Background To assess the achievement of adequate gentamicin exposure for dosing regimens used across Swiss neonatal intensive care units (NICUs) and interna-tional guidelines.
Methods Gentamicin dosing regimens were collected from 7 Swiss level III NICUs and 8 international guidelines (Frank Shann`s, BNF for children, Nelson Textbook of Pedi-atrics, Neonatal Formulary 7th edition, The Blue Book, Lex-icomp Paediatric and Neonatal Dosage Handbook, The Red Book and Neofax). Variables used for selection of individ-ualized dosing regimen (single dose, dosing interval, total daily dose and demographic characteristics) from each guideline were assessed. Model-based simulations were performed to compare the various dosing regimens with respect to their ability to achieve effective peak drug con-centrations according to predefined minimum inhibitory concentrations (MICs), peak concentrations (Cmax/MIC >10) and safe trough concentration (Cmin <2 mg/L). Model-based simulations were based on demographic data from the ARPEC database.
Results Gentamicin dosing regimens based on Swiss NICUs and international guidelines showed consider-able variability with respect to dose, dosing interval and demographic variables (weight, gestational age, post-menstrual age and postnatal age) to determine a priori individual dosing regimens. Doss and dosing intervals ranged from 4 mg/kg to 6 mg/kg and from 24 hours to 48 hours, respectively. Overall, this resulted in seven possible dosing regimens for gentamicin in neonates, which can vary between neonatal subgroups when neonates were categorised based on demographic variables. Based on demographic variables, six different alternatives could be distinguished for the determination of individualised dos-ing regimens of gentamicin; either based on one patient characteristic (GA: n=1; PNA: n=1), a combination of characteristics (WT and PNA: n=3; GA and PNA: n=5; PMA and PNA: n=2) or no characteristics at all (n=2). Model-based simulations suggested that for a MIC breakpoint of 0.5 mg/L (i.e. target Cmax >5 mg/L), a high proportion of neonates [range: 26%–36%] did not reach the target af-ter the first dose according to current dosing approaches. Assuming a target MIC breakpoint of 2 mg/L, an effective.
Cmax is not achieved with any evaluated dosing recom-mendation. On the safety side, potential toxic trough con-centrations (≥2 mg/L) were observed in less than 5% of neonates.
Conclusion Current neonatal dosing approaches for gentamicin are associated with subtherapeutic drug ex-posures in a considerable portion of neonates. These sub-therapeutic exposures are associated with increasing MIC breakpoint. Therefore, there is a clear need for harmoniza-tion and simplification of dosing regimen for gentamicin in the neonatal patient population, based on quantitative rationale to achieve the effective and safe exposure.
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