Aspergilosis invasiva: definiciones, diagnóstico y tratamiento / Invasive aspergillosis: definitions, diagnosis, and treatment

Resumen La aspergilosis invasiva (AI) es una enfermedad grave y con alta mortalidad. Existen factores de riesgo y se describen brotes intrahospitalarios relacionados con construcciones. También se des cribe una entidad relacionada con la infección por COVID-19, conocida como aspergilosis pulmonar asociada a COVID-19 (APAC). Es de vital importancia implementar un tratamiento adecuado y precoz, especialmente en pacientes inmunocomprometidos y críticamente enfermos. El diagnóstico se basa en reconocer los factores predisponentes, la clínica, la obtención de imágenes, exámenes directos, cultivos, histopatología y biomarca dores como el galactomanano. La droga de elección es el voriconazol, pero se deben conocer las alternativas terapéuticas dada la creciente presencia de aislamientos resistentes.

Abstract Invasive aspergillosis (IA) is a serious disease with high mortality. There are several risk factors and in-hospital outbreaks related with construction have been described. An entity related to COVID-19 infection, known as COVID-19 associated pulmonary aspergillosis (CAPA), has recently appeared. Early and appropriate treatment is of paramount importance, especially in immunocompromised and critically ill patients. Diagnosis is based on recognition of predisposing factors, clinical signs, imaging, direct examination, culture, histopathology, and biomarkers such as galactomannan. The drug of choice is voriconazole, but alternative therapies must be taken into account given the increasing presence of resistant isolates.

Una experiencia de siete años en el laboratorio de Micología del Hospital de Pediatría Juan P. Garrahan / A seven-year experience in the Mycology Laboratory of Hospital de Pediatría Juan P. Garrahan

En noviembre del año 2015 nos incorporamos al Laboratorio de Micología del Servicio de Microbiología del Hospital Garrahan. En este breve resumen queremos compartir los avances logrados a través de nuestra experiencia durante siete años de trabajo profesional. Debido a los diagnósticos realizados y su complejidad, consideramos que el Hospital Garrahan, sus pacientes y la comunidad toda necesitan contar con un laboratorio de Micología que responda a sus necesidades. Creemos haber iniciado un camino que esperamos continúe y culmine con la creación de la Unidad de Micología (AU)

In November 2015 we joined the Mycology Laboratory of the Microbiology Service of the Hospital Garrahan. In this brief summary we want to share the advances achieved through our experience during seven years of professional work. Due to the diagnosis made and their complexity, we believe that the Hospital Garrahan, its patients and the entire community, need to have a Mycology laboratory that responds to their requirements. We believe we have started a path that we hope will continue and culminate with the creation of the Mycology Unit (AU)

Scedosporiosis pulmonar post COVID-19 en paciente diabético: a propósito de un caso

Las especies de Scedosporium son consideradas patógenos oportunistas emergentes, que afectan a pacientes inmunocomprometidos o con respuesta inmunológica normal. La enfermedad invasiva grave supera tasas de mortalidad del 80 %. Se describe caso con afectación pulmonar causada por el complejo de especies de Scedosporium en un paciente masculino de 75 años de edad, procedente de Caracas, Venezuela, con diabetes mellitus tipo 2, infección respiratoria baja, dos infecciones previas por enfermedad por coronavirus 2019 (COVID-19) e imagen radiológica de lesión de ocupación de espacio pulmonar basal izquierdo. Se envió al laboratorio de microbiología porción de aproximadamente 1 cm2 de tejido pulmonar, solicitando estudios micológicos y para micobacterias. Al examen directo con KOH al 20 % se observó un fragmento de hifa hialina tabicada. A los 12 días de incubación hubo crecimiento en agar Sabouraud dextrosa más gentamicina de colonias vellosas con pigmentado difusible color amarillo pálido a mostaza. Se realizó examen directo a las colonias con azul de algodón, observándose estructuras compatibles con el complejo de especies de Scedosporium. Scedosporium spp., es el segundo hongo filamentoso, después de Aspergillus spp., causante de infecciones respiratorias bajas. El paciente fue tratado con voriconazol después del diagnóstico micológico con una evolución satisfactoria. Las infecciones por especies de Scedosporium afectan órganos internos como los pulmones, similar al caso descrito. La infección por COVID-19 es un factor predisponente para adquirir infecciones fúngicas poco frecuentes. El laboratorio de microbiología cumple un rol importante en el diagnóstico de micosis causadas por hongos inusuales.

Scedosporium species are considered emerging opportunistic pathogens affecting immunocompromised patients or patients with normal immune response. Mortality rates exceed 80 % in severe invasive disease. We describe a case of lung involvement caused by Scedosporium species complex in a 75-year-old male patient from Caracas, Venezuela, with type 2 diabetes mellitus, lower respiratory tract infection, two previous coronavirus disease infections 2019 (COVID-19) and radiological findings of a left basal lung space-occupying lesion. A piece of lung tissue measuring approximately one cm2 was sent to the microbiology laboratory, requesting mycology and mycobacteria studies. Direct examination with 20 % KOH revealed a hyaline septate hyphal fragment. Growth of hairy colonies with diffusible pale yellow to mustard pigment was observed on Sabouraud dextrose plus gentamicin agar after 12 days of incubation. Structures compatible with the Scedosporium species complex were observed on direct examination of the colonies with cotton blue. Scedosporium spp. is the second most common filamentous fungus causing infections of the lower respiratory tract after Aspergillus spp. The patient was treated with voriconazole after mycological diagnosis with satisfactory outcome. Infections with Scedosporium spp. affect internal organs such as the lungs, similar to the case described. COVID-19 infection predisposes to the acquisition of uncommon fungal infections. The microbiology laboratory plays an important role in the diagnosis of mycoses caused by unusual fungi.

Adverse Drug Reactions to Antifungals Used in the Management of COVID-19 Associated Rhino-Orbito-Cerebral Mucormycosis

Objectives: To determine the incidence and frequency of adverse drug reactions (ADRs) to find out factors, if any contributing to the same, while also exploring the use of amphotericin B deoxycholate as a cheaper and safe alternative to liposomal amphotericin B. Materials and Methods: It was a cross-sectional observational study, with a study population of 50 conducted over three months after ethics approval. All adult patients admitted to a tertiary care center, in a metropolitan city of Maharashtra, diagnosed with Rhino-orbito-cerebral mucormycosis, with a history of previous COVID-19 infection and receiving antifungals for the treatment of the same were included in the study. Central Drugs Standard Control Organization (CDSCO) ADR reporting forms were used to collect data. Results: Electrolyte disturbances mainly hypokalemia were the most frequently encountered ADR with both Amphotericin formulations (39/50; 20.31%) followed by pain at the injection site (33/50; 17.19%). Nephrotoxicity occurred slightly more frequently with Amphotericin B Deoxycholate (19/29; 65%), compared to Liposomal Amphotericin B (11/19; 57%), while Posaconazole was mainly associated with gastrointestinal (GI) disturbances and hepatotoxicity. Conclusion: Amphotericin B Deoxycholate was associated most with ADRs, hypokalemia, and pain at the injection site being the most frequent. However, concerning nephrotoxicity, both Amphotericin formulations showed only a modest difference. Posaconazole was associated with the least number of ADRs and had a favorable safety profile.

Comparison of the effect of miconazole and clotrimazole in the treatment of vulvovaginal candidiasis among women seen in a tertiary medical center from 2016 to 2020 / Philippine Journal of Obstetrics and Gynecology

Background@#Vulvovaginal Candidiasis (VVC) is one of the frequent infections of the female genital tract and is the second most common cause of vaginal infections after bacterial vaginosis. According to the Centers for Disease Control and Prevention, azoles are the first‑line treatment for VVC. Among the azoles available in the Philippines, only miconazole and clotrimazole are recommended for both pregnant and non‑pregnant women.@*Objective@#Compare the effect of miconazole versus clotrimazole in the treatment of vulvovaginal candidiasis among patients seen at the out‑patient department in a tertiary hospital@*Materials and Methods@#This involved review of the records of patients diagnosed with VVC in a tertiary medical center from 2016 to 2020. All records of women, pregnant and non‑pregnant, wherein single‑dose 1200 mg miconazole or 6‑day 100 mg clotrimazole given vaginally were included@*Results@#Eleven out of the 316 records (3.46%) remained symptomatic after treatment, about 18.1% (2/161) from those who used miconazole and 81.8% (9/155) from those treated with clotrimazole (p 0.027). In terms of failure rate, for miconazole it was 1.2% (2/161), whereas for clotrimazole it was 5.8% (9/155). None of the charts were found to have recorded adverse reaction to the given treatment@*Conclusion@#Single‑dose miconazole intravaginal regimen has a higher clinical cure rate than the 6‑day clotrimazole intravaginal treatment. Thereby, single‑dose intravaginal miconazole has the potential to improve patient compliance and treatment outcome at a lower cost

Validación del método comercial ATB FUNGUS 3 frente al método de referencia M27 - A2, para determinar la susceptibilidad de Candida albicans a diferentes antifúngicos / Validation of the commercial method ATB FUNGUS 3 against the reference method M27-A2, to determine the susceptibility. of Candida albicans to different antifungals

INTRODUCCIÓN: el aumento de la incidencia de las micosis ha generado la necesidad de desarrollar técnicas in vitro para el estudio de la susceptibilidad a los antifùngicos; El documento CLSI M27-A2 es el método de referencia para estudios de sensibilidad en levaduras. No obstante, este no subsana las necesidades de rutina de los laboratorios, principalmente por ser laboriosos; en consecuencia, métodos alternativos surgen ante la necesidad de contar con técnicas más sencillas, una de ellos es el ATB FUNGUS 3 que permite determinar la sensibilidad de Candida frente a diferentes antifùngicos. OBJETIVO: validar el método comercial ATB FUNGUS 3, frente al método de referencia M27-A2, con el fin de conocer su valor diagnóstico. MATERIAL Y MÉTODOS: se determinó la eficacia del método a través de parámetros de test diagnóstico; además, se evaluó la sensibilidad de 50 cepas de Candida albicans frente a Fluconazol (FLZ) e Itraconazol (ITZ) mediante el método comercial y el de referencia. RESULTADOS: se encontró que el ATB - FUNGUS 3 presenta una especificidad para FLZ de 100%, sensibilidad de 91%, valor predictivo positivo (VPP) de 56%, valor predictivo negativo (VPN) de 100%, con una eficacia diagnóstica de 92%, calculados para un intervalo de confianza (IC) de 95%; para ITZ la especificidad y sensibilidad fue de 88 % y 90% respectivamente, con un VPP de 64%, un VPN de 97%, eficacia diagnóstica de 90%, IC 95%. Para las pruebas de concordancia, el índice Kappa para FLZ e ITZ fue de 0,67 y 0,68 respectivamente. La prueba de Likelihood ratio para el FLZ fue (LR+) de 11,25 mientras que el (LR-) fue 0; para el ITZ (LR+) de 9,19 y el (LR-) fue 0,14. Reproducibilidad de 90 % (FLZ) y 85% (ITZ). CONCLUSIONES: el ATB FUNGUS 3, es una técnica rápida, de fácil realización y reproducible; pero el desempeño global de la técnica, sugiere que aún no es confiable para el diagnóstico en laboratorios, debido a los valores bajos obtenidos en los VPP, que indican que se podría derivar en errores al momento de determinar una cepa como sensible o resistente, punto importante al momento de decidir la conducta terapéutica.

INTRODUCTION: the higher incidence of mycoses has generated the need to develop in vitro techniques for susceptibility study to antifungal agents. CLSI M27-A2 is a reference method for yeast susceptibility studies. However, this method does not meet the needs of routine laboratories because it is difficult to follow all the processes. Consequently, alternative methods arise due to the need for simpler techniques. Then, one of them is ATB FUNGUS 3 which allows determining Candida's sensitivity to different antifungal agents. OBJECTIVE: validate the commercial method ATB FUNGUS 3 compared with the reference method M27-A2 in order to know its diagnostic value. MATERIAL AND METHODS: efficacy was determined by diagnostic test parameters. Moreover, sensitivity of 50 strains of Candida albicans at Fluconazole (FLZ) and Itraconazole (ITZ) was evaluated by the commercial and reference methods. RESULTS: ATB - FUNGUS 3 presents a specificity for FLZ of 100%, sensitivity of 91%, positive predictive value (PPV) 56%, negative predictive value (NPV) 100% with a diagnostic efficacy of 92%, calculated for a 95% confidence interval (CI). For ITZ, the specificity and sensitivity were 88% and 90% respectively, with a PPV 64%, a NPV 97% with a diagnostic efficacy of 90%, 95% CI. For the concordance tests, the Kappa index for FLZ and ITZ was 0.67 and 0.68 respectively. The Likelihood ratio test for FLZ was (LR +) of 11.25 while the (LR-) was 0; for ITZ (LR +) of 9.19 and the (LR-) was 0.14. Reproducibility of 90% (FLZ) and 85% (ITZ). CONCLUSIONS: the ATB FUNGUS 3 is a fast, easy and reproducible technique. However, the overall performance of the technique suggests that this method hasn't been reliable for diagnostic laboratory yet, because PPVS obtained low values. These PPVS indicate that it could lead to errors when determining a strain as sensitive or resistant. This is an important point when deciding the therapeutic conduct.

Estudo do potencial antifúngico e do mecanismo de ação do timol contra cepas de Candida parapsilosis resistentes ao fluconazol e a anfotericina B / Study of the antifungal potential and mechanism of action of thymol against strains of Candida parapsilosis resistant to fluconazole and amphotericin B

Objetivo: investigar a suscetibilidade de cepas fúngicas de Candida parapsilosis isoladas de sangue humano frente ao timol, bem como seu mecanismo de ação. Metodologia: foram utilizadas técnicas de microdiluição em placas de 96 poços para determinar a concentração inibitória mínima (CIM) e concentração fungicida mínima (CFM). Além disso, foram realizados testes com o sorbitol e o ergosterol para investigar a ação do timol na parede e na membrana celular fúngica respectivamente. Resultados: nos testes de CIM e CFM, foi observado que as cepas de C. parapsilosis são resistentes ao fluconazol e a anfotericina B, no entanto, o timol desempenhou efeito fungicida com razão CFM/CIM entre 1 e 2. Além disso, a CIM do timol não aumentou quando o sorbitol ou o ergosterol foi adicionado no meio, sugerindo fortemente que este monoterpeno não age na parede celular fúngica ou por ligação ao ergosterol na membrana plasmática. Conclusão: portanto, esses resultados contribuem para a elucidação do mecanismo de ação do timol, sugerindo outros possíveis alvos de interação fármaco-receptor. No entanto, mais investigações de caráter enzimático e molecular em modelos in vitro são necessários para que se possa elucidar completamente o modo de ação desse promissor monoterpeno.

Objective: to investigate the susceptibility of fungal strains of Candida parapsilosis isolated from human blood against thymol, as well as its mechanism of action. Methodology: microdilution techniques were used in 96-well plates to determine minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). In addition, tests were performed with sorbitol and ergosterol to investigate the action of thymol on the wall and on the fungal cell membrane respectively. Results: in the CIM and CFM tests, it was observed that C. parapsilosis strains are resistant to fluconazole and amphotericin B, however, thymol had a fungicidal effect with MFC/MIC ratio between 1 and 2. In addition, thymol MIC did not increase when sorbitol or ergosterol was added in the medium, strongly suggesting that this monoterpene does not act on the fungal cell wall or by binding to ergosterol on the plasma membrane. Conclusion: therefore, these results contribute to the elucidation of the mechanism of action of thymol, suggesting other possible targets of drug-receptor interaction. However, further investigations of enzymatic and molecular character in in vitro models are necessary to fully elucidate the mode of action of this promising monoterpene.

Study of the antifungal activity of ibuprofen and its association with amphotericin B or ketoconazole against Candida spp / Estudio de la actividad antifúngica del ibuprofeno y su asociación con anfotericina B o ketoconazol contra Candida spp / Estudo da atividade antifúngica do ibuprofeno e sua associação com anfotericina B ou cetoconazol contra Candida spp

SUMMARY The objective was evaluating the antifungal activity of ibuprofen alone and when associated with amphotericin B or ketoconazole against Candida species. Strains of C. albicans, C. tropicalis, C. guilliermondii, C. krusei and C. parapsilosis were used. The minimum inhibitory concentration (MIC) was determined by the microdilution method and the association study performed through the checkerboard assay. The concentration of 512 μg/mL inhibited approximately 65% of the tested strains, while against 35% of the strains presented MIC values above 2048 μg/mL. Associations of ibuprofen with amphotericin B against C. tropicalis and ibuprofen with ketoconazole against C. krusei showed synergistic effect. Antagonistic effects were evidenced in the combination of ibuprofen with amphotericin B against C. guilliermondii and C. albicans, as well as in the association of ibuprofen with ketoconazole against C. albicans and C. tropicalis. Through the experiments, it was found that ibuprofen showed antifungal activity against most of the Candida species tested. The combinations of ibuprofen and antifungals had synergistic effects. However, antagonistic results were evidenced in the association with ibuprofen, which would make clinical applicability difficult. Therefore, studies of this combined activity should be investigated, considering that this association may be positive for anti-fungal therapy.

RESUMEN El objetivo fue evaluar la actividad antifúngica del ibuprofeno solo y asociado con anfotericina B o ketoconazol contra especies de Candida. Se utilizaron cepas de C. albicans, C. tropicalis, C. guilliermondii, C. krusei y C. parapsilosis. La concentración inhibitoria mínima (MIC) se determinó mediante el método de microdilución y el estudio de asociación fue realizado a través del ensayo de checkboard. La concentración de 512 μg/mL inhibió aproximadamente el 65% de las cepas analizadas, mientras 35% de las cepas presentaron valores de MIC superiores a 2048 μg/mL. Las asociaciones de ibuprofeno con anfotericina B contra C. tropicalis e ibuprofeno con ketoconazol contra C. krusei mostraron un efecto sinérgico. Se evidenciaron efectos antagonistas en la combinación de ibuprofeno con anfotericina B contra C. guilliermondii y C. albicans, así como en la asociación de ibuprofeno con ketoconazol contra C. albicans y C. tropicalis. Se descubrió, a través de los experimentos, que el ibuprofeno mostró actividad antifúngica contra la mayoría de las especies de Candida probadas. Las combinaciones de ibuprofeno y antifúngicos tuvieron efectos sinérgicos. Sin embargo, se evidenciaron resultados antagónicos en la asociación con ibuprofeno, lo que dificultaría la aplicabilidad clínica. Por lo tanto, los estudios de esta actividad combinada deben investigarse, considerando que esta asociación puede ser positiva para la terapia antimicótica.

RESUMO O objetivo do estudo foi avaliar a atividade antifúngica do ibuprofeno sozinho e quando associado com anfotericina B ou cetoconazol contra espécies de Candida. Foram utilizadas cepas fúngicas de C. albicans, C. tropicalis, C. guilliermondii, C. krusei e C. parapsilosis, entre isolados clínicos e cepas padrão. A concentração inibitória mínima (CIM) foi determinada pela técnica de microdiluição e o estudo de associação realizado através do ensaio checkerboard. A concentração de 512 μg/mL foi capaz de inibir, aproximadamente, 65% das cepas ensaiadas, enquanto que 35% das estirpes apresentaram valores da CIM acima de 2048 μg/mL. Associações do ibuprofeno com anfotericina B contra C. tropicalis e ibuprofeno mais cetoconazol contra C. krusei mostraram efeito sinérgico. Efeitos antagônicos foram evidenciados na combinação do ibuprofeno com anfotericina B contra C. guilliermondii e C. albicans, como também na associação do ibuprofeno com cetoconazol contra C. albicans e C. tropicalis. Por meio dos experimentos, pôde-se afirmar que o ibuprofeno exerceu atividade antifúngica contra a maioria das espécies de Candida ensaiadas. Os efeitos das combinações entre o ibuprofeno e os antifúngicos promoveram efeitos sinérgicos. No entanto, resultados antagônicos foram evidenciados na associação com o ibuprofeno, o que dificultaria aplicabilidade clínica. Logo, estudos dessa atividade combinada devem ser investigados, pois esta associação pode traçar pontos positivos na terapia antifúngica.

Actividad antifúngica del aceite volátil de Hedyosmum sp, frente a especies del género Candida / Antifungal activity of the volatile oil of Hedyosmum sp, Against species of the genus Candida

El objetivo del estudio fue determinar la actividad antifúngica del aceite volátil de las partes aéreas de la especie vegetal Hedyosmum sp., frente al complejo Candida albicans, C. glabrata, C. tropicalis y C. parapsilosis. El material vegetal se recolectó del bosque natural Jacarón, Provincia de Chimborazo, Ecuador. La extracción del aceite volátil se realizó por hidrodestilación, obteniéndose un rendimiento de 0,09%. La actividad antifúngica fue estudiada mediante el método de difusión en agar y los resultados se interpretaron mediante detección-medición de halos de inhibición y concentración mínima inhibitoria. El estudio se realizó partiendo del aceite puro y diluciones con dimetil sulfóxido. Los resultados se validaron mediante controles positivos (Fluconazol) y negativos (dimetil sulfóxido). El aceite puro mostró actividad antifúngica frente a C. albicans, C. tropicalis, C. parapsilosis, pero no frente a C. glabrata. Mientras que, la actividad antifúngica determinada empleando diluciones del aceite permitió establecer la concentración mínima inhibitoria para C. tropicalis, C. parapsilosis, en 0,25x106 µg/mL y para C. albicans en 0,5x106 µg/mL. Estos resultados concluyeron que el aceite volátil de Hedyosmum sp., presenta actividad antifúngica poco significativa frente a tres de las cuatro especies de Candida estudiadas

The objective of the study was to determine the antifungal activity of the volatile oil of the aerial parts of the plant species Hedyosmum sp., against Candida albicans, C. glabrata, C. tropicalis and C. parapsilosis complex. The plant material was collected from the Jacarón natural forest, Chimborazo Province, Ecuador. The extraction of the essential oil was carried out by hydro-distillation, obtaining a yield of 0.09%. Antifungal activity was studied by means of the diffusion in agar method and the results were interpreted by detection-measurement of inhibition halos and minimum inhibitory concentration. The study was carried out starting from the pure oil and dilutions with dimethyl sulfoxide. The results were validated by positive controls (Fluconazole) and negative controls (dimethyl sulfoxide). The pure oil showed antifungal activity against C. albicans, C. tropicalis, and C. parapsilosis complex, but not against C. glabrata. While, the antifungal activity determined using dilutions of the oil allowed establishing the minimum inhibitory concentration for C. tropicalis, C. parapsilosis complex, at 0,25x106 µg/mL and for C. albicans at 0,5x106 µg/mL. These results concluded that the volatile oil of Hedyosmum sp., Presents little antifungal activity against three of the four Candida species studied

Efficacy of topical clotrimazole vs. topical tolnaftate in the treatment of otomycosis. A randomized controlled clinical trial / Eficácia do clotrimazol tópico versus tolnaftato tópico no tratamento da otomicose: um ensaio clínico controlado randomizado

Abstract Introduction: Otomycosis, an infection of the ear canal by fungi, is prevalent in hot and humid weather. Nevertheless, there is not sufficient evidence for the effectiveness of different topical antifungal treatments. Tolnaftate, is a topical antifungal agent described to be effective in the treatment of otomycosis. Currently there are not sufficient studies that prove its efficacy. Objectives: To compare the efficacy of clotrimazole and tolnaftate administration in the treatment of otomycosis. Material and methods: A controlled, randomized and open clinical trial included patients diagnosed with fungal external otitis who were treated with topical antifungals, randomized into two treatment groups: (1) clotrimazole cream; (2) tolnaftate solution. They were microscopically evaluated at one and two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed. Follow-up and final outcomes (absence of infection) were compared between groups. Results: Forty eight patients were included, 28 in the clotrimazole group and 20 in the tolnaftate group. Spring was the weather most commonly associated with otomycosis, while otic manipulation was the risk factor more common in both groups. Predominant symptoms were itching and otic fullness. Aspergillus niger organism was isolated most frequently. Treatment with clotrimazole resulted in 75% resolution vs 45% resolution with treatment with tolnaftate at one week of treatment (p = 0.007). The Tolnaftate treatment group demonstrated higher recurrence rates and treatment failures, 20% and 15% respectively. Conclusions: Clotrimazole cream treatment is more effective than tolnaftate for uncomplicated otomycosis. More studies are needed to corroborate our results.

Resumo Introdução: Otomicose, uma infecção fúngica do canal auditivo externo, é prevalente em climas quentes e úmidos. No entanto, a literatura não apresenta evidências suficientes sobre os diferentes tratamentos antifúngicos tópicos. O tolnaftato é um antifúngico tópico descrito como eficaz no tratamento da otomicose; entretanto, sua eficácia não está suficientemente comprovada. Objetivo: Comparar a eficácia do uso de clotrimazol e tolnaftato no tratamento da otomicose. Material e método: Ensaio clínico controlado e randomizado; incluiu pacientes diagnosticados com otite externa fúngica tratados com antifúngicos tópicos, randomizados em dois grupos de tratamento: 1) clotrimazole (creme); 2) solução de tolnaftato. Eles foram avaliados microscopicamente uma e duas semanas após o início do tratamento para avaliar a resolução da doença. Recorrência e intercorrências foram registradas; além disso, as variáveis demográficas e clínicas foram coletadas e analisadas. Os dados do acompanhamento e desfechos finais (ausência de infecção) foram comparados entre os grupos. Resultados: O estudo incluiu 48 pacientes, 28 dos quais foram alocados ao grupo clotrimazole e 20 ao grupo tolnaftato. A primavera foi a estação mais comum; a manipulação foi o fator de risco mais comum em ambos os grupos. Os sintomas mais comuns foram coceira e plenitude auricular. Aspergillus niger foi o micro-organismo mais comumente isolado. Após uma semana, o tratamento com clotrimazol apresentou uma taxa de resolução de 75% vs. 45% com o tratamento com tolnaftato (p = 0,007). O tratamento com tolnaftato apresentou maiores taxas de recidiva e falhas: 20% e 15%, respectivamente. Conclusões: Em casos de otomicose não complicada, o uso de clotrimazol (creme) é mais eficaz do que o de tolnaftato. Mais estudos são necessários para corroborar os presentes resultados.

Formación de biopelículas por Candida parapsilosis sensu stricto y su perfil de susceptibilidad en Venezuela / Biofilm-forming of Candida parapsilosis sensu stricto and its susceptibility profile in Venezuela

Una de las principales consecuencias del desarrollo de biopelículas es la resistencia a los antifúngicos. Se determinó la formación de biopelículas por Candida parapsilosis sensu stricto aisladas de sangre y su perfil de susceptibilidad. Se evaluaron 30 cepas de C. parapsilosis sensu stricto de la Red de Candidemias del Dpto. de Micología del Instituto Nacional de Higiene Rafael Rangel-Venezuela, por el método cuantitativo en microplaca con tinción de cristal violeta y el método cualitativo en agar Sabouraud dextrosa suplementado con rojo Congo. Se utilizó el método de microdilución según el documento M-27 del Clinical and Laboratory Standards Institute. La formación de biopelículas de C. parapsilosis sensu stricto por el método cuantitativo fue de 63% y por el método cualitativo de 50%. El método cualitativo presentó valores de sensibilidad, especificidad, valores predictivos positivo y negativo de 61,1%, 23%, 78,6%, 43,8% respectivamente frente al método cuantitativo. Los aislados en forma planctónica fueron 100% sensibles a anfotericina B y caspofungina, con susceptibilidad variable a los azoles. El método cuantitativo es una técnica confiable para determinar la formación de biopelículas. El método cualitativo puede usarse como método pantalla inicial. No se encontró relación entre la susceptibilidad de las formas planctónicas y la capacidad de producción de biopelículas

One of the main consequences of biofilm development is resistance to antifungals. Biofilmforming by Candida parapsilosis sensu stricto isolated from blood and its susceptibility profile was determined. Thirty strains of C. parapsilosis sensu stricto belonging to the Candidemia Network of the Mycology Department of the Instituto Nacional de Higiene Rafael Rangel-Venezuela, were evaluated by microplate quantitative method with violet crystal staining, and Sabouraud dextrose agar supplemented with Congo red qualitative method. The microdilution method was used to determine the susceptibility, according to the Clinical and Laboratory Standards Institute M-27 document. Biofilm formation of C. parapsilosis sensu stricto by both quantitative and qualitative method was 63% and 50%, respectively. Sensitivity, specificity, and positive and negative predictive values of the qualitative method were 61.1%, 23%, 78.6%, and 43.8% respectively, when compared with quantitative method. Planktonic isolates were 100% sensitive to amphotericin B and caspofungin, with variable susceptibility to azoles. Quantitative method is a reliable assay to determine biofilm formation, while qualitative method can be used as an initial screening assay. No relationship was found between susceptibility of planktonic isolates and the ability to biofilm-forming

Study on synthesis and antifungal activities of galloyl piperazine derivatives / 药学实践杂志

Objective To design, synthesize and measure antifungal activities of galloyl piperazine derivatives. Methods Trimethoxyl gallic acid was used as starting material, reacted with piperazine in the presence of PyBOP/DIEA to afford the intermediates. The target compounds were obtained through the reaction with corresponding acids after deprotection gave. The antifungal activities of the target compounds were evaluated by FLC-resistant Candida albican isolated according to the CLSI recommended method. Results 11 target compounds were synthesized and six of them showed more potent antifungal activities than gallic acid. Conclusion Galloyl piperazine derivatives could enhance antifungal activities. Galloyl moiety was an important pharmacophore, which could improve antifungal activities with the introduction of cinnamic acid and 2,3-dichlorobenzoic acid.

Combination antifungals as an effective means of salvage in paediatric leukaemia patients with invasive fungal infections

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in paediatric leukaemias. Antifungal combinations to treat these patients are being explored. Fourteen children with leukaemias and IFIs were treated with a combination of antifungal agents at our centre. The first antifungal was amphotericin-B in 13 children and voriconazole in one child. In view of no improvement and clinical deterioration, in nine patients, voriconazole was added as the second antifungal agent and in four, it was caspofungin. All patients completed 4�weeks of antifungal therapy. The overall mortality attributable to IFI for the cohort was 4/14 (28%).

Desenlaces clínicos en una cohorte colombiana de pacientes con síndrome de flujo vaginal tratadas con antimicóticos y antibióticos / Clinical outcomes in a Colombian cohort of patients with vaginal discharge syndrome treated with antifungals and antibiotics

Resumen Objetivo: Reportar el desempeño clínico de dos medicamentos indicados para tratamiento del síndrome de flujo vaginal (fluconazol, secnidazol y terconazol, clindamicina) y comparar el efecto clínico. Materiales y métodos: Estudio observacional, comparativo y analítico de cohortes al que se incluyeron pacientes con diagnóstico de síndrome de flujo vaginal susceptibles de ser tratadas con fluconazol-secnidazol o terconazol-clindamicina en 12 ciudades de Colombia, con seguimiento de 8 días (± 3 días). Este proyecto fue aprobado por un comité de ética en investigación con seres humanos. Resultados: Se incluyeron 176 pacientes, pero solo 153 (87%) completaron el seguimiento. Los límites de edad fueron 18 y 67 años; 134 (76%) iniciaron con fluconazol-secnidazol y 42 (24%) con terconazol-clindamicina. Por lo que se refiere a la comparación en disminución de los síntomas, fluconazol-secnidazol y terconazol-clindamicina: flujo (p = 0.0000), prurito (p = 0.002), irritación (p = 0.0000), mal olor (p = 0.001) y dispareunia (p = 0.4). Conclusión: La prescripción de la combinación fluconazol-secnidazol fue más frecuente. El apego al tratamiento fue de 86%. La proporción de disminución de los síntomas tuvo límites de 15 y 40%; para el flujo vaginal fue superior a 70% (fluconazol-secnidazol: 115 de 121 y terconazol-clindamicina: 29 de 41).

Abstract Objective: To know the real life clinical performance of the prescription of two drugs for the treatment of vaginal discharge syndrome (Fluconazole-Secnidazole and Terconazole-Clindamycin) and to compare the clinical outcomes. Materials and methods: An analytical cohort study was conducted. We included women older than 18 years with a diagnosis of vaginal discharge syndrome who were candidates to be treated with Fluconazole-Secnidazole or Terconazole-Clindamycin with 8 days (±3) of follow-up, in 12 cities of Colombia. This project was approved by a research with human being's ethics committee. Results: 176 patients were included, 153 (86.9%) completed the follow-up, their age ranged between 18 and 67 years. 134 (76.1%) started treatment with Fluconazole-Secnidazole and 42 (23.8%) Terconazole-Clindamycin. Symptoms improvement was compared (Enrollment vs. Control), finding for Fluconazole-Secnidazole and Terconazole-Clindamycin: discharge (p=0.0000), pruritus (p=0.002), irritation (p=0.0000), bad smell (p=0.001) and dyspareunia (p=0.4). Conclusions: The prescription of the combination Fluconazole-Secnidazole was more frequent. The adherence to treatment was 86%. The proportion of improvement in symptoms ranged between 15% and 40%, however, for the case of vaginal discharge it was greater than 70% (Fluconazole-Secnidazole: 115/121 and Terconazole-Clindamycin: 29/41).

Antifungal efficacy of three medicinal plants Glycyrrhiza glabra, Ficus religiosa, and Plantago major against oral Candida albicans: A comparative analysis.

Introduction: From ancient times, plants with medicinal values are being tested and used in the treatment of various infectious diseases. Aims and Objectives: The present in vitro study was designed to assess the antifungal activity of three commonly available medicinal plants Glycyrrhiza glabra, Ficus religiosa, and Plantago major on inhibiting oral Candida albicans in comparison to standard antifungal agents. Materials and Methods: Bark of G. glabra, stem of F. religiosa, and husk of P. major were collected, crushed into fine powder, and dissolved in 67% ethanol. Extracts were subjected to antifungal efficacy test against oral C. albicans (ATCC 66027) using Kirby–Bauer disc diffusion method. Mean zone of inhibition (ZOI) was measured by HI antibiotic zone scale. One‑way ANOVA using Tukey’s post hoc and t‑test were applied for statistical analysis. Results: G. glabra was found to be most effective among the three with highest mean ZOI measuring 19.8 ± 0.83, 19.4 ± 0.54, and 18.2 ± 1.09 at 24, 48, and 72 h, respectively. Tukey’s post hoc test showed statistically nonsignificant difference between antifungal activity of F. religiosa and P. major with itraconazole 10 mcg. Conclusion: G. glabra, F. religiosa, and P. major showed acceptable potency against C. albicans (ATCC 66027) comparable to that of synthetic antifungal agents. However, further studies should be undertaken to affirm the same and test their efficacy in different concentrations and clinical utility.

Caracterização de leveduras isoladas da corrente sanguínea em pacientes atendidos em hospitais públicos do município de Salvador, Bahia, Brasil / Characterization of yeasts isolated from the bloodstream in patients attended at public hospitals in the city of Salvador, Bahia, Brazil

Infecções de corrente sanguínea (ICS) por leveduras são um grave problema de saúde pública. O conhecimento sobre as ICS deve ser regionalizado e este estudo descreve essas características quanto a ocorrência das espécies e o perfil de sensibilidade ao fluconazol pelo método de Disco Difusão como também, utilizando Vitek2 para determinar a concentração inibitória mínima (CIM) em isolados obtidos de pacientes atendidos em hospitais públicos de Salvador/BA...

Bloods tream infections (BSI) yeast are a major public health problem. Knowledge about the ICS should be regionalized and this study describes these characteristics and the occurrence of species and the sensitivity profile to fluconazole by disk diffusion method but also using Vitek2 to determine the minimum inhibitory concentration (MIC) in isolates from patients treated in public hospitals in Salvador / BA...

Anti- Sporothrix spp. activity of medicinal plants

ABSTRACT Cases of sporotrichosis in humans and animals without satisfactory clinical response have increased, a warning sign of strains resistant to conventional antifungal agents. The urgent search for alternative therapies was an incentive for research on medicinal plants with anti-Sporothrix spp. properties. A bibliographic survey was performed based on scientific papers about in vitro and in vivo antifungal activity of essential oils and extracts of plants in differents solvents against the fungal of the Sporothrix schenckii complex. The study methodology consisted of a literature review in Google Scholar, Science Direct, Pubmed, Bireme and Springer link with papers from 1986 to 2015. We found 141 species of plants that were investigated, of which 100 species were concentrated in 39 botanical families that had confirmed anti-Sporothrix activity. Combretaceae, Asteraceae and Lamiaceae represented the botanical families with the greatest number of plants species with antifungal potential, using different methodologies. However, there are few studies with medicinal plants in experimental infection in animals that prove their activity in the treatment of sporotrichosis. It reinforces the need for further research related to standardization of in vitro methodologies and in vivo studies related to safety and to toxicity potential of these plants with anti-Sporothrix spp. activity.

RESUMO Casos de esporotricose em humanos e animais sem resposta clínica satisfatória têm aumentado, sinal de alarme para o surgimento de cepas resistentes aos antifúngicos convencionais. A urgente busca por alternativas terapêuticas tem incentivado as pesquisas em plantas medicinais com atividade anti-Sporothrix spp. Um levantamento bibliográfico foi realizado com base em artigos científicos sobre a atividade antifúngica in vitro e in vivo de óleos essenciais e extratos de plantas preparados em diferentes solventes contra o complexo Sporothrix schenckii. A metodologia do estudo consistiu em uma revisão bibliográfica em Google Scholar, Science Direct, Pubmed, Bireme e Springer link com artigos desde 1986 até 2015. Foram encontradas 141 espécies de plantas já investigadas, das quais 100 espécies concentradas em 39 famílias botânicas apresentaram atividade anti-Sporothrix spp. confirmada. Combretaceae, Asteraceae e Lamiaceae representaram as famílias botânicas com maior número de espécies vegetais com potencial antifúngico, empregando diferentes metodologias. Entretanto, há poucos estudos com plantas medicinais em infecção experimental animal comprovando sua atividade no tratamento da esporotricose. Reforça-se a necessidade de mais pesquisas relacionadas à padronização de metodologias in vitro e a estudos in vivo relacionados à segurança e potencial tóxico dessas plantas com atividade anti-Sporothrix spp.

Progress on pharmacokinetics/pharmacodynamics of antimicrobial agents / 中华临床感染病杂志

The pharmacokinetics/pharmacodynamics ( PK/PD) of antimicrobials aims to establish and evaluate dose-concentration-response relationship, and subsequently to describe and predict the effect-time courses resulting from a drug dose.Nowadays, PK/PD is playing an important role in dosage regimen optimizing, reducing toxicity and drug tolerance of antibiotics.And it is also of great significance in determining susceptibility breakpoints and development in new drug.This paper reviews the progress on PK/PD studies of antibacterial and antifungal agents to provide theoretical basis for safe and effective individual dosage regimens.

Gel de própolis mucoadesivo versus solução de cloridrato de benzidamina na prevenção da mucosite oral em pacientes irradiados em região de cabeça e pescoço. Ensaio clinico, cego, randomizado: fase II / Propolis mucoadhesive gel versus Benzydamine Hydrochloride Solution to Prevention of Oral Mucositis in Patients Irradiated in Head and Neck Region. A phase II study randomized and blind

Os efeitos colaterais mais conhecidos em cavidade bucal, durante a radioterapia para o tratamento de câncer em região da cabeça e pescoço, são a mucosite e a candidose. Essas alterações são potencializadas pela hipossalivação em decorrência de alterações nas glândulas salivares. Existem diversos protocolos para o controle da mucosite, hipossalivação e candidose bucais nesses pacientes, entretanto, nenhum deles é totalmente eficaz. A Própolis possui atividade analgésica, anti-inflamatória, antifúngica e cicatrizante. Essas características farmacológicas conferem à Própolis um grande potencial para prevenir as alterações na cavidade bucal dos pacientes que serão submetidos à radioterapia. O objetivo deste trabalho foi avaliar a efetividade do Gel contendo Própolis na prevenção da mucosite e candidose em comparação com o cloridrato de benzidamina. Vinte e seis pacientes foram incluídos no estudo. Os pacientes foram aleatorizados em dois grupos, sendo que o grupo 1 usou o cloridrato de benzidamina e o grupo 2 o gel de Própolis. Tanto os pacientes do grupo 1 , como os pacientes do grupo 2 usaram os produtos 3 (três) vezes ao dia, durante todo o período da radioterapia e duas semanas após o término do tratamento e todos foram avaliados semanalmente. Os resultados obtidos mostraram que 84,6% dos pacientes eram do sexomasculino e que 19,2% dos pacientes mantinham o hábito de fumar e consumir bebidas alcoólicas. A dose média de radioterapia foi 6466,1 Gys. Após a análise final dos dados, observou-se que o Gel de Própolis apresentou melhor efetividade na prevenção da mucosite, a partir da 17a sessão de radioterapia, quando comparado ao grupo cloridrato de benzidamina. Setenta e oito por cento (78,6%) dos pacientes avaliaram o produto como bom, enquanto 85,7% o indicariam para pacientes com a mesma condição. O estudo mostrou que o controle da inflamação na mucosa bucal pelo Gel contendo Própolis foi melhor...

The best known side effects in the oral cavity during radiotherapy for the treatment of cancer in the head and neck, are mucositis and candidiasis. These changes are enhanced by hyposalivation due to changes in the salivary glands. There are many protocols for the control of mucositis, hyposalivation, and oral candidiasis in these patients however, none iscompletely effective. Propolis has analgesic, anti-inflammatory, antifungal and healing activity. These pharmacological characteristics give propolis great potential to prevent changes in the oral cavity of patients undergoing radiotherapy. The aim of this study was to evaluate the effectiveness of the gel containing propolis in preventing mucositis and candidiasis compared with benzydamine hydrochloride. Twenty-six patients were included in this study. Patients were divided into two groups with group 1 used the benzydamine hydrochloride and group 2 gel propolis. Both group used the products three times a day during the whole period of radiotherapy and two weeks after the end of treatment and all patients were evaluated weekly...

SUSCEPTIBILITY OF Candida spp. ISOLATED FROM BLOOD CULTURES AS EVALUATED USING THE M27-A3 AND NEW M27-S4 APPROVED BREAKPOINTS / Suscetibilidade de Candida spp. isoladas de hemocultivos, avaliadas pelos breakpoints dos documentos M27-A3 e M27-S4 do CLSI

The high mortality rates associated with candidemia episodes and the emergence of resistance to antifungal agents necessitate the monitoring of the susceptibility of fungal isolates to antifungal treatments. The new, recently approved, species-specific clinical breakpoints (SS-CBPs)(M27-S4) for evaluating susceptibility require careful interpretation and comparison with the former proposals made using the M27-A3 breakpoints, both from CLSI. This study evaluated the susceptibility of the different species of Candida that were isolated from candidemias based on these two clinical breakpoints. Four hundred and twenty-two isolates were identified and, among them, C. parapsilosis comprised 46.68%, followed by C. albicans (35.78%), C. tropicalis (9.71%), C. glabrata (3.55%), C. lusitaniae (1.65%), C. guilliermondii (1.65%) and C. krusei (0.94%). In accordance with the M27-A3 criteria, 33 (7.81%) non-susceptible isolates were identified, of which 16 (3.79%) were resistant to antifungal agents. According to SS-CBPs, 80 (18.95%) isolates were non-susceptible, and 10 (2.36%) of these were drug resistant. When the total number of non-susceptible isolates was considered, the new SS-CBPs detected 2.4 times the number of isolates that were detected using the M27-A3 interpretative criteria. In conclusion, the detection of an elevated number of non-susceptible species has highlighted the relevance of evaluating susceptibility tests using new, species-specific clinical breakpoints (SS-CBPs), which could impact the profile of non-susceptible Candida spp. to antifungal agents that require continuous susceptibility monitoring.

As elevadas taxas de mortalidade associadas com episódios de candidemia e a emergência da resistência aos antifúngicos, requerem o monitoramento da suscetibilidade de Candida spp., isoladas das candidemias, frente aos agentes antifúngicos. Os novos breakpoints, chamados “espécie-específicos,” foram recentemente aprovados (M27-S4) requerendo, pois, cuidadosa interpretação e comparações com aqueles até agora utilizados (M27-A3); ambos são propostos pelo Clinical Laboratory Standard Institute (CLSI). O presente estudo avaliou a suscetibilidade de espécies de Candida isoladas de candidemias baseando-se nestes dois breakpoints. Quatrocentos e vinte e dois isolados de Candida foram identificados e assim distribuídos: C. parapsilosis (48,68%), C. albicans (35,78%), C. tropicalis (9,71%), C. glabrata (3,55%), C. lusitaniae (1,65%), C. guilliermondii (1,65%), C. krusei (0,94%). Com base nos critérios do M27-A3, um total de 33 (7,81%) isolados foram julgados não-sensíveis, dos quais 16 (3,79%) como resistentes aos antifúngicos. De acordo com os breakpoints espécie-específicos (M27-S4) um total de 80 (18,95%) isolados foram considerados não-sensíveis, dos quais 10 (2,36%) resistentes a algum dos antifúngicos testados. Com base nos novos breakpoints espécie-específicos, o número de isolados não-sensíveis foi 2,4 vezes maior do que o número de não-sensíveis detectado pelos breakpoints do documento M27-A3. A detecção de um elevado número de isolados não-sensíveis através dos breakpoints propostos pelo M27-S4 destaca a importância dos testes de suscetibilidade, os quais trarão impactos no reconhecimento de isolados de Candida spp. não-sensíveis em episódios de candidemias, requerendo, portanto, continua avaliação.