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Dosing guidance for intravenous colistin in critically-ill patients.

ABSTRACT: Background:Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient 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 2mg/L. Methods:Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon 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 on 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 ?4mg/L. Results:When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved Css,avg ?2mg/L; but for patients with creatinine clearance ?80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg 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 ?4mg/L. Conclusions:The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate.

SUBMITTER: Nation RL

PROVIDER: S-EPMC5850520 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Dosing guidance for intravenous colistin in critically-ill patients.

Nation Roger L RL Garonzik Samira M SM Thamlikitkul Visanu V Giamarellos-Bourboulis Evangelos J EJ Forrest Alan A Paterson David L DL Li Jian J Silveira Fernanda P FP

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20161223 5

<h4>Background</h4>Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (C<sub>ss,avg</sub>) of 2mg/L.<h4>Methods</h4>Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/m ...[more]

PMID: 28011614

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Project description:Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).

Project description:BackgroundA substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding.MethodIn this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500-4500 IU tinzaparin or 2500-5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis.ResultsA total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13-0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43-1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04.ConclusionsAmong critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.Trial registrationClinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

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Dosing guidance for intravenous colistin in critically-ill patients.

Publications

Dosing guidance for intravenous colistin in critically-ill patients.

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