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.

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.

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.

Corticosteroid therapy associated with COVID-19: an ally or a risk factor for the establishment of secondary fungal co-infections?

Corticosteroid therapy to combat inflammation caused by SARS-CoV-2 seems to be a risk factor for developing secondary fungal co-infections. PubMed and ScienceDirect databases were searched, with the following word groups: [(aspergillosis OR mucormycosis OR candidiasis) AND (coronavirus disease) AND (corticoids). The selected articles present the main risk factors related to the establishment of secondary fungal co-infections in COVID-19 patients. Corticosteroid therapy used to combat inflammation caused by SARS-CoV-2 has been shown to be strongly associated with the establishment of mucormycosis and aspergillosis. Mucormycosis has been the main fungal co-infection related to corticosteroid therapy, causing a high number of deaths in COVID-19 patients. Diabetes mellitus was the most prevalent comorbidity, especially for the establishment of mucormycosis. Dexamethasone use seems to be associated with mucormycosis emergence and death. However, aspergillosis showed a greater relationship with patient recovery. Thus, risk factors such as diabetes mellitus, combined with corticosteroid use, have shown a relationship to the establishment of mucormycosis. The corticosteroids used in COVID-19 patients should be individually analyzed, considering the patient's medical history and the risk/benefit ratio of the use of these drugs.

Antifungal susceptibility profile of Aspergillus fumigatus isolates from avian lungs / Perfil de suscetibilidade antifúngica de isolados de Aspergillus fumigatus provenientes de pulmões de aves

Susceptibility testing is essential to inform the correct management of Aspergillus infections. In this study we present antifungal susceptibility profile of A. fumigatus isolates recovered from lungs of birds with and without aspergillosis. Fifty three isolates were tested for their antifungal susceptibility to voriconazole (VRC), itraconazole (ITZ), amphotericin (AMB) and caspofungin (CSP) using the M38-A2 broth microdilution reference method. Five isolates were resistant to more than one antifungal drug (CSP + AMB, VRC + ITZ and AMB + ITZ). Fifteen (28%) isolates with susceptible increased exposure (I) to ITZ were sensible to VRC. Resistance to AMB (>2µg/mL) was observed in only four isolates. Eleven (21%) A. fumigatus present resistance to ITZ (13%) and VRC (8%). Fungal isolation from respiratory samples has been regarded as being of limited usefulness in the ante mortem diagnosis of aspergillosis in birds. However, the results suggest that the detection and antifungal susceptibility profile may be helpful for monitoring of therapy for avian species and where antifungal resistance might be emerging and what conditions are associated to the event.(AU)

Os testes de suscetibilidade são essenciais para informar o correto manejo das infecções por Aspergillus. Neste estudo apresentamos o perfil antifúngico de isolados de A. fumigatus provenientes de pulmões de aves com e sem aspergilose. Cinqüenta e três isolados foram testados quanto à susceptibilidade antifúngica ao voriconazol (VRC), itraconazol (ITZ), anfotericina B (AMB) e caspofungina (CSP) pelo método de referência de microdiluição do caldo M38-A2. Cinco isolados foram resistentes a mais de um antifúngico (CSP + AMB, VRC + ITZ e AMB + ITZ). Quinze (28%) isolados suscetíveis - com exposição aumentada (I) ao ITZ foram sensíveis ao VRC. A resistência ao AMB (>2µg/mL) foi observada em apenas quatro isolados. Onze (21%) A. fumigatus apresentaram resistência a ITZ (13%) e VRC (8%). O isolamento de fungos de amostras respiratórias tem sido considerado de utilidade limitada no diagnóstico ante mortem de aspergilose em aves. No entanto, os resultados sugerem que a detecção e o perfil de suscetibilidade a antifúngicos podem ser úteis para o monitoramento da terapia de espécies aviárias, assim como a emergência da resistência antifúngica e quais condições podem estar associadas ao evento.(AU)

Epidemiología de la enfermedad fúngica invasora por hongos filamentosos en el período 2005 a 2015, en un hospital universitario en Santiago, Chile / Epidemiology of invasive fungal disease by filamentous fungi in the period 2005 to 2015, in a university hospital in Santiago, Chile

Resumen Introducción: La enfermedad fúngica invasora (EFI) por hongos filamentosos es cada vez más frecuente. Objetivo: Estudiar la epidemiología de la EFI en adultos hospitalizados en nuestro centro. Metodología: Estudio retrospectivo de pacientes adultos de un hospital universitario en Santiago, Chile, con EFI por hongos filamentosos entre enero de 2005 y diciembre de 2015. Resultados: Se identificaron 125 episodios, siendo 48% categoria probada, 40% probable y 11% posible según criterios EORTC/MSG, incidencia global 0,47 x 1.000 egresos, 57% pacientes masculinos y edad de 50 ± 16 años. El 66,4% tenía patología hematológica, 11,2% trasplante de órgano sólido, 11,2% enfermedad reumatológica, 11,2% otra condición. Los factores de riesgo fueron neutropenia 44%, corticoterapia 21%, inmunosupresores 13%. Los hongos más frecuentemente identificados fueron Aspergillus spp (53,6%), Mucorales (16%), Fusarium spp (8,8%), Alternaria spp (5,6%), otros filamentosos (3,2%). Todos recibieron antifúngicos, 82% monoterapia, 18% terapia combinada, hubo defocación quirúrgica en 90% de mucormicosis. La mortalidad global fue 42%. Al comparar 2005-2009 vs 2010-2015, hubo un aumento significativo de la incidencia y una tendencia a menor mortalidad en el segundo período. Conclusiones: Durante un período de 10 años, observamos un aumento de la incidencia de EFI por filamentosos, aspergilosis fue la etiología más frecuente y la mortalidad global fue 42%.

Background: Invasive fungal disease (IFD) due to filamentous fungi is increasingly common. Aim: To study the epidemiology of EFI in hospitalized adults in our center. Methods: Retrospective study of adult patients of a university hospital in Santiago, Chile, with EFI due to filamentous fungi between January 2005 and December 2015. Results: 125 episodes were identified, being 48% proven, 40% probable and 11% possible according to EORTC/MSG criteria, overall incidence was 0.47/1,000 admissions, 57% male patients and age 50 ± 16 years. 66.4% had hematological pathology, 11.2% solid organ transplant, 11.2% rheumatology diseases, 11.2% other conditions. The risk factors were neutropenia 44%, corticosteroid therapy 21%, immunosuppressants 13%. The most frequent mould identified were Aspergillus spp (53.6%), Mucorales (16%), Fusarium spp (8.8%), Alternaria spp (5.6%) and other filamentous (3.2%). All received antifungals, 82% monotherapy, 18% combined therapy, there was surgical defocation in 90% of mucormycosis. The overall mortality was 42%. When comparing 2005-2009 vs 2010-2015, there was a significant increase in incidence and a tendency to lower mortality in the second period. Conclusions: Over a period of 10 years, we observed an increase in the incidence of EFI by filamentous, aspergillosis was the most frequent etiology and the overall mortality was 42%.

Galactomannan use in clinical practice: providing free testing is not the full answer

ABSTRACT Introduction: Invasive aspergillosis is a condition associated with a high mortality rate mostly due to difficulties in performing an early diagnosis. In recent years, galactomannan detection has markedly improved the diagnosis of invasive aspergillosis, but very little is known on how physicians deal with this test in clinical practice. Methods: This cross-sectional study aimed to analyze the indications for the use of serum galactomannan in a large Brazilian hospital, between 2015 and 2016. No specific protocol was in place for GM request. We reviewed the medical records of adult (>18 years-old) patients who were tested for galactomannan due to one the following indications: screening, diagnosis, or treatment follow-up. Additional variables included demographic data, underlying diseases, presence of neutropenia, and use of previous antifungal (anti-Aspergillus) drugs. Results: The mean age of the patients was 51 years-old (sd ± 15.8), and 63.3% of patients were male. Patients with hematological malignancies accounted for 60.1% of the cases, mostly acute myeloid leukemia (19.6%). Galactomannan testing was positive in 12.2% of patients, including 1.6% of occasions in which the test was used for screening purposes, 13.2% for diagnosis, and 32.4% during follow-up. Median time for chest imaging request was two days before GM testing. Previous antifungal therapy was reported for 35.1% of patients, mostly amphotericin B (57.1%). Conclusion: The correct use of galactomannan testing is essential for an early diagnosis of invasive aspergillosis, which may improve the prognosis of the disease. We demonstrated that clinicians usually ask for galactomannan tests to confirm imaging findings in patients who frequently were on antifungal drugs, something that could be improved by medical education. We observed a low frequency of galactomannan use for preemptive antifungal therapy (25.7%), which is worrying considering the well-known beneficial use of GM testing in this scenario.

Actualización en el diagnóstico y manejo de aspergilosis invasora en pacientes adultos / Update in the diagnostic and therapeutic approach of invasive aspergillosis in adult population

Resumen La enfermedad fúngica invasora producida por Aspergillus spp., es la infección por hongos filamentosos más frecuentemente reportada en individuos inmunocomprometidos y responsable de una muy alta mortalidad en este grupo de pacientes. En los últimos años se han logrado importantes avances, tanto en su diagnóstico como terapéuticos. Al momento actual se ha identificado una serie de factores de riesgo asociados a su desarrollo, permitiendo la categorización de pacientes en condición de alto, intermedio y bajo riesgo de aspergilosis invasora (AI); y también se han establecido criterios diagnósticos que consideran factores del hospedero, laboratorio micológico tradicional, biomarcadores como galactomanano y 1→3-β-d-glucano, junto a la mejor comprensión e interpretación de las imágenes tomográficas que han permitido consensuar las categorías diagnósticas. Esto, sumado a la incorporación de nuevos antifúngicos y estrategias terapéuticas en diferentes escenarios, ha permitido lograr una disminución de la mortalidad asociada. En este artículo se realiza una puesta al día de los aspectos epidemiológicos, los factores de riesgo, el diagnóstico, la prevención y profilaxis además del enfrentamiento terapéutico, incluyendo las estrategias de uso de terapia antifúngica empírica, precoz y dirigida, así como los aspectos más relevantes de los antifúngicos de primera elección y alternativos para el manejo actualizado de AI.

The invasive fungal disease produced by Aspergillus spp., is the infection by filamentous fungi most frequently reported among immunocompromised individuals and responsible for a very high mortality in this group of patients. In recent years, important advances have been made both from the diagnostic and therapeutic point of view. At present, a series of risk factors associated with its development have been identified, allowing the categorization of patients in high, intermediate and low risk of invasive aspergillosis (IA); and diagnostic criteria have also been established that consider factors of the host, traditional mycological laboratory, biomarkers such as galactomannan and 1→3-β-d-glucan, together with the better understanding and interpretation of the tomographic images that have allowed to reach a consensus on the diagnostic categories. This added to the incorporation of new antifungals and therapeutic strategies in different scenarios, have allowed decreasing the associated mortality. In this review, are updated the epidemiological aspects, the risk factors, the diagnosis, prevention and prophylaxis as well as the therapeutic confrontation, including strategies for the use of empirical, precocious and directed antifungal therapy, as well as the most relevant aspects of the first-choice and alternative antifungals for the IA management.

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.

Aspergilosis invasora post-quirúrgica: presentación de caso clínico / Invasive aspergillosis post surgical: presentation of case

La aspergilosis invasora es una infección oportunista causada por hongos del género Aspergillus spp, considerándose la con peor pronóstico producida por este organismo. Presenta una elevada tasa de mortalidad a pesar del avance en los tratamientos antifúngicos, afectando principalmente a pacientes inmunosuprimidos. Dentro de las formas clínicas se encuentra la que sucede posterior a una cirugía conllevando una elevada morbi-mortalidad. Presentamos un caso clínico del Hospital Roberto Del Río. Recién nacido de término diagnosticado de transposición de grandes vasos, quien a los 9 días de vida es sometido a cirugía correctora. Egresa de pabellón con tórax abierto y con requerimiento de drogas vasoactivas. Al décimo día postoperatorio presenta deterioro hemodinámico, se realiza ecocardiograma que muestra líquido con ecorefringencias y se realiza aseo quirúrgico, extrayendo muestra para cultivo que resulta positivo para Aspergillus terreus. Por consiguiente, se inicia tratamiento con voriconazol con buena respuesta clínica...

Invasive aspergillosis is an opportunistic infection caused by fungi of the genus Aspergillus spp, considered the worst prognosis produced by this organism. It has a high mortality despite progress in antifungal treatments, affecting mainly immunocompromised patients. Clinically can occur following surgery , leading to high morbidity and mortality. We report a case of Roberto Del Río Hospital. Term newborn diagnosed with transposition of the great vessels, who at 9 days of life undergoes corrective surgery. Leaves the pavilion with open chest and requirement of vasoactive drugs. On the tenth day after surgery presents hemodynamic deterioration, the echocardiogram shows refringence and surgical cleaning is performed, a sample is removed and cultured resulting positive for Aspergillus terreus. Therefore, treatment with voriconazole starts with good clinical response...

Diagnostic-driven antifungal therapy in neutropenic patients using the D-index and serial serum galactomannan testing

Abstract Introduction Invasive mold disease is an important complication of patients with hematologic malignancies, and is associated with high mortality. A diagnostic-driven approach has been an alternative to the classical empiric antifungal therapy. In the present study we tested an algorithm that incorporated risk stratification using the D-index, serial serum galactomannan and computed tomographic-scan to guide the decision to start antifungal therapy in neutropenic patients. Patients and methods Between May 2010 and August 2012, patients with acute leukemia in induction remission were prospectively monitored from day 1 of chemotherapy until discharge or death with the D-index and galactomannan. Patients were stratified in low, intermediate and high risk according to the D-index and an extensive workup for invasive mold disease was performed in case of positive galactomannan (≥0.5), persistent fever, or the appearance of clinical manifestations suggestive of invasive mold disease. Results Among 29 patients, 6 (21%), 11 (38%), and 12 (41%) were classified as high, intermediate, and low risk, respectively. Workup for invasive mold disease was undertaken in 67%, 73% and 58% (p = 0.77) of patients in each risk category, respectively, and antifungal therapy was given to 67%, 54.5%, and 17% (p = 0.07). Proven or probable invasive mold disease was diagnosed in 67%, 45.5%, and in none (p = 0.007) of high, intermediate, and low risk patients, respectively. All patients survived. Conclusion A risk stratification using D-index was a useful instrument to be incorporated in invasive mold disease diagnostic approach, resulting in a more comprehensive antifungal treatment strategy, and to guide an earlier start of treatment in afebrile patients under very high risk.

Aspergillus niger – a possible new etiopathogenic agent in Tinea capitis? Presentation of two cases

Abstract Tinea capitis is generally considered as the most frequent fungal infection in childhood, as it accounts for approximately 92% of all mycosis in children. The epidemiology of this disease varies widely ranging from antropophillic, zoophilic, and geophillic dermatophytes, as the main causative agent in different geographic areas, depending on several additional factors. Nowadays, the etiology is considered to vary with age, as well with gender, and general health condition. The former reported extraordinary Tinea capitis case reports have been replaced by original articles and researches dealing with progressively changing patterns in etiology and clinical manifestation of the disease. This fact is indicative that under the umbrella of the well-known disease there are facts still hidden for future revelations. Herein, we present two rare cases of Tinea capitis in children, which totally differ from the recently established pattern, in their clinical presentation, as well as in the etiological aspect, as we discuss this potential new etiological pattern of the disease, focusing on our retrospective and clinical observation. Collected data suggest that pathogenic molds should be considered as a potential source of infection in some geographic regions, which require total rationalization of the former therapeutic conception, regarding the molds’ higher antimitotic resistance compared to dermatophytes. Molds-induced Tinea capitis should be also considered in clinically resistant and atypical cases, with further investigations of the antifungal susceptibility of the newest pathogens in the frame of the old disease. Further investigations are still needed to confirm or reject this proposal.

Análisis de concentraciones plasmáticas de voriconazol y su perfil de seguridad en pacientes oncológicos pediátricos / Analysis of voriconazole serum concentrations and safety profile in pediatric oncology patients

Background: Voriconazole (VCZ) serum drug levels (SDL) vary widely and are associated with increased mortality when they are below the therapeutic range for invasive aspergillosis (IA). Aim: To describe VCZ SDL in oncology pediatric patients in order to reach adequate concentrations for prophylaxis (≥ 0.5 mg/L) and treatment (≥ 1.0 y 2.0 mg/L) for IA and their relationship with toxicity. Patients and Methods: Retrospective analysis of VCZ SDL and toxicities recorded in oncology pediatric patients between February 2013 and November 2014. The daily dosage and SDLs were analyzed according to administration route: intravenous (IV) and oral (PO), type of therapy (prophylaxis and treatment) and patient age (< 12 y ≥ 12 years old). Results: 112 through levels from 26 patients were analyzed and the average age was 9.3 years-old. The SDL obtained from the IV route were 43.7%. There were more SDL ≥ 0.5 mg/L and ≥ 1.0 mg/L with the IV route than the PO route (p < 0.05). Patients younger than 12-years-old received a higher dosage than those ≥ 12 years old (median 18.6 and 9.2 mg/kg/d, respectively, p < 0.05). To reach SDL ≥ 0,5 mg/L with the PO route, a dosage of 200 mg every 12 hours showed the best results for all patients (80-100% SDL ≥ 0.5 mg/L). With an IV dosage between 14 and 20 mg/kg/day in patients > 12-years-old, 80% of the SDL were ≥ 1 mg/L and ≥ 2 mg/L. In patients younger than 12-year-old, dosages between 8-30 mg/ kg/day showed similar results (50-63% of SDL ≥ 1 mg/L and 36-40% of SDL ≥ 2 mg/L). Eight patients (30.8%) presented an adverse drug reaction and no relationship with the SDL was found. Conclusión: A VCZ standard dosage of 200 mg every 12 hours PO showed the best results for IA prophylaxis in all patients. Patients younger than 12-years-old would require higher dosages than the doses used in this study to attain adequate SDL for IA treatment. No relation with SDL and adverse reactions was found.

Introducción: Las concentraciones plasmáticas (CPs) de voriconazol (VCZ) son erráticas y en el caso de encontrarse bajo rango terapéutico para el tratamiento de aspergilosis invasora (AI) se asocian a un aumento de mortalidad. Objetivo: Analizar las CPs de VCZ obtenidas en pacientes pediátricos para alcanzar valores que se estiman efectivos para profilaxis (≥ 0,5 mg/L) y tratamiento (≥ 1,0 y 2,0 mg/L) de AI y su relación con toxicidades. Pacientes y Métodos: Análisis retrospectivo de CPs de VCZ y toxicidades asociadas obtenidas en pacientes oncológicos pediátricos desde febrero de 2013 hasta noviembre 2014. Se analizó la dosis diaria y CPs de acuerdo a la vía de administración: intravenosa (iv) u oral (vo), tipo de terapia (profilaxis y tratamiento) y edad (< 12 y ≥ 12 años). Resultados: Se analizaron 112 CPs valle de 26 pacientes, con una edad promedio de 9,3 años. El 43,7% de las CPs correspondió a administración iv. Se obtuvieron más CPs ≥ 0,5 mg/L y ≥ 1,0 mg/L con la vía iv en relación a vo (p < 0,05). Pacientes bajo 12 años de edad recibieron mayor dosis en comparación a los ≥ 12 años (medianas 18,6 y 9,2 mg/kg/día, respectivamente, p < 0,05). La dosis vo más efectiva para alcanzar CPs ≥ 0,5 mg/L fue de 200 mg cada 12 h en todos los pacientes (80-100% de CPs ≥ 0,5 mg/L). En pacientes ≥ 12 años con dosis iv entre 14 y 20 mg/kg/día, 80% de las CPs fueron ≥ 1 mg/L y ≥ 2 mg/L. En pacientes bajo 12 años de edad, dosis entre 8-30 mg/ kg/día generaron similares resultados (50-63% para CPs ≥ 1 mg/L y 36-40% para CPs ≥ 2 mg/L). Ocho pacientes (30,8%), tuvieron alguna reacción adversa al fármaco, no encontrándose relación con la CP alcanzada. Conclusión: Una dosis estándar vo de 200 mg c/12 h de VCZ mostró los mejores resultados para profilaxis de AI en todos los pacientes. Pacientes bajo 12 años de edad requerirían dosis mayores a las utilizadas en este estudio para obtener CPs efectivas para tratamiento de AI. No se encontró relación entre CPs tóxicas y reacciones adversas.

An unusual case of invasive aspergillus ulcerative tracheobronchitis without involvement of lung parenchyma in a post-renal transplant patient.

We present the case of a 54-year-old male, who presented with respiratory complaints four months after he underwent renal transplantation. Bronchoscopy showed ulcerated mucosa of the left main bronchus and computed tomography (CT) of the thorax showed foci of air within the bronchial wall. A biopsy from the lesion showed septate fungal hyphae, dichotomously branching at acute angles. A locally invasive Aspergillus ulcerative tracheobronchitis with no parenchymal involvement is an important cause of tracheobronchitis in post-renal transplant patients. An early diagnosis and institution of appropriate treatment can improve the outcome. A combination treatment of caspofungin and voriconazole can be considered if patient is not responding to voriconazole alone.

Molecular characterization of drug-resistant and drug-sensitive Aspergillus isolates causing infectious keratitis.

Purpose: To study the susceptibilities of Aspergillus species against amphotericin B in infectious keratitis and to find out if drug resistance had any association with the molecular characteristics of the fungi. Materials and Methods: One hundred and sixty Aspergillus isolates from the corneal scrapings of patients with keratitis were tested for susceptibilities to amphotericin B by broth microdilution method. These included Aspergillus flavus (64 isolates), A. fumigatus (43) and A. niger (53). Fungal DNA was extracted by glass bead vertexing technique. Polymerase chain reaction (PCR) assay was standardized and used to amplify the 28S rRNA gene. Single-stranded conformational polymorphism (SSCP) of the PCR product was performed by the standard protocol. Results: Of the 160 isolates, 84 (52.5%) showed low minimum inhibitory concentration (MIC) values (≤ 1.56 μg/ml) and were designated as amphotercin B-sensitive. Similarly, 76 (47.5%) had high MICs (≥ 3.12 μg/ml) and were categorized as amphotericin B-resistant. MIC50 and MIC90 values ranged between 3.12-6.25 μg/ml and 3.12-12.5 μg/ml respectively. A. flavus and A. niger showed higher MIC50 and MIC90 values than A. fumigatus. The SSCP pattern exhibited three extra bands (150 bp, 200 bp and 250 bp each) in addition to the 260 bp amplicon. Strains (lanes 1 and 7) lacking the 150 bp band showed low MIC values (≤ 1.56 μg/ml). Conclusion: A. niger and A. flavus isolates had higher MICs compared to A. fumigatus, suggesting a high index of suspicion for amphotericin B resistance. PCR-SSCP was a good molecular tool to characterize Aspergillus phenotypes in fungal keratitis.

Voriconazole-refractory fungal infection of phacoemulsification tunnel.

A 44-year-old man presented 28 days after cataract surgery (phacoemulsification) in right eye with multiple pinpoint infiltrates in posterior stroma at cataract surgery wound site. Visual acuity was 20/60. Corneal scraping from the floor of the corneal tunnel revealed fungus which was later identified to be Aspergillus flavus. The patient was started on oral voriconazole 200 mg twice daily and topical voriconazole 1% every hour. Two intracameral injections of voriconazole (50 micrograms/ 0.1 ml) were given 72 h apart, five days after starting initial therapy. Infiltrates increased in size and density in spite of 20 days of voriconazole therapy. Full-thickness patch graft was done to arrest progressive necrosis. Four months after surgery, patient had 20/60 best-corrected visual acuity. There was no recurrence in one-year follow-up. Present case illustrates the therapeutic challenge in fungal tunnel infections and possibility of voriconazole-resistant Aspergillus species.

Estudio de costo del tratamiento de la aspergilosis invasora en pacientes oncológicos pediátricos: Santiago. Chile / Economical evaluation of the treatment of invasive aspergillosis in pediatric oncology patients: Santiago. Chile

Introducción: La aspergilosis invasora (AI) es una infección oportunista grave en pacientes inmunocompro- metidos. Pacientes receptores de transplantes y oncológicos representan el grupo de mayor riesgo. El tratamiento antifúngico involucra hospitalización prolongada y altos recursos económicos. Objetivo: Estimar los costos involucrados en el tratamiento de la AI como complicación intercurrente en pacientes con cáncer. Pacientes y Método: Estudio caso-control, retrospectivo. Estima el costo del tratamiento de AI en pacientes pediátricos oncológicos del Hospital Luis Calvo Mackenna durante los años 2007 y 2008. Resultados: Se incluyeron 13 pacientes con AI y sus respectivos 13 controles. El costo atribuible de la hospitalización en aquellos pacientes que cursaron con AI fue de US $23.600. El costo atribuible para cada indicador fue: US $16.500 para días de hospitalización; US $7.000 para medicamentos antifúngicos y US $100 para galactomanano sérico. Discusión: En este estudio, el costo del tratamiento de AI se debe principalmente a la estadía hospitalaria y fármacos antifúngicos. Encontramos tres pacientes que desarrollaron AI estando en ambiente protegido.

Introduction: Invasive aspergillosis (IA) is a serious opportunistic infection in immunocompromised patients. Transplant recipients and patients with cancer represent the highest risk group. The antifungal treatment involves prolonged hospitalization and high economic resources. Objective: to estimate costs represented by IA as an intercurrent complication of oncologic treatment. Patients and Method: Retrospective case-control study. Estimation of the cost of treatment in pediatric oncologic patients with IA in the Hospital Luis Calvo Mackenna during the years 2007-2008 was done. A control for each case of IA paired by sex, age, number of diagnosis and clinical department was selected. Results: There were 13 patients during the observation period. The attributable cost of treatment of aspergillosis was US $ 23,600 and the cost for each indicator was: hospital days US $ 16,500; antifungal therapy US $ 7,000; and serum galactomannan US $ 100. Discussion: In this study, the cost of treating IA is mainly due to hospitalization and antifungal medications. Three patients acquired IA in spite of staying in a protected environment.