Cornelia B Landersdorfer1,2,3, Jiping Wang1, Veronika Wirth1, Ke Chen1, Keith S Kaye4, Brian T Tsuji3,5, Jian Li1,6, Roger L Nation1. 1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 2. Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 3. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo State University of New York, Buffalo, NY, USA. 4. Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. 5. Laboratory for Antimicrobial Pharmacodynamics, NYS Centre of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA. 6. Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Abstract
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.
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 neutropenicmice 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.
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