Biology subjects

Lutsar, I.

Publications and source records attributed to Lutsar, I..

3 recordsLinked to original sources

bioRxiv2018

Drug prescription pattern in European neonatal units

BackgroundHospitalized neonates receive the highest number of drugs compared to all other age groups, but consumption rates vary between studies depending on patient characteristics and local practices. There are no large scale international studies on drug use in neonatal units. We aimed to describe drug use in European neonatal units and characterize its associations with geographic region and gestational age (GA).\n\nMethodsA one-day point prevalence study (PPS) was performed as part of the European Study of Neonatal Exposure to Excipients (ESNEE) from January to June 2012. All neonatal prescriptions and demographic data were registered in a web-based database. The impact of GA and region on prescription rate were analyzed with logistic regression.\n\nResultsIn total, 21 European countries with 89 neonatal units participated. Altogether 2173 prescriptions given to 726 neonates were registered. The 10 drugs with the highest prescription rate were multivitamins, vitamin D, caffeine, gentamicin, amino acids for parenteral nutrition, phytomenadione, ampicillin, benzylpenicillin, fat emulsion for parenteral nutrition and probiotics. The six most commonly prescribed ATC groups (alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous, respiratory and cardiovascular system) covered 98% of prescriptions. GA significantly affected the use of all commonly used drug groups. Geographic region influenced the use of alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous and respiratory system drugs.\n\nConclusionsWhile GA-dependent differences in neonatal drug use were expected, regional variations (except for systemic anti-infectives) indicate a need for cooperation in developing harmonized evidence-based guidelines and suggest priorities for collaborative work.

pharmacology and toxicology↗

bioRxiv2018

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial

BackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, were single centre or country, insufficiently powered, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad spectrum antibiotic is superior to standard of care regimen (SOC) in empiric treatment of LOS and thus aimed to compare the efficacy and safety of meropenem to SOC in infants aged <90 days with LOS.\n\nMethods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of [≤]44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or SOC (ampicillin+gentamicin or cefotaxime+gentamicin) for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and day 28 for meropenem-resistant Gram-negative organisms (CRGNO).\n\nThe primary analysis was performed in all randomised patients (full analysis set) and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors.\n\nFrom September 3rd 2012 to November 30th 2014, in total 136 patients in each arm were randomized; 140 (52%) were culture positive. Success at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p=0.087); 17/63 (27%) vs. 10/77 (13%) in patients with positive cultures (p=0.022). The main reason of failure was modification of allocated therapy. Adverse events occurred in 72% and serious adverse events in 17% of patients, the mortality rate was 6% with no differences between study arms. Cumulative acquisition of CRGNO by day 28 occurred in 4% in the meropenem and 12% in the SOC arm (p=0.052).\n\nConclusionsMeropenem was not superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality and did not outselect colonization with CRGNOs. Meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing ESBL and AmpC beta-lactamases are circulating.

clinical trials↗

bioRxiv2018

External evaluation of population pharmacokinetic models for vancomycin in neonates

IntroductionNumerous vancomycin population pharmacokinetic (PK) models of neonates have been published. We aimed to comparatively evaluate a set of these models by quantifying their model-based and Bayesian concentration prediction performances using an external retrospective dataset, and estimate their attainment rates in predefined therapeutic target ranges.\n\nMethodsImplementations of 12 published PK models were added in the Bayesian dose optimisation tool, DosOpt. Model based concentration predictions informed by variable number of individual concentrations were evaluated using multiple error metrics. A simulation study assessed the probabilities of target attainment (PTA) in trough concentration target ranges 10-15 mg/L and 10-20 mg/L.\n\nResultsNormalized prediction distribution error analysis revealed external validation dataset discordances (global P < 0.05) with all population PK models. Inclusion of a single concentration improved both precision and accuracy. The model by Marques-Minana et al. (2010) attained 68% of predictions within 30% of true concentrations. Absolute percentage errors of most models were within 20-30%. Mean PTA with Zhao et al. (2013) was 40.4% [coefficient-of-variation (CV) 0.5%] and 62.9% (CV 0.4%) within 10-15 mg/L and 10-20 mg/L, respectively.\n\nConclusionPredictive performances varied widely between models. Population based predictions were discordant with external validation dataset but Bayesian modelling with individual concentrations improved both precision and accuracy. Current vancomycin PK models achieve relatively low attainment of commonly recommended therapeutic target ranges.

pharmacology and toxicology↗