Dose optimization of β-lactam antibiotics in children: from population pharmacokinetics to individualized therapy

ABSTRACT

Introduction

β-lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most β-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today.

Areas covered

β-lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed.

Expert opinion/commentary

Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

KEYWORDS:

• Beta-lactam
• therapeutic drug monitoring
• toxicity
• Model-informed precision dosing
• PK/PD
• dosing optimization

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

GJ Wijnant was postdoctoral fellow from the BEWARE program of the Region Wallonne (program REBEL). F Van Bambeke is research Director from the Belgian Fonds de Recherche Scientifique (FRS-FNRS).

Article Highlights

• Antibiotic dosing in pediatrics is too often based on allometric scaling from the adult dose.

• Pharmacokinetics are often unpredictable in sick children.

• Therapeutic drug monitoring (TDM) of β-lactams is not performed in routine but may help to adjust the dose once the steady state has been reached.

• Defining the dose a priori based on model-informed precision dosing (MIPD) is a promising approach but we are lacking well conducted clinical trials to establish strong pharmacokinetic models.

Additional information

Funding

This paper was not funded.