The Growing Menace of Community-Acquired Methicillin-Resistant Staphylococcus aureus

As we read anxiously about the possibility of a worldwide pandemic of avian influenza, another epidemic is actually happening in the United States and elsewhere. Methicillin-resistant strains of Staphylococcus aureus (MRSA) have now emerged as community-acquired pathogens capable of causing serious disease. We have known about MRSA since the early 1960s (1). Until recently, however, infection with these strains was primarily limited to hospitals and other institutional settings. Sporadic reports of community-acquired (or community-associated) MRSA infections have appeared since 1980, but 1999 marked the beginning of the current epidemic in the United States. The sentinel event was a series of fatal cases of community-acquired MRSA infections due to a clone of MRSA known as USA 400 in Native American children living in the Midwest (2). The USA 400 type has subsequently caused infections throughout the country. A second clone, USA 300, has rapidly established predominance in Atlanta, Georgia (and elsewhere), as clearly demonstrated in the article in this issue by King and colleagues (3). The authors based their findings on a study of 384 persons in Atlanta. Each person had documented community-acquired skin and soft-tissue infections due to S. aureus, and 63% of these infections were community-acquired MRSA. More strikingly, 99% of the community-acquired MRSA isolates were the USA 300 clone. Not surprisingly, two thirds of these cases had inadequate initial therapy, presumably because the attending physicians did not recognize the possibility that the organisms were methicillin-resistant. The proliferation of community-acquired MRSA and especially the USA 300 clone in the United States has been truly remarkable. In other parts of the United States, 60% to 75% of all community-acquired isolates of S. aureus are now methicillin-resistant (4). Because these organisms can infect healthy people in the community, they are a growing threat. To help physicians manage patients with these infections, I will describe the nature and epidemiology of community-acquired MRSA infections, define the populations that are most at risk, and discuss appropriate therapy. Community-acquired MRSA are not merely hospital-acquired strains that have escaped to the community. The genes encoding methicillin resistance in these strains reside on genetic elements (usually SCCmecA type IV) that are different from those encoding methicillin resistance in hospital-acquired MRSA. Another key difference is that hospital-acquired MRSA are usually resistant to multiple antimicrobial agents, while community-acquired MRSA in the United States until now have remained susceptible to antimicrobial agents, such as the tetracyclines and trimethoprimsulfamethoxazole (5). The genome of USA 400 differs substantially from classic hospital-acquired MRSA (6). Almost all community-acquired MRSA isolates in the United States (but few, if any, hospital-acquired MRSA isolates) contain genes encoding the PantonValentine leukocidin, which is a cytotoxin that causes leukocyte destruction and tissue necrosis. Although the exact role of PantonValentine leukocidin in the serious infections caused by these organisms is unclear (perhaps PantonValentine leukocidin plus another toxin or toxins is causing the trouble), it is a marker for community-acquired MRSA (7). The number of populations at risk for community-acquired MRSA infections is steadily expanding. Initial reports included infections among young children, prisoners, men who have sex with men, and persons competing in contact sports (especially American football) (2). Thus far, these organisms seem to preferentially infect children and young adults. Infections caused by community-acquired MRSA range from minor skin infections to rapidly fatal, overwhelming pneumonia and sepsis accompanied by the WaterhouseFriderichsen syndrome (8-12). Because skin infections caused by these organisms often have necrotic centers, physicians may misdiagnose them as spider bites. Community-acquired MRSA can cause severe necrotizing fasciitis. In children, community-acquired MRSA can cause septic thrombophlebitis of the extremities and a pelvic syndrome consisting of septic arthritis of the hips, osteomyelitis of the pelvic bones, pelvic abscesses, and septic thrombophlebitis. Our knowledge of community-acquired MRSA epidemiology is incomplete, which adds to the challenge of controlling infection by community-acquired MRSA. The better-established hospital-acquired MRSA strain has long presented a challenge to hospital epidemiologists, but they have devised methods for limiting its spread, including the identification of carriers, the isolation or cohorting of colonized or infected patients, and the use of barrier precautions. Unfortunately, the situation seems considerably more complicated for community-acquired MRSA. Whereas nasal colonization commonly precedes serious infection with methicillin-susceptible S. aureus (MSSA), nasal colonization may not precede community-acquired MRSA infections. Several studies suggest that the nasal carriage rate for MRSA in the community is considerably lower than that for MSSA, which can approach 30% or more (2). The accompanying article in this issue by Graham and colleagues (13) provides additional data on the surprisingly low prevalence of nasal carriage of community-acquired MRSA strains. The low prevalence in Graham and colleagues' study has several potential explanations. Graham and colleagues' data are from 20012002, when the prevalence of community-acquired MRSA in the United States was considerably lower than it is today. Thus, the surveillance studies may simply lag behind the advancing epidemic. An alternative and more disturbing possibility is that the epidemiology of community-acquired MRSA differs from that of MSSA and hospital-acquired MRSA and that nasal carriage is not the prime predictor of subsequent infection. If so, the lack of a colonization site that is easily accessible for culturing will make it more difficult to identify and control populations that are at risk for developing and spreading infections due to community-acquired MRSA. A recent publication has described colonization of the gastrointestinal tract with these organisms, suggesting that the organisms spread differently than hospital-acquired MRSA (14). Recent studies suggest that household pets may be additional reservoirs for community-acquired MRSA (15). Moreover, community-acquired MRSA are now being introduced into hospitals, thus blurring the borders between community-acquired and hospital-acquired strains (16). Therapy for infections due to community-acquired MRSA presents additional challenges for the clinician. The first challenge is to recognize these organisms, since they are resistant to the oral cephalosporins and antistaphylococcal penicillins, which have been the mainstay for treating skin and skin structure infections in the community. Most community-acquired MRSA isolated in the United States are susceptible to the tetracyclines (including minocycline and doxycycline), as well as trimethoprimsulfamethoxazole. However, no clinical trials of these agents in community-acquired MRSA infections have been performed (5). Clindamycin presents an additional challenge because some strains are susceptible to clindamycin in vitro but contain genes encoding inducible resistance to macrolides, lincosamides, and streptograminB (MLSB) that confer the potential to develop resistance to clindamycin during therapy (17). Milder infections often respond to local incision and drainage alone. For severe and overwhelming infections caused by these organisms, antimicrobial agents may be ineffective because the patient receives treatment too late. It will be interesting to see whether in such cases the addition of agents like clindamycin or linezolid (which may decrease production of toxins such as PantonValentine leukocidin) or the addition of intravenous immune globulin (which has been shown to contain antibodies against the PantonValentine leukocidin toxin) has any effect on the ultimate outcome (18). The epidemic of community-acquired MRSA in the United States and elsewhere raises basic questions for which we have no answers. We know very little about the epidemiology of these organisms, and we know even less about the pathogenesis of the severe and overwhelming infections that they cause. The role of host factors in determining severity of infection is also unclear. Optimal antimicrobial agent therapy is unknown. Finally, we have no idea of the cellular mechanisms that have allowed clones such as USA 300 to become dominant in the community. Recently, 2 groups have reported the sequencing of the entire genome of USA 300 (19; Diep BA, Perdreau-Remington F. Personal communication). Comparing these genomes with those of USA 400 and previously sequenced standard MRSA strains should enable us to begin to answer some of these important questions. In addition, careful epidemiologic studies and clinical observations will be necessary to control this remarkable epidemic. Given these uncertainties, what should the clinician do? First, and most important, the clinician must be aware that the prevalence of community-acquired MRSA is rapidly increasing in the United States. The clinician should have a correspondingly low threshold for obtaining material for culture and susceptibility testing from community-acquired abscesses and other skin infections, especially those that initially resemble spider bites with areas of necrosis. Second, the clinician should know when to use drugs with activity against community-acquired MRSA (minocycline, doxycycline, trimethoprimsulfamethoxazole, clindamycin [if the organism is susceptible to erythromycin], or vancomycin). These drugs are indicated if the patient does not respond rapidly to appropriate drainage (when indicated) and standard antimicrobial agent therapy or in settings with a high incid