Case Report: Monitoring Vancomycin Concentrations and Pharmacokinetic Parameters in Continuous Veno-Venous Hemofiltration Patients to Guide Individualized Dosage Regimens: A Case Analysis

There are limited pharmacokinetic (PK) studies on vancomycin in patients treated with continuous renal replacement therapy (CRRT), and the results have been inconsistent. Because of individual differences, proposing a definite recommendation for the clinical regimen is not possible. Rapidly reaching target vancomycin concentrations will facilitate effective treatment for critically ill patients treated with CRRT. In this study, to understand the dynamic change in drug clearance rates in vivo, analyze the effect of PK changes on drug concentrations, and recommend loading and maintenance dosage regimens, we monitored the blood concentrations of vancomycin and calculated the area under the curve in two critically ill patients treated with vancomycin and continuous veno-venous hemofiltration (CVVH). On the basis of real-time therapeutic drug monitoring results and PK parameters, an individualized vancomycin regimen was developed for patients with CVVH. Good clinical efficacy was achieved, which provided support and reference for empirical vancomycin therapy in these patients.

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Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

ACTA MEDICA IRANICA ◽

10.18502/acta.v60i1.8323 ◽

2022 ◽

Author(s):

Seyedeh Sana Khezrnia ◽

Bita Shahrami ◽

Mohammad Reza Rouini ◽

Atabak Najafi ◽

Hamid Reza Sharifnia ◽

...

Keyword(s):

Brain Injury ◽

Critically Ill ◽

Critically Ill Patients ◽

Normal Population ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Uv Detector ◽

Therapeutic Goals ◽

The Impact

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

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Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Aerosolized Colistin in a Mouse Lung Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01965-17 ◽

2017 ◽

Vol 62 (3) ◽

Cited By ~ 4

Author(s):

Yu-Wei Lin ◽

Qi Tony Zhou ◽

Mei-Ling Han ◽

Nikolas J. Onufrak ◽

Ke Chen ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Pharmacodynamic Modeling ◽

Mouse Lung ◽

Infection Model ◽

Bacterial Reduction ◽

Bacterial Killing ◽

Deterministic Simulation ◽

Dosage Regimens

ABSTRACTOptimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients.In vivotime-kill experiments were carried out with three different strains ofPseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidalEmaxmodel whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a ≥2-log10bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

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Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement

Critical Care Research and Practice ◽

10.1155/2020/8831138 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Bita Shahrami ◽

Farhad Najmeddin ◽

Saeideh Ghaffari ◽

Atabak Najafi ◽

Mohammad Reza Rouini ◽

...

Keyword(s):

Renal Function ◽

Creatinine Clearance ◽

Critically Ill ◽

Normal Renal Function ◽

Critically Ill Patients ◽

Area Under The Curve ◽

Total Daily Dose ◽

Pharmacokinetic Parameters ◽

Concentration Data ◽

Urine Creatinine

Background. The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CLvan), any parameter estimating CLvan will be able to achieve the goal of 24-hour AUC (AUC24 h). The present study was aimed to determine CLvan based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function. Method. 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CLvan with the measured creatinine clearance in 6-hour urine collection (CL6 h) and estimated creatinine clearance by the Cockcroft–Gault formula (CLCG) was investigated. Results. Data analysis revealed that CL6 h had a stronger correlation with CLvan rather than CLCG (r = 0.823 vs. 0.594; p < 0.001 vs. 0.003). The relationship between CLvan and CL6 h was utilized to develop the following equation for estimating CLvan: CLvan (mL/min) = ─137.4 + CL6 h (mL/min) + 2.5 IBW (kg) (R2 = 0.826, p < 0.001 ). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL6-h (mL/min) + 2.5 IBW (kg)) × 0.06 AUC24 h (mg.hr/L). Conclusion. For AUC estimation, CLvan can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.

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Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz463 ◽

2019 ◽

Author(s):

Heleen Aardema ◽

Wouter Bult ◽

Kai van Hateren ◽

Willem Dieperink ◽

Daan J Touw ◽

...

Keyword(s):

Critical Care ◽

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Prolonged Treatment ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Pharmacodynamic Profile ◽

Continuous Dosing ◽

Critical Care Patients

Abstract Background In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population. Objectives To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime. Methods Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207. Results Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission. Conclusions These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

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Vancomycin Area under the Curve and Pharmacokinetic Parameters during the First 24 Hours of Treatment in Critically Ill Patients using Bayesian Forecasting

Infection and Chemotherapy ◽

10.3947/ic.2020.52.4.573 ◽

2020 ◽

Vol 52 (4) ◽

pp. 573

Author(s):

Manat Pongchaidecha ◽

Dhitiwat Changpradub ◽

Kanjana Bannalung ◽

Kajeewan Seejuntra ◽

Sutthanuch Thongmee ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Bayesian Forecasting

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Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00892-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 94-101 ◽

Cited By ~ 8

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.

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Pharmacokinetic Analysis of Meropenem and Piperacillin in Critically-Ill Patients Requiring Continuous Ven-Venous Hemodiafiltration

INNOVATIONS in pharmacy ◽

10.24926/iip.v6i2.386 ◽

2015 ◽

Vol 6 (2) ◽

Author(s):

Brandon Ferlas ◽

Kristina Nelson ◽

Milind Junghare ◽

Kimberly Boeser

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Complex Nature ◽

Original Research ◽

Beta Lactam ◽

Post Dose ◽

Drug Concentrations ◽

Trough Concentrations

Background: Literature has demonstrated proper antibiotic selection and prompt initiation of antibiotics are associated with lower morbidity and mortality. Septic patients have altered pharmacokinetics and often require continuous renal replacement therapy which contributes to altered drug clearance and metabolism. The current study evaluates the pharmacokinetics of meropenem and piperacillin/tazobactam in critically-ill patients requiring continuous veno-venous hemodiafiltration. Purpose: This observational, prospective, single-center, nonrandomized study evaluated the pharmacokinetics of meropenem and piperacillin/tazobactam in critically-ill patients requiring continuous veno-venous hemodiafiltration. Methods: Plasma drug concentrations were determined via high-performance liquid chromatography using three post-dose blood samples after steady-state antimicrobial agent administration. Results: Meropenem peak drug concentrations ranged from 35.9 to 61 mcg/mL, while trough concentrations ranged from 3.9 to 16.7 mcg/mL. Piperacillin peak drug concentrations ranged from 240 to 331.8 mcg/mL, while trough concentrations ranged from 152.7 to 194.9 mcg/mL. Both drugs examined displayed peak concentrations relatively consistent with those expected from the literature, but observed trough concentrations for meropenem and piperacillin were uniformly high. Conclusions: Intravenous doses of meropenem and piperacillin result in peak drug concentrations similar to those previously reported and trough concentrations significantly greater than those in the literature. While concentrations above an organism’s MIC are desirable given the time-dependent nature of these beta-lactam antibiotics, decreased renal clearance of patients maintained on CVVHDF therapy while receiving higher doses of antimicrobials creates a situation in which drug accumulation and toxicity may occur. Given the complex nature of ICU patient care, increased pharmacovigilance and therapeutic drug monitoring are necessary in this unique population. Type: Original Research

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A Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed Meninges

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01998-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01998-20

Author(s):

Nilesh Kumta ◽

Jason A. Roberts ◽

Jeffrey Lipman ◽

Wai Tat Wong ◽

Gavin M. Joynt ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Pharmacokinetic Data ◽

Significant Heterogeneity ◽

Related Factors ◽

Meningeal Inflammation

ABSTRACTVentriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically appraise studies with reported antibiotic concentrations or pharmacokinetic data in cerebrospinal fluid of critically ill patients without meningeal inflammation. We systematically reviewed the literature to identify published reports and studies describing antibiotic concentrations, pharmacokinetics, and pharmacokinetics/pharmacodynamics in cerebrospinal fluid of critically ill patients with uninflamed meninges. Fifty-eight articles met the inclusion criteria. There was significant heterogeneity in methodologies and results. When available, antibiotic pharmacokinetic parameters displayed large intersubject variability. Intraventricular dosing achieved substantially higher antibiotic concentrations in cerebrospinal fluid than did intravenous doses. Few studies conducted a robust pharmacokinetic analysis and described relevant clinical pharmacokinetic/pharmacodynamic indices and exposure targets in cerebrospinal fluid. Robust and clinically relevant antibiotic pharmacokinetic data describing antibiotic disposition in cerebrospinal fluid are necessary. Such studies should use a standardized approach to accurately describe pharmacokinetic variability. These data should ideally be tied to clinical outcomes whereby therapeutic targets in the cerebrospinal fluid can be better defined. Altered dosing strategies, in conjunction with exploring the utility of therapeutic drug monitoring, can then be developed to optimize antibiotic exposure with the goal of improving outcomes in this difficult-to-treat patient group.

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Imipenem Population Pharmacokinetics: Therapeutic Drug Monitoring Data Collected in Critically Ill Patients with or without Extracorporeal Membrane Oxygenation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00385-20 ◽

2020 ◽

Vol 64 (6) ◽

Author(s):

Wenqian Chen ◽

Dan Zhang ◽

Wenwen Lian ◽

Xiaoxue Wang ◽

Wenwen Du ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Extracorporeal Membrane Oxygenation ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Small Sample ◽

Therapeutic Drug ◽

Blood Concentrations ◽

Membrane Oxygenation ◽

Population Pk

ABSTRACT Carbapenem pharmacokinetic (PK) profiles are significantly different in critically ill patients because of the drastic variability of the patients’ physiological parameters. Published population PK studies have mainly focused on specific diseases, and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). A two-compartment population PK model with creatinine clearance (CLCR), body weight (WT), and ECMO as fixed effects was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (ƒ%T>MIC) for the range of clinically relevant MICs. The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750 mg every 6 h (q6h) could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than those in non-ECMO patients; therefore, dosages may need to be increased. The dosage may need adjustment for patients with a CLCR of ≤70 ml/min, but the dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients with WT ranging from 50 to 80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, therapeutic drug monitoring (TDM) should be carried out to optimize drug regimens.

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Pharmacokinetics/Pharmacodynamics of β-Lactams and Therapeutic Drug Monitoring: From Theory to Practical Issues in the Intensive Care Unit

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-1693498 ◽

2019 ◽

Vol 40 (04) ◽

pp. 476-487 ◽

Cited By ~ 3

Author(s):

Paul Williams ◽

Menino Osbert Cotta ◽

Jason A. Roberts

Keyword(s):

Steady State ◽

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Product Information ◽

Dose Optimization ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Increased Risk

AbstractDespite therapeutic advances over recent decades, the mortality rate for sepsis and septic shock is still approximately 25% worldwide. Early administration of appropriate intravenous antibiotics in the right dose is one of the cornerstones of treatment of sepsis. β-Lactam antibiotics are the most commonly prescribed in critically ill patients, and dosages that do not achieve specific pharmacokinetic/pharmacodynamic targets may increase the likelihood of treatment failure and even emergence of antibiotic resistance. Fluctuations in physiological parameters are often observed in critically ill patients, leading to altered pharmacokinetics and increased risk of suboptimal exposures, especially if standard dosing according to the product information is prescribed. Contemporary evidence illustrates that therapeutic β-lactam concentrations are inconsistently achieved at steady state. This review will investigate alternative β-lactam dose optimization strategies including prolonged infusions, guideline-based dosing, therapeutic drug monitoring (TDM), and the use of dose optimization software, all of which aim to increase the likelihood of achieving therapeutic drug concentrations and improve clinical outcomes as compared with the standard dosing approach. These dose optimization strategies have been the subject of a growing body of evidence; however, further investigation into the outcome benefits and validity of both non-TDM and TDM dosing strategies is required. For the clinician, it is important to select a feasible dosing strategy tailored for the individual patient, which will maximize the likelihood of achieving therapeutic concentrations at steady state and maintain these exposures throughout the course of therapy.

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