A mechanism-based pathway toward administering highly active N-phage cocktails

Abstract

Bacteriophage (phage) therapy is being explored as a possible response to the antimicrobial resistance public health emergency. Administering a mixture of different phage types as a cocktail is one proposed strategy for therapeutic applications, but the optimal method for formulating phage cocktails remains a major challenge. Each phage strain has complex pharmacokinetic/pharmacodynamic (PK/PD) properties which depend on the nano-scale size, target-mediated, self-dosing nature of each phage strain, and rapid selection of resistant subpopulations. The objective of this study was to explore the pharmacodynamics (PD) of three unique and clinically relevant anti-<i>Pseudomonas</i> phages after simulation of dynamic dosing strategies. The Hollow Fiber Infection Model (HFIM) is an <i>in vitro</i> system that mimics <i>in vivo</i> pharmacokinetics (PK) with high fidelity, providing an opportunity to quantify phage and bacteria concentration profiles over clinical time scales with rich sampling. Exogenous monotherapy-bolus (producing <i>max</i> concentrations of <i>C</i>_max = 7 log₁₀ PFU/mL) regimens of phages LUZ19, PYO2, and E215 produced <i>Pseudomonas aeruginosa</i> nadirs of 0, 2.14, or 2.99 log₁₀ CFU/mL after 6 h of treatment, respectively. Exogenous combination therapy bolus regimens (LUZ19 + PYO2 or LUZ19 + E215) resulted in bacterial reduction to <2 log₁₀ CFU/mL. In contrast, monotherapy as a continuous infusion (producing a <i>steady-state</i> concentration of <i>C</i>_ss,avg = 2 log₁₀PFU/mL) was less effective at reducing bacterial densities. Specifically, PYO2 failed to reduce bacterial density. Next, a mechanism-based mathematical model was developed to describe phage pharmacodynamics, phage-phage competition, and phage-dependent adaptive phage resistance. Monte Carlo simulations supported bolus dose regimens, predicting lower bacterial counts with bolus dosing as compared to prolonged phage infusions. Together, <i>in vitro</i> and <i>in silico</i> evaluation of the time course of phage pharmacodynamics will better guide optimal patterns of administration of individual phages as a cocktail.