The high rate of age-related off-label prescribing for neonates calls for urgent action from medical professionals and others to reinforce effective and safe pharmacotherapy for this age group. The existing SPCs should be regularly updated and more closely harmonised to each other.

Background and Purpose-There are not very many epidemiological studies on perinatal stroke, and many authors suggest that this may be an underdiagnosed condition. The aim of the study was to estimate the incidence of perinatal arterial ischemic and hemorrhagic stroke in Estonia, to study the first clinical signs and to identify possible differences in predisposing factors and outcome between acutely and retrospectively diagnosed cases of perinatal stroke. Methods-A retro-and prospective study of acutely (within the first month) and retrospectively diagnosed ischemic and hemorrhagic cases of perinatal stroke was conducted in a children population born in the eastern and southern regions of Estonia during the years 1994 to 2003. Patients were identified from a pilot study, hospital records, and an inquiry of child neurologists and general practitioners. The diagnosis was confirmed in 38 (12 were diagnosed acutely and 26 retrospectively) cases by neuroradiology (MRI or CT). Results-The incidence rate of perinatal stroke in Estonia is 63 per 100 000 live births. Main clinical findings in the neonatal period were seizures, abnormalities of muscular tone, and disturbed level of alertness. Previously identified risk factors occurred in 32% of cases. Children with early diagnosis had more often adverse events during pregnancy and delivery (PϽ0.05) and developed more severe stage of hemiparesis compared with children with late diagnosis (PϽ0.05). Conclusions-The incidence rate of 63 per 100 000 live birth is higher than previously reported. Detailed analysis of the first signs of perinatal stroke may improve the early diagnostics of perinatal stroke.

BackgroundAntibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.MethodsA sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.ResultsIn 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics – gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin – covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5th minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.ConclusionsThe current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12887-015-0359-y) contains supplementary material, which is available to authorized users.

The value of CBF velocity changes to predict poor outcome in asphyxiated infants is low 2-6 h after asphyxia, but increases by the age of 12 ho.

Antibiotic licensing studies remain a problem in neonates. The classical adult clinical syndrome-based licensing studies do not apply to neonates, where sepsis is the most common infection. The main obstacle to conducting neonatal antibiotic trials is a lack of consensus on the definition of neonatal sepsis itself and the selection of appropriate endpoints. This article describes the difficulties of the clinical and laboratory definitions of neonatal sepsis and reviews the varying designs of previous neonatal sepsis trials. The optimal design of future trials of new antibiotics will need to be based on pharmacokinetic/pharmacodynamic parameters, combined with adequately powered clinical studies to determine safety and efficacy.

T he aminoglycoside antibiotic gentamicin is the most commonly used antimicrobial in neonatal units (1, 2) and is effective against Gram-negative bacteria. Gentamicin use is limited by its narrow therapeutic index and risk of toxicity, specifically, nephro-and ototoxicity (3). It is not metabolized in the liver (4) and is almost entirely eliminated by the kidneys; clearance therefore depends on renal function. During the first 2 weeks of life, renal and intrarenal blood flow increase rapidly, causing a steep rise in the glomerular filtration rate (GFR) (5, 6).Therapeutic drug monitoring (TDM) is required to ensure maximal efficacy and, in particular, minimal toxicity, particularly in the neonatal population, where the variability in pharmacokinetic (PK) parameters is large. Dose individualization approaches focus on toxicity (7, 8) and include single-level methods and nomograms (9, 10), area under the curve (AUC) methods (11), and Bayesian methods (12). The use of nomograms is limited as they cannot readily incorporate covariates affecting PK parameters. AUC methods use a simplified 1-compartment PK model and require at least two gentamicin measurements, which is not appropriate in neonates with limited blood volumes. These drawbacks make Bayesian approaches the most attractive for newborn infants.Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13-24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period. Although gentamicin is not a new drug, its dosing and monitoring are still current issues as identified in the United Kingdom National Patient Safety alert (http://www.nrls .npsa.nhs.uk/alerts/?entryid45ϭ66271) and in a recent publication by Valitalo et al. (27), who used simulations to define dosing guidelines.We aimed to investigate whether opportunistic sampling can predict trough gentamicin concentrations so that standard TDM can be performed using a blood sample taken for other purposes Citation Germovsek E, Kent A, Metsvaht T, Lutsar I, Klein N, Turner MA, Sharland M, Nielsen EI, Heath PT, Standing JF, the neoGent Collaboration. 2016. Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.

European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

BackgroundSepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.ObjectivesTo determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).MethodsData were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.ResultsA one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.ConclusionsSimulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.