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Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2009 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, no 8, 3430-3436 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2009. Vol. 53, no 8, 3430-3436 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-113826DOI: 10.1128/AAC.01361-08ISI: 000268098300037PubMedID: 19433570OAI: oai:DiVA.org:uu-113826DiVA: diva2:291980
Available from: 2010-02-04 Created: 2010-02-04 Last updated: 2013-04-29Bibliographically approved
In thesis
1. Optimization of Colistin Dosage in the Treatment of Multiresistant Gram-negative Infections
Open this publication in new window or tab >>Optimization of Colistin Dosage in the Treatment of Multiresistant Gram-negative Infections
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As multidrug resistance in Gram-negative bacilli increases, the old antibiotic colistin has rapidly gained attention as one of few last line treatment options in the form of colistin methanesulfonate (CMS), which is hydrolyzed to colistin both in vitro and in vivo. There is a dearth of knowledge on fundamental aspects of colistin, including pharmacokinetics and optimal dosing regimens. The aim of this thesis was to improve the basis for optimal colistin therapy.

To be able to study colistin, an LC-MS/MS assay method was developed which is sensitive, specific and useful in both in vivo and in vitro studies. Using this method we detected a significant loss of colistin during standard laboratory procedures. This loss was characterized and quantified, the hypothesis being that the loss is mainly caused by adsorption to labware.

The pharmacokinetics of colistin was studied in two populations of critically ill patients, one with normal renal function and one with renal replacement therapy. Plasma concentrations were assayed with the method above, and population modeling was employed to describe the data. The results include a previously unseen, long elimination half-life of colistin. The data from the population on renal replacement therapy was described without modeling, and showed that both CMS and colistin are cleared by hemodiafiltration.

Combination therapy is an approach that is often used when treating patients infected with multidrug-resistant pathogens. The thesis discusses how the joint effect of antibiotics can be measured using colistin and meropenem as a model, and proposes a method for testing antibiotic combinations. Furthermore, a PKPD model was adapted to describe the pharmacodynamics of the combination.

In conclusion, a specific and sensitive method for analysis of colistin was developed and the adsorption of colistin to materials was described. The assay method has been well accepted internationally. The pharmacokinetics of colistin and CMS was described in two important patient populations, partly with surprising results that have influenced dosages of colistin worldwide. The pharmacodynamics of combination therapy was investigated and quantified, and the methods applied could be further developed into clinically useful tools for selection of antibiotic combinations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 56 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 889
Colistin, CMS, Pharmacology, Pharmacokinetics, PKPD, Antibiotics, Combination therapy, Pharmacometrics, Dosing regimens, Antibiotic resistance
National Category
Infectious Medicine Pharmacology and Toxicology Microbiology in the medical area
Research subject
Infectious Diseases
urn:nbn:se:uu:diva-197724 (URN)978-91-554-8640-2 (ISBN)
Public defence
2013-05-20, Hörsalen, Klinisk mikrobiologi, Dag Hammarskjölds väg 17, Uppsala, 09:15 (English)
Available from: 2013-04-26 Created: 2013-04-02 Last updated: 2013-08-30Bibliographically approved

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Friberg, L. E.
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