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Bacteriophage Therapy for Staphylococcus aureus Biofilm-Infected Wounds: A New Approach to Chronic Wound Care
Akhil K. Seth, MD1, Matthew R. Geringer, BS1, Khang Nguyen, BS1, Sonya P. Agnew, MD1, Zari Dumanian, MD1, Seok J. Hong, PhD1, Robert D. Galiano, MD1, Kai P. Leung, PhD2, Thomas A. Mustoe, MD1.
1Division of Plastic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 2Microbiology Branch, US Army Dental and Trauma Research Detachment, Institute of Surgical Research, Fort Sam Houston, TX, USA.
Purpose
Bacterial biofilms, a critical mediator of chronic wound pathogenesis, remain difficult to treat with traditional wound care partly due to a complex, self-secreted extrapolysaccharide (EPS) matrix. The use of bacteriophages as potential therapeutic agents against biofilm has not been rigorously studied in vivo. We evaluate the efficacy of a species-specific bacteriophage against Staphylococcus aureus (SA)-infected biofilm wounds using a validated, quantitative, rabbit ear model.
Methods
Six-mm dermal punch wounds in New Zealand rabbit ears were inoculated with wild-type SA (UAMS-1) or mutant, biofilm-deficient SA (UAMS-929). Bacteria were allowed to proliferate in vivo using the wound care timeline in our published rabbit ear biofilm model. Wounds were left untreated, treated with topical SA-specific bacteriophage every other day (QOD), or treated with QOD bacteriophage after disruption of biofilm structure with sharp debridement. Wounds were harvested on day 12 with measurement of histological wound healing parameters or viable bacterial counts. Biofilm structure was studied using scanning electron microscopy (SEM).
Results
Wild-type SA biofilm wounds demonstrated no differences in healing and no change in viable bacteria levels following bacteriophage treatment or sharp debridement alone. However, the combination of debridement and bacteriophage significantly improved all measured wound healing parameters (p<0.05) while lowering viable bacteria counts (p=0.03). Treatment of biofilm-deficient SA mutant wounds with bacteriophage alone also resulted in increased epithelial (p=0.02) and granulation tissue (p=0.03), with a concurrent decrease in bacterial burden (p<0.0001) as compared to untreated mutant wounds. SEM confirmed differences in morphology and decreased EPS density in SA mutant bacteria wounds as compared to wild-type, as well as increased healing of SA wild-type wounds following treatment with debridement and bacteriophage.
Conclusions
Bacteriophages can be an effective topical therapy against SA biofilm-infected wounds in the setting of a deficient or disrupted biofilm EPS. Combination treatment aimed at disturbing biofilm structure, allowing for increased penetration of species-specific bacteriophages, represents a new and potentially effective approach to chronic wound care. These results establish principles for biofilm therapy that may be applied to several different clinical and surgical problems. 
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