Μελέτη της φαρμακοκινητικής της κολιμυκίνης και μελέτη της φαρμακοκινητικής μετά από χορήγηση δόσης φόρτισης στους ασθενείς της μονάδας εντατικής θεραπείας (Μ.Ε.Θ) ; Pharmacokinetic analysis of colistin methanesulfonate and colistin and application of a loading dose of colistin in critically ill patients

The increase in the incidence of antimicrobial resistance among Gram – negative bacteria in combination with the dry antimicrobial drug development pipeline poses a serious threat in the management of infections and has led to the revival of colistin. Colistin is systemically administered in the form of colistin methanesulfonate (CMS), an inactive pro-drug which is hydrolyzed to colistin that exhibits bactericidal activity. The optimal dose of colistin is unclear due to the lack of accurate pharmacokinetic information, since most available data are based on microbiological assays that are considered erroneous. In the present study we analyzed the pharmacokinetics of colistin in 18 critically ill patients with infections caused by Gram negative bacteria after a dose of 3 million IU every 8 hours. Venous blood samples were collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin were determined by a liquid chromatography-tandem mass spectrometry method and population pharmacokinetic analysis was performed with the NONMEM program. The estimated half-life was 14.4 hours, whereas the maximum concentrations of the drug in plasma were 0.60 mg/L and 2.3 mg/L after the first dose and at steady state respectively. The implications of these findings are very important since the obtained plasma colistin concentrations were insufficient for the 48 hours after initiation of treatment and the administration of a loading dose would be beneficial. Subsequently, a pharmacokinetic study of CMS and colistin following a loading dose of 6 million IU and a maintenance dose of 3 million IU every 8 hours was conducted in 10 critically ill patients and the colistin concentrations were found 1.34mg/L after the first dose. The present study was completed by evaluating the pharmacokinetics of CMS and colistin in a population of 19 critically ill patients with the application of a loading dose of 9 million IU and a maintenance dose of 4.5 million IU every 12 hours. The maximum ...