Fowler VG, Das AF, Lipka-Diamond J, et al. - This superiority-design study was conducted to examine the therapeutic impacts of exebacase [a first-in-class antistaphylococcal lysin, a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics] vs placebo in patients with S. aureus (Staphylococcus aureus) BSI (bloodstream infection)/endocarditis. The participants (n = 121) were randomized to receive a single dose of exebacase or placebo. Standard-of-care antibiotics were administered to all patients. Clinical outcome (responder rate) on day 14 was the primary efficacy endpoint. In the exebacase + antibiotics and antibiotics-alone groups, clinical responder rates on day 14 were estimated to be 70.4% and 60.0%, respectively, and these rates were 42.8 percentage points higher in the prespecified exploratory MRSA (methicillin-resistant S. aureus) subgroup. Among MRSA patients in the US, the exebacase-treated group vs antibiotics alone was identified to have 4 days shorter median length of stay and 48% lower 30-day hospital readmission rates. This work establishes proof of concept for exebacase as well as direct lytic agents as potential therapeutics. Performing a confirmatory investigation focused on exebacase to treat MRSA BSIs is supported in view of these findings.