RESUMO
BACKGROUND: Recurrent vulvovaginal candidiasis affects nearly 138 million women globally each year. In the United States, fluconazole is considered the standard of care for acute vulvovaginal candidiasis, but until recently there was no US Food and Drug Administration-approved drug for the treatment of recurrent vulvovaginal candidiasis. Oteseconazole is a novel oral selective inhibitor of fungal lanosterol demethylase (sterol 14α-demethylase cytochrome P450, an enzyme required for fungal growth) approved for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: This study was conducted to evaluate the efficacy and safety of oral oteseconazole (VT-1161) in the prevention of recurrent culture-verified acute vulvovaginal candidiasis episodes through 50 weeks in participants with recurrent vulvovaginal candidiasis and to compare the efficacy of oteseconazole and fluconazole in the treatment of the presenting acute vulvovaginal candidiasis episode. STUDY DESIGN: Women and postmenarcheal girls aged ≥12 years with a history of recurrent vulvovaginal candidiasis (N=219) were enrolled at 38 US sites. Eligible participants presenting with an active vulvovaginal candidiasis infection entered an induction phase in which they were randomly assigned 2:1 to receive 600 mg oral oteseconazole on day 1 and 450 mg on day 2, with matching placebo capsules, or to 3 sequential 150-mg oral doses (once every 72 hours) of fluconazole, with matching placebo capsules. Following the 2-week induction phase, the 185 participants with resolved acute vulvovaginal candidiasis infection (a clinical signs and symptoms score of <3) entered the maintenance phase and received 150 mg of oteseconazole or placebo weekly for 11 weeks. Participants were observed for an additional 37 weeks. RESULTS: In the induction phase, oteseconazole was noninferior to fluconazole in the proportion of participants in the intent-to-treat population with resolved acute vulvovaginal candidiasis infection at the week 2 (day 14) test-of-cure visit, with 93.2% of participants on oteseconazole vs 95.8% on fluconazole achieving resolution. In the maintenance phase, oteseconazole was superior to placebo in the proportion of participants in the intent-to-treat population with ≥1 culture-verified acute vulvovaginal candidiasis episode through 50 weeks, 5.1% compared with 42.2%, respectively (P<.001). Overall, treatment-emergent adverse event rates were similar in both groups: 54% for participants who received oteseconazole in the induction and maintenance phases vs 64% for participants who received fluconazole in the induction phase and placebo in the maintenance phase. Most treatment-emergent adverse events in each group were mild or moderate, with 3.4% of treatment-emergent adverse events graded as severe or higher in the OTESECONAZOLE/oteseconazole group vs 4.2% in FLUCONAZOLE/placebo group. CONCLUSION: In participants with recurrent vulvovaginal candidiasis, oteseconazole was safe and efficacious in the treatment and prevention of recurrent acute vulvovaginal candidiasis episodes and was noninferior to vulvovaginal candidiasis standard-of-care fluconazole in the treatment of the presenting acute vulvovaginal candidiasis infection.
Assuntos
Candidíase Vulvovaginal , Infecções , Feminino , Humanos , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/induzido quimicamente , Fluconazol/uso terapêutico , Fluconazol/efeitos adversos , Administração Oral , Antifúngicos/efeitos adversosRESUMO
INTRODUCTION: Adrenal insufficiency (AI) is a potentially life-threatening endocrine abnormality rarely associated with azole antifungals. Patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) are at high risk of invasive fungal infection and frequently receive azoles. Signs and symptoms of AI, such as gastrointestinal symptoms, lethargy, and electrolyte disturbances frequently overlap with common alloHCT toxicities, such that azole-induced AI may be under-reported in this population. CASE REPORT: We report the first published case of azole-induced AI following alloHCT. The patient presented with orthostasis and nonspecific gastrointestinal and failure to thrive symptoms in the setting of roughly 6 weeks of fluconazole prophylaxis. The patient was found to have primary AI diagnosed via low serum cortisol and inadequate response to cosyntropin. MANAGEMENT & OUTCOME: AI symptoms resolved with hydrocortisone supplementation and recurred upon rechallenge with fluconazole. The patient had fluconazole permanently discontinued with resolution of symptoms. We rate this case as a probable adverse drug reaction on the Naranjo scale. DISCUSSION: AI may be underreported and misdiagnosed in the alloHCT population given the presence of multiple toxicities with overlapping features. Clinicians must be diligent in investigating adrenal function in patients undergoing alloHCT on azole antifungals who present with symptoms of AI.
Assuntos
Insuficiência Adrenal , Transplante de Células-Tronco Hematopoéticas , Humanos , Fluconazol/efeitos adversos , Antifúngicos/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Azóis/efeitos adversos , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/tratamento farmacológicoRESUMO
OBJECTIVES: Vulvovaginal candidiasis (VVC) is an infection of the vagina's mucous membranes, caused by Candida albicans in more than 90% of acute VVC. Several topical and oral azole agents are available in a variety of formulations, and all seem to have similar effectiveness. Azoles are fungistatic, meaning that the fungi are inhibited from growth or replication but are not eradicated. Recurrent infection and developing azole resistance demonstrate a significant need for alternative treatments. MATERIALS AND METHODS: One hundred twenty-six women were randomized to 1 of the following 3 treatment cohorts: CD101 3% gel (n = 50) applied intravaginally on days 1 and 2, CD101 6% ointment (n = 50) applied intravaginally on day 1, or oral fluconazole 150 mg (n = 26) on day 1. Primary outcomes of clinical and mycological cure, as demonstrated by changes in the vaginal scores and mycological culture, were assessed on day 7 (±2 days), day 14 (±2 days), and day 28 (±7 days). Safety assessments included treatment-emergent adverse events. RESULTS: Ninety-nine women with positive Candida culture remained in the modified intent-to-treat population with 40 in each CD101 arm and 19 in the fluconazole arm. In the CD101 gel, CD101 ointment, and oral fluconazole groups, 35%, 30%, and 52.6% demonstrated clinical cure and 45%, 40%, and 57.9% had mycological cure at day 28, respectively. CONCLUSIONS: CD101 3% gel and CD101 6% ointment were well tolerated and produced similar rates of clinical and mycological cure in patients with an acute, moderate-to-severe episode of VVC. However, cure rates for these 2 formulations and regimens of CD101 were lower than those in patients treated with fluconazole.
Assuntos
Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Equinocandinas/administração & dosagem , Fluconazol/administração & dosagem , Administração Oral , Administração Tópica , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Equinocandinas/efeitos adversos , Feminino , Fluconazol/efeitos adversos , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: The treatment of cutaneous leishmaniasis (CL) caused by Leishmania braziliensis in Brazil with pentavalent antimony (Sbv) is associated with a high rate of failure, up to 45% of cases. In addition, Sbv can only administered parenterally and has important toxic effect. An effective, safe, and oral treatment for CL is required. METHODS: A randomized controlled clinical trial was conducted to compare the efficacy and safety of high-dosage oral fluconazole (6.5-8.0 mg/kg/d for 28 days) versus a standard Sbv protocol (20 mg/kg/d for 20 days) for the treatment of CL in Bahia, Brazil. RESULTS: A total of 53 subjects were included in the trial; 26 were treated with Sbv, and 27 with fluconazole. Intention-to-treat analysis showed initial cure rates (2 months after treatment) of 22.2% (6 of 27) in the fluconazole and 53.8% (14 of 26) in the Sbv group (P = .04). Six months after treatment, the final cure rate remained the same in both groups, without any relapses. The frequencies of adverse effects in the Sbv and fluconazole groups were similar, 34.6% versus 37% respectively. One patient treated with fluconazole discontinued treatment owing to malaise, headache, and moderate dizziness (Common Terminology Criteria for Adverse Events grade 2). CONCLUSIONS: Oral fluconazole at a dosage of 6.5-8 mg/kg/d for 28 days should not be considered an effective treatment for CL caused by L. braziliensisClinical Trials Registration. NCT01953744.
Assuntos
Antiprotozoários/uso terapêutico , Fluconazol/uso terapêutico , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Adolescente , Adulto , Antimônio/administração & dosagem , Antimônio/efeitos adversos , Antimônio/uso terapêutico , Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Brasil , Feminino , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Leishmania braziliensis/genética , Leishmaniose Cutânea/diagnóstico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso Anidulafungina en pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol. Aspectos Generales: La candidiasis sistémica es una patología con alta morbilidad y mortalidad (1). La colonización por candida spp. se desarrolla en hasta el 80 % de los pacientes críticos que permanecen más de una semana en cuidados intensivos, mientras que la candidiasis invasiva se documenta en sólo un 5 a un 10% de ellos. El tiempo de diagnóstico puede ser afectado por la complejidad que representa en sus criterios, causando retrasos en el inicio del tratamiento adecuado, haciendo que las candidemia y las candidiasis invasivas tengan peores pronósticos que otras infecciones de reconocimiento más sencillo. Tecnologia Sanitaria de Interés: La anidulafungina es una equinocandina semisintética, un lipopéptido obtenido a partir de un producto de fermentación de Aspergillus nidulans. Este producto farmacéutico actúa inhibiendo selectivamente la 1,3-3-D glucanosintetasa, enzima presente en las células fúngicas, pero no en las células de mamíferos. Como resultado no se forma 1,3-13- D glucano, el cual es esencial en la pared celular fúngica. La anidulafungina ha demostrado actividad fungicida frente a candida spp. y actividad frente a Aspergillus fumigatus; la actividad in vitro de anidulafungina frente a las especies de candida spp. no es homogénea. En concreto, la concentración mínima inhibitoria de la anidulafungina en el caso de la C. parapsilosis es superior a la observadas en otras especies de candida spp. METODOLOGIA: Estrategia de Búsqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), la Agencia Europea de Medicamentos (EMA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guideline Clearinghouse (NGC), UpToDate y Health Systems Evidence (HSE). Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en ww.clinicaltrials.gov , para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Sinopsis de la Evidencia: Se realizó búsqueda bibliográfica y de evidencia científica que sustente el uso de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol según la pregunta PICO establecida. En relación a los estudios encontrados para la población de interés descrita en la pregunta PICO no se encontraron estudios que comparen directamente mediante un ensayo clínico las equinocandinas (anidulafungina, caspofungina y micafungina) en pacientes con candidemia o infecciones sistémicas por candida spp. Se encontraron 2 revisiones sistemáticas con evidencia indirecta. Además, se encontró un ensayo clínico de evidencia indirecta que puede ser usada para responder la pregunta PICO, que compara Anidulafungina con Fluconazol en pacientes con candidiasis invasiva. CONCLUSIONES: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de anidulafungina según el esquema planteado en la pregunta PICO para pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol.
Assuntos
Humanos , Candidemia/tratamento farmacológico , Equinocandinas/administração & dosagem , Análise Custo-Benefício , Fluconazol/efeitos adversos , Avaliação da Tecnologia Biomédica , Resultado do TratamentoRESUMO
The incidence of fungal infections and, in particular, the incidence of fungal antibiotic resistance, which is associated with biofilm formation, have significantly increased, contributing to morbidity and mortality. Thus, new therapeutic strategies need to be developed. In this context, natural products have emerged as a major source of possible antifungal agents. Berberine is a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, and Hydrastis canadensis, and of Phellodendron amurense Berberine has been proven to have broad antibacterial and antifungal activity. In the present study, the potential antifungal effect of berberine against fluconazole-resistant Candida and Cryptococcus neoformans strains, as well as against the biofilm form of Candida spp., was assessed. The antifungal effect of berberine was determined by a broth microdilution method (the M27-A3 method of the Clinical and Laboratory Standards Institute) and flow cytometry techniques, in which the probable mechanism of action of the compound was also assessed. For biofilm assessment, a colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine the susceptibility of sessile cells. The isolates used in the study belonged to the Laboratory of Bioprospection and Experiments in Yeast (LABEL) of the Federal University of Ceará. After 24 and 72 h, fluconazole-resistant Candida and Cryptococcus neoformans strains showed berberine MICs equal to 8 µg/ml and 16 µg/ml, respectively. Cytometric analysis showed that treatment with berberine caused alterations to the integrity of the plasma and mitochondrial membranes and DNA damage, which led to cell death, probably by apoptosis. Assessment of biofilm-forming isolates after treatment showed statistically significant reductions in biofilm cell activity (P < 0.001).
Assuntos
Antifúngicos/farmacologia , Berberina/farmacologia , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Animais , Berberina/efeitos adversos , Biofilmes/crescimento & desenvolvimento , Candida/classificação , Candida/genética , Candidíase/microbiologia , Linhagem Celular , Proliferação de Células , Criptococose/microbiologia , Cryptococcus neoformans/classificação , Cryptococcus neoformans/genética , DNA Fúngico/genética , Farmacorresistência Fúngica , Fluconazol/efeitos adversos , Humanos , Células L , Camundongos , Testes de Sensibilidade Microbiana , Membranas Mitocondriais/efeitos dos fármacos , Tipagem Molecular , Técnicas de Tipagem MicológicaRESUMO
We report for the first time the successful use of fluconazole to treat cutaneous leishmaniasis due to Leishmania braziliensis. We used escalating doses from 5 to 8 mg/kg per day. At a dose of 5 mg/kg per day, 75% patients were cured, and at 8 mg/kg per day, the cure rate was 100%. Fluconazole was well tolerated.
Assuntos
Antiprotozoários/administração & dosagem , Fluconazol/administração & dosagem , Leishmania braziliensis/efeitos dos fármacos , Leishmania braziliensis/isolamento & purificação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiprotozoários/efeitos adversos , Criança , Pré-Escolar , Feminino , Fluconazol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
En este artículo se recopilan y describen los distintos farmacos antifúngicos para el tratamiento de micosis sistémicas (AU)