STRATEGIC DEVELOPMENT OF BACTERIOPHAGE THERAPEUTICS: TREATMENT OPTIMIZATION AND PHARMACEUTICAL FORMULATION SCIENCE FOR PSEUDOMONAS AERUGINOSA PULMONARY INFECTION

Abstract

Antimicrobial resistance, causing over 1.27 million deaths annually, severely limits treatment of multidrug-resistant respiratory infections. Pseudomonas aeruginosa poses particular challenges due to biofilm formation, poor antibiotic penetration, and rapid resistance development. Bacteriophage therapy provides targeted antibacterial activity, self-amplification, and biofilm disruption, yet its clinical translation is constrained by resistance emergence, formulation instability, and delivery barriers.

This thesis integrates phage scheduling with solid-state formulation engineering to address these limitations. Sequential treatment, beginning with an LPS-targeting phage followed by a type IV pili–targeting phage, produced sustained suppression and reduced resistance compared with simultaneous dosing. Resistance profiling and AFM-IR analysis revealed receptor-specific adaptations and differential fitness costs that could be strategically exploited.

Formulation studies established stable, inhalable phage powders. High-molecular-weight PVP matrices maintained long-term viability under low humidity by preserving thermal stability, while lactose–leucine systems supported multi-phage stability for up to four years, though aerosol performance declined at elevated temperature. A novel HSA–lactose formulation achieved superior fine particle fractions and delayed recrystallisation while maintaining phage viability.

Together, these findings demonstrate that combining evolutionary dosing strategies with advanced powder engineering provides a robust platform for inhalable bacteriophage therapy. This multidisciplinary approach addresses resistance management, stability, and targeted pulmonary delivery, offering a viable pathway toward clinical application in multidrug-resistant respiratory infections.