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Background: Studies have shown that community-acquired methicillin-resistant Staphylococcus aureus (MRSA) causes S. aureus skin and soft-tissue infection in selected populations. Objective: To determine the proportion of infections caused by community-acquired MRSA, the clinical characteristics associated with community-acquired MRSA, and the molecular epidemiology of community-acquired MRSA among persons with community-onset S. aureus skin and soft-tissue infection. Design: Active, prospective laboratory surveillance to identify S. aureus recovered from skin and soft-tissue sources. Setting: 1000-bed urban hospital and its affiliated outpatient clinics in Atlanta, Georgia. Patients: 384 persons with microbiologically confirmed community-onset S. aureus skin and soft-tissue infection. Measurements: Proportion of infections caused by and clinical factors associated with community-acquired MRSA among persons with community-onset S. aureus skin and soft-tissue infection. Pulsed-field gel electrophoresis and antimicrobial susceptibility patterns were used to epidemiologically classify community-onset S. aureus infections. Community-acquired MRSA was defined by MRSA isolates that either demonstrated a USA 300 or USA 400 pulsed-field type or had a susceptibility pattern showing resistance only to β-lactams and erythromycin (for isolates not available for pulsed-field gel electrophoresis). Results: Community-onset skin and soft-tissue infection due to S. aureus was identified in 389 episodes, with MRSA accounting for 72% (279 of 389 episodes). Among all S. aureus isolates, 63% (244 of 389 isolates) were community-acquired MRSA. Among MRSA isolates, 87% (244 of 279 isolates) were community-acquired MRSA. When analysis was restricted only to MRSA isolates that were available for pulsed-field gel electrophoresis, 91% (159 of 175 isolates) had a pulsed-field type consistent with community-acquired MRSA; of these, 99% (157 of 159 isolates) were the MRSA USA 300 clone. Factors independently associated with community-acquired MRSA infection were black race (prevalence ratio, 1.53 [95% Cl, 1.16 to 2.02]), female sex (prevalence ratio, 1.16 [Cl, 1.02 to 1.32]), and hospitalization within the previous 12 months (prevalence ratio, 0.80 [Cl, 0.66 to 0.97]). Inadequate initial antibiotic therapy was statistically significantly more common among those with community-acquired MRSA (65%) than among those with methicillin-susceptible S. aureus skin and soft-tissue infection (1%). [ABSTRACT FROM AUTHOR]