Dosing Guidelines of Aminoglycosides in Neonates: A Balance Between Physiology and Feasibility

Once daily dosing of aminoglycosides has been introduced and validated in non-neonatal patient cohorts. This is because aminoglycosides display peak concentration dependent bacterial killing, have a postantibiotic effect and adaptive resistance. In addition, this strategy reduces toxicity. Although aminoglycosides are also frequently administered to neonates, there is still debate about how to integrate and extrapolate these extended interval dosing regimens into dosing schedules tailored for neonates. There is a growing body of knowledge on aminoglycoside disposition and its covariates (e.g. asphyxia, ibuprofen or indomethacin exposure, serum creatinine, sepsis, dose accuracy) in neonates. In essence, integration of developmental physiology with clinical pharmacology unveils a discrepancy between aspects related to either body composition (higher distribution volume necessitates higher dose, to attain peak concentration) or to elimination clearance (lower renal clearance necessitates prolonged time interval between administrations). Such discrepancy can be solved by introducing more complex dosing guidelines (based on weight, postnatal age, serum creatinine, ibuprofen, asphyxia) in neonates. However, the introduction of more complex dosing guidelines should be balanced with its clinical feasibility. At least, there are reports that these more complex dosing guidelines result in a higher incidence of dosing errors. Besides errors in prescription, these errors also relate to the number of dilutions or manipulations needed before the prescribed dose can be administered. Since an integrated approach is needed, we discuss in this overview both the available pharmacokinetic data in support of the use of extended dosing regimens in neonates as well as the strategies suggested to reduce dosing errors.