The treatment of Staphylococcus aureus bloodstream infections (SABSI) remains a major challenge. With an emphasis on complicated methicillin–sensitive S. aureus (MSSA), a comprehensive analysis of initial antibiotic treatment was conducted. The influence of treatment gaps on clinical outcomes were examined. Strategies were developed to improve the use of available antibiotics. Patient- and infection-related variables predictive for end-of-treatment failure included higher Charlson Comorbidity Index and healthcare-associated infection. Treatment variables of shorter duration of optimal targeted, shorter duration of optimal or adequate and lower TSE score were also predictive for end-of-treatment failure when tested separately in their own models. Strategies to optimize the treatment of complicated MSSA BSI at minimum should include: 1) Initiating at least an adequate therapy within 24 hours following the index blood culture draw and 2) Maintaining uninterrupted treatment, especially during the initial 7 days including at least 4 days of cloxacillin or cefazolin.