Skin and soft tissue infections (SSTI) rank as one of the top causes of pediatric hospitalization and account for more than 14 million outpatient visits each year in the United States. Staphylococcus aureus is the most common cause of SSTI. Incision and drainage (I&D) has been considered the mainstay of treatment for uncomplicated S. aureus skin abscesses, consistent with guidelines from the Infectious Diseases Society of America (IDSA). For patients with purulent cellulitis and skin abscesses for whom antibiotics are prescribed in the outpatient setting, the guidelines recommend empiric treatment with non-β-lactam antibiotics, including clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), a tetracycline, or linezolid.  Scientists hypothesized that including systemic antibiotics in the management of S. aureus SSTI, in conjunction with incision and drainage, would reduce S. aureus colonization and incidence of recurrent infection. Participants prescribed guideline-recommended empiric antibiotics for purulent SSTI were less likely to remain colonized at follow-up sampling and less likely to have recurrent SSTI than those not receiving guideline-recommended empiric antibiotics for their SSTI. Additionally, clindamycin was more effective than trimethoprim-sulfamethoxazole (TMP-SMX) in eradicating S. aureus colonization, but the mechanism by which clindamycin differentially affects colonization and recurrent SSTI compared to TMP-SMX warrants further study.