Translating Phage-Antibiotic Synergy to Combat Multi-Drug Resistant Staphylococcus aureus Infections

About This Grant

Summary/Abstract Vancomycin (VAN) is the primary antibiotic therapy for serious MRSA infections such as infective endocarditis, despite increasing failure rates and the emergence of VAN resistant strains on therapy. Daptomycin (DAP) is the alternative therapy of choice for VAN failures. However, there have been increasingly frequent reports of DAP non-susceptibility and cross resistance with VAN especially post-VAN failures. This treatment outcome has prompted the use of “off-labeled” salvage combination therapy of high-dose DAP plus ceftaroline (CPT), often with poor treatment efficacy outcomes. Bacteriophages (phages) are viruses that infect and kill bacteria and have been used with some success to treat various infections. Yet, bacterial resistance to phages has been observed when individual phage therapy is used. We have generated exciting new data that suggest phage-antibiotic combinations (PAC) may act synergistically and circumvent phage or antibiotic resistance. However, the specific mechanisms for this optimal synergy MRSA are not known. We hypothesize that phage cocktails plus DAP alone or in combination with CPT exert strong efficacy against MRSA and prevent resistance to both phage and DAP. To define and optimize synergistic mechanisms, we will perform experiments to logically translate these regimens. First, we will determine their mechanisms of synergistic action using an innovative method for mechanistic fingerprinting in vitro. Next, we will use our validated ex vivo model of simulated endocardial vegetation infection with humanized antibiotic and phage to optimize the efficacy of PAC against MRSA and avert resistance. Strategies will include simultaneous and sequential dosing and extended exposure for best durability in achieving mechanistic and pharmacologic synergy. Finally, we will optimize regimens for anti-MRSA efficacy in a robust pre-clinical challenge model of infective endocarditis in vivo to maximize treatment efficacy and prevent the emergence of MRSA resistance to phage or antibiotics. This progressive translational strategy will result in phage-antibiotic regimens with optimal anti- MRSA synergies, durability and minimized resistance that are poised for advancement to human clinical trials.