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Antimicrobial Agents and Chemotherapy, August 2009, p. 3430-3436, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.01361-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria
,
D. Plachouras,1*
M. Karvanen,2
L. E. Friberg,3
E. Papadomichelakis,4
A. Antoniadou,1
I. Tsangaris,4
I. Karaiskos,1
G. Poulakou,1
F. Kontopidou,1
A. Armaganidis,4
O. Cars,2 and
H. Giamarellou1
4th Department of Internal Medicine,1 2nd Department of Critical Care Medicine, Medical School, Athens University, Athens, Greece,4 Department of Medical Sciences,2 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden3
Received 10 October 2008/ Returned for modification 8 January 2009/ Accepted 4 May 2009
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.
* Corresponding author. Mailing address: 4th Department of Internal Medicine, Attikon University General Hospital, Haidari 12462, Greece. Phone: (30) 210 5831990. Fax: (30) 210 5326446. E-mail: dplach{at}med.uoa.gr
Published ahead of print on 11 May 2009.
Supplemental material for this article may be found at http://aac.asm.org/.
Antimicrobial Agents and Chemotherapy, August 2009, p. 3430-3436, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.01361-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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