Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria
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- 1 August 2009
- journal article
- clinical trial
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 53 (8), 3430-3436
- https://doi.org/10.1128/aac.01361-08
Abstract
Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.Keywords
This publication has 25 references indexed in Scilit:
- Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programmingComputer Methods and Programs in Biomedicine, 2004
- Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonateJournal of Antimicrobial Chemotherapy, 2004
- Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosisJournal of Antimicrobial Chemotherapy, 2003
- Use of High-Performance Liquid Chromatography To Study the Pharmacokinetics of Colistin Sulfate in Rats following Intravenous AdministrationAntimicrobial Agents and Chemotherapy, 2003
- Synergistic Activity of Colistin and Ceftazidime against Multiantibiotic-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic ModelAntimicrobial Agents and Chemotherapy, 2003
- Simple Method for Assaying Colistin Methanesulfonate in Plasma and Urine Using High-Performance Liquid ChromatographyAntimicrobial Agents and Chemotherapy, 2002
- Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.International Journal of Clinical Pharmacy, 1998
- Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEMComputer Methods and Programs in Biomedicine, 1998
- Prediction of Creatinine Clearance from Serum CreatinineNephron, 1976
- Serum Concentrations of Colistin in Patients with Normal and Impaired Renal FunctionThe New England Journal of Medicine, 1964