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

The Journal of Antimicrobial Chemotherapy
Soon-Ee CheahRoger L Nation

Abstract

This study investigated the exposure-response relationships between unbound colistin in plasma and antibacterial activity in mouse thigh and lung infections. Dose fractionation studies (subcutaneous colistin sulphate at 1.25-160 mg/kg/day) were conducted in neutropenic mice in which infection (three strains of Pseudomonas aeruginosa and three strains of Acinetobacter baumannii) had been produced by intramuscular thigh injection or aerosol lung delivery. Bacterial burden was measured at 24 h after initiation of colistin treatment. Plasma protein binding was measured by rapid equilibrium dialysis and ultracentrifugation. The inhibitory sigmoid dose-effect model and non-linear least squares regression were employed to determine the relationship between exposure to unbound colistin and efficacy. Plasma binding of colistin was constant over the concentration range ∼2-50 mg/L. The average ± SD percentage bound for all concentrations was 92.9 ± 3.3% by ultracentrifugation and 90.4 ± 1.1% by equilibrium dialysis. In the thigh model, across all six strains the antibacterial effect of colistin was well correlated with fAUC/MIC (R(2) = 0.82-0.94 for P. aeruginosa and R(2) = 0.84-0.95 for A. baumannii). Target values of fAUC/MIC for 2 log1...Continue Reading

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Citations

Nov 27, 2015·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Roger L NationFernanda P Silveira
Mar 18, 2016·The Journal of Antimicrobial Chemotherapy·David D KhanElisabet I Nielsen
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Jan 16, 2019·Antimicrobial Agents and Chemotherapy·M J MelchersJ W Mouton
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Sep 13, 2017·Antimicrobial Agents and Chemotherapy·Alan ForrestRoger L Nation
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Aug 10, 2021·Antimicrobial Agents and Chemotherapy·Arianne LoveyDavid S Perlin

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