Pulmonary Target Delivery of Polymyxin B for Enhanced Efficacy

Objective: Polymyxin B is increasingly used as the last resort for multidrug resistant (MDR) Gram-negative bacterial infections. Limited by high polarity of the drug and poor penetration into the pulmonary epithelial lining fluid (ELF), polymyxin B does not distribute well to the lung tissues to achieve an effective concentration. In this study, polymyxin B liposomes were developed as well as the pharmacokinetics, exposure in the ELF and efficacy of a polymyxin B liposomal formulation were investigated. Methods: A rapid, sensitive and robust UPLC-MS/MS method had been developed for the quantification of four major polymyxin B components (PB1, PB2, PB3 and ile-PB1) in various biological matrices. Polymyxin B liposomes were developed and characterized. Two groups of 24 Swiss Webster mice were intravenously administrated polymyxin B liposomes, and aqueous solution, respectively, at approximately 3 mg/kg. Serial serum, ELF and kidney samples were collected for up to 6 hours to quantify major polymyxin B components. Treatment efficacy of the liposomal formulation was evaluated by two clinically relevant endpoints, bacterial burden in lung tissues at 24 h and survival, respectively. Results: The validated method was used to characterize the pharmacokinetics (serum, ELF and kidneys) of polymyxin B in mice. The limited exposure of polymyxin B in ELF observed was consistent with the less favorable efficacy of polymyxin B reported for the treatment of pulmonary infections. Compared with aqueous solution, the liposomal formulation was shown to have a slower total clearance. The AUC ratio in the ELF between liposome and aqueous solution group ranged from 5.0 to 7.0 for various major polymyxin B components. In the efficacy study, a significantly lower bacterial burden was seen in the liposomal group (3.8 ± 0.7 vs. 7.9 ± 0.8 Log10 CFU/g in solution group), which subsequently prolonged survival of infected animals. Conclusions: Treatment with a polymyxin B liposomal formulation yielded higher penetration into pulmonary ELF, which resulted in superior efficacy.