Optimising β -lactam Dosing in Neonates: A Review of Pharmacokinetics, Drug Exposure and Pathogens

Abstract

Background: β-lactams are among the most frequently prescribed antibiotics for the treatment of neonatal sepsis. Survival of extremely preterm neonates necessitates an improved understanding of how β-lactams should be used in this vulnerable population. Appropriate dosing regimens for neonates remain unclear. We reviewed available data on the pharmacokinetics (PK) of β -lactam drugs in neonates. Pharmacokinetic/ pharmacodynamic (PK/PD) efficacy index surrogates and minimum inhibitory concentrations (MICs) used to support dosing regimens recommendation in the studies were also investigated.

Methods: A comprehensive literature search was undertaken to identify studies that have investigated the PK/PD of β-lactam drugs in neonates.

Results: Data available for the PK/PD of β-lactams in neonates are limited but confirm the importance of weight, gestational age and postnatal age as markers of growth and renal maturation. The contribution of tubular secretion in addition to glomerular filtration is highlighted. The development of methods to assay β-lactam protein binding in vivo has added greater understanding. Modelling and simulation techniques have aided dosing optimisation. However, there remains a gap in the understanding of PD parameters and the appropriate PK/PD index to target for improved clinical outcome which partly explains the various dosing recommendations. Improved data on the efficacy of β -lactams are needed in a context of increasing global antimicrobial resistance and variable geographic MIC distribution.

Conclusion: Prospective in vivo studies are required to validate PK/PD indexes associated with clinical efficacy. Current antimicrobial stewardship efforts should integrate PK/PD principles and dosing optimization, taking into account susceptibility of isolated microorganisms.

Keywords: PK/PD index; Paediatrics; carbapenems.; cephalosporins; dosing optimization; penicillins; pharmacodynamics; pharmacokinetics.