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 Pseudomonas aeruginosa. However, dosing and delivery strategies for phage therapy remain underdeveloped. In a mouse wound infection model specifically designed to evaluate the treatment of established infections—a critical gap in existing preclinical models—we investigated the impact of administration route, dose, and frequency on phage therapy efficacy. In this model, topical, but not systemic, delivery reduced wound bacterial burden. In vitro and in vivo data revealed rapid emergence of phage resistance and suggested potential benefit of using high and repeated doses. Building on these insights, we developed HydroPhage, a phage-containing hyaluronan-based hydrogel formed with dynamic covalent crosslinks that delivers high-titer phages over one week. Here, we show that sustained hydrogel-based delivery is a practical and effective approach for topical phage application. Here, the authors develop a mouse model of wound infection to evaluate the efficacy of phage therapy for established infections and generate “HydroPhage”, a phage-containing hydrogel, as a means for sustained delivery and topical phage application.