Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen

Abstract INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

Fluconazole levels in serum and cerebrospinal fluid according to daily dosage in patients with cryptococcosis and other fungal infections

ABSTRACT Fluconazole is extensively used for the treatment of candidiasis and cryptococcosis. Among other factors, successful treatment is related to appropriate fluconazole levels in blood and cerebrospinal fluid. In the present study, fluconazole levels were determined in 15 patients, 14 of whom had AIDS and 13 had neurocryptococcosis. The only selection criterion was treatment with fluconazole, which was performed with a generic or similar form of the drug. Fluconazole level was determined by high performance liquid chromatography and the susceptibility profile of Cryptococcus spp. isolated from the patients was assessed by broth microdilution. Blood and cerebrospinal fluid fluconazole levels were found to be related to the fluconazole daily dose, and exceeded the minimum inhibitory concentration of this antifungal for the Cryptococcus spp. isolates. A good correlation was observed between serum and cerebrospinal fluid drug concentration. In conclusion, treatment with non-original fluconazole under usual medical practice conditions results in appropriate blood and cerebrospinal fluid levels of the drug for inhibiting Cryptococcus spp. susceptible to this antifungal drug. The relatively common failures of neurocryptococcosis treatment appear not to be due to insufficient fluconazole levels in the cerebrospinal fluid, especially with the use of daily doses of 400-800 mg.

Farmacocinética de posaconazol en la profilaxis y tratamiento de la infección fúngica invasora en niños inmunocomprometidos en un hospital pediátrico / Pharmacokinetics of posaconazol in the prophylaxis and treatment of invasive fungal infection in immunocompromised children in a pediatric hospital

Resumen Introducción En pediatría no existe consenso en la dosificación de posaconazol (PSC) para profilaxis y tratamiento de la infección fúngica invasora (IFI), usándose la medición de concentraciones plasmáticas (CPs) del fármaco. Objetivo Describir la experiencia de monitoreo de las CPs de PSC en niños inmunocomprometidos con IFI y determinar si las dosis recomendadas alcanzan CPs efectivas en profilaxis (≥ 0,7 µg/mL) y tratamiento (≥ 1,25 µg/mL). Método Análisis retrospectivo en niños que recibieron PSC suspensión como profilaxis o tratamiento entre enero de 2012 y octubre de 2016, en las unidades de Oncología y Trasplante de Médula Ósea del Hospital Calvo Mackenna. Resultados 78 CPs en seis pacientes (4 indicaciones de profilaxis y 4 tratamientos) fueron revisados. La mediana de dosis de PSC fue de 12,5 y 18,8 mg/kg/d para profilaxis y tratamiento, respectivamente, resultando CP mediana de 0,97 y 1,8 μg/mL, respectivamente. En profilaxis, se registraron 40/67 (60%) con CP ≥ 0,70 μg/mL recibiendo una mediana de dosis de 12,5 mg/kg/d. Mientras que para el tratamiento: 5/11 (46%), presentaron CP ≥ 1,25 μg/mL, recibiendo una mediana de dosis de 18 mg/kg/d. Conclusión Nuestros resultados se ajustan a lo recomendado para la dosificación de PSC, pero evidencian una necesidad de realizar una monitorización individualizada para mantener adecuadas CPs.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 μg/ml and ≥ 1.25 μg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 μg/mL) and treatment (≥ 1.25 μg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 μg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 μg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 μg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

Evaluación de interacción medicamentosa de voriconazol-ciclosporina en pacientes pediátricos que reciben trasplante de precursores hematopoyéticos (2013-2014) / Drug interaction of voriconazole-cyclosporine in children undergoing hematopoietic stem cell transplantation (2013-2014)

Background: Drug interactions (DI) in patients receiving hematopoietic stem cell transplantation (HSCT) are common and clinically significant, highlighting: anticonvulsants, voriconazole (VCZ) and cyclosporine (CsA), which require monitoring. Objective: To describe the interactions between CsA-VCZ in children undergoing HSCT. Methods: Retrospective, descriptive study in immunocompromised children hospitalized since January 2013 to December 2014 at Bone Marrow Transplant Unit, Hospital Dr. Luis Calvo Mackenna, who received CsA and VCZ. Results: The median age was 5 years (3-6) and the median weight was 20 kg (17-30). Sixtythree baseline drug levels were analyzed, of those, 27 were CsA drug levels obtained previous to using VCZ and 36 were CsA drug levels collected concomitantly with VCZ. In the group CsA previous to VCZ, the CsA dose was 4.6 ± 2.6 (mg/ kg/ day) and the CsA average level was 188.8 ± 84.1 (μg/ml). In the group of CsA concomitantly with VCZ, the dose of CsA was 5.5 ± 3.0 (mg/ kg/day) (p = 0.07) and CsA average level was significantly higher: 232.5 ± 106.7 (μg/ml) (p = 0.04). Conclusion: This study shows an increased level of CsA when it is used together with VCZ. Therapeutic drug monitoring could improve the management of the DI and optimize the co-administration of CsA and VCZ.

Introducción: Las interacciones medicamentosas (IM) en el trasplante de progenitores hematopoyéticos (TPH) son comunes y clínicamente significativas, especialmente en: anticonvulsivantes, voriconazol (VCZ) y ciclosporina (CsA). Objetivo: Describir las interacciones de CsA-VCZ en pacientes con TPH. Métodos: Estudio descriptivo, retrospectivo, en pacientes receptores de TPH entre enero de 2013 y diciembre de 2014 en la Unidad de Trasplante de Médula Ósea del Hospital Dr. Luis Calvo Mackenna, que recibieran CsA y VCZ. Resultados: Edad media: 5 años (3-6), peso promedio: 20 kg (17-30). Se analizaron 63 concentraciones plasmáticas de CsA, 27 eran concentraciones de CsA previas al uso de VCZ y 36 concentraciones plasmáticas de CsA concomitantes con VCZ. En el grupo de CsA previo a VCZ, la dosis de CsA fue 4,6 ± 2,6 (mg/kg/día) y la concentración media de CsA 188,8 ± 84,1 (μg/ml). En el grupo de CsA en forma concomitante con VCZ, la dosis de CsA fue de 5,5 ± 3,0 (mg/kg/día) (p 0,07) y la concentración media de CsA fue: 232,5 ± 106,7 (μg/ml) (p = 0,04). Conclusión: Se demostró un aumento de las concentraciones plasmáticas de CsA en IM con VCZ. La monitorización terapéutica podría mejorar el manejo de la IM y optimizar la coadministración de CsA y VCZ.

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.

Central nervous system paracoccidioidomycosis: report of a case successfully treated with Itraconazol

Paracoccidioidomycosis (PCM) is a primary pulmonary infection that often disseminates to other organs and systems. Involvement of the central nervous system (CNS) is rare and due to the fact that both clinical alertness and establishment of the diagnosis are delayed, the disease progresses causing serious problems. We report here a case of neuroparacoccidioidomycosis (NPCM), observed in a 55 year-old male, who consulted due to neurological symptoms (left hemiparesis, paresthesias, right palpebral ptosis, headache, vomiting and tonic clonic seizures) of a month duration. Upon physical examination, an ulcerated granulomatous lesion was observed in the abdomen. To confirm the diagnosis a stereotactic biopsy was taken; additionally, mycological tests from the ulcerated lesion and a bronchoalveolar lavage were performed. In the latter specimens, P. brasiliensis yeast cells were visualized and later on, the brain biopsy revealed the presence of the fungus. Treatment with itraconazole (ITZ) was initiated but clinical improvement was unremarkable; due to the fact that the patient was taking sodium valproate for seizure control, drug interactions were suspected and confirmed by absence of ITZ plasma levels. The latter medication was changed to clonazepam and after several weeks, clinical improvement began to be noticed and was accompanied by diminishing P. brasiliensis antigen and antibody titers. In the PCM endemic areas, CNS involvement should be considered more often and the efficacy of itraconazole therapy should also be taken into consideration.