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

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03508-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7324-7330 ◽

Cited By ~ 50

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.

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Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab649 ◽

2021 ◽

Author(s):

Alison R Novak ◽

Martin Krsak ◽

Tyree H Kiser ◽

Robert T Neumann ◽

Luis Cava Prado ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Critically Ill ◽

Therapeutic Option ◽

Area Under The Curve ◽

Population Based ◽

Pharmacodynamic Modeling ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Relative Distribution ◽

Critically Ill Adults

Abstract: Background The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin to the CSF in non-infected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVD) in neurologically injured adults. Methods Blood and CSF was collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000mg IV every 8 hours or the renal dose equivalent for EVD prophylaxis. Results A median of 3 blood (range 2-4) and 3 CSF (range 2-5) samples were collected in each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). Median calculated cefazolin CSF Cmax and Cmin (IQR) were 2.97mg/L (1.76-8.56) and 1.59mg/L (0.77-2.17), respectively. Median (IQR) CSF to serum area under-the-curve ratio was 6.7% (3.7%-10.6%), with time matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration 4 hours or greater following administration were 1.87 and 0.78 mg/L, respectively. Conclusion Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.

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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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Limited-Sampling Strategies for Anidulafungin in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03375-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1177-1181 ◽

Cited By ~ 5

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.)

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.763575 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jihui Chen ◽

Xiaohui Huang ◽

Zhiyan Lin ◽

Chao Li ◽

Haoshu Ding ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Dynamic Change ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Blood Concentrations ◽

Dosage Regimens ◽

Drug Concentrations

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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