AUTHOR=Smith Nicholas M. , Nguyen Thomas D. , Chin Wai Hoe , Sanborn Jacob T. , de Souza Harriet , Ho Brian M. , Luong Tiffany , Roach Dwayne R. 

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

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1292618

DOI=10.3389/fmicb.2023.1292618

ISSN=1664-302X

ABSTRACT=<p>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-<italic>Pseudomonas</italic> phages after simulation of dynamic dosing strategies. The Hollow Fiber Infection Model (HFIM) is an <italic>in vitro</italic> system that mimics <italic>in vivo</italic> 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 <italic>max</italic> concentrations of <italic>C</italic><sub>max</sub> = 7 log<sub>10</sub> PFU/mL) regimens of phages LUZ19, PYO2, and E215 produced <italic>Pseudomonas aeruginosa</italic> nadirs of 0, 2.14, or 2.99 log<sub>10</sub> CFU/mL after 6 h of treatment, respectively. Exogenous combination therapy bolus regimens (LUZ19 + PYO2 or LUZ19 + E215) resulted in bacterial reduction to &lt;2 log<sub>10</sub> CFU/mL. In contrast, monotherapy as a continuous infusion (producing a <italic>steady-state</italic> concentration of <italic>C</italic><sub>ss,avg</sub> = 2 log<sub>10</sub>PFU/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, <italic>in vitro</italic> and <italic>in silico</italic> evaluation of the time course of phage pharmacodynamics will better guide optimal patterns of administration of individual phages as a cocktail.</p>