671. Impact of Dose-Administration Strategies of the Antistaphylococcal Lysin Exebacase, (CF-301), in Addition to Daptomycin (DAP) in an Experimental Infective Endocarditis (IE) Model due to Methicillin-Resistant Staphylococcus aureus (MRSA)

Abstract

BackgroundMRSA infections, especially involving the endovascular system (e.g., IE), are associated with unacceptably high morbidity and mortality rates. The use of bacteriophage-derived lysin, which acts as direct lytic agents, represents a novel adjunctive approach against virulent Gram-positive bacteria, such as MRSA. The current study examined the efficacy of DAP alone or DAP plus CF-301administered on a single day using various dosing regimens, in a rabbit model of MRSA IE.MethodsAortic valve IE due to MRSA strain MW2 was induced by the IV administration of ~1 × 105–2 × 105 cfu in aortic-catheterized rabbits. At 24-hour post-infection, animals were randomized into one of the 13 groups: (1) vehicle controls given once daily (QD); 2–13) DAP alone (at 4 mg/kg iv QD × 4d; this dose yields significant but modest clearance of MRSA in experimental IE); DAP + CF-301 (given as an IV dose on the first day of DAP treatment only by 5–10 min slow bolus at (mg/kg): 0.70 QD, 0.35 Q12h, 0.23 Q8h, 0.35 QD, 0.175 Q12h, 0.117 Q8h, 0.09 QD, 0.045 Q12h, 0.03 Q8h, 0.06 QD, 0.03 Q12h or 0.03 QD. At 24 hours after the last DAP dose, three target organs were quantitatively cultured (cardiac vegetations; kidneys and spleen). Data for each organ were calculated as mean log10 cfu/g of tissue (±SD).ResultsTreatment with DAP alone caused ~2–3 log10 cfu/g reduction in MRSA densities in all three target tissues vs. vehicle controls. All CF-301 doses given in addition to DAP, even at the lowest CF-301 dose (0.03 mg/kg), significantly reduced MRSA densities further in all target tissues vs. DAP alone (~3 log10 cfu/g) and vehicle control groups (~6 log10 cfu/g). In general, DAP plus CF-301 given as a single dose trended toward better microbiologic efficacy than CF-301 given at Q12h or Q8h, although this difference was not statistically significant.ConclusionThese results demonstrate that CF-301, given at multiple dose strategies and at different dose regimens, in addition to sublethal DAP, had significant efficacy in further decreasing MRSA densities in relevant target tissues in the IE model (vs. DAP alone and untreated controls). DAP plus a single dose of CF-301 trended to better efficacy than when it was administered in fractionated dose-strategies.Disclosures All authors: No reported disclosures.