Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Abstract

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (/MIC ≥ 10) and safe trough concentrations ( ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study

“…Reduced target attainment of antibiotics is common in critically ill neonates and children. Other studies that used population, dose, dose interval, and pharmacodynamic targets relatively similar to those in our study found similar results for vancomycin [ 15 , 16 ] and gentamicin [ 17 ]. De Cock et al [ 15 ] showed an even lower target attainment of vancomycin in PICU patients of only 8% compared with our 33.9%.…”

Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age

“…They have a reduced number of nephrons at birth and are often exposed to nephrotoxic drugs (i.e., aminoglycosides), while nephrogenesis is still ongoing [136]. TDM is advised for treatment beyond three days [137]. Preterm infants are at higher risk of overdosing due to the immature renal function [90]: acute kidney injury is considered an independent predictor of mortality, especially when the birthweight is less than 1500 g, and different biomarkers and definitions have been identified for the early detection of renal damage in these neonates, however they need validation [138].…”

Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants

“…During this earliest stage mortality is directly related to the effects of the life-threatening infection and managing toxicity is less central. As the causative organism generally remains unknown, selection of the antibiotic regimen needs to take into account the overall epidemiology of sepsis in the age group of the patient ( 19 ).…”

“…Shifts in MIC can lead to a situation where dosing recommendations need to be revised to achieve optimal treatment. For gentamicin, for example, an increase in MIC from 0.5 to 1.0 mg/L means that, in order to achieve similar efficacy (similar ratio of Cmax/MIC ), the dose should be increased from 5 to 7.5 mg/kg in neonates ( 19 ).…”

“…In the first 2 years of life, maturational processes affect drug clearance and make antibiotic dosing more challenging, compared to older infants where dosing is mainly adjusted by body weight and renal function. Most of the current dosing guidelines for antibiotic treatment are simply extrapolated from adult studies and it has been reported that dosing recommendations across intensive care units and international guidelines are highly variable and inconsistent ( 19 ). We review and discuss key components and their underlying relationships relevant to antibiotic dose optimization in neonates and infants with suspected or confirmed sepsis (Figure 1 ).…”