RESUMEN
Aspergillus fumigatus is the primary etiological agent of aspergillosis. Here, we show that the host defense peptide mimetic brilacidin (BRI) can potentiate ibrexafungerp (IBX) against clinical isolates of A. fumigatus. BRI + IBX can inhibit the growth of A. fumigatus voriconazole- and caspofungin-resistant clinical isolates. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against viruses, bacteria, and fungi. In vitro, combination of BRI + IBX plays a fungicidal role, increases the fungal cell permeability, decreases the fungal survival in the presence of A549 epithelial cells, and appears as a promising antifungal therapeutic alternative against A. fumigatus. IMPORTANCE: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Aspergillus fumigatus causes a series of distinct invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. A. fumigatus causes a spectrum of distinct clinical entities named aspergillosis, which the most severe form is the invasive pulmonary aspergillosis. There are few therapeutic options for treating aspergillosis and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a synergizer o fibrexafungerp (IBX) against A. fumigatus. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. We propose the combination of BRI and IBX as a new antifungal combinatorial treatment against aspergillosis.
Asunto(s)
Antifúngicos , Aspergillus fumigatus , Aspergillus fumigatus/efectos de los fármacos , Humanos , Antifúngicos/farmacología , Sinergismo Farmacológico , Pruebas de Sensibilidad Microbiana , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Células A549 , Péptidos Antimicrobianos/farmacología , Farmacorresistencia Fúngica/efectos de los fármacosRESUMEN
Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD+-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.
Asunto(s)
Aspergilosis , Aspergillus fumigatus , Sirtuinas , Aspergillus fumigatus/patogenicidad , Aspergillus fumigatus/genética , Aspergillus fumigatus/enzimología , Sirtuinas/genética , Sirtuinas/metabolismo , Virulencia , Animales , Ratones , Aspergilosis/microbiología , Aspergilosis/tratamiento farmacológico , Acetilación , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulación Fúngica de la Expresión Génica , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Mariposas Nocturnas/microbiologíaAsunto(s)
Antifúngicos , Aspergilosis , Terbinafina , Humanos , Terbinafina/uso terapéutico , Antifúngicos/uso terapéutico , Resultado del Tratamiento , Aspergilosis/tratamiento farmacológico , Masculino , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Femenino , Persona de Mediana EdadRESUMEN
Aspergillus fumigatus and Fusarium solani infections have become severe health threat; both pathogens are considered a priority due to the increasing emergence of antifungal-resistant strains and high mortality rates. Therefore, the discovery of new therapeutic strategies has become crucial. In this study, we evaluated the antifungal and antivirulence effects of vanillin and tannic acid against Aspergillus fumigatus and Fusarium solani. The minimum inhibitory concentrations of the compounds were determined by the microdilution method in RPMI broth in 96-well microplates according to CLSI. Conidial germination, protease production, biofilm formation, and in vivo therapeutic efficacy assays were performed. The results demonstrated that vanillin and tannic acid had antifungal activity against Aspergillus fumigatus, while tannic acid only exhibited antifungal activity against Fusarium solani. We found that vanillin and tannic acid inhibited conidial germination and secreted protease production and biofilm formation of the fungal pathogens using sub-inhibitory concentrations. Besides, vanillin and tannic acid altered the fungal membrane permeability, and both compounds showed therapeutic effect against aspergillosis and fusariosis in an infection model in Galleria mellonella larvae. Our results highlight the antivirulence effect of vanillin and tannic acid against priority pathogenic fungi as a possible therapeutic alternative for human fungal infections.
Asunto(s)
Antifúngicos , Aspergillus fumigatus , Benzaldehídos , Biopelículas , Fusarium , Pruebas de Sensibilidad Microbiana , Polifenoles , Taninos , Benzaldehídos/farmacología , Fusarium/efectos de los fármacos , Taninos/farmacología , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Aspergillus fumigatus/efectos de los fármacos , Animales , Aspergilosis/microbiología , Aspergilosis/tratamiento farmacológico , Virulencia/efectos de los fármacos , Larva/microbiología , Larva/efectos de los fármacos , Fusariosis/tratamiento farmacológico , Fusariosis/microbiología , Esporas Fúngicas/efectos de los fármacos , Mariposas Nocturnas/microbiología , Mariposas Nocturnas/efectos de los fármacosAsunto(s)
Aspergilosis , Trasplante de Células Madre Hematopoyéticas , Intususcepción , Trasplante Autólogo , Humanos , Persona de Mediana Edad , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergilosis/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Huésped Inmunocomprometido , Intususcepción/etiología , Intususcepción/cirugía , Intususcepción/microbiologíaRESUMEN
OBJECTIVES: This study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS). METHODS: In this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022. RESULTS: The economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year. CONCLUSION: Compared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Nitrilos , Piridinas , Humanos , Voriconazol/uso terapéutico , Brasil , Triazoles/uso terapéutico , Aspergilosis/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológicoAsunto(s)
Aspergilosis , Infecciones por Herpesviridae , Gripe Humana , Leucemia Mieloide Aguda , Humanos , Gripe Humana/complicaciones , Gripe Humana/tratamiento farmacológico , Aspergilosis/complicaciones , Aspergilosis/diagnóstico por imagen , Aspergilosis/tratamiento farmacológico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Infecciones por Herpesviridae/tratamiento farmacológico , Antifúngicos/uso terapéuticoRESUMEN
Aspergillus niger causes infections such as otitis and pulmonary aspergillosis in immunocompromised individuals. Treatment involves voriconazole or amphotericin B, and due to the increase in fungal resistance, the search for new compounds with antifungal activity has intensified. In the development of new drugs, cytotoxicity and genotoxicity assays are important, as they allow predicting possible damage that a molecule can cause, and in silico studies predict the pharmacokinetic properties. The aim of this study was to verify the antifungal activity and the mechanism of action of the synthetic amide 2-chloro-N-phenylacetamide against Aspergillus niger strains and toxicity. 2-Chloro-N-phenylacetamide showed antifungal activity against different strains of Aspergillus niger with minimum inhibitory concentrations between 32 and 256 µg/mL and minimum fungicides between 64 and 1024 µg/mL. The minimum inhibitory concentration of 2-chloro-N-phenylacetamide also inhibited conidia germination. When associated with amphotericin B or voriconazole, 2-chloro-N-phenylacetamide had antagonistic effects. Interaction with ergosterol in the plasma membrane is the probable mechanism of action.2-Chloro-N-phenylacetamide has favorable physicochemical parameters, good oral bioavailability and absorption in the gastrointestinal tract, crosses the blood-brain barrier and inhibits CYP1A2. At concentrations of 50 to 500 µg/mL, it has little hemolytic effect and a protective effect for type A and O red blood cells, and in the cells of the oral mucosa it promotes little genotoxic change. It is concluded that 2-chloro-N-phenylacetamide has promising antifungal potential, favorable pharmacokinetic profile for oral administration and low cytotoxic and genotoxic potential, being a promising candidate for in vivo toxicity studies.
Asunto(s)
Antifúngicos , Aspergilosis , Aspergillus , Humanos , Antifúngicos/toxicidad , Anfotericina B/toxicidad , Voriconazol/toxicidad , Voriconazol/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Acetanilidas/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
Infection by Aspergillus covers a broad clinical spectrum, including invasive pulmonary aspergillosis (IPA) and its disseminated extrapulmonary form, invasive aspergillosis (IA). It typically occurs in severely immunocompromised hosts, but it sometimes affects the immunocompetent population, especially patients with acute diseases being treated at the intensive care unit (ICU) and less often those with chronic conditions. In this article, we report the case of a 50-year-old male, with diabetes mellitus (DM) as the only risk factor, treated for IPA and IA with cardiac and central nervous system (CNS) involvement at a high complexity institution in Cali-Colombia. Clinical presentation and radiological findings are unspecific and require a high level of suspicion. To confirm the case, histological or cytological of the fungus is required; histopathological examination of lung tissue is the gold standard, but it is difficult to perform due to respiratory compromise and high risk of bleeding, so bronchoscopy and bronchoalveolar lavage (BAL) plays an essential role in the diagnostic process. A diagnostic algorithm that includes risk assessment, symptoms, imaging findings, and isolation in cultures is essential to allow the diagnosis and initiation of treatment promptly, which includes a combination of surgery and antifungal medications for long periods, even life-long treatment.
Asunto(s)
Aspergilosis , Diabetes Mellitus , Aspergilosis Pulmonar Invasiva , Masculino , Humanos , Persona de Mediana Edad , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/etiología , Aspergillus , Aspergilosis Pulmonar Invasiva/complicaciones , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Antifúngicos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
BACKGROUND: Untreated HIV infection can lead to profound immunosuppression and increase susceptibility of people living with HIV/AIDS (PLHA) to aspergillosis. OBJECTIVES: Reporting the burden and natural history of aspergillosis documented in PLHA admitted in five medical centres in Brazil. PATIENTS AND METHODS: Clinical, epidemiological and laboratory data were collected in all sequential cases of proven or probable aspergillosis documented in PLHA hospitalised in five medical centres between 2012 and 2020. RESULTS: We enrolled 25 patients ageing between 23 and 58 years (mean = 39) including 11 patients with invasive aspergillosis (IA) and 14 with chronic pulmonary aspergillosis (CPA). The prevalence rate of aspergillosis was 0.1% of 19.616 PLHA. Overall, 72.7% of patients with IA exhibited CD4 < 100 cells/mL and 42.8% of patients with CPA exhibited CD4 count >200 cells/mL. Most patients had a history of tuberculosis, especially those with CPA (85.7%). IA was documented after a mean of 16.5 days of hospitalisation, mainly in critically ill patients exposed to corticosteroids and broad-spectrum antibiotics. In the CPA group, a positive culture (71.4%) and radiological alterations were the most frequent findings supporting their diagnosis. Episodes of IA were mostly documented by tissue biopsies. Crude mortality rates were 72.7% and 42.8% in patients with IA and CPA, respectively. CONCLUSIONS: Despite being considered an unusual complication in PLHA (0.1%), IA should be considered in patients with profound immunosuppression and pneumonia refractory to conventional therapy. CPA should be investigated in PLHA with chronic deterioration of pulmonary function and previous diagnosis of tuberculosis.
Asunto(s)
Aspergilosis , Infecciones por VIH , Aspergilosis Pulmonar , Humanos , Infecciones por VIH/complicaciones , Aspergilosis/tratamiento farmacológico , Aspergilosis Pulmonar/complicaciones , Brasil/epidemiologíaRESUMEN
Invasive aspergillosis (IA) is a serious disease with high mortality. There are several risk factors and in-hospital outbreaks related with construction have been described. An entity related to COVID-19 infection, known as COVID-19 associated pulmonary aspergillosis (CAPA), has recently appeared. Early and appropriate treatment is of paramount importance, especially in immunocompromised and critically ill patients. Diagnosis is based on recognition of predisposing factors, clinical signs, imaging, direct examination, culture, histopathology, and biomarkers such as galactomannan. The drug of choice is voriconazole, but alternative therapies must be taken into account given the increasing presence of resistant isolates.
La aspergilosis invasiva (AI) es una enfermedad grave y con alta mortalidad. Existen factores de riesgo y se describen brotes intrahospitalarios relacionados con construcciones. También se describe una entidad relacionada con la infección por COVID-19, conocida como aspergilosis pulmonar asociada a COVID-19 (APAC). Es de vital importancia implementar un tratamiento adecuado y precoz, especialmente en pacientes inmunocomprometidos y críticamente enfermos. El diagnóstico se basa en reconocer los factores predisponentes, la clínica, la obtención de imágenes, exámenes directos, cultivos, histopatología y biomarcadores como el galactomanano. La droga de elección es el voriconazol, pero se deben conocer las alternativas terapéuticas dada la creciente presencia de aislamientos resistentes.
Asunto(s)
Aspergilosis , COVID-19 , Humanos , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Prueba de COVID-19RESUMEN
OBJECTIVE: The aim of this study was to evaluate the demographic data, molecular epidemiology, and in vitro antifungal susceptibility results of patients with Aspergillus isolated from various clinical specimens. METHODS: A total of 44 Aspergillus strains were studied. The definition of invasive aspergillosis in patients was made according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Strains were phenotypically and molecularly identified. Demographic characteristics of patients and genotypes of strains were evaluated. Phylogenetic analysis was done by the The Unweighted Pair-Group Method with Arithmetic Mean (UPGMA). Antifungal susceptibility of strains was determined according to The Clinical and Laboratory Standards Institute (CLSI)-M61-Ed2 and The European Committee on Antimicrobial Susceptibility Testing (EUCAST). RESULTS: A total of 11 patients were classified as proven and 33 as probable invasive aspergillosis. There was a statistically significant difference in age groups, subdisease, neutropenic, and receiving chemotherapy between groups. A total of 23 strains were identified as Aspergillus fumigatus, 12 as Aspergillus niger, 6 as Aspergillus flavus, and 3 as Aspergillus terreus. Phylogenetic analysis revealed five different genotypes. No statistical difference was found in the comparisons between patients groups and genotype groups. There was a statistically significant difference between genotype groups and voriconazole, posaconazole, and itraconazole Minimum Inhibition Concentration (MIC). CONCLUSION: Accurate identification of strains and antifungal susceptibility studies should be performed due to azole and amphotericin B resistance. Genotyping studies are important in infection control due to identifying sources of infection and transmission routes.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Humanos , Antifúngicos , Epidemiología Molecular , Filogenia , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Aspergilosis/microbiología , Aspergillus/genéticaRESUMEN
BACKGROUND: The epidemiology of invasive aspergillosis (IA) in patients with acute lymphoid leukemia (ALL) has not been well characterized. OBJECTIVES: To identify potential peculiarities in the natural history, treatment response and outcome of IA diagnosed in patients with ALL and AML. METHODS: This is a retrospective cohort study conducted in seven tertiary-care hospitals between 2009 and 2017 of all consecutive episodes of IA occurring in adult patients with acute leukemia. Demographic characteristics, underlying disease and recent treatment, antifungal prophylaxis, neutropenia, receipt of corticosteroids, clinical and radiological findings, mycological results, antifungal therapy, and 6-week and 12-week survival were recorded. RESULTS: We identified 77 cases of IA in 54 patients with AML and 23 patients with ALL. The majority of patients developed IA in the context of induction chemotherapy for newly diagnosed (48.0%) or relapsed (41.6%) leukemia, with no differences between ALL and AML. Lung involvement was more frequent in AML (96.3% vs. 82.6%, p = 0.06) and rhinosinusitis was more common in ALL (43.5% vs. 24.1%, p = 0.09). Galactomannan was the microbiologic documentation of IA in 76.6%, with similar patterns of positivity in AML and ALL. The 6-week survival of IA in patients with AML and ALL was 63.0% and 56.5%, respectively (p = 0.60). CONCLUSIONS: The epidemiology, clinical presentation, diagnosis and outcome of IA in ALL patients are similar to patients with AML.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Antifúngicos/uso terapéutico , Estudios Retrospectivos , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/epidemiologíaRESUMEN
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.
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus , Comorbilidad , Fluconazol/uso terapéutico , Niño Hospitalizado , Anfotericina B/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Huésped Inmunocomprometido/inmunología , Criptococosis/diagnóstico , Criptococosis/tratamiento farmacológico , Cryptococcus neoformans , Candidiasis Invasiva/diagnóstico , Candidiasis Invasiva/tratamiento farmacológico , Voriconazol/uso terapéutico , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/mortalidad , Caspofungina/uso terapéutico , Antifúngicos/uso terapéuticoRESUMEN
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.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adulto Joven , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus , Terapéutica , Enfermedades de la Laringe , Diagnóstico , Inmunocompetencia , Aspergillus , Aspergillus niger , Itraconazol , Tos , Disnea , Ecuador , Disfonía , Voriconazol , Laringe/patologíaRESUMEN
We read the excellent viewpoint by Slavin et al. (J Antimicrob Chemother 2022; 77: 16-23) that draws upon the experience of an advisory board of notable experts to comprehensively address many of the clinical factors that drive the need for changes in antifungal therapy for invasive aspergillosis (IA). As noted by the authors, there remains a paucity of quality data to support many of the decisions faced by clinicians managing patients with IA. However, we would like to highlight several other important issues, not fully addressed in that viewpoint, that play an important role in deciding when to change antifungal therapy for IA.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Aspergilosis Pulmonar Invasiva , Humanos , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológicoRESUMEN
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 < 12 years old exposed to TID dosages are 4.65 times (OR: 4.65, 95% CI 1.93-11.2) more likely to have PC > 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.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Antifúngicos , Aspergilosis/tratamiento farmacológico , Niño , Humanos , Preparaciones Farmacéuticas , VoriconazolRESUMEN
CONTEXTO: A aspergilose é uma doença cujas manifestações clínicas são determinadas pela resposta imune do indivíduo, podendo apresentar-se de forma alérgica, saprofítica ou invasiva. A aspergilose invasiva é considerada uma infecção fúngica oportunista, progressiva, aguda e severa, de mau prognóstico, com o maior risco de vida em doentes imunodeprimidos ou que são sujeitos a terapias agressivas pelo uso de corticoides, antibióticos e drogas imunossupressoras. Os sintomas incluem febre, calafrios, choque, delírio e coágulos sanguíneos. Insuficiência renal e hepática (causando icterícia), além de dificuldade respiratória podem surgir. A morte pode ocorrer rapidamente. A taxa de incidência anual de infeção invasiva por Aspergillus spp. é de 12 casos por 1.000.000 hab. O Aspergillus fumigatus é responsável por mais de 90% das infeções humanas. Se iniciado precocemente, o tratamento gera um melhor prognóstico. TECNOLOGIA: Voriconazol versus anfotericina B (desoxicolato ou formulações lipídicas). PERGUNTA DE PESQUISA: O voriconazol é eficaz e seguro, quando comparado a anfotericina B (desoxicolato ou formulações lipídicas) para o tratamento de pessoas com aspergilose invasiva? EVIDÊNCIAS CLÍNICAS: A busca de evidências foi realizada nas bases de dados científicas: Medline (PUBMED), EMBASE, The Cochrane Library, Literatura Latino-americana e do Caribe em Ciências da Saúde (LILACS), Scopus e Web of Science. Foram 986 registros e ao final do processo de seleção de estudos, foram escolhidos três artigos científicos, sendo um estudo clínico randomizado multicêntrico e duas análises post-hoc da amostra original do estudo clínico randomizado multicêntrico citado anteriormente. De acordo com análise dos estudos incluídos, há evidência "baixa" favorável ao uso da tecnologia para o sucesso do tratamento em 12 semanas (RR: 1,67; IC95%: 1,25-2,24; p = 0,0006), sobrevida em 12 semanas (RR: 1,22; IC95%: 1,02-1,46; p = 0,03) e redução de efeitos adversos diretamente relacionados a droga (RR: 0,55; IC95%: 0,36-0,85; p = 0,008) quando comparada a Anfotericina B desoxicolato. Não houve diferença significativa em relação ao tempo de internação hospitalar e internação na UTI. Porém, deve ser salientado que não foram encontrados estudos comparando diretamente o voriconazol e formulações lipídicas da anfotericina B (anfotericina B lipossomal ou complexo lipídico de anfotericina B). Em uma revisão sistemática com metanálise, a eficácia do desoxicolato de anfotericina B e das formulações à base de lipídios foi semelhante. Não há estudo clínico randomizado com amostra grande do complexo lipiÌdico de anfotericina B. EVIDÊNCIAS ECONÔMICAS: Foi conduzida avaliação econômica do tipo árvore de decisão, com horizonte temporal de doze semanas. Considerou-se como desfechos primários de efetividade: sobrevivência ao final do tratamento e sucesso terapêutico como medidas de efetividade. A análise de custo-efetividade mostrou que voriconazol é custo-efetivo, dominando todas alternativas. A análise de sensibilidade determinística não produziu alterações nas conclusões. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) foi realizada para um horizonte temporal de cinco anos. Para a pergunta 1 de pesquisa, a incorporação de voriconazol teria um custo adicional de aproximadamente 198 milhões de reais. Estimou-se também o impacto orçamentário de 100% de voriconazol no tratamento farmacológico de pacientes com aspergilose invasiva. Nesse contexto, ocorreria uma economia da ordem de 83 milhões para a substituição do CLAB pelo voriconazol e de 144 milhões para substituição o ABD pelo voriconazol, em cinco anos. RECOMENDAÇÕES INTERNACIONAIS: Foi realizada busca por recomendações de uso do voriconazol em instituições e agências de ATS. Não foi identificada recomendação do NICE para a tecnologia. CADTH emitiu uma recomendação de reembolso em 2004. SMC e TGA recomendam o uso da tecnologia para o tratamento de pacientes com aspergilose invasiva. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foi detectada uma tecnologia para compor o esquema terapêutico da candidíase invasiva. CONSIDERAÇÕES FINAIS: Foi identificada evidência baixa ou muito baixa de benefício no uso da tecnologia para o sucesso do tratamento, sobrevida em 12 semanas e redução de efeitos adversos diretamente relacionados a droga. Porém, deve ser salientado que não foram encontrados estudos comparando diretamente o voriconazol e formulações lipídicas da anfotericina B (anfotericina B lipossomal ou complexo lipídico de anfotericina B). Dadas as evidências apresentadas, o uso de voriconazol tem potencial custo-efetivo para o tratamento da aspergilose invasiva. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 107ª Reunião Ordinária da Conitec, no dia 06 de abril de 2022, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação de voriconazol para tratamento de pacientes com aspergilose invasiva. Dentre as justificativas para a recomendação, considerou-se a tecnologia custo-efetiva e que, de acordo com uma certeza de evidência baixa, resulta em maior no sucesso do tratamento, sobrevida em 12 semanas e redução de efeitos adversos diretamente relacionados a droga. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública no 29/2022 foi realizada entre os dias 29/04/2022 a 18/05/2022. Foram recebidas 11 contribuições, sendo quatro pelo formulário para contribuições técnico-científicas e sete pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. As contribuições foram recebidas na consulta pública foram todas a favor da recomendação preliminar da Conitec que recomendava a recomendar a incorporação da anidulafungina. As argumentações destacaram os benefícios clínicos que o medicamento oferece com base em evidências já apresentadas na discussão inicial do tema e reitera que o medicamento se trata de opção terapêutica com melhor eficácia do que as opções de tratamento atualmente disponíveis no SUS, levando a maior sobrevida e menor incidência de efeitos colaterais. Não foram adicionadas na CP referências que alterassem a análise das evidências científicas e econômicas apresentadas no relatório preliminar de recomendação. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário presentes na 109ª reunião ordinária da Conitec, no dia 09 de junho de 2022, deliberaram, por unanimidade, recomendar a incorporação, no SUS, do voriconazol para tratamento de pacientes com aspergilose invasiva. Não foram adicionadas na consulta pública referências que alterassem a recomendação preliminar. Foi assinado o Registro de Deliberação nº741/2022. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, o voriconazol para tratamento de pacientes com aspergilose invasiva conforme a Portaria nº 59, publicada no Diário Oficial da União nº 142, seção 1, página 130, em 28 de julho de 2022.
Asunto(s)
Humanos , Aspergilosis/tratamiento farmacológico , Voriconazol/uso terapéutico , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economíaRESUMEN
BACKGROUND: The prevalence of pulmonary aspergillosis and the importance of its early diagnosis are recognized. However, non-pulmonary involvement, including the sinuses region, is not frequently reported, and an infection in this area can affect all paranasal sinuses (pansinusopathy), being a rare pathology that affects immunocompromised hosts. Recent studies have highlighted the occurrence of Aspergillus flavus resistant to antifungal therapy. Therefore, a nasal sinus infection by resistant Aspergillus strains in immunocompromised patients may be linked to a high risk of lethality. CASE REPORT: We are reporting a resistant A. flavus infection in an allogeneic hematopoietic stem cell transplant recipient with episodes of febrile neutropenia, and prolonged use of various antibacterial drugs and antifungal prophylaxis. The patient underwent brain magnetic resonance, which showed the presence of pansinusopathy, and presented necrosis in the left nasal region. Direct microscopic examination of a sample taken from the nasal mucosa revealed the presence of septate hyphae and conidiophores resembling those of A. flavus, that species being the identification achieved with MALDI-TOF MS. Antifungigram was performed by microdilution in broth (EUCAST-E.DEF. 9.3.2) and E-test, and resistance to amphotericin B was shown in both tests. The patient died after septic shock and hemorrhage. CONCLUSIONS: Invasive fungal infections due to amphotericin-B resistant A. flavus may lead to the death of the patient due to an ineffective therapeutic management. Therefore, antifungal susceptibility testing are of utmost importance for administering the proper treatment.