Isavuconazole use and TDM in real-world pediatric practice.

Isavuconazole (ISA) is approved for treating invasive aspergillosis and mucormycosis in adults, but its use in children remains off-label. We report on the use of ISA in real-world pediatric practice with 15 patients receiving ISA for treatment of invasive fungal infections. Therapeutic drug monitoring (TDM) was performed in all patients, with 52/111 (46.8%) Ctrough determinations out of range, thus supporting the need for TDM in children, especially those receiving extracorporeal membrane oxygenation (ECMO).

Ertapenem blood concentration: A retrospective cohort study to analyse risk of neurotoxicity.

AIMS: Several cases of ertapenem-related neurotoxicity have been published in the current literature. However, studies evaluating the ertapenem blood concentration (EBC) as a risk of these adverse events are scarce. We aimed to evaluate the relationship between the trough EBC and the risk of neurological toxicity. METHODS: This was a retrospective study, including patients who underwent ertapenem treatment between October 2019 and February 2021. We excluded patients in the critical care unit and those whose blood samples were not properly taken in order to analyse ertapenem trough concentration. We also excluded patients whose clinical follow-up was not properly realized for the entire period of ertapenem treatment. The main outcome was the presence of any suspicious neurological side effect owing to ertapenem administration and its relationship with the plasma concentration. Secondary outcomes were to identify clinical and analytical data contributing to a higher risk of neurotoxicity. RESULTS: The initial cohort comprised 158 individuals. For the final analysis we evaluated 102 patients, reporting a neurological alteration in 13/102 (12.7%). Mean trough EBC was significantly higher in patients showing neurotoxicity in comparison with those who did not (37.8 mcg mL-1 , standard deviation [SD] ± 35.7 vs. 14.6 mcg mL-1 , SD ± 15.2; P = .002). In multivariable logistic regression analysis, EBC (odds ratio [OR] = 1.07; P = .006), a moderate renal insufficiency (OR = 9.2; P = .02) and a history of previous neurologic disease (OR = 9.9; P = .02) were identified as risk factors of neurological alteration during ertapenem treatment. CONCLUSIONS: In patients at risk, determining the ertapenem plasma concentration may help to minimize the risk of neurotoxicity.

Comparing Aluminum Concentrations in Adult and Pediatric Parenteral Nutrition Solutions: Multichamber-Bag versus Compounded Parenteral Nutrition.

Aluminum contamination in parenteral nutrition (PN) solutions can lead to neurotoxicity, reduced bone mass, and liver toxicity, especially in pediatric patients. Ingredients commonly used in PN compounding, such as vitamins, trace elements, calcium, and phosphate salts, contain significant amounts of aluminum. This study aimed to compare aluminum concentrations in multichamber-bag (MCB) and compounded PN for adults and pediatrics. A prospective study assessed aluminum concentrations in various types of MCB and compared them with compounded PN formulations with similar compositions. The types of MCB included Lipoflex® (without electrolytes), Omegaflex®, Finomel®, Smofkabiven® (with and without electrolytes), Olimel®, Clinimix®, and Numeta®. Overall, 80 aluminum determinations were included: 36 for MCBs and 44 for compounded PN. MCBs showed significantly lower aluminum concentrations than compounded PN: 11.37 (SD 6.16) vs. 21.45 (8.08) µg/L, respectively. Similar results were observed for adult (n = 40) and pediatric (n = 40) PN formulations (12.97 (7.74) vs. 20.78 (10.28) µg/L, and 9.38 (2.23) vs. 22.01 (5.82) µg/L, respectively). Significant differences were also found between MCBs depending on the manufacturing company. These findings suggest that MCBs PN offer a safer option for reducing aluminum contamination in PN. Harmonizing regulations concerning aluminum concentrations in PN solutions could help mitigate differences between PN formulations.

Impact of Omega-3 Fatty Acid Supplementation in Parenteral Nutrition on Inflammatory Markers and Clinical Outcomes in Critically Ill COVID-19 Patients: A Randomized Controlled Trial.

The heightened inflammatory response observed in COVID-19 patients suggests that omega-3 fatty acids (O3FA) may confer anti-inflammatory benefits. This randomized, double-blind, single-center clinical trial aimed to evaluate the effect of O3FA supplementation in parenteral nutrition (PN) on inflammatory markers in COVID-19 patients admitted to the intensive care unit (ICU). A total of 69 patients were randomized into three groups: one received standard lipid emulsion, and two received O3FA (Omegaven®) at doses of 0.1 g/kg/day and 0.2 g/kg/day, respectively, in addition to Smoflipid®. The primary outcomes measured were serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) on days 1, 5, and 10 of PN initiation. Secondary outcomes included additional inflammatory markers (TNF-α, IFN-γ, IL-1Ra, CXCL10), hepatic function, triglyceride levels, and clinical outcomes such as mortality and length of ICU and hospital stay. Results indicated a significant reduction in CRP, IL-6, and CXCL10 levels in the group receiving 0.1 g/kg/day O3FA compared to the control. Additionally, the higher O3FA dose was associated with a shorter ICU and hospital stay. These findings suggest that O3FA supplementation in PN may reduce inflammation and improve clinical outcomes in critically ill COVID-19 patients.

National Survey and consensus document on dosing strategies for beta-lactam antibiotics against multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients undergoing extracorporeal life support techniques: The DOSEBL study protocol. / Encuesta nacional y elaboración de un documento de consenso sobre estrategias de dosificación de antibióticos beta-lactámicos frente a bacterias gramnegativas multirresistentes (BGN-MDR) en pacientes críticos que son tratados con técnicas de soporte vital extracorpóreas: protocolo de estudio DOSEBL.

INTRODUCTION: Infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients present a challenge for timely and appropriate antibiotic treatment. This is particularly important in patients undergoing extracorporeal life support techniques such as renal replacement therapy and extracorporeal membrane oxygenation. These techniques can introduce additional pharmacokinetic alterations, potentially leading to suboptimal exposure to antibiotics. This study aims to outline dosing strategies and therapeutic drug monitoring protocols for new ß-lactam antibiotics effective against MDR-GNB in critically ill patients undergoing extracorporeal life support techniques at a national level. Additionally, the study seeks to develop a consensus document, based on available evidence. METHODS: The project will comprise two main phases: I) A national survey, and II) the development of a consensus document. This consensus document, undertaken according to ACCORD guidelines, will encompass: a) establishment of a multidisciplinary panel of experts, b) prospective registration of the consensus, c) evidence synthesis, d) modified Delphi rounds. The antimicrobials to be included will be: meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and aztreonam. Extracorporeal life support techniques will include continuous renal replacement therapy, conventional intermittent hemodialysis, and extracorporeal membrane oxygenation. DISCUSSION: The availability of extracorporeal life support techniques has expanded significantly in recent years, alongside a rise in the prevalence of infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB). There is a need to develop evidence-based tools of high quality to standardize dosing and monitoring strategies for new ß-lactam antibiotics.

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.

Aluminum blood concentration in adult patients: effect of multichamber-bag versus hospital-compounded parenteral nutrition.

Introduction: Background: the administration of aluminum-contaminated parenteral nutrition (PN) leads to an accumulation of aluminum. The aim of this study was to assess blood aluminum concentrations (BACs) of inpatients receiving multichamber-bag (MCB) PN compared to those receiving compounded PN. Methods: available BACs were retrospectively gathered from patient charts of adult inpatients receiving PN from 2015 to 2020, and compared depending on the type of PN administered. Long-term PN patients, defined as ≥ 20 days of PN, receiving at least > 10 days of compounded PN, were compared to long-term patients receiving only MCB. Results: a total of 160 BACs were available from 110 patients. No differences were found according to type of PN (mean BAC: 3.11 ± 2.75 for MCB versus 3.58 ± 2.08 µg/L for compounded PN). Baseline total bilirubin, surgery and days with PN were related to higher BACs (coefficient: 0.30 [95 % CI, 0.18-0.42], 1.29 [95 % CI, 0.52-2.07], and 0.06 [95 % CI: 0.01-0.11], respectively). Regarding long-term PN, patients receiving only MCB (n = 21) showed lower BACs compared to the compounded PN (n = 17) [2.99 ± 1.55 versus 4.35 ± 2.17 µg/L, respectively; p < 0.05]. Conclusions: although there were no differences in BAC according to type of PN administered, in long-term PN, MCB PN was associated with lower BACs as compared to compounded PN.

Introducción: Antecedentes: la administración de nutrición parenteral (NP) contaminada con aluminio conduce a su acumulación. El objetivo de este estudio fue evaluar las concentraciones de aluminio en sangre (CAS) en pacientes hospitalizados que recibieron NP elaboradas en el hospital o bolsas tricamerales. Métodos: se recogieron retrospectivamente las CAS disponibles de los pacientes hospitalizados con NP durante el período entre 2015 y 2020, comparándose los valores en función del tipo de NP administrada. Se comparan igualmente los valores de pacientes de larga duración, definida como ≥ 20 días de NP, que recibieron al menos > 10 días de NP elaborada frente aquellos de larga duración que recibieron solo NP tricameral. Resultados: se incluyeron un total de 160 CAS de 110 pacientes. No se encontraron diferencias con respecto al tipo de NP (CAS media: 3,11 ± 2,75 para la tricameral frente a 3,58 ± 2,08 µg/L para la elaborada). La bilirrubina total basal, la cirugía y los días con NP se relacionaron con un mayor valor de CAS (coeficiente: 0,30 [IC 95 %: 0,18-0,42], 1,29 [IC 95 %: 0,52-2,07] y 0,06 [IC 95 %: 0,01-0,11], respectivamente). En la NP a largo plazo, los pacientes que recibieron solo NP tricameral (n = 21) mostraron una CAS menor en comparación con el grupo que recibió al menos 10 NP elaboradas (n = 17) [2,99 ± 1,55 versus 4,35 ± 2,17 µg/L, respectivamente; p < 0,05]. Conclusiones: aunque no hubo diferencias de CAS con respecto al tipo de NP administrada, en la NP a largo plazo, la administración de NP tricameral se asoció con CAS menores en comparación con la NP elaborada.

COVID-19 in Solid Organ Transplantation: A Matched Retrospective Cohort Study and Evaluation of Immunosuppression Management.

BACKGROUND: The epidemiological and clinical characteristics of solid organ transplant (SOT) patients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We conducted a matched retrospective cohort study to compare clinical outcomes among SOT recipients with the general population and to assess immunosuppression management. METHODS: Adult SOT recipients with laboratory polymerase chain reaction-confirmed SARS-CoV-2 infection admitted to a tertiary-care hospital in Barcelona, Spain, from March 11 to April 25, 2020, were matched to controls (1:4) on the basis of sex, age, and age-adjusted Charlson's Index. Patients were followed for up to 28 days from admission or until censored. Primary endpoint was mortality at 28 days. Secondary endpoints included admission to the intensive care unit and secondary complications. Drug-drug interactions (DDI) between immunosuppressants and coronavirus disease 2019 (COVID-19) management medication were collected. RESULTS: Forty-six transplant recipients and 166 control patients were included. Mean (SD) age of transplant recipients and controls was 62.7 (12.6) and 66.0 (12.7) years, 33 (71.7%) and 122 (73.5%) were male, and median (interquartile range) Charlson's Index was 5 (3-7) and 4 (2-7), respectively. Mortality was 37.0% in SOT recipients and 22.9% in controls (P = 0.51). Thirty-three (71.7%) patients underwent transitory discontinuation of immunosuppressants due to potential or confirmed DDI. CONCLUSIONS: In conclusion, hospitalized SOT recipients with COVID-19 had a trend toward higher mortality compared with controls, although it was not statistically significant, and a notable propensity for DDI.

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)

Caracterización y resultados del uso de voriconazol nebulizado en un entorno real: un estudio observacional unicéntrico / Characterization and real-live results of nebulized voriconazole: A single-center observational study

Objetivo la administración de voriconazol nebulizado implica ventajas, incluyendo la optimización de la penetración pulmonar y la reducción de los efectos adversos e interacciones; sin embargo, la evidencia sobre su utilización es escasa y no existen presentaciones comerciales específicas para nebulización. Nuestro objetivo es caracterizar las soluciones de voriconazol elaboradas para nebulización y describir su uso en nuestro centro. Método estudio observacional retrospectivo incluyendo pacientes que reciben voriconazol nebulizado para el tratamiento de enfermedades pulmonares (infecciones fúngicas o colonizaciones). La solución de voriconazol se preparó a partir de los viales comerciales para la administración intravenosa. Resultados el pH y la osmolaridad de las soluciones de voriconazol fueron adecuados para su nebulización. Se incluyeron 10 pacientes, 9 adultos y un niño. La dosis fue de 40 mg en los adultos y 10 mg en el paciente pediátrico, diluido a 10 mg/ml, administrados cada 12-24 horas. La duración mediana del tratamiento fue de 139 (rango: 26-911) días. No se reportaron efectos adversos y no se detectó voriconazol en plasma cuando se administró únicamente vía nebulizada. Conclusiones la nebulización de voriconazol es bien tolerada y no se absorbe hacia la circulación sistémica. Son necesarios más estudios de investigación para evaluar su eficacia (AU)

Objective Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. Method This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. Results The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, nine adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 hours. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. Conclusion Voriconazole nebulization is well tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy (AU)

Aluminum blood concentration in adult patients: effect of multichamber-bag versus hospital-compounded parenteral nutrition / Concentración sanguínea de aluminio en pacientes adultos: efecto de la nutrición parenteral tricameral frente a la nutrición parenteral elaborada en el hospital

Background: the administration of aluminum-contaminated parenteral nutrition (PN) leads to an accumulation of aluminum. The aim of this study was to assess blood aluminum concentrations (BACs) of inpatients receiving multichamber-bag (MCB) PN compared to those receiving compounded PN. Methods: available BACs were retrospectively gathered from patient charts of adult inpatients receiving PN from 2015 to 2020, and compared depending on the type of PN administered. Long-term PN patients, defined as ≥ 20 days of PN, receiving at least > 10 days of compounded PN, were compared to long-term patients receiving only MCB. Results: a total of 160 BACs were available from 110 patients. No differences were found according to type of PN (mean BAC: 3.11 ± 2.75 for MCB versus 3.58 ± 2.08 µg/L for compounded PN). Baseline total bilirubin, surgery and days with PN were related to higher BACs (coefficient: 0.30 [95 % CI, 0.18-0.42], 1.29 [95 % CI, 0.52-2.07], and 0.06 [95 % CI: 0.01-0.11], respectively). Regarding long-term PN, patients receiving only MCB (n = 21) showed lower BACs compared to the compounded PN (n = 17) [2.99 ± 1.55 versus 4.35 ± 2.17 µg/L, respectively; p < 0.05]. Conclusions: although there were no differences in BAC according to type of PN administered, in long-term PN, MCB PN was associated with lower BACs as compared to compounded PN. (AU)

Antecedentes: la administración de nutrición parenteral (NP) contaminada con aluminio conduce a su acumulación. El objetivo de este estudio fue evaluar las concentraciones de aluminio en sangre (CAS) en pacientes hospitalizados que recibieron NP elaboradas en el hospital o bolsas tricamerales. Métodos: se recogieron retrospectivamente las CAS disponibles de los pacientes hospitalizados con NP durante el período entre 2015 y 2020, comparándose los valores en función del tipo de NP administrada. Se comparan igualmente los valores de pacientes de larga duración, definida como ≥ 20 días de NP, que recibieron al menos > 10 días de NP elaborada frente aquellos de larga duración que recibieron solo NP tricameral. Resultados: se incluyeron un total de 160 CAS de 110 pacientes. No se encontraron diferencias con respecto al tipo de NP (CAS media: 3,11 ± 2,75 para la tricameral frente a 3,58 ± 2,08 µg/L para la elaborada). La bilirrubina total basal, la cirugía y los días con NP se relacionaron con un mayor valor de CAS (coeficiente: 0,30 [IC 95 %: 0,18-0,42], 1,29 [IC 95 %: 0,52-2,07] y 0,06 [IC 95 %: 0,01-0,11], respectivamente). En la NP a largo plazo, los pacientes que recibieron solo NP tricameral (n = 21) mostraron una CAS menor en comparación con el grupo que recibió al menos 10 NP elaboradas (n = 17) [2,99 ± 1,55 versus 4,35 ± 2,17 µg/L, respectivamente; p < 0,05]. Conclusiones: aunque no hubo diferencias de CAS con respecto al tipo de NP administrada, en la NP a largo plazo, la administración de NP tricameral se asoció con CAS menores en comparación con la NP elaborada. (AU)