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Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic/Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model.

ABSTRACT

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD) and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were conducted in neutropenic infected mice and the data were analyzed by a population PK model. Dose-fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC = 1 mg/L for all three strains). Histopathological examination of lung was undertaken at 24 h post treatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. AUC/MIC was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R(2)=0.70-0.88 for ELF and R(2)=0.70-0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1326-1506 in ELF and 3.14-4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.