Quantitative Models of Phage-Antibiotic Combination Therapy

Abstract

This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa . In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes.