Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3 / Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

Objetivo analizar y describir las concentraciones de eculizumab y el bloqueo del complemento en los pacientes con síndrome hemolítico urémico atípico (SHUa) y glomerulopatía C3, y definir un margen terapéutico donde se alcance una alta probabilidad de conseguir eficacia terapéutica. Métodos estudio observacional, ambispectivo y multicéntrico que incluyó pacientes adultos y pediátricos diagnosticados de SHUa y glomerulopatía C3 desde septiembre de 2020 hasta octubre de 2022 en 5 hospitales de España. Eculizumab se administró a las dosis recomendadas por la ficha técnica. Se determinaron las concentraciones pre y posdosis de eculizumab, así como del bloqueo de la vía clásica del complemento (CH50). Se recogieron variables sociodemográficas, analíticas y clínicas, y se calcularon los parámetros farmacocinéticos. Para establecer el punto de corte de las concentraciones de eculizumab que predecían el bloqueo del complemento se realizó un análisis de curvas ROC (Receiver Operating Characteristic). Se utilizó el test de Kruskal-Wallis para contrastar las diferencias en distintos parámetros según las concentraciones de eculizumab. Resultados se incluyeron 25 pacientes, 19 adultos (76,0%) y 6 pediátricos (24,0%), con edades medianas de 43,4 (RIC 35,7-48,8) y 10,1 (RIC 9,6-11,3) años, respectivamente. De ellos, 22 (88,0%) pacientes fueron diagnosticados con SHUa y 3 (12,0%) con glomerulopatía C3. Se determinaron un total de 111 concentraciones de eculizumab. Las concentraciones predosis y posdosis medias detectadas durante la fase de mantenimiento fueron 243,8 (SD 240,6) μg/ml y 747,4 (SD 444,3) μg/ml, respectivamente (AU)

Objective The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. Methods Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. Results Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined (AU)

Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy. / Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (SD 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

[Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (standard deviation (SD) 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Use of Monoclonal Antibodies in a Pediatric Patient With Severe Combined Immunodeficiency and Persistent SARS-CoV-2 Infection.

We describe the use of monoclonal antibodies for the treatment of persistent SARS-CoV-2 infection in a pediatric patient with severe combined immunodeficiency who required urgent stem cell transplantation to cure his disease.

Antimicrobial Defined Daily Dose in Neonatal Population: Validation in the Clinical Practice.

BACKGROUND: Currently, there is no validated method for estimating antimicrobial consumption in the neonatal population, as it exists for adults using Defined Daily Doses (DDD). In neonatology, although there are different methods, each one with advantages and disadvantages, there is no unified criterion for use. The aim of this study is to validate the neonatal DDD designed as a new standardised form of antimicrobial consumption over this population. METHODS: The validation of the neonatal DDD, Phase II of the research project, was carried out through a descriptive observational study. Periodic cut-offs were performed to collect antimicrobial prescriptions of neonates admitted to the neonatology and intensive care units of nine Spanish hospitals. The data collected included demographic variables (gestational age, postnatal age, weight and sex), antimicrobial dose, frequency and route of administration. The selection of the optimal DDD value takes into account power value, magnitude obtained from the differences in the DDD, statistical significance obtained by the Wilcoxon test and degree of agreement in the stipulated doses. RESULTS: Set of 904 prescriptions were collected and finally 860 were analysed based on the established criteria. The antimicrobials were mostly prescribed in the intensive care unit (63.1%). 32 different antimicrobials were collected, and intravenous administration was the most commonly used route. Neonatal DDD were defined for 11 different antimicrobials. A potency > 80% was obtained in 7 antibiotics. The 57.1% of the selected DDD correspond to phase I and 21.4% from phase II. CONCLUSION: DDD validation has been achieved for the majority of intravenously administered antimicrobials used in clinical practice in the neonatal population. This will make it possible to have an indicator that will be used globally to estimate the consumption of antimicrobials in this population, thus confirming its usefulness and applicability.

Standardisation of intravenous infusion therapy for paediatrics: big challenges for the little patients.

BACKGROUND: Worldwide organisations advocate standardising the management of intravenous drugs as an essential strategy to increase safety in paediatric healthcare settings. Intravenous administration is a route associated with some potential complications. Many adverse events are related to the use of intravenous medications, and the great variability in their handling and preparation represents an added risk that jeopardises the safety of children. PURPOSE: To standardise the dilutions of intravenous drugs most commonly administered to Spanish hospitalised paediatric and neonatal patients. METHODS: The process leading to the standardisation of concentrations was undertaken following a two-round modified Delphi procedure. The consensus included the most common drugs administered by continuous or intermittent intravenous infusion to hospitalised and/or critically ill paediatric patients. RESULTS: For paediatric patients, the proposal included a total of 102 drugs (45 continuous infusion and 59 intermittent infusion), with 192 concentrations to be standardised. The final consensus included 101 drugs (99%), of which 44 were continuous infusion and 59 intermittent infusion; 160 concentrations were standardised (72.7%). For neonates, the initial proposal included 80 drugs (38 continuous infusion and 43 intermittent infusion), with 189 concentrations to be standardised. The final consensus included 80 drugs (100%), of which 38 were continuous infusion and 43 were intermittent infusion; 120 concentrations were standardised (49.2%). CONCLUSIONS: This proposal showed that standardisation is a feasible approach that can be reached by other healthcare institutions. It can be used in other centres and contribute in the future to unifying paediatric clinical practice.

Adecuacy of pediatric antimicrobial prescribing in the Emergency Department at discharge.

INTRODUCTION: In January 2019, the Community of Madrid's Health Department published a guide about the use of antimicrobials in outpatient children. Taking this regional Guide as reference, this study was aimed at estimating the adequacy of the antimicrobial stewardship at discharge from a pediatric Emergency Department (ED). Secondarily, the differences in adequacy according to the diagnosis and the prescriber were studied, and the agreement between this Guide and the protocols of the ED was assessed. MATERIAL AND METHODS: An observational, descriptive, retrospective study was conducted on patients under 16 years old, with a diagnosis included in the regional Guide who were discharged from a pediatric ED between March of 2018 and February of 2019. Prescription was considered adequate when the indication, the antibiotic and the posology (dosage, dosing interval, length of treatment and route of administration) were correct. RESULTS: 165 out of 648 (25,5%) infectious diseases processes analyzed received antimicrobial treatment. In 23 processes treated with antimicrobial, the adequacy could not be evaluated due to the absence of data necessary to assess any aspect of posology. Therapy was considered appropriate in 550/625 processes (88.0%). When antimicrobial treatment was prescribed, 70/142 (49.3%) were appropriate and no statistically significant differences in adequacy were found between prescribers. Posology was the worst handled point of the prescription (26.3%). Tract urinary infection, conjunctivitis and otitis media were the pathologies with the lowest adecuacy (44.4%; 50.0% and 52.2%) and presented the highest discrepancy between the Guide and the center protocols (κ = 0.308; κ = 0.000; κ = 0.586). CONCLUSIONS: The adequacy of the management of infectious processes to the reference Guide in our pediatric ED was high, but it was below 50% when antimicrobial treatment was required. The degree of adequacy to the local protocols of the center was greater than to the regional Guide. This reveals a discrepancy between the 2 documents that should be analyzed and corrected according to the available scientific evidence.

Multicenter randomized clinical trial comparing dexamethasone versus placebo in preventing upper airway obstruction after extubation in critically ill children.

To analyze the effectiveness of dexamethasone in preventing upper airway obstruction (UAO) symptoms after extubation and the need of reintubation in critically ill children. Multicenter, prospective, double-blind, randomized, phase IV clinical trial involving five pediatric intensive care units. Children between 1 month and 16 years-of-age intubated for more than 48 h were included. Patients were randomized to receive placebo or dexamethasone 0.25 mg/kg every 6 h, 6-to-12 h prior to extubation (four doses). 48 h follow-up was carried out after extubation. Severity of UAO symptoms (Taussig score, stridor) and reintubation requirement were compared. 147 patients were randomized (10 were excluded), 70 patients received dexamethasone and 67 placebo. No global differences were found in the presence of stridor or moderate-to-severe UAO symptoms (Taussig ≥ 5), but Taussig ≥ 5 was less frequent in patients less than 2 years-of-age treated with steroids (p = 0.014). Median Taussig score was lower in the dexamethasone group 1 h after extubation, p < 0.001. 27 patients required reintubation, 9 due to UAO: 3 (4.3%) in the dexamethasone group and 6 (8.9%) in the placebo group, p = 0.319. In those intubated > 5 days, reintubation due to UAO was higher in the placebo group (2.4% vs. 14.3, p = 0.052). Nebulized epinephrine and budesonide were required more frequently in the placebo group in the first 2 h (p = 0.041) and 1 h (p = 0.02) after extubation, respectively. No relevant side effects were observed. Dexamethasone prior to extubation did not significantly reduce moderate-severe UAO symptoms, except for patients under 2-years of age. Dexamethasone could decrease Taussig score and the need of rescue therapies, as well as reintubation rates in those intubated for more than 5 days.

Adecuación de la prescripción de antimicrobianos en procesos ambulatorios atendidos en Urgencias / Adecuacy of pediatric antimicrobial prescribing in the Emergency Department at discharge

Introducción: En enero del 2019 la Consejería de Sanidad de la Comunidad de Madrid publicó una guía acerca del uso de antimicrobianos en niños con tratamiento ambulatorio. El objetivo de este trabajo fue estimar la adecuación de la prescripción de antimicrobianos al alta desde el Servicio de Urgencias Pediátricas (SUP) en pacientes con enfermedades infecciosas, tomando como referencia esta guía regional. Secundariamente, se estudió la variación en la adecuación según el diagnóstico realizado y el facultativo prescriptor, y se valoró la concordancia entre dicha guía y los protocolos del centro. Material y métodos:Estudio observacional, descriptivo y retrospectivo en el que se incluyó a pacientes de 0-16 años con diagnóstico al alta del SUP incluido en la guía regional, entre marzo del 2018 y febrero del 2019. La prescripción se consideró adecuada cuando lo era la indicación, y en su caso, el fármaco elegido, la posología (dosis, intervalo y duración) y la vía de administración. Resultados: Se obtuvo una muestra de la que se analizaron 648 procesos infecciosos, siendo tratados con antimicrobianos 165 (25,5%). En 23 procesos no pudo evaluarse la adecuación a la guía por ausencia de algún dato posológico de la prescripción de antimicrobiano. El manejo terapéutico fue adecuado globalmente en 550/625 procesos (88,0%). En los procesos tratados con antimicrobiano, la adecuación fue de 70/142 (49,3%), sin encontrarse diferencias estadísticamente significativas entre facultativo prescriptor. El motivo de inadecuación más frecuente fue el error posológico (26,3%). Infección urinaria, conjuntivitis y otitis media aguda fueron las entidades clínicas con peor adherencia (el 44,4, el 50,0 y el 52,2% respectivamente) y en las que existió una mayor discrepancia entre guía y protocolos (κ=0,308; κ=0,000; κ=0,586). (AU)

Introduction: In January 2019, Community of Madrid's Health Department published a guide about the use of antimicrobials in outpatient children. Taking this regional Guide as reference, this study was aimed at estimating the adequacy of the antimicrobial stewardship at discharge from a pediatric Emergency Department (ED). Secondarily, the differences in adequacy according to the diagnosis and the prescriber were studied, and the agreement between this Guide and the protocols of the ED was assessed. Material and methods: An observational, descriptive, retrospective study was conducted on patients under 16 years old, with a diagnosis included in the regional Guide who were discharged from a pediatric ED between March of 2018 and February of 2019. Prescription was considered adequate when the indication, the antibiotic and the posology (dosage, dosing interval, length of treatment and route of administration) were correct. Results: 165 out of 648 (25,5%) infectious diseases processes analyzed received antimicrobial treatment. In 23 processes treated with antimicrobial, the adequacy could not be evaluated due to the absence of data necessary to assess any aspect of posology. Therapy was considered appropriate in 550/625 processes (88.0%). When antimicrobial treatment was prescribed, 70/142 (49.3%) were appropriate and no statistically significant differences in adequacy were found between prescribers. Posology was the worst handled point of the prescription (26.3%). Tract urinary infection, conjunctivitis and otitis media were the pathologies with the lowest adecuacy (44.4%; 50.0% and 52.2%) and presented the highest discrepancy between the Guide and the center protocols (k=0.308; k=0.000; k=0.586). (AU)

Antimicrobial defined daily dose in neonatal population.

BACKGROUND: Antimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates. METHODS: Neonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method. RESULTS: A total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01). CONCLUSIONS: A useful method for antimicrobial DDD measurement in neonatology has been designed to monitor antimicrobial consumption in hospital settings. It should be validated in further studies and thereby included in the design for neonatal antimicrobial stewardship programs in the future.

Antimicrobial defined daily dose in neonatal population / Dosis diaria definida de antimicrobianos en la población neonatal

BackgroundAntimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates.MethodsNeonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method.ResultsA total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01).

AntecedentesLa dosis diaria definida de antimicrobianos (DDD), un método estandarizado para evaluar el consumo de antimicrobianos en la población adulta, tiene limitaciones que dificultan su uso en la población neonatal. Este estudio propone un diseño alternativo de la DDD aplicable a los recién nacidos.MétodosSe incluyeron neonatos (<1 mes) de 6 hospitales españoles durante un período de 12 meses. El peso y las semanas de edad gestacional de cada recién nacido fueron las variables recogidas. Las DDD (g) de cada antimicrobiano se calcularon multiplicando el peso obtenido por la dosis recomendada (mg/kg) del antimicrobiano para la indicación infecciosa más común seleccionada por el método Delphi.ResultadosSe incluyeron un total de 4.820 recién nacidos. La edad media fue de 36,72 semanas de edad gestacional y el peso medio fue de 2,687kg. La DDD estandarizado (intravenoso; oral) para antimicrobianos seleccionados fueron: amoxicilina (0,08; 0,08), amoxicilina-ácido clavulánico (0,27; 0,08), ampicilina (0,27; x), cloxacilina (0,13; 0,13), penicilina G sódica (0,12), cefazolina (0,13), cefuroxima (0,27; x), cefotaxima (0,27), ceftazidima (0,27), ceftriaxona (0,13), cefepima (0,27) piperacilina-tazobactam (0,54), aztreonam (0,24), azitromicina (0,03; 0,03) clindamicina (0,04; 0,04), amikacina (0,04), gentamicina (0,01), metronidazol (0,04; 0,08), ciprofloxacina (0,04; 0,05), levofloxacina (x; x), fluconazol (0,02; 0,02), itraconazol (0,01; 0,01), fosfomicina (0,27). Antimicrobianos restringidos: meropenem (0,11), teicoplanina (0,02), vancomicina (0,08; 0,11), linezolid (0,08; 0,08), daptomicina (x), anfotericina B liposomal (0, 01).ConclusionesSe ha diseñado un método útil para la medición de las DDD de antimicrobianos en neonatología para controlar el consumo de antimicrobianos en entornos hospitalarios. Debería validarse en estudios posteriores para incluirse en el diseño de los programas de administración de antimicrobianos neonatales en el futuro.

Antimicrobial defined daily dose in neonatal population.

BACKGROUND: Antimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates. METHODS: Neonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method. RESULTS: A total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01). CONCLUSIONS: A useful method for antimicrobial DDD measurement in neonatology has been designed to monitor antimicrobial consumption in hospital settings. It should be validated in further studies and thereby included in the design for neonatal antimicrobial stewardship programs in the future.

[Adecuacy of pediatric antimicrobial prescribing in the Emergency Department at discharge]. / Adecuación de la prescripción de antimicrobianos en procesos ambulatorios atendidos en Urgencias.

INTRODUCTION: In January 2019, Community of Madrid's Health Department published a guide about the use of antimicrobials in outpatient children. Taking this regional Guide as reference, this study was aimed at estimating the adequacy of the antimicrobial stewardship at discharge from a pediatric Emergency Department (ED). Secondarily, the differences in adequacy according to the diagnosis and the prescriber were studied, and the agreement between this Guide and the protocols of the ED was assessed. MATERIAL AND METHODS: An observational, descriptive, retrospective study was conducted on patients under 16 years old, with a diagnosis included in the regional Guide who were discharged from a pediatric ED between March of 2018 and February of 2019. Prescription was considered adequate when the indication, the antibiotic and the posology (dosage, dosing interval, length of treatment and route of administration) were correct. RESULTS: 165 out of 648 (25,5%) infectious diseases processes analyzed received antimicrobial treatment. In 23 processes treated with antimicrobial, the adequacy could not be evaluated due to the absence of data necessary to assess any aspect of posology. Therapy was considered appropriate in 550/625 processes (88.0%). When antimicrobial treatment was prescribed, 70/142 (49.3%) were appropriate and no statistically significant differences in adequacy were found between prescribers. Posology was the worst handled point of the prescription (26.3%). Tract urinary infection, conjunctivitis and otitis media were the pathologies with the lowest adecuacy (44.4%; 50.0% and 52.2%) and presented the highest discrepancy between the Guide and the center protocols (k=0.308; k=0.000; k=0.586). CONCLUSIONS: The adequacy of the management of infectious processes to the reference Guide in our pediatric ED was high, but it was below 50% when antimicrobial treatment was required. The degree of adequacy to the local protocols of the center was greater than to the regional Guide. This reveals a discrepancy between the 2documents that should be analyzed and corrected according to the available scientific evidence.

Clinical course of severe patients with COVID-19 treated with tocilizumab: report from a cohort study in Spain.

Background: We report the long-term outcomes, changes in laboratory parameters, the incidence of secondary nosocomial infections and treatment cost of a Spanish cohort of patients with severe COVID-19 that received tocilizumab (TCZ).Methods: Retrospective cohort of PCR confirmed adult patients who received TCZ from March 1 to 24, 2020 in a tertiary hospital was analyzed. Patients were followed up until 10 May 2020.Results: We included 162 patients (median age 64 years; 70.4% male). At time of TCZ administration, 48.1% of patients were on invasive mechanical ventilation (IMV). Over a median follow-up of 53 days, 46.9% of patients were discharge in good conditions and 19.8% were still hospitalized. The overall mortality was 33.3%, being higher in patients on IMV than those who did not (46.2% vs 26.7%, P < 0.001). A significant improvement in the lymphocyte count, C-reactive protein, lactate dehydrogenase, and D-dimer was observed. Overall, 43.2% patients presented nosocomial infections, causing death in 8%. Infections were more prevalent in ICU units (63.0% vs 17.1%, P < 0.001). The total cost of TCZ was €371,784.Conclusions: Among the patients who used TCZ, one third died, regardless the improvement in some inflammatory biomarkers. The incidence of secondary nosocomial infections was high.

Standardization and Chemical Characterization of Intravenous Therapy in Adult Patients: A Step Further in Medication Safety.

BACKGROUND: Intravenous drug administration is associated with potential complications, such as phlebitis. The physiochemical characteristics of the infusate play a very important role in some of these problems. AIM: The aim of this study was to standardize the dilutions of intravenous drugs most commonly used in hospitalized adult patients and to characterize their pH, osmolarity and cytotoxic nature to better guide the selection of the most appropriate vascular access. METHODS: The project was conducted in three phases: (i) standardization of intravenous therapy, which was conducted using a modified double-round Delphi method; (ii) characterization of the dilutions agreed on in the previous phase by means of determining the osmolarity and pH of each of the agreed concentrations, and recording the vesicant nature based on the information in literature; and (iii) algorithm proposal for selecting the most appropriate vascular access, taking into account the information gathered in the previous phases. RESULTS: In total, 112 drugs were standardized and 307 different admixtures were assessed for pH, osmolarity and vesicant nature. Of these, 123 admixtures (40%), had osmolarity values >600 mOsm/L, pH < 4 or > 9, or were classified as vesicants. In these cases, selection of the most suitable route of infusion and vascular access device is crucial to minimize the risk of phlebitis-type complications. CONCLUSIONS: Increasing safety of intravenous therapy should be a priority in the healthcare settings. Knowing the characteristics of drugs to assess the risk involved in their administration related to their physicochemical nature may be useful to guide decision making regarding the most appropriate vascular access and devices.

Bromocriptine for the treatment of postoperative cerebellar mutism syndrome in pediatric patients: Three case reports.

INTRODUCTION: Cerebellar mutism syndrome (CMS) is a common complication after posterior fossa tumor resection. It is characterized by a significant lack or loss of speech. Its biological origin remains unclear and there are no standardized treatments. However, bromocriptine seems to be a possible treatment for this condition. CASE REPORT: In this paper, we present three cases of pediatric patients (4, 5, and 17-year old) who developed CMS after posterior fossa tumor surgery. They were treated with bromocriptine to improve neurological symptoms.Management and outcome: Bromocriptine was started at a low dose and was progressively increased to reach the minimum effective dose. After four months of treatment, a normal and fluid speech was observed in the three patients. No discontinuation due to adverse events were reported. DISCUSSION: Bromocriptine has shown to be an effective and safe treatment for CMS in pediatric patients after posterior fossa tumor resection.

COVID-19 in hospitalised patients in Spain: a cohort study in Madrid.

Few large series describe the clinical characteristics, outcomes and costs of COVID-19 in Western countries. This cohort reports the first 1255 adult cases receiving anti-COVID-19 treatment at a Spanish hospital (1-24 March 2020). Treatment costs were calculated. A logistic regression model was used to explore risk factors on admission associated with ARDS. A bivariate Cox proportional hazard ratio (HR) model was employed to determine the HR between individual factors and death. We included 1255 patients (median age 65 years; 57.8% male), of which 92.3% required hospitalisation. The prevalence of hypertension, cardiovascular disease and diabetes mellitus (DM) was 45.1%, 31.4% and 19.9%, respectively. Lymphocytopenia (54.8%), elevated alanine aminotransferase (33.0%) and elevated lactate dehydrogenase (58.5%) were frequent. Overall, 36.7% of patients developed ARDS, 10.0% were admitted to an ICU and 21.3% died. The most frequent antiviral combinations were lopinavir/ritonavir plus hydroxychloroquine (44.2%), followed by triple therapy with interferon beta-1b (32.7%). Corticosteroids and tocilizumab were used in 25.3% and 12.9% of patients, respectively. Total cost of anti-COVID-19 agents was €511 825 (€408/patient). By multivariate analysis, risk factors associated with ARDS included older age, obesity, DM, severe hypoxaemia, lymphocytopenia, increased creatine kinase and increased C-reactive protein. In multivariate Cox model, older age (HR 1.07, 95% CI 1.06-1.09), cardiovascular disease (HR 1.34, 95% CI 1.01-1.79), DM (HR 1.45, 95% CI 1.09-1.92), severe hypoxaemia (HR 2.01, 95% CI 1.49-2.72), lymphocytopenia (HR 1.62, 95% CI 1.20-2.20) and increased C-reactive protein (HR 1.04, 95% CI 1.02-1.06) were risk factors for mortality.

Estandarizar por seguridad: un reto asumible / Standardization for safety: a feasible challenge

No disponible