Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria

A. N. Kristoffersson, V. Rognås, M. J.E. Brill, Y. Dishon-Benattar, E. Durante-Mangoni, V. Daitch, A. Skiada, J. Lellouche, A. Nutman, A. Kotsaki, R. Andini, N. Eliakim-Raz, R. Bitterman, A. Antoniadou, M. O. Karlsson, U. Theuretzbacher, L. Leibovici, G. L. Daikos, J. W. Mouton, Y. CarmeliM. Paul, L. E. Friberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. Methods: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. Results: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14–1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. Discussion: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Original languageEnglish
Pages (from-to)1644-1650
Number of pages7
JournalClinical Microbiology and Infection
Volume26
Issue number12
DOIs
StatePublished - Dec 2020

Funding

FundersFunder number
FP7 EUF3-2011-278348
FP7 EU-project AIDAHealth-F3-2011-278348
Uppsala Antibiotic Centre
Roche
Joint Programming Initiative on Antimicrobial Resistance
European Commission
Vetenskapsrådet2015-06826, 2018-03296
Seventh Framework Programme
Ministry of Science and Technology, Israel312075
Uppsala Universitet
Innovative Medicines Initiative

    Keywords

    • Carbapenem resistance
    • Colistin
    • Population pharmacokinetics
    • Renal function
    • Survival
    • Survival analysis

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