Pharmacokinetics and safety evaluation of intravenously administered Pseudomonas phage PA_LZ7 in a mouse model

Abstract

ABSTRACT Phage therapy has become one of the most promising alternatives to antibiotics as the surge of multi-drug-resistant (MDR) bacteria severely threatens global public health. The lack of a thorough understanding of pharmacokinetics (PK) and the safety study of phage has limited its clinical application. In this study, we aimed to evaluate the PK and safety of a lytic phage PA_LZ7 that infects MDR Pseudomonas aeruginosa using intravenous (IV) route in an uninfected immune-competent mice model. The active phage of PA_LZ7 exhibited an exponential decay in plasma at 2*108 (low dosage), 2*1010 [medium dosage (MD)], and 2*1011 PFU/kg [high dosage (HD)] after IV administration, and the phage titer dropped to ~4 log10 PFU/mL over 24 h for all dosages. Phages primarily accumulated in the spleen at 1 h post-administration and gradually decreased in all dosages. The active phage titer in other organs decreased globally within 72 h as well. Plasma cytokines IL-6, IL-10, KC/GRO, and tumor necrosis factor-alpha sharply increased 1 h post-administration in mice of MD and HD groups and dropped to a normal range within 24 h. No obvious toxic effect was observed, except for the increased spleen weight and relative spleen weight in the MD and HD group and the slight lymphocytosis in the white pulp of the spleen in the HD group. In conclusion, PA_LZ7 possesses good PK properties and shows no obvious toxicity; it could be considered as a potent therapeutic candidate for the treatment of MDR P. aeruginosa infections in future phage therapy. IMPORTANCE Phage therapy is gaining traction as an alternative to antibiotics due to the rise of multi-drug-resistant (MDR) bacteria. This study assessed the pharmacokinetics and safety of PA_LZ7, a phage targeting MDR Pseudomonas aeruginosa, in mice. After intravenous administration, the phage showed an exponential decay in plasma and its concentration dropped significantly within 24 h for all dosage groups. Although there was a temporary increase in certain plasma cytokines and spleen weight at higher dosages, no significant toxicity was observed. Therefore, PA_LZ7 shows potential as an effective and safe candidate for future phage therapy against MDR P. aeruginosa infections.

Keywords

• phage therapy
• safety
• antibiotic resistance
• pharmacokinetics