Avaliação da interação farmacológica de antifúngicos e quimioterápicos: uma revisão sistemática / Evaluation of pharmacological interaction of antifungals and chemotherapy: a systematic review

Objetivo: avaliar, por meio da literatura existente, a interação farmacológica de antifúngicos e quimioterápicos. Métodos: foi realizado um estudo de revisão sistemática de acordo com o diagrama de fluxo do processo de pesquisa PRISMA. Os descritores escolhidos foram: drug interactions, CYP inhibitors, antifungal e antineoplastic, mediante análise realizada no MESH. As bases de dados escolhidas foram: Pubmed, Lilacs e Scielo. O período considerado para busca de artigos publicados foi de 2015 a 2020. Resultados: no banco de dados PubMed, foram encontrados 54 artigos, enquanto, nas bases Lilacs e Scielo, não foram encontrados artigos de acordo com os critérios estabelecidos. Dos 54 artigos, 7 foram selecionados para esta revisão. O intervalo com maior número de publicações foi de 2015-2016. Os antifúngicos mais citados nos resultados foram os inibidores fortes da CYP (Cetoconazol, Itraconazol e Voriconazol). Conclusão: a revisão sistemática da literatura mostrou que não existe uma correlação exata entre a interação farmacológica dos antifúngicos com os antineoplásicos, quando administrados de forma simultânea. São necessários mais estudos atuais que possam monitorar e estabelecer, de forma precisa, a relação dessas interações.

Objective: to evaluate, through the existing literature, the pharmacological interaction of antifungals and chemotherapeutics. Methods: a systematic review study was conducted according to the PRISMA research process flow diagram. The descriptors were chosen by analysis performed in MESH. The descriptors chosen were: drug interactions, CYP inhibitors, antifungal and antineoplastic. The databases chosen were: Pubmed, Lilacs, and Scielo. The period considered for the search of published articles was from 2015 to 2020. Results: in the PubMed database, 54 articles were found, while in the Lilacs and Scielo databases, no articles were found according to the established criteria. Of the 54 articles, 8 were selected for this review. The interval that had the highest number of publications was 2015-2016. The most cited antifungal drugs in the results were the strong CYP inhibitors. Conclusion: the systematic review of the literature showed that there is no exact correlation between the pharmacological interaction of antifungals with antineoplastic drugs when administered simultaneously. More current studies are needed that can accurately monitor and establish the relationship between these interactions.

Evaluation of susceptibility and response in the surface of agents of surface mycoses (Trichophyton mentagrophytes; T. tonsurans) to antifungal drugs of interest in a medical clinic / Avaliação da susceptibilidade e resposta in vitro de agentes de micoses superficiais (Trichophyton mentagrophytes; T. tonsurans) à drogas antifúngicas de interesse em clínica médica

INTRODUCTION: The resistance of fungal species to drugs usually used in clinics is of great interest in the medical field. OBJECTIVE: To evaluate susceptibility and in vitro response of species of Trichophyton spp. to antifungal drugs of interest in clinical medicine. METHODS: 12 samples of clinical isolates from humans were used, nine of T. mentagrophytes and three of T. tonsurans. Susceptibility tests were performed according to the agar diffusion (AD) and broth microdilution (BM) methods. RESULTS: In the AD method, the species T. tonsurans presented a percentage of sensitivity of 33% in relation to amphotericin B and 66% to itraconazole, with 100% resistance to ketoconazole and fluconazole. T. mentagrophytes also showed 100% resistance to ketoconazole in this technique, with 11% sensitivity to ketoconazole, 22% to itraconazole and 22% of samples classified as sensitive dose dependent. In the MC method, the species T. tonsurans presented a sensitivity percentage of 66%, 55% and 33% in relation to ketoconazole, fluconazole and itraconazole, respectively. The T. mentagrophytes species presented sensitivity percentages of 11%, 11%, 33% and 55% for amphotericin B, itraconazole, ketoconazole and fluconazole, respectively. CONCLUSION: There was resistance in vitro of the species of T. mentagrophytes and T. tonsurans against the antifungal fluconazole and relative resistance against ketoconazole in the AD method. In BM, however, important percentages of sensitivity were observed for the two species analyzed in relation to the antifungals fluconazole and ketoconazole when compared to itraconazole and amphotericin B.

INTRODUÇÃO: A resistência de espécies fúngicas às drogas usualmente empregadas no meio clínico é motivo de grande interesse na área médica. OBJETIVO: Avaliar susceptibilidade e resposta in vitro de espécies de Trichophyton spp. a drogas antifúngicas de interesse em clínica médica. MÉTODOS: Foram utilizadas 12 amostras de isolados clínicos de humanos, sendo nove de T. mentagrophytes e três de T. tonsurans. Foram realizados testes de susceptibilidade segundo os métodos de difusão em ágar (DA) e microdiluição em caldo (MC). RESULTADOS: No método de DA, a espécie T. tonsurans apresentou percentual de sensibilidade de 33% em relação à anfotericina B e de 66% ao itraconazol, com 100% de resistência frente ao cetoconazol e ao fluconazol. A espécie T. mentagrophytes também apresentou 100% de resistência frente ao cetoconazol nesta técnica, com 11% de sensibilidade ao cetoconazol, 22% ao itraconazol e 22% das amostras classificadas como sensível dose dependente. No método de MC, a espécie T. tonsurans apresentou percentual de sensibilidade de 66%, 55% e 33% em relação ao cetoconazol, fluconazol e itraconazol, respectivamente. A espécie T. mentagrophytes apresentou percentuais de sensibilidade de 11%, 11%, 33% e 55% para anfotericina B, itraconazol, cetoconazol e fluconazol, respectivamente. CONCLUSÃO: Houve resistência in vitro das espécies do T. mentagrophytes e T. tonsurans frente ao antifúngico fluconazol e resistência relativa frente ao cetoconazol no método de DA. Na MC, no entanto, foram observados importantes percentuais de sensibilidade das duas espécies analisadas frente aos antifúngicos fluconazol e cetoconazol quando comparadas ao itraconazol e à anfotericina B.

Uso de testosterona en mujeres: un comentario sobre el consenso global sobre el uso de la terapia de testosterona para mujeres / Global consensus position statement on the use of testosterone therapy for women

Las mujeres han sido tratadas por décadas con testosterona intentando aliviar una gran variedad de síntomas con riesgos y beneficios inciertos. En la mayoría de los países, la testosterona se prescribe "off-label", de modo que las mujeres están utilizando compuestos y dosis ideadas para tratamientos en hombres. En este sentido, varias sociedades médicas de distintos continentes adoptaron recientemente por consenso una toma de posición sobre los beneficios y potenciales riesgos de la terapia con testosterona en la mujer, explorar las áreas de incertidumbre e identificar prácticas de prescripción con potencial de causar daño. Las recomendaciones con respecto a los beneficios y riesgos de la terapia con testosterona se basan en los resultados de ensayos clínicos controlados con placebo de al menos 12 semanas de duración. A continuación se comentan las recomendaciones. (AU)

There are currently no clear established indications for testosterone replacement therapy for women. Nonetheless, clinicians have been treating women with testosterone to alleviate a variety of symptoms for decades with uncertainty regarding its benefits and risks. In most countries, testosterone therapy is prescribed off-label, which means that women are using testosterone formulations or compounds approved for men with a modified dose for women. Due to these issues, there was a need for a global Consensus Position Statement on testosterone therapy for women based on the available evidence from placebo randomized controlled trials (RCTs). This Position Statement was developed to inform health care professionals about the benefits and potential risks of testosterone therapy intended for women. The aim of the Consensus was to provide clear guidance as to which women might benefit from testosterone therapy; to identify symptoms, signs, and certain conditions for which the evidence does not support the prescription of testosterone; to explore areas of uncertainty, and to identify any prescribing practices that have the potential to cause harm. (AU)

Surface morphology and in vitro leachability of soft liners modified by the incorporation of antifungals for denture stomatitis treatment

Abstract Objective: To evaluate the surface morphology and in vitro leachability of temporary soft linings modified by the incorporation of antifungals in minimum inhibitory concentrations (MIC) for Candida albicans biofilm. Methodology:Specimens of soft lining materials Softone and Trusoft were made without (control) or with the addition of nystatin (Ny), miconazole (Mc), ketoconazole (Ke), chlorhexidine diacetate (Chx), or itraconazole (It) at their MIC for C. albicans biofilm. The surface analyses were performed using Confocal laser scanning microscopy after 24 h, 7 days, or 14 days of immersion in distilled water at 37ºC. In vitro leachability of Chx or Ny from the modified materials was also measured using Ultraviolet visible spectroscopy for up to 14 days of immersion in distilled water at 37ºC. Data (µg/mL) were submitted to ANOVA 1-factor/Bonferroni (α=0.05). Results: Softone had a more irregular surface than Trusoft. Morphological changes were noted in both materials with increasing immersion time, particularly, in those containing drugs. Groups containing Chx and It presented extremely porous and irregular surfaces. Both materials had biexponential release kinetics. Softone leached a higher concentration of the antifungals than Trusoft (p=0.004), and chlorhexidine was released at a higher concentration than nystatin (p<0.001). Conclusions: The surface of the soft lining materials changed more significantly with the addition of Chx or It. Softone released a higher concentration of drugs than Trusoft did, guiding the future treatment of denture stomatitis.

Antifungal and Antioxidant Activities of Vernonia Chalybaea Mart. ex DC. Essential Oil and their Major Constituent β -caryophyllene

Abstract: This article describes the chemical composition of Vernonia chalybaea essential oil, and investigates its antimicrobial, antioxidant and hemolytic activities. The evaluation of the antifungal activity was performed by the broth microdilution method using strains of yeasts and dermatophytic fungi. The checkerboard technique to find antimicrobial modulatory effects was performed using ketoconazole as standard drug. The antioxidant activity was evaluated by DPPH scavenging assay and β-carotene/linoleic-acid system. The toxicity was characterized by the brine shrimp lethality test and hemolysis bioassays. The essential oil was obtained by hydrodistillation and analyzed by GC-MS method, showing to be rich in the sesquiterpenes β-caryophyllene (39.06%) and bicyclogermacrene (19.69%), and also demonstrated a relevant antifungal activity against strains of Trichophyton rubrum. In the modulatory activity assay, the essential oil of V. chalybaea and β-caryophyllene demonstrated a synergistic interaction with ketoconazole, with increasing of its antifungal action. The antioxidant activity was evidenced mainly by β-carotene/linoleic acid system, with IC50 value of 35.87 ± 0.32 µg/mL. The results suggest that V. chalybaea essential oil and β-caryophyllene are valuable natural medicinal agents with antioxidant and antimicrobial activities.

Desenvolvimento e avaliação de nova preparação de anfotericina B e/ou cetoconazol em dispersão de bixina, pullulan e trealose / Development and evaluation of novel preparation of amphotericin B and/or ketoconazole in dispersion of bixin, pullulan and trehalose

Muitos pacientes acometidos por infecções fúngicas sucumbem devido a não eficácia dos antibióticos ou por toxicidade dos mesmos. Anfotericina B é um dos antifúngicos mais eficientes do mercado apesar de sua alta toxicidade, tem estrutura poliênica e é um composto insolúvel em água, sendo necessário o uso de adjuvantes e novas tecnologias para preparo de formulações eficazes. Cetoconazol é um composto imidazólico, também com ação antifúngica de grande espectro de ação e difícil solubilização em meio aquouso, porém solúvel somente em baixos valores de pH. Estudos têm demonstrado a utilização de bixina na preparação de dispersões aquosas de compostos insolúveis ou pouco solúveis em água. Bixina é o principal composto das cascas de semente de Bixa orellana (urucum), sendo um carotenoide insolúvel em água, porém, permite preparações na forma de nanodispersões aquosas com incorporação de fármacos apolares ou lipofílicos. O objetivo deste trabalho foi preparar anfotericina B e cetoconazol na forma de nanodispersões a partir de bixina, utilizando pullulan e trealose como adjuvantes e avaliar estabilidade e eficácia antimicrobiana por ensaios físico-químicos e microbiológicos. Pullulan é um polissacarídeo constituído por unidades de maltotriose, com propriedades adesivas e capacidade de formar biofilmes, enquanto trealose é um composto com duas unidades de glicose, com boa estabilidade em faixas de pH de 3 a 10 e capaz de suportar altas temperaturas, como processos de esterilização por calor úmido. Ensaios físico-químicos demonstraram boa manutenção das características das preparações propostas neste projeto, como, por exemplo, diâmetro hidrodinâmico e potencial zeta das estruturas das nanodispersões de bixina e antifúngicos e também eficácia antimicrobiana frente a Candida albicans ATCC 10231. Os resultados apresentam perspectivas para aprimoramentos de formulações com fármacos pouco solúveis ou insolúveis em água, pesquisa de novos biomateriais e outras aplicações nas áreas farmacêutica e cosmética

Many patients with fungal infections succumb due to ineffectiveness or toxicity of antibiotics. Amphotericin B is one of the most efficient antifungals on the market despite its high toxicity. It presents polyenic structure and is a water-insoluble compound. In this case, it is necessary to use adjuvants and new technologies to prepare effective formulations. Ketoconazole is an imidazolic compound, also with broad spectrum antifungal action and difficult solubilization in aqueous medium but it is soluble at low pH values. Studies have demonstrated the use of bixin in the preparation of aqueous dispersions of insoluble or poorly soluble compounds in water. Bixin is the main compound of Bixa orellana (annatto) seed husks, being a water-insoluble carotenoid, but it allows preparations in the form of aqueous nanodispersions with incorporation of apolar or lipophilic drugs. The objective of this work was to prepare amphotericin B and ketoconazole as nanodispersions from bixin, using pullulan and trehalose as adjuvants and to evaluate them under aspects of stability and efficacy by physicochemical and microbiological assays. Pullulan is a polysaccharide consisting of maltotriose units with adhesive properties and ability to form biofilms, while trehalose is a compound with two glucose units with good stability at pH ranges from 3 to 10 and capable of withstanding high temperatures such as processes of sterilization by moist heat. Physicochemical tests demonstrated good maintenance of the characteristics of the preparations proposed in this project, such as hydrodynamic diameter and zeta potential of bixin and antifungal nanodispersions and also antimicrobial efficacy against Candida albicans ATCC 10231. The results present prospects for improvement. of poorly soluble or water-insoluble drug formulations, research on new biomaterials and other applications in the pharmaceutical and cosmetic fields

Systematic review and meta-analysis on oral azoles for the treatment of pityriasis versicolor

@#<p style="text-align: justify;"><strong>Background:</strong> Oral azole drugs are a second-line option for the treatment of pityriasis versicolor but evidence on their efficacy and safety is unclear. Objectives. To determine the efficacy and safety of oral azoles in the treatment of patients with pityriasis Versicolor.</p><p style="text-align: justify;"><strong>Methods</strong>: We searched MEDLINE, CENTRAL, EMBASE, LILACS, and HERDIN, from inception to the period between January to February 2014. We did not restrict the search by language or publication status. We included randomized controlled trials (RCTs) that compared the efficacy of oral azoles with placebo or no treatment, with topical agents, other oral azoles or dosing regimens in the treatment of pityriasis Versicolor, and that measured any of the pre-specified outcomes (mycologic cure, clinical cure, recurrence, duration to cure, time-to-cure, and quality of life). For adverse effects, we also included non-randomized studies (NRS). We used Cochrane methods to select studies, extract data, assess the risk of bias, pool studies, and calculate for treatment effects.</p><p style="text-align: justify;"><strong>Results:</strong> We included 38 RCTs (n=2894) and 56 NRS (n=3452). Overall, there were few pooled studies and evidence was low to moderate quality. Oral azoles were more effective than placebo (mycologic cure, RR 11.34, 95% CI 4.90, 26.28; 3 RCTs, n=131; I2=0%; low quality of evidence) and as effective as topical agents (mycologic cure, RR 1.02, 95% CI 0.86, 1.21; 4 RCTs, n=232; I2=60%; moderate quality of evidence).There were few adverse effects and were mostly minor and transient.</p><p style="text-align: justify;"><strong>Conclusions:</strong> Oral azoles may be more effective than placebo, and are probably as effective as topical agents in the treatment of PV. Triazoles are probably as effective as ketoconazole. Adverse effects were few, mostly minor, and transient.</p>

Systemic review and meta-analysis on oral azoles for the treatment of pityriasis versicolor

Background: Oral azole drugs are a second-line option for the treatment of pityriasis versicolor but evidence on their efficacy and safety is unclear.Objectives: To determine the efficacy and safety of oral azoles in the treatment of patients with pityriasis versicolor.Methods: We searched MEDLINE, CENTRAL, EMBASE, LILACS, and HERDIN, from inception to the period between January to February 2014. We did not restrict the search by language or publication status. We included randomized controlled trials (RCTs) that compared the efficacy of oral azoles with placebo or no treatment, with topical agents, other oral azoles or dosing regimens in the treatment of pityriasis versicolor, and that measured any of the pre-specified outcomes (mycologic cure, clinical cure, recurrence, duration to cure, timeto- cure, and quality of life). For adverse effects, we also included non-randomized studies (NRS). We used Cochrane methods to select studies, extract data, assess risk of bias, pool studies, and calculate for treatment effects.Results: We included 38 RCTs (n=2894) and 56 NRS (n=3452). Overall, there were few pooled studies and evidence was low to moderate quality.Oral azoles were more effective than placebo (mycologic cure, RR 11.34, 95% CI 4.90, 26.28; 3 RCTs, n=131; I2=0%; low quality of evidence) and as effective as topical agents (mycologic cure, RR 1.02, 95% CI 0.86, 1.21; 4 RCTs, n=232; I2=60%; moderate quality of evidence). There were few adverse effects and were mostly minor and transient.Conclusions: Oral azoles may be more effective than placebo, and are probably as effective as topical agents in the treatment of PV. Triazoles are probably as effective as ketoconazole. Adverse effects were few, mostly minor, and transient.

Evaluación de formulaciones de ketoconazol para uso tópico en leishmaniasis cutánea por Leishmania(Viannia) / Evaluation of ketoconazole formulations for topical use in cutaneous leishmaniasis caused by Leishmania (Viannia)

RESUMEN Se evaluó la efectividad de diversas formulaciones farmacéuticas de ketoconazol en modelos experimentales de leishmaniasis cutánea (LC) en ratones BALB C. Fueron preparadas formulaciones tópicas tipo gel, lipogel y crema conteniendo potenciadores de la permeación y diferentes concentraciones de ketoconazol. Se determinó la estabilidad, la toxicidad y la actividad anti-Leishmania in vitro. Además, se evaluó in vivo la efectividad de las formulaciones aplicadas tópicamente en ratones con LC infectados con Leishmania (Viannia) braziliensis. Las formulaciones tipo crema fueron evaluadas adicionalmente en ratones infectados con L. (V.) panamensis. Los sistemas evaluados mantuvieron in vitro la actividad del ketoconazol contra los parásitos; sin embargo, ninguna de las formulaciones fue efectiva en curar las lesiones de LC en los ratones. El tratamiento tópico con miltefosina (utilizado como control) curó las lesiones. Se concluye que las formulaciones que contienen ketoconazol diseñados en este estudio, no fueron efectivos contra la LC en los ratones infectados.

ABSTRACT The effectiveness of various pharmaceutical formulations of ketoconazole was evaluated in experimental models of cutaneous leishmaniasis (LC) in BALB C mice. Topical gel, lipogel, and cream formulations containing permeation enhancers and different concentrations of ketoconazole were prepared. Stability, toxicity and anti-Leishmania activity were determined in vitro. In addition, the effectiveness of topically applied formulations in LC-infected mice infected with Leishmania (Viannia) braziliensis was evaluated in vivo. Cream formulations were additionally evaluated in mice infected with L. (V.) panamensis. The systems evaluated maintained in vitro the activity of ketoconazole against parasites; however, none of the formulations were effective in curing LC lesions in mice. Topical treatment with miltefosine (used as a control) cured the lesions. It is concluded that the ketoconazole-containing formulations designed in this study were not effective against LC in infected mice.

Seguimiento e impacto de la divulgación de cinco alertas sanitarias de medicamentos en f1Colombia / Monitoring and impact of the disclosure of five health alerts for drugs in Colombia

RESUMEN Objetivo Realizar la notificación y verificar el seguimiento de cinco alertas sanitarias de medicamentos a un grupo de prestadores de salud en Colombia. Métodos Estudio cuasi-experimental, prospectivo, antes y después, sin grupo control, mediante una intervención en médicos prescriptores de ketoconazol, metoclopramida, nimesulida, diacereina, ranelato de estroncio. Se tomó como población universo a los afiliados al régimen contributivo del Sistema de Salud Colombiano en 13 entidades promotoras de salud (EPS) de Colombia. Se identificaron los pacientes que recibían mensualmente estos medicamentos previamente a la alerta. Se realizó una intervención educativa y posteriormente se midió la proporción de cambio en la dispensación. Resultados Se realizaron en total unas 26 actividades diferentes a 500 médicos prescriptores. De un total de 4 121 954 de personas se identificaron 13 979 pacientes mensuales en 2013 que recibían alguno de los cinco medicamentos y se observó una reducción en 1 470 sujetos al mes (-10,5%) para 2014. El medicamento con el que se consiguió la mayor reducción fue ketoconazol (-31,1% de casos), seguido de ranelato de estroncio (-30,3%) y metoclopramida (-8,6%). Para nimesulida (+0,7%) y diacereina (+16,4%) no se obtuvieron resultados favorables. Conclusiones Se mantienen prescripciones potencialmente riesgosas en pacientes de Colombia. Con intervenciones basadas en farmacovigilancia posterior al reporte de alertas por agencias reguladoras sanitarias, se puede disminuir la proporción de pacientes que utilizan estos medicamentos.(AU)

ABSTRACT Objective Make the notification and monitoring compliance with five health drug alerts to a group of health care providers in Colombia. Methods Quasi-experimental, prospective, before-after study, without control group, by intervening in physician prescribers of ketoconazole, metoclopramide, nimesulide, diacerein, strontium ranelate. The affiliated population of the contributory system of the Colombian Health System was taken as the universe population sample from 13 health promoting entities (EPS) of Colombia. Patients receiving monthly these drugs prior to the alert were identified. An educational intervention was performed and then the rate of change in the dispensation was measured. Results About 26 different activities were conducted on 500 prescribers. Out of a total of 4 121 954 people, 13 979 patients were identified monthly in 2013, who received some of the five medications. Likewise, a reduction in 1,470 subjects per month (-10.5%) for 2014 was observed. The drug which achieved the greatest reduction was ketoconazole (-31.1% of cases), followed by strontium ranelate (-30.3%) and metoclopramide (-8.6%). For nimesulide (+ 0.7%) and diacerein (+ 16.4%) no favorable results were obtained. Conclusions Patients with potentially risky prescriptions remain in Colombia; educational pharmacovigilance interventions made after the report alerts given by drug regulatory agencies may decrease the proportion of patients using these drugs.(AU)

Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells

Breast cancer is currently the most prevalent cancer in women, and its incidence increases every year. Azole antifungal drugs were recently found to have antitumor efficacy in several cancer types. They contain an imidazole (clotrimazole and ketoconazole) or a triazole (fluconazole and itraconazole) ring. Using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231), we evaluated the effects of azole drugs on cell proliferation, apoptosis, cell cycle, migration, and invasion, and investigated the underlying mechanisms. Clotrimazole and ketoconazole inhibited the proliferation of both cell lines while fluconazole and itraconazole did not. In addition, clotrimazole and ketoconazole inhibited the motility of MDA-MB-231 cells and induced G₁-phase arrest in MCF-7 and MDA-MB-231 cells, as determined by cell cycle analysis and immunoblot data. Moreover, Transwell invasion and gelatin zymography assays revealed that clotrimazole and ketoconazole suppressed invasiveness through the inhibition of matrix metalloproteinase 9 in MDA-MB-231 cells, although no significant changes in invasiveness were observed in MCF-7 cells. There were no significant changes in any of the observed parameters with fluconazole or itraconazole treatment in either breast cancer cell line. Taken together, imidazole antifungal drugs showed strong antitumor activity in breast cancer cells through induction of apoptosis and G₁ arrest in both MCF-7 and MDA-MB-231 cells and suppression of invasiveness via matrix metalloproteinase 9 inhibition in MDA-MB-231 cells. Imidazole drugs have well-established pharmacokinetic profiles and known toxicity, which can make these generic drugs strong candidates for repositioning as antitumor therapies.

Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis

BACKGROUND Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs) are available. In this situation, minimal inhibitory concentration (MIC) distributions and epidemiological cutoff values (ECVs) support the detection of identification of resistant strains. OBJECTIVES To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs. METHODS MICs of amphotericin B (AMB), itraconazole (ITR), ketoconazole (KET), posaconazole (POS), and terbinafine (TRB) against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method. FINDINGS The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively. MAIN CONCLUSIONS These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

The clinical safety and efficacy of ketoconazole in the prevention of postoperative erection: A systematic review

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> To identify and assess the available literature in evaluating the efficacy and safety of ketoconazole in preventing postoperative erection among patients who underwent penile or urethral reconstructive surgery.<br /><strong>METHODS:</strong> From the period of 1990 to September 2016, the investigators assessed Cochrane Central Register of Controlled Trials, EMBASE, HERDIN, and PubMed for studies evaluating the efficacy and safety of ketoconazole in preventing post operative erection among patients who underwent penile or urethral reconstructive surgery. Review authors selected articles for inclusion, extracted date and and assessed trial quality.<br /><strong>RESULTS:</strong> One randomized controlled study and 2 retrospective studies were included in the review. Three studies for a total of 83 patients ages 17-32 comprised the evidence for this review. All trials investigated the efficacy and safety of ketoconazole in the prevention of post operative erection. In both retrospective studies, ketoconazole had significant prevention of erection in however both of these studies were non-RCTs. In the randomized control study by DeCastro et.al.,ketoconazole had no significant difference in the prevention of post operative erection against placebo. Sixteen out of 19 patients (84%) taking ketoconazole had episodes of erection and 15 out of 18 patients in the placebo group (83%) had episodes of erection. Common side effects include nausea (9-21%) and elevated liver enzymes (0-5.3%). Other reported adverse events include feet swelling,pruritus,frequent urination and headache. Present in only 1 out of the 31 patients (3.2%) in the study of DeCastro. All these adverse events were not statistically significant.<br /><strong>CONCLUSION:</strong> This review demonstrated that the use of Ketoconazole in the prevention of postoperative erection remains inconclusive. Further prospective randomized controlled trials with testosterone assay will help determine the appropriate dose and its efficacy in the prevention of postoperative erections. Ketoconazole is relatively safe if target testosterone levels are achieved using the 400mg/tab TID dosing.</p>

[Drug susceptibility testing of clinical isolates of Candida albicans against Amphotericin B and Ketoconazole by microdilution and disk diffusion methods]

Background and Objective: Candida albicans is the normal flora of the body as opportunistic fungi. It causes candidiasis in immunocompromised condition. This study was done to drug susceptibility testing of Candida albicans isolated from patients against Amphotericin B and Ketoconazole

Methods: In this descriptive - analytic study, drug susceptibility of 30 Candida albicans isolated from patients admitted to Tehran hospitals, Iran was tested against Amphotericin B and Ketoconazole by micro dilution method in accordance with CLSI M27-A2 guideline and disk diffusion method in accordance with CLSI M44-S2 guideline. Standard isolate Candida albicans PTCC [5027] and Candida krusei PTCC [5295] were used for quality control

Results: The minimum and maximum MIC against Amphotrericin B was 0.0625 micro g.ml[-1] and 4 micro g.ml[-1], respectively. The minimum and maximum MIC against Ketoconazole was 0.5 micro g/ml[-1] and 32 micro g/ml[-1], respectively. The minimum and maximum zone diameter was 6 and 28 mm for both drugs. The results of drug susceptibility testing by two methods did not show significant differences. 25 isolates [83.3%] against ketoconazole and 2 isolates [6.7%] against Amphotericin B were resistant

Conclusion: Amphotericin B administration seems better choice in candidiasis treatment in comparision with Ketoconazole

The clinical safety and efficacy of ketoconazole in the prevention of postoperative erection: A systematic review

OBJECTIVE: To identify and assess the available literature in evaluating the efficacy and safety of ketoconazole in preventing postoperative erection among patients who underwent penile or urethral reconstructive surgery.METHODS: From the period of 1990 to September 2016, the investigators assessed Cochrane Central Register of Controlled Trials, EMBASE, HERDIN, and PubMed for studies evaluating the efficacy and safety of ketoconazole in preventing post operative erection among patients who underwent penile or urethral reconstructive surgery. Review authors selected articles for inclusion, extracted date and and assessed trial quality.RESULTS: One randomized controlled study and 2 retrospective studies were included in the review. Three studies for a total of 83 patients ages 17-32 comprised the evidence for this review. All trials investigated the efficacy and safety of ketoconazole in the prevention of post operative erection. In both retrospective studies, ketoconazole had significant prevention of erection in however both of these studies were non-RCTs. In the randomized control study by DeCastro et.al.,ketoconazole had no significant difference in the prevention of post operative erection against placebo. Sixteen out of 19 patients (84%) taking ketoconazole had episodes of erection and 15 out of 18 patients in the placebo group (83%) had episodes of erection. Common side effects include nausea (9-21%) and elevated liver enzymes (0-5.3%). Other reported adverse events include feet swelling,pruritus,frequent urination and headache. Present in only 1 out of the 31 patients (3.2%) in the study of DeCastro. All these adverse events were not statistically significant.CONCLUSION: This review demonstrated that the use of Ketoconazole in the prevention of postoperative erection remains inconclusive. Further prospective randomized controlled trials with testosterone assay will help determine the appropriate dose and its efficacy in the prevention of postoperative erections. Ketoconazole is relatively safe if target testosterone levels are achieved using the 400mg/tab TID dosing.

Candida albicans urinary tract infection in a Shih Tzu dog with immune-mediated hemolytic anemia

An 8-year-old castrated male Shih Tzu dog (weighing 7.0 kg) presented with anemia and lethargy. Initial diagnosis indicated immune-mediated hemolytic anemia. During therapy, a secondary urinary infection, probably due to the immune suppressive therapy, was diagnosed. Subsequent diagnostic tests, including urinalysis and urine culture, indicated candidal cystitis. Despite ketoconazole therapy for candidal cystitis, the dog died suddenly. A Candida albicans infection was confirmed upon postmortem evaluation. Prolonged immunosuppressive therapy might be the cause of this infection. This is the first case report describing a Candida albicans urinary tract infection accompanied by hemolytic anemia in a dog in Korea.

Impacto de la clindamicina in vitro en la combinación clindamicina - ketoconazol sobre el exopolímero de biopelículas de candida spp de origen urogenital / Impact of in vitro clIndamycIn on the combInatIon of clIndamycIn and ketoconazole on exopolymer of candida spp bIofIlms of urogenItal orIgIn

La mucosa vaginal ha sido utilizada largamente para la administración de antimicrobianos destinados al tratamiento de infecciones endógenas del tracto genital inferior (IETGI) en mujeres embarazadas y no embarazadas. Candida spp elabora biopelículas (BP) y su formación es un proceso complejo que requiere que las células fúngicas establezcan múltiples interacciones con el medio. Las BP están rodeadas por un exopolímero (EPM) que puede restringir la actividad de anticuerpos, la difusión de sustancias y unirse a los antimicrobianos (AM), limitando su acción. Los antimicrobianos (AM) en general y los antimicóticos en particular (AMC) pueden tener dificultades para llegar a las células dentro del EPS. Muchas de las fórmulas que se emplean para el tratamiento empírico usan combinaciones inapropiadas con limitada o nula actividad sobre las biopelículas (BP). La presencia de moléculas que provoquen su inhibición anulando los inductores del EPM o por otro mecanismo, permitirá la actividad del AM específico. Objetivo: demostrar que la actividad de la clindamicina (CLI) en fórmula dual con ketoconazol (KET) actúa sobre BP Candida albicans (CA) y especies no albicans de Candida . (NAC). Métodos: estudiamos la actividad de clindamicina-ketoconazol (CK) sobre la adherencia y dispersión de BP de 8 aislamientos vaginales de CA y 7 de CNA. Se inocularon en 3 tubos con caldo Sabouraud y un dispositivo de vidrio para la formación de la BP según técnica ya descrita. Adherencia: Se incubaron durante 6 horas y se agregó una combinación de CK proveniente del material de óvulos, diluido convenientemente (62,5/260,4 ug/ml), a uno de los tubos de cada aislamiento tomándose como hora 0. Dispersión: esa misma dilución se agregó a otro tubo a las 16 horas. El tercer tubo quedó como testigo sin antimicrobianos. La lectura se efectuó con microscopio óptico a las 24 horas de agregada la combinación CK previa tinción con cristal violeta y se evaluaron con programas fotográficos. Por separado analizamos la actividad de CLI (62,5 ug/ml) y KET (260,4 ug/ml) con técnica similar. Seleccionamos las muestras de 7 pacientes que demostraron candidiasis vulvovaginal (CVV) y las estudiamos con la técnica de capas celulares. Se empleó la combinacion CK para el estudio de la adherencia y dispersión. Resultados: Adherencia se demostró poca influencia de CK en la adherencia con respecto a cada testigo. Dispersión: la influencia de CK se demostró en la mayoría de los aislamientos particularmente en los de CNA que mostraron una mayor presencia de EPM. Las hifas solo se observaron en 1/15 de los aislamientos de Candida spp cuando se agregó CK a las 16 horas. En las BP de las muestras clínicas no aparecieron hifas ni otro elemento micótico en 5/7 con respecto a los testigos. Conclusión: Según estos resultados el uso de una combinación de CK en BP de Candida spp, resulta en una adecuada penetración del AMC demostrada por la dispersión de la BP al cabo de 24 horas. Clindamicina no interfiere con la acción del ketoconazol sino que promovería su actividad anti-candida modificando posiblemente estructuras de superficie y la del EP por inhibición de las moléculas que facilitan la expresión del mismo. In vivo promueve la actividad inmunomoduladora que no se puede demostrar con este modelo in vitro. Su uso combinado en fórmulas duales facilitaría la actividad del AMC sobre Candida spp actuando como inhibidora o modificadora de las BP mediante la dispersión del EPM

The vaginal mucosa has been widely used for administering antimicrobial agents to treat endogenous infections of the lower genital tract in pregnant and non-pregnant women. Candida spp. elaborates biofilms, and its formation is a complex process requiring that fungal cells establish multiple interactions with the medium. Biofilms are surrounded by an exopolymer matrix that can restrict the activity of antibodies, the diffusion of substances, and be associated with antimicrobials, therefore limiting its actions. General antimicrobials and particular anti-mycotic agents can face difficulties to access the cells within the exopolymer matrix. Many formulas used for empirical treatment have improper combinations with limited or null activity on the biofilms. The presence of molecules that cause its inhibition, thus eliminating the exopolymer matrix inducers, or by other mechanism, will allow the specific antimicrobial activity. Objective: To show that the activity of clindamycin used in dual formula with ketoconazole works on Candida albicans biofilm and on non- albicans species of Candida . Methods: We studied the activity of clindamycin and ketoconazole regarding the adherence and dispersion of biofilms from eight vaginal isolates of C. albicans and 7 of non- albicans Candida . The isolates were inoculated in three tubes with Sabouraud agar and a glass device to form the biofilm according to a known technique. Adherence : Each isolate was incubated for a six-hour period and a combination of clindamycin and ketoconazole from the material of ovules was added and conveniently diluted to one of the tubes of each isolate (62.5/260.4 ug/mL), considering 0 hour. Dispersion: The same dilution was added to another tube after 16 hours. The third tube was used as a control without antimicrobials. The reading was carried out with an optical microscope after 24 hours that the clindamycin and ketoconazole combination had been added and colored with crystal violet. They were then evaluated using photographic programs. The activity of clindamycin (62.5 ug/mL) and ketoconazole (260.4 ug/mL) was analyzed alone with a similar technique. We chose vaginal samples from seven patients with vulvovaginal candidiasis and studied them through the cell layer technique. The clindamycin and ketoconazole combination was used for studying the adherence and dispersion. Results: Adherence: Little influence of clindamycin and ketoconazole was seen in adherence regarding each control. Dispersion: The clindamycin and ketoconazole influence was seen in most of the isolates, especially in those of non- albicans Candida that showed higher presence of exopolymer matrix . The hyphae were only seen in 1 of 15 isolates of Candida spp after the clindamycin and ketoconazole were added at the 16th hour. In biofilms of clinical samples, neither hyphae nor mycotic elements were seen in 5 of 7 compared with the controls. Conclusion: According to these results, the use of a clindamycin and ketoconazole combination in biofilms of Candida spp results in proper penetration of the antimicrobial agent, which is seen by the biofilm dispersion during 24 hours. Clindamycin does not interfere with the action of ketoconazole, but it would promote its anti- Candida activity and would possibly modify surface and EP structures through inhibition of the molecules that facilitate its expression. The in vivo model promotes the immunomodulatory activity that in vitro models do not. Its combined use in dual formulas would facilitate the antimicrobial activity on Candida spp, therefore working as an inhibitor or modifier of the biofilms after dispersion of the exopolymer matrix