Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models
| Autor: | Roger L. Nation, Ke Chen, Veronika Wirth, Brian T. Tsuji, Cornelia B. Landersdorfer, Jian Li, Keith S Kaye, Jiping Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microbiology (medical) medicine.drug_class Klebsiella pneumoniae Polymyxin Injections Subcutaneous 030106 microbiology Population Microbial Sensitivity Tests Pharmacology 03 medical and health sciences Mice Plasma Pharmacokinetics Medicine Animals Pharmacology (medical) education Original Research Polymyxin B education.field_of_study biology business.industry Blood Proteins biology.organism_classification Bacterial Load Anti-Bacterial Agents Klebsiella Infections Disease Models Animal Infectious Diseases Anesthesia Pharmacodynamics Colistin Female business Antibacterial activity medicine.drug Protein Binding |
| Popis: | Background The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known. Methods Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose-effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity. Results The pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P > 0.05) over the range ∼0.9-37 mg/L; average (±SD) percentage bound was 91.4 ± 1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2 = 0.89). Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P > 0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice. Conclusions The results will assist in the design of optimized dosage regimens of polymyxin B. |
| Databáze: | OpenAIRE |
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