Phage-Antibiotic Cooperation Emerges Through Ecological Partitioning in Heterogeneous Pseudomonas Infection

Bacteriophage (phage) therapy provides a precision strategy against refractory bacterial infections, but translation into durable clinical success remains limited by poor understanding of how phages, antibiotics, and host immunity interact in vivo. Here, we present a multi-omic case analysis of intravenous phage-antibiotic co-therapy in a patient with cystic fibrosis during an acute-on-chronic pulmonary exacerbation caused by multidrug-resistant Pseudomonas aeruginosa. Treatment was safe and clinically effective, yielding rapid functional recovery and a two-log reduction in bacterial burden. Efficacy emerged not through direct pharmacologic synergy but from ecological partitioning, with ciprofloxacin suppressing the dominant mucoid population and phages P1A and PYO2 depleting the multidrug-resistant nonmucoid lineage. The therapeutic window was brief, with phage activity concentrated in the first few days and waning thereafter, while ciprofloxacin failed late in therapy, coinciding with mucoid regrowth. Durability was limited by humoral immunity, with pre-existing IgM, likely from the patient's virome, blocking PYO2 early and an IgM response arising during therapy neutralizing P1A later. This anti-phage pressure enabled resistant subvariants to emerge, but their reduced fitness limited expansion and preserved overall efficacy. These findings define a systems-level therapeutic logic-chemobiotherapy-where distinct chemical and biological mechanisms achieve coordinated control through mechanistic complementarity rather than pharmacologic synergy.