Combination ofin vivophage therapy data within silicomodel highlights key parameters for treatment efficacy

Abstract

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactions in vivo. Here we developed a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain of Escherichia coli. The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.

The dynamic interplay of bacteriophage, bacteria and the mammalian host during phage therapy

“…These studies have advanced the quantitative understanding of the factors affecting phage therapy outcomes, such as the bacterial strain, infected tissue, and chosen delivery route for the therapeutic phage. 31 , 32 , 33 , 34 After delivery to the host, therapeutic phage can adsorb to, infect, and lyse bacterial pathogens and then subsequently interact – whether directly or indirectly – with resident phage, resident bacteria, and the eukaryotic host immune system. As a result, the success or failure of phage therapy should be assessed as part of a complex, tripartite system involving phage, bacteria, and immune defense ( Figure 1 ).…”