Ecological and Immune Pressures Shape Outcomes of Precision Phage Therapy in Advanced Cystic Fibrosis Lung Disease

ABSTRACT Chronic Pseudomonas aeruginosa infection remains a defining and increasingly drug-resistant complication in cystic fibrosis (CF). Here, we report phage-antibiotic co-therapy in an elderly individual with CF and a multidrug-resistant pulmonary exacerbation. Treatment was safe, well-tolerated, and associated with rapid clinical improvement, including enhanced lung function, reduced obstruction, and a 100-fold decrease in bacterial burden. Multi-omic profiling revealed in situ phage replication, transient suppression of non- mucoid P. aeruginosa , and virome restructuring. Bacterial isolates evolved resistance with associated fitness costs, while the host developed phage-specific neutralizing antibodies that limited systemic activity. Despite this, one phage persisted in the lung beyond therapy. These findings offer in vivo insight into phage–host– microbiome dynamics during treatment and underscore the importance of integrating microbial ecology and immune profiling into phage therapy design. This case highlights the potential for phage therapy in late-stage CF and the value of personalized, immune-informed strategies for managing chronic infection.