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 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.

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 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 Insufficient plasma concentrations of empiric anti‐pseudomonal beta‐lactam antibiotics in critically ill patients with suspected sepsis

2020 ◽  
Vol 50 (4) ◽  
pp. 345-350
Author(s):  
Rekha Pai Mangalore ◽  
Alexander A. Padiglione ◽  
Emma‐Leah Martin ◽  
Hans G. F. Schneider ◽  
Lam Lan Ngo‐Thai ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Beta Lactam ◽  
Suspected Sepsis ◽  
Beta Lactam Antibiotics

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.

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.

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 Prone positioning of patients with moderate hypoxia due to COVID-19: A multicenter pragmatic randomized trial [COVID-PRONE]

2021 ◽  
Author(s):  
Mike Fralick ◽  
Michael Colacci ◽  
Laveena Munshi ◽  
Kevin Venus ◽  
Lee Fidler ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Critically Ill ◽  
Median Time ◽  
Critically Ill Patients ◽  
Primary Outcome ◽  
Standard Of Care ◽  
High Flow ◽  
Hospital Death ◽  
Prone Positioning ◽  
High Flow Oxygen

What is already known on this topic: Prone positioning is considered standard of care for mechanically ventilated patients who have severe acute respiratory distress syndrome. Recent data suggest prone positioning is beneficial for patients with COVID-19 who are requiring high flow oxygen. It is unknown of prone positioning is beneficial for patients not on high flow oxygen. What this study adds: Prone positioning is generally not well tolerated and innovative approaches are needed to improve adherence. Clinical and physiologic outcomes were not improved with prone positioning among hypoxic but not critically ill patients hospitalized with COVID-19. Objectives: To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients hospitalized with COVID-19 Design: Pragmatic randomized clinical trial of prone positioning of patients hospitalized with COVID-19 across 15 hospitals in Canada and the United States from May 2020 until May 2021. Settings: Patients were eligible is they had a laboratory-confirmed or a clinically highly suspected diagnosis of COVID-19, required supplemental oxygen (up to 50% fraction of inspired oxygen [FiO2]), and were able to independently prone with verbal instruction. (NCT04383613). Main Outcome Measures: The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as requiring at least 60% FiO2 for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to FiO2 (S/F ratio). Results: A total of 248 patients were included. The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomization was 1 day, the median age of patients was 56 years (interquartile range [IQR] 45,65), 36% were female, and 90% of patients were receiving oxygen via nasal prongs at the time of randomization. The median time spent prone in the first 72 hours was 6 hours total (IQR 1.5,12.8) for the prone arm compared to 0 hours (0,2) in the control arm. The risk of the primary outcome was similar between the prone group (18 [14.3%] events) and the standard care group (17 [13.9%] events), odds ratio 0.92 (95% CI 0.44 to 1.92). The change in the S/F ratio after 72 hours was similar for patients randomized to prone compared to standard of care. Conclusion: Among hypoxic but not critically patients with COVID-19 in hospital, a multifaceted intervention to increase prone positioning did not improve outcomes. Adherence to prone positioning was poor, despite multiple efforts. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.

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