Ecological partitioning enables phage-antibiotic cooperation in a human Pseudomonas infection.

Abstract

Bacteriophage-antibiotic coadministration is increasingly used for refractory infections, yet the in vivo interactions among phages, bacteria, antibiotics, and host immunity remain poorly defined. We report a longitudinal, multiomic case analysis of a male in his seventies with cystic fibrosis (CF) experiencing an acute-on-chronic pulmonary exacerbation caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. After colistin discontinuation due to nephrotoxicity, ciprofloxacin was initiated, with an intravenous two-phage cocktail introduced days later. Distinct mucoid and nonmucoid bacterial subpopulations associated differentially with antibiotic versus phage exposure, consistent with nonoverlapping selective pressures. Phage activity was temporally constrained, with one phage dominating early bacterial and genomic signals before attenuating after approximately seven days, despite continued genomic detectability. In contrast, the second phage showed no evidence of productive activity. This asymmetry coincided with phage-reactive humoral immunity: pre-existing IgM was associated with lack of recoverability of one phage, while treatment-associated IgM emergence temporally tracked attenuation of the dominant phage. Although phage-resistant variants arose during therapy, they showed limited expansion relative to susceptible populations. These findings define a mechanistic framework-chemobiotherapy-in which chemical and biological antimicrobials coordinate through ecological and immunologic complementarity rather than direct pharmacologic synergy.