Exebacase is Active In Vitro in Pulmonary Surfactant and is Efficacious Alone and Synergistic with Daptomycin in a Mouse Model of Lethal Staphylococcus aureus Lung Infection.

Swift, Steven M; Sauve, Karen; Cassino, Cara; Schuch, Raymond

Exebacase (CF-301) is a novel antistaphylococcal lysin (cell wall hydrolase) in Phase 3 of clinical development for the treatment of Staphylococcus aureus bacteremia including right-sided endocarditis used in addition to standard of care antibiotics. In the current study, the potential for exebacase to treat S. aureus pneumonia was explored in vitro using bovine pulmonary surfactant (Survanta®) and in vivo using a lethal murine pneumonia model. Exebacase was active against a set of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA, respectively), with an MIC90 of 2 μg/mL (n=18 strains), in the presence of a surfactant concentration (7.5%) inhibitory to the antistaphylococcal antibiotic, daptomycin, which is inactive in pulmonary environments due to specific inhibition by surfactant. In a rigorous test of the ability of exebacase to synergize with antistaphylococcal antibiotics, exebacase synergized with daptomycin in the presence of surfactant in vitro, resulting in daptomycin MIC reductions up to 64-fold against 9 MRSA and 9 MSSA strains. Exebacase was also observed to facilitate binding of daptomycin to S. aureus and elimination of biofilm-like structures formed in the presence of surfactant. Exebacase (5 mg/kg, q24d, administered intravenously for 3 days) was efficacious in a murine model of staphylococcal pneumonia, resulting in 50% survival compared to 0% survival in vehicle control; exebacase in addition to daptomycin (50 mg/kg, q24d, 3 days) resulted in 70% survival, compared to 0% survival in the daptomycin alone control. Overall, exebacase in active in pulmonary environments and may be appropriate for development as a treatment for staphylococcal pneumonia.