scholarly journals Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!

2022 ◽  
Vol 9 ◽  
Author(s):  
Pascal André ◽  
Léonore Diezi ◽  
Kim Dao ◽  
Pierre Alex Crisinel ◽  
Laura E. Rothuizen ◽  
...  
Keyword(s):  
Renal Function ◽  
Continuous Infusion ◽  
Renal Clearance ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Augmented Renal Clearance ◽  
Oncology Patients ◽  
Pediatric Hematology ◽  
Trough Plasma

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

Use of continuous infusion ceftolozane–tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis

2019 ◽  
Vol 76 (8) ◽  
pp. 501-504 ◽  
Author(s):  
Sarah Elizabeth Davis ◽  
Jared Ham ◽  
Jennifer Hucks ◽  
Alyssa Gould ◽  
Rachel Foster ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Drug Monitoring ◽  
Continuous Infusion ◽  
Renal Clearance ◽  
Drug Monitoring ◽  
Adverse Drug Events ◽  
Pulmonary Function Tests ◽  
Therapeutic Drug ◽  
Augmented Renal Clearance ◽  
Definitive Therapy

Abstract Purpose The safe and effective use of ceftolozane–tazobactam delivered via continuous infusion in a cystic fibrosis (CF) patient with reduced body weight and presumed augmented renal clearance is reported. Summary A 30-year-old woman with CF was admitted for acute pulmonary exacerbations with positive respiratory cultures for Pseudomonas aeruginosa and extended-spectrum β-lactamase-producing Escherichia coli. Susceptibility testing confirmed multidrug resistance, and the patient was transitioned to ceftolozane–tazobactam for definitive therapy. A novel strategy of administering ceftolozane–tazobactam 6 g by continuous i.v. infusion over 24 hours was initiated during hospitalization and continued at discharge for a total of 10 days. Therapeutic drug monitoring over the first 36 hours of the continuous infusion confirmed adequate exposure. The patient had clinical resolution with return to baseline of pulmonary function tests and no noted adverse drug events. Conclusion A continuous infusion regimen of ceftolozane–tazobactam was successfully used in a CF patient with augmented renal clearance.

scholarly journals Effect of augmented renal clearance on the therapeutic drug monitoring of vancomycin in patients after neurosurgery

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052094907
Author(s):  
Yue Chen ◽  
Lei Liu ◽  
Man Zhu
Keyword(s):  
Renal Function ◽  
Therapeutic Drug Monitoring ◽  
Renal Clearance ◽  
Normal Renal Function ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Augmented Renal Clearance ◽  
Achievement Rate ◽  
Baseline Characteristics

Objective To study the effect of augmented renal clearance (ARC) on vancomycin therapeutic drug monitoring in patients undergoing neurosurgery. Methods A retrospective observational analysis was conducted in a neurosurgery department from January 2019 to June 2019. Patients undergoing vancomycin therapeutic drug monitoring were assigned to the normal renal function or ARC group. The baseline characteristics, vancomycin therapeutic drug monitoring data, and prognosis were compared and analyzed. Results In total, 104 patients were enrolled, including 78 and 26 patients in the normal renal function and ARC groups, respectively. There were significant differences in age, weight, creatinine clearance, the vancomycin treatment duration, the total dose, the trough concentration, and the trough concentration achievement rate between the two groups. Prognosis did not differ between the two groups. The trough concentration achievement rate in the ARC group was only 19.23%. Conclusion For young, obese, or otherwise healthy patients undergoing neurosurgery, attention should be paid to the possibility of ARC and the need for individualized dose adjustment based on the results of therapeutic drug monitoring.

scholarly journals Augmented Renal Clearance: What Have We Known and What Will We Do?

2021 ◽  
Vol 12 ◽  
Author(s):  
Yifan Luo ◽  
Yidan Wang ◽  
Yue Ma ◽  
Puxiu Wang ◽  
Jian Zhong ◽  
...  
Keyword(s):  
Risk Factors ◽  
Renal Function ◽  
Animal Models ◽  
Treatment Failure ◽  
Renal Clearance ◽  
Clinical Treatment ◽  
Research Progress ◽  
Therapeutic Drug ◽  
Augmented Renal Clearance ◽  
Drug Concentrations

Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

scholarly journals Pharmacokinetics of 13-cis-Retinoic acid in high-risk neuroblastoma patients

2020 ◽  
Vol 19 (4) ◽  
pp. 20-31
Author(s):  
E. A. Litvin ◽  
D. T. Utalieva ◽  
D. Yu. Kachanov ◽  
A. V. Pshonkin ◽  
M. Ya. Yadgarov ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Medical Research ◽  
High Performance ◽  
Plasma Concentrations ◽  
Neuroblastoma Cells ◽  
Research Center ◽  
Therapeutic Drug ◽  
Pediatric Hematology ◽  
National Medical

13-cis-Retinoic acid is a differentiation agent for neuroblastoma cells and is a part of post-consolidation therapy for high-risk patients. The effectiveness of this therapeutic approach is currently under study. 26 patients with high-risk neuroblastoma treated at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology were included in the study of 13-cis-Retinoic acid pharmacokinetics by high-performance liquid chromatography assay with ultraviolet detector depending on the method of administration of drug (swallowed capsules or opened capsules before administration). This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The current study showed that the therapeutic concentration of > 2 μM when taking 13-cis-Retinoic acid at a dose of 160 mg/m2/day was achieved in two groups, regardless of the method of drug administration. However, plasma concentrations of 13-cis-Retinoic acid at 4 hours after administration on the 14th day of therapy were higher in the group of patients who swallowed the capsules (4.1 ± 1.8 μM), compared to those who could not do it (1.9 ± 1.5 μM) (p = 0.022). The introduction into the clinical practice of therapeutic drug monitoring of 13-cis-retinoic acid in high-risk neuroblastoma patients with an assessment of peak concentration and dose adjustment of the following courses may be an important point in the attempt to optimize postconsolidation therapy and improve prognosis.

scholarly journals Influence of CYP3A Metabolizer Status on the Pharmacokinetics and Pharmacodynamics of Amiodarone

2000 ◽  
Vol 43 (3) ◽  
pp. 95-101
Author(s):  
Stanislav Mičuda ◽  
Martin Hodač ◽  
Petr Pařízek ◽  
Miloslav Pleskot ◽  
Luděk Šišpera ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Inverse Correlation ◽  
Urinary Free Cortisol ◽  
Information Value ◽  
Therapeutic Drug ◽  
Amiodarone Therapy ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Electrophysiologic Study ◽  
Free Cortisol ◽  
Trough Plasma

The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. Methods: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6β-hydroxycortisol (6β-OHC and the ratio of 6β-hydroxycortisol to urinary free cortisol (6β-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 ± 11 days (2nd period) and after 182 ± 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 ± 11 days (during the second period). Results: Both the 6β-OHC excretion and 6β-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6β-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6β-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. Conclusion: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.

scholarly journals Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
François Danion ◽  
Vincent Jullien ◽  
Claire Rouzaud ◽  
Manal Abdel Fattah ◽  
Simona Lapusan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Drug Monitoring ◽  
Invasive Aspergillosis ◽  
Drug Monitoring ◽  
Standard Treatment ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Life Threatening ◽  
Trough Plasma

ABSTRACT Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.

scholarly journals β-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Alexandra Jacobs ◽  
Fabio Silvio Taccone ◽  
Jason A. Roberts ◽  
Frédérique Jacobs ◽  
Frederic Cotton ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Renal Clearance ◽  
Total Body Clearance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Augmented Renal Clearance ◽  
Drug Concentrations ◽  
Trough Concentrations ◽  
Total Body ◽  
Body Clearance

ABSTRACTAugmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of ≥120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due toPseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r= −0.21,P= 0.01), trough concentrations of piperacillin (r= −0.28,P= 0.0071), concentrations at 50% of the dosage interval (r= −0.41,P< 0.0001), and total body clearance of piperacillin (r= 0.39,P= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain β-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

scholarly journals P050 Analysis of posaconazole therapeutic drug monitoring in paediatric haematology and oncology patients

2019 ◽  
Vol 104 (7) ◽  
pp. e2.55-e2 ◽  
Author(s):  
Natalie Donald ◽  
Ruth Edwards ◽  
Alison Thomson
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Fungal Infection ◽  
Broad Spectrum ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Paediatric Cancer ◽  
Oncology Patients ◽  
Paediatric Haematology ◽  
Paediatric Patients ◽  
Trough Levels

Posaconazole is a broad spectrum triazole antifungal with activity against a range of invasive fungal pathogens including Candida and Aspergillus species.1 Due to its range of activity it has been shown, by randomised controlled trials, to be superior to fluconazole and itraconazole for prevention of fungal infection in neutropenic patients,2 as well as being cost saving.1 Fungal prophylaxis with posaconazole has become the drug of choice within a paediatric cancer unit due to its broad spectrum of activity however there are significant differences in bioavailability of the suspension and tablet preparations and there is limited data relating to its use in the paediatric population.ObjectiveTo determine if the paediatric cancer unit is undertaking effective dosing and appropriate therapeutic drug monitoring (TDM) of posaconazole in paediatric haematology and oncology patients.MethodsA retrospective analysis of clinical data from 38 paediatric patients treated with posaconazole was undertaken. Patients received either 18–24-mg/kg/day posaconazole suspension in divided doses (maximum 800-mg/day,3 or 6–8-mg/kg/day posaconazole tablets (maximum 300-mg/day). Compliance with this guidance, initial and subsequent levels, efficacy and tolerability were analysed.SettingThe study was undertaken within the XXXX cancer unit; data for patients treated with posaconazole between January 2016 and August 2017 was reviewed.Key findingsThere was good compliance with the dosing advice for liquid and tablet posaconazole with 82% of patients dosed correctly. Due to this, the initial trough level of ≥0.7 mg/L was achieved in 82% of patients within 14 days of treatment initiation; there were no significant differences between formulations. Trough levels were monitored on a monthly basis for 71% of patients but dose adjustments were necessary in 34% of patients. Posaconazole had a good tolerability profile during the study with most side effects resolving on continuation of treatment however one patient had to discontinue the drug due to widespread rash. No patients developed a fungal infection whilst on posaconazole.ConclusionSafe and effective dosing and monitoring of posaconazole suspension and tablet formulations has been undertaken at the XXXX. Trough levels attained the desired target concentration of ≥0.7 mg/L in the majority of patients but dose adjustments were required with both formulations emphasising the need for regular TDM. Posaconazole was well tolerated and clinically effective in preventing fungal infection indicating its appropriateness in this patient group. From this review, a guideline for initiation and appropriate TDM of posaconazole can be developed.ReferencesDranitsaris G, Khoury H. Posaconazole versus fluconazole or itraconazole for prevention of invasive fungal infections in patients undergoing intensive cytotoxic therapy for acute myeloid leukemia or myelodysplasia: a cost effectiveness analysis. Supportive Care in Cancer. 2011; 19(11): 1807–1813.Cornely O, Maertens J, Winston D, et al. Posaconazole vs. Fluconazole or Itraconazole in Patients with Neutropenia. New England Journal of Medicine. 2007; 356(4): 348–359.Bernardo V, Cross S, Crews K, et al. Posaconazole Therapeutic Drug Monitoring in Paediatric Patients and Young Adults with Cancer. The Annals of Pharmacotherapy. 2013; 47: 976–983.

scholarly journals Evaluation of standard dosing for selected broad spectrum Hydrophilic antibiotics in critically ill patients with Augmented renal clearance: An observational Study

2021 ◽  
Author(s):  
Majed Almutairi ◽  
Khalid Al Sulaiman ◽  
Sultan Alenazi ◽  
Ramesh Vishwakarma ◽  
Ohoud Aljuhani
Keyword(s):  
Renal Clearance ◽  
Clinical Outcomes ◽  
Critically Ill ◽  
Broad Spectrum ◽  
Critically Ill Patients ◽  
P Value ◽  
Augmented Renal Clearance ◽  
Medical City ◽  
Calculated Creatinine Clearance ◽  
Inappropriate Antibiotics

Abstract Background: Inappropriate antibiotics dosing in critically ill patients with augmented renal clearance (ARC) may be associated with pathogens resistance and worse outcomes. Unfortunately, studies regarding the relationship between ARC and clinical outcomes in patients treated with antibiotics medication are rare. The study evaluates the efficacy and clinical outcomes of selected broad-spectrum hydrophilic antibiotics in ARC critically ill patients with confirmed infections. Methods: A retrospective cohort study in adult critically ill patients who were admitted to intensive care units (ICUs) at King Abdulaziz Medical City (KAMC)-Riyadh and received standard dosing of selected broad-spectrum hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) with confirmed infection. All the patients who met our inclusion criteria during the study period (01/01/2018 – 31/12/2019) were included. Eligible patients have been divided into two groups (ARC Vs. non-ARC) according to the calculated creatinine clearance using the Cockcroft-Gault equation. The primary outcome was to assess pathogen eradication at 10-14 days; other outcomes were considered secondary. Multivariate logistic and generalized linear regression analyses were used. We considered a P value of < 0.05 statistically significant. Results: A total of 133 patients were included in the study; 67 Patients had ARC. The distribution of infections and types of pathogens between the groups were the same. The pathogen eradication at 10-14 days was similar between the two groups (OR 1.08; 95% CI, 0.41–2.78 p = 0.88). Moreover, the odds of resistance development and persistence after 3 days were not significantly different between the groups ((OR 0.78; 95% CI, 0.25–2.40 p = 0.66) and (OR 0.88; 95% CI, 0.35–2.18 p = 0.78) respectively). Conclusion: Using standard dosing of Meropenem, Imipenem, or Piperacillin/Tazobactam in ARC patients was not associated with therapy failure. Further randomized clinical and interventional studies are required to confirm our findings.

scholarly journals Evaluation of Standard Dosing for Selected Broad Spectrum Hydrophilic Antibiotics in Critically Ill Patients with Augmented Renal Clearance: An Observational Study

2021 ◽  
Author(s):  
Majed Almutairi ◽  
Khalid Al Sulaiman ◽  
Sultan Alenazi ◽  
Ramesh Vishwakarma ◽  
Ohoud Aljuhani
Keyword(s):  
Renal Clearance ◽  
Clinical Outcomes ◽  
Critically Ill ◽  
Broad Spectrum ◽  
Critically Ill Patients ◽  
Augmented Renal Clearance ◽  
Icu Length Of Stay ◽  
Medical City ◽  
Inappropriate Antibiotics ◽  
The Relationship

Abstract Background: Inappropriate antibiotics dosing in critically ill patients with augmented renal clearance (ARC) may be associated with pathogens resistance and worse outcomes. Unfortunately, studies regarding the relationship between ARC and clinical outcomes in patients treated with antibiotics medication are rare. The study aims to evaluate the efficacy and clinical outcomes of selected broad spectrum hydrophilic antibiotics (Meropenem, Imipinem, Piperacillin/Tazobactam) in augmented renal function critically ill patients with confirmed infections.Methods: A retrospective cohort study in critically ill patients who were admitted to intensive care units (ICUs) at King Abdulaziz Medical City (KAMC)-Riyadh and received broad-spectrum Hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) with confirmed infection. All the patients who met our inclusion criteria during the study period (01/01/2018 – 31/12/2019) were included. Eligible patients have been divided into two groups (augmented renal clearance (ARC) Vs. Non-ARC) according to the estimated creatinine clearance (CrCl) to assess pathogen eradication at 10-14 days. Results: A total of 2682 patients were screened; 133 patients were included in the study. The eradication of pathogen at 10-14 days in ARC group was non-inferior to non-ARC group (OR 1.08; 95% CI, 0.41–2.78 p = 0.88). The Resistance (OR 0.78; 95% CI, 0.25–2.40 p = 0.66), and Persistence after 3 days (OR 0.88; 95% CI, 0.35–2.18 p = 0.78) were not significantly different between the groups. In other words, patients with ARC have the same rate of resistance and persistence of pathogen after three days. There was no difference in the 30-day mortality between the two groups (OR 0.22; 95% CI, 0.04–1.40 p = 0.11). Also, there was no difference in the ICU length of stay (LOS) nor in hospital LOS between the two groups (22.0 days vs. 17.5 days, p = 0.37), and (51.0 days vs. 30.0 days, p = 0.07) respectively. Conclusion: Using standard dosing of hydrophilic broad-spectrum antibiotics in ARC patients was not inferior to non-ARC patients in terms of the pathogen eradication, resistance, and persistence. Further randomized clinical and interventional studies are required to confirm our findings.

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