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
| Autor: | Qi Tony Zhou, Alan Forrest, Jiping Wang, Hak-Kim Chan, Ke Chen, Veronika Wirth, Nikolas J. Onufrak, Jian Li, Yu-Wei Lin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.drug_class Polymyxin 030106 microbiology Population Microbial Sensitivity Tests Pharmacology medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Pharmacokinetics Administration Inhalation medicine Animals Humans Pharmacology (medical) Pseudomonas Infections 030212 general & internal medicine Intensive care medicine education Lung Respiratory Tract Infections Polymyxin B education.field_of_study business.industry Pseudomonas aeruginosa Area under the curve respiratory system Anti-Bacterial Agents Disease Models Animal Infectious Diseases medicine.anatomical_structure Pharmacodynamics Female business medicine.drug |
| Popis: | 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 examined 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 of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment 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. The ratio of the area under the curve to the MIC (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 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 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. |
| Databáze: | OpenAIRE |
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