New pharmacokinetic/pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection

摘要: Objectives This study investigated the exposure-response relationships between unbound colistin in plasma and antibacterial activity mouse thigh lung infections. Methods Dose fractionation studies (subcutaneous sulphate at 1.25-160 mg/kg/day) were conducted neutropenic mice which infection (three strains of Pseudomonas aeruginosa three Acinetobacter baumannii) had been produced by intramuscular injection or aerosol delivery. Bacterial burden was measured 24 h after initiation treatment. Plasma protein binding rapid equilibrium dialysis ultracentrifugation. The inhibitory sigmoid dose-effect model non-linear least squares regression employed to determine relationship exposure efficacy. Results constant over concentration range ∼2-50 mg/L. average ± SD percentage bound for all concentrations 92.9 3.3% ultracentrifugation 90.4 1.1% dialysis. In model, across six effect well correlated with fAUC/MIC (R(2) = 0.82-0.94 P. R(2) 0.84-0.95 A. baumannii). Target values 2 log10 kill 7.4-13.7 7.4-17.6 baumannii. only two one strain baumannii it possible achieve (fAUC/MIC target 36.8-105), even highest dose tolerated mice. not able bacteriostasis other Conclusions Colistin substantially less effective infection. pharmacokinetic/pharmacodynamic will assist design optimized dosage regimens.