Population Pharmacokinetics of Vancomycin and Meropenem in Pediatric Extracorporeal Membrane Oxygenation Support.

Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target. Design: Prospective, multicentric, population PK analysis. Setting: Two hospitals with pediatric intensive care unit. Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support. Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of >400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% > 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30-550) ml/min/1.73 m2. The median dose was 13.6 (range 10-15) mg/kg every 6-12 h and 40 mg/kg every 8-12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin. Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.

Garantía de calidad en nutrición parenteral: Implementación de control de calidad químico y microbiológico / Quality guarantee in parenteral nutrition: Implementation of chemical and microbiological quality controls

La elaboración de una nutrición parenteral (NP) no está exenta de riesgos debido a su compleja composición y fabricación, susceptible de errores en adición u omisión de nutrientes (composición química) o ruptura de la técnica aséptica estricta (contaminación microbiológica).La farmacopea y legislación nacional vigente sólo sugiere controles básicos, algunos no cuantitativos, además de la supervisión del personal y áreas de trabajo. Considerando la importancia de la composición y esterilidad de una NP, se analizaron controles de calidad analíticos y microbiológicos que den cuenta del proceso de preparación, así como de estabilidad química y esterilidad, previo a la administración considerando un almacenamiento de 5 días.Como control de calidad químico se cuantificó: glucosa, sodio, calcio, magnesio, fósforo, potasio y cloro en 40 muestras en los equipos Cobas®B221 y Vitros®4600. Los controles microbiológicos (agar sangre) se realizaron posterior a la preparación y a los 5 días de almacenamiento, previo a la administración. Los resultados de día 0, muestran que para glucosa, sodio y calcio las concentraciones se correlacionan con la concentración teórica, mientras que para el día 5 post almacenamiento; glucosa, sodio, calcio, magnesio, fósforo, potasio y cloro se correlacionan con la concentración teórica del día 0. En ninguna muestra se observó crecimiento de microorganismos.De acuerdo a los resultados se establece como control de preparación de NP: glucosa, sodio y calcio, como controles de estabilidad química: glucosa, sodio, calcio, magnesio, fósforo, potasio y cloro, además se asegura la esterilidad a los 5 días de almacenamiento. (AU)

The elaboration of a parenteral nutrition (NP) is not exempt of risks due to its complex composition and manufacture, susceptible to errors in addition or omission of nutrients (chemical composition) or rupture of the strict aseptic technique (microbiological contamination).The current pharmacopoeia and national legislation only suggests basic controls, some not quantitative, in addition to the supervision of personnel and work areas. Considering the importance of the composition and sterility of a NP, analytical and microbiological quality controls that account for the preparation process, as well as chemical stability and sterility, were analyzed prior to administration considering a 5-day storage.As chemical quality control, glucose, sodium, calcium, magnesium, phosphorous, potassium and chlorine were quantified in 40 samples in the Cobas®B221 and Vitros®4600 kits. Microbiological controls (blood agar) were performed after preparation and at 5 days of storage, prior to administration.The results from day 0 show that for glucose, sodium and calcium the concentrations correlate with the theoretical concentration, while for day 5 post storage; glucose, sodium, calcium, magnesium, phosphorus, potassium and chlorine are correlated with the theoretical concentration on day 0. In no sample was growth of microorganisms observed.According to the results, it is established as control of NP preparation: glucose, sodium and calcium, as chemical stability controls: glucose, sodium, calcium, magnesium, phosphorus, potassium and chlorine, and sterility is ensured 5 days after storage. (AU)

[Analysis of voriconazole serum concentrations and safety profile in pediatric oncology patients]. / Análisis de concentraciones plasmáticas de voriconazol y su perfil de seguridad en pacientes oncológicos pediátricos.

BACKGROUND: Voriconazole (VCZ) serum drug levels (SDL) vary widely and are associated with increased mortality when they are below the therapeutic range for invasive aspergillosis (IA). AIM: To describe VCZ SDL in oncology pediatric patients in order to reach adequate concentrations for prophylaxis (≥ 0.5 mg/L) and treatment (≥ 1.0 y 2.0 mg/L) for IA and their relationship with toxicity. PATIENTS AND METHODS: Retrospective analysis of VCZ SDL and toxicities recorded in oncology pediatric patients between February 2013 and November 2014. The daily dosage and SDLs were analyzed according to administration route: intravenous (IV) and oral (PO), type of therapy (prophylaxis and treatment) and patient age (< 12 y ≥ 12 years old). RESULTS: 112 through levels from 26 patients were analyzed and the average age was 9.3 years-old. The SDL obtained from the IV route were 43.7%. There were more SDL ≥ 0.5 mg/L and ≥ 1.0 mg/L with the IV route than the PO route (p < 0.05). Patients younger than 12-years-old received a higher dosage than those ≥ 12 years old (median 18.6 and 9.2 mg/kg/d, respectively, p < 0.05). To reach SDL ≥ 0,5 mg/L with the PO route, a dosage of 200 mg every 12 hours showed the best results for all patients (80-100% SDL ≥ 0.5 mg/L). With an IV dosage between 14 and 20 mg/kg/day in patients > 12-years-old, 80% of the SDL were ≥ 1 mg/L and ≥ 2 mg/L. In patients younger than 12-year-old, dosages between 8-30 mg/ kg/day showed similar results (50-63% of SDL ≥ 1 mg/L and 36-40% of SDL ≥ 2 mg/L). Eight patients (30.8%) presented an adverse drug reaction and no relationship with the SDL was found. Conclusión: A VCZ standard dosage of 200 mg every 12 hours PO showed the best results for IA prophylaxis in all patients. Patients younger than 12-years-old would require higher dosages than the doses used in this study to attain adequate SDL for IA treatment. No relation with SDL and adverse reactions was found.

Análisis de concentraciones plasmáticas de voriconazol y su perfil de seguridad en pacientes oncológicos pediátricos / Analysis of voriconazole serum concentrations and safety profile in pediatric oncology patients

Background: Voriconazole (VCZ) serum drug levels (SDL) vary widely and are associated with increased mortality when they are below the therapeutic range for invasive aspergillosis (IA). Aim: To describe VCZ SDL in oncology pediatric patients in order to reach adequate concentrations for prophylaxis (≥ 0.5 mg/L) and treatment (≥ 1.0 y 2.0 mg/L) for IA and their relationship with toxicity. Patients and Methods: Retrospective analysis of VCZ SDL and toxicities recorded in oncology pediatric patients between February 2013 and November 2014. The daily dosage and SDLs were analyzed according to administration route: intravenous (IV) and oral (PO), type of therapy (prophylaxis and treatment) and patient age (< 12 y ≥ 12 years old). Results: 112 through levels from 26 patients were analyzed and the average age was 9.3 years-old. The SDL obtained from the IV route were 43.7%. There were more SDL ≥ 0.5 mg/L and ≥ 1.0 mg/L with the IV route than the PO route (p < 0.05). Patients younger than 12-years-old received a higher dosage than those ≥ 12 years old (median 18.6 and 9.2 mg/kg/d, respectively, p < 0.05). To reach SDL ≥ 0,5 mg/L with the PO route, a dosage of 200 mg every 12 hours showed the best results for all patients (80-100% SDL ≥ 0.5 mg/L). With an IV dosage between 14 and 20 mg/kg/day in patients > 12-years-old, 80% of the SDL were ≥ 1 mg/L and ≥ 2 mg/L. In patients younger than 12-year-old, dosages between 8-30 mg/ kg/day showed similar results (50-63% of SDL ≥ 1 mg/L and 36-40% of SDL ≥ 2 mg/L). Eight patients (30.8%) presented an adverse drug reaction and no relationship with the SDL was found. Conclusión: A VCZ standard dosage of 200 mg every 12 hours PO showed the best results for IA prophylaxis in all patients. Patients younger than 12-years-old would require higher dosages than the doses used in this study to attain adequate SDL for IA treatment. No relation with SDL and adverse reactions was found.

Introducción: Las concentraciones plasmáticas (CPs) de voriconazol (VCZ) son erráticas y en el caso de encontrarse bajo rango terapéutico para el tratamiento de aspergilosis invasora (AI) se asocian a un aumento de mortalidad. Objetivo: Analizar las CPs de VCZ obtenidas en pacientes pediátricos para alcanzar valores que se estiman efectivos para profilaxis (≥ 0,5 mg/L) y tratamiento (≥ 1,0 y 2,0 mg/L) de AI y su relación con toxicidades. Pacientes y Métodos: Análisis retrospectivo de CPs de VCZ y toxicidades asociadas obtenidas en pacientes oncológicos pediátricos desde febrero de 2013 hasta noviembre 2014. Se analizó la dosis diaria y CPs de acuerdo a la vía de administración: intravenosa (iv) u oral (vo), tipo de terapia (profilaxis y tratamiento) y edad (< 12 y ≥ 12 años). Resultados: Se analizaron 112 CPs valle de 26 pacientes, con una edad promedio de 9,3 años. El 43,7% de las CPs correspondió a administración iv. Se obtuvieron más CPs ≥ 0,5 mg/L y ≥ 1,0 mg/L con la vía iv en relación a vo (p < 0,05). Pacientes bajo 12 años de edad recibieron mayor dosis en comparación a los ≥ 12 años (medianas 18,6 y 9,2 mg/kg/día, respectivamente, p < 0,05). La dosis vo más efectiva para alcanzar CPs ≥ 0,5 mg/L fue de 200 mg cada 12 h en todos los pacientes (80-100% de CPs ≥ 0,5 mg/L). En pacientes ≥ 12 años con dosis iv entre 14 y 20 mg/kg/día, 80% de las CPs fueron ≥ 1 mg/L y ≥ 2 mg/L. En pacientes bajo 12 años de edad, dosis entre 8-30 mg/ kg/día generaron similares resultados (50-63% para CPs ≥ 1 mg/L y 36-40% para CPs ≥ 2 mg/L). Ocho pacientes (30,8%), tuvieron alguna reacción adversa al fármaco, no encontrándose relación con la CP alcanzada. Conclusión: Una dosis estándar vo de 200 mg c/12 h de VCZ mostró los mejores resultados para profilaxis de AI en todos los pacientes. Pacientes bajo 12 años de edad requerirían dosis mayores a las utilizadas en este estudio para obtener CPs efectivas para tratamiento de AI. No se encontró relación entre CPs tóxicas y reacciones adversas.