Efficacy of the Benznidazole+Posaconazole combination therapy in parasitemia reduction: An experimental murine model of acute Chagas

Abstract INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. METHODS Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. RESULTS All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.

Uso de posaconazol en niños: experiencia en un hospital pediátrico de alta complejidad / Use of posaconazole in children: Experience in a tertiary pediatric hospital

La información sobre el uso de posaconazol en niños es escasa. Se realizó este estudio descriptivo retrospectivo entre agosto de 2010 y marzo de 2017 para evaluar las características clínicas, microbiológicas y la evolución de los pacientes tratados con posaconazol. Se incluyeron 16 niños. Mediana de edad: 161 meses (rango intercuartílico -RIC- 69-173 m). Todos tenían enfermedad subyacente y presentaban infección fúngica invasiva probada. Los aislamientos más frecuentes fueron Mucor spp. y Aspergillus spp. La dosis media de posaconazol fue 600 mg/día (400-800 mg/día) y la mediana de duración del tratamiento, 223 días (RIC 48-632). Diez pacientes presentaron efectos adversos, pero solo uno requirió suspensión del antifúngico debido a alteraciones hidroelectrolíticas.

There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR-69-173m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg /day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders.

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.

Posaconazol (Noxafil®) suspensión y comprimidos no deben utilizarse indistintamente sin realizar un ajuste de dosis / Posaconazole (Noxafil®) suspension and tablets should not be used interchangeably without making a dose adjustment

El posaconazol es un antifúngico de amplio espectro de la familia de los triazólicos que se utiliza en el tratamiento y profilaxis de infecciones micóticas invasivas en pacientes de 13 años de edad o mayores, en las cuales otros tratamientos no han sido eficaces o tolerados. En junio de 2016 la Agencia Europea de Medicamentos y la Agencia Española de Medicamentos y Productos Sanitarios emitieron un alerta donde advierten que debido a diferencias en la frecuencia de dosificación, interacción con los alimentos y en los niveles plasmáticos alcanzados por el medicamento, los comprimidos y la suspensión de posaconazol no son intercambiables. (AU)

Posaconazole is a broad-spectrum triazole family antifungal used in the treatment and prophylaxis of invasive fungal infections in patients 13 years of age or older, in which other treatments have not been effective or tolerated. In June 2016 the European Medicines Agency and the Spanish Agency for Medicines and Health Products issued a warning alerting that because of differences in the frequency of dosing, interactions with food and plasma levels achieved by the drug, tablets and posaconazole suspension are not interchangeable. (AU)

Minimal Stimulation Using Gonadotropin Combined with Clomiphene Citrate or Letrozole for Intrauterine Insemination

PURPOSE: To evaluate the efficacy of minimal stimulation using discretely administered gonadotropin combined with clomiphene citrate (CC) or letrozole (LTZ) for intrauterine insemination (IUI) cycles. MATERIALS AND METHODS: Total 257 IUI cycles from 158 infertile couples were assessed. A CC dose of 100 mg/day (n=126 cycles) or a LTZ dose of 5 mg/day (n=131 cycles) was administered on days 3-5 of the menstrual cycle for 5 days. Each group received human menopausal gonadotropin at a dose of 150 IU by two or three alternative day: CC combined with alternate-day regimen for 2 or 3 days (CC+300, n=37; CC+450, n=89) and LTZ combined with alternate-day regimen for 2 or 3 days (LTZ+300, n=36; LTZ+450, n=95). RESULTS: The clinical pregnancy rate was comparable between the CC and LTZ groups (18.3% vs. 13.0%, p=0.243). The clinical pregnancy rate also showed no significant difference among the 4 groups (21.6% vs. 16.9% vs. 11.1% vs. 12.6%, p=0.507). The multiple pregnancy rate was significantly higher in LTZ compared to CC group (37.5% vs. 8.7%, p=0.028) and in the LTZ+450 compared to CC+450 group (50% vs. 13.3%, p=0.038). Overall, there were 15 cases of ovarian hyperstimulation syndrome (OHSS), with the prevalence being significantly lower in the LTZ compared to CC group (1.5% vs. 10.3%, p=0.003). OHSS was more prevalent in the CC+450 compared to the LTZ+450 group (12.4% vs. 1.1%, p=0.002). CONCLUSION: Our findings suggest that minimal stimulation using two alternate-day gonadotropin with LTZ decreases the development of OHSS and multiple pregnancies, while maintaining comparable pregnancy rates in IUI cycles.

Minimal Stimulation Using Gonadotropin Combined with Clomiphene Citrate or Letrozole for Intrauterine Insemination

PURPOSE: To evaluate the efficacy of minimal stimulation using discretely administered gonadotropin combined with clomiphene citrate (CC) or letrozole (LTZ) for intrauterine insemination (IUI) cycles. MATERIALS AND METHODS: Total 257 IUI cycles from 158 infertile couples were assessed. A CC dose of 100 mg/day (n=126 cycles) or a LTZ dose of 5 mg/day (n=131 cycles) was administered on days 3-5 of the menstrual cycle for 5 days. Each group received human menopausal gonadotropin at a dose of 150 IU by two or three alternative day: CC combined with alternate-day regimen for 2 or 3 days (CC+300, n=37; CC+450, n=89) and LTZ combined with alternate-day regimen for 2 or 3 days (LTZ+300, n=36; LTZ+450, n=95). RESULTS: The clinical pregnancy rate was comparable between the CC and LTZ groups (18.3% vs. 13.0%, p=0.243). The clinical pregnancy rate also showed no significant difference among the 4 groups (21.6% vs. 16.9% vs. 11.1% vs. 12.6%, p=0.507). The multiple pregnancy rate was significantly higher in LTZ compared to CC group (37.5% vs. 8.7%, p=0.028) and in the LTZ+450 compared to CC+450 group (50% vs. 13.3%, p=0.038). Overall, there were 15 cases of ovarian hyperstimulation syndrome (OHSS), with the prevalence being significantly lower in the LTZ compared to CC group (1.5% vs. 10.3%, p=0.003). OHSS was more prevalent in the CC+450 compared to the LTZ+450 group (12.4% vs. 1.1%, p=0.002). CONCLUSION: Our findings suggest that minimal stimulation using two alternate-day gonadotropin with LTZ decreases the development of OHSS and multiple pregnancies, while maintaining comparable pregnancy rates in IUI cycles.

An unusual case of invasive aspergillus ulcerative tracheobronchitis without involvement of lung parenchyma in a post-renal transplant patient.

We present the case of a 54-year-old male, who presented with respiratory complaints four months after he underwent renal transplantation. Bronchoscopy showed ulcerated mucosa of the left main bronchus and computed tomography (CT) of the thorax showed foci of air within the bronchial wall. A biopsy from the lesion showed septate fungal hyphae, dichotomously branching at acute angles. A locally invasive Aspergillus ulcerative tracheobronchitis with no parenchymal involvement is an important cause of tracheobronchitis in post-renal transplant patients. An early diagnosis and institution of appropriate treatment can improve the outcome. A combination treatment of caspofungin and voriconazole can be considered if patient is not responding to voriconazole alone.

Induction of oxidative stress and histopathological changes by sub-chronic doses of triazophos.

The effect of triazophos (O, O-diethyl O-1-phenyl-1 H-1, 2, 4-triazol-3-yl phosphorothioate), a widely used insecticide was studied on the induction of oxidative stress and histological alterations at sub-chronic doses in male albino rats. Oral administration of triazophos at concentrations of 1.64, 3.2 and 8.2 mg/kg body wt for 30 days produced dose as well as time-dependent increase in the lipid peroxidation (determined by malondialdehyde levels) and glutathione-S-transferase (GST) activity in serum with a concomitant decrease in ferric reducing ability of plasma (FRAP) and blood glutathione (GSH) content. Histopathological examination of liver of triazophos-treated rats showed significant and progressive degenerative changes as compared to control, which could be due to induction of oxidative stress. However, no significant histopathological changes were observed in spleen, kidney and brain at either dose of triazophos with respect to control. These results indicated that oral administration of triazophos was associated with enhanced lipid peroxidation and compromised antioxidant defence in rats in dose and time-dependent manner. Thus the present study demonstrated for the first time the role of oxidative stress as the important mechanism involved in the stimulation of hepatic histo-architectural alterations at sub-chronic doses of triazophos in rats.

In vitro Evaluation of Antibiotic Lock Technique for the Treatment of Candida albicans, C. glabrata, and C. tropicalis Biofilms

Candidaemia associated with intravascular catheter-associated infections is of great concern due to the resulting high morbidity and mortality. The antibiotic lock technique (ALT) was previously introduced to treat catheter-associated bacterial infections without removal of catheter. So far, the efficacy of ALT against Candida infections has not been rigorously evaluated. We investigated in vitro activity of ALT against Candida biofilms formed by C. albicans, C. glabrata, and C. tropicalis using five antifungal agents (caspofungin, amphotericin B, itraconazole, fluconazole, and voriconazole). The effectiveness of antifungal treatment was assayed by monitoring viable cell counts after exposure to 1 mg/mL solutions of each antibiotic. Fluconazole, itraconazole, and voriconazole eliminated detectable viability in the biofilms of all Candida species within 7, 10, and 14 days, respectively, while caspofungin and amphotericin B did not completely kill fungi in C. albicans and C. glabrata biofilms within 14 days. For C. tropicalis biofilm, caspofungin lock achieved eradication more rapidly than amphotericin B and three azoles. Our study suggests that azoles may be useful ALT agents in the treatment of catheter-related candidemia.

Successful management of presumed Candida endogenous endophthalmitis with oral voriconazole.

Endogenous fungal endophthalmitis is most commonly caused by Candida species and usually occurs in patients with chronic diseases such as diabetes mellitus and renal insufficiency. Voriconazole, a broad-spectrum triazole antifungal agent, attains therapeutically significant concentrations in the vitreous cavity after systemic administration. We report, the successful management of presumed endogenous Candida endophthalmitis in a patient with multiple diseases and unstable systemic status with oral voriconazole. Though fungal endophthalmitis has been successfully treated with a combination of intravenous and intravitreal voriconazole, to the best of our knowledge this is the first report in ophthalmic literature (Medline Search) on the treatment of fungal endophthalmitis with only the oral route of administration of voriconazole.

Topical and Oral Voriconazole in the Treatment of Fungal Keratitis

We describe two patients with fungal keratitis refractory to standard antifungal therapy whose conditions were managed with voriconazole. The first case is a patient with endophthalmitis and corneal ulcer due to Candida parapsilosis after receiving a corneal transplant. The patient was treated with amphotericin but showed no signs of improvement. Topical voriconazole, oral voriconazole, and intravitreal voriconazole yielded signs of improvement. The second case is a 63-year-old male who underwent a month of empiric treatment with 0.2% topical amphotericin for fungal keratitis but showed no signs of improvement. Treatment was then provided with 1% voriconazole. Both cases showed effective treatment with voriconazole. Voriconazole may be considered as a new method to treat fungal keratitis refractory to standard antifungal therapy.

Treatment of invasive fungal infections: stability of voriconazole infusion solutions in PVC bags

Voriconazole is a novel broad-spectrum antifungal drug, employed in the treatment of invasive fungal infections, and represents an alternative to amphotericin B treatment. The manufacturer recommends that any unused reconstituted product should be stored at 2ºC to 8ºC, for no more than 24 h, but no recommendations about i.v. infusion solutions are given. Previous works have reported on the stability of voriconazole in polyolefin bags and just one in 5 percent dextrose polyvinyl chloride (PVC) bags, at a 4 mg.mL-1 concentration. In this work, the stability of voriconazole as an i.v. infusion solution in 0.9 percent sodium chloride and in 5 percent dextrose, in PVC bags, at 0.5 mg.mL-1, stored at 4 ºC and at room temperature, protected from light, was evaluated. These infusion solutions were analyzed for a 21-day period. Chemical stability was evaluated by HPLC assay. Visual inspection was performed and pH of the solutions was measured. No color change or precipitation in the solutions was observed. The drug content remained above 90 percent for 11 days in 0.9 percent sodium chloride and for 9 days in 5 percent dextrose solutions. The i.v. infusion solutions stored at room temperature were not stable. At room temperature, the voriconazole content dropped down to 88.3 and 86.6 percent, in 0.9 percent sodium chloride or 5 percent dextrose solutions, respectively, two days after admixture. Assays performed at the end of the study suggest the sorption of voriconazole by the PVC bags. The results of this study allow cost-effective batch production in the hospital pharmacy.

Anterior chamber exudative mass due to Scedosporium apiospermum in an immunocompetent individual.

Endogenous intraocular infection of fungal etiology is extremely rare in an immunocompetent individual. Usually, an antecedent history of trauma, surgery, intravenous drug abuse or an immunocompromized state can be elicited. Scedosporium apiospermum is a known cause of keratomycosis after traumatic implantation and can cause fatal disseminated infection in immunocompromized patients. However, cases of S. apiospermum intraocular infection in immunocompetent individuals have been very rarely reported in literature. We report here a case of an anterior chamber exudative mass due to S. apiospermum in an immunocompetent individual which was managed successfully with anterior chamber wash and intravitreal injection of voriconazole.

Use of oral voriconazole as adjunctive treatment of severe cornea fungal infection: case report

O presente trabalho descreve o emprego do voriconazol sistêmico como adjuvante no tratamento de ceratite micótica grave por Aspergillus flavus.

Efficacy of letrozole for advanced breast cancer in postmenopausal patients

To evaluate the clinical benefit and tolerability of letrozole after tamoxifen failure in locally advanced, recurrent or metastatic breast cancer in postmenopausal patients. A phase II non-randomized trial Oncology Department, Combined Military Hospital, Rawalpindi, from March 1999 to February 2001 over a period of 2 years. One hundred and seventeen patients with tamoxifen failure were treated with letrozole 2.5 mg once daily, through oral route. All the accrued patients were either estrogen/progesterone receptor positive or unknown with KPS of more than 50%. Patients who had prior hormone therapy other than tamoxifen, or more than one chemotherapy for recurrent or advanced disease were not enrolled in the study. Time to progression [TTP] was the primary objective, whereas objective response [OR], duration and rate of clinical benefit [complete response + partial response + stable disease >6 months], tolerability and effects on quality of life were the secondary end points. The clinical benefit was 47.0% with an objective response of 28.2%. The objective response and median time to progression in soft tissue disease was better than in the visceral and bone disease. The median time to progression for patients having positive estrogen receptor / progesterone receptors [ER/PR] was 9.5 months which is slightly higher than in patients having unknown ER/PR status. The treatment with letrozole was well-tolerated with side effects observed in only 14 patients. Letrozole is an effective hormone therapy after tamoxifen failure since it has significant clinical benefit and objective response. It can be safely used as second line hormone therapy in postmenopausal patients with locally advanced or metastatic breast cancer

Itraconazol en el tratamiento de dermatomicosis del cuerpo, ingles e interdigital de pies: valoración de la eficacia de una dosis de 200 mg por 7 días / Itraconazole 200 mg orally once daily for seven days in the treatment of tinea corporis, tinea cruris and pedis

Se trataron 62 pacientes entre 14 y 59 años de edad, con diagnóstico de dermatomicosis del cuerpo, crural o interdigital. El tratamiento consistió en la administración de 200 mg de itraconazol por 7 días. En 43 pacientes se tuvieron cultivos positivos, siendo el hongo más frecuente T. rubrum (28 por ciento), seguido por C. albicans (19 por ciento). Se evaluaron los síntomas de eritema, descamación, fisura, prurito y vesículas. Se encuentra diferencia significativa en la mejoría de los síntomas entre el inicio y los 7 días de tratamiento. Al final del estudio se evalúan 25 pacientes como éxito terapéutico, 36 como mejoría marcada y sólo se presenta un fracaso en el tratamiento. Se concluye la eficacia de este plan de tratamiento

Compuestos triazólicos en el tratamiento de la histoplasmosis diseminada experimental del hamster / Triazoles compound in the treatment of disseminated experimental histoplasmosis in hamsters

Se llevó a cabo un estudio comparativo de la eficacia de cuatro compuestos triazólicos en el tratamiento de la histoplasmosis experimental del hamster. Fueron utilizados en total 110 hamsters, de ambos sexos. Estos animales se inocularon por vía intracardíaca con una suspensión de la fase levaduriforme del Histoplasma capsulatum. Los tratamientos comenzaron 1 semana después de la infección y se prolongaron por 3 semanas. Todas las drogas fueron administradas por gastroclisis una vez por día, a las dosis de 8 y 16 mg/kg de peso. Tres grupos de hamsters fueron empleados como control y recibieron los solventes de los antifúngicos estudiados. Fueron administrados los siguientes triazoles: itraconazol, fluconazol, Sch 39.304 y Bay r 3783. Todos los animales se sacrificaron una semana después de terminados los tratamientos. La evaluación de los resultados se realizó en base a los siguientes criterios: 1)Aspecto macroscópico de higado y bazo, 2)examen microscópico de frotis teñidos con Giemsa de los mismos órganos, 3)cortes histológicos de bazo teñidos por el método de P.A.S.y 4)cultivos de bazo (cultivos masivos de un homogeneizado del órgano y determinación de U.F.C/g). El itraconazol y el Sch 39.304 redujeron en forma muy marcada las alteraciones macroscópicas, la positividad de los exámenes microscópicos y los cultivos. Los animales tratados con fluconazol y con Bay r 3783 a la dosis de 16 mg/kg/día, sólo mostraron escasa reducción del número de U.F.C/g de bazo, en relación a los controles. El itraconazol es una droga de probada eficacia en la histoplasmosis humana. El Sch 39.304 parece ser un antifúngico interesante en el tratamiento de esta enfermedad, en especial si se tienen en cuenta sus propiedades fármaco-cinéticas distintas de las itraconazol lo que facilitaría su aplicación en otras localizaciones de la histoplasmosis diseminada

Terconazol creme 0,8%: tratamento da candidíase vaginal em 5 dias / Terconazole cream 0,8%: treatment of vaginal candidiasis during 5 days

Foram estudadas 30 pacientes, näo grávidas, portadoras de candidíase vaginal comprovada por exames micológicos, na Clínica Ginecológica da Faculdade de Medicina da Universidade de Säo Paulo, entre 1986 e 1987. A média etária foi 36 anos. Todas as pacientes foram medicadas com terconazol creme 0,8%, uma aplicaçäo vaginal por dia, durante 5 dias. Aos parceiros sexuais administrou-se cetoconazol na dose de 2 comprimidos de 200 mg por dia, durante 5 dias. Na avaliaçäo global o efeito terapêutico foi considerado excelente ou bom em 80,0% dos casos, regular em 7,0% e nulo em 13.0%. Tanto a microscopia como a cultura revelaram índice de cura de 87,0% nos controles. Nenhuma paciente apresentou efeitos colaterais, sendo a tolerabilidade considerada boa em todos os casos. Concluem os autores que a aplicaçäo tópica do terconazol a 0,8% é terapêutica efetiva e bem tolerada na candidíase vaginal