Antifungal resistance: why are we losing this battle?

The emergence of fungal pathogens and changes in the epidemiological landscape are prevalent issues in clinical mycology. Reports of resistance to antifungals have been reported. This review aims to evaluate molecular and nonmolecular mechanisms related to antifungal resistance. Mutations in the ERG genes and overexpression of the efflux pump (MDR1, CDR1 and CDR2 genes) were the most reported molecular mechanisms of resistance in clinical isolates, mainly related to Azoles. For echinocandins, a molecular mechanism described was mutation in the FSK genes. Furthermore, nonmolecular virulence factors contributed to therapeutic failure, such as biofilm formation and selective pressure due to previous exposure to antifungals. Thus, there are many public health challenges in treating fungal infections.

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Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Ebselen improves fungal keratitis through exerting anti-inflammation, anti-oxidative stress, and antifungal effects.

Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on Aspergillus fumigatus (A. fumigatus), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1ß, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.

Searching for Conjugates as New Structures for Antifungal Therapies.

The progressive increase in fungal infections and the decrease in the effectiveness of current therapy explain research on new drugs. The synthesis of compounds with proven antifungal activity, favorable physicochemical and pharmacokinetic properties affecting their pharmaceutical availability and bioavailability, and limiting or eliminating side effects has become the goal of many studies. The publication describes the directions of searching for new compounds with antifungal activity, focusing on conjugates. The described modifications include, among others, azoles or amphotericin B in combination with fatty acids, polysaccharides, proteins, and synthetic polymers. The benefits of these combinations in terms of activity, mechanism of action, and bioavailability were indicated. The possibilities of creating or using nanoparticles, "umbrella" conjugates, siderophores (iron-chelating compounds), and monoclonal antibodies were also presented. Taking into account the role of vaccinations in prevention, the scope of research related to developing a vaccine protecting against fungal infections was also indicated.

COVID-19 associated candidemia: From a shift in fungal epidemiology to a rise in azole drug resistance.

Our understanding of fungal epidemiology and the burden of antifungal drug resistance in COVID-19-associated candidemia (CAC) patients is limited. Therefore, we conducted a retrospective multicenter study in Iran to explore clinical and microbiological profiles of CAC patients. Yeast isolated from blood, were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and subjected to antifungal susceptibility testing (AFST) using the broth microdilution method M27-A3 protocol. A total of 0.6% of the COVID-19 patients acquired CAC (43/6174). Fluconazole was the most widely used antifungal, and 37% of patients were not treated. Contrary to historic candidemia patients, Candida albicans and C. tropicalis were the most common species. In vitro resistance was high and only noted for azoles; 50%, 20%, and 13.6% of patients were infected with azole-non-susceptible (ANS) C. tropicalis, C. parapsilosis, and C. albicans isolates, respectively. ERG11 mutations conferring azole resistance were detected for C. parapsilosis isolates (Y132F), recovered from an azole-naïve patient. Our study revealed an unprecedented rise in ANS Candida isolates, including the first C. parapsilosis isolate carrying Y132F, among CAC patients in Iran, which potentially threatens the efficacy of fluconazole, the most widely used drug in our centers. Considering the high mortality rate and 37% of untreated CAC cases, our study underscores the importance of infection control strategies and antifungal stewardship to minimize the emergence of ANS Candida isolates during COVID-19.

[Antimicrobial peptides: A new alternative for the treatment of aspergillosis]. / Peptides antimicrobiens : une nouvelle alternative pour le traitement des aspergilloses.

Aspergillus fumigatus is the predominant fungal species causing pulmonary aspergillosis. The present-day anti-aspergillosis arsenal is limited, with a number of molecules occasioning severe side effects (amphotericin B) or provoking significant drug interactions (azole derivatives). Moreover, the recent emergence of azole-resistant A. fumigatus strains is a cause for concern. In this context, antimicrobial peptides (AMPs) are emerging as a promising therapeutic approach and alternative or complement to conventional antifungals.

Clinical evaluation of antifungal de-escalation in Candida infections: A systematic review and meta-analysis.

OBJECTIVES: De-escalation (DES) from echinocandins to azoles is recommended by several medical societies in Candida infections. We summarise the evidence of DES on clinical and microbiological cure and 30-day survival and compare it with continuing the treatment with echinocandins (non-DES). METHODS: We searched MEDLINE, Embase, Web of Science and Scopus. Studies describing DES in inpatients and reporting any of the outcomes evaluated were included. Pooled estimates of the tree outcomes were calculated with a fixed or random-effects model. Heterogeneity was explored stratifying by subgroups and via meta-regression. This systematic review is registered with PROSPERO (CRD42023475486). RESULTS: Of 1853 records identified, 9 studies were included, totalling 1575 patients. Five studies stepped-down to fluconazole; one to voriconazole and three to any of azoles. The mean day of DES was 5.2 (4.6-6.5) days. The clinical cure OR was 1.29 (95% CI: 0.88-1.88); the microbiological cure 1.62 (95% CI: 0.71-3.71); and 30-day survival 2.17 (95% CI: 1.09-4.32). The 30-day survival data into subgroups showed higher effect on critically ill patients and serious-risk bias studies. Meta-regression did not identify significant effect modifiers. CONCLUSIONS: DES is a safe strategy; it showed no higher 30-day mortality and a trend towards greater clinical and microbiological cure.

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Antifungal Therapies for Aspergillus spp.: Present and Future.

Currently available and recommended options for the treatment of pulmonary aspergillosis include the triazoles, echinocandins, and amphotericin B products. These therapies have significant limitations. Only the azoles are available orally, but their use is often limited by toxicities, drug-drug interactions, pharmacokinetic variability, and emerging resistance. While the echinocandins are safe agents and may have a role in combination therapy, they are unproven as monotherapy. Amphotericin B preparations are toxic and require intensive monitoring. Finally, aspergillosis continues to be a disease conferring substantial morbidity and mortality, and clinical trials have not identified a therapeutic approach clearly associated with improved outcomes. As a result, there is a great need for new options in the treatment of invasive aspergillosis. Ideally, such options would be safe, have high oral bioavailability, have favorable pharmacokinetics to sequestered sites and retain activity against azole-resistant isolates. Reassuringly, there is a robust pipeline of novel therapies in development. Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same mechanism of action as echinocandins) will likely be reserved for combination therapy or refractory/intolerance scenarios with no other options. Inhaled opelconazole is an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis. Development of an oral form of amphotericin B that avoids nephrotoxicity and electrolyte disturbances is an exciting development. Finally, olorofim and fosmanogepix, two agents with novel mechanisms of action and oral formulations, hold significant potential to challenge the triazole antifungals place as preferred therapies. However, many questions remain regarding these novel agents, and at the time of this writing, none of these agents have been robustly studied in Phase III studies of aspergillosis, and so their promise remains investigational.

Chronic Pulmonary Aspergillosis: Clinical Presentation and Management.

Chronic pulmonary aspergillosis (CPA) refers to a number of clinical syndromes resulting from the presence and local proliferation of Aspergillus organisms in the lungs of patients with chronic lung disease. CPA is more common than was realized two decades ago. Recognition remains poor, despite recent studies from many countries highlighting the high prevalence in at-risk populations. In low- and middle-income countries, CPA may be misdiagnosed and treated as tuberculosis (TB). In addition, CPA may develop following successful TB treatment. The coronavirus disease pandemic has resulted in significant disruption to provision of TB care, likely leading to more extensive lung damage, which could increase the risk for CPA.Although CPA refers to various syndromes, the classic presentation is that of chronic cavitary pulmonary aspergillosis, which manifests as one or more progressive cavities with or without a fungal ball, accompanied by systemic and respiratory symptoms for at least 3 months. Diagnosis relies on Aspergillus immunoglobulin G in serum, as sputum culture lacks sensitivity. Differential diagnosis includes mycobacterial infection, bacterial lung abscess or necrotizing pneumonia, lung cancer, and endemic fungi.The aim of antifungal treatment in CPA is to improve symptoms and quality of life, and to halt progression, and possibly reverse radiological changes. Current recommendations suggest treatment for 6 months, although in practice many patients remain on long-term treatment. Improvement may manifest as weight gain and improvement of symptoms such as productive cough, hemoptysis, and fatigue. Surgical management should be considered in cases of diagnostic uncertainty, in significant hemoptysis, and when there is concern for lack of response to therapy. Itraconazole and voriconazole are the first-line azoles, with more experience now accumulating with posaconazole and isavuconazole. Side effects are frequent and careful monitoring including therapeutic drug monitoring is essential. Intravenous antifungals such as echinocandins and amphotericin B are used in cases of azole intolerance or resistance, which often develop on treatment. Relapse is seen after completion of antifungal therapy in around 20% of cases, mostly in bilateral, high-burden disease.Several research priorities have been identified, including characterization of immune defects and genetic variants linked to CPA, pathogenetic mechanisms of Aspergillus adaptation in the lung environment, the contribution of non-fumigatus Aspergillus species, and the role of new antifungal agents, immunotherapy, and combination therapy.

Seroprevalencia y transmisión vertical de enfermedad de Chagas en una cohorte de gestantes latinoamericanas en un hospital terciario de Madrid / Seroprevalence and vertical transmission of Chagas disease in a cohort of Latin-american pregnant women in a tertiary hospital in Madrid

Introducción: La enfermedad de Chagas, causada por Trypanosoma cruzi (T. cruzi), es endémica en Latinoamérica y emergente en España, ligada a inmigración. La transmisión vertical se estima de alrededor del 5%. Se recomienda cribado selectivo en el embarazo para identificar al recién nacido infectado, permitiendo tratamiento precoz y curación de la enfermedad. Objetivo: El objetivo de este estudio fue estimar la prevalencia de serología positiva para T. cruzi en una cohorte de gestantes latinoamericanas y la tasa de transmisión vertical de la misma. Pacientes y métodos: Estudio observacional prospectivo de gestantes con serología positiva para T. cruzi en hospital terciario, desde enero del 2013 hasta abril del 2015. El seguimiento de recién nacidos se realizó con PCR al nacimiento, repetida al mes, y serología a los 9-12 meses. Se consideró infectado al niño con PCR positiva y no infectado al niño con PCR negativa y/o negativización de anticuerpos. Resultados: Se realizó cribado en 1.244 gestantes latinoamericanas, siendo positivas 40 (prevalencia 3,2%, IC del 95%: 2,4-4,4%), 85% procedentes de Bolivia. Solo un niño resultó infectado (transmisión vertical 2,8%, IC del 95%: 0-15%) con PCR positiva al nacimiento. La detección de la embarazada permitió estudiar a los hermanos, detectándose caso asintomático en paciente de 8 años. Ambos tratados con benznidazol con buena tolerancia, evolución favorable y negativización de PCR y anticuerpos. Conclusión: El cribado de embarazadas latinoamericanas ha permitido la detección de gestantes con enfermedad de Chagas. La transmisión vertical fue del 2,3%, coincidente con la literatura. El cribado ha permitido la detección y el tratamiento de casos familiares no identificados previamente (AU)

Background: Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is endemic in Latin-America and is emerging in Spain due to immigration. The vertical transmission rate is around 5%. A routine prenatal screening with serology of all pregnant women from endemic areas is recommended to identify infected newborns, allowing early treatment and cure. Objective: The aim of this study was to estimate the prevalence of positive Chagas serology in a cohort of pregnant women from Latin-America and its vertical transmission. Patients and methods: An observational, prospective, follow-up study was conducted on women with positive serology to T. cruzi, as well as their newborns, from January 2013 to April 2015. Congenital Chagas was ruled out using a PCR technique at birth and at 1 month, and with serology at 9-12 months old. A child was considered infected when PCR was positive, and uninfected when PCR was negative, and/or it had a negative serology. Results: Screening was performed on 1244 pregnant women from Latin-America, and there were positive results in 40 (prevalence 3.2%, 95% CI: 2.4-4.4%), with 85% of them from Bolivia. There was only one infected newborn (rate of vertical transmission 2.8% (95% CI: 0-15%)), who had a positive PCR at birth. Relative studies enabled an 8-year-old sister with an asymptomatic disease to be diagnosed and treated. Both were treated successfully with benznidazole (later the PCR and serology were negative). Conclusion: Screening during pregnancy in Latin-American women helped to detect those with Chagas disease. The rate of vertical transmission was 2.8%, in keeping with literature. Screening led to the detection and treatment of previously unidentified familial cases (AU)

Characterisation of an ABC transporter of a resistant Candida glabrata clinical isolate

BACKGROUND Candida glabrata ranks second in epidemiological surveillance studies, and is considered one of the main human yeast pathogens. Treatment of Candida infections represents a contemporary public health problem due to the limited availability of an antifungal arsenal, toxicity effects and increasing cases of resistance. C. glabrata presents intrinsic fluconazole resistance and is a significant concern in clinical practice and in hospital environments. OBJECTIVE The aim of this study was to characterise the azole resistance mechanism presented by a C. glabrata clinical isolate from a Brazilian university hospital. METHODS Azole susceptibility assays, chemosensitisation, flow cytometry and mass spectrometry were performed. FINDINGS Our study demonstrated extremely high resistance to all azoles tested: fluconazole, voriconazole, posaconazole and itraconazole. This isolate was chemosensitised by FK506, a classical inhibitor of ABC transporters related to azole resistance, and Rhodamine 6G extrusion was observed. A mass spectrometry assay confirmed the ABC protein identification suggesting the probable role of efflux pumps in this resistance phenotype. MAIN CONCLUSIONS This study emphasizes the importance of ABC proteins and their relation to the resistance mechanism in hospital environments and they may be an important target for the development of compounds able to unsettle drug extrusion.

Delphi-based study and analysis of key risk factors for invasive fungal infection in haematological patients / Análisis de los factores de riesgo clave para infecciones fúngicas invasoras en pacientes onco-hematológicos: estudio Delphi

Introduction. Mortality caused by invasive fungal infections due to filamentous fungi (IFI-FF) is high. Predisposing factors to IFI-FF are multiple and should be stratified. The objective of this study was to identify key risk factors for IFI-FF in onco-haematological patients in different clinical settings. Methods. Prospective national Delphi study. Risk factors for IFI-FF in patients with onco-haematological diseases were identified by a systematic review of the literature. An anonymous survey was sent by e-mail to a panel of experts. A key risk factor was defined when at least 70% of the surveyed participants assigned a 'maximal' or 'high' risk. Results. In allogenic stem cell transplantation, 18 of the 42 risk factors analyzed were classified as key risk factors, including neutropenia, previous IFI-FF, grade III/IV acute or extensive chronic graft-versus-host disease (GVHD), umbilical cord blood transplantation, HLA mismatching transplantation, graft failure, absence of HEPA filters, absence of laminar air flow, diagnosis of acute myeloid leukaemia, haploidentical transplantation, anti-TNF-α drugs, alemtuzumab, anti-thymocyte globulin, immunosuppressive prophylaxis for GVHD, lymphocytopenia, cytomegalovirus infection, and proximity to construction areas. In acute leukaemia/myelodysplastic syndrome (AL/MDS), 7 of 25 risk factors were defined as key risk factors, including neutropenia, consolidation therapy without response, induction therapy, antifungal prophylaxis with azoles, proximity to construction areas, and absence of HEPA filters. In lymphoma/ multiple myeloma (MM), the five key risk factors among 21 analyzed were use of steroids, neutropenia, progressive disease, anti-CD52 therapies, and proximity to construction areas. Conclusions. The Delphi method was useful for the classification and stratification of risk factors for IFI-FF in patients with onco-haematological diseases. Identifying key risk factors will contribute to a better management of IFI-FF in this group of patients at high or changing risk (AU)

Introducción. La mortalidad por infecciones fúngicas invasoras por hongos filamentosos (IFI-HF) es elevada. Los factores predisponentes de IFI-HF son múltiples y deben ser estratificados. El objetivo de este estudio fue identificar factores de riesgo clave para IFI-HF en pacientes oncohematológicos en diversos contextos clínicos. Métodos. Estudio Delphi, nacional y prospectivo. Mediante revisión sistemática de la literatura se identificaron los factores de riesgo de IFI-HF en pacientes con patología onco-hematológica. Se envió por correo electrónico una encuesta anónima a un panel de expertos. Se definió factor de riesgo clave cuando al menos el 70% de los encuestados le asignaba un riesgo 'máximo' o 'alto'. Resultados. Los factores de riesgo considerados clave fueron: en trasplante alogénico de progenitores hematopoyéticos 18/42 analizados (neutropenia, IFI-HF previa, enfermedad injerto contra huésped aguda III-IV o crónica extensa, trasplante de cordón umbilical, trasplante HLA incompatible, fracaso del injerto, ausencia filtros HEPA, ausencia flujo laminar, diagnóstico de leucemia aguda mieloblástica, trasplante haploidéntico, antiTNF-α, alemtuzumab, globulina antitimocítica, profilaxis inmunosupresora para enfermedad injerto contra huésped, linfocitopenia, citomegalovirus y proximidad a construcciones). En LA/SMD 7/25 (neutropenia, consolidación sin respuesta, IFI-HF previa, inducción, profilaxis con 'azoles', proximidad a construcciones y ausencia filtros HEPA). En linfoma/MM 5/21 analizados (esteroides, neutropenia, enfermedad en progresión, terapias anti-CD52 y proximidad a construcciones). Conclusiones. El método Delphi ha demostrado ser útil para clasificar los factores de riesgo de IFI-HF en pacientes con patología onco-hematológica. La identificación de factores de riesgo clave permitirá adecuar el manejo de IFI-HF en este grupo de pacientes con riesgo alto o cambiante (AU)

First itraconazole resistant Aspergillus fumigatus clinical isolate harbouring a G54E substitution in Cyp51Ap in South America / Primer aislamiento clínico en Sudamérica de una cepa de Aspergillus fumigatus resistente a itraconazol con la sustitución G54E en Cyp51Ap

Background. A 27-year-old male rural worker was admitted with a fungal keratitis due to an injury involving plant detritus. Materials and methods. Specimens were collected for microscopy examination and culture. The isolate was identified by morphological and molecular criteria. Susceptibility testing was performed using CLSI methods. CYP51A gene was PCR amplified and sequenced. Results. An Aspergillus fumigatus strain resistant to itraconazole (MIC>8μg/ml) was isolated. The isolate was susceptible to amphotericin B, posaconazole, voriconazole and caspofungin. CYP51A sequencing showed two mutations leading on the G54E substitution. The patient received natamycin as treatment. Conclusions. This is the first report in South America of a clinical A. fumigatus strain carrying the substitution G54E at Cyp51Ap associated with itraconazole resistance. Considering the patient was azole-naive, this resistant isolate may have been acquired from the environment (AU)

Antecedentes. Un trabajador rural de 27años de edad fue hospitalizado con una queratitis fúngica debido a un traumatismo con un resto vegetal. Materiales y métodos. Se tomaron las muestras para los exámenes de microscopía y cultivo. El aislamiento se identificó mediante criterios morfológicos y moleculares. Se realizaron pruebas de sensibilidad a los antifúngicos siguiendo el documento del CLSI. Se amplificó y secuenció el gen CYP51A de la cepa. Resultados. Se aisló una cepa de Aspergillus fumigatus resistente a itraconazol (CIM>8μg/ml). El aislamiento resultó sensible a la anfotericina B, el posaconazol, el voriconazol y la caspofungina. La secuenciación del gen CYP51 reveló 2 mutaciones que generan la sustitución G54E. El paciente fue tratado con natamicina oftálmica. Conclusiones. Este es el primer caso informado en Sudamérica de una cepa clínica de A. fumigatus con la sustitución G54E en el Cyp51Ap, asociada con resistencia al itraconazol. Teniendo en cuenta que el paciente no había recibido nunca antes tratamiento alguno con azoles, podría haber adquirido esta cepa resistente del ambiente (AU)

Antifungal pharmacodynamics: Latin America's perspective

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

Rinosinusitis fúngica no invasiva producida por micetomas. Presentación de 2 casos y revisión de la literatura / Non-invasive fungal rhinosinusitis produced by mycetomas. Presentation of 2 cases and a review of the literature

La invasión de los senos paranasales por hongos o rinosinusitis fúngica es una enfermedad relativamente infrecuente que puede manifestarse como distintos cuadros clínicos, en función de la agresividad del microorganismo causante, la edad y las enfermedades asociadas del paciente. Presentamos 2 casos de rinosinusitis fúngica no invasiva en pacientes inmunocompetentes, donde se observan imágenes radiológicas de bolas fúngicas intrasinusales de una inusual radioopacidad metálica. Realizamos una revisión de la literatura de las rinosinusitis fúngicas, con el objetivo de actualizar la terminología y clasificación de estos cuadros y revisamos la descripción de las bolas fúngicas intrasinusales (AU)

The invasion of the paranasal sinuses by fungi, or fungal rhinosinusitis, is a relatively uncommon disorder that may present as different clinical pictures depending on the aggressiveness of the microorganism responsible, age and other illnesses associated with the patient. Two cases are presented on two immunocompetent patients with non-invasive fungal rhinosinusitis, in whom sinus fungal balls of unusual metallic radio-opacity were observed in the X-ray images. A literature review was performed on fungal rhinosinusitis, with the aim of updating the terminology and classification of these clinical pictures, as well as a review on the description of sinus fungal balls (AU)

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

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

Eficacia y seguridad de posaconazol en pacientes adultos con mucormicosis y respuesta inadecuada o eventos adversos al uso de amfotericina B / Efficacy and safety of posaconazole in adult patients with mucormycosis and inadequate response or adverse events to the use of amphotericin B

INTRODUCCIÓN: El presente dictamen presenta la evaluación de tecnología de la eficacia y seguridad de posaconazol en pacientes adultos con mucormicosis con reacción adversa secundaria al uso de amfotericina deoxicolato (Cualquier RAM III - IV) o refractariedad. La mucormicosis es una Infección oportunista poco frecuente y potencialmente letal, causada por hongos pertenecientes al orden Mucorales. Su distribución es mundial y afecta fundamentalmente a individuos con inmunidad alterada en quienes puede ocasionar infecciones graves e incluso mortales, de presentación fulminante o lenta e insidiosa, por lo que se le considera una de las infecciones micóticas más letales en seres humanos. Al ser una enfermedad de alta mortalidad aún con los pacientes en tratamiento y ser una infección de muy baja prevalencia, existe muy escasa evidencia de calidad que respalde el tratamiento de mucormicosis con diferentes esquemas. El tratamiento actual se encuentra basado en Amfotericina B, sin embargo para los pacientes que presentan falla al tratamiento o que son intolerantes por eventos adversos, no existe una segunda línea definida. Es así, que en los últimos años posaconazol ha sido descrito como un medicamento de segunda línea de tratamiento para pacientes con mucromicosis refractarios a amfotericina B o con toxicidad por la misma. Así, la presente evaluación tiene el objetivo de analizar la evidencia que apoya el uso de posaconazol como segunda línea de tratamiento para mucormicosis en casos en los que no se tiene una adecuada respuesta a la primera línea de tratamiento. METODOLOGIA: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de posaconazol en pacientes adultos con mucormicosis (zygomicosis) y con respuesta inadecuada (eventos adversos que no permitan continuar con la terapia o falla al tratamiento) a amfotericina. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guideline Clearinghouse (NGC), y Health Systems Evidence (HSE). Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov, para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Tras la búsqueda bibliográfica se encontraron documentos que evaluaron la eficacia y seguridad de posaconazol con respecto a la eficacia y seguridad en pacientes adultos con mucormicosis y con respuesta inadecuada a amfotericina deoxicolato. CONCLUSIONES: En la presente evaluación de tecnología sanitaria no se ha encontrado evidencia directa de calidad que muestre que el posaconazol ofrece beneficios para los pacientes con diagnóstico de mucormicosis con eventos adversos serios al uso de Amfotericina B deoxicolato (AMB). Sin embargo, se ha identificado evidencia indirecta proveniente de revisiones de casos en las cuales el uso de posaconazol como terapia de rescate en mucormicosis ha sido beneficioso para los pacientes que no pueden recibir amfotericina y que no tienen más opción de tratamiento. Al ser la mucormicosis una infección que viene incrementando su incidencia en los últimos años, y además con una alta letalidad, es importante contar con herramientas para su rápido diagnostico y tratamiento. Los estudios presentados si bien no son de una alta calidad debido a la baja prevalencia de la enfermedad, posicionan a posaconazol como un tratamiento de rescate para pacientes con Mucormicosis que no tengan indicación para recibir o a continuar con terapia con Amfotericina deoxicolato debido a intolerancia al tratamiento o a eventos adversos al mismo. El costo y la via de administración podrían ser de beneficio para la elección del tratamiento de los pacientes con mucormicosis que en muchos casos son pacientes que cuentan con enfermedades o tratamientos de fondo que implican inmunidad comprometida. Además, en estos pacientes incrementar las vías de acceso endovenosa siempre significa un riesgo agregado de infecciones. Los especialistas infectólogos opinan que el uso de posaconazol en mucormicosis refractaria o con eventos adversos a amfotericina constituiría la única alternativa terapéutica disponible para los pacientes con dicho diagnóstico y en los que el anfotericina B no constituye más una alternativa por falta de respuesta, intolerancia o efectos adversos. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación - IETSI, aprueba, el uso de posaconazol para el manejo de los pacientes con diagnóstico de mucormicosis que hayan presentado eventos adversos o sean refractarios o intolerantes al uso de Amfotericina B Deoxicolato, según lo establecido en el Anexo 1. La vigencia del presente dictamen preliminar es de dos años. Dado que la evidencia que respalda este uso de posaconazol en la mucormicosis es aún limitada, se actualizará la evaluación de tecnología sanitaria tanto con nueva evidencia científica publicada como con los datos clínicos de los pacientes que hayan recibido este tratamiento bajo lo establecido en el presente dictamen preliminar. Esta información será tomada en cuenta para efectos de un nuevo dictamen al terminar la vigencia del presente. Al no encontrarse evidencia sólida que respalde el uso de posaconazol en menores de 13 años de edad, no se puede recomendar su uso en este grupo etário. Dado que la evidencia que respalda el uso de posaconazol es aún limitada, se establece que el efecto de posaconazol se evaluará con los datos de los pacientes que lo hayan recibido por el periodo de vigencia de este dictamen para determinar el impacto de su uso en los desenlaces de interés de este dictamen. Esta información será tomada en cuenta en la reevaluación de este medicamento para efectos de un nuevo dictamen al terminar la vigencia del presente Dictamen Preliminar.

Paracoccidioidomycosis treatment / Tratamento da paracoccidioidomicose

SUMMARYConsidered to be an emerging endemic mycosis in Latin America, paracoccidioidomycosis is characterized by a chronic course and involvement of multiple organs in immunocompromised hosts. Infection sequelae are mainly related to pulmonary and adrenal insufficiency. The host-parasite interaction results in different expressions of the immune response depending on parasite pathogenicity, fungal load and genetic characteristics of the host. A few controlled and case series reports have shown that azoles and fast-acting sulfa derivatives are useful treatment alternatives in milder forms of the disease. For moderate/severe cases, more prolonged treatments or even parenteral routes are required especially when there is involvement of the digestive tract mucosa, resulting in poor drug absorption. Although comparative studies have reported that shorter treatment regimens with itraconazole are able to induce cure in chronically-infected patients, there are still treatment challenges such as the need for more controlled studies involving acute cases, the search for new drugs and combinations, and the search for compounds capable of modulating the immune response in severe cases as well as the paradoxical reactions.

RESUMOConsiderada micose endêmica emergente na América Latina, a paracoccidioidomicose é caracterizada por uma evolução crônica e envolvimento de múltiplos órgãos em pacientes com comprometimento imunológico. Sequelas da infecção estão relacionadas principalmente à insuficiência pulmonar e adrenal. A interação hospedeiro-parasito resulta em diferentes expressões da resposta imune dependendo da patogenicidade do parasito, carga fúngica e características genéticas do hospedeiro. Alguns estudos controlados e séries de casos têm demonstrado que azóis de ação rápida e derivados de sulfa constituem alternativas terapêuticas úteis nas formas mais leves da doença. Para casos moderados/graves, tratamentos mais prolongados ou mesmo por via parenteral são necessários especialmente quando há envolvimento de mucosa do trato digestivo, resultando em absorção deficiente de drogas. Embora estudos comparativos tenham relatado que esquemas terapêuticos mais curtos com itraconazol sejam capazes de induzir cura em pacientes cronicamente infectados, ainda existem desafios no tratamento, tais como a necessidade de maior número de estudos controlados envolvendo casos agudos, busca por novas drogas e combinações, compostos capazes de modular a resposta imune nos casos graves, e reações paradoxais.

Infecciones por mohos en el trasplante pulmonar / Mold infections in lung transplants

Las infecciones invasivas por mohos, fundamentalmente por Aspergillus, suponen más del 10% de las complicaciones infecciosas en el trasplante pulmonar. Suelen tener una presentación bimodal: precoces, principalmente invadiendo la vía aérea, y tardías, más frecuentemente localizadas en pulmón o diseminadas. La colonización en cualquier momento postrasplante es uno de los principales factores de riesgo. Dicha colonización es, junto con el rechazo crónico, una de las principales causas de las formas tardías. Un valor de 0,5 de galactomanano en el lavado broncoalveolar se considera actualmente indicativo de infección invasiva. No hay una estrategia universal de actuación en materia de profilaxis. La profilaxis dirigida y el tratamiento anticipado van teniendo más adeptos, en contraposición a la profilaxis universal. La monitorización de las concentraciones de los azoles en los enfermos se considera altamente indicada durante el tratamiento. La monoterapia con voriconazol es el tratamiento de elección en la aspergilosis, y solo se recomiendan terapias combinadas ante aspergilosis graves, diseminadas y por otros mohos (AU)

Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds (AU)