Therapeutic drug monitoring of aminoglycosides in neonates

Abstract

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to extended-interval dosing. This evolution has also taken place in neonates. Neonates, however, display large interindividual differences in the pharmacokinetics of aminoglycosides due to developmental differences early in life. The volume of distribution of aminoglycosides shows a strong relationship with bodyweight, which tends to be larger (corrected for bodyweight) in more premature infants and those with sepsis. Renal clearance of aminoglycosides increases with gestational age and accelerates immediately after birth. Because of these developmental influences, there is great inter- and intraindividual variability in the volume of distribution and clearance of these drugs, and investigators have established aminoglycoside dosing regimens based on bodyweight and/or gestational age. Widely practised dosing regimens comprise 4-5 mg/kg bodyweight of gentamicin every 24-48 hours as a first dose, followed by dose adjustment based on therapeutic drug monitoring. Although formal toxicity studies are scarce, there is no evidence that aminoglycoside toxicity in neonates differs from that in adults. Monitoring of blood drug concentrations and intelligent reconstruction of individual pharmacokinetic behaviour using a population pharmacokinetic model, optimally chosen blood sampling times and appropriate pharmacokinetic software, help clinicians to quickly optimize aminoglycoside dosing regimens to maximize the clinical effect and minimize the toxicity of these drugs.