A quantitative method for the analysis of total and unbound concentrations of amoxicillin, ampicillin, ceftazidime, ceftriaxone, ertapenem, fosfomycin and penicillin G in human plasma with liquid chromatography-tandem mass spectrometry assay.

Monitoring antibiotic plasma levels is critical in populations with altered pharmacokinetics, such as critically ill patients in neonatal or adult intensive care units. This study aimed to develop and validate a rapid, reproducible and sensitive liquid chromatography-tandem mass spectrometry assay (LC-MS/MS) for measuring total and unbound concentrations of amoxicillin, ampicillin, ceftazidime, ceftriaxone, ertapenem, fosfomycin and penicillin G in human plasma. The method required 20 and 250 μl sample volumes for measuring total and unbound concentrations, respectively.

Brain MRI Injury Patterns across Gestational Age among Preterm Infants with Perinatal Asphyxia.

Introduction: Brain injury patterns of preterm infants with perinatal asphyxia (PA) are underreported. We aimed to explore brain magnetic resonance imaging (MRI) findings and associated neurodevelopmental outcomes in these newborns.

Methods: Retrospective multicenter study included infants with gestational age (GA) 24.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

Aims: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment.

Methods: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study.

Association Between Seizures and Neurodevelopmental Outcome at Two and Five Years in Asphyxiated Newborns With Therapeutic Hypothermia.

Objective: To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years.

Methods: Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming.

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.

Background: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH.

Benzylpenicillin concentrations in umbilical cord blood and plasma of premature neonates following intrapartum doses for group B streptococcal prophylaxis.

Background And Method: Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline.

Results: Forty-six neonates were included.

Therapeutic drug monitoring of amikacin in preterm and term neonates with late-onset sepsis. Can saliva samples replace plasma samples?

Unlabelled: Amikacin is an aminoglycoside antibiotic that is frequently used for the treatment of neonatal late-onset sepsis, for which therapeutic drug monitoring (TDM) is advised. In order to decrease the TDM associated burden of plasma sampling, a noninvasive TDM method using saliva samples was investigated.

Methods: This was a prospective single-centre, observational feasibility study with 23 premature and term neonates from whom up to 8 saliva samples were collected, together with residual plasma from clinical routine.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study.

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study.

While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). VLBW and premature neonates with suspected LOS were included in a prospective observational study.

Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study.

Background: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates.

Methods: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (≥36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region.

Outcome Prediction and Inter-Rater Comparison of Four Brain Magnetic Resonance Imaging Scoring Systems of Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

Introduction: The brain magnetic resonance imaging (MRI) result is a major predictor for the outcome of term infants with perinatal asphyxia who underwent therapeutic hypothermia. In daily practice, no uniform method is used to assess these images.

Purpose: The aim of this study was to determine which MRI-score best predicts adverse outcome at 24 months of age and has the highest inter-rater reliability.

Saliva as a sampling matrix for therapeutic drug monitoring of gentamicin in neonates: A prospective population pharmacokinetic and simulation study.

Aims: Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated.

Methods: This was a multicentre, prospective, observational cohort study including 54 neonates.

Correction to: Neonatal bacterial meningitis versus ventriculitis: a cohort-based overview of clinical characteristics, microbiology and imaging.

This article originally published with all author names incorrectly listed. All author names have now been transposed and appear correctly above.

Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites.

Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy.

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.

Aims: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use.

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance.

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now.

Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria.

The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin.

The Thompson Encephalopathy Score and Short-Term Outcomes in Asphyxiated Newborns Treated With Therapeutic Hypothermia.

Background: The Thompson encephalopathy score is a clinical score to assess newborns suffering from perinatal asphyxia. Previous studies revealed a high sensitivity and specificity of the Thompson encephalopathy score for adverse outcomes (death or severe disability). Because the Thompson encephalopathy score was developed before the use of therapeutic hypothermia, its value was reassessed.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia.

Aim(s): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients

Methods: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin.

Predicting developmental outcomes in premature infants by term equivalent MRI: systematic review and meta-analysis.

Background: This study aims to determine the prognostic accuracy of term MRI in very preterm born (≤32 weeks) or low-birth-weight (≤1500 g) infants for long-term (>18 months) developmental outcomes.

Methods: We performed a systematic review searching Central, Medline, Embase, and PsycInfo. Two independent reviewers performed study selection, data extraction, and quality assessment.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

Objective: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage.

Design: A randomised double-blind placebo controlled multicentre trial.

Patients: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery.

Meta-analysis shows that infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications.

Unlabelled: Infants suffering from neonatal sepsis face an increased risk of early death and long-term neurodevelopmental delay. This paper analyses and summarises the existing data on short-term and long-term outcomes of neonatal sepsis, based on 12 studies published between January 2000 and 1 April 2012 and covering 3669 neonates with sepsis.

Conclusion: Infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications such as brain damage and, or, neurodevelopmental delay.