Search Results (73)

Fungi are one of the major causes of opportunistic infections in people living with HIV/AIDS. Pneumocystis jirovecii, Cryptococcus neoformans, Histoplasma capsulatum, and Candida spp. are especially more likely to affect HIV-infected individuals. Introduction and broad use of antiretroviral therapy have led to a significant decrease in invasive fungal infections in HIV-positive patients. Still, in untreated/abandoned HIV-infected individuals or patients with poor adherence to antiretroviral therapy, fungal infections may lead to severe clinical complications and death. In recent years, data have shown a growing number of immunocompromised patients due to malignancies, immunosuppressive therapies, and transplantations in the general population, and the number of susceptible individuals to fungal infections is increasing. Moreover, rising antifungal resistance is a serious threat to public health. This article provides an overview of common fungal infections in patients with HIV and discusses the changes in epidemiology and etiology, as well as current therapeutic challenges. Full article

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has emerged as a candidate for therapeutic repurposing due to its reported antifungal activity. We systematically reviewed in vitro, in vivo, and clinical evidence up to July 2025 (PubMed, Scopus, Web of Science). As a result, 322 records were screened and 63 studies were found to meet the inclusion criteria (PRISMA 2020). We close a critical gap by consolidating relevant evidence on Candida auris, including preclinical in vivo models, which have been under-represented in previous summaries. Outcomes included minimum inhibitory and fungicidal concentrations (MIC/MFC), biofilm inhibition, fungal burden, survival, and pharmacokinetic/pharmacodynamic parameters. Preclinical data indicate its activity against clinically relevant fungi—particularly Cryptococcus neoformans and Candida spp., including C. auris—as well as consistent anti-biofilm effects and synergy with amphotericin B, fluconazole, micafungin, or voriconazole. Mechanistic evidence implicates mitochondrial dysfunction, membrane perturbation, impaired protein synthesis, and calcium homeostasis disruption. However, its potential for clinical translation remains uncertain: in cryptococcal meningitis, small phase II studies suggested improved early fungicidal activity, whereas a phase III randomized trial did not demonstrate a benefit regarding survival. Pharmacokinetic constraints at conventional doses, the absence of an intravenous formulation, and safety considerations at higher doses further limit its immediate applicability. Overall, the available evidence supports sertraline as a promising adjuvant candidate, rather than a stand-alone antifungal. Future research should define PK/PD targets, optimize doses and formulations, and evaluate rational combinations through rigorously designed trials, particularly for multidrug-resistant and biofilm-associated infections. Full article

Invasive fungal infections and the emergence of antifungal resistance pose significant challenges to public health. This study evaluates the antifungal activity of two 8-hydroxyquinoline derivatives, PH265 and PH276, against Cryptococcus spp., Candida auris, and Candida haemulonii. Using the EUCAST protocol, both compounds demonstrated broad-spectrum antifungal activity, with MICs ranging from 0.5 to 8 μg/mL. PH276 exhibited synergistic effects with fluconazole and caspofungin against C. haemulonii (FIC ≤ 0.5). The derivatives inhibited C. neoformans biofilm formation at higher concentrations and modulated polysaccharide capsule formation in Cryptococcus spp. In vivo toxicity assays in Tenebrio molitor, Galleria mellonella, and Caenorhabditis elegans revealed no significant adverse effects, with survival rates comparable to controls. These findings highlight PH265 and PH276 as promising antifungal agents with biofilm-disrupting properties, capsule-modulating effects, and low toxicity, supporting their potential for therapeutic development. Full article

Leishmania spp. are obligatory intracellular parasites that primarily infect macrophages. The macrophage immune response plays a pivotal role in determining the control or progression of infection. “M1-like” macrophages mediate parasite clearance through the production of nitric oxide, pro-inflammatory cytokines, and reactive oxygen species, whereas “M2-like” macrophages contribute to infection progression by exerting anti-inflammatory effects. The capsular polysaccharides Glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal) from Cryptococcus neoformans are capable of immunomodulating the macrophage response. GXM exhibits immunoregulatory activity, whereas GXMGal induces a pro-inflammatory response. Although the activity of these polysaccharides has been studied in cryptococcosis, their immunomodulatory potential in other infectious models remains largely unexplored. Here, we investigated the effects of GXM and GXMGal on Leishmania major infection in murine peritoneal macrophages. Murine peritoneal macrophages were infected with L. major and, 24 h post-infection, treated with 50 μg of either GXM or GXMGal. Our data revealed that GXM treatment enhanced L. major infection, while GXMGal treatment had no significant effect on the parasitic load in infected macrophages. Full article

Cryptococcosis, caused by the Cryptococcus neoformans and Cryptococcus gattii species complexes (pathogenic Cryptococcus spp.), is an environmentally acquired mycosis of One Health relevance. This study integrates a PRISMA-compliant systematic review (2000–2025) of Portuguese animal, human, and environmental reports with a 13-year retrospective dataset of laboratory-confirmed veterinary cryptococcosis cases (2013–2025). Clinical specimens were cultured and identified by MALDI-TOF mass spectrometry, and associations were assessed using χ² and Fisher’s exact tests. Of 1059 submissions, 48 (4.5%) were culture-positive: 6.8% of canine, 5.3% of feline samples, and 4.0% of avian samples, with no detections in other vertebrate groups (p = 0.705). Cryptococcus neoformans predominated in carnivores (73.7%), while Papiliotrema laurentii (formerly Cryptococcus laurentii) was most frequent in birds (86.2%). Infection was not associated with sex or age. Seasonality was evident, with a July peak and summer predominance (p = 0.010). Most cases were from the Centre region (62.5%), with significant regional variation of Cryptococcus spp. distribution (p < 0.001). The systematic review confirmed autochthonous C. gattii complex disease and widespread C. neoformans contamination in pigeon guano and arboreal niches. These findings demonstrate a compartmentalised eco-epidemiology, reinforcing the need for integrated molecular typing, antifungal susceptibility testing, and coordinated human–animal–environment surveillance to inform targeted prevention and control strategies in Portugal. Full article

Invasive yeast infections (IYIs) remain a significant cause of morbidity and mortality in patients with hematologic diseases. We retrospectively analyzed 193 IYI episodes among 179 patients admitted to a tertiary hematology hospital (2012–2023). Candida species accounted for 91.7% (n = 177), while non-Candida yeasts comprised 8.3% (n = 16). Among invasive candidiasis, non-albicans Candida spp. were predominant, representing 76.8% (136/177), with C. tropicalis (36.2%, 64/177) being the most frequently isolated species. Among non-Candida yeasts, Cryptococcus neoformans (n = 10) was the most commonly identified pathogen. The incidence and 42-day mortality rate of IYIs were 0.199 and 0.095 per 1000 patient-days, respectively. The 42-day case-fatality rate remained high at 47.7%. In categorical analysis, age >65 years, corticosteroid use, elevated lactate (>2 mmol/L), neutropenia (<500/mm³), vasopressor use, and mechanical ventilation were more common in non-survivors. Primary bloodstream infections were more frequent in non-survivors, whereas catheter-related and abdominal-origin infections were predominant among survivors. Concomitant bacteremia was observed in 32.6% of IYI cases (n = 63), with Enterococcus faecium being the most frequently isolated co-pathogen. Our findings illustrate the evolving epidemiology of IYIs in hematologic patients, marked by the emergence of C. tropicalis as the predominant species, sustained mortality, and frequent bacterial co-infections, collectively reflecting the substantial clinical burden of IYIs. Full article

Background/Objectives: Actinobacteria are one of the largest bacterial phyla. These microbes produce bioactive compounds, such as antifungals, antibiotics, immunological modulators, and anti-tumor agents. Studies on actinobacteria isolated from the Brazilian Savannah biome (Cerrado) are scarce and mostly address metagenomics or the search for hydrolytic enzyme-producing microbes. Solanum lycocarpum (lobeira) is a tree widely employed in regional gastronomy and pharmacopeia in Central Brazil. Methods: In this work, 60 actinobacteria isolates were purified from the rhizosphere of S. lycocarpum. Eight Streptomyces spp. isolates were selected for in vitro antifungal activity against Cryptococcus neoformans H99, the C. neoformans 89-610 fluconazole-tolerant strain, C. gattii NIH198, Candida albicans, C. glabrata, and C. parapsilosis. The ability of the aqueous extracts of the isolates to induce the in vitro secretion of tumor necrosis factor (TNF-α), nitric oxide (NO), interleukin-6 (IL-6), and IL-10 by murine macrophages was also evaluated. Results: All extracts showed antifungal activity against at least two yeast species. Streptomyces spp. LAP11, LDB2, and LDB17 inhibited C. neoformans growth by 40–93%. Most extracts (except LAP2) also inhibited C. gattii. None inhibited C. albicans, but all inhibited C. glabrata (40–90%). Streptomyces sp. LAP8 extract increased nitric oxide production by approximately 347-fold in murine macrophages, while LDB11 extract suppressed LPS-induced TNF-α production by 70% and simultaneously increased IL-10 secretion, suggesting immunosuppressive potential. Conclusions: The results revealed that Cerrado actinobacteria-derived aqueous extracts are potential sources of antifungal and immunomodulatory biocompounds. Full article

Pulmonary nocardiosis (PN) is a rare, opportunistic, and potentially life-threatening infection, especially in disseminated cases. This retrospective study aimed to characterize the clinical features of PN and assess the diagnostic utility of metagenomic next-generation sequencing (mNGS). We reviewed data from 19 patients diagnosed with PN between September 2019 and August 2022, including 3 with disseminated disease. Common symptoms included fever, cough, and sputum production, while chest imaging frequently revealed nodules, consolidations, exudates, cavities, and pleural effusions. The sensitivity of mNGS for detecting Nocardia was significantly higher than that of culture (100% vs. 36.84%, p < 0.001). mNGS successfully identified Nocardia species and co-infected pathogens. The most common species was Nocardia farcinica. Four PN cases were co-infected with Rhizomucor pusillus, Cryptococcus neoformans, Lichtheimia ramosa, and Aspergillus spp. Eighteen patients (94.7%) received trimethoprim-sulfamethoxazole (TMP-SMZ). Sixteen cases (84.2%) were improved or cured. Misdiagnosis is common due to the nonspecificity of clinical and imaging presentations of pulmonary nocardiosis. The timely combination of mNGS represents a promising approach to enhance the diagnosis of pulmonary nocardiosis and inform targeted antimicrobial therapy. TMP-SMZ is the first line of treatment. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells that play a central role in regulating host immune responses during fungal infections. Their recruitment is mediated by pathogen recognition receptors, particularly Dectin-1 and CARD9 signaling, which promote the production of reactive oxygen species (ROS) and IL-1β. Once activated, MDSCs suppress T-cell and natural killer cell functions through immunosuppressive cytokines like IL-10 and TGF-β, as well as enzymes such as arginase-1 and indoleamine 2,3-dioxygenase 1 (IDO-1). This review explores the role of MDSCs in fungal infections caused by Candida spp., Paracoccidioides brasiliensis, Aspergillus spp., and Cryptococcus neoformans, emphasizing their impact on immune modulation and disease progression. The emerging evidence suggests that fungal bioactive compounds, such as polysaccharides, can influence MDSC activity and restore immune balance. Notably, therapies targeting MDSCs have demonstrated promise in both fungal infections. In particular, infections with P. brasiliensis and C. neoformans show improved T-cell responses following MDSC-targeted interventions. Additionally, polysaccharides from Grifola frondosa and exposure to Aspergillus sydowii affect MDSC behavior, supporting the potential of modulating these cells therapeutically. Together, these findings highlight the relevance of MDSCs in fungal pathogenesis and underscore their potential as targets for immunotherapeutic strategies in infectious diseases. Full article

Background/Objectives: Cryptococcosis, caused by Cryptococcus neoformans and Cryptococcus gattii species complexes, remains a significant health concern, particularly among immunocompromised patients. The emergence of antifungal resistance and toxicity of conventional treatment underscore the urgent need for novel therapeutic approaches. Combination therapies represent a promising strategy to enhance efficacy and overcome resistance. This study investigated the antifungal activity of five naphthoquinones against nine isolates of Cryptococcus spp. and assessed their synergistic effects with amphotericin B (AmB). Methods: In this study, five selected naphthoquinones were evaluated for their antifungal activity against Cryptococcus spp. isolates using broth microdilution assays to determine minimum inhibitory concentrations (MICs), according to CLSI guidelines. The potential synergistic effect with AmB was assessed using checkerboard assays, with synergy interpreted based on the fractional inhibitory concentration index (FICI). Cytotoxicity was evaluated in MRC-5 human lung fibroblast cells using the MTT assay. Results: Among the compounds tested, 2-methoxynaphthalene-1,4-dione (2-MNQ) demonstrated antifungal activity, with MIC values ranging from 3.12 to 12.5 µg/mL. Checkerboard assays revealed a synergistic interaction between 2-MNQ and AmB, with a fractional inhibitory concentration index (FICI) of 0.27. The combination reduced the MIC of AmB by 4.17-fold. These findings highlight the potential of synthetic naphthoquinones, particularly 2-MNQ, as effective antifungal agents with synergistic properties when combined with AmB. The observed synergy suggests complementary mechanisms, including increased fungal membrane permeability and oxidative stress induction. Conclusions: This study highlights the potential of 2-MNQ and 2,3-DBNQ as antifungal candidates against Cryptococcus spp., with emphasis on the synergistic interaction observed between 2-MNQ and amphotericin B. The findings reinforce the importance of structural modifications in naphthoquinones to enhance antifungal activity and support the need for further preclinical studies investigating combination therapies aimed at improving treatment efficacy in patients with cryptococcosis. Full article

Background: Cryptococcus species constitute opportunistic fungi that seldom cause infections in individuals with competent immune systems. In the rare case of cryptococcal endocarditis, the fungus infiltrates the endocardium. This disease occurs almost exclusively in patients with active immunosuppression, implanted cardiac devices, or prosthetic valves. Objectives: This study aims to analyze all documented cases of Cryptococcus spp. endocarditis in humans, emphasizing the epidemiology, microbiology, clinical manifestations, therapeutic approaches, and infection outcomes. Methods: A comprehensive review was performed by searching the PubMed and Scopus databases. Results: A total of 16 studies reported data on 16 patients diagnosed with cryptococcal endocarditis. The mean patient age was 46.6 years, with males comprising 81.25% of cases. Immunosuppression was the most prevalent predisposing factor (31.25%), followed by a history of end-stage renal disease and prosthetic cardiac valves (25%). The most commonly affected intracardiac sites were the mitral (60%) and aortic valve (46.6%), while in 33.3% of cases, multiple-valve infection was observed. Cryptococcus neoformans was detected as the causative organism in the majority of cases (87.5%). The most frequently administered antifungal treatments included amphotericin B (87.5%) and fluconazole (43.75%), with combination therapy used in 62.5% of cases. Overall mortality was relatively high at 56.25%, with 50% of deaths directly attributed to the infection. Conclusions: Considering the ability of Cryptococcus spp. to induce severe systemic infections, healthcare providers should consider this pathogen in the differential diagnosis when yeast microorganisms are identified in microbiological samples. This is particularly crucial for patients with underlying comorbidities or immunodeficiency, as early recognition is crucial to ensure precise diagnosis and treatment. Full article

The identification of fungal pathogens in formalin-fixed paraffin-embedded (FFPE) tissues is an unmet need in human and animal medicine, and sequence-agnostic approaches are needed to identify emerging pathogens. Eleven FFPE biopsy specimens with etiologic diagnoses of fungal disease based on standard testing of paired fresh tissue samples were utilized here to evaluate metabarcoding approaches. The cases included tissues from three dogs, three cats, one box turtle, one goat, one common loon, and one gray tree frog. The diagnoses from the fresh tissues in these cases were Microsporum canis, Penicillium sp., Exophiala sp. (likely E. jeanselmei), Verticillium sp., Rhizopus sp., atypical Cryptococcus neoformans, Conidiobolus spp., Aspergillus fumigatus, Cryptococcus neoformans var grubii, Batrachochytrium dendrobatidis, Fusarium solani, Blastomyces dermatitidis, Coccidiodes immitis, and Histoplasma capsulatum. We compared the ITS1 and 28S D1 rRNA gene genetic markers in combination with several bioinformatic strategies to identify fungal pathogens in the FFPE tissue samples, with a success rate of 9/11. These methods could allow diagnosticians who receive only FFPE tissues and see fungal pathogens to speciate the pathogens and could be of value in retrospective studies wherein FFPE tissue is the only archived tissue. Furthermore, these techniques could be of use to researchers investigating polymicrobial communities where DNA preservation is suboptimal. Full article

We analyzed data on pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of a total of eight Pediatric Hematology-Oncology Departments in Greece for 16 years (2007–2022). A total of twelve patients (11 boys, median age: 9.5 years, range: 2–16) were reported suffering from CNS-IFDs. The underlying malignancy was acute lymphoblastic leukemia in 9/12 and acute myeloid leukemia, Ewing sarcoma, and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e., seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n = 2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n = 1 each). Causative pathogens in probable cases were Aspergillus spp. (n = 2) and Candida spp. (n = 1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19–364). Two patients underwent additional surgical treatment. Six patients were admitted to the Intensive Care Unit due to complications. Three patients (25%) died, two due to IFD and one due to an underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival. Full article

Synanthropic birds might play an important role as reservoirs of many zoonotic endoparasites; however, little information is available on many parasites and their prevalence. Here, we use an approach based on targeted metagenomic detection through the use of DNA metabarcoding of faecal samples to screen for circulating parasites in alien parakeets (Myiopsitta monachus and Psittacula krameri) and urban landfill-feeding storks (Ciconia ciconia) and gulls (Larus fuscus). We focus especially on potentially zoonotic parasites, with the aim of better understanding the zoonotic risk that these birds’ faeces may pose. We detected a total of 23 genera of eukaryotic parasites: six fungi, three protists, five nematodes, two cestodes and seven trematodes. Among them, six stood out for their relevance to human health: Cryptococcus spp., Aspergillus spp. and Candida spp. (fungi); Cryptosporidium spp. (a protist); and Ascaris spp. and Halicephalobus spp. (nematodes). In parakeets, we detected Cryptococcus spp. and Ascaris spp., the latter being detected in 10–20% of the samples. In the White Stork and the Lesser Black-backed Gull, we found a high prevalence of Aspergillus spp. (in 15% and 50% of the samples, respectively) and Candida spp. (in 63% and 82% of the samples, respectively), and the presence of Cryptosporidium spp. in 10% of the samples. We detected Halicephalobus spp. in one gull sample (2%). Our results show that synanthropic birds may act as vectors and reservoirs of zoonotic parasites and their faeces could pose a risk to human health associated with the zoonotic parasites present in them. This should be taken into account when developing management plans for urban populations of these bird species. Full article

This study aimed to estimate the prevalence of cryptococcal antigenemia detected by lateral flow assay (LFA) in AIDS patients and its accuracy in the diagnosis of cryptococcosis. Conducted at a university hospital in Brazil from March 2015 to July 2017, it included AIDS patients over 18 years old with a CD4+ count ≤ 200 cells/mm³. Cryptococcal antigen (CrAg) detection using LFA and latex agglutination (LA), along with blood and urine cultures, were performed. The reference standard was the identification of Cryptococcus spp. in clinical specimens through microbiological or histopathological examination. Among 230 patients, the prevalence of CrAg detected by LFA (CrAg LFA) was 13.0%. Factors associated with cryptococcal antigenemia included fever, vomiting, seizures, and a lack of antiretroviral therapy. The sensitivity and specificity of CrAg LFA were 83.9% and 98.0%, respectively. The positive predictive value (PPV) was 86.7%, the negative predictive value (NPV) was 97.5%, and overall accuracy was 96.1%. Cross-reactions were observed in patients with histoplasmosis and paracoccidioidmycosis, but not with aspergillosis or positive rheumatoid factor. The study concludes that the LFA is a useful tool for detecting cryptococcal antigenemia in severely immunocompromised AIDS patients due to its high NPV, specificity, and PPV. Full article