Pharmacokinetics and Time-Kill Study of Inhaled Antipseudomonal Bacteriophage Therapy in Mice.

Abstract

Inhaled 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 from 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 immune-suppressed 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 posttreatment and various tissues (lungs, kidney, spleen, and liver), bronchoalveolar lavage fluid, and blood were collected for phage quantification. In a separate study combining phage with bacteria, mice (n = 4) were treated with PEV31 (109 PFU) or phosphate-buffered saline (PBS) at 2 h postinoculation with MDR P. aeruginosa Infective PEV31 and bacteria were enumerated from the lungs. In the phage-only study, the PEV31 titer gradually decreased in the lungs over 24 h, with a half-life of approximately 8 h for both doses. In the presence of bacteria, in contrast, the 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. Of the 10 colonies tested, four phage-resistant isolates were observed from the lung homogenates sampled at 24 h after 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.