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Multicenter population pharmacokinetic study of colistimethate sodium and colistin dosed as in normal renal function in patients on continuous renal replacement therapy


Leuppi-Taegtmeyer, Anne B; Decosterd, Laurent; Osthoff, Michael; Mueller, Nicolas J; Buclin, Thierry; Corti, Natascia (2018). Multicenter population pharmacokinetic study of colistimethate sodium and colistin dosed as in normal renal function in patients on continuous renal replacement therapy. Antimicrobial Agents and Chemotherapy, 63(2):e01957-18.

Abstract

Intravenous colistimethate sodium (CMS) is used to treat infections with multi-resistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemofiltration (CVVHD), median blood flow 100 ml/min). Intensive sampling was performed on treatment day 1, 3 and 5 after a 9 MU intravenous CMS loading dose (6 MU if body weight < 60 kg) with a consecutive 8-hourly 3 MU (respectively 2 MU) maintenance dose. CMS and colistin were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for on average 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady state trough concentrations of at least 2.5 mg/L were achieved in all patients receiving 3 MU 8-hourly. A loading dose of 9 MU followed after 8 h by a maintenance dosage of 3 MU 8 hourly independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients.

Abstract

Intravenous colistimethate sodium (CMS) is used to treat infections with multi-resistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemofiltration (CVVHD), median blood flow 100 ml/min). Intensive sampling was performed on treatment day 1, 3 and 5 after a 9 MU intravenous CMS loading dose (6 MU if body weight < 60 kg) with a consecutive 8-hourly 3 MU (respectively 2 MU) maintenance dose. CMS and colistin were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for on average 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady state trough concentrations of at least 2.5 mg/L were achieved in all patients receiving 3 MU 8-hourly. A loading dose of 9 MU followed after 8 h by a maintenance dosage of 3 MU 8 hourly independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:26 November 2018
Deposited On:29 Jan 2019 11:32
Last Modified:01 Jun 2019 15:09
Publisher:American Society for Microbiology
ISSN:0066-4804
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/AAC.01957-18
PubMed ID:30478168

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