Antibiotic Dosing in Pediatric Critically Ill Patients

Cock, Pieter De; Allegaert, Karel; Linakis, Matthew W.; Sherwin, Catherine M.T.

doi:10.1007/978-981-10-5336-8_12

Cited by 4 publications

(10 citation statements)

References 94 publications

(130 reference statements)

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“…The arrows indicate the difference in clearance between both cohorts for the respective PNA. Adapted from De Cock et al, antibiotic dosing in pediatric critically ill patients, Chapter in Antibiotic pharmacokinetic/pharmacodynamic considerations in the critically ill, Springer Nature Signapore 2018:239-263, with permission from Springer Nature (De Cock et al, 2018). clinicaltrials.gov/; https://www.ema.europa.eu/en).…”

Section: Ongoing Drug Development Plans As Add-on Interventions To Whmentioning

confidence: 99%

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

et al. 2020

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Section: Ongoing Drug Development Plans As Add-on Interventions To Whmentioning

confidence: 99%

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

et al. 2020

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“…In the last decades, preclinical and clinical research have provided preliminary evidence of the causative mechanisms for reduced drugs' bioavailability. Pending specific PK studies, the loading dose (LD) is usually based on Vd, while the maintenance dose (MD) is driven by the estimated Cl (72). Moreover, PK changes are strictly dependent on equipment material and circuit design (73).…”

Section: The Role Of Non-maturational Determinants On Drug Dispositiomentioning

confidence: 99%

“…Furthermore, over the course of an ECMO run, the frequent administration of blood products and crystalloids contribute to worsen the hemodilution (94). Hydrophilic drugs are the most affected, as their Vd is limited to the extracellular compartment, with no intracellular drug reservoir available for retrograde diffusion (72). The extension of the plasma compartment during the ECMO start or in critical illness affects the LD, which is the first dose needed to guarantee the therapeutic concentration (72, 95).…”

Section: The Role Of Non-maturational Determinants On Drug Dispositiomentioning

confidence: 99%

“…Hydrophilic drugs are the most affected, as their Vd is limited to the extracellular compartment, with no intracellular drug reservoir available for retrograde diffusion (72). The extension of the plasma compartment during the ECMO start or in critical illness affects the LD, which is the first dose needed to guarantee the therapeutic concentration (72, 95). LD is directly proportional to the enlarged Vd and, hence, should be increased accordingly (95).…”

Section: The Role Of Non-maturational Determinants On Drug Dispositiomentioning

confidence: 99%

“…During ECMO, gentamicin has been found to have an increased Vd, as a result of the large exogenous blood volume for circuit priming and decreased Cl, leading to a prolonged elimination half-life (4, 126, 128). The renal dysfunction, which is a common multifactorial condition during ECMO, may be considered as the main determinant of the prolonged elimination half-life of gentamicin (72). Given the concentration-dependent antimicrobial activity of aminoglycosides, it is highly recommended to perform TDM to ensure adequate antimicrobial exposure.…”

Section: Disposition Of Antimicrobial and Antiviral Drugs During Neonmentioning

confidence: 99%

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Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge

et al. 2019

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Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.

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Pharmacokinetic Modeling Using Real‐World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement–Clinical Outcomes Relationship

Salem

Smith

Wilkes

et al. 2023

The Journal of Clinical Pharma

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Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) but evidence is lacking on the ideal dosing. We aimed to: (i) develop a population pharmacokinetic (PK) model for UFH, measured through anti‐factor Xa assay, (ii) optimize UFH starting infusions and dose titrations through simulations, and (iii) explore UFH exposure‐clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A one‐compartment PK model with time‐varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and, ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first‐order rate constant to reach steady‐state CL were 0.57 L/(h·10 kg) and 0.02 h−1. Comparable to non‐ECMO patients, the typical steady‐state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 & 20 IU/h/kg for patients < 6 & ≥ 6 years, respectively, achieved the therapeutic target in 56.6% of all patients while only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in > 90% of patients while < 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti‐factor Xa target rapidly and safely.This article is protected by copyright. All rights reserved

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Antibiotic Dosing in Pediatric Critically Ill Patients

Cited by 4 publications

References 94 publications

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge

Pharmacokinetic Modeling Using Real‐World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement–Clinical Outcomes Relationship

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