Development of spray-dried phage-aztreonam microparticles for inhalation therapy of Pseudomonas aeruginosa lung infections.

Despite considerable efforts in antibiotic therapy, pulmonary infections caused by Pseudomonas aeruginosa remain a major challenge, particularly in diseases such as cystic fibrosis. Bacteriophage-antibiotic combinations have recently emerged as a potential alternative due to synergistic effects and the ability to overcome resistance. However, phage instability and sensitivity continue to hinder clinical translation. In this study, we developed an inhalable spray-dried microparticle formulation co-encapsulating bacteriophages against P. aeruginosa and the β-lactam antibiotic aztreonam using mannitol, leucine, and trehalose as excipients. The particles exhibited favorable aerosol properties for deep lung delivery (geometric diameter: 1.39 ± 0.11 µm, mass median aerodynamic diameter: 2.42 ± 0.14 µm) and a burst release profile enabling immediate antimicrobial activity. Aztreonam was efficiently encapsulated (97.87 ± 0.91 %), while phage viability could be maintained through processing, remaining stable for 28 days at 4 and -20 °C. Therapeutic efficacy was confirmed by treatment of P. aeruginosa biofilms. A reduction in bacterial load by 99.90 % was achieved within 24 h. Microparticle biocompatibility was demonstrated in vitro using human lung epithelial cells. The spray-dried phage-aztreonam microparticles enabled phage viability and stability in a formulation and highlight the feasibility of phage-antibiotic co-delivery through dry powder inhalation therapy for treating pulmonary P. aeruginosa infections.