[Individualized antifungal therapy in critically ill patients with invasive fungal infection]. / Tratamiento antifúngico individualizado en el paciente crítico con infección fúngica invasora.

Invasive candidiasis (IC) is the most common invasive fungal infection (IFI) affecting critically ill patients, followed by invasive pulmonary aspergillosis (IPA). International guidelines provide different recommendations for a first-line antifungal therapy and, in most of them, echinocandins are considered the first-line treatment for IC, and triazoles are so for the treatment of IPA. However, liposomal amphotericinB (L-AmB) is still considered a second-line therapy for both clinical entities. Although in the last decade the management of IFI has improved, several controversies persist. The antifungal drugs currently available may have a suboptimal activity, or be wrongly used in certain IFI involving critically ill patients. The aim of this review is to analyze when to provide individualized antifungal therapy to critically ill patients suffering from IFI, emphasizing the role of L-AmB. Drug-drug interactions, the clinical status, infectious foci (peritoneal candidiasis is discussed), the fungal species involved, and the need of monitoring the concentration of the antifungal drug in the patient are considered.

Candidiasis invasora: un enfoque a la infección en el sistema nervioso central

Resumen La candidemia es la micosis invasora más frecuente en los pacientes internados en hospitales de alta complejidad en el mundo. La infección fúngica en el sistema nervioso central constituye una complicación potencialmente mortal que agrava el pronóstico de los pacientes. El presente artículo aborda aspectos relevantes sobre las características clínicas de esta enfermedad, los mecanismos de invasión del hongo, la respuesta inmunitaria local frente a Candida albicans y el impacto de los defectos genéticos en receptores de la inmunidad innata, que aumentan la susceptibilidad a la neurocandidiasis.

[Invasive candidiasis: A view to central nervous system infection]. / Candidiasis invasora: un enfoque a la infección en el sistema nervioso central.

Candidemia is the most frequent invasive mycosis in hospitalized patients worldwide. Fungal infection in central nervous system is a life-threatening complication which aggravates patients' prognosis. This article summarizes relevant aspects on the clinical characteristics of this pathology, mechanisms of fungus invasion, local immune response to Candida albicans and the impact of genetic defects on innate immune receptors that increase susceptibility to the acquisition of this form of mycosis.

Recent changes in candidemia trends in a tertiary hospital (2011-2018).

BACKGROUND: The epidemiology of candidemia has changed over the last decades and varies widely among geographic areas. AIMS: We examined in children (aged 0-14) with candidemia the trends in the incidence rate of this infection, as well as the clinical characteristics of the patients, in order to optimize the prognosis and the control measures of this serious disease. METHODS: A retrospective cohort study of candidemia in the period 2011-2018 in the neonatal intensive care unit (NICU), pediatric ICU (PICU) and pediatric wards of a tertiary hospital, was conducted. The clinical course, Candida species isolated, antifungal susceptibility, outcome and incidence rates were analyzed and compared. RESULTS: We diagnosed 68 episodes of candidemia in 62 children, 48% occurred in the NICU, 31% in the PICU and 21% in pediatric wards. Candida albicans was the most frequent species isolated in NICU infants (53%), and Candida parapsilosis predominated among PICU patients (59%) and pediatric wards (50%). One third of NICU infants had invasive candidiasis (IC), most of them having extremely low birth weight (ELBW) (35%). All isolates were susceptible to the antifungal administered. Over time, the incidence of candidemia decreased in the PICU (from 2.2 to 0.3 episodes/1000 patient-days, OR=0.6; 95%CI 0.5-0.8), whereas in the NICU and in the wards remained stable. Mortality occurred mostly in NICU patients (26%), predominated in ELBW infants and did not change over time. CONCLUSIONS: The higher incidence and mortality of candidemia and IC observed in preterm infants requires a continuous evaluation of practices and diagnostic methods which will allow improving the prognosis of this most vulnerable population.

Colombian consensus on the diagnosis, treatment, and prevention of Candida Spp. disease in children and adults, / Consenso Colombiano Para el Diagnóstico, Tratamiento y Prevención de la Enfermedad por Candida Spp. en Niños y Adultos

Invasive Candidiasis (IC) and candidemia (as its most frequent manifestation) have become the main cause of opportunistic mycosis at hospital settings. This study, made by members of the Colombian Association of Infectious Diseases (ACIN), was aimed at providing a set of recommendations for the management, follow-up and prevention of IC / candidemia and mucous membrane candida infection in adult, pediatric and neonatal patients in a hospital setting, including the hemato-oncological and critical care units. All the data obtained through an exhaustive search were reviewed and analyzed in a comprehensive manner by all the members of the group, and the recommendations issued are being made after a careful review of the scientific literature available and the consensus of all specialists involved; the emergence of Candida Spp. problem is highlighted and a correct orientation to health professionals regarding the management of patients with candidiasis is provided in a rational and practical way, emphasizing patient evaluation, diagnostic strategies, prophylaxis, empirical treatment, directed treatment and preventative therapy.

La Candidiasis Invasora (CI) y la candidemia, como su manifestación más frecuente, se ha convertido en la principal causa de micosis oportunista a nivel hospitalario. Este manuscrito realizado por miembros de la Asociación Colombiana de Infectología (ACIN), tuvo como objetivo proporcionar un conjunto de recomendaciones para manejo, seguimiento y prevención de la CI/candidemia y de la infección candidiásica de mucosas, en población adulta, pediátrica y neonatal, en un entorno hospitalario, incluyendo las unidades hemato-oncológicas y unidades de cuidado crítico. Todos los datos obtenidos mediante una búsqueda exhaustiva, fueron revisados y analizados de manera amplia por todos los miembros del grupo, y las recomendaciones emitidas se elaboraron luego de la evaluación de la literatura científica disponible, y el consenso de todos los especialistas involucrados, reconociendo el problema de la emergencia de las infecciones por Candida Spp. y brindando una correcta orientación a los profesionales de la salud sobre el manejo de pacientes con enfermedad candidiásica, de una forma racional y práctica, enfatizando en la evaluación del paciente, estrategias de diagnóstico, profilaxis, tratamiento empírico, tratamiento dirigido y terapia preventiva.

Anti-Candidaalbicans germ tube antibodies reduce in vitro growth and biofilm formation of C. albicans.

BACKGROUND: Invasive candidiasis by Candida albicans is associated with high morbidity and mortality, due in part to the late implementation of an appropriate antifungal therapy hindered by the lack of an early diagnosis. AIMS: We aimed to evaluate the in vitro antifungal activity of the antibodies against C. albicans germ tubes (CAGTA) raised in a rabbit model of candidemia. METHODS: We measured the effect of CAGTA activity by colorimetric XTT and crystal violet assays, and colony forming units count, both on C. albicans planktonic cells and during the course of biofilm formation and maturation. Viability and cell morphology were assessed by optical, fluorescent or scanning electron microscopy. RESULTS: CAGTA ≥50µg/ml caused a strong inhibition of C. albicans blastospores growth, and DiBAC fluorescent staining evidenced a fungicidal activity. Moreover, electron microscopy images revealed that CAGTA induced morphological alterations of the surface of C. albicans germ tubes grown free as well as in biofilm. Interestingly, CAGTA ≥80µg/ml reduced the amount of C. albicans biofilm, and this effect started at the initial adhesion stage of the biofilm formation, during the first 90min. CONCLUSIONS: This is the first report showing that CAGTA reduce C. albicans growth, and impair its metabolic activity and ability to form biofilm in vitro. The antigens recognized by CAGTA could be the basis for the development of immunization protocols that might protect against Candida infections.

[Microbiological diagnosis of invasive mycosis]. / Diagnóstico microbiológico de las micosis invasoras.

The prognosis of invasive fungal infections (IFI) depends on the speed of diagnosis and treatment. Conventional diagnostic methods are of low sensitivity, laborious and too slow, leading to the need for new, faster, and more efficient diagnostic strategies. There are several techniques for diagnosing a candidemia that are faster than the conventional blood culture (BC). Once yeast growth in BC is detected, species identification can be speeded up by mass spectrometry (30minutes), commercialised molecular techniques (60-80minutes) or fluorescent in situ hybridization (90minutes). The combined detection of biomarkers (antimicellium, mannan and anti-mannan or ß-glucan) has shown to be of greater use than their individual use. Commercialised nucleic acid amplification techniques (Septifast®, T2Candida®) are very reliable alternatives to BC. The detection of the capsular antigen of Cryptococcus, by means of latex agglutination or immuno-chromatography, is a valuable technique for cryptococcosis diagnosis. Direct microscopic examination and culture of representative specimens is used for the conventional diagnosis of IFI by filamentous fungi. Detection of galactomannan and ß-glucan are considered diagnostic criteria for probable invasive aspergillosis and probable IFI, respectively, despite the lack of specificity of the latter. The detection of fungal volatile organic compounds in breath is an interesting diagnostic strategy in pulmonary infections. Although widely used, nucleic acid detection techniques are not considered diagnostic criteria for IFIs caused by moulds in consensus documents, due to their lack of standardisation. However, they are the only alternative to culture methods in invasive infections by Scedosporium/Lomentospora, Fusarium, zygomycetes, or dematiaceous fungi.

T2 magnetic resonance for the diagnosis of deep-seated invasive candidiasis in a liver recipient without candidemia.

BACKGROUND: T2 magnetic resonance imaging (T2MR) is a new method for the diagnosis of invasive candidiasis, although most studies have analyzed its role in patients with candidemia or not infection. CASE REPORT: We present the case of a patient with arteritis and thrombosis of the hepatic graft resulted from an undocumented fungal infection in the explanted liver.T2MR in serum was a suitable diagnostic tool for the diagnosis of the deep-seated invasive candidiasis in the absence of candidemia or the isolation of the yeast in culture. CONCLUSIONS: T2MR allowed the diagnosis of deep-seated invasive candidiasis in an immunodepressed patient without candidemia, even before the onset of symptoms.

Evaluación del rendimiento de 1, 3-β -d-glucano como apoyo diagnóstico de infecciones invasoras por Candida spp. en pacientes críticos adultos / The 1,3-β -d-glucan in critical adult patients as diagnostic tool for invasive Candida spp. infection, performance evaluation

Resumen Introducción: La enfermedad fúngica invasora (EFI) se reconoce como causa importante de morbi-mortalidad en pacientes críticos. La mayoría de estas infecciones son provocadas por Candida spp. para cuyo diagnóstico existen importantes limitaciones. Objetivo: Realizar una evaluación inicial de la utilidad de la medición del 1,3-β-D- glucano (BDG) como herramienta diagnóstica de apoyo de las infecciones invasoras por Candida spp. en pacientes críticos. Pacientes y Método: Estudio prospectivo de pacientes mayores de 18 años hospitalizados en unidades de pacientes críticos por más de cinco días, con fiebre sin foco claro y dos o más factores de riesgo para EFI por Candida spp. Se obtuvieron muestras para BDG en dos días consecutivos. Los resultados se confrontaron con el diagnóstico definitivo de candidemia/candidiasis invasora (C/CI) demostrado según cultivos. Resultados: El valor promedio de BDG en los pacientes con diagnóstico de C/CI fue 224,3 ± 213,7 pg/ml y en aquellos sin C/CI 63,8 ± 76,7 pg/ml (p: 0,02). La sensibilidad y especificidad de BDG para diagnóstico de C/CI fue 60 y 92%, respectivamente. El valor predictor positivo fue 60% y el valor predictor negativo de 92%. Conclusión: BDG puede considerarse como un examen de apoyo en el diagnóstico de C/CI en pacientes críticos con factores de riesgo.

Background: Invasive fungal infections are important causes of morbimortality in critical patients. Most of these infections are caused by Candida spp. which diagnosis has important limitations. Aim: Initial evaluation of the utility of 1,3-β-D-glucan (BDG) as a diagnostic tool for invasive candida infections in critical patients. Patients and Methods: Adult patients over 18 years old, hospitalized in intensive care units for more than five days, with fever > 38 °C of unclear origin and two or more risk factors for invasive Candida spp. infection were included. Samples for BDG were obtained on two consecutive days. The results were compared with definitive diagnosis of candidemia/invasive candidiasis (C/IC) confirmed by cultures. Results: Median value of BDG in patients with C/IC was 224.3 ± 213.7 pg/ml and in patients without C/IC was 63.8 ± 76.7 pg/ml (p: 0.02). Sensitivity and specificity for the diagnosis of C/IC were 60 and 92%, respectively. Positive predictive value was 60% and negative predictive value was 92%. Conclusion: BDG could be considered as a complementary diagnostic tool for the diagnosis of C/IC in critical patients with risk factors.

[Update on invasive candidiasis in non-neutropenic critically ill adult patients]. / Puesta al día en la candidiasis invasora en el paciente crítico no neutropénico.

Invasive candidiasis in non-neutropenic critically ill patients remains a challenge for clinicians due to its association with high morbidity and mortality rates, increased incidence, and health-care costs. It is well known that early diagnosis and treatment are associated with a better prognosis. For these reasons a thorough update has been performed in this setting focused on recent Spanish epidemiology, new predictive scores and microbiological tests such as mannan antigen, mannan antibodies, Candida albicans germ-tube antibodies or (1→3)-ß-D-glucan detection, molecular techniques for the detection of fungal-specific DNA, advances in antifungal treatment and educational programs in Spain. An early diagnostic and therapeutic algorithm is proposed based on the combination of scores and microbiological test. The aim of this review is to provide physicians with the best information available in order to improve the prognosis of these patients.

[Invasive yeast infections in neutropenic patients]. / Enfermedades invasoras por hongos levaduriformes en pacientes neutropénicos.

Invasive fungal diseases caused by yeasts still play an important role in the morbidity and mortality in neutropenic patients with haematological malignancies. Although the overall incidence of invasive candidiasis has decreased due to widespread use of antifungal prophylaxis, the incidence of non-Candida albicans Candida species is increasing compared with that of C.albicans, and mortality of invasive candidiasis continues to be high. In addition, there has been an increase in invasive infections caused by an array of uncommon yeasts, including species of the genus Malassezia, Rhodotorula, Trichosporon and Saprochaete, characterised by their resistance to echinocandins and poor prognosis.

[Invasive yeast diseases in solid organ transplant recipients]. / Enfermedades invasoras por hongos levaduriformes en el receptor de un trasplante de órgano sólido.

Invasive yeast diseases are uncommon nowadays in solid organ transplant recipients. Invasive candidiasis (2%) usually presents during the first month after transplantation in patients with risk factors. Both common and transplant-specific risk factors have been identified, allowing very efficacious targeted prophylaxis strategies. The most common clinical presentations are fungaemia and local infections near the transplantation area. Cryptococcosis is usually a late infection. Its incidence remains stable and the specific risk factors have not been identified. When cryptococcosis is detected very early, transmission with the allograft should be considered. The most common clinical presentations include meningitis, pneumonia, and disseminated infection. Intracranial hypertension and immune reconstitution syndrome have to be considered. No therapeutic clinical trials have been conducted in solid organ transplant recipients, thus treatment recommendations are derived from data obtained from the general population. It is particularly important to consider the possibility of drug-drug interactions, mainly between azoles and calcineurin inhibitors. Both invasive candidiasis and cryptococcosis increase the mortality significantly in solid organ transplant recipients.

Formas lipídicas de anfotericina / Lipid formulations of amphotericin

Amphotericin B deoxycholate use has increased during the past years in parallel with the increase in the number of immunosuppressed patients suffering invasive fungal infections. This drug is associated with a high rate of side effects, especially renal toxicity. Lipid formulations (liposomal, lipid complex, colloidal suspension and the Indian liposomal formulation) have been developed, which share the same antifungal spectrum but differ in efficacy and toxicity. A review of amphotericin lipid formulations is presented, focusing on differences in efficacy and, especially renal toxicity. The main problem for use of these formulations in Latin America is their highcost.

Dado el aumento en el número de pacientes inmunosuprimidos en los últimos años, el uso de anfotericina B desoxicolato también se incrementó debido a una mayor incidencia de las infecciones fúngicas invasoras en esta población. Este medicamento tiene una alta frecuencia de efectos adversos, especialmente nefrotoxicidad. Se han desarrollado modificaciones de la presentación de anfotericina B con el desarrollo de formas lipídicas (liposomal, complejo lipídico, suspensión coloidal y fórmula liposomal procedente de la India) que tienen el mismo espectro y con variaciones en su efectividad y toxicidad. Se presenta una revisión de las formas lipídicas de anfotericina, sus diferencias en efectividad y, especialmente, nefrotoxicidad. El principal problema para su implementación en América Latina es el alto costo de estas presentaciones.

Susceptibilidad de candida spp, aislados de sangre, a fluconazol, voriconazol, anfotericina B, y caspofungina, por los métodos de microdilución en caldo (EUCAST) y el método de difusión en agar (ETEST) / Susceptibility of candida spp; blood isolates to fluconazole, voriconazole, amphotericin B, and caspofungin by broth microdilution methods (EUCAST) and the agar diffusion method (ETEST)

La Candidiasis invasora es una de las principales infecciones Nosocomiales. El desarrollo de los triazoles, inició el uso masivo de la profilaxis antifúngica y de la terapia empírica. Estas prácticas terapéuticas han generado cambios epidemiológicos, entre los que destacan la aparición de cepas que han desarrollado resistencia secundaria a los antifúngicos y la sustitución de algunas especies sensibles por otras con resistencia intrínseca. En este estudio se evaluaron 189 aisladas de sangre de la Red de Candidemia del INHRR determinando la Concentración Mínima Inhibitoria (CMI) a fluconazol, voriconazol, caspofungina y anfotericina b por los métodos Microdilución en caldo EUCAST y Etest, de cada una de las levaduras, siguiendo los procedimientos del método documento E. Dis. 7.1 del EUCAST y del fabricante. Se utilizaron las cepas C. parapsilosis ATCC 22019 y C. krusei ATCC 6258 como control de calidad. Los aislados fueron 89% sensibles para fluconazol por EUCAST y 87% por Etest, para voriconazol por ambos métodos 97% sensibles y para caspofungina y anfotericina B tasas muy bajas de resistencia se obtuvier. Se obtuvo una Concordancia del 94,8% y una Especificidad de 82,4%. Voriconazol 88,4% de Concordancia con unos límites de confianza de 82,9 a 92,5% y una Especificidad del 100%. Caspofungina se obtuvo un Concordancia de 98,4%y Sensibilidad del 100%. Se obtuvo una excelente concordancia entre los métodos evaluados, de manera que pueden ser utilizados indistintamente en la detección de susceptibilidad y/o resistencia antifúngica. Se determinaron puntos de corte epidemiológicos locales para fluconazol, voriconazol, caspofungina y anfotericina B en las especies de Candida frecuentemente aisladas mucho más sensible para detectar la posible emergencia de cepas resistente en nuestro medio.

Invasive candidiasis is a major nosocomial infections. With the development of the triazoles, began the widespread use of antifungal prophylaxis and empiric therapy, which has generated epidemiological changes. In this study, we evaluated 189 blood isolates from Network Candidemia INHRR of determining the minimum inhibitory concentration (MIC) to fluconazole, voriconazole, amphotericin B and caspofungin by EUCAST broth microdilution methods and ETEST. Strains were used C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 as quality control. The group was 16.4% C. albicans and 83.6% C no albicans. C. parapsilosis (48%) the most frequently isolated species. The susceptibility of the total was isolated by EUCAST and Etest of 89/87% 97/97%, m99.5/98% 98/99% to fluconazole, voriconazole, amphotericin B and caspofungin respectively. General resistance to fluconazole was 9% and 11% EUCAST Etest for voriconazole amphotericin B, and caspofungin resistance did not exceed 4% of the total. Were determined epidemiological cutoff value (ECV) local to fluconazole, voriconazole, caspofungin and amphotericin B for C. albicans, C. parapsilosis and C. tropicalis which accounted for 89% of the total. The ECV is more sensitive to detect the possible emergence of resistant strains in our setting. The agreement obtained for the 4 antifungal was between 97.4 and 100% with a sensitivity of 95.9 to 100%. The data obtained are recommended ETEST for their sensitivity and consistency with respect to the reference method proving to be even more effective in detecting resistance. With the support of our local data allow the clinician to establish early and adequate therapy to finally benefit the patient.

Perfil epidemiológico de la candidiasis invasora en unidades de pacientes críticos en un hospital universitario / Epidemiologial profile of invasive candidiasis in intensive care units at a university hospital

Invasive candidiasis (IC) epidemiology has changed in critically ill patients and limited data are available in Chile. Objective: To describe the epidemiological and microbiological profile of IC in critically ill patients. Methods: Observational prospective study conducted from October 2001 to August 2003 in critically ill adults with suspected or confirmed IC. Results: 53 patients met criteria for IC, finding 18 (33.9 percent) candidemias, 22 (41.5 percent) disseminated IC, and 13 (24.5 percent) local IC. We identified 8 (44.4 percent) C. albicans and 10 (55.6 percent) non-albicans Candida in candidemias. C. tropicalis was the predominant non-albicans species (27.7 percent). An 88.8 percent of Candidas sp recovered in candidemias were fluconazole susceptible. Overall hospital mortality was 24.5 percent. Mortality in candidemia was significantly lower than in disseminated IC (16.6 vs 31.8 percent, p = 0.02). Conclusions: A higher proportion of non-albicans Candida was observed in candidemias from critically ill patients. However, most of these strains were fluconazole susceptible. A lower overall mortality was observed in candidemias.

La epidemiología de candidiasis invasora (CI) ha cambiado, lo cual no ha sido suficientemente estudiado en Chile. Objetivo: Describir el perfil epidemiológico y microbiológico de CI en pacientes críticos. Métodos: Estudio observacional prospectivo entre octubre 2001 y agosto 2003, en pacientes críticos adultos con sospecha o confimnación de CI. Resultados: 53 pacientes cumplieron criterios de CI. De ellos, 18 (33,9 por ciento) tuvieron candidemia, 22(41,5 por ciento) CI diseminada y 13(24,5 por ciento) CI local. Entre las candidemias, hubo 8 C. albicans (44,4 por ciento) y 10 Candida no albicans (55,6 por ciento), predominando C. tropicalis (27,7 por ciento). Un 88,8 por ciento de las candidemias fueron susceptibles a fluconazol. La mortalidad hospitalaria global fue 24,5 por ciento, significativamente menor en pacientes con candidemias vs CI diseminada (16,6 vs 31,8 por ciento, p = 0,02). Conclusiones: Se observó una mayor proporción de Candida no albicans en candidemias de pacientes críticos. Sin embargo, la mayoría de estas cepas fue susceptible a fluconazol. La mortalidad global fue menor en candidemias.