Aspectos da abordagem terapêutica sobre candidíase vulvovaginal / Aspects of the therapeutic approach to vulvovaginal candidiasis / Aspectos del abordaje terapéutico de la candidiasis vulvovaginal

A candidíase vulvovaginal, é uma infecção da vulva e vagina causada por vários tipos de Candida spp. Essa patologia afeta 75% de todas as mulheres pelo menos uma vez durante a vida, ocorrendo com mais frequência durante a idade fértil. A transmissão dessa infeção fúngica ocorre por meio de contato com mucosas e secreções em pele de portadores ou doentes, contato sexual, água contaminada e transmissão vertical. Alguns outros sintomas característicos mais vistos em casos de CVV, são lesões brancas, cremosas e planas, sendo mais intensos no período pré-menstrual, quando a acidez vaginal aumenta. numerosos antifúngicos estão disponíveis no mercado, os quais são encontrados para administração oral na forma de comprimidos ou, para uso tópico, na forma de cremes, loções, comprimidos vaginais, supositórios e tampões revestidos. O objetivo geral do trabalho foi analisar através da revisão de literatura, tratamentos convencionais e alternativos para abordagem terapêutica da Candidíase Vulvovaginal contextuando a mesma, utilizando definições, dados epidemiológicos e sua sintomatologia frente à sociedade. O presente trabalho é uma revisão integrativa, que teve a coleta de dados realizada de março de 2021 a outubro de 2021 nas bases de dados Lilacs, Scielo, Google acadêmico, A busca resultou em 902 artigos, dos quais 14 atenderam ao critério de inclusão. A busca por tratamentos frente a candidíase vulvovaginal tem se mostrado ampla de acordo com os artigos selecionadas. Concluímos que a patologia candidíase vulvovaginal, vem apresentando resistência em algumas abordagens terapêuticas, assim como algumas mulheres não aderem há algum tipo de tratamento, devido à falta de conhecimento sobre a patologia.

Vulvovaginal candidiasis is an infection of the vulva and vagina caused by various types of Candida spp. This condition affects 75% of all women at least once in their lifetime, occurring more frequently during their childbearing years. The transmission of this fungal infection occurs through contact with mucous membranes and secretions on the skin of patients or patients, sexual contact, contaminated water and vertical transmission. Some other characteristic symptoms more seen in cases of VVC are white, creamy and flat lesions, being more intense in the premenstrual period, when the vaginal acidity increases. numerous antifungals are available on the market which are available for oral administration in tablet form or, for topical use, in the form of creams, lotions, vaginal tablets, suppositories and coated tampons. The general objective of the work was to analyze, through a literature review, conventional and alternative treatments for the therapeutic approach of Vulvovaginal Candidiasis in its context, using definitions, epidemiological data and its symptoms in society. The present work is an integrative review, which had data collection carried out from March 2021 to October 2021 in the Lilacs, Scielo, Google academic databases. The search resulted in 902 articles, of which 14 met the inclusion criteria. The search for treatments against vulvovaginal candidiasis has been shown to be wide according to the selected articles. We conclude that the vulvovaginal candidiasis pathology has been showing resistance in some therapeutic approaches, as well as some women do not adhere to any type of treatment, due to lack of knowledge about the pathology.

La candidiasis vulvovaginal es una infección de la vulva y la vagina cau- sada por diversos tipos de Candida spp. Esta afección afecta al 75% de las mujeres al menos una vez en la vida, siendo más frecuente durante la edad fértil. La transmisión de esta infección fúngica se produce por contacto con mucosas y secreciones de la piel de pacientes o enfermos, contacto sexual, agua contaminada y transmisión vertical. Otros síntomas característicos más observados en los casos de CVV son las lesiones blancas, cremosas y planas, siendo más intensas en el período premenstrual, cuando aumenta la acidez vaginal. Existen en el mercado numerosos antifúngicos disponibles para adminis- tración oral en forma de comprimidos o, para uso tópico, en forma de cremas, lociones, comprimidos vaginales, supositorios y tampones recubiertos. El objetivo general del tra- bajo fue analizar, a través de una revisión bibliográfica, los tratamientos convencionales y alternativos para el abordaje terapéutico de la Candidiasis Vulvovaginal en su contexto, utilizando definiciones, datos epidemiológicos y su sintomatología en la sociedad. El pre- sente trabajo es una revisión integradora, que tuvo recolección de datos realizada de marzo de 2021 a octubre de 2021 en las bases de datos académicas Lilacs, Scielo, Google. La búsqueda resultó en 902 artículos, de los cuales 14 cumplieron los criterios de inclu- sión. La búsqueda de tratamientos contra la candidiasis vulvovaginal se ha mostrado am- plia según los artículos seleccionados. Concluimos que la patología de la candidiasis vul- vovaginal viene mostrando resistencia en algunos abordajes terapéuticos, así como algu- nas mujeres no se adhieren a ningún tipo de tratamiento, debido al desconocimiento de la patología.

Endocarditis infecciosa debida a candida lusitaniae en un lactante menor: Reporte de caso / Infectious endocarditis due to Candida lusitaniae in an infant: A case report

Resumen Introducción: La endocarditis fúngica es una enfermedad infecciosa agresiva e infrecuente, considerada una emergencia en los servicios hospitalarios. Se ha evidenciado una incidencia de 0-12% del total de las admisiones pediátricas por endocarditis infecciosa. La mortalidad por Candida spp se encuentra alrededor del 50-80% en todos los casos. La Candida lusitaniae afecta principalmente a pacientes inmunocomprometidos, con uso de dispositivos intravasculares y el empleo de antibióticos de amplio espectro. Reporte de caso: Se presenta el caso de un lactante menor quien es diagnosticado con fungemia y endocarditis infecciosa por Candida lusitaniae en válvula nativa posterior a cirugía de corrección por transposición de grandes vasos. Discusión y Conclusiones: La endocarditis infecciosa por Candida lusitaniae es una entidad poco frecuente, con una prevalencia menor al 2% constituyéndose un escenario desafiante en la práctica clínica. Se describen las características de un lactante menor quien presentó endocarditis fúngica ya definidas en la literatura mundial. Es imprescindible la detección temprana y una intervención terapéutica vertiginosa; puesto que, la persistencia del inoculo, la resistencia antimicótica y el retraso en el diagnóstico conllevan a una condición amenazante para la vida del paciente.

Abstract Introduction: Fungal infective endocarditis is an aggressive and infrequent disease, considered an emergency in hospital services. Candida mortality is around 50-80% in all cases. The Candida lusitaniae mainly affects immunocompromised patients with chronic venous access and the use of broad-spectrum antibiotics. Case report: A minor infant is presented who is diagnosed with fungemia and infective endocarditis due to Candida lusitaniae in a native valve secondary to surgery by transposition of large vessels. Discussion and Conclusions: Candida lusitaniae infectious endocarditis is very rare, with a prevalence of less than 2% constituting a challenging scenario in clinical practice. The characteristics of fungemia and endocarditis already defined in the world literature are described. Early detection and a vertiginous therapeutic intervention are essential, since; latent infection, antifungal resistance and delay in diagnosis lead to a threatening condition for the patient's life.

Distribuição das espécies de crípticas de Candida em isolados de corrente sanguínea: identificação e perfil de sensibilidade antifúngica / Distribution of Candida cryptic species in bloodstream isolates: identification and antifungal sensitivity profile

Candidemias caracterizam um grave problema de saúde pública em todo mundo pela alta mortalidade dos casos, onde as espécies apresentam variação epidemiológica e na sensibilidade aos antifúngicos. Objetivou-se demonstrar a frequência de espécies de Candida, enfatizando as espécies crípticas e caracterizar o perfil de sensibilidade antifúngica de cepas em casos de candidemia, internados em hospitais do estado de São Paulo, onde Instituto Adolfo Lutz é o laboratório de referência. As cepas, únicas de cada paciente, foram recebidas de 22 hospitais públicos gerais, filantrópico, escola e especializado em infectologia. A identificação fenotípica para determinação dos complexos deu-se por análise morfológica e bioquímica, por métodos auxanográficos. Para discriminar espécies crípticas aplicaram-se técnicas moleculares das mais simples às complexas, sendo elas: PCR, PCR-RFLP, MALDI-TOF e sequenciamento. Os antifúngicos utilizados nos testes de sensibilidade foram: fluconazol, voriconazol, caspofungina, micafungina, anidulafungina e anfotericina B. Nos anos de 2017 e 2018, foram estudadas 144 cepas de candidemia com as seguintes espécies crípticas: C. parapsilosis sensu stricto (47/144; 32,6%), C. orthopsilosis (4/144; 2,7%), C. metapsilosis (2/144; 1,4%), C. albicans ssss (40/144; 27,8%), C. dubliniensis (2/144, 1,4%), C. glabrata (14/144; 9,7%), C. haemulonii (2/144; 1,4%), C. haemulonii var. vulnera (3/144; 2,1); C. duobushaemulonii (1/144; 0,7%) e C. guilliermondii (2/144; 1,4%). As demais espécies foram: C. tropicalis (21/144; 14,6%), C. krusei (4/144; 2,8%), C. pelliculosa (1/144; 0,7%) e C. kefyr (1/144; 0,7%). Para FCZ foram encontradas 3 cepas de C. parapsilosis (3/46; 6,5%; 0,12->64 µg/mL) e em uma de C. tropicalis (1/21; 4,76%; 64 µg/mL) resistentes; observou-se uma cepa non-wild type de C. guilliermondii (1/2; 50%; 64 µg/mL) e altos MICs para 2 cepas de C. haemulonii var. vulnera (2/3; 66,6%; 16-32 µg/mL) e para a única cepa de C. duobushaemulonii (64 µg/mL). Alta taxa de cepas non-wild type ao VCZ (6/14; 42,8%) foi encontrada em C. glabrata. Reafirma-se neste estudo que as espécies do complexo C. haemulonii, consideradas multirresistentes aos antifúngicos, despontam com maior frequência em nosso estado, se comparado aos dados da literatura. De acordo com os resultados obtidos, a identificação por métodos moleculares representou importante estratégia para demonstrar a variedade de espécies causais de candidemias e alertar para necessidade de terapias apropriadas. A determinação de espécies crípticas propensas à resistência pode ter impacto na sobrevida de pacientes por fornecer subsídios para terapia empírica com base no perfil epidemiológico da candidemia em cada hospital, região e país. (AU)

Candidemia is a serious public health problem worldwide due to the high mortality of the cases. The species present epidemiological diversity and different profiles of sensitivity to antifungals. The aim is to show the frequency of Candida species, emphasizing the cryptic species and to characterize the antifungal sensitivity profile of strains in cases of candidemia, admitted to hospitals in the state of São Paulo, where Adolfo Lutz Institute is the reference laboratory. The strains, unique to each patient, were received from 22 general public hospitals, philanthropic, sshool, and specialized in infectious diseases. The phenotypic identification to determine the complex was done by morphological and biochemical analysis, using auxanographic methods. To discriminate cryptic species, molecular techniques from the simplest to the most complex were applied, namely: PCR, PCR-RFLP, MALDI-TOF, and Sequencing. The antifungals used in the susceptibility tests were: fluconazole, voriconazole, caspofungin, micafungin, anidulafungin and amphotericin B. In the years 2017 and 2018, 144 strains of candidemia were studied with the following cryptic species: C. parapsilosis sensu stricto ss (47/144; 32.6%), C. orthopsilosis (4/144; 2.7%), C. metapsilosis (2/144; 1.4%), C. albicans ssss (40/144; 27.8%), C. dubliniensis (2/144, 1.4%), C. glabrata (14/144; 9 , 7%), C. haemulonii (2/144; 1.4%), C. haemulonii var. vulnera (3/144; 2.1); C. duobushaemulonii (1/144; 0.7%) and C. guilliermondii (2/144; 1.4%). The other species were: C. tropicalis (21/144; 14.6%), C. krusei (4/144; 2.8%), C. pelliculosa (1/144; 0.7%) and C. kefyr (1/144; 0.7%). Resistance to FCZ was found in 3 strains of C. parapsilosis (3/46; 6.5%; 0.12-> 64 µg / mL) and 1 of C. tropicalis (1/21; 4.76%; 64 µg / mL) and non-wild type for a strain of C. guilliermondii (1/2; 50%; 64 µg / mL) and high MICs for 2 C. haemulonii var. vulnera (2/3; 66.6%; 16-32 µg / mL) and in the single strain of C. duobushaemulonii (64 µg / mL). A high rate of non-wild type to VCZ (6/14; 42.8%) was found for C. glabrata. It is reaffirmed in this study that the species of the C. haemulonii complex, considered multiresistant to antifungals, appear more frequently in our state when compared to the literature data. According to the results, the identification by molecular methods becomes an important tool for the construction of surveillance strategies in hospitals. The determination of cryptic species prone to resistance may have an impact on patient survival by providing subsidies for empirical therapy based on the epidemiological profile of candidemia in each hospital, region, and country. (AU)

Antifungal stewardship: consensus on the diagnosis, treatment, and prevention of Candida spp. disease is a fundamental step in the road map to achieve it: [Editorial]

Antimicrobial resistance is a major public health problem and a principal threat to contemporary medicine. A fundamental principle of controlling antimicrobial resistance are antimicrobial drug stewardship programs, which seeks to preserve the future effectiveness of antimicrobials and improve patient outcome; thus, the selection of the optimal antimicrobial drug regimen, dose, route of administration, and duration of therapy are key to limit inappropriate antimicrobial usage and avoiding unnecessary prescribing, including discontinuing antibiotic therapy if it is not required. However, within the context of stewardship programs, insufficient attention has been given to fungal infections. Furthermore, the importance of the accurate and timely diagnosis of fungal infections in overwhelming antimicrobial resistance has been absent from policy discussions. On the other hand, all serious fungal infections need appropriate antifungal therapy for successful patient outcome. Only a few classes of antifungal drugs are available, so the emergence of resistance to single drug classes and now multidrug resistance threatens the appropriate patient management. Azole resistance among Candida and Aspergillus species is one of the greatest challenges to clinical success, followed by echinocandin and multidrug resistance among some Candida species, especially Candida glabrata. Recently, Candida auris, a cryptic species uncommon in most hospitals around the world, including Colombia, has appeared as an emerging species and a global threat capable of developing resistance to multiple antifungals and with great potential for nosocomial transmission.

La resistencia a los antimicrobianos es un importante problema de salud pública y una de las principales amenazas para la medicina contemporánea. Un principio fundamental del control de la resistencia a los antimicrobianos son los programas de administración de medicamentos antimicrobianos, que buscan preservar la eficacia futura de los antimicrobianos y mejorar el resultado de los pacientes; por lo tanto, la selección del régimen óptimo de medicamentos antimicrobianos, la dosis, la vía de administración y la duración de la terapia son clave para limitar el uso inapropiado de antimicrobianos y evitar la prescripción innecesaria, incluyendo la interrupción de la terapia antibiótica si no es necesaria. Sin embargo, en el contexto de los programas de administración, no se ha prestado suficiente atención a las infecciones fúngicas. Además, la importancia del diagnóstico preciso y oportuno de las infecciones fúngicas en la abrumadora resistencia a los antimicrobianos ha estado ausente de los debates políticos. Por otra parte, todas las infecciones fúngicas graves necesitan un tratamiento antifúngico adecuado para que el paciente tenga éxito. Sólo se dispone de unas pocas clases de fármacos antifúngicos, por lo que la aparición de la resistencia a clases de fármacos individuales y ahora la resistencia a múltiples fármacos amenaza el tratamiento adecuado de los pacientes. La resistencia a los azoles entre las especies de Candida y Aspergillus es uno de los mayores retos para el éxito clínico, seguido de la resistencia a las equinocandinas y a los múltiples fármacos entre algunas especies de Candida, especialmente Candida glabrata. Recientemente, Candida auris, una especie críptica poco común en la mayoría de los hospitales del mundo, incluyendo Colombia, ha aparecido como una especie emergente y una amenaza global capaz de desarrollar resistencia a múltiples antifúngicos y con gran potencial de transmisión nosocomial.

Candida species: the silent enemy

Candida species are known to causeserious infections in immunocompromised patients but uncommon cases have been reported in immunocompetent individuals regardless of the harmless co-existence of the fungi with the host. Recently, the incidence rate of candidiasis has increased dramatically alongside the emergence of antifungal resistance. Although conventional methods to ensure prompt diagnosis of candidiasisfor effective therapy have been established, thescientific world is witnessing progress in the development of more accurate, timelyand cost-effective methods that is coinciding with the molecular revolutionand advanced DNA analysis. Moreover, the challenges of resistance of Candida to available antifungal agents are being met with the deployment of molecular techniques to investigate the mechanisms of resistance. This review is an attempt to provide up-to-date information on the persistent problems of Candidawith highlights on the clinical importance, molecular diagnosis,and resistance to candidate antifungal drugs;azoles and echinocandins

Species Distribution and Antifungal Susceptibility of Yeasts Isolated from Ear Specimens / 대한임상미생물학회지

BACKGROUND: Candida auris was first isolated from the ears of Japanese and Korean patients. However, the prevalence of yeast isolates from ear cultures and their antifungal susceptibility profiles in these nations remain unclear.METHODS: We assessed yeast isolates recovered from ear cultures from a university hospital in Korea over a 4-year period from January 2014 to December 2017. Species identification was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and/or sequence analysis. Antifungal minimal inhibitory concentrations (MICs) were determined using the broth microdilution method of the Clinical and Laboratory Standards Institute.RESULTS: Among 81 non-duplicate isolates from ear cultures, Cadida parapsilosis was the most frequently detected yeast species (34.6%), followed by C. auris (28.4%), Candida metapsilosis (9.9%), Candida orthopsilosis (8.6%), Candida albicans (7.4%), and others (11.1%). The MICs of the isolates were 0.125 to > 64 µg/mL, ≤0.03 to 4 µg/mL, 0.25 to 1 µg/mL, 0.125 to 1 µg/mL, and ≤0.03 to 2 µg/mL for fluconazole, voriconazole, amphotericin B, caspofungin, and micafungin, respectively. Of the 81 isolates, 44.4% (36/81) showed decreased susceptibility to fluconazole (MIC ≥4 µg/mL). Of the 23 C. auris isolates, 19 (82.6%) had a fluconazole MIC of ≥32 µg/mL. None of the isolates showed resistance to amphotericin B or echinocandins. Most of these patients suffered from chronic otitis media (84%).CONCLUSION: Candida parapsilosis complex and C. auris were the yeast species identified most frequently from ear cultures and they exhibited a high rate of fluconazole non-susceptibility, particularly C. auris.

Biofilm-forming capacity of blood-borne Candida albicans strains and effects of antifungal agents / Capacidad de formación de biopelículas de las cepas de Candida albicans de transmisión sanguínea y efectos de los agentes antifúngicos

Infections related to Candida albicans biofilms and subsequent antifungal resistance have become more common with the increased use of indwelling medical devices. Regimens for preventing fungal biofilm formation are needed, particularly in high-risk patients. In this study, we investigated the biofilm formation rate of multiple strains of Candida albicans (n = 162 clinical isolates), their antifungal susceptibility patterns, and the efficacy of certain antifungals for preventing biofilm formation. Biofilm formation was graded using a modified Christensen's 96-well plate method. We further analyzed 30 randomly chosen intense biofilm-forming iso lates using the XTT method. Minimum biofilm inhibition concentrations (MBIC) of caspofungin, micafungin, anidulafungin, fluconazole, voriconazole, posaconazole, itraconazole, and amphotericin B were determined using the modified Calgary biofilm method. In addition, the inhibitory effects of antifungal agents on biofilm formation were investigated. Our study showed weak, moderate, and extensive biofilm formation in 29% (n = 47), 38% (n = 61), and 23% (n = 37) of the isolates, respectively. We found that echinocandins had the lowest MBIC values and that itraconazole inhibited biofilm formation in more isolates (26/32; 81.3%) than other tested agents. In conclusion, echinocandins were most effective against formed biofilms, while itraconazole was most effective for preventing biofilm formation. Standardized methods are needed for biofilm antifungal sensitivity tests when determining the treatment and prophylaxis of C. albicans infections.

Las infecciones relacionadas con las biopelículas de Candida albicans y la consiguiente resistencia antifúngica se han vuelto fenómenos habituales con el uso creciente de dispositivos médicos permanentes. Son necesarios regímenes para prevenir la formación de biopelículas fúngicas, en especial en los pacientes de alto riesgo. En este estudio se investigó la tasa de formación de biopelículas de numerosas cepas de Candida albicans (162 aislados clínicos), sus patrones de sensibilidad a los antifúngicos y la eficacia de algunos de estos agentes para prevenir la formación de biopelículas. La formación de biopelículas se clasificó utilizando el método de Christensen modificado de 96 pocillos. Posteriormente se analizaron 30 aislados de formación intensa de biopelículas elegidos al azar, utilizando el método XTT. Se calcularon las concentraciones mínimas de inhibición de biopelículas (minimum biofilm inhibition concentrations, MBIC) de la caspofungina, la micafungina, la anidulafungina, el fluconazol, el voriconazol, el posaconazol, el itraconazol y la anfotericina B, utilizando el método modificado de biopelículas de Calgary. Además, se investigaron los efectos inhibitorios de los agentes antifúngicos sobre la formación de biopelículas. Nuestro estudio encontró una formación débil, moderada e intensa de biopelículas en el 29% (n = 47), 38% (n = 61) y 23% (n = 37) de los aislados, respectivamente. Encontramos que las equinocandinas mostraron los menores valores MBIC, y que el itraconazol inhibió la formación de biopelículas en más aislados (26/32; 81,3%) que otros agentes ensayados. En conclusión, las equinocandinas resultaron más eficaces frente a las biopelículas formadas, mientras que el itraconazol resultó más eficaz para prevenir la formación de biopelículas. Se necesita contar con métodos estandarizados para efectuar las pruebas de sensibilidad a los antifúngicos en términos de formación de biopelículas a la hora de determinar el tratamiento y la profilaxis de las infecciones por C. albicans.

Opciones terapéuticas frente a especies de Candida resistentes a las equinocandinas / Therapeutic options in the management of echinocandin resistant Candida species

Introducción: La infección por levaduras del género Candida representa la causa más común de infecciones fúngicas invasivas. Su alta incidencia y la creciente resistencia frente a los azoles y, recientemente, a las equinocandinas ha generado la necesidad de buscar nuevas alternativas farmacológicas. Esta revisión presenta las principales alternativas farmacológicas en estudio frente a Candida resistente a equinocandinas. Métodos: Se buscó literatura referente al tema en las bases de datos Bireme, Clinical Key, Embase, Cochrane, Lilacs, Pubmed y Scopus. Se incluyeron 15 artículos en esta revisión. Resultados: Se exploran diferentes alternativas, incluyendo el aumento de dosis de las equinocandinas, su combinación con otros medicamentos y nuevos compuestos en estudio. Conclusión: A pesar de que las infecciones por Candida resistente a equinocandinas aún representan un desafío, dos alternativas farmacológicas se presentan como promisorias: la combinación con medicamentos existentes como el diclofenaco y nuevos compuestos que se encuentran actualmente en fase II de estudios clínicos.

Introduction: Candida yeasts infections represent the most common cause of invasive fungal infections. Its high incidence and increasing resistance to azoles and, recently, to echinocandins has generated the need to find new therapeutic options. This review presents the main pharmacological alternatives in research against echinocandins resistant Candida. Methods: A search was conducted in the databases of Bireme, Clinical Key, Embase, Cochrane, Lilacs, Pubmed and Scopus. 15 articles were included in this review. Results: Several alternatives are explored, including increased doses of echinocandins, combination with other drugs and new compounds under study. Conclusion: Although resistant Candida infections still represent a challenge, two pharmacological approaches show promise: The combination with existing medicaments such as diclofenac, and new compounds that are currently in Phase II of clinical trials.

Activador tisular del plasminógeno recombinante para el tratamiento de la vegetación intracardíaca en un lactante de muy bajo peso al nacer / Recombinant tissue plasminogen activator treatment for intracardiac vegetation in a very low birth weight infant

Las nuevas opciones de tratamiento prolongan la hospitalización y aumentan las infecciones intrahospitalarias bacterianas y fúngicas, pero también mejoran la sobrevida de los recién nacidos hospitalizados en la unidad de cuidados intensivos neonatales. Las infecciones fúngicas invasivas en neonatos están asociadas con una morbimortalidad significativa. También pueden diseminarse a órganos específicos y causar endocarditis, endoftalmitis, artritis séptica, nefropatía obstructiva y meningitis. En el caso de la endocarditis, se recomiendan tratamientos antimicóticos sistémicos agresivos y, en algunos casos, la intervención quirúrgica del neonato. Informamos el caso de un lactante prematuro, de bajo peso al nacer, con vegetación intracardíaca. Esta es una complicación rara y potencialmente mortal de infecciones fúngicas invasivas. El paciente recibió tratamiento con caspofungina y un activador tisular del plasminógeno recombinante, en vez de una intervención quirúrgica.

Developing treatment options have resulted in prolonged admission and increased bacterial and fungal nosocomial infections as well as improved survival in neonatal intensive care unit. Invasive fungal infections in newborns are associated with significant morbidity and mortality and can cause endorgan dissemination such as endocarditis, endophthalmitis, septic arthritis, obstructive nephropathy and meningitis. Endocarditis requires aggressive systemic antifungal therapy and sometimes surgical intervention in neonates. We report a low birth weight premature infant with intracardiac vegetation that is rare and a life-threatening complication of invasive fungal infections. He was treated with caspofungin and recombinant tissue plasminogen activator in stead of surgical intervention.

Successful treatment of fungal endophthalmitis using intravitreal caspofungin / O primeiro relato de caspofungina intravítrea no tratamento de endoftalmite fúngica

ABSTRACT Fungal endophthalmitis is a rare condition often associated with poor prognosis. We present a case of postoperative acute fungal endophthalmitis caused by the yeast-like fungus Stephanoascus ciferrii (Candida ciferrii). The fungus was resistant to fluconazole, voriconazole, and amphotericin B but susceptible to caspofungin. Because the degree of vitreal penetration of caspofungin after its intravenous administration is unclear, we performed multiple intravitreal injections, first with 50 µg/0.1 ml and then with 250 µg/0.1 ml caspofungin. Despite the recurrence of symptoms, intravitreal injection of caspofungin finally abolished the inflammation and achieved ambulatory vision that persisted until 1 year of follow-up. To our knowledge, this is the first report of S. ciferrii endophthalmitis and its successful treatment with intravitreal caspofungin.

RESUMO Endoftalmite fúngica é uma ocorrência rara, muitas vezes associada com mau prog nóstico. Apresentamos um caso de endoftalmite fúngica aguda pós-operatória causada por fungo de levedura incomum, Stephanoascus ciferrii (Candida ciferrii). O fungo foi resistente ao fluconazol, ao voriconazol e à anfotericina B e susceptível à caspofun gina. Dado que a penetração vítrea da caspofungina após administração intravenosa não é clara, optou-se por realizar múltiplas injecções intravítreas, primeiro de 50 µg e depois de 250 µg de caspofungina, e finalmente obteve-se a resolução da inflamação e a visão recuperada foi mantida por pelo menos um ano após o ocorrido. No nosso conhecimento, este é o primeiro relato de endoftalmite por Stephanoascus ciferrii e o primeiro relato de endoftalmite fúngica tratada com sucesso com caspofungina intravítrea.

Antifungal activity of caspofungin in experimental infective endocarditis caused by Candida albicans

BACKGROUND Infective endocarditis is a disease characterised by heart valve lesions, which exhibit extracellular matrix proteins that act as a physical barrier to prevent the passage of antimicrobial agents. The genus Candida has acquired clinical importance given that it is increasingly being isolated from cases of nosocomial infections. OBJECTIVE To evaluate the activity of caspofungin compared to that of liposomal amphotericin B against Candida albicans in experimental infective endocarditis. METHODS Wistar rats underwent surgical intervention and infection with strains of C. albicans to develop infective endocarditis. Three groups were formed: the first group was treated with caspofungin, the second with liposomal amphotericin B, and the third received a placebo. In vitro sensitivity was first determined to further evaluate the effect of these treatments on a rat experimental model of endocarditis by semiquantitative culture of fibrinous vegetations and histological analysis. FINDINGS Our semiquantitative culture of growing vegetation showed massive C. albicans colonisation in rats without treatment, whereas rats treated with caspofungin showed significantly reduced colonisation, which was similar to the results obtained with liposomal amphotericin B. CONCLUSIONS The antifungal activity of caspofungin is similar to that of liposomal amphotericin B in an experimental model of infective endocarditis caused by C. albicans.

Anidulafungina en niños: Experiencia en niños con trasplante de médula ósea / Anidulafungin in children: experience in children undergoing bone marrow transplantation

Introducción: Las infecciones fúngicas invasoras (IFI) son un problema de salud cada vez mayor, y se asocian con una alta morbilidad y mortalidad. Las nuevas opciones terapéuticas, tales como las equinocandinas y entre estos anidulafungina, se han utilizado en la población adulta, pero en pacientes pediátricos con trasplante de médula ósea la experiencia es escasa. Objetivo: El objetivo de este estudio descriptivo es presentar nuestra experiencia con el uso de la anidulafungina como profilaxis o tratamiento en pacientes con trasplante de médula ósea. Material y métodos: Entre enero hasta junio 2016, 29 pacientes trasplantados de médula ósea recibieron anidulafungina como profilaxis o tratamiento de infecciones fúngicas invasivas (IFI) probadas, probables o posibles. En todos los casos se monitorizó el valor de transaminasas, bilirrubina, creatinina y el recuento de glóbulos blancos al inicio y al final del tratamiento. Resultados: La anidulafungina se administró por vía intravenosa en una dosis de carga de 3 mg/kg/día, seguida de 1,5 mg/kg/día durante una mediana (Md) de 16 días (intervalo intercuartílico: 2-65 d). La Md de la edad de los pacientes fue de 97 meses (rango: 6-211m). La anidulafungina fue indicada como tratamiento en 7 casos (24%) y como profilaxis primaria o secundaria,en 22 (76%). En un paciente se confirmó microbiológicamente una IFI, por Candida albicans. Las Md de los parámetros bioquímicos en el inicio del tratamiento y al final, fueron: transaminasas GOT 29,5 U/l y 32 U/l (p 0,44); bilirrubina 0,35 y 0,30 mg/dL (p: 0,20); creatinina, 0,52 y 0,60 mg/dl (p:0,67). El recuento de glóbulos blancos mostró una gran variabilidad debido a la enfermedad subyacente, pero la diferencia de su valor entre el inicio y al final de la administración del fármaco, no fue significativo: Md 2810 células/mm3 y 5160 células/mm3, respectivamente (p: 0,07). Ninguno de los pacientes tuvo eventos adversos o murieron por causas relacionadas con anidulafungina. En el seguimiento a 30 días no se registró recaída de la infección o mortalidad relacionada a la droga. Conclusiones: Los resultados de nuestra serie sugieren que la anidulafungina podría ser una opción para la profilaxis o el tratamiento de las IFI en los niños con trasplante de médula ósea. Se requieren más estudios para confirmar estas observaciones (AU)

Introduction: Invasive fungal infections (IFI) are an increasing health problem associated with high morbidity and mortality. New treatment options, such as echinocandins and among these anidulafungin, have been used in the adult population, but experience in children undergoing bone marrow transplantation is scarce. Aim: The aim of this descriptive study is to present our experience with the use of anidulafungine as prophylaxis or treatment in patients undergoing bone marrow transplantation. Material and methods: Between January and June 2016, 29 patients who underwent bone marrow transplantation received anidulafungin as prophylaxis against or treatment for confirmed, probable, or possible (IFI). In all cases transaminase, bilirubin, and creatinine levels as well as total white blood cell count were monitored at treatment initiation and completion. Results: Anidulafungine is administered intravenously in a loading dose of 3 mg/kg/day, followed by 1.5 mg/kg/day for a mean of 16 days (interquartile range: 2-65 d). Mean age of the patients was 97 months (range: 6-211m). Anidulafungine was used as treatment in 7 cases (24%) and as primary or secondary prophylaxis in 22 (76%). IFI was microbiologically confirmed to be Candida albicans in one patient. Mean biochemical parameters at treatment onset and completion were: transaminases AST 29.5 U/l and 32 U/l (p 0.44); bilirubin 0.35 and 0.30 mg/dL (p 0.20); creatinine, 0.52 and 0.60 mg/dl (p : 0.67). White blood cell count was highly variable due to the underlying disease; however, the difference between values at treatment initiation and completion were not significant: Mean 2810 cells/mm3 and 5160 cells/mm3, respectively (p: 0.07). None of the patients had adverse effects or died because of anidulafungin-related causes. At 30 days of follow-up no relapse of infection or drug-related mortality was observed. Conclusions: The results in our series suggest that anidulafungin is an option for the prophylaxis against or treatment of IFI in children undergoing bone marrow transplantation. Further studies are necessary to confirm these findings (AU)

Antifungal pharmacodynamics: Latin America's perspective

Abstract The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

Voriconazole plus caspofungin for treatment of invasive fungal infection in children with acute leukemia

BACKGROUND: Invasive fungal infections (IFIs) are a life-threatening problem in immunocompromised patients. Despite timely diagnosis and appropriate antifungal therapy, clinical outcomes of IFIs remain unsatisfactory, necessitating treatment with a combination of antifungal agents. Therefore, childhood leukemic patients treated with voriconazole plus caspofungin were evaluated for the safety and efficacy of the combination antifungal therapy to treat IFIs. METHODS: In this retrospective study, medical records were retrieved for patients admitted to the Pediatric Department of Yeungnam University Hospital, Daegu, South Korea, between April 2009 and May 2013. Medical records of 22 patients were analyzed. RESULTS: Of the 22 patients studied, nine (41%) had been diagnosed with probable IFI, and 13 (59%) with possible IFI. All patients, except one, were already receiving antifungal monotherapy for the treatment of neutropenic fever. After a diagnosis of IFI was confirmed, antifungal monotherapy was replaced with combination therapy. The study's overall response rate was 90.9%, with complete responses in 86.3% of the patients. Two patients experienced a side effect of a small increase in liver enzyme levels. CONCLUSION: Voriconazole plus caspofungin combination therapy is an effective and safe treatment for serious IFI in pediatric patients with acute leukemia.

Extracellular phospholipase production of oral Candida albicans isolates from smokers, diabetics, asthmatics, denture wearers and healthy individuals following brief exposure to polyene, echinocandin and azole antimycotics

Abstract Objective Candida albicans is the primary causative agent of oral candidosis, and one of its key virulent attributes is considered to be its ability to produce extracellular phospholipases that facilitate cellular invasion. Oral candidosis can be treated with polyenes, and azoles, and the more recently introduced echinocandins. However, once administered, the intraoral concentration of these drugs tend to be sub-therapeutic and rather transient due to factors such as the diluent effect of saliva and cleansing effect of the oral musculature. Hence, intra-orally, the pathogenic yeasts may undergo a brief exposure to antifungal drugs. We, therefore, evaluated the phospholipase production of oral C. albicans isolates following brief exposure to sub-therapeutic concentrations of the foregoing antifungals. Materials and methods Fifty C. albicans oral isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, partial denture wearers and healthy individuals were exposed to sub-therapeutic concentrations of nystatin, amphotericin B, caspofungin, ketoconazole and fluconazole for one hour. Thereafter the drugs were removed and the phospholipase production was determined by a plate assay using an egg yolk-agar medium. Results The phospholipase production of these isolates was significantly suppressed with a percentage reduction of 10.65, 12.14, 11.45 and 6.40% following exposure to nystatin, amphotericin B, caspofungin and ketoconazole, respectively. This suppression was not significant following exposure to fluconazole. Conclusions Despite the sub-therapeutic, intra oral, bioavailability of polyenes, echinocandins and ketoconazole, they are likely to produce a persistent antifungal effect by suppressing phospholipase production, which is a key virulent attribute of this common pathogenic yeast.

Antifungal activities of tacrolimus in combination with antifungal agents against fluconazole-susceptible and fluconazole-resistant Trichosporon asahii isolates

ABSTRACT The antifungal activity of tacrolimus in combination with antifungal agents against different fungal species has been previously reported. Here we report the in vitro interactions between tacrolimus and amphotericin B, fluconazole, itraconazole, and caspofungin against 30 clinical isolates of both fluconazole-susceptible and fluconazole-resistant Trichosporon asahii. For these analyses, we used the broth microdilution method based on the M27-A3 technique and checkerboard microdilution method. Tacrolimus showed no activity against T. asahii strains (minimal inhibitory concentrations, MICs > 64.0 µg mL−1). However, a larger synergistic interaction was observed by the combinations tacrolimus + amphotericin B (96.67%) and tacrolimus + caspofungin (73.33%) against fluconazole-susceptible isolates. Combinations with azole antifungal agents resulted in low rates of synergism for this group (fluconazole + tacrolimus = 40% and itraconazole + tacrolimus = 10%). Antagonistic interactions were not observed. For the fluconazole-resistant T. asahii group, all tested combinations showed indifferent interactions. The synergism showed against fluconazole-susceptible T. asahii isolates suggests that the potential antifungal activity of tacrolimus deserves in vivo experimental investigation, notably, the combination of tacrolimus with amphotericin B or caspofungin.

Eficacia y seguridad del uso de anidulafungina en pacientes no neutropénicos con candidemia y respuesta inadecuada o reaccion adversa a fluconazol / Efficacy and safety of the use of anidulafungin in non-neutropenic patients with candidemia and inadequate response or adverse reaction to fluconazole

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso Anidulafungina en pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol. Aspectos Generales: La candidiasis sistémica es una patología con alta morbilidad y mortalidad (1). La colonización por candida spp. se desarrolla en hasta el 80 % de los pacientes críticos que permanecen más de una semana en cuidados intensivos, mientras que la candidiasis invasiva se documenta en sólo un 5 a un 10% de ellos. El tiempo de diagnóstico puede ser afectado por la complejidad que representa en sus criterios, causando retrasos en el inicio del tratamiento adecuado, haciendo que las candidemia y las candidiasis invasivas tengan peores pronósticos que otras infecciones de reconocimiento más sencillo. Tecnologia Sanitaria de Interés: La anidulafungina es una equinocandina semisintética, un lipopéptido obtenido a partir de un producto de fermentación de Aspergillus nidulans. Este producto farmacéutico actúa inhibiendo selectivamente la 1,3-3-D glucanosintetasa, enzima presente en las células fúngicas, pero no en las células de mamíferos. Como resultado no se forma 1,3-13- D glucano, el cual es esencial en la pared celular fúngica. La anidulafungina ha demostrado actividad fungicida frente a candida spp. y actividad frente a Aspergillus fumigatus; la actividad in vitro de anidulafungina frente a las especies de candida spp. no es homogénea. En concreto, la concentración mínima inhibitoria de la anidulafungina en el caso de la C. parapsilosis es superior a la observadas en otras especies de candida spp. METODOLOGIA: Estrategia de Búsqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), la Agencia Europea de Medicamentos (EMA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guideline Clearinghouse (NGC), UpToDate y Health Systems Evidence (HSE). Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en ww.clinicaltrials.gov , para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Sinopsis de la Evidencia: Se realizó búsqueda bibliográfica y de evidencia científica que sustente el uso de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol según la pregunta PICO establecida. En relación a los estudios encontrados para la población de interés descrita en la pregunta PICO no se encontraron estudios que comparen directamente mediante un ensayo clínico las equinocandinas (anidulafungina, caspofungina y micafungina) en pacientes con candidemia o infecciones sistémicas por candida spp. Se encontraron 2 revisiones sistemáticas con evidencia indirecta. Además, se encontró un ensayo clínico de evidencia indirecta que puede ser usada para responder la pregunta PICO, que compara Anidulafungina con Fluconazol en pacientes con candidiasis invasiva. CONCLUSIONES: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de anidulafungina según el esquema planteado en la pregunta PICO para pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol.

Eficacia y seguridad de la caspofungina en pediatría: revisión sistemática y metaanálisis / Efficacy and safety of caspofungin in children: systematic review and meta-analysis

Las infecciones fúngicas invasivas son una importante causa de morbimortalidad en pediatría. La caspofungina es una equinocandina utilizada como alternativa en la prevención y/o tratamiento de ciertas infecciones fúngicas invasivas en niños, aunque con poca evidencia sobre su eficacia y seguridad en comparación con el tratamiento habitual. Objetivos. Evaluar la eficacia y seguridad de la caspofungina comparada con otros antifúngicos en la prevención y/o tratamiento de infecciones fúngicas invasivas en pediatría. Material y métodos. La estrategia de búsqueda inicial tuvo como objetivo identificar estudios controlados aleatorizados de aceptable calidad metodológica (escala de Jadad > 3) mediante la palabra clave "caspofungin" realizados en pacientes de entre los 0 y los 18 años. Resultados. Solo 3 publicaciones cumplieron los criterios de inclusión. De ellas, 2 fueron en población pediátrica y una en neonatal. No se documentó una mayor incidencia de efectos adversos para la caspofungina y su eficacia no se diferenció de otros antifúngicos (RR típico 1,47; IC 95%: 0,78-2,79). Conclusiones. Esta revisión sistemática sugiere que la caspofungina podría considerarse como una alternativa para su indicación en pediatría en la prevención y tratamiento de las infecciones fúngicas invasivas. Sin embargo, dado el pequeño número de publicaciones existentes, se requieren más estudios para alcanzar conclusiones definitivas.

Invasive fungal infections are a significant cause of morbidity and mortality in children. Caspofungin is an echinocandin used as an alternative treatment in the prevention and/or treatment of certain invasive fungal infections in children, although compared to the standard treatment there is little evidence on its efficacy and safety. Objectives. To evaluate the efficacy and safety of caspofungin compared with other antifungal drugs for the prevention and/or treatment of invasive fungal infections in children. Material and methods. The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old. Results. Only 3 publications met the inclusion criteria. Two of them were studies conducted in children and one in newborn infants. A higher incidence of adverse events was not documented for caspofungin and its efficacy was not different from that of other antifungal drugs (typical RR 1.47; CI 95%: 0.78-2.79). Conclusions. This systematic review suggests that caspofungin could be considered as an alternative drug in children for the prevention and treatment of invasive fungal infections. However, given the small number of existing publications, more studies are required to reach definite conclusions.

Rare severe mycotic infections in children receiving empirical caspofungin treatment for febrile neutropenia

ABSTRACTEmpirical antifungal therapy is most often given to patients with leukemia. However breakthrough fungal infections under antifungal therapy are not uncommon. Four children, with hematologic malignant disease developed mycotic breakthrough infections while on empirical caspofungin treatment for a median of 14 (range 11-19) days. Trichosporon asahii was detected in the blood culture of two patients and Geotrichum capitatum in the other two (one patient also had positive cerebrospinal fluid culture). Because the patients' clinical situation worsened, voriconazole was empirically added for two patients three and five days before the agent was detected. The first sterile blood culture was obtained 3-7 days of voriconazole treatment. All patients reached clear cultures but one patient died. One patient with central nervous system infection with G. capitatum had severe neurological sequelae. Very severe fungal infections can occur during empirical caspofungin therapy. Therefore, patients should be followed closely.

Tratamiento exitoso de una mucormicosis rinocerebral persistente en un paciente pediátrico durante el debut de una leucemia aguda / Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia

The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models. We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin.

Los hongos del orden Mucorales causan la mucormicosis, que se presenta habitualmente como una enfermedad fúngica invasora con rápida angioinvasión en pacientes inmunocomprometidos. La presentación rino-cerebral es la más frecuente. Las formulaciones lipídicas de anfotericina B se usan como tratamiento primario en las mucormicosis invasoras; el uso combinado de posaconazol podría permitir reducir la dosis de anfotericina B generando una mejor tolerancia y adherencia al tratamiento. La asociación de caspofungina con anfotericina ha demostrado acción sinérgica in vitro y eficacia en modelos murinos. Se presenta el caso de una niña preescolar que durante el debut de una leucemia linfoblástica aguda evolucionó con una mucormicosis rino-cerebral persistente, que respondió en forma exitosa al tratamiento antifúngico combinado de anfotericina liposomal y caspofungina.