Dosing and Delivery of Bacteriophage Therapy In a Murine Wound Infection Model

Abstract

Lytic bacteriophages, viruses that lyse (kill) bacteria, hold great promise for treating infections, including wound infections caused by antimicrobial-resistant <i>Pseudomonas aeruginosa.</i> However, dosing and delivery strategies for phage therapy remain underdeveloped. In a mouse wound infection model, we investigated the impact of administration route, dose, and frequency on the efficacy of phage therapy. We find that topical but not systemic delivery is effective in this model. <i>In vitro</i> and <i>in vivo</i> data supported the use of high doses of phage. Repeated dosing achieves the highest eradication rates <i>in vivo.</i> Building on these insights, we developed "HydroPhage", a hyaluronan-based hydrogel system that uses dynamic covalent crosslinking to deliver high-titre phages over one week, a substantial improvement over existing burst-release systems. We conclude that hydrogel-based sustained phage delivery offers a practical, efficacious, and well-tolerated option for topical phage application.