Lysin CF-301 Demonstrates In Vitro Synergy with Conventional Antibiotics against Staphylococcus aureus

BACKGROUND: CF-301 is a novel, recombinantly-produced bacteriophage-derived lysin (cell wall hydrolase) and is the first agent of this class to enter clinical development in the US for the treatment of bacteremia including endocarditis due to S.aureus. This study evaluated the in vitro activity of CF-301 combined with each of 7 antistaphylococcal antibiotics including those considered to be current standard of care treatments for S.aureus bacteremia (daptomycin, vancomycin, oxacillin, nafcillin, and cefazolin) as well as linezolid and telavancin. METHODS: MICs for CF-301 were determined using a new AST medium for broth microdilution recently endorsed by the CLSI for use with CF-301. The testing medium consisted of cation-adjusted MHB supplemented with 25% horse serum and 0.5 mM DTT. Synergy was determined by checkerboard microdilution using the fractional inhibitory concentration index (FICI) for each combination in triplicate. For each antibiotic tested, an FIC mean was derived from each set of checkerboards by averaging 3 consecutive FIC values along the growth/no growth interface for each plate. Thus, 9 values were, used to generate the final mean. Synergy was defined as an FICI of ≤0.5; indifference was >0.5 to <2; and antagonism was ≥2. Each combination was examined against 10 MSSA and 10 MRSA strains. RESULTS: CF-301 synergized with daptomycin and vancomycin against each MSSA and MRSA strain, with FICI values between 0.254 and 0.5. Synergy was similarly observed against all 20 strains tested with oxacillin and nafcillin (FICI = 0.25–0.5); for the third β-lactam, cefazolin, synergy was observed with 17 strains (FICI = 0.75, for the remaining 3 strains). CF-301 synergized with televancin against 70% of the strains (FICI = 0.375–0.5), and was indifferent with the remainder (FICI = 0.625–1). CF-301 synergized with linezolid against 55% of the strains (FICI = 0.375–0.5), and was indifferent with the remainder (FICI = 0.625–0.75). CONCLUSION: The broadly synergistic activity of CF-301 with conventional antistaphylococcal antibiotics against MSSA and MRSA suggests that CF-301 may afford therapeutic benefit by potentiating the activity antibiotics to treat serious infections for which there is an unmet medical need to improve outcomes. DISCLOSURES: K. Sauve, ContraFect Corp: Employee, Salary; A. Jandourek, ContraFect Corp: Employee, Salary; C. Cassino, ContraFect Corp: Employee, Salary; R. Schuch, ContraFect Corp: Employee, Salary