A broad-host-range inhalable phage cocktail for treatment of multidrug-resistant Pseudomonas aeruginosa pulmonary infections

Abstract

Introduction The growing threat of multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa) has created an urgent need for novel therapeutic strategies to combat refractory lung infections. The limited efficacy of traditional antibiotics against this pathogen highlights the necessity of developing alternative treatments. Our study aims to develop a broad-spectrum bacteriophage cocktail suitable for nebulization and to evaluate its antibacterial efficacy and safety in respiratory infections caused by MDR P. aeruginosa. Methods We constructed a seven-phage cocktail by selecting phages with complementary host ranges, strong lytic activity, and different receptor targets. The antimicrobial and anti-biofilm activity of the cocktail was assessed in vitro against clinical MDR P. aeruginosa isolates. The therapeutic efficacy and safety were further investigated in a murine pneumonia model following nebulized administration. Results The phage cocktail demonstrated lytic activity against nearly 90% of 152 clinical P. aeruginosa isolates, indicating broad coverage. Compared to single phages or antibiotics, the cocktail showed superior activity in both inhibiting and disrupting biofilms. In the murine pneumonia model, nebulized phage therapy improved survival, reduced bacterial burdens in lung and liver, and alleviated infection-related histopathological damage. Safety assessment revealed no obvious hematological, biochemical or histopathological abnormalities in both acute and long-term administration. Conclusion High-dose nebulized administration of this phage cocktail reduced bacterial burden and showed favorable tolerability in a murine model of MDR P. aeruginosa pneumonia. These findings provide preclinical evidence supporting further evaluation of inhaled phage cocktails as a potential therapeutic strategy for refractory respiratory infections.