Chronic relapsing sinus infections with antibiotic resistant S. aureus (golden staph superbugs) are associated with chronic rhinosinusitis (CRS) disease recalcitrance. There is an urgent need for the development of new treatments for these difficult to treat patients. Bacteriophage (phage) is a virus that targets and kills one specific bacterial species, leaving the human mucosa and commensal species unaffected. However, phage’s suitability for therapeutic application is hindered by (1) the existence and/or rapid emergence of Bacteriophage Insensitive Mutants (BIM) in the presence of phage and (2) the inability of phage to eradicate the bacteria. We have found that low dosages of antibiotics can re-sensitize S. aureus BIM to phage and eradicates antibiotic resistant S. aureus. The overall objective of this translational research project is to develop a novel phage-based therapy to combat acute exacerbations of CRS with multidrug resistant S. aureus (MRSA) in recalcitrant CRS patients. Specifically, optimization of the pharmaceutical formulation and delivery will be followed by preclinical safety and efficacy studies and a Phase 1 Human Clinical Trial in recalcitrant CRS patients.