Summary/Abstract Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are problematic because of the high associated treatment failures and elevated mortality rates. Staphylococci including MRSA are the major cause of medical device infections (MDIs) due to their strong capability to form biofilms. These bacterial biofilms resist host immune system and lead to antibiotic failure due to limited antibiotic penetration, bacterial tolerance and development of antibiotic resistance. Vancomycin is the recommended therapy for MRSA MDIs and daptomycin is the primary antibiotic alternative to vancomycin for these infections; however, the development of daptomycin resistance especially post vancomycin therapy has been reported with increasing frequency. Although combination therapy of vancomycin or daptomycin with beta-lactam antibiotics such as ceftaroline have demonstrated improved activity in vitro, these combinations have not shown significant enhancements in MDIs caused by Staphylococci. Therefore, due to the lack of effective MDI treatments, novel antibacterial options are critically needed. Obligately lytic bacteriophages (phages) infect bacteria, replicate within the cell, lyse the cell to release their progeny and reinitiate the infection cycle. These phages eradicate both antibiotic susceptible and resistant bacteria in planktonic and biofilm forms. The combination of phage and antibiotics have shown to re-sensitize previously multi-drug resistant bacteria to antibiotics. Synergistic and antagonistic interactions in phage-antibiotic combinations are highly dependent on the mechanism of bacterial inhibition of the antibiotic paired to the phage, bacterial host state (biofilm versus planktonic) and bacterial growth age. Here we are offering a systematic investigation of phage antibiotic combination using various standard of care antibiotics (SOC) to examine the aforementioned parameters. The proposed research is significant especially due to lack of information regarding the use of phage with SOC antibiotics against biofilm embedded MRSA strains. Our central hypothesis is that the combination of phage-antibiotic will reduce the vancomycin and daptomycin exposures required for efficacy against biofilm embedded MRSA and further prevent the emergence of antibiotic resistance. We will test our central hypothesis by first evaluating susceptibility of biofilm embedded MRSA to various phage-antibiotic combinations and then performing in vitro two-compartment PK/PD biofilm models with humanized pharmacokinetics to optimize novel phage-antibiotic combination therapies. We expect that through optimizing therapy of MRSA-biofilm infections, we will improve patient care and prolong the useful life of vancomycin and daptomycin for the management of MRSA MDIs.