Dosing guidance for intravenous colistin in critically ill patients

Nation, Roger L., Garonzik, Samira M., Thamlikitkul, Visanu, Giamarellos-Bourboulis, Evangelos J., Forrest, Alan, Paterson, David L., Li, Jian and Silveira, Fernanda P. (2017) Dosing guidance for intravenous colistin in critically ill patients. Clinical Infectious Diseases, 64 5: 565-571. doi:10.1093/cid/ciw839


Author Nation, Roger L.
Garonzik, Samira M.
Thamlikitkul, Visanu
Giamarellos-Bourboulis, Evangelos J.
Forrest, Alan
Paterson, David L.
Li, Jian
Silveira, Fernanda P.
Title Dosing guidance for intravenous colistin in critically ill patients
Journal name Clinical Infectious Diseases   Check publisher's open access policy
ISSN 1058-4838
1537-6591
Publication date 2017-03-01
Year available 2016
Sub-type Article (original research)
DOI 10.1093/cid/ciw839
Open Access Status PMC
Volume 64
Issue 5
Start page 565
End page 571
Total pages 7
Place of publication Cary, NC, United States
Publisher Oxford University Press
Language eng
Subject 2726 Microbiology (medical)
2725 Infectious Diseases
Abstract Background. Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large interpatient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2 mg/L. Methods. Plasma concentration-time data from 214 adult critically ill patients (creatinine clearance, 0-236 mL/min; 29 receiving renal replacement therapy [RRT]) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based on the relationship between the dose of colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were receiving RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg ≥2 and <30% for Css,avg ≥4 mg/L. Results. When algorithm doses were applied back to individual patients not receiving RRT (including those prescribed intermittent dialysis on a nondialysis day), >80% of patients with creatinine clearance <80 mL/min achieved Css,avg ≥2 mg/L, but for patients with creatinine clearance ≥80 mL/min, the target attainment was <40%, even with the maximum allowed daily dose of 360 mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg ≥4 mg/L. Conclusions. The project has generated clinician-friendly dosing algorithms and pointed to circumstances in which intravenous monotherapy may be inadequate.
Formatted abstract
Background: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large interpatient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2 mg/L.

Methods: Plasma concentration-time data from 214 adult critically ill patients (creatinine clearance, 0-236 mL/min; 29 receiving renal replacement therapy [RRT]) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based on the relationship between the dose of colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were receiving RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg ≥2 and <30% for Css,avg ≥4 mg/L.

Results: When algorithm doses were applied back to individual patients not receiving RRT (including those prescribed intermittent dialysis on a nondialysis day), >80% of patients with creatinine clearance <80 mL/min achieved Css,avg ≥2 mg/L, but for patients with creatinine clearance ≥80 mL/min, the target attainment was <40%, even with the maximum allowed daily dose of 360 mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg ≥4 mg/L.

Conclusions: The project has generated clinician-friendly dosing algorithms and pointed to circumstances in which intravenous monotherapy may be inadequate.
Keyword Intravenous colistin
Critically ill patients
Population pharmacokinetics
Influence of renal impairment and renal replacement modalities
Dosing guidance
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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