Περίληψη:
Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter. Copyright © 2020 American Society for Microbiology. All Rights Reserved.
Συγγραφείς:
Kontou, A.
Sarafidis, K.
Begou, O.
Gika, H.G.
Tsiligiannis, A.
Ogungbenro, K.
Dokoumetzidis, A.
Agakidou, E.
Roilides, E.
Λέξεις-κλειδιά:
albumin; amikacin; amphotericin B; cefepime; ciprofloxacin; diuretic agent; fentanyl; inotropic agent; iron; meropenem; teicoplanin; vitamin D; antiinfective agent; teicoplanin, adult; Article; controlled study; creatinine clearance; female; gestational age; human; liquid chromatography-mass spectrometry; loading drug dose; major clinical study; male; necrotizing enterocolitis; newborn sepsis; pharmacokinetic parameters; plasma concentration-time curve; prematurity; priority journal; prospective study; Staphylococcus aureus; Staphylococcus epidermidis; steady state; treatment duration; volume of distribution; blood; drug effect; microbial sensitivity test; microbiology; Monte Carlo method; newborn; prematurity; sepsis; Staphylococcus; Staphylococcus infection, Anti-Bacterial Agents; Female; Gestational Age; Humans; Infant, Newborn; Male; Microbial Sensitivity Tests; Monte Carlo Method; Premature Birth; Sepsis; Staphylococcal Infections; Staphylococcus; Teicoplanin
