to personnel regarding their performance.
**Evaluation of interventions — A retrospective study of four infection control interventions evaluated the impact of each intervention on MRSA bacteremia in a tertiary care hospital (ie, 800-beds with eight ICUs) [22]. The four interventions (maximal sterile barrier precautions during CVC placement, institution of alcohol-based hand rubs, hand hygiene campaign, and routine nares surveillance for MRSA in ICU patients at admission, then weekly) were introduced one at a time over a nine year period.
Only routine surveillance cultures and subsequent contact isolation precautions resulted in substantial reductions in MRSA bacteremia both in ICUs and hospital-wide. Following a 16-month surveillance culture intervention period, the incidence density of MRSA bacteremia decreased by 75 percent in ICUs, by 40 percent in non-ICU's, which resulted in a 67 percent hospital-wide reduction. Methicillin-susceptible S. aureus (MSSA) bacteremia rates were monitored as a control and were stable during this time.
Community-associated — Optimal measures for the control and prevention of CA-MRSA infections remain under investigation, since this is a relatively new problem [23]. Community-associated infections frequently recur in individuals and can spread within families. In addition, healthcare-associated MRSA can spread to community contacts [24].
The CDC makes the following recommendations to prevent MRSA infections [25]: Keep hands clean by washing thoroughly with soap and water or using an alcohol-based hand sanitizer. Keep cuts and scrapes clean and covered with a bandage until healed. Avoid contact with other people's wounds or bandages. Avoid sharing personal items such as towels, washcloths, razors, clothing, or uniforms.
Although reports of family clusters of invasive MRSA infection are rare, they have important implications for treatment of those in close contact with patients. Current guidelines do not recommend antimicrobial prophylaxis for the family members of patients with CA-MRSA infection but decolonization therapy may be warranted for specific circumstances [26]. (See "Epidemiology and clinical manifestations of methicillin-resistant Staphylococcus aureus infection in adults" section on "Community-associated MRSA infections").
Eradication of MRSA carriage — A number of approaches can be tried to eliminate MRSA carriage in patients and/or HCWs. However, few studies have been performed about the efficacy of such treatments.
**In patients — During outbreaks, administering decolonization therapy to patients colonized with MRSA may help to control the spread of the organism [27,28]. However, the independent contribution of decolonization therapy in reducing transmission is difficult to assess, since it is usually used in conjunction with multiple other control measures.
Nasal mupirocin therapy appears to be effective in patients who are S. aureus carriers in settings with low MRSA carriage rates [29]. However, in a setting where MRSA was endemic (60 percent carriage in the nares), nasal mupirocin was only marginally effective in the eradication of carriage (relative risk 0.57; 95% CI 0.31-1.04 with mupirocin compared to placebo) [30]. The usual mupirocin treatment is to apply twice daily into each nostril for five days.
A 2003 meta-analysis from the Cochrane database [31] evaluated six randomized controlled trials of patients colonized with MRSA comparing monotherapy or combination therapy with topical or systemic antimicrobials to placebo or no treatment for eradication of MRSA colonization [30,32-36].
No difference in MRSA eradication was detected in four trials: one that compared mupirocin to placebo [30], two that compared one systemic agent to no treatment (fusidic acid in one [34] and rifampin or minocycline in the other [33]) and one that compared mupirocin to topical fusidic acid and oral trimethoprim-sulfamethoxazole [32]. In the trial comparing minocycline to rifampin, rifampin was more effective in eradicating MRSA at day 30, but there was no difference at 90 days.
The authors of the meta-analysis concluded that there was insufficient evidence to support use of topical or systemic antimicrobial therapy for eradicating nasal or extranasal MRSA [31]. Furthermore, randomized trials have not demonstrated efficacy of routine intranasal mupirocin for the prevention of surgical site infection with S. aureus or for the prevention of healthcare-associated S. aureus infection in nonsurgical patients [29,37]. (See "Controversies in control measures to prevent surgical site infection", section on Mupirocin).
When eradication of MRSA carriage has been tried, the regimen of choice has been application of topical mupirocin ointment to the anterior nares (two to three times per day for three to five days). Such patients should be recultured following treatment to confirm that MRSA carriage has been eradicated.
Affected patients often carry MRSA on areas of intact skin as well as in the anterior nares. As a result, bathing MRSA carriers with chlorhexidine gluconate-containing soap during the course of mupirocin decolonization therapy is commonly recommended, although the efficacy of this measure has not been established [38].
A trial published after the meta-analysis evaluated a more comprehensive regimen [39]. In this open-label trial, 146 hospitalized patients who were colonized with MRSA were randomly assigned in a 1:3 allocation to no treatment or to a seven day course of daily washing with chlorhexidine gluconate, intranasal mupirocin ointment (2 percent) three times daily, and oral rifampin (300 mg twice daily) and doxycycline (100 mg twice daily). Monthly cultures were obtained from the nares, perineum, skin lesions, and catheter exit sites.
The primary end point, detection of MRSA at three months, was significantly less frequent with active therapy in the 112 patients followed {74 versus 32 percent). The difference remained significant at eight months, when 54 percent of treated patients remained culture negative. The main predictor of treatment failure was a mupirocin-resistant isolate at baseline. Most patients who relapsed did so with their baseline strain.
The clinical significance of this trial is uncertain [40]. The trial was not designed to assess the effect of therapy on infection. In addition, side effects of systemic antibiotics were important as 25 percent developed adverse gastrointestinal reactions and 5 percent discontinued therapy. In addition, drug interactions with rifampin may be important.
A potential complication of mupirocin therapy is the development of mupirocin resistance [41,42]. Mupirocin-resistant MRSA has been described in a patient who had received eight courses of mupirocin over a nine month period; spread of this organism was demonstrated by pulsed-field gel electrophoresis in 12 additional patients and 11 staff members [41]. In the above trial, mupirocin-resistance emerged in only 5 percent of follow-up isolates [39]. However, 19 percent had high-
**In HCWs — If transmission continues despite appropriate identification and isolation of MRSA cases, it is reasonable to consider culturing HCWs on the involved unit(s), especially if a single strain is responsible for most cases. Eradication of nasal carriage of MRSA should be performed in any HCWs who are epidemiologically implicated in the transmission of MRSA. Follow-up culturing of treated HCWs to document elimination of MRSA carriage is also important.
VACCINATION — A vaccine directed against S. aureus capsular polysaccharide showed short-term efficacy in hemodialysis patients [43]. However, development of the vaccine was stopped after it failed to show long-term efficacy in a confirmatory phase III trial that included 3600 dialysis patients. (See "Immunizations in patients with end-stage renal disease", section on Staphylococcus aureus vaccine).
VISA AND VRSA — S. aureus isolates with a vancomycin MIC 4 microgram/mL are considered susceptible. Vancomycin MIC values of 8 to 16 microgram/mL and 32 microgram/mL define isolates that have intermediate susceptibility and are resistant, respectively [44]. (See "Mechanisms of antibiotic resistance in Staphylococcus aureus" for a discussion of the mechanisms of decreased susceptibility or resistance to vancomycin).
In May 1996, a strain of MRSA with reduced susceptibility to vancomycin (MIC = 8 microgram/mL) was recovered in Japan from a patient who appeared to respond poorly to vancomycin therapy [45]. Subsequently, similar strains with vancomycin MICs of 8 to 16 microgram/mL were recovered from a number of patients in the United States [46,47]. All of the isolates were also resistant to methicillin.
Such strains are called glycopeptide (or vancomycin) intermediate S. aureus (GISA or VISA). Some of these patients received long courses of vancomycin prior to recovery of VISA isolates, suggesting that prolonged vancomycin therapy is a major risk factor for VISA [45,46]. Two of the patients were treated with repeated courses of vancomycin for catheter-related MRSA infections. This observation highlights the need to promptly remove infected foreign bodies whenever possible.
The first description of a large outbreak of colonization and infection with a single GISA strain from January 2000 to December 2000 was reported from an ICU in France [48]. Severe infection (eg, pneumonia, bacteremia, endocarditis) was diagnosed in 11 of 21 patients; eight patients died. Extensive colonization of the inanimate environment was found and the outbreak continued despite maximum contact-isolation procedures. Addition of a policy of restricted admissions, twice daily environmental cleaning, and implementation of hand decontamination with an alcohol-based product led to outbreak termination.
VISA strains are not detected reliably by routine disk diffusion tests [49,50]. Such strains can be identified by testing for vancomycin resistance using broth dilution, agar dilution, or agar gradient diffusion (E test) [44]. A full 24-hour incubation period should be used with all methods. Also, if 0.01 mL of a bacterial suspension equivalent to a 0.5 McFarland is inoculated onto commercially available Brain Heart Infusion agar containing 6 microgram/mL of vancomycin and incubated for 24 hours, VISA strains will yield at least two or more colonies, whereas most non-VISA strains will not [50].
Patients infected with vancomycin-resistant S. aureus (VRSA) also have been reported in the United States since 2002. (See "Treatment of methicillin-resistant or vancomycin resistant Staphylococcus aureus infection in adults", section on Treatment of VRSA infections).
Control measures — HICPAC and the CDC have published guidelines for the prevention and control of staphylococcal infections associated with reduced susceptibility to vancomycin [44,51]. These recommendations are summarized below. Infection control and primary care providers should be immediately notified by laboratory personnel when a VISA isolate is identified. Infection control personnel, with assistance of state and federal health authorities, should conduct an epidemiologic and laboratory investigation. The patient should be placed in a private room. Contact precautions should be used as described by HICPAC. (See "Role of infection control" above). The number of personnel who have access to patients with VISA should be minimized. Dedicated HCWs should care for patient(s) with VISA. HCWs should be informed of the implications of such strains, and the recommended precautions for limiting their spread. Compliance with contact precautions and other recommended practices should be monitored and enforced. HCWs, roommates, and other close contacts should be screened for VISA by culture of the nares and hands at baseline and culture of the nares at weekly intervals. The patient and colonized HCWs should be decolonized with mupirocin. Transferring patients between facilities should be avoided, if possible; the receiving unit or facility should be informed of the presence of VISA if transfer is unavoidable. Isolation is continued until cultures of the nares and infected sites are negative times three over a three week period. State health department and CDC personnel should be consulted before discharging the patient.
SUMMARY AND RECOMMENDATIONS MRSA is differentiated from other strains of S. aureus by the presence of the mecA gene. (See "Role of microbiology laboratory" above). Healthcare-associated (HA) MRSA is most commonly transmitted on the hands of healthcare workers; as a result, good hand hygiene is considered an essential measure for reducing the spread of this pathogen. (See "Nosocomial" above). Guidelines to prevent transmission of multidrug resistant strains of S. aureus are available to aid infection control personnel. (See "Nosocomial" above). Community-associated infections frequently recur in individuals and can spread within families. (See "Community-associated" above). A number of approaches can be tried to eliminate MRSA carriage in patients and/or HCWs, however, the efficacy of such treatments is controversial. (See "Eradication of MRSA carriage" above). HICPAC and the CDC have published guidelines for the prevention and control of staphylococcal infections associated with reduced susceptibility to vancomycin. (See "Control measures" above).
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