scholarly journals Nonstationary Pharmacokinetics of Caspofungin in ICU Patients

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Agnieszka Borsuk-De Moor ◽  
Justyna Sysiak-Sławecka ◽  
Elżbieta Rypulak ◽  
Michał Borys ◽  
Paweł Piwowarczyk ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Population Pharmacokinetic ◽  
Relative Standard Error ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Albumin Concentration ◽  
Relative Standard

ABSTRACT Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0–24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies, including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Caspofungin was administered as empirical 70 mg antifungal therapy administered intravenously (i.v.) on the first day and at 50 mg i.v. on the consecutive days once daily, and the concentrations were measured after three subsequent doses. Population pharmacokinetic data were analyzed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by two-compartment model. A particular drift of the individual clearance (CL) and the volume of distribution of the central compartment (V1) with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at days 1, 2, and 3 were 0.563 liters/h (6.7% relative standard error [6.7%RSE]), 0.737 liters/h (6.1%RSE), and 1.01 liters/h (9.1%RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT03399032.)

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Continuous versus Short-Term Infusion of Imipenem-Cilastatin in Critically Ill Patients in a Randomized, Controlled Trial

2007 ◽  
Vol 51 (9) ◽  
pp. 3304-3310 ◽  
Author(s):  
Samir G. Sakka ◽  
Anna K. Glauner ◽  
Jürgen B. Bulitta ◽  
Martina Kinzig-Schippers ◽  
Wolfgang Pfister ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Population Pharmacokinetic ◽  
Beta Lactams ◽  
Target Attainment ◽  
Short Term ◽  
Randomized Controlled ◽  
Drug Concentrations

ABSTRACT Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT >MIC) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT >MIC value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT >MIC. The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT >MIC of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.

scholarly journals Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

2013 ◽  
Vol 58 (1) ◽  
pp. 94-101 ◽  
Author(s):  
Thomas Horvatits ◽  
Reinhard Kitzberger ◽  
Andreas Drolz ◽  
Christian Zauner ◽  
Walter Jäger ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
High Performance ◽  
Area Under The Curve ◽  
Antiviral Agent ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Target Area ◽  
Continuous Venovenous Hemodiafiltration

ABSTRACTGanciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.

Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

2016 ◽  
Vol 56 (2) ◽  
pp. 127-138 ◽  
Author(s):  
Amélie Marsot ◽  
Romain Guilhaumou ◽  
Camille Riff ◽  
Olivier Blin
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies

scholarly journals Limited-Sampling Strategies for Anidulafungin in Critically Ill Patients

2014 ◽  
Vol 59 (2) ◽  
pp. 1177-1181 ◽  
Author(s):  
Marjolijn J. P. van Wanrooy ◽  
Johannes H. Proost ◽  
Michael G. G. Rodgers ◽  
Jan G. Zijlstra ◽  
Donald R. A. Uges ◽  
...  
Keyword(s):  
Linear Regression ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Sampling Strategies ◽  
Time Curve ◽  
Limited Sampling ◽  
Concentration Time

ABSTRACTEfficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW\Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC0–24) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression (R2= 0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model (R2= 0.89; bias, −0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.)

scholarly journals Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

2018 ◽  
Vol 62 (6) ◽  
pp. e00242-18 ◽  
Author(s):  
Fekade B. Sime ◽  
Janine Stuart ◽  
Jenie Butler ◽  
Therese Starr ◽  
Steven C. Wallis ◽  
...  
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Central Venous Access ◽  
Plasma Concentrations ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Albumin Concentration ◽  
Data Set

ABSTRACT To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period (Cmax), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC0–∞), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution (V), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC0–∞ was 39% of the values reported for heathy volunteers. The AUC0–∞ was only 52% of the steady-state AUC0–24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

scholarly journals Usefulness of sialic acid for diagnosis of sepsis in critically ill patients: a retrospective study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Bo Yao ◽  
Wen-juan Liu ◽  
Di Liu ◽  
Jin-yan Xing ◽  
Li-juan Zhang
Keyword(s):  
Sialic Acid ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Incomplete Data ◽  
Acid Level ◽  
Operating Characteristic ◽  
Area Under The Curve ◽  
Diagnostic Efficacy ◽  
Receiver Operating Characteristic Curves ◽  
Sensitivity Specificity

Abstract Background Early diagnosis of sepsis is very important. It is necessary to find effective and adequate biomarkers in order to diagnose sepsis. In this study, we compared the value of sialic acid and procalcitonin for diagnosing sepsis. Methods Newly admitted intensive care unit patients were enrolled from January 2019 to June 2019. We retrospectively collected patient data, including presence of sepsis or not, procalcitonin level and sialic acid level. Receiver operating characteristic curves for the ability of sialic acid, procalcitonin and combination of sialic acid and procalcitonin to diagnose sepsis were carried out. Results A total of 644 patients were admitted to our department from January 2019 to June 2019. The incomplete data were found in 147 patients. Finally, 497 patients data were analyzed. The sensitivity, specificity and area under the curve for the diagnosis of sepsis with sialic acid, procalcitonin and combination of sialic acid and procalcitonin were 64.2, 78.3%, 0.763; 67.9, 84.0%, 0.816 and 75.2, 84.6%, 0.854. Moreover, sialic acid had good values for diagnosing septic patients with viral infection, with 87.5% sensitivity, 82.2% specificity, and 0.882 the area under the curve. Conclusions Compared to procalcitonin, sialic acid had a lower diagnostic efficacy for diagnosing sepsis in critically ill patients. However, the combination of sialic acid and procalcitonin had a higher diagnostic efficacy for sepsis. Moreover, sialic acid had good value for diagnosing virus-induced sepsis.

Performance of Automated Telemetry in Diagnosing QT Prolongation in Critically Ill Patients

2021 ◽  
Vol 30 (6) ◽  
pp. 466-470
Author(s):  
Enrique Calvo-Ayala ◽  
Vince Procopio ◽  
Hayk Papukhyan ◽  
Girish B. Nair
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Demographic Data ◽  
Area Under The Curve ◽  
Qt Prolongation ◽  
Altman Analysis ◽  
Poor Agreement ◽  
Bland Altman Analysis ◽  
Prolonged Qt ◽  
Definition Of

Background QT prolongation increases the risk of ventricular arrhythmia and is common among critically ill patients. The gold standard for QT measurement is electrocardiography. Automated measurement of corrected QT (QTc) by cardiac telemetry has been developed, but this method has not been compared with electrocardiography in critically ill patients. Objective To compare the diagnostic performance of QTc values obtained with cardiac telemetry versus electrocardiography. Methods This prospective observational study included patients admitted to intensive care who had an electrocardiogram ordered simultaneously with cardiac telemetry. Demographic data and QTc determined by electrocardiography and telemetry were recorded. Bland-Altman analysis was done, and correlation coefficient and receiver operating characteristic (ROC) coefficient were calculated. Results Fifty-one data points were obtained from 43 patients (65% men). Bland-Altman analysis revealed poor agreement between telemetry and electrocardiography and evidence of fixed and proportional bias. Area under the ROC curve for QTc determined by telemetry was 0.9 (P < .001) for a definition of prolonged QT as QTc ≥ 450 milliseconds in electrocardiography (sensitivity, 88.89%; specificity, 83.33%; cutoff of 464 milliseconds used). Correlation between the 2 methods was only moderate (r = 0.6, P < .001). Conclusions QTc determination by telemetry has poor agreement and moderate correlation with electrocardiography. However, telemetry has an acceptable area under the curve in ROC analysis with tolerable sensitivity and specificity depending on the cutoff used to define prolonged QT. Cardiac telemetry should be used with caution in critically ill patients.

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