Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

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.

Urine metabolomic profile in neonates with hypoxic-ischemic encephalopa-thy.

BACKGROUND: Metabolomics could provide valuable insights into hypoxemic-ischemic encephalopathy (HIE) revealing new disease-associated biochemical derangements. The study aimed to investigate urine metabolic changes in neonates with HIE compared to healthy controls, using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). PATIENTS AND METHODS: In this prospective, single-center study we enrolled neonates born at ≥ 36 weeks gestation with HIE (HIE group) and healthy controls (control group). We collected urine samples for metabolomic analysis on days one, three, and nine of life. RESULTS: Twenty-one full-term newborns were studied, 13 in the HIE group and eight in the control group. Six of the affected neonates had moderate/severe HIE and seven mild HIE. Therapeutic hypothermia was applied only in four neonates with moderate/severe HIE. Multivariate and univariate statistical analysis showed a clear separation between the HIE and the control groups. Discriminant metabolites involved pyruvic acid, amino acids, acylcarnitines, inositol, kynurenine, hippuric acid, and vitamins. CONCLUSIONS: We have identified a specific metabolic profile in neonates with HIE, adding to the existing knowledge on the disease biochemistry that may potentially help in biomarker development. HIPPOKRATIA 2017, 21(2): 80-84.

Comparable effect of conventional ventilation versus early high-frequency oscillation on serum CC16 and IL-6 levels in preterm neonates.

OBJECTIVE: Clara cell 16 kD protein (CC16) and interleukin (IL)-6 have been used as peripheral blood biomarkers of alveolar leakage and inflammation, respectively. Thus, their measurement in the bloodstream could be used to assess ventilator-induced lung injury. The objective of this study was to evaluate the effect of optimized synchronized intermittent mandatory ventilation (SIMV) and high-frequency oscillatory ventilation (HFOV) on circulating CC16 and IL-6 levels when used as the initial ventilation modes in preterm neonates. STUDY DESIGN: Single center, prospective, randomized clinical study in preterm neonates (gestational age 30 weeks) requiring mechanical ventilation within the first 2 h of life. Serum CC16 and IL-6 were measured on establishment of the assigned ventilation mode after admission, at days 3 and 14 of life as well as at 36 weeks postmenstrual age. Demographic-perinatal data and clinical parameters were also recorded. RESULT: Of the 30 neonates studied, 24 (gestational age 27.1±1.7 weeks, birth weight 942±214 g) were finally analyzed, equally assigned into the SIMV and HFOV groups. Both groups had comparable demographic-perinatal characteristics and clinical parameters. Serum CC16 and IL-6 altered significantly over time (repeated-measures analysis of variance, both P<0.001). However, changes were not affected by the ventilation mode. Post hoc analysis showed a significant decrease in CC16 and IL-6 from birth up to 36 weeks postmenstrual age in both groups. CONCLUSION: In preterm neonates, SIMV and HFOV are associated with comparable circulating CC16 and IL-6 levels. These findings suggest a similar alveolar leakage and systemic inflammation with any of the ventilation modes evaluated when their usage is optimized.