1264 - Assessment of In Vivo Efficacy of CF-296 in addition to Vancomycin (VAN) and Daptomycin (DAP) against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model

Background: CF-296 is a novel lysin in pre-clinical development for the treatment of methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections, used in addition to standard of care antibiotics including VAN and DAP. We evaluated the in vivo efficacy of CF-296 alone and in addition to VAN and DAP against S. aureus.

Methods: Eight isolates (1 MSSA and 7 MRSA) were studied. Murine ICR MIC (100% serum) and human MIC (100% serum) for CF-296 ranged from 32-256 mg/L to 0.5-1 mg/L respectively. Broth microdilution MICs for DAP ranged from 0.5-1 mg/L while all isolates exhibited a VAN MIC of 1 mg/L. Neutropenic ICR mice were thigh inoculated with bacterial suspensions (10⁷ CFU/mL). Mice were administered three monotherapy regimens subcutaneously (SC) or intravenously (IV): i) sub-therapeutic VAN, SC (i.e., a dose that yielded bacteria stasis or growth in order to evaluate further bacterial killing), ii) sub-therapeutic DAP, SC, or iii) CF-296 50 mg/kg, IV. Combination of sub-therapeutic VAN or DAP in addition to 5 escalating CF-296 doses ranging from 0.5 to 50 mg/kg were also examined. Control mice were vehicle-dosed. Efficacy was measured as the change in mean thigh bacterial density at 24h relative to 0h controls.

Results: Relative to starting inoculum (5.71 ± 0.27 at 0h), bacterial density in controls increased by +2.49 ± 0.98 log₁₀ CFU/thigh across all 8 strains. On average, VAN, DAP, and CF-296 monotherapy resulted in +0.90 ± 1.21, +1.47 ± 0.80, and +0.87 ± 1.39 log₁₀ CFU/thigh bacteria growth, respectively. In addition to VAN, escalating CF-296 exposures (0.5 – 50 mg/kg) resulted in an augmented dose-response, ranging from bacterial reduction of -0.26 ± 1.10 (with addition of CF-296 0.5 mg/kg) to -1.01 ± 0.41 log₁₀ CFU/thigh (with addition of CF-296 50 mg/kg). Similarly, escalating CF-296 exposures in addition to DAP resulted in an augmented dose-response, ranging from bacterial density of +0.80 ± 1.19 to -0.72 ± 0.59 log₁₀ CFU/thigh.

Conclusion: Compared with 24h control, VAN, DAP, and CF-296 alone displayed modest CFU reduction while CF-296 synergized with VAN and DAP to cause further bacterial killing highlighting a potential role for CF-296 adjunctive therapy against MSSA and MRSA isolates.