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

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

scholarly journals Protein Binding of β-Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?

2013 ◽  
Vol 57 (12) ◽  
pp. 6165-6170 ◽  
Author(s):  
Gloria Wong ◽  
Scott Briscoe ◽  
Syamhanin Adnan ◽  
Brett McWhinney ◽  
Jacobus Ungerer ◽  
...  
Keyword(s):  
Protein Binding ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Albumin Concentration ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Unbound Concentration

ABSTRACTThe use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P< 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R2= 0.81 to 1.00;P< 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (R2= 0.776;P< 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.

Barriers and facilitators in the clinical implementation of beta-lactam therapeutic drug monitoring in critically ill patients

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Alan Abdulla ◽  
Puck van den Broek ◽  
Tim M.J. Ewoldt ◽  
Anouk E. Muller ◽  
Henrik Endeman ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Barriers And Facilitators ◽  
Therapeutic Drug ◽  
Clinical Implementation ◽  
Beta Lactam

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

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.

scholarly journals Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 131
Author(s):  
Christina Scharf ◽  
Michael Paal ◽  
Ines Schroeder ◽  
Michael Vogeser ◽  
Rika Draenert ◽  
...  
Keyword(s):  
Renal Function ◽  
Clinical Practice ◽  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Target Attainment ◽  
Number Of Patients

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.

Evaluation of studies on extended versus standard infusion of beta-lactam antibiotics

2019 ◽  
Vol 76 (18) ◽  
pp. 1383-1394 ◽  
Author(s):  
Melanie Chen ◽  
Valerie Buurma ◽  
Monica Shah ◽  
Germin Fahim
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Outcomes ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Clinical Success ◽  
Beta Lactam ◽  
Therapeutic Success ◽  
Gram Negative ◽  
Beta Lactam Antibiotics ◽  
Drug Concentrations

AbstractPurposeTo summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin–tazobactam, meropenem, and cefepime.SummaryGram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin–tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.ConclusionBased on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

scholarly journals Target-Controlled Infusion of Cefepime in Critically Ill Patients

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Stijn Jonckheere ◽  
Nikolaas De Neve ◽  
Jan Verbeke ◽  
Koen De Decker ◽  
Inger Brandt ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Standard Of Care ◽  
Antimicrobial Treatment ◽  
Beta Lactam ◽  
Target Drug ◽  
Target Controlled Infusion ◽  
Drug Concentrations ◽  
Performance Error

ABSTRACT Attainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of sedatives and analgesics in anesthesia. We conducted a clinical trial in an intensive care unit (ICU) to investigate the performance of TCI for adequate target attainment of cefepime. Twenty-one patients treated with cefepime according to the standard of care were included. Cefepime was administered through continuous infusion using TCI for a median duration of 4.5 days. TCI was based on a previously developed population PK model incorporating the estimated creatinine clearance based on the Cockcroft-Gault formula as the input variable to calculate cefepime clearance. A cefepime blood concentration of 16 mg/liter was targeted. To evaluate the measured versus predicted plasma concentrations, blood samples were taken (median of 10 samples per patient), and total cefepime concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. The performance of the TCI system was evaluated using Varvel criteria. Half (50.3%) of the measured cefepime concentrations were within ±30% around the target value of 16 mg liter−1. The wobble was 11.4%, the median performance error (MdPE) was 21.1%, the median absolute performance error (MdAPE) was 32.0%, and the divergence was −3.72% h−1. Based on these results, we conclude that TCI is useful for dose optimization of cefepime in ICU patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02688582.)

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

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.

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

2019 ◽  
Vol 40 (04) ◽  
pp. 476-487 ◽  
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.

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

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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