For many decades, methicillin-resistant Staphylococcus aureus (MRSA) has been regarded as an important microorganism within acute healthcare, and much has been described pertaining to MRSA as a cause of healthcareassociated infections (HAIs), factors that place patients at risk for MRSA infections, and the impact of such infections on patients, hospitals, and the healthcare system at large in countries all over the world. Researchers have provided scientific evidence describing how MRSA emerged, how the microorganism has been transmitted, and measures that have been effective for prevention and control. Of note, within the last 15 years, the epidemiology of MRSA has changed considerably with emergence of the microorganism as a cause of infections among community members who lack traditional risks for MRSA acquisition. This has not only captured the interest of scientists and clinicians, but also that of public health officials, consumer groups, print and television media, as well as government officials. There is renewed focus on MRSA and despite all we have learned about this pathogen, many facilities and communities continue to struggle from its effects and with how to implement evidence-based practices for control.

This chapter describes several aspects of the epidemiology of MRSA including its laboratory characteristics, molecular typing characteristics, clinical and surveillance definitions, as well as its emergence and importance within healthcare and the community. Information regarding how to characterize the reservoir for MRSA are also discussed including methods for detecting colonized individuals. Finally, discussion is provided of basic as well as advanced strategies to prevent transmission both within and outside of healthcare.

S. aureus is a gram-positive, nonmotile, facultatively anaerobic coccus. In the laboratory, staphylococci tend to grow in grape like clusters of cells, hence the genus name Staphylococcus, which is derived from the Greek word staphylé or “bunch of grapes.” The species name, aureus, Latin for golden, describes the color of S. aureus colonies growing in culture. Unlike many other bacteria, staphylococci can grow in environments in which there is a high concentration of salt. This feature is commonly used to assist in the laboratory identification of Staphylococcus species. The presence of catalase activity can be used to distinguish staphylococcal species from several other genera of gram-positive cocci, including Streptococcus and Enterococcus. The production of the enzyme coagulase differentiates S. aureus from the other staphylococcal species (i.e., the coagulase-negative staphylococci). Similarly, mannitol fermentation can also differentiate S. aureus from most other staphylococcal species.

Penicillin-resistant strains of S. aureus were identified relatively soon after penicillin became widely available in the 1940s. The mechanism of resistance was production of penicillinase, a beta-lactamase enzyme encoded by the bla gene. Subsequently, rates of penicillin resistance increased rapidly among hospital and community isolates of S. aureus. By the early 1950s, penicillin was no longer effective for the treatment of most S. aureus infections in many parts of the world. In response to the emergence of penicillin-resistant S. aureus, semisynthetic penicillinase-resistant penicillins were developed and introduced into clinical practice in the late 1950s and early 1960s. Methicillin was the first of these agents to be developed. In 1961, shortly after methicillin became available for clinical use, the first isolates of MRSA were reported (9). The prevalence of resistance to methicillin among S. aureus isolates did not increase as rapidly as had occurred with penicillin resistance in the 1940s, and, in fact, the prevalence remained low until the 1970s and 1980s. Since that time, however, MRSA has become endemic in most hospitals in the United States, Europe (with a few notable exceptions such as Denmark and the Netherlands), Australia, and many other parts of the world.

Until relatively recently, MRSA was considered to be almost exclusively a healthcare-associated pathogen. During the past decade, however, MRSA has emerged as a significant pathogen among persons without typical healthcare-related risks associated with MRSA (10,11,12). In fact, MRSA has become the most commonly identified cause of purulent skin and soft tissue infections in persons presenting to emergency departments and other outpatient settings in many parts of the United States (13,14,15), and its prevalence in this type of infection is increasing in many other countries as well (16, 17 and 18). Based on data from the CDC’s Active Bacterial Core surveillance program, it has been estimated that almost 14% of invasive MRSA disease in the United States in 2004 to 2005 occurred in persons without typical healthcare-associated risks (19). The emergence of community-associated MRSA (CA-MRSA) is the result of clonal dissemination of MRSA that is genetically distinct from typical healthcare-associated MRSA (HA-MRSA). The epidemiologic and genetic differences between CA-MRSA and HA-MRSA will be discussed in greater detail later in this chapter.

General Laboratory Characteristics Although typically referred to as MRSA, these strains are resistant not only to the antistaphylococcal penicillins, such as methicillin, nafcillin, and oxacillin, but also to all other currently available beta-lactam antibiotics (with the exception of the recently FDA-approved ceftaroline), including the first- through fourth-generation cephalosporins and the carbapenems.

The antibacterial effect of beta-lactam antibiotics is the result of inhibition of penicillin-binding proteins (PBPs), which are bacterial proteins acting as catalysts of cell wall assembly. S. aureus resistance to the antistaphylococcal penicillins, currently available cephalosporins, with the exception of ceftaroline, and carbapenems is the result of production of an altered PBP known as “PBP2a” or “PBP2′.” PBP2a has very low affinity for binding beta-lactam antibiotics, which results in the inability of these drugs to exert their antibacterial effect. PBP2a is encoded by the mecA gene located on a resistance island, known as the “staphylococcal cassette chromosome mec” (SCCmec), which can integrate into chromosomal DNA. Several different types of SCCmec, known as “SCCmec types I-VIII,” have been identified to date.

Heteroresistance refers to the situation in which only a subpopulation of the S. aureus cells with the resistance determinant (i.e., the mecA gene) actually express resistance in vitro. This has important implications for detection of resistance because, in the laboratory, the subpopulation that is susceptible to the penicillinase-resistant penicillins may grow more rapidly than the resistant subpopulation at temperatures above 35°C. In order to improve the ability to detect these heteroresistant strains, the Clinical Laboratory Standards Institute (CLSI) recommends incubation of S. aureus isolates at 33°C to 35°C for a minimum of 24 hours before assessing susceptibility to oxacillin, methicillin, or nafcillin (20).

In addition to resistance to the beta-lactam antibiotics, most strains of MRSA are also resistant to one or more other classes of antimicrobial agents. This can be the result of mutations in chromosomal DNA or acquisition of exogenous antibiotic resistance genes. In HA-MRSA strains, resistance to several classes of antibiotics is common. In many instances, these additional resistance determinants reside within the SCCmec. Two of the more common chromosomal mutations associated with antibiotic resistance are mutation of the DNA gyrase gene (gyrA) leading to fluoroquinolone resistance and mutation of rpoB leading to rifampin resistance. In S. aureus, intermediate resistance to the glycopeptides (vancomycin and teicoplanin), defined by CLSI as a vancomycin MIC of 4 to 8 µg/mL and teicoplanin MIC of 16 µg/mL, is also due to mutations in the bacterial chromosome. These mutations cause changes in the structure of the peptidoglycan component of the cell wall, leading to a thicker wall with more uncrosslinked D-alanyl-D-alanine terminals. These excess D-ala-D-ala terminals bind to glycopeptide molecules preventing them from reaching their true target (21). Although the terms “vancomycin-intermediate S. aureus” (VISA) and “glycopeptide- intermediate S. aureus” (GISA) are often used interchangeably, some VISA isolates retain in vitro susceptibility to the glycopeptide teicoplanin.

Acquisition of exogenous resistance genes is responsible for resistance to several other classes of antimicrobials among MRSA isolates. Some of the more common and well-described acquired resistance determinants include erm (conferring macrolide and lincosamide resistance), mupA (conferring high-level mupirocin resistance), tet (conferring resistance to the tetracyclines), msrA (conferring macrolide resistance), and dfrA (conferring high-level trimethoprim resistance). One of the most feared scenarios has been the potential for the development of high-level vancomycin resistance in S. aureus (VRSA) due to acquisition by MRSA of the plasmid-mediated vancomycin resistance gene, vanA, from vancomycin-resistant Enterococcus (VRE). Conjugative transfer of vanA from E. faecalis to S. aureus was achieved in the laboratory in 1992 (22), raising concerns that this transfer of genetic material could occur spontaneously in vivo as well. The first clinical isolate of VRSA was identified a decade later (23). Since this first description in Michigan, nine additional cases have been identified between 2002 and 2007 (24,25). In each case, vancomycin resistance was the result of the presence of the vanA gene, localized to a plasmid, within a methicillin-resistant strain of S. aureus. Commonalities identified among most of the reported cases include significant underlying medical conditions (such as diabetes, end-stage renal disease, and chronic lower-extremity wounds), prior history of VRE colonization or infection, prior history of MRSA colonization or infection, and prior receipt of vancomycin therapy. It is thus presumed that each of these cases developed in the setting of cocolonization with MRSA and VRE with transfer of the vanA gene from VRE to MRSA. Fortunately, these all appear to have been isolated, rare events and contact investigations have found no evidence of transmission of VRSA from case patients to their household or healthcare contacts.

A variety of options exist for detection of MRSA in clinical and surveillance specimens. These include conventional culture methods, novel culture-based techniques, and molecular methods. Each method has its own advantages and disadvantages relative to the issues of cost, turnaround time, complexity, performance characteristics (e.g., sensitivity and specificity), and approved uses. Detection of the mecA gene or PBP2a, the protein expressed by mecA, is the most accurate method for prediction of methicillin resistance (20). In this section, laboratory methods used specifically for the detection of methicillin-resistant strains of S. aureus will be discussed. A detailed discussion of the various laboratory methods available for isolation and identification of S. aureus in general is beyond the scope of this chapter.

Oxacillin Screen Agar The CLSI-recommended agar dilution screening test for oxacillin-resistance in S. aureus isolates is known as the oxacillin screen agar test. Oxacillin screen agar consists of Mueller-Hinton agar containing 4% sodium chloride and 6 µg/mL oxacillin. In this test, a standardized suspension of S. aureus is inoculated onto oxacillin screen agar and incubated at 33°C to 35°C. Identification of growth of one or more colonies after 24 hours of incubation indicates that the tested isolate is oxacillin resistant. The sensitivity of the oxacillin screen agar test is 82.5% to 98%. Specificity has been reported to range from 46% to 100%, with most studies reporting specificities at the higher end of this range (26, 27, 28 and 29).

Cefoxitin Disk Test The cefoxitin disk diffusion screening test can be used to determine the presence of mecA-mediated oxacillin resistance. Because cefoxitin is a more potent inducer of the mecA gene, the use of cefoxitin disks, rather than oxacillin disks, is preferred for disk diffusion testing. In this test, standard disk diffusion procedures are used to inoculate Mueller-Hinton agar with a suspension of S. aureus that has been isolated from a primary specimen. A 30-µg cefoxitin disk is applied, and the plate is incubated at 33°C to 35°C for 16 to 18 hours. If the zone diameter is <21 mm, the isolate is deemed to be mecA-positive and reported as oxacillin resistant (30). The reported sensitivity and specificity of the cefoxitin disk diffusion test have ranged from 89.7% to 100% and 87.5% to 100%, respectively (28,31,32).

Chromogenic Agar Chromogenic agars that allow for simple and relatively rapid identification of methicillinresistant strains of S. aureus are available for use in screening patients for MRSA colonization using swab specimens obtained from the nares, throat, groin, axilla, and perineum. These are selective agars that inhibit the growth of methicillin-susceptible strains of S. aureus and many other microorganisms and produce specific color changes in colonies of S. aureus. This distinctive color change allows MRSA to be distinguished from other methicillin-resistant microorganisms that grow on the agar plate. Unlike the previously described culture-based methods for detection of methicillin-resistance, specimens can be plated directly onto chromogenic agar, reducing the time interval between specimen collection and detection of MRSA. Positive results can be obtained in as little as 24 hours and final results, positive or negative, are available in 48 hours. The sensitivity and the specificity of chromogenic agars for the detection of MRSA, as compared with conventional culturebased methods and PCR, have ranged from 73% to 100% and 89.7% to 100%, respectively (32, 33, 34, 35, 36 and 37). Use of an overnight broth enrichment step prior to plating samples on chromogenic agar has been shown to increase the sensitivity of this method (38), although it also increases the turnaround time of the test by approximately 1 day. Because similar color changes may occur in colonies of some other microorganisms (e.g., coagulase-negative staphylococci, Corynebacterium species, some gram-negative bacilli), false-positive results can occur. The use of additional tests (e.g., Gram stain, coagulase test, and S. aureus latex agglutination test) to confirm that isolates suspected to be MRSA based on colony color are truly S. aureus has been shown to improve the specificity of these media (33,34).

Detection of PBP2a In addition to conventional phenotypic tests, tests that detect the presence of the mechanism of resistance, the altered drug target PBP2a, are available for use in the laboratory to identify MRSA in clinical specimens. As compared with traditional methods of testing for antimicrobial resistance, tests that detect PBP2a allow for more rapid detection of resistance (24-48 vs. <1 hour, respectively). Methodologies for detection of PBP2a include latex agglutination and immunochromatographic
assays. Latex agglutination assays use latex particles that have been sensitized with monoclonal antibodies against PBP2a. These latex particles react with PBP2a that has been extracted from a clinical isolate to result in macroscopically visible agglutination. Isolates that do not produce PBP2a do not cause agglutination of the latex particles. Sensitivity of latex agglutination tests has ranged from 83% to100%, and specificity has been reported to be as high as 100% (28,29,39, 40 and 41). More recently, immunochromatographic membrane assays for the detection of PBP2a have been developed. In a study that used a tube coagulase test and an immunochromatographic assay for the identification of MRSA in blood cultures positive for gram-positive cocci in clusters, the sensitivity and the specificity of the immunochromatographic assay were 94.4% and 100%, respectively, as compared with PCR-based testing (42).

Polymerase Chain Reaction (PCR) In recent years, PCRbased assays for the detection of MRSA in nasal swab samples have been developed for use in MRSA screening programs. Commercially available PCR assays detect a unique gene sequence at the junction created by the integration of the SCCmec (the mecA-containing transposon) into the S. aureus chromosome. As compared with culturebased methods, these assays have been shown to be highly sensitive (80-100%) and specific (91-98.6%) for the detection of MRSA (38,43, 44, 45 and 46). Positive and negative predictive values for these assays have ranged from 66% to 95.8% and 96.6% to 100%, respectively. The low positive predictive values reported in some studies may be due in part to the identification of a larger number of MRSA carriers by the more sensitive PCR-based technology than detected by the culture-based reference standard due to the ability of PCR to detect a lower density of microorganisms than is possible with culture-based methods. The turnaround time for PCR-based detection of MRSA directly from nasal swabs is shorter than that associated with culture-based testing. As compared to a minimum turnaround time of 24 to 48 hours for culture-based testing, PCR has the potential to provide results within a few hours.

Although the first commercially available PCR assays were approved for use only for nasal specimens, PCR-based assays are also now available for use in detecting MRSA in some clinical specimens. Currently approved assays allow for the detection of MRSA directly from swabs taken from sites of skin or soft tissue infection and from blood cultures in which growth of gram-positive cocci in clusters has been identified. These assays detect sequences within the S. aureus chromosome, the SCC insertion site, and the mecA gene. As compared with broth-enriched culture methods, this assay demonstrated sensitivity, specificity, positive predictive value, and negative predictive value for the detection of MRSA in skin wounds of 97.1%, 96.2%, 91.9%, and 98.7%, respectively, in a population in which the prevalence of MRSA in wounds was 30% (47). For the detection of MRSA in positive blood cultures, the sensitivity, specificity, positive predictive value, and negative predictive values were 98.3%, 99.4%, 96.6%, and 99.7%, respectively. A second study found the test to be 100% sensitive and 98.4% specific for the detection of MRSA directly from positive blood cultures (48). The ability to more rapidly determine the presence or the absence of MRSA with the use of such PCR-based assays has the potential to improve clinical outcomes of gram-positive bacteremia and skin or soft tissue infection and to reduce unnecessary antimicrobial use. In addition, more rapid detection of MRSA infection may allow more rapid implementation of infection control measures designed to reduce the risk of MRSA transmission. These potential benefits, however, have not yet been fully evaluated.

Strain characterization and typing of MRSA isolates has helped describe the epidemiology of the microorganism in many different circumstances such as the evolution of MRSA, epidemic and endemic spread within healthcare and the community, as well as for patient care when it has been necessary to determine the strain causing infection or colonization. Bacteriophage typing was relied upon for decades; however, newer methods such as multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), staphylococcal protein A (spa) typing, and SCCmec typing are the most common techniques utilized today (49, 50, 51 and 52). Each method of strain typing uses different nomenclature leading to multiple characterizations of the same strain. Furthermore, there is no universally accepted nomenclature for strain typing MRSA and thus, comparison analysis between different labs in different geographic locations has been difficult. Each typing method has its own advantages and disadvantages that include the level of training and equipment necessary to conduct the procedure and interpret the results, discriminatory power, and cost.

Multilocus Sequence Typing MLST is based on sequencing DNA fragments of seven highly conserved housekeeping genes within S. aureus. Housekeeping genes are used because they are always present in the species (as they encode for the enzymes necessary for cell survival) but have sufficient variation to produce numerous alleles at a given locus. The resulting sequences of these genes are compared to known alleles at each locus via an electronic database located on the MLST Web site (http://www.mlst.net). Here, each isolate has been described by a seven-integer allelic profile defining a sequence type (ST), and clusters of related STs are defined as clonal complexes (CCs) (53). The sequences that serve as the target for MLST are not subject to rapid change as they are not influenced greatly by selective pressures such as antibiotic-resistance encoding genes. Because of this, MLST has been useful for studying the evolutionary genetic relationships between known MRSA lineages and their precursor MSSA strains (54). In 2000, Enright and colleagues (52) validated the use of MLST for S. aureus and subsequent studies performed on numerous MRSA isolates have supported the notion that the species population is strongly clonal, but gives rise to well-defined divergent lineages capable of rapid dissemination (52, 53, 54 and 55). After initial dissemination, the strains may evolve regionally (56).

MLST is particularly useful for these types of large population studies, and its Web-based data analysis system allows it to be extremely portable. However, this method does lack some discriminatory power (when compared to methods such as PFGE) for detecting more subtle differences between strains. Thus, it is often not
the method of choice for smaller outbreak investigations, determination of the relatedness of strains in the same patient, or in any situation where it is imperative to study close genetic relationships between isolates (49). Additionally, MLST is costly and requires special equipment, as well as laboratory expertise.

Pulsed-Field Gel Electrophoresis PFGE is the method most often used for strain typing of MRSA. The procedure involves incorporating the entire bacterial isolate into an agarose plug, which is then subjected to detergents and enzymes that lyse the bacteria and deproteinate the plug. The DNA is then digested with a restriction enzyme (usually SmaI for MRSA), and slices of the plug (containing the digested chromosomal DNA) are placed into wells of an agarose gel. The gel is exposed to an electrophoretic current that switches direction according to a predetermined pattern. During this process, the restricted DNA is resolved into a pattern of discrete fragments, which are visualized by staining the gel with a fluorescent dye. The PFGE restriction profiles from different isolates are then commonly compared visually by pairwise fragment for fragment analysis (49). It is relatively easy for the examiner to evaluate the relatedness of strains from a single or a limited number of gels, as is typically the case when evaluating an outbreak, or a limited number of isolates from a single center. However, computerized gel scanning and analysis software is available and allows users to create databases of PFGE patterns that can be used to compare gels from different laboratories or a large number of isolates over an extended period of time (57). The advantages of PFGE over other typing methods include its reproducibility and high discriminatory ability. Thus, it has been an effective tool for outbreak investigations and for determining the relatedness of individual patient isolates. Additionally, the procedure is relatively straightforward. Specialized equipment and training is required, but the cost is not prohibitive (49,58). PFGE can be time consuming, and it is often difficult to compare banding profiles from gels created at different times or at different facilities if the procedure conditions have not been standardized.

Spa Typing spa typing is a DNA sequencing analysis method that targets a polymorphic region of the spa gene. This region consists of 24 to 27 base pair repeats that may vary in number and nucleotide sequence. Each resulting unique combination detected through the analysis is assigned a distinct spa type, and this allows objective comparison between bacterial strains (50,51). The method is highly reproducible and with the creation of Web-based tools, which have been developed for classification of the sequences, the data are also portable. There are two major nomenclature models, one described by Ridom (http://www.ridom.net) and the other described by Kreiswirth (http://tools.egenomics.com) (50). Because spa typing relies on a single genetic locus and requires only a single PCR reaction, it is much less complex and less costly than MLST but it has discriminatory power approaching that of PFGE (59). The portability of the data simplifies information sharing between laboratories and facilities creating large-scale databases for studying global and local epidemiology (60).

SCCmec Typing Several molecular methods for identifying SCCmec types have been reported (61,62). Eight major SCCmec types have been described (SCCmec type I to SCCmec type VIII), and their presence in MRSA has been useful for designating whether or not the MRSA strain is of healthcare origin or community origin. Often, SCCmec typing is combined with MLST typing as SCCmec has been associated with a limited subset of MLST CCs. With this, each MRSA isolate would be classified by a specific chromosomal background defined by MLST as well as the SCCmec type (Table 29-1) (20). Understanding the evolution of MRSA isolates and particularly the emergence of the new community-acquired strains requires characterization of the isolate’s SCCmec element (20). To date, HA-MRSA strains possess only a limited number of SCCmec types, including SCCmec I first described in the United Kingdom in 1961, SCCmec II first described in Japan in 1982, and SCCmec III first described in New Zealand in 1985; whereas CAMRSA strains possess smaller SCCmec types IV described in the United States in 1996, type V described in Australia in 1993, type VI described in Portugal in 1996, VII described in Sweden in 2007, and VIII described in Canada in 1996 (20).

As stated previously, the first MRSA was described from London in 1961, only a year after methicillin was introduced into the clinical arena (9) and within that decade came the first reports of healthcare-associated outbreaks due to MRSA in the United States (63). By the early 1990s, MRSA strains were on the rise as a prevalent cause of HAI (64). In a report released by the National Nosocomial Infections Surveillance system, the percentage of S. aureus HAIs caused by strains that were resistant to methicillin, oxacillin, or nafcillin was found to have increased among all hospitals more than 10-fold from just 2.4% in 1975 to 29% in 1991. Furthermore, the rate differed depending on bed size of the hospital. For example, in 1991, in hospitals with < 200 beds, 14.9% of S. aureus were MRSA; for hospitals with 200 to 499 beds, 20.3% were MRSA; and for hospitals with 500 or more beds, 38.3% were MRSA. The authors concluded that hospitals of all sizes were facing the growing problem of MRSA and that control measures, which were being advocated at the time, should be re-evaluated (64). Throughout the 1990s, MRSA infections were largely reported to occur among those who frequented healthcare facilities (e.g., hemodialysis units) or among those admitted into acute or long-term care. It was only on rare occasions that infections originating in the community were due to MRSA and this was typically reported among special populations such as injection drug users (65).

Historically, the major determinant in characterizing an MRSA infection as either “healthcare-acquired” or “community-acquired” has been the time of onset, or the time to identification of the infection after admission to the hospital. For example, if the patient had an infection incubating at the time of admission or if the infection was identified within 48 hours of admission, the infection would be classified as community-acquired; and if the patient had an infection develop after 48 hours of admission, it would be classified as healthcare-associated. Over the past 10 to
15 years, the healthcare delivery system has undergone substantial changes, the most striking of which has been the shift of treatment of more acute illnesses into the outpatient arena, home, and the long-term care facility (LTCF). With these newer models for delivering healthcare and with the continued emerging epidemiology of MRSA and its associated risk factors, it became more difficult to accurately classify MRSA as strictly healthcare-associated or community-acquired. Recently, in two landmark studies by Klevens and colleagues, which described the incidence of invasive MRSA infections in the United States, the epidemiologic classifications of MRSA infections were redefined using two broad categories, “healthcare-associated” and “community-associated”(19,66). HA-MRSA infections were characterized as MRSA infections occurring among persons with at least one of the following healthcare-related risk factors: presence of an invasive device at the time of admission, previous history of MRSA colonization or infection, history of surgery, hospitalization, dialysis, or residence in an LCTF in the previous 12 months prior to culture date. Community-associated infections were characterized as occurring in persons who have none of these healthcare-related risk factors. HA-MRSA infections were further characterized as either community or hospital onset. Community onset refers to cases with a positive culture within 48 hours of admission and with at least one healthcare-associated risk. Hospital onset refers to cases with a positive culture result obtained >48 hours after hospital admission (19).

Unfortunately, today, most would consider MRSA infections endemic in the majority of healthcare centers not only in the United States, but also in many countries throughout the world. In the United States, the proportion of S. aureus HAI resistant to methicillin has continued to increase, with rates of 63% reported from intensive care units (ICUs) in 2004. However, even though this proportion has continued to increase, recent data suggest that the incidence of MRSA CLABSIs has actually decreased in several ICU types since 2001 (Fig. 29-1) (67). Although these findings are encouraging and highlight success in prevention of HAI, it is still important to realize that MRSA remains high in most facilities and many patient groups continue to be at risk for acquisition and infection from the pathogen.

In 2008, the NHSN released a report of antimicrobialresistant pathogens associated with HAI in the United States between 2006 and 2007. The pooled mean proportion of all device-related HAI due to MRSA was 8%; however, this varied by type of infection and by patient care area within the healthcare facility (8). For example, higher rates of MRSA CLABSI were reported from burn ICUs (0.93 per 1,000 device days), moderate rates from trauma ICUs (0.30 per 1,000 device days), inpatient medical wards (0.28 per 1,000 device days), and medical cardiac ICUs (0.27 per 1,000 device days), and lower rates ranging from 0.11 to 0.20 per 1,000 device days from other areas of the hospitals. Similarly, higher rates of MRSA VAP were reported from trauma ICUs (1.36 per 1,000 device days) and neurosurgical ICUs (1.08 per 1,000 device days), lower rates from pediatric ICUs (0.17 per 1,000 device days), and more moderate rates ranging from 0.43 to 0.75 per 1,000 device days from other areas of the hospitals (8).

In 2009, a report similar to the NHSN document was released by the International Nosocomial Infection Control Consortium (INICC), which presented data regarding antimicrobial-resistant pathogens associated with HAI among 173 ICUs from 25 countries in Latin America, Asia, Africa, and Europe (68). Rates of methicillin resistance among
S. aureus HAI in INICC ICUs were significantly higher than the rates reported from NHSN ICUs. For example, the proportion of S. aureus CLABSI resistant to methicillin among INICC ICUs was 84.1% versus the 56.8% reported among NHSN ICUs. The authors speculated that these higher rates were likely a reflection of the limited resources available for hospitals in these countries to devote toward effective infection control programs, invariably low nurse to patient staffing ratios, and furthermore that the majority of hospitals lacked official regulations for infection control training or compliance (68). Similarly, methicillin-resistance rates reported among S. aureus VAP from INICC were 77.5% and among catheter- CAUTIs were 74.4%.

Since 1999, the European Antimicrobial Resistance Surveillance System (EARSS) has been collecting and reporting data from now 33 different European countries (http://www.rivm.nl/earss/Images/EARSS%202008_ final_tcm61-65020.pdf). The median incidence rate for MRSA bloodstream infections (BSIs) among all countries reporting data was 4.8 per 100,000 patient days in 2008, increased from 3.5 per 100,000 patient days in 2007; however, this incidence rate varied considerably among the different countries from <1.0 per 100,000 patient days in Germany, Estonia, Finland, Iceland, the Netherlands, Norway, and Sweden to more than 8.0 per 100,000 patient days in Cypress, France, Ireland, Israel, Malta, Portugal, Turkey, and the United Kingdom. In 2008, these 33 countries reported susceptibility data for more than 30,000 invasive S. aureus isolates and found that 21% were MRSA. These proportions also varied from <1% in Northern Europe to >50% in Southern Europe; however, for the first time since EARSS began reporting summary resistance data, more countries showed decreasing MRSA proportions instead of increasing trends. Nevertheless, MRSA proportions are still above 25% in one third of European countries and >50% in the Mediterranean.

Healthcare-Associated Infections Caused by MRSA MRSA is a well-described and common cause of many HAI including CLABSI, hospital-acquired pneumonia (including VAP), CAUTIs, wound infections, and SSIs. The impact of MRSA infections in the acute-care facility may be substantial. For example, a recent study by Filice and colleagues retrospectively analyzed excess costs and utilization associated with methicillin resistance for patients with S. aureus infections in their large VA hospital (69). The median 6-month unadjusted cost for patients with MRSA infections was $34,657 compared with $15,923 for patients with MSSA. For patients with Charlson scores ≤3, the adjusted 6-month mean cost for an MRSA infection was $51,252 compared to $30,158 for MSSA, and for patients with Charlson scores 4 and above the adjusted 6-month mean cost for MRSA was $84,436 versus $59,245 for those with MSSA. Additionally, the mortality rate for those with MRSA infection was significantly higher compared to those with MSSA infection (23.6% vs. 11.5%; p < .001).

Bloodstream Infections The outcomes and impact associated with MRSA BSI have been the focus of numerous reports and depending on the type of study, patient population, and the methodologies used, results have varied (7,70, 71, 72, 73, 74, 75, 76 and 77). Mortality rates for MRSA BSI patients have ranged from 20% to more than 35% (7,71,73, 74 and 75,77) and among studies controlling for confounding variables, including severity of illness, when compared to mortality from MSSA, that from MRSA has been reported as significantly higher (71,73,74) as well as no different (7,75,77). Regarding outcomes other than mortality, the impact of methicillin resistance has been described in terms of increased length of stay (LOS) and increased costs. An early study by Abramson et al. reported that the median LOS attributable to methicillin resistance among patients with healthcare-associated S. aureus BSI was 8 days (4 days for MSSA vs. 12 days for MRSA; p = .023), and the excess hospital cost was $17,422 ($9,661 for MSSA vs. $27,083 for MRSA; p = .043) (76). A retrospective cohort study at a large academic hospital reported LOS attributable to methicillin resistance among patients with S. aureus BSI as increased by 1.29-fold (p = .016) and hospital charges as increased by 1.36-fold (p = .017) (7), and another found that the average total charge during hospitalization for MRSA BSI was $45,920 as compared to $9,699 for MSSA BSI (p = .0003) After stratifying by case mix index (CMI), for those with a CMI >2 the average cost per day for a patient with MRSA was $9,744 versus $4,442 for patients with MSSA (75). A recent
study of 182 patients with healthcare-associated S. aureus BSI found that compared to ICU patients with MSSA BSI, those with MRSA BSI had increased median total hospital costs ($42,137 vs. $113,852), increased costs after diagnosis of infection ($17,603 vs. $51,492), and increased LOS after infection (10.5 vs. 20.5 days); however, after analyzing the data utilizing a propensity score to estimate the predicted probability of acquiring a methicillin-resistant pathogen (and thus analyzing the effect among comparable patient populations) no significant differences were found (70).

The impact of MRSA has also been studied outside the tertiary-care academic hospital. Kaye and colleagues conducted a cohort study to compare the outcomes of patients with MRSA infection (BSI or SSI) in community hospitals to that in tertiary care. One third of patients with MRSA infections died during hospitalization and of those that survived, 36.4% required readmission within 90 days and 57% of all MRSA-infected patients died within the subsequent year after diagnosis. Patients treated in community hospitals were less likely to receive effective antimicrobial therapy within 7 days of diagnosis compared to tertiary care (58.9% vs. 74.8%; p < .001), and they had a significantly higher 1-year mortality rate (62.5% vs. 52.5%; p = .02) (72).

Healthcare-Associated Pneumonia The prevalence of MRSA as the cause of hospital-associated pneumonia has been recently reported by several investigators. For example, a retrospective cohort study of 59 hospitals from 2002 to 2003 to characterize the microbiology and outcomes among patients with pneumonia (78) reported MRSA as the cause of 56.8% of S. aureus healthcare-associated pneumonia, 48.6% of S. aureus hospital-acquired pneumonia, and 34.4% of S. aureus VAP. In another retrospective analysis of patients with healthcare-associated pneumonia, 16% to 18% were due to MRSA (79). Similarly, a four country prevalence survey of HAI in England, Wales, Northern Ireland, and the Republic of Ireland found that MRSA was the cause of 7.6% of pneumonias and 18.1% of other lower respiratory tract infections (80).

The attributable mortality that methicillin resistance contributes to those who suffer from S. aureus VAP has been debated. Older studies, which compared patients with MRSA VAP to those with MSSA VAP, reported that crude mortality was significantly increased for those with MRSA. For example, Rello and colleagues prospectively analyzed the outcome of 49 patients with S. aureus VAP who were similar with regards to sex, severity of illness, prior surgery, and presence of renal failure, diabetes, and coma. They reported that mortality related to pneumonia was significantly higher for those with MRSA compared to those with MSSA (RR, 20.72; 95% CI, 2.78-154.35) (81). Other more recent, larger studies that have controlled for confounding variables such as receipt of appropriate empiric antibiotic therapy and LOS have reported that mortality is not increased for patients with MRSA VAP compared to those with MSSA VAP (82, 83 and 84). One large retrospective study of 154 patients with S. aureus VAP in 59 US hospitals (16 teaching hospitals and 43 nonteaching hospitals) reported that there was no increased mortality due to MRSA compared to MSSA (29% vs. 36%) (82). Similarly, a prospective study of 134 patients with S. aureus VAP who had received appropriate initial empiric antibiotic therapy in 12 French ICUs found that after adjusting for differences in populations and controlling for length of ICU stay at time of VAP diagnosis, there was no difference in ICU or hospital death among those with MRSA compared to MSSA (OR, 2.06 and 1.75; p = .07 and .10, respectively) (84). However; the impact of methicillin resistance goes beyond mortality with several studies describing increased morbidity and cost of care. Shorr et al. (82) found that the average cost of an MRSA VAP was $40,734 and after multivariate analysis, compared to those with MSSA VAP, those with MRSA consumed excess resources of 4.4 days on mechanical ventilation (p = .03), 3.8 inpatient days (p = .05), 5.3 days in the ICU (p = .02), and $7,731. Furthermore, among those with S. aureus VAP who received appropriate antibiotic therapy, when controlling for demographics, reason for ICU admission and mechanical ventilation, severity of illness, and duration of mechanical ventilation prior to VAP, infection with MRSA (vs. MSSA) doubled the probability of needing continued ICU care (HR, 2.08; 95% CI, 1.09-3.95; p = .025) and increased median ICU stay by 11 days (33 vs. 22 days; p = .047) (82). Similarly, a large prospective study in three teaching hospital ICUs found that there was a significant delay in resolution of hypoxemia for those with MRSA (10 vs. 2 days) and after multivariate analysis, regardless of receiving appropriate antibiotic therapy, MRSA required significantly longer mechanical ventilation compared to other pathogens (85). Excess resources included 6.8 days of antibiotic receipt, 13.8 days of mechanical ventilation, and 11 days of ICU care. Another study reported that among 160 patients with MRSA pneumonia, the expected estimated median daily billed hospital charges were $2,888 to $2,993 and the median total hospital charges were $32,024 to $32,636 (79).

Surgical Site Infections As with other HAI, MRSA has increased as a cause of SSI. Among 2,045 S. aureus SSI reported to NHSN from 2006 to 2007, 49% were due to MRSA (8). In a study conducted to describe the epidemiology of severe SSI among patients from 26 community hospitals in the southeastern United States, from 2000 to 2005, the prevalence of MRSA doubled from 0.12 infections per 100 procedures to 0.23 infections per 100 procedures (86). Another study of patients with microbiologically confirmed SSI from 97 US hospitals conducted from 2003 to 2007 reported that the proportion of MRSA as the cause of SSI significantly increased from 10.6% to 20.6% (p < .0001) (87), and another study reported that among the elderly, MRSA increased as the cause of SSI from 15% in 2000 to 20% by 2005 (88). A recent large retrospective cohort study of adults undergoing orthopedic, neurosurgical, cardiothoracic, and plastic surgeries at 11 hospitals in North Carolina and Virginia (nine community hospitals and two tertiary-care hospitals) found that MRSA was responsible for 50% of SSI in community hospitals and 43% of SSI in tertiary-care hospitals. Among those with S. aureus SSI, MRSA was the cause in 62% of cardiothoracic SSI, 54% of orthopedic SSI, 43% of neurosurgical SSI, and in 35% of plastic surgeries (89).

Patients with MRSA SSI also suffer increased morbidity, mortality, and hospital costs. This was initially described by Engemann and colleagues in 2003 (90). This cohort study compared the outcomes of patients who suffered MRSA SSI to patients who suffered MSSA SSI and to patients who
did not develop an SSI. Compared to those with MSSA SSI, those with MRSA had a greater 90-day mortality (adjusted OR, 3.4; 95% CI, 1.5-7.2; p = .003) and after controlling for ASA score, hospital, surgery duration, diabetes, renal disease, and LOS prior to infection, methicillin resistance was responsible for a 1.20-fold increase in LOS (2.6 excess days) and 1.19-fold increase in mean hospital charges ($13,901). The median hospital cost for an MRSA SSI was $92,363 (90). Two more recent studies have also described increased morbidity and costs (87,91). One reported that compared to patients without an SSI, those with SSI due to MRSA had an independently increased risk for readmission within 90 days (OR, 35.0; 95% CI, 17.3-70.7), death within 90 days (OR, 7.27; 95% CI, 2.83-18.7), 23 days of additional hospitalization, and $61,681 in excess charges. Compared to patients with MSSA SSI, those with MRSA SSI had 5.5 days of additional hospitalization and $24,113 in excess charges (91). Another study found that compared to SSI due to other microorganisms, those caused by MRSA had significantly higher mortality (1.4% vs. 0.8%; p = .03) and that the MRSA SSI risk-adjusted attributable LOS was 0.93 days and attributable increased cost was $1,157 (87).

MRSA has also emerged as an epidemiologically important microorganism in other types of healthcare facilities including those that provide long-term care. Epidemiologic descriptions of MRSA in LTCFs are heterogeneous likely because the patient populations cared for in LTCF are heterogeneous, ranging from patients who require longterm physical rehabilitation, long-term psychiatric care, long-term acute care, and those that require permanent or long-term residence. Additionally, LTCF may differ in bed size, geographic location, and through an association with a large tertiary-care hospital, an academic teaching hospital, or a Veterans Administration hospital. Thus, it is important to consider these variables when reviewing studies conducted in LTCF of the prevalence of MRSA colonization or infection (92). Recent studies from the United States have reported a wide range of MRSA prevalence rates (93, 94, 95, 96 and 97). For example, Mermel and colleagues conducted a multicenter prevalence study of 6 LTCF and found that among 125 residents who had nares cultures performed, overall, 25 (20%) were positive for MRSA; however, this ranged from 10% to 100% among the facilities (93). Furuno et al. reported a prevalence rate of 30% among residents of a 180 bed long-term acute care (LTAC) facility associated with a large university affiliated hospital in Baltimore, and Mody et al. reported that among 73 residents of a VA LTCF, 58% were MRSA-colonized and that among 54 residents of community-based LTCF, 35% were MRSA-colonized (94,96). Another study performed in a 100-bed VA-associated LTCF in Atlanta prospectively assessed colonization rates by performing weekly surveillance cultures and classified carriers as persistently colonized or intermittently colonized. 49 of 83 (59%) residents had at least one nasal swab positive for MRSA, 30 (36%) were persistent carriers, and 19 (23%) were intermittent carriers. Of the 83 subjects who had enough surveillance cultures to be included, 43 initially negative subjects were designated as being at risk for intrafacility MRSA acquisition and ultimately 9 (21%) had a subsequent positive culture for MRSA (95). A large study among nursing homes in four Canadian provinces (Ontario, Manitoba, Saskatchewan, and Alberta) and four nursing homes in adjacent US states (Michigan, Montana, North Dakota, and Minnesota) specifically designed to include only those facilities not associated with an acute care, university, or VA hospital reported that 33% of clinical S. aureus isolates were MRSA (97). Outside the United States, MRSA prevalence in LTCF has also varied (98, 99, 100, 101 and 102). Two recent point prevalence studies from Italy reported disparate results. The first conducted among 551 residents of two LTCF reported that 43 (7.8%) were positive for MRSA and the other conducted in a 120 bed LTCF reported that 38.7% of residents were colonized (98,100). The prevalence of MRSA in LTCF in France has been reported at 37.6% (102), and in Spain a study among nine community LTCF reported an overall MRSA prevalence rate of 16.8%; however, this rate ranged from 6.7% to 35.8% (101).

Risk factors for MRSA carriage in LTCF have also been well described and include antibiotic exposure (98,100, 101 and 102), recent hospitalization (95,100), certain comorbidities (98,100), and presence of medical devices (101,102). Recently, Mazur and colleagues performed a cross-sectional study of MRSA prevalence and risks for MRSA carriage. Multivariate analysis found that compared to residents who were non-MRSA carriers, those older than 85 years (OR, 1.60; 95% CI, 1.16-2.21), those with impaired functional status, those with a Charlson Index of two or more (OR, 1.50; 95% CI, 1.09-2.08), those with decubitus ulcers (OR, 2.56; 95% CI, 1.58-4.17), those who had received antibiotics (OR, 2.44; 95% CI, 1.75-3.39), those with medical devices (OR, 2.47; 95% CI, 1.35-4.53) and those transferred from acute care (OR, 2.15; 95% CI, 1.39-2.41) were significantly more likely to be MRSA carriers (101). With regards to antibiotic exposure as a risk for MRSA carriage in LTCF, exposure within 3 months of sampling to a fluoroquinolone (98) has been associated with a more than fivefold increased risk for MRSA, exposure to three or more antibiotic courses within 1 year of sampling (100) has been associated with a more than fivefold increased risk for MRSA, and exposure to third-generation cephalosporins or fluoroquinolones has been associated with a more than 12-fold increased risk of MRSA (102). Decreased risk for MRSA carriage has been associated with use of antimicrobial soaps within the facility and with an increased staff to patient ratio (number of registered nurses per 100 residents) (97).

Risk of MRSA infection among colonized individuals has been well described in acute care (and is discussed below); however, this risk has not been well described in long-term care. Bradley retrospectively reviewed data from six US studies from 1990 to 1997 and found that overall, the incidence of MRSA infection was 6.5% among carriers and that the associated mortality was just 1% (103). Muder compared MRSA carriers to MSSA carriers and noncarriers and found that staphylococcal infections developed 3.6 times more often among MRSA carriers compared to the other groups (104). The most frequently reported MRSA infections among residents of long-term care are skin and soft tissue infections; however, more serious invasive infections such as BSI and pneumonias have been reported (92,105,106). In a recent prospective study among community LTCF located in Spain, the incidence of
MRSA infection among colonized residents was 0.12 per 1,000 patient days and only two of those patients required hospital admission; however, MRSA colonization in LTCF should not be viewed as benign as when colonized LTCF residents enter acute care they are at increased risk for MRSA infection (101).

There is also evidence to suggest that the epidemiology of MRSA within the LTCF is changing. In 2009, Tattevin and colleagues conducted a study to describe the prevalence and the genotypes of MRSA clinical isolates over a 10-year period at a large 1,000-bed LTCF in San Francisco (99). Among S. aureus isolates, the proportion due to MRSA increased from 38.1% in 1997 to 72.3% in 2006 (p <.0001) and the USA300 CA-MRSA clone increased from 11.3% of MRSA isolates in 2002 to 64% of MRSA isolates in 2006 (p < .0001). The USA300 clone was most often isolated from skin and skin structure sites and of note, up to 30.9% of USA300 isolates were multi-drug resistant suggesting that these isolates were likely acquired under increased antibiotic use pressure within the facility (99).

A relatively large proportion of asymptomatic carriers of MRSA in acute care will progress to invasive MRSA infection. A recent systematic review of ten observational studies determined that colonization with MRSA was associated with a fourfold increase in the risk of infection as compared to persons with colonization with methicillin-susceptible S. aureus (107). This risk, however, is likely to vary substantially among individuals and populations depending on the setting and individual risk factors for infection. In a study of patients who were found to be colonized or infected with HA-MRSA during hospitalization, 29% of colonized and infected persons developed at least one episode of MRSA infection within 18 months (108). Another study of nasal carriers of HA-MRSA identified at the time of hospital admission found that 18.3% of carriers had invasive MRSA infection documented concurrently (29%) or within 18 months of detection of nasal carriage (71%) (109). In a similar study in which patients were tested for nasal S. aureus carriage at the time of evaluation for admission to the ICU, 24.1% of MRSA carriers developed an MRSA infection within 60 days. In contrast, only 0.6% of patients with nasal carriage of methicillin-susceptible S. aureus developed an MSSA infection (110). One potential explanation for the higher rate of invasive infection among carriers of HAMRSA as compared with carriers of MSSA is that carriers of MRSA may be at greater risk of infection due to greater or more severe underlying medical conditions and/or a more frequent need for medical interventions that place them at increased risk of infection with their endogenous flora. However, one recent study of patients who were screened for nasal S. aureus carriage at the time of ICU admission found that MRSA-colonized patients were more likely to develop S. aureus infection while in the ICU than MSSA-colonized patients, even after adjustment for patient-specific factors that are associated with MRSA carriage (adjusted hazard ratios of 4.70 and 2.47, respectively, as compared with patients without nasal carriage of S. aureus) (111).

A number of risk factors associated with HA-MRSA carriage have been established. Some of these risks are at the level of the individual patient (112, 113, 114 and 115). These patient-level factors include a variety of chronic medical conditions such as diabetes mellitus, chronic obstructive pulmonary disease, leukemia, HIV infection, and end-stage renal disease. Other patient-specific risk factors include older age, admission to a hospital or a LTCF within the preceding 12 months, prolonged duration of hospitalization, receipt of antibiotic therapy within 3 months, invasive procedures, and the presence of foreign bodies (such as indwelling urinary and vascular catheters, tracheostomy tubes, and feeding tubes). These factors likely all represent exposure to the healthcare system resulting in an increased risk of exposure to or prolonged exposure to HA-MRSA and perhaps an increased risk of acquisition and persistent carriage if exposed to MRSA as compared to persons without these factors.

In addition to patient-specific risk factors, a variety of factors associated with the healthcare system and the healthcare delivery process have been associated with acquisition or transmission of MRSA. Studies have demonstrated that the risk of acquisition of MRSA during hospitalization increases as the prevalence of MRSA among hospital patients increases. In one study, it was observed that when the weekly colonization pressure (i.e., weekly prevalence) exceeded 30%, the risk of MRSA acquisition was five times higher than that when colonization pressure was <10% (116). This finding may be the result of an increased environmental burden of MRSA with subsequent patient-topatient spread by contaminated healthcare workers and equipment. The role of the environment in MRSA transmission is further highlighted by a study that demonstrated that the odds of acquiring MRSA were significantly higher among persons admitted to a hospital room in which the prior room occupant was colonized or infected with MRSA (OR, 1.4; p = .04) (112). Several studies have reported an association between healthcare worker hand hygiene practices and the incidence of MRSA within healthcare facilities (117, 118, 119, 120 and 121). These studies have observed reductions in MRSA infection and acquisition in temporal association with improved rates of adherence to hand hygiene guidelines or increased consumption of alcohol-based hand rubs (ABHRs). Other investigators have associated increased rates of MRSA infection and colonization with staffing deficits and patient overcrowding (122,123). These findings may reflect an increase in the environmental burden of MRSA or reduced compliance with infection prevention measures such as hand hygiene and Contact Precautions in the setting of understaffing and overcrowding.

Historically, MRSA was considered to be almost exclusively acquired in healthcare; however, over the past 10 to 15 years, MRSA has emerged as a significant pathogen among persons without typical healthcare-associated risk factors (10,11,12,144). Data from the CDC’s Active Bacterial Core surveillance and Emerging Infections Program Network indicate that 13.7% of the 95,000 cases of invasive MRSA disease in the United States between July 2004 and December 2005 occurred in persons without established healthcare-associated risks (19). This rapid change in the epidemiology of MRSA is the result of clonal dissemination of novel strains of MRSA that are genetically and epidemiologically distinct from typical HA-MRSA strains (Table 29-2). CA-MRSA appears to have arisen as the result of migration of SCCmec type IV into methicillin-susceptible strains of S. aureus. More recently, SCCmec types V-VIII have been identified but SCCmec type IV continues to be identified in the vast majority of CA-MRSA isolates. Unlike SCCmec types I-III that are common among strains of HA-MRSA, SCCmec type IV is smaller and more mobile and has thus been able to move into several lineages of MSSA. In the United States, pulsed-field type USA400 (multilocus sequence type ST1) was the first identified clone, but since that time USA300 (ST8) has become the predominant clone. Other than the mecA gene, SCCmec type IV typically contains few or no additional antibiotic resistance determinants. Thus, CA-MRSA strains are frequently resistant only to currently available beta-lactam antibiotics and perhaps one or two additional classes of antibiotics (such as the macrolides and, increasingly common, the fluoroquinolones) (145). However, resistance to additional classes of antibiotics is being reported with increasing frequency (146, 147 and 148). For example, isolates of CA-MRSA with resistance to oxacillin and erythromycin as well as clindamycin, mupirocin, and, in many cases, tetracycline have been reported from Boston and San Francisco (147). In those isolates, resistance to the additional antimicrobial agents was due to the presence of the pUSA03 conjugative plasmid that contains multiple resistance determinants, including the genes ermC and mupA that result in constitutive resistance to macrolides and clindamycin, and mupirocin, respectively. Related plasmids, presumed to have been transferred from USA100 strains of HA-MRSA, have been detected in other USA300 MRSA isolates (148). These findings suggest that the problem of multidrug resistance that has been associated with HA-MRSA for many years may begin to complicate the treatment of CA-MRSA infections as well. An additional genetic difference between most CA-MRSA isolates and typical HA-MRSA strains is the presence of genes encoding the Panton-Valentine leukocidin (PVL) in the former. Because most CA-MRSA strains are PVL-positive and CA-MRSA has been associated with severe purulent skin and soft tissue infections and necrotizing pneumonias, some have questioned whether PVL is responsible for the increased virulence associated with CA-MRSA strains. Studies performed to date have not provided conclusive evidence that PVL is a major virulence factor in CA-MRSA, but the clinical significance of PVL remains controversial and continues to be investigated (149, 150, 151, 152, 153, 154, 155 and 156).

Skin and soft tissue infections, especially furuncles, abscesses, and other purulent infections, are the most common type of infection caused by CA-MRSA (14,145,157). In fact, CA-MRSA has become the most common cause of purulent skin and soft tissue infections among patients presenting to emergency departments in several regions of the United States (13). Clusters of CA-MRSA skin infections have also been described among several specific populations, including men who have sex with men (147,158,159), sports participants (160,161), military personnel (162), prisoners (163), rural communities (164,165), and families (166,167). These populations likely represent groups at increased risk for the spread of MRSA and/or for invasive infection if exposed to MRSA due to close skin-to-skin contact, the presence of cuts or abrasions that can serve as portals of entry for MRSA, shared use of contaminated items and surfaces (such as towels and razors), crowded living conditions, and/or poor hygiene. CA-MRSA infections
are not, however, limited to the skin and soft tissues. CA-MRSA is also a well-described cause of respiratory tract infections, particularly necrotizing pneumonia (including postinfluenza pneumonia), BSI, otitis media and externa, and joint infections (109,168).