| Summary: | <i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a leading cause of skin and soft-tissue infections (SSTIs) in the community. In this study, we characterized a collection of 34 <i>S. aureus</i> from SSTIs in ambulatory patients in Portugal and analyzed the presence of Panton–Valentine leucocidin (PVL)-encoding genes and antibiotic-resistance profile, which was correlated with genetic determinants, plasmid carriage, and clonal lineage. Nearly half of the isolates (15, 44.1%) were methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and/or multidrug resistant (MDR). We also detected resistance to penicillin (33/34, 97.1%), fluoroquinolones (17/34, 50.0%), macrolides and lincosamides (15/34, 44.1%), aminoglycosides (6/34, 17.6%), and fusidic acid (2/34, 5.9%), associated with several combinations of resistance determinants (<i>blaZ</i>, <i>erm</i>(A), <i>erm</i>(C), <i>msr</i>(A), <i>mph</i>(C), <i>aacA-aphD</i>, <i>aadD</i>, <i>aph</i>(3′)-<i>IIIa</i>, <i>fusC</i>), or mutations in target genes (<i>fusA</i>, <i>grlA/gyrA</i>). The collection presented a high genetic diversity (Simpson’s index of 0.92) with prevalence of clonal lineages CC5, CC22, and CC8, which included the MRSA and also most MDR isolates (CC5 and CC22). PVL-encoding genes were found in seven isolates (20.6%), three methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA) (ST152-<i>agr</i>I and ST30-<i>agr</i>III), and four MRSA (ST8-<i>agr</i>I). Plasmid profiling revealed seventeen distinct plasmid profiles. This work highlights the high frequency of antimicrobial resistance and PVL carriage in SSTIs-related <i>S. aureus</i> outside of the hospital environment.
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