Infecciones fúngicas invasivas en niños hospitalizados en un centro de referencia de Uruguay / Invasive fungal infections in children hospitalized at a pediatric reference hospital in Uruguay / Infecções fúngicas invasivas em crianças internadas em um centro hospitalar de referência no Uruguai

Introducción: las infecciones fúngicas invasivas (IFI) son un problema de salud en creciente aumento. Objetivo: describir las características epidemiológicas, microbiológicas y clínicas de los menores de 15 años con IFI hospitalizados en el Hospital Pediátrico, Centro Hospitalario Pereira Rossell entre 2010- 2019. Metodología: estudio retrospectivo, mediante revisión de historias clínicas. Variables: edad, sexo, comorbilidades, factores de riesgo, clínica, patógenos, tratamiento y evolución. Resultados: se registraron 26 casos de IFI en 23 niños. La mediana de edad fue 8 años, de sexo femenino 17, con comorbilidades 17: infección por VIH 5, enfermedad hematooncológica 4. Todos presentaban factores de riesgo para IFI. Las manifestaciones clínicas de sospecha fueron: fiebre en 19, síntomas neurológicos 11, respiratorios 9, gastrointestinales 6, urinarios 2, sepsis/shock en 3. Los agentes identificados fueron: Candida spp en 14, Cryptococcus neoformans complex 8 y Aspergillus fumigatus complex 4. Tratamiento: se indicó fluconazol en 15, asociado a anfotericina B 11. Todas las infecciones por candida fueron sensibles a los azoles. Fallecieron 7 niños, la mediana de edad fue 1 año. En 4 se identificó Candida spp, Aspergillus fumigatus complex 2 y Cryptococcus neoformans complex 1. Conclusiones: las IFI son poco frecuentes, afectan en su mayoría a niños inmunocomprometidos asociando elevada mortalidad. El diagnóstico requiere alto índice de sospecha. Candida spp y Cryptococcus spp fueron los agentes más involucrados. El inicio precoz del tratamiento acorde a la susceptibilidad disponible se asocia a menor mortalidad.

Summary: Introduction: invasive fungal infections (IFI) are an increasing health problem. Objective: describe the epidemiological, microbiological and clinical characteristics of children under 15 years of age with IFI hospitalized at the Pereira Rossell Hospital Center between 2010-2019. Methodology: retrospective study, review of medical records. Variables: age, sex, comorbidities, risk factors, symptoms, pathogens, treatment and evolution. Results: 26 cases of IFI were recorded involving 23 children. Median age 8 years, female 17, comorbidities 17, HIV infection 5, hematological-oncological disease 4. All with risk factors. Suspicion symptoms: fever 19, neurological symptoms 11, respiratory 9, gastrointestinal 6, urinary 2, sepsis / shock 3. Identified agents: Candida spp 14, Cryptococcus neoformans complex 8 and Aspergillus fumigatus complex 4. Treatment: fluconazole 15, associated with amphotericin B 11. All candida infections were sensitive to azoles. 7 died, median age 1 year. In 4, Candida spp was isolated, Aspergillus fumigatus complex in 2 and Cryptococcus neoformans complex in 1. Conclusions: IFI are rare, mostly affecting immunocompromised children, associated with high mortality. The diagnosis requires a high index of suspicion. Candida spp and Cryptococcus spp were the most involved agents. Early treatment according to available susceptibility is associated with lower mortality.

Introdução: as infecções fúngicas invasivas (IFI) são um problema de saúde crescente. Objetivo: descrever as características epidemiológicas, microbiológicas e clínicas de crianças menores de 15 anos com IFI internadas no Centro Hospitalar Pereira Rossell entre 2010 e 2019. Metodologia: estudo retrospectivo, revisão de prontuários. Variáveis: idade, sexo, comorbidades, fatores de risco, sintomas, patógenos, tratamento e evolução. Resultados: foram registrados 26 casos de IFI em 23 crianças. Idade mediana 8 anos, sexo feminino 17, comorbidades 17, infecção por HIV 5, doença hemato-oncológica 4. Todos com fatores de risco. Suspeita clínica: febre 19, sintomas neurológicos 11, respiratórios 9, gastrointestinais 6, urinários 2, sepse/choque 3. Agentes identificados: Candida spp 14, Cryptococcus neoformans complexo 8 e Aspergillus fumigatus complexo 4. Tratamento: fluconazol 15, associado à anfotericina B 11. Todas as infecções por cândida foram sensíveis aos azóis. 7 morreram, idade média de 1 ano. Em 4 das crianças Cândida spp foi isolada, Aspergillus fumigatus complexo em 2 e Cryptococcus neoformans complexo em 1. Conclusões: IFIs são raras, afetando principalmente crianças imunocomprometidas, associadas a alta mortalidade. O diagnóstico requer alto índice de suspeita. Cândida spp e Cryptococcus spp são os agentes mais envolvidos. O tratamento precoce de acordo com a suscetibilidade disponível está associado a menor mortalidade.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Aspectos clínicos asociados al diagnóstico y tratamiento de la aspergilosis laríngea en pacientes inmunocompetentes / Clinical aspects associated with the diagnosis and treatment of laryngeal aspergillosis in immunocompetent patients

INTRODUCCIÓN. La aspergilosis laríngea en individuos inmunocompetentes, aunque rara, se reporta cada vez con más frecuencia; por lo cual, es necesario comprender mejor los aspectos clínicos y terapéuticos más adecuados para abordar su atención. OBJETIVO. Documentar los aspectos clínicos asociados al diagnóstico y el tratamiento de la aspergilosis laríngea en sujetos inmunocompetentes. METODOLOGÍA. Se realizó un estudio Bibliográfico Narrativo de carácter retrospectivo, donde se evaluaron los casos clínicos reportados de personas inmunocompetentes con aspergilosis laríngea desde el año 1983 hasta el 2022. Se hizo una revisión bibliográfica en las bases de datos PubMed/Medline y ScienceDirect, y se incluyeron todos los casos reportados en sujetos inmunocompetentes. RESULTADOS. Se identificaron 30 casos clínicos que cumplieron con los criterios de inclusión dentro de un grupo de 586 artículos revisados. El patógeno más reportado fue Aspergillus fumigatus y la evaluación histopatológica la principal herramienta para diagnosticar la aspergilosis. Se reportaron más casos en mujeres con un 58%. La mayor incidencia se observó en sujetos entre 20 y 49 años de edad. Los síntomas más comunes fueron disfonía, disnea y tos. El tratamiento farmacológico empleado actualmente es el Itraconazol seguido por el Voriconazol. CONCLUSIONES. La evidencia reportada mostró que la aspergilosis laríngea en pacientes inmunocompetentes podría estar dejando de ser un evento "poco común" por lo que debe prestarse más atención a su diagnóstico y tratamiento.

INTRODUCTION. Laryngeal aspergillosis in immunocompetent individuals, although rare, is reported with increasing frequency; therefore, it is necessary to better understand the most appropriate clinical and therapeutic aspects to address its care. OBJECTIVE. To document the clinical aspects associated with the diagnosis and treatment of laryngeal aspergillosis in immunocompetent subjects. METHODOLOGY. A retrospective Narrative Bibliographic study was performed, where clinical case reports of immunocompetent subjects with laryngeal aspergillosis from 1983 to 2022 were evaluated. A literature review was performed in PubMed/Medline and ScienceDirect databases, and all reported cases in immunocompetent subjects were included. RESULTS. Thirty clinical cases that met the inclusion criteria were identified from a pool of 586 articles reviewed. The most reported pathogen was Aspergillus fumigatus and histopathologic evaluation the main tool for diagnosing aspergillosis. More cases were reported in women with 58%. The highest incidence was observed in subjects between 20 and 49 years of age. The most common symptoms were dysphonia, dyspnea and cough. The pharmacological treatment currently used is Itraconazole followed by Voriconazole. CONCLUSIONS. The evidence reported showed that laryngeal aspergillosis in immunocompetent patients may no longer be a "rare" event and more attention should be paid to its diagnosis and treatment.

Importancia de la monitorización de concentraciones plasmáticas de voriconazol y dificultad en ajuste de dosis en un paciente pediátrico / Voriconazole monitorization in pediatric patients, difficulties in dose adjustment

Resumen Presentamos el caso de un escolar de 10 años, con el diagnóstico de una recaída de una leucemia mieloide aguda que cursó con un episodio de una neutropenia febril de alto riesgo, posterior a un ciclo intensivo de quimioterapia, evolucionando con una infección fúngica invasora demostrada por histopatología. Se inició tratamiento con voriconazol intravenoso, evolucionando con concentraciones plasmáticas erráticas que requirieron sucesivos ajustes de dosis, lo que también ocurrió con la administración oral del medicamento. Finalmente, tuvo una respuesta favorable al tratamiento, a pesar de la dificultad de la dosificación para alcanzar niveles terapéuticos. La búsqueda activa y la terapia antifúngica anticipada, así como la monitorización seriada de concentraciones terapéuticas de voriconazol, permitieron un tratamiento antifúngico óptimo y oportuno, mejorando el pronóstico del paciente.

Abstract We present a 10-year-old male patient with a diagnosis of relapsed acute myeloid leukemia (AML), presenting with high-risk febrile neutropenia (HRFN), after a cycle of intensive chemotherapy, evolving with an invasive fungal infection demonstrated by histopathology. Treatment with intravenous voriconazole was started, with erratic plasmatic levels, which require successive dose adjustments which also occurred with oral administration. Finally, he had a favorable response to treatment, despite of the dosing difficulties to reach therapeutic levels. Active search as well as preemptive antifungal therapy, together with plasmatic level monitorization of voriconazole allowed a prompt recovery and improved the patient prognosis.

Evaluación de la dosificación de voriconazol intravenoso tres veces al día vs dos veces al día para el tratamiento de aspergilosis invasora en niños inmunocomprometidos: monitorización terapéutica y seguridad / Evaluation dosing intravenous voriconazole three times a day vs twice daily for the treatment of invasive aspergillosis in immunocompromised children: therapeutic drugs monitoring and safety

INTRODUCCIÓN: Voriconazol es el antifúngico de elección para el tratamiento de la aspergilosis invasora (AI). Concentraciones plasmáticas (CPs) > 1 μg/mL se han asociado a mejores resultados terapéuticos, las que no siempre se alcanzan durante el tratamiento en niños inmunocomprometidos. Dada la necesidad de iniciar una terapia precoz y efectiva de la infección, es relevante establecer el régimen de administración de voriconazol que se asocie con CPs óptimas en esta población. OBJETIVO: Comparar las CPs y seguridad de voriconazol intravenoso (IV), dosificado BID y TID en niños inmunocomprometidos con indicación de tratamiento antifúngico. MÉTODO: Estudio observacional retrospectivo de enero de 2015 a julio de 2018 en un hospital pediátrico de alta complejidad de Santiago de Chile, en pacientes de 0 a 17 años que recibieron tratamiento con voriconazol IV. Se excluyeron aquellos con terapia de reemplazo renal, falla hepática y/o falla renal. Se compararon las CPs valles entre un grupo con régimen de dosificación BID y otro grupo con administración TID. Se evaluaron las reacciones adversas en ambos grupos. RESULTADOS: Se obtuvieron 137 CPs valles en 76 niños, con una mediana de edad de 9 años (0-17 años) en el grupo BID y 9 años (0-16 años) en el grupo TID, con una mediana de peso de 27 kg (6-83 kg) y 28 kg (9,3-60 kg), respectivamente. Resultados: Pacientes 1 gg/mL en comparación con la administración BID (p = 0,001). Se reportaron ocho reacciones adversas, principalmente fotofobia, sin encontrarse diferencias significativas entre grupo BID y TID. CONCLUSIÓN: Dosificaciones TID están asociadas a una mayor probabilidad de obtener una adecuada exposición a voriconazol en pacientes < 12 años en comparación a dosificaciones BID, con baja frecuencia de reacciones adversas.

BACKGROUND: Voriconazole is the antifungal of choice for the treatment of invasive aspergillosis (IA). Plasma concentrations (PCs) > 1 μg / mL llave been associated with better therapeutic results which have not always been achieved during treatment in immunocompromised children. In the necessity to initiate early and effective therapy for the infection, it is relevant to establish the voriconazole administration regimen that is associated with optimal PCs in this population. AIM: To compare the PC and safety of intravenous (IV) voriconazole, dosed BID and TID in immunocompromised children with indication of antifungal treatment. METHOD: Retrospective observational study since January 2015 until July 2018 in a highly complex pediatric hospital in Santiago of Chile, in patients aged 0 to 17 years who received treatment with IV voriconazole. Those with renal replacement therapy, liver failure and / or renal failure were excluded. Trough PCs were compared between a group with BID dosing regimen versus another group with TID administration. Adverse reactions were evaluated in both groups. RESULTS: 137 trough PCs were obtained in 76 children, with a median age of 9 years (0-17 years) in the BID group and 9 years (0-16) in the TID group with a median weight of 27 kg (6-83 kg) and 28 kg (9.3-60 kg), respectively. Patients 1 gg/mL compared to BID administration (p = 0.001). Eight adverse reactions were reported, mainly photophobia, with no significant difference found between the BID and TID groups. CONCLUSION: TID dosages are associated with a greater probability of obtaining adequate exposure to voriconazole in patients < 12 years old compared to BID dosages, with a low frequency of adverse reactions.

Aspergilosis pulmonar invasiva en paciente pediátrico / Invasive pulmonary aspergillosis in a pediatric patient

La creciente emergencia de las enfermedades infecciosas y el aumento del número de individuos que tienen afectada su competencia inmunológica se ha convertido en un reto. Por otro lado, considerando el género Aspergillus, como un agente etiológico de infección, causa importante de morbilidad y mortalidad en pacientes inmunocomprometidos. Presentamos el caso de preescolar femenino de 3 años y 8meses con antecedente de teratoma maduro fetiforme, quien posterior a 6 meses de su exéresis, se realiza tomografía axial computarizada (TAC) de Tórax control evidenciándose bronquiectasias centrales con opacidades tubulares y saculares de distribución bronquial, con localización principalmente en lóbulo superior de hemitórax izquierdo, disminución del volumen pulmonar ipsilateral con incipiente desplazamiento del cardiomediastino a la izquierda y escaso derrame pleural izquierdo, examen físico sin alteraciones, por lo que ingresa con diagnóstico de enfermedad granulomatosa en estudio. Se realiza detección de antígeno galactomanano que reporta positivo en dos determinaciones por lo que se replantea el diagnóstico a Aspergilosis Pulmonar Invasiva, cumple tratamiento con voriconazol por 21 días, con mejoría significativa de las lesiones pulmonares en TAC de tórax, egresando con tratamiento con itraconazol a cumplir por 6 semanas. El inicio precoz del tratamiento constituye un factor pronóstico fundamental de la aspergilosis invasiva, siendo el voriconazol la primera línea(AU)

The growing emergence of infectious diseases and increasing the number of individuals that have affected their immune competence has be come a challenge. Furthermore, considering the genus Aspergillus, as an etiologic agent of infection, which causes significant morbidity and mortality in immunocompromised patients. We present a case of a female preschool 3 years and 8 months with a history of matureteratoma fetiforme, who after 6 months of excision, compute dtomography (CT) scan control is performed where central bronchiectasis are evident with tubular opacities and saculares bronchial distribution, located mainly in the upper lobe of left chest, decreased left lung volume with incipient displacement of the heart and medistino left and low left pleural effusion, physical examination no alterations to income, so you enter with diagnosis of granulomatous disease study. antigen detection galactomannan reporting positive in two determinations so the diagnosis of invasive pulmonary aspergillosis rethinks meets voriconazole for 21 days, with significant improvement of lunglesions in chest CT scan, graduating with itraconazole therapy is performed to meet for 6 weeks. The early initiation of treatmentis a fundamental prognostic factor of invasive aspergillosis, constituting the first line in voriconazole(AU)

Infección ocular invasora por Scedosporium apioespermum en un paciente inmunocomprometido / Invasive ocular fungal infection by Scedosporium apiospermum in an immunocompromised patient

Resumen Presentamos el caso clínico de una infección fúngica invasora con una conjuntivitis necrosante, escleritis y panuveitis unilateral por Scedosporium apiospermum en una mujer de 78 años con artritis reumatoidea con neutropenia secundaria a fármacos. El diagnóstico etiológico fue confirmado por cultivo micológico de secreción ocular con apoyo de MALDI-TOF-TOF e histopatología. El tratamiento incluyó aseos quirúrgicos asociado a terapia tópica y sistémica con voriconazol y corticoesteroides, con una evolución favorable a los dos meses de tratamiento. Una recaída obligó a un segundo curso terapéutico por 12 meses adicionales con mejoría y erradicación del agente. La conjuntivitis fúngica por S. apiospermum es un evento infrecuente asociado a pacientes inmunocomprometidos. Su tratamiento involucra desbridamientos quirúrgicos y terapia antifúngica prolongada.

Abstract We report a case of invasive fungal infection with necrotizing conjunctivitis, scleritis and unilateral panuveitis caused by Scedosporium apiospermum in a 78-year-old woman that developed neutropenia by drugs indicated for rheumatoid arthritis. The etiological diagnosis was confirmed by mycological culture of an ocular secretion with the support of MALDI-TOF-TOF analysis and histopathological findings. The treatment involved surgical debridements together with topical solution and systemic therapy with voriconazole and steroids with a favorable evolution after 2 months of treatment. A relapse required a second therapeutic course for an additional 12 months with improvement and eradication of the agent. Fungal conjunctivitis due to S. apiospermum is a rare event associated with immunosuppressed patients. Its treatment involves surgical debridements and prolonged antifungal therapy.

Evaluación de susceptibilidad en cándidas spp por colorimetría obtenida en gestantes de un hospital obstétrico / Susceptibility evaluation in candida spp by colorimetry obtained in pregnant women from an obstetric hospital / Avaliação da suscetibilidade em cândida spp por colorimetria obtida em gestantes de um hospital obstétrico

INTRODUCCIÓN: las infecciones fúngicas ocasionadas por levaduras del género Cándida son extremadamente comunes en mujeres de edad reproductiva, y constituyen un motivo de atención medica de salud. OBJETIVO: evaluar la susceptibilidad de Cándidas spp, mediante el método colorimétrico (Integral Yeast System Plus). MÉTODO: fue de tipo descriptivo, transversal; se recopiló información mediante observación directa en campo y el análisis documental para obtener información bibliográfica de tipo secundaria. RESULTADOS: de los 72 casos encontrados de Cándida Albicans revela que son susceptibles a la anfotericina B (2ug/ml); de los 5 casos encontrados de Cándida Krusei revela que son sensibles a la Anfotericina B (2ug/ml); De 1 caso encontrado de Cándida Parapsilosis revela sensibilidad en la Nistatina (1.25ug/ml). En este estudio la prevalencia de la infección por Cándida fue del (44.98%). CONCLUSIONES: Cándida Albicans fue la especie más común aislada en las mujeres embarazadas representando un 72%, En la evaluación de la susceptibilidad a través del kit Integral System Yeast Plus se obtuvo que Cándida Albicans es susceptible a Anfotericina B, Flucitosina entre otros, en Cándida Glabrata se obtuvo que es sensible a la Nistatina, Anfotericina B, susceptible entre otros, en Cándida Krusei se obtuvo que es sensible a la Anfotericina B, Clotrimazol, Miconazol, susceptibles a la Nistatina, Voriconazol y resistente a la Flucitosina, Ketoconazol, Itraconazol y Fluconazol.

INTRODUCTION: fungal infections caused by yeast of the genus Candida are extremely common in women of reproductive age, and constitute a reason for medical health care. OBJECTIVE: to evaluate the susceptibility of Candida spp, using the colorimetric method (Integral Yeast System Plus). METHOD: it was descriptive, transversal; Information was collected through direct observation in the field and documentary analysis to obtain secondary bibliographic information. RESULTS: of the 72 cases found, Candida Albicans reveals that they are susceptible to amphotericin B (2ug / ml); of the 5 cases found, Candida Krusei reveals that they are sensitive to Amphotericin B (2ug / ml); Of 1 case found of Candida Parapsilosis reveals sensitivity in Nystatin (1.25ug / ml). In this study, the prevalence of Candida infection was (44.98%). CONCLUSIONS: Candida Albicans was the most common species isolated in pregnant women, representing 72%. In the evaluation of susceptibility through the Integral System Yeast Plus kit it was obtained that Candida Albicans is susceptible to Amphotericin B, Flucytosine among others, in Candida Glabrata was obtained that it is sensitive to Nystatin, Amphotericin B, susceptible among others, in Candida Krusei it was obtained that it is sensitive to Amphotericin B, Clotrimazole, Miconazole, susceptible to Nystatin, Voriconazole and resistant to Flucytosin, Ketoconazole, Itraconazole and Fluconazole.

INTRODUÇÃO: as infecções fúngicas causadas por leveduras do gênero Candida são extremamente comuns em mulheres em idade reprodutiva e constituem motivo de cuidados médicos. OBJETIVO: avaliar a suscetibilidade de Candida spp, por meio do método colorimétrico (Integral Yeast System Plus). MÉTODO: foi descritivo, transversal; as informações foram coletadas por meio de observação direta em campo e análise documental para obtenção de informações bibliográficas secundárias. RESULTADOS: Dos 72 casos encontrados, Cândida Albicans revelou ser suscetíveis à anfotericina B (2ug /ml); dos 5 casos encontrados, Candida Krusei revela que são sensíveis à Anfotericina B (2ug / ml); de 1 caso encontrado de Candida Parapsilosis revela sensibilidade na Nistatina (1,25ug / ml). Neste estudo, a prevalência de infecção por Candida foi (44,98%). CONCLUSÕES: Cândida Albicans foi a espécie mais comum isolada em gestantes, representando 72%. Na avaliação da susceptibilidade através do kit Integral System Yeast Plus foi obtido que Candida Albicans é suscetível à Anfotericina B, Flucitosina entre outras, em Cândida Glabrata foi obtido que é sensível a Nistatina, Anfotericina B, suscetível entre outras, em Candida Krusei foi obtido que é sensível a Anfotericina B, Clotrimazol, Miconazol, suscetível a Nistatina, Voriconazol e resistente a Flucitosina, Cetoconazol, Itraconazol e Fluconazol.

Multisystemic fusariosis with fulminant evolution

Abstract This report presents the case of a 13-year-old female patient with history of acute myeloid leukemia, who, after a bone marrow transplant, began to vomit and experienced rapidly progressive deterioration of consciousness, in addition to disseminated erythematous-violaceous macules, and some blisters with hemorrhagic content inside. Skin biopsy evidenced intravascular filamentous structures. A blood culture confirmed the presence of Fusarium oxysporum. Intravenous treatment with voriconazole was initiated. The patient evolved unfavorably with multiple necrotic skin lesions, ischemic brain lesions, and death.

Disseminated fusariosis in a patient with bone marrow aplasia

Abstract Fusariosis is a superficial or systemic infection, which occurs mainly in immunocompromised hosts, especially in patients with hematological neoplasia; 70%-75% of the cases present cutaneous manifestations. The disseminated form is rare and difficult to diagnose; even with specific treatment, the evolution is usually fatal. Currently, it is considered an emerging disease; in some centers, it is the second most common cause of invasive mycosis, after aspergillosis. The authors describe a case of a female patient with idiopathic bone marrow aplasia and disseminated fusariosis, who initially appeared to benefit from voriconazole and amphotericin B; however, due to persistent neutropenia, her clinical condition deteriorated with fatal evolution.

Endoftalmite fúngica bilateral endógena / Bilateral endogenous fungal endophthalmitis

Resumo É apresentado o caso de uma paciente do sexo feminino, 77 anos, internada por pielonefrite e tratada com antibóticos de amplo espectro, tendo desenvolvido endoftalmite endógena bilateral presumida por Candida. Foi submetida à vitrectomia via pars plana e injeção intravítrea de anfotericina B, além de voriconazol oral. São abordados, ainda, os aspectos clínicos da endoftalmite endógena por meio de revisão da literatura.

Abstract A 77 year-old female patient suffering from pyelonephritis developed bilateral endogenous endophthalmitis presumed by Candida after have been treated with global spectrum antibiotics. Early vitrectomy and intravitreal amphotericin B injection were performed, in addition to oral voriconazole. Clinical aspects of endogenous endophthalmitis are also pointed out by a literature review.

Azoles de antes y ahora: una revisión / Azoles of then and now: a review

Resumen Los azoles son fármacos que inhiben la enzima 14α-esteroldemetilasa, impidiendo la unión de ergosterol; esto altera la estructura y función de la pared celular fúngica. Especialmente el grupo de los triazoles: fluconazol, itraconazol, voriconazol, posaconazol e isavuconazol, son una alternativa farmacológica para el tratamiento de la enfermedad fúngica invasora causada por Aspergillus spp, Candida spp, Cryptococcus spp, patógenos emergentes como los Mucorales, y de micosis endémicas como las ocasionadas por Histoplasma spp y Coccidioides spp. Los efectos adversos de los triazoles son menos frecuentes comparados con los ocasionados por anfotericina B, un antifúngico de uso común para estas micosis. Los principales efectos adversos de los triazoles son hepáticos, gastrointestinales y cardiovasculares como la prolongación del intervalo QT. Las interacciones farmacológicas son usuales y se presentan con moléculas que usan sustratos del citocromo CYP3A4, lo que incluye anti-retrovirales, anti-tuberculosos e inmunomoduladores. En este trabajo se revisan la historia, características farmacológicas y los ensayos clínicos que evidencian su eficacia clínica en los diferentes escenarios clínicos.

Abstract The azoles are drugs that inhibit the 14α-sterol-demethylase enzyme preventing the binding of ergosterol, altering the functionality and structure of the fungal cell wall. Especially the group of triazoles: fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole, are a pharmacological alternative for the treatment of the invasive fungal disease, caused by Aspergillus spp, Candida spp, Cryptococcus spp, by emerging pathogens for example, the Mucoral and finally of endemic mycosis as those caused by Histoplasma spp. and Coccidioides spp. The adverse effects of the triazoles are less frequent compared to those caused by amphotericin B, the main ones being hepatics, gastrointestinals and cardiovasculars, such as the prolongation of the QT interval. The pharmacological interactions are common and occur with molecules that use the substrates of the CYP3A4 cytochrome, for example: antiretroviral, anti-tuberculous and immunomodulators. The history, pharmacological characteristics and clinical trials are reviewed.

Fatores de virulência e susceptibilidade a antifúngicos de Cryptococcus Spp / Virulence factors and susceptibility to Cryptococcus Spp. antifungals

Criptococose é uma doença grave que afeta tanto imunocomprometidos quanto imunocompetentes, com isso analisar a virulência é fundamental para novas terapêuticas. Objetivo: Analisar a capacidade de virulência e susceptibilidade aos antifúngicos de Cryptococcus spp. isolados de líquor de pacientes de hospital do norte do Paraná. Métodos: A partir de dois isolados clínicos C. neoformans e C. gattii, realizou-se a confirmação da identificação. Para a virulência, avaliou-se o tamanho da cápsula, capacidade de sobrevivência após exposição a neutrófilos, produção de melanina e urease. No antifungigrama por difusão em disco utilizou-se: anfotericina B, cetoconazol, voriconazol, itraconazol e miconazol. Resultados: C. gattii destaca-se por maior desenvolvimento da cápsula além da melhor capacidade de sobreviver a fagocitose em relação ao C. neoformans. No antifungigrama, ambos os isolados se apresentam sensíveis às drogas estudadas. Conclusão: Esses achados contribuem para a compreensão das diferentes patogêneses entre C. gattii e C. neoformans.

Cryptococcosis is a serious disease that can affect both immunocompromised and immunocompetent individuals, thus the virulence analysis is fundamental for the development of new treatments. Objective: To analyze the virulence and susceptibility of Cryptococcus spp. isolated from cerebrospinal fluid of patients from a hospital in the north of Paraná. Methods: From two clinical isolates, C. neoformans and C. gattii were confirmed and identified. For virulence, capsule size, survival capacity after exposure to neutrophils, melanin production and urease were evaluated. In the disc-diffusion method, the following antifungals were used: amphotericin B, ketoconazole, voriconazole, itraconazole and miconazole Results: It was observed that C. gattii presents greater results for development of the capsule beside presenting the best ability to survive phagocytosis in relation to C. neoformans. In the disc-diffusion method, both isolates presented sensitivity to the studied drugs. Conclusion: These findings contribute to the understanding of the different pathogens between C. gattii and C. neoformans.

Post-laser in situ keratomileusis interface Arthrographis kalrae keratitis / Interface de pós-laser ceratomileuse in situ Arthographis Kalrae ceratite

ABSTRACT We describe a case of keratomycosis caused by Arthographis kalrae after excimer laser keratomileusis. A 38-year-old female developed stromal keratitis eight weeks after refractive surgery. She developed severe corneal stromal infiltration and mild anterior segment inflammation, which could not be treated with topical voriconazole 1%, but topical natamycin 5% ameliorated her condition. A reactivation of keratomycosis symptoms was observed; therefore, longer treatment was administered to the patient. It has been reported that A. kalrae keratomycosis is associated with exposure to soil and contact lens usage. However, the patient, who lived in a rural location, was neither involved in gardening activities nor had a history of wearing contact lenses. This is the first case of post-refractive A. kalrae keratomycosis.

RESUMO Descrevemos um caso de ceratomicose por Arthographis kalrae após ceratomileusis por excimer laser. Uma mulher de 38 anos desenvolveu ceratite estromal oito semanas após a cirurgia refrativa. Ela desenvolveu infiltração estromal grave da córnea e uma leve inflamação do segmento anterior, que não pode ser tratada com voriconazol tópico a 1%, mas a natamicina tópica a 5% melhorou sua condição. Uma reativação dos síntomas de ceratomicose foi observada; portanto, tratamento mais prolongado foi administrado a paciente. Tem sido relatado que a ceratomicose por A. kalrae está associada à exposição ao solo e ao uso de lentes de contato. No entanto, a paciente, que vivía em um local rural, não estava envolvida em atividades de jardinagem e nem tinha histórico de uso de lentes de contato. Este é o primeiro caso de ceratomicose pós-refrativa por A. kalrae.

A case of recurrent keratitis caused by Paecilomyces lilacinus and treated by voriconazole / Uso do voriconazol na ceratite recorrente causada por fungo Paecilomyces lilacinus

ABSTRACT - We describe here a case of a 21-year-old woman who presented with low visual acuity, pain, and hyperemia in the left eye for 45 days. Her eye had extensive corneal infiltrate, with melting and a central perforation that was glued with cyanoacrylate, but with Seidel (+). She underwent tectonic corneal transplantation, and anterior chamber lavage with subconjunctival infiltration with voriconazole, as well as intracameral injections of amphotericin B. Laboratory tests revealed Paecilomyces lilacinus as the infectious agent. The patient was then maintained with oral voriconazole and eye drops for three months, after which the infection was considered cured. However, in the sixth postoperative month she presented with endothelial rejection, and two weeks later signs of recurrence of the fungal infection. She was treated with two further washes of the anterior chamber and subconjunctival injection of voriconazole, followed by intravenous voriconazole that was replaced with drops after ten days. The infection initially worsened, but then regressed, and at last follow-up, the patient was still infection-free.

RESUMO - Descrevemos aqui um caso de uma mulher de 21 anos que apresentou baixa acuidade visual, dor e hiperemia no olho esquerdo por 45 dias. O olho apresentava infiltrado corneano extenso, com fusão e perfuração central colada com cianoacrilato, mas com Seidel (+). Ela foi submetida a transplante de córnea tectônica e lavagem de câmara anterior com infiltração subconjuntival com voriconazol, além de injeções intracamerais de anfoterecina B. Testes laboratoriais revelaram Paecilomyces lilacinus como agente infeccioso. A paciente foi então mantida com voriconazol oral e colírio por período de três meses, após o qual a infecção foi considerada curada. No entanto, no sexto mês de pós-operatório, ela apresentou rejeição endotelial e, duas semanas após, sinais de recidiva de infecção fúngica. Ela foi tratada com mais duas lavagens de câmara anterior e injeção subconjuntival de voriconazol, seguida por voriconazol intravenoso que foi substituído por gotas após 10 dias. A infecção piorou inicialmente, mas depois regrediu e, no último seguimento, o paciente ainda estava livre de infecção.

Aspergilosis pulmonar invasora en pacientes reumatológicos: presentación de dos casos / Invasive pulmonary aspergillosis in rheumatological patients: presentation of two cases

La aspergilosis pulmonar invasora (API) es una infección causada por hongos del género Aspergillus que afecta principalmente a pacientes inmunocomprometidos y corresponde a la forma más grave de aspergilosis. Se asocia a una alta morbi-mortalidad, siendo fundamental un diagnóstico y tratamiento oportuno. Las manifestaciones clínicas son inespecíficas, por lo que un estudio adecuado es importante para el diagnóstico, principalmente en pacientes con factores de riesgo poco habituales. En la actualidad se han establecido categorías diagnósticas que consideran factores del hospedero, laboratorio micológico tradicional y biomarcadores como galactomanano. Éstos, junto a la mejor comprensión e interpretación de las imágenes tomográficas permiten ofrecer un manejo adecuado. En este artículo, se presentan dos casos clínicos de API en pacientes reumatológicos, y se discute la utilidad de los métodos diagnósticos.

Invasive pulmonary aspergillosis (IPA) is an infection caused by fungi of the genus Aspergillus that mainly affects immunocompromised patients and corresponds to the most severe form of aspergillosis. It is associated with high morbidity and mortality, and diagnosis and timely treatment are essential. Clinical manifestations are nonspecific, so an adequate study is important for diagnosis, mainly in patients with unusual risk factors. At present, diagnostic categories have been established that consider factors of the host, traditional mycological laboratory and biomarkers such as galactomannan. These, together with the better understanding and interpretation of the tomographic images, allow us to offer an adequate management. In this article, two clinical cases of API in rheumatological patients are presented, and the usefulness of the diagnostic methods is discussed.

Criptococosis cerebral, voriconazol, niveles plasmáticos y síndrome de reconstitución inmune: reporte de un caso / Cerebral cryptococcosis and immune reconstitution inflammatory syndrome: case report

We report a 45-year-old male with AIDS who had a Cryptococcus neoformans central nervous system infection. He was treated with amphotericin B deoxycholate subsequently changed to voriconazole due to systemic toxicity of the former. Plasma levels of voriconazole were insufficient with a standard dose (0.7 μg/mL), therefore, the dose was increased thereafter to reach appropriate levels (4.5 μg/mL). Anti-retroviral therapy was started five weeks after voriconazole initiation with non-interacting drugs and he was discharged after a favorable evolution. He was re-admitted three months later due to seizures; a brain magnetic resonance showed new sub-cortical nodules. After excluding alternative causes and demonstrating fungal eradication, an immune reconstitution inflammatory syndrome (IRIS) event was suspected and treated with a short course of steroids. His evolution was satisfactory.

Identification of Fungal Pathogens in Otomycosis and Their Drug Sensitivity: Our Experience

Abstract Introduction Otomycosis is a common problem in otolaryngology practice. However, we usually encounter some difficulties in its treatment because many patients show resistance to antifungal agents, and present high recurrence rate. Objectives To determine the fungal pathogens that cause otomycosis as well as their susceptibility to the commonly used antifungal agents. Additionally, to discover the main reasons for antifungal resistance. Methods We conducted an experimental descriptive study on 122 patients clinically diagnosed with otomycosis from April 2016 to April 2017. Aural discharge specimens were collected for direct microscopic examination and fungal culture. In vitro antifungal susceptibility testing was performed against the commonly used antifungal drugs. We tested the isolated fungi for their enzymatic activity. Results Positive fungal infection was found in 102 samples. The most common fungal pathogens were Aspergillus and Candida species, with Aspergillus niger being the predominant isolate (51%). The antifungal susceptibility testing showed that mold isolates had the highest sensitivity to voriconazole (93.48%), while the highest resistance was to fluconazole (100%). For yeast, the highest sensitivity was to nystatin (88.24%), followed by amphotericin B (82.35%), and the highest resistance was to terbinafine (100%), followed by Itraconazole (94.12%). Filamentous fungi expressed a high enzymatic ability, making them more virulent. Conclusion The Aspergillus and Candida species are the most common fungal isolates in otomycosis. Voriconazole and Nystatin are the medications of choice for the treatment of otomycosis in our community. The high virulence of fungal pathogens is owed to their high enzymatic activity. Empirical use of antifungals should be discouraged.

Tratamiento exitoso de una fusariosis diseminada en un paciente neutropénico febril con terapia antifúngica combinada de voriconazol más anfotericina B deoxicolato / Successful treatment of disseminated fusariosis in a febrile neutropenic patient with combined antifungal therapy of voriconazol plus amphotericin B deoxycholate

Resumen Presentamos el caso clínico de un paciente con una leucemia linfoblástica aguda (LLA) que desarrolló una fusariosis diseminada por Fusarium verticillioides durante un episodio prolongado de neutropenia febril post quimioterapia. Fue exitosamente tratado cuando se usó terapia combinada de voriconazol más anfotericina B deoxicolato.

We report a case of a patient with acute lymphoblastic leukemia (ALL), who developed a disseminated infection by Fusarium verticillioides during chemotherapy-induced neutropenia. He was successfully treated only after combination therapy with voriconazole plus amphotericin B deoxycolate was used, but not when these compounds were used in an isolated form.

Monitorización terapéutica de antimicrobianos en pediatría: revisión de la experiencia latinoamericana / Therapeutic monitoring of antimicrobial agents in pediatrics: review based on Latin American experiences

Resumen La presente revisión resume la evidencia sobre la monitorización terapéutica de tres antimicrobianos basada en datos regionales: vancomicina, amikacina y voriconazol en la población pediátrica. Estos datos coinciden con la literatura internacional en relación al requerimiento de dosis mayores que 40 mg/kg/día de vancomicina, la posibilidad de usar monodosis diarias de amikacina y el requerimiento de dosis mayores de voriconazol en relación a las iniciales recomendadas de 8 mg/kg/día. Contar con datos locales sobre el comportamiento farmacocinético/farmacodinámico de diversos antimicrobianos en la pediatría es de gran valor para adecuar la dosificación de los mismos en nuestra población. Se deberían incrementar los estudios de monitorización terapéutica en el uso de antimicrobianos en pediatría que permitan generar pautas de tratamiento adecuadas para este grupo etario.

This review summarizes recommendations of therapeutic monitoring of three antimicrobials based in regional data: vancomycin, amikacin and voriconazole in pediatric population. Regional evidence agrees with international literature regarding the requirement of higher daily doses than 40 mg/kg/day of vancomycin, as well as with the possibility of use one daily doses of amikacin and to recommend higher doses of voriconazole compared to the initially recommended doses of 8 mg/kg/day. Local data on the pharmacokinetic/pharmacodynamic behavior of various antimicrobials in pediatrics are of great value for dosing adjustment in our pediatric population. More studies in therapeutic monitoring in the use of antimicrobials in pediatrics should be performed in order to allow the generation of adequate treatment guidelines for this age group.