Bacteriophages for P.aeruginosa VAP

Background: The compassionate use of bacteriophage cocktails as an adjunct to antibiotics has shown 69% clinical improvement and 48% pathogen eradication in lower respiratory infections. This approach may be superior to antibiotics alone, particularly for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant P. aeruginosa. Objectives: This study aims to evaluate the safety and efficacy of a novel phage cocktail, alone and in combination with ceftolozane/tazobactam (C/T), for treating VAP caused by carbapenem-resistant P. aeruginosa. Secondary objectives include assessing resistance evolution, respiratory microbiota impact, and biofilm characteristics in endotracheal tubes. Methods: A new phage library (n=20) will be characterized based on morphology, genomics, lytic activity, and host range against P. aeruginosa clinical strains (n=100). Optimized phage cocktails (n=12) will be tested in vitro, and endotoxin-free formulations will ensure safety. In a porcine VAP model (n=20), animals will be randomized to receive: Control (NaCl 0.9%), C/T (50 mg/kg /25 mg/kg), Phages Cocktail (4 lytic phages, ~1x10^9 PFU/mL), and CT+Phages. Outcomes include P.aeruginosa and phage counts, histopathology, resistances, biofilm and microbiota analysis, inflammatory markers and transcriptomics. Expected Results: The CT+phages approach is expected to enhance bacterial eradication, reduce histopathological damage, minimize resistances and maintain microbiota balance, highlighting its potential for clinical application.