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Background: Aminoglycosides are the most prescribed antibiotics in neonatal intensive care units (NICU). Reducing exposure to antibiotics in the NICU is highly desirable, particularly through benchmarking methods. Methods: Description of aminoglycosides prescriptions in 23 French NICU using the same computerized system over a 4-year period (2017–2020). A benchmarking program of antibiotics prescription was associated. Results: The population included 53,818 patients. Exposition rates to gentamicin and amikacin were 31.7% (n = 17,049) and 9.1% (n = 4894), respectively. Among neonates exposed to gentamicin, 90.4% of gentamicin and 77.6% of amikacin treatments were started within the 1st week of life. Among neonates exposed to amikacin, 77.6% started amikacin within the 1st week. The average daily dose of gentamicin at first prescription increased over the study period from 3.9 in 2017 to 4.4 mg/kg/d in 2020 (p &lt, 0.0001). Conversely, the corresponding amikacin daily doses decreased from 13.0 in 2017 to 12.3 mg/kg/d in 2020 (p = 0.001). The time interval between the first 2 doses of gentamicin was mainly distributed in 3 values during the first week of life: 49.4% at 24 h, 26.4% at 36 h, and 22.9% at 48 h. At first amikacin prescription, the time interval was distributed in 4 categories: 48% at 24 h, 4.1% at 30 h, 8.5% at 36 h, and 37.1% at 48 h. As compared to literature guidelines, the rates of overdose and underdose in gentamicin (1.5% and 2.7%) and amikacin (0.3% and 1.0%). They significantly decreased for gentamicin over the study period. In multivariate analysis, the factors significantly associated with GENT overdose were the year of admission, prematurity, length of stay, and duration of the treatment. Conclusion: This prescription strategy ensured a low rate of overdose and underdose, and some benefits of the benchmarking program is suggested.

The pediatric population suffers from a lack of age-appropriate medicines leading to unsafe situations when off-labelled or unlicensed drugs are used. Assessing the best option to administrate medicines when manipulations are required is essential in order to improve child care. This study aimed to compare the accuracy of the administered dose provided by three dosage forms and their techniques of administration. Different techniques of administration were assessed, covering three oral dosage forms (commercially available tablets, capsules, oral suspensions) using two APIs not available in a children-adapted dosage form. Techniques of administration were simulated and administered doses were determined using HPLC-UV. Means were compared to the target dose while distributions of doses were compared between each technique. For both APIs, mean administered doses obtained with capsules and tablets were significantly different from the target dose, whereas there was no statistical difference with oral suspensions. Distributions of doses showed significant difference between the three dosage forms. This study demonstrates that manipulations of solid oral dosage forms provide dramatic underdosing leading to unsafe situations. Compounded oral suspension is the best option to avoid underdosing and dose variation. This solution should be prioritized when age-appropriate commercial medicines are not available.

International audience; In the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, hydroxychloroquine has been proposed as a potential agent to treat patients with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 infection. Older adults are more susceptible to COVID-19 and some patients may require admission to the intensive care unit, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, a liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and SyrSpend(Ⓡ) SF PH4 (dry) suspending vehicle. Moreover, a fully validated stability-indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3 °C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Resume Objectifs L’objectif de cette etude a ete de quantifier l’apport en parabenes du a l’administration des medicaments chez les nouveau-nes durant l’hospitalisation qui fait suite a leur naissance. Methodes Une etude monocentrique prospective a ete realisee dans un service de neonatalogie afin de recueillir l’ensemble des prescriptions. Une liste exhaustive des medicaments contenant des parabenes commercialises en France a ete repertoriee a partir de la base de donnees Theriaque. Cette liste a ete croisee avec les prescriptions recueillies afin d’etablir un profil d’exposition aux parabenes. Pour chaque medicament prescrit contenant des parabenes, un dosage par HPLC-UV a ete realisee afin de determiner la dose journaliere de parabenes moyenne recue par les nouveau-nes hospitalises. Resultats Plus de 300 specialites commercialisees en France contiennent au moins un parabene. Dans la majorite des cas, les medicaments contiennent une association de methylparabene et de propylparabene. Tous les nouveau-nes hospitalises (n = 22) ont ete exposes au moins une fois au methylparabene et au propylparabene via les medicaments tandis que 50 % ont ete exposes au propylparabene. La dose journaliere moyenne recue etait plus importante chez les nouveau-nes a terme (572,0 ± 249,0 versus 414,6 ± 294,1 μg/kg/j pour le methylparabene) mais la frequence d’exposition etaient plus importantes chez les nouveau-nes prematures (65,0 versus 78,6 % pour le methylparabene) ainsi que les doses cumulees (1421,5 ± 758,8 versus 8618,7 ± 7922,3). Ces doses sont inferieures aux valeurs toxicologiques de reference mais ces dernieres ne prennent pas en compte l’effet perturbateur endocrinien de ces composes. Conclusions Ces resultats demontrent que les medicaments sont une source importante d’exposition aux parabenes chez les nouveau-nes hospitalises apres leur naissance. Ces resultats doivent inciter les industriels et les professionnels de sante a privilegier des prises en charge therapeutiques sans parabenes.

Highlights • Hydroxychloroquine has been proposed as a potential agent to treat COVID-19 patients • Oral drug administration of solid forms may be comprised in many patients • Liquid formulation of hydroxychloroquine is not commercially available • Compounded hydroxychloroquine oral suspension is stable over 60 days, In the context of the SARS-CoV-2 pandemic, hydroxychloroquine has been proposed as a potential agent to treat COVID-19 patients. Older adults are more susceptible to COVID-19 and some patients may require admission in intensive care units, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and Syrspend SF dry pH4® suspending vehicle. Moreover, a fully validated stability indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3°C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Bisphenol A (BPA) is a well-known ubiquitous chemical found in polycarbonate, polysulfone and epoxy resins, used in mass production for many consumer products. BPA exhibits endocrine disruptor properties that can potentially induce adverse health effects. In aquatic environments, it can react with chlorine to produce chlorinated derivatives (ClxBPAs). ClxBPAs exhibit oestrogenic activity 10 to 105 times higher than BPA itself. Assessing human exposure to endocrine disrupting chemicals is mandatory to assess health risk. Blood, as well as urine matrix, are commonly used to perform human biomonitoring. We therefore developed, fully validated and applied a method based on Ultra High Performance Liquid Chromatography couples to a Triple Quad Mass Spectrometer to determine BPA, monochlorobisphenol A (MCBPA), dichlorobisphenol A (DCBPA), trichlorobisphenol A (TCBPA) and tetrachlorobisphenol A (TTCBPA) in human blood plasma. The European Medicines Agency guidelines for bioanalytical method validation have been applied. Precision and trueness of the method were15% at medium and high levels of quality control and20% at the limits of quantification (LOQs). The LOQs were settled at 0.1 ng/mL for BPA, 0.02 ng/mL for TTCBPA and 0.005 ng/mL for MCBPA, DCBPA, and TCBPA. The analytical method was applied to ten patients suffering from end stage renal disease. BPA was quantified in all ten patients while MCBPA, DCBPA and TTCBPA were determined in three and TCBPA in four. In conclusion, we have successfully developed a highly sensitive method to determine BPA and ClxBPAs in human plasma. Thanks to this method, for the first time, we could demonstrate ClxBPAs occurrence in human blood.

BackgroundDexamethasone is commonly used to treat a wide variety of diseases including oncological disorders. The aim of this study was to propose a liquid formulation of dexamethasone. Therefore we have developed and assessed the stability of a 5 mg/mL dexamethasone oral suspension.MethodsA stability-indicating analytical method, using HPLC-UV, was developed and fully validated according to well-recognized international guidelines. The dexamethasone suspension was prepared using dexamethasone acetate powder and Ora-SweetResultsThe mean dexamethasone concentration of the compounded oral suspensions was equal to 5.07±0.17 mg/mL. No colour modifications, precipitate or suspending troubles was observed throughout the storage period and the pH of the oral suspensions was decreased slightly, from 4.41±0.01 to 4.20±0.02. According to the dexamethasone content determined by HPLC-UV, whatever storage condition was used, no significant degradation of dexamethasone occurred over the 60 days of the study period.ConclusionDexamethasone oral suspension prepared according to our conditions is stable over 60 days under regular storage temperatures (at 4±2 °C or at 21±3 °C).

Introduction Les patients porteurs d’infections osteoarticulaires (IOA) relevent d’un parcours de soins souvent complexe. Interactions medicamenteuses, rupture de traitement, mauvaise observance, absence de suivi sont autant de risques pouvant conduire a l’echec de la prise en charge. Dans ce contexte, nous avons instaure des entretiens pharmaceutiques de sortie pour les patients d’orthopedie avec une antibiotherapie de longue duree. Notre demarche implique une conciliation medicamenteuse des traitements pendant l’hospitalisation, une analyse/optimisation a l’instauration des antibiotiques, un entretien pharmaceutique a la sortie puis a 6 semaines (S6) par Telesoin pharmaceutique. L’objectif de l’etude est d’evaluer l’impact des entretiens pharmaceutiques sur la prise en charge de ces patients. Materiels et methodes Pendant 8 mois, nous avons recueilli le nombre de patients inclus, les divergences non intentionnelles (DNI) au cours de l’hospitalisation, l’observance par le score Morisky-Green a la sortie et a S6, les interventions pharmaceutiques, les difficultes rencontrees par ces patients avec leurs traitements ainsi que leur satisfaction. Pour l’entretien, les outils utilises sont des fiches d’informations antibiotiques, un carnet de surveillance biologique et des plans de prises. Resultats Soixante quatre patients ont beneficie d’un bilan medicamenteux car ils presentaient lors de l’hospitalisation une IOA. Quatorze pour cent des prescriptions de ces patients contenaient des DNI qui ont pu etre modifiees. Quarante quatre entretiens pharmaceutiques ont eu lieu pour des patients sortants sous antibiotherapie pour des durees de 6 a 12 semaines. L’observance mesuree lors des entretiens est en moyenne de 6 [4:8]. En preparant les entretiens, 16 interventions pharmaceutiques ont ete signalees puis corrigees (90 %) avant la sortie des patients. Au terme de l’entretien, les informations importantes sont transmises de facon securisee aux medecins et pharmacies de ville. Vingt six entretiens ont ete realises a S6. L’observance est en moyenne de 8 : augmentation de 20 % par rapport a la sortie. Nous abordons les difficultes des patients telles que : la diarrhee, la perte de poids, la consommation d’alcool, la toxidermie, les demangeaisons, les mycoses. Le suivi biologique regulier renseigne sur le carnet de surveillance a ete correctement realise dans 92 % des cas. Ces elements sont retranscrits dans des comptes-rendus puis partages avec l’infectiologue et l’orthopediste en amont des consultations de suivi. Conclusion Cette nouvelle activite necessite une coordination des equipes qui doivent s’adapter pour accompagner le patient dans sa prise en charge et son retour a domicile. Il devient acteur en etant informe et implique, ce qui renforce l’adhesion aux traitements, securise sa prise en charge et favorise le succes de l’antibiotherapie. Cependant, pour approfondir l’impact de ces entretiens il faudrait comparer la reponse clinique et l’observance des patients ayant eu des entretiens pharmaceutiques avec un bras controle.

ObjectivesThe primary objective of this study is to determine the current level of patient medication exposure in Level 3 Neonatal Wards (L3NW). The secondary objective is to evaluate in the first month of life the rate of medication prescription not cited in the Summary of Product Characteristics (SmPC). A database containing all the medication prescriptions is collected as part of a prescription benchmarking program in the L3NW.Material and methodsThe research is a two-year observational cohort study (2017-2018) with retrospective analysis of medications prescribed in 29 French L3NW. Seventeen L3NW are present since the beginning of the study and 12 have been progressively included. All neonatal units used the same computerized system of prescription, and all prescription data were completely de-identified within each hospital before being stored in a common data warehouse.ResultsThe study population includes 27,382 newborns. Two hundred and sixty-one different medications (International Nonproprietary Names, INN) were prescribed. Twelve INN (including paracetamol) were prescribed for at least 10% of patients, 55 for less than 10% but at least 1% and 194 to less than 1%. The lowest gestational ages (GA) were exposed to the greatest number of medications (18.0 below 28 weeks of gestation (WG) to 4.1 above 36 WG) (pConclusionNeonates remain therapeutic orphans. The consequences of polypharmacy in L3NW should be quickly assessed, especially in the most immature infants.

Dexamethasone, hydrochlorothiazide, spironolactone, and phenytoin are commonly used in neonates, but no age-appropriate formulation containing these active pharmaceutical ingredients (APIs) is commercially available. Thus, pharmaceutical compounding of the liquid oral dosage form is required to enable newborn administration. A problem common to the compounded preparations described in the literature is that they include potentially harmful excipients (PHEs). Therefore, the aim of this study was to evaluate the feasibility of compounding oral liquid dosage forms free of PHE, containing dexamethasone, hydrochlorothiazide, phenytoin, or spironolactone and to assess their physicochemical stability. Due to the poor water solubility of the targeted APIs, oral suspensions were compounded using Syrspend&reg, SF-PH4 Dry, a suspending vehicle free of PHE. Four HPLC coupled to UV spectrometry (HPLC-UV) stability-indicating methods were developed and validated according to international guidelines to assay the strength of the targeted APIs. Whatever storage condition was used (5 &plusmn, 3 &deg, C or 22 &plusmn, 4 &deg, C), no significant degradation of API occurred in compounded oral suspensions. Overall, the results attest to the physical and chemical stability of the four oral liquid dosage forms over 60 days under regular storage temperatures. Finally, the use of the proposed oral suspensions provides a reliable solution to reduce the exposure of children to potentially harmful excipients.

Objectif Les parabenes sont des conservateurs utilises dans les medicaments et l’alimentation, mais ils sont principalement retrouves dans les cosmetiques et produits de soins corporels. Les femmes, y compris les femmes enceintes, peuvent donc y etre particulierement exposees. De par leur capacite a se lier aux recepteurs œstrogeniques, les parabenes sont suspectes d’etre des perturbateurs endocriniens (PE), et la grossesse constitue alors une periode de vulnerabilite face a ces molecules. L’objectif de ce travail est de presenter les mesures d’exposition aux 4 principaux parabenes a partir des concentrations urinaires mesurees au sein d’une cohorte perinatale de 164 femmes. Description Dans le cadre de la cohorte prospective de femmes enceintes Endocrine Disruptors Deux-Sevres (EDDS), dont le recrutement a ete mene de 2011 a 2014 dans les Deux-Sevres, des prelevements d’urines ont ete effectues au deuxieme et troisieme trimestre de la grossesse en vue de rechercher et de quantifier des PE, dont le methyl-, l’ethyl, le propyl- et le butyl-parabene. Methodes Les urines recueillies ont ete stockees a −20 °C jusqu’a leur analyse. La methode utilisee a ete validee selon les guides de validation de bioanalyse (EMA). Elle consiste en une extraction liquide/liquide simple, suivie d’une analyse par UHPLC-MS/MS en mode MRM (Xevo TQ-S). La limite de detection a ete definie comme correspondant a trois fois l’ecart-type de l’aire obtenue lors de l’analyse de cinq blancs. La limite de quantification (LOQ) etait de 0,025 ng/mL pour les 4 parabenes. Resultats Les urines de 152 femmes pour lesquelles les deux prelevements ont pu etre recueillis ont ete analysees. La valeur 0 a ete attribuee en cas de non detection et LOQ/√2 en cas de non quantification. Les concentrations moyennes retrouvees sont presentees dans le Tableau 1 . Les taux de detection et de quantification des 4 parabenes sont presentes dans le Tableau 2 . Conclusion Les 4 parabenes ont ete retrouves dans la majorite des urines du deuxieme et du troisieme trimestre de la grossesse. Les concentrations moyennes en methyl-parabene sont largement superieures a celles des 3 autres cumulees (de 12 a 33 fois plus). Le methyl-parabene est le plus frequemment retrouve, ce qui est en accord avec son utilisation tres repandue dans les produits de soins corporels. Ces observations confirment l’importance d’informer les femmes enceintes ou desireuses d’avoir des enfants sur ces perturbateurs endocriniens, leurs sources d’exposition et les moyens de les eviter.