Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Abstract

AbstractInhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different to antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8 and 24 h post-treatment and various tissues (lungs, kidney, spleen and liver), bronchoalveolar lavage and blood were collected for phage quantification. In a separate study, mice (n = 4) were treated with PEV31 (109 PFU) or PBS at 2 h post-inoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage only study, PEV31 titer gradually decreased in the lungs over 24 hours with a half-life of approximately 8 h for both doses. In the presence of bacteria, PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Some phage-resistant colonies were observed from the lung homogenates sampled at 24 h post-phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.