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Breast implant-associated infections (BIAIs) are a common complication following breast prostheses placement and account for ∼100,000 infections annually. The frequency, high cost of treatment, and morbidity make BIAIs a significant health burden for women. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) againstStaphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant pocket during surgery. We usedin vitroandin vivoassays to test the efficacy of each antibiotic in TAPI, as well as TAPI at the concentration used during surgery. We found that planktonically grownS. aureusBIAI isolates displayed susceptibility to gentamicin, cefazolin, and TAPI. However, TAPI treatment enhanced biofilm formation of BIAI strains. Furthermore, we compared TAPI treatment of aS. aureusreference strain (JE2) to a BIAI isolate (117) in a mouse BIAI model. TAPI significantly reduced infection of JE2 at 1- and 7-days post infection (dpi). In contrast, BIAI strain 117 displayed high bacterial burdens in tissues and implants, which persisted out to 14-dpi despite TAPI treatment. Lastly, we demonstrated that TAPI was effective againstP. aeruginosareference (PAO1) and BIAI strainsin vitroandin vivo. Together, these data suggestS. aureusBIAI strains employ unique mechanisms to resist antibiotic prophylaxis treatment and promote chronic infection.