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.

Criptococosis cerebral, voriconazol, niveles plasmáticos y síndrome de reconstitución inmune: reporte de un caso / Cerebral cryptococcosis and immune reconstitution inflammatory syndrome: case report

We report a 45-year-old male with AIDS who had a Cryptococcus neoformans central nervous system infection. He was treated with amphotericin B deoxycholate subsequently changed to voriconazole due to systemic toxicity of the former. Plasma levels of voriconazole were insufficient with a standard dose (0.7 μg/mL), therefore, the dose was increased thereafter to reach appropriate levels (4.5 μg/mL). Anti-retroviral therapy was started five weeks after voriconazole initiation with non-interacting drugs and he was discharged after a favorable evolution. He was re-admitted three months later due to seizures; a brain magnetic resonance showed new sub-cortical nodules. After excluding alternative causes and demonstrating fungal eradication, an immune reconstitution inflammatory syndrome (IRIS) event was suspected and treated with a short course of steroids. His evolution was satisfactory.

Efectos adversos de anfotericina B desoxicolato en neonatos del Hospital Nacional de Itauguá / Adverse effects of amphotericin B deoxycholate in neonates of the National Hospital of Itauguá

Introducción En las últimas décadas, el agente de elección para el tratamiento de la mayoría de las micosis sistémicas ha sido la anfotericina B que, a pesar de los efectos tóxicos, sigue teniendo un papel importante en el tratamiento de las infecciones micóticas. Objetivo Determinar los efectos adversos asociados al empleo de anfotericina B en neonatos del Servicio de Neonatología del Hospital Nacional de Itauguá, en el periodo 2013 - 2015. Materiales y métodos Estudio de serie de casos, retrospectivo, de recién nacidos con tratamiento con anfotericina B. Resultados: Entre 28 recién nacidos tratados con anfotericina B, hubo mayor prevalencia en el sexo masculino. Con respecto a la edad más de la mitad de los recién nacidos fueron pre-término en el grupo estudiado. Hubo predominio de bajo peso al nacer (32,14%). Los factores de riesgo arrojaron que 53,5% no contaba con antecedentes de sepsis. La edad media de inicio de anfotericina fue 19±9 días, más de la mitad de los neonatos utilizó dosis progresiva de 0,5 mg/kp/día a 1 mg/kp/día, en 24 hs.El 96,4% recibió infusión de anfotericina B de 4 horas, 1 caso requirió 6 horas. Entre los efectos secundarios, 35,7% de los pacientes presentó anemia, el disturbio hidroelectrolítico más frecuente fue la hipokalemia, entre los signos se destacaron la taquicardia e hipotensión. Conclusiones Los efectos secundarios más llamativos encontrados durante el tratamiento con anfotericina B fueron la anemia, alteraciones de Sodio y Potasio

Introduction In recent decades, the agent of choice for the treatment of most systemic mycoses has been amphotericin B which, despite the toxic effects, continues to play an important role in the treatment of fungal infections. Objective To determine the adverse effects associated with the use of amphotericin B in neonates of the Neonatology Service of the National Hospital of Itauguá, in the period 2013 - 2015. Materials and methods: retrospective case series study of newborns treated with amphotericin B. Results Among 28 newborns treated with amphotericin B, there was a higher prevalence in males. With regard to age, more than half of the newborns were pre-term in the group studied. There was a predominance of low birth weight (32.14%). The risk factors showed that 53.5% did not have a history of sepsis. The mean age of onset of amphotericin was 19 ± 9 days, more than half of the infants used progressive dose from 0.5 mg / kp / day to 1 mg / kp / day, in 24 hours. 96.4% received infusion of amphotericin B for 4 hours, 1 case required 6 hours. Among the side effects, 35.7% of the patients presented anemia, the most frequent water and electrolyte disturbance was hypokalemia, among the signs were tachycardia and hypotension. Conclusions The most striking side effects found during treatment with amphotericin B were anemia, Sodium and Potassium alterations.

Relapse of kala-azar after use of multiple drugs: A case report and brief review of literature.

We present a case of kala-azar infection that recurred in a patient after completion of the standard treatment course of miltefosine, amphotericin B-deoxycholate (short course), and amphotericin B lipid formulations. The patient was cured after continuous amphotericin B-deoxycholate administration for 4 weeks. This is a unique case of relapse following the use of three important drugs. Although amphotericin B-deoxycholate is a second line drug in Nepal, it has shown a satisfactory clinical response with continuous treatment for 4 weeks. Therefore, an extended course of amphotericin B-deoxycholate may be beneficial in patients with resistance to the standard short course and other anti-leishmania drugs.

Mecanismos moleculares desencadenados por el deoxicolato de sodio en intestino: implicancias en la absorción intestinal de calcio / Molecular mechanisms triggered by sodium deoxycholate in intestine: implications in intestinal calcium absorption

Altas concentraciones de deoxicolato de sodio (DXCS) producen efectos tóxicos en el intestino. Este estudio explora el efecto de concentraciones fisiológicas altas de DXCS sobre la absorción intestinal de Ca2+ y los mecanismos moleculares involucrados. Para ello, se usaron pollos de 4 semanas de edad, los cuales se dividieron en dos grupos: controles y tratados con DXCS en la luz intestinal, a diferentes tiempos y concentraciones. La absorción intestinal de Ca2+ se midió por la técnica del asa intestinal ligada in situ. Se estudió la expresión de genes y de proteínas involucradas en la vía transcelular de la absorción del catión. El contenido de glutatión (GSH) y la actividad de enzimas del sistema antioxidante se evaluaron por espectrofotometría. La producción de ROS se determinó por espectrometría de resonancia de espín y los cambios en la permeabilidad de la membrana interna itocondrial mediante la técnica de swelling. La apoptosis se estudió a través de la localización subcelular de citocromo c por Western blot y la fragmentación del ADN por la técnica de TUNEL. DXCS inhibió la absorción intestinal de Ca+2, efecto que fue dependiente de la concentración de la sal biliar. La expresión del ARNm de la Ca+2- ATPasa disminuyó por el tratamiento con la sal biliar y lo mismo ocurrió con la expresión de las proteínas involucradas en el proceso de absorción del catión: Ca+2- ATPasa, intercambiador Na+/Ca+2 y calbindina D28k. DXCS produjo estrés oxidativo, a juzgar por la generación de ROS, la depleción de glutatión y el swelling mitocondrial. Además, la presencia del antioxidante quercetina en el medio de incubación bloqueó el efecto inhibitorio del DXCS sobre la absorción intestinal de Ca+2.

SUMMARY: High concentrations of sodium deoxycholate (NaDOC) produce toxic effects. This study explores the effect of a single high concentration of NaDOC on the intestinal Ca2+ absorption and the underlying mechanisms. Chicks were divided into two groups: 1) controls, 2) treated with different concentrations of NaDOC in the duodenal loop for variable times. Intestinal Ca2+ absorption was measured as well as the gene and protein expression of molecules involved in the Ca2+ transcellular pathway. Glutathione (GSH) content and the activity of antioxidant enzymes were assessed by spectrophotometry. ROS was determined by spin resonance spectrometry and permeability changes of the internal mitochondrial membrane by the swelling technique. Apoptosis was studied by cytochrome localization through Western blot and DNA fragmentation (TUNEL procedure). NaDOC inhibited the intestinal Ca2+ absorption, which was dose dependent. Ca2+- ATPase mRNA decreased by the ile salt and the same occurred with the protein expression of Ca2+-ATPase, calbindin D28k and Na+/Ca2+ exchanger. NaDOC produced oxidative stress as judged by ROS generation, mitochondrial swelling and glutathione depletion. Furthermore, the antioxidant quercetin blocked the inhibitory effect of NaDOC on the intestinal Ca2+ bsorption. Apoptosis was also triggered by the bile salt, as indicated by the TUNEL staining and the cytochrome crelease from the mitochondria. As a compensatory mechanism, enzyme activities of the antioxidant system were all increased, but the cellular redox state was not normalized. In conclusion, a single high dose of NaDOC inhibits intestinal Ca2+.

Uso de anfotericina B deoxicolato y sus reacciones adversas en un hospital universitario en Chile / Amphotericin B deoxycholate prescription and adverse events in a Chilean university hospital

Amphotericin B deoxycholate is associated with infusion-related toxicity and renal toxicity. Purpose: To evaluate medical indications of this compound in a tertiary care center, analyze adverse reactions, infusion protocols and outcome of treated patients. Patients and methods: Retrospective analysis of 39 treatments indicated in 33 patients during 2007, exploring indications, infusion protocols and renal protective measures, infusion-related adverse reactions, nephrotoxicity, hypokalemia and outcomes. Results: On average, therapy lasted 12 days (2 to 39) and reached 600 mg of accumulated dose (100 to 1950) respectively. 24-hours infusions were applied in 63.2 percent of prescriptions and 35.9 percent received a 4-6 hour infusion schedule. In addition, 36.8 percent received daily a saline infusion before amphotericin. Adverse reactions were observed in 40 percent of treatments, predominating fever (25 percent). Nonetheless, nephrotoxicity was infrequent (9.4 percent), of low magnitude, only affecting patients without previous renal disease, and not requiring dialysis. Hypokalemia developed in 21.6 percent of treatments. More than half of medical indications were empirical (59 percent), for presumed infections by either filamentous fungi or yeasts. In the subgroup with microbiological information, main indications were invasive aspergillosis (15.4 percent of total), systemic candidiasis (12.8 percent) or meningeal cryptococcosis (10.3 percent). A favorable response was registered in 41 percent, and only 48.5 percent of patients survived. In a multivariate analysis, only age > 60 years remained as an independent factor for developing infusion-related adverse reactions. In the same manner, a SOFA score > 3 and corticosteroids administration at the same time than amphotericin B, were independently associated to a fatal outcome. Conclusion: infusion-related adverse reactions are frequent during amphotericin B deoxycholate therapy, but renal...

Anfotericina B deoxicolato se asocia a reacciones adversas durante la infusión y a nefrotoxicidad. Objetivo: Evaluar las indicaciones de anfotericina B deoxicolato en un hospital universitario, las reacciones adversas asociadas, los protocolos de administración y el desenlace de los pacientes tratados. Pacientes y Métodos: Se efectuó un estudio retrospectivo con el total de tratamientos efectuados durante el año 2007 en el Hospital Clínico de la Universidad de Chile, identificando 39 tratamientos en 33 pacientes. Se analizaron las indicaciones, dosis, protocolos de administración, efectos adversos relacionados a la infusión (fiebre, calofríos, vómitos o flebitis), nefrotoxicidad, hipokalemia y además la evolución de los pacientes. Resultados: La duración promedio del tratamiento fue de 12 días (2-39) con una dosis acumulada promedio de 600 mg totales (100-1.950 mg). Un 63,2 por ciento de los tratados recibió infusiones de 24 horas y 35,9 por ciento, infusiones de 4 a 6 horas. Además, 36,8 por ciento fue sometido a precargas salinas. Un 40 por cientoo de los tratamientos se acompañó de reacciones adversas asociadas a la infusión, predominando la fiebre (25 por ciento). Sin embargo, la nefrotoxicidad fue de baja magnitud (9,4 por cientoo), sólo presente en pacientes sin falla renal previa y en ningún caso determinó el inicio de diálisis. La hipokalemia se presentó en ocho tratamientos (21,6 por ciento). Más de la mitad de las indicaciones fueron empíricas (59 por cientoo), ya fuese para el tratamiento presunto de hongos filamentosos (aspergilosis o mucormicosis) o levaduras (candidiasis sistémica). En el subgrupo con datos micro-biológicos, las principales indicaciones fueron aspergilosis invasora (15,4 por ciento de los 39 tratamientos), candidiasis sistémica (12,8 por ciento) o criptococosis meníngea (10,3 por ciento). Un 41 por cientoo de los pacientes tuvo una respuesta favorable a los tratamientos y sólo 48,5 por cientoo sobrevivió...

Implementation of clinical practice policy on the continuous intravenous administration of amphotericin B deoxycholate.

BACKGROUND: Systemic fungal infections have significantly increased. The mainstay of treatment is amphotericin B deoxycholate. A limitation of using amphotericin B includes infusion-related reactions and nephrotoxicity. A continuous infusion of amphotericin B was found to reduce nephrotoxicity and infusion-related reactions. OBJECTIVE: To implement clinical practice policy on the continuous intravenous administration of amphotericin B in the patients hospitalized in general medical wards at Siriraj Hospital. METHOD: A one-page evidence-based clinical practice policy on continuous intravenous administration of amphotericin B was prepared and disseminated to all general medical wards in Siriraj Hospital. The information on the patients who received amphotericin B treatment between March 2004 and March 2006 was collected. The data were analyzed using descriptive statistics, univariate analysis and multivariate analysis as appropriate. A p-value of < 0. 05 was considered statistically significant. RESULTS: Of 166 courses of amphotericin B treatment in 148 patients, 102 courses (61.4%) were given continuous intravenous administration of amphotericin B (CI group) and 64 courses (38.6%) were given conventional 4-to 6-hour intravenous administration (RI group). The mean age of the patients in the CI group was significantly greater than that in the RI group. The CI group had more patients with neutropenia with persistent fever whereas the RI group had more patients with HIV/AIDS and cryptococcal meningitis. The incidence of amphotericin B-related nephrotoxicity was 27.5% in the CI group compared with 39.1% in the RI group (p = 0.164). Chills were observed in 6.9% of the patients in the CI group compared with 26.6% in the RI group (p = 0. 001). Overall mortality at the end of therapy was significantly higher in the CI group. However, most of the deaths in the CI group were unrelated to fungal infections or amphotericin administration. CONCLUSION: Continuous infusion of amphotericin B was associated with a decrease in infusion-related reactions and tended to have less nephrotoxicity than those in the 4-to 6-hour infusion group.

Continuous infusion of amphotericin B: preliminary experience at Faculdade de Medicina da Fundação ABC

CONTEXTO E OBJETIVO: Pacientes neutropênicos com febre persistente podem apresentar infecções fúngicas com freqüência. A administração de anfotericina B deoxicolato tem sido padrão para estes pacientes, no entanto sua infusão endovenosa, usualmente administrada em quatro horas, pode levar a nefrotoxicidade, hepatotoxicidade e efeitos adversos relacionados à infusão, como tremores e calafrios. A literatura evidencia que o uso de anfotericina B deoxicolato em infusão contínua de 24 horas pode ser menos tóxica em relação à administração usual. O objetivo do estudo foi avaliar a eficácia, segurança e toxicidade da anfotericina B infusional contínua em pacientes onco-hematológicos após quimioterapia com neutropenia febril persistente. TIPO DE ESTUDO E LOCAL: Estudo observacional e retrospectivo de nossa experiência com anfotericina B deoxicolato em infusão contínua de 24 horas, na Faculdade de Medicina da Fundação ABC e Hospital Estadual Mário Covas, em Santo André. MÉTODOS: No período entre outubro de 2003 e maio de 2004, 12 pacientes com neoplasias hematológicas e neutropenia febril induzida por quimioterapia receberam 13 ciclos de anfotericina B deoxicolato infusional. RESULTADOS: A dose média da infusão foi de 0,84 mg/kg/dia. O uso concomitante de outras drogas nefrotóxicas ocorreu em 92% dos ciclos. Foram observados nefrotoxicidade em 30,76%, hipocalemia em 16,67%, hepatotoxicidade em 30% e efeitos adversos relacionados à infusão em 23% dos ciclos. Todos os pacientes sobreviveram aos sete primeiros dias após o início do tratamento e a resolução clínica ocorreu em 76% dos ciclos. CONCLUSÃO: A infusão contínua de anfotericina B é exeqüível para uso em nossa instituição como alternativa à infusão em quatro horas (mais tóxica) e possivelmente às caras formulações lípidicas desta droga.

Comparison of regimens of amphotericin B deoxycholate in kala-azar.

A total of 288 parasitologically proved patients of kala-azar were randomly allocated to three treatment groups. Patients in groups A, B and C received amphotericin B (AMB) in a dose of 1 mg/kg body weight (bw)/day, 0.75 mg/kg bw/day and 0.5 mg/kg bw/day for 20 days respectively. Apparent cure (afebrile at the end of therapy) occurred in all patients and parasitological cure in 96 (100%), 92 (96%) and 84 (88%) patients respectively in groups A, B and C. Ultimate cure (no relapse in six months of follow up) occurred in 95 (99%), 87 (91%) and 79 (82%) patients in groups A, B and C respectively. The difference between the ultimate cure in the three groups was significant (P < 0.05). The incidence of adverse events (rise in serum creatinine and fall in serum potassium, loss of appetite and shivering, rigor and fever during infusion indicative of renal, GIT and infusion related toxicities respectively) was similar in the three groups. This study showed that amphotericin B should be given at a dosage of 1 mg/kg bw/day for 20 days for Indian kala-azar patients to minimise relapses and prevent development of drug unresponsiveness.

Inability of amphotericin B(Fungizone) or of sodium deoxycholate to alter natural drug resistance or sensitivity of transplanted murine leukemias.

The ability of Amphotericin B ('Fungizone') to alter the natural resistance of leukemia L1210 to vincristine was studied in BDF1 mice Neither Fungizone nor the "solubilizing agent" sodium deoxycholate, when used in combination with vincristine potentiated the activity of the drug against L1210. There was no change in the activity pattern of 5-fluorouracil against L1210 or vincristine against P388 lymphocytic leukemia respectively, which are sensitive to these drugs. Thus, both Fungizone and sodium deoxycholate failed to improve the activity of the drugs in either a naturally resistant or sensitive murine leukemia in vivo.