Bridging in vitro and in vivo insights: A PKPD model for effective phage therapy against multidrug-resistant Pseudomonas aeruginosa

Abstract

Bacteriophage therapy provides a promising solution for multidrug-resistant Pseudomonas aeruginosa. However, optimizing phage combinations and dosages remains challenging. Here, we developed and validated a pharmacokinetic-pharmacodynamic (PKPD) model integrating in vitro and in vivo efficacy data using three phage strains (MP-A, PP-A, and PP-B), administered both alone and in combination. In vitro phage resistance was substantially delayed by combining phages that exhibit collateral sensitivity. However, multiple phage resistance eventually emerged. In vivo, growth of phage-resistant mutants was minimal. Our model suggests that this outcome was due to an initial phage-induced reduction in bacterial load, followed by immune clearance of the phage-resistant bacteria. Simulations indicated that higher phage exposure at the site of infection caused a faster decline in bacterial levels below the immune clearance threshold and prevented excessive immune activation. Overall, this study offers crucial guidance for treatment strategies and highlights the importance of mathematical modeling in advancing phage therapy.