Medical mycology最新文献

Candida auris is an emerging fungal pathogen with high rates of multidrug resistance, posing a significant global health threat. Immunosuppressed patients are particularly vulnerable to multidrug-resistant (MDR) C. auris infections. This systematic review and meta-analysis (SR-MA) aimed to assess the global prevalence of MDR-C. auris isolates in humans and their resistance to antifungal drugs, primarily fluconazole (FLZ), voriconazole (VOR), and amphotericin B (AmB). A comprehensive search was conducted in PubMed, Scopus, and ScienceDirect databases on published studies regarding clinical C. auris isolates and the use of antifungal susceptibility testing assay from 17 March 2015 to 1 February 2024. Meta-analysis was conducted using random-effects models to determine the estimated pooled prevalence of MDR-C. auris isolates and their antifungal resistance profiles from immunosuppressed humans. A total of 81 research studies were included in the final analysis, with the overall pooled prevalence of the three most important antifungal drugs; FLZ (92.5% | 95% CI: 89.5-94.7), VOR (49.0% | 95% CI: 37.6-60.4), and AmB (51.0% | 95% CI: 42.3-59.7). According to the subgroup analyses, FLZ-resistant C. auris was the most prevalent isolate observed in the five continents reporting compared to the VOR- and AmB-resistant C. auris having lower pooled prevalence. Further, higher pooled prevalence of MDR-C. auris isolates were observed from males (68.2%, n = 578) compared to females (37.1%, n = 283). Finally, the global pooled prevalence for mortality in immunosuppressed patients with MDR-C. auris from 13 research studies was 41.5% (95% CI: 29.9-54.2). This SR-MA study establishes the variation of MDR-C. auris resistance patterns observed from different continents and the importance to conduct further research studies using potent antifungal drugs. Accordingly, it is imperative to establish stringent surveillance on the increasing prevalence of antifungal resistance particularly in low-income regions with limited research resources to prevent increasing prevalence of MDR-C. auris.

Neurotropic dematiaceous fungi are primary agents of cerebral phaeohyphomycosis, a life-threatening brain infection with high mortality. However, the genomic basis underlying their virulence, stress tolerance, and antifungal resistance is poorly understood. In this study, we present high-quality hybrid genome assemblies of three major neurotropic dematiaceous fungi, Cladophialophora bantiana, Fonsecaea monophora, and Cladosporium cladosporioides, using Nanopore long-read and Illumina short-read sequencing platforms. The assembled genomes ranged from 31.5 to 39.9 Mb, with high completeness (>98.9%). Functional annotation revealed diverse coding and non-coding elements associated with stress responses, iron metabolism, and antifungal resistance. The Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses uncovered metabolic versatility, enriched xenobiotic degradation pathways, and lineage-specific functional divergence. Notably, C. bantiana and F. monophora exhibited greater genomic plasticity, higher transposable element content, and broader repertoires of virulence factors, extracellular peptidases, and secondary metabolite biosynthetic gene clusters, suggesting enhanced pathogenic potential. All three genera harbored conserved stress tolerance mechanisms, melanin biosynthesis pathways, and pathogenicity-related genes linked to immune evasion and neuroinvasion. Additionally, we identified distinct multidrug efflux transporter families linked to antifungal resistance. Orthology analysis revealed a shared core proteome alongside genus-specific adaptations likely underpinning niche specialization. While the findings highlight critical genomic features driving fungal resilience and neurotropism, functional validation through transcriptomics and phenotypic assays remains essential. Despite current limitations in experimental tractability, this work provides a foundational resource for understanding the molecular basis of fungal pathogenesis and offers valuable targets for future diagnostic and therapeutic strategies against cerebral phaeohyphomycosis and related infections.

Mould pneumonia can be life-threatening, and its incidence is increasing in Asia. Due to significant variability in diagnostic setups and the availability of antifungal agents, especially in resource-limited settings, the current treatment practices and recommendations for local clinicians are poorly described. This study aimed to develop a consensus statement on the clinical management of mould pneumonia in Asia, particularly within resource-limited settings. Clinicians and infectious disease experts from the Asia Fungal Working Group answered questions about the regional epidemiology as well as diagnostic and resource-limited treatment approaches of mould pneumonia. Guided by a literature review, 22 initial questions were generated and voted upon anonymously using a Delphi-based methodology with predefined consensus criteria. The study comprised two rounds: one to generate summary statements based on the panelists' questionnaire responses, and the other to review, confirm and rate the level of agreement of the consensus statements using a five-point Likert scale. The panelists generated 21 summary statements on the epidemiology (5), diagnosis (8), and treatment (8) of mould pneumonia, 20 of which achieved ≥ 70% consensus. Through a consensus-building exercise, clinical experts from Asia developed a set of 21 consensus statements for the diagnosis and management of mould pneumonia in resource-limited settings.

The changing epidemiology and diagnostic challenges of coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis in Latin America are reviewed. The agents responsible for these three systemic endemic mycoses are dimorphic fungi from the Onygenales order, all of which are classified as World Health Organization fungal priority pathogens. However, the mycoses they cause span a notable diversity of contrasting etiologies, target populations, geographic distributions, and factors (including climate changes) that determine their incidence. New, updated maps are presented that reflect the current geographical distributions of these systemic endemic mycoses within Latin America, and the epidemiological dynamics that gave rise to them.

Candida (Candidozyma) auris is well known for its limited susceptibility to conventional antifungal agents, underscoring the need for novel alternative therapeutic approaches. One such approach, which involves restricting the availability of micronutrients-including iron-is a promising antimicrobial strategy and proven to enhance the efficacy of various antimicrobial agents in vitro. In this study, we evaluated the activity of deferiprone, a clinically approved iron-chelating agent, in combination with echinocandins, amphotericin B and fluconazole against C. auris strains, including three echinocandin-resistant isolates representing the four major clades. Drug-drug interactions were assessed using the chequerboard methodology. Fractional inhibitory concentration index scores ranged from 0.5 to 2.25 and 0.1875 to 4.125 for anidulafungin; 0.375 to 1.5 and 0.125 to 1.5 for micafungin; 0.3125 to 1.5 and 0.3125 to 2 for caspofungin; 0.375 to 2.0625 and 0.375 to 2 for amphotericin B; and 0.625 to 2 and 0.625 to 2 for fluconazole at 24 and 48 h, respectively. Synergistic interactions were most frequently observed with echinocandins, while interactions with fluconazole and amphotericin B were generally additive or indifferent, except in Clade II. Antagonism was observed in only one instance. These findings suggest that iron chelation may potentiate the antifungal activity of echinocandins against C. auris in a clade- and isolate-specific manner.

Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in immunocompromised patients. (1→3)-β-D-glucan (BDG) is a fungus-derived biomarker used for IFD diagnosis. We aimed to evaluate the diagnostic performance of a novel rapid colourimetric assay, the β-glucan single M30 test WAKO (M30), and compare its performance with the conventional turbidimetric β-glucan test WAKO (GT). We retrospectively analysed plasma samples collected from 1289 patients at Kyoto University Hospital. IFD diagnoses were based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, excluding BDG. Forty-one patients had confirmed IFDs (22 with invasive candidiasis, 11 with invasive aspergillosis, 6 with Pneumocystis pneumonia, and 2 with other IFDs). The area under the receiver operating characteristic (AUROC) of the M30 assay was 0.892 (95% confidence interval [CI], 0.836-0.949). At an optimal cutoff of 6.7 pg/ml, its sensitivity was 0.732 (95% CI, 0.571-0.858), specificity was 0.990 (95% CI, 0.889-0.922), positive predictive value was 0.204 (95% CI, 0.142-0.278), and negative predictive value was 0.990 (95% CI, 0.983-0.995). For a subset of 537 samples, comparative analysis between M30 and GT was performed. The AUROC for the M30 and GT assays was 0.899 and 0.868, respectively (P = .285). At a cutoff of 11.0 pg/ml, the sensitivity was 72.2% for both assays, and the specificity was 93.5% vs. 93.3% (P = 1.000). The M30 assay demonstrated comparable diagnostic performance to the GT assay, with a shorter assay time that may facilitate earlier clinical decision-making in patients with suspected IFD.

Filamentous fungal, or mould, infections are a major cause of morbidity and mortality in immunocompromised patients, requiring rapid and accurate identification for appropriate clinical management. Conventional culture-based identification of moulds may require long culture times and careful gross and microscopic morphologic identification by highly experienced technologists. However, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has shown promise for faster identification of cultured moulds. We compared the agreement of Bruker MALDI Biotyper Filamentous Fungi Library 4.0 identification with VITEK MS Knowledgebase Library 3.2 identification of 149 mould culture isolates collected for routine patient care from two hospitals, comprising 35 species or species-complexes. Sequencing and/or culture morphology were used to identify moulds that were discordantly identified by the two platforms. Sequencing was performed on all Fusarium species isolates, which cannot be differentiated morphologically. All isolates were concordantly identified by the two MALDI-TOF MS systems at the genus level except for one isolate (99%). Species-level concordance between the two systems was achieved at 81% (120/149). Five (9.8%) isolates of Fusarium species were concordantly identified by the MALDI-TOF MS systems but identified as a different species or species-complex by gene sequencing. Three fungal species considered concordantly identified by MALDI-TOF MS systems exhibited nomenclatural inconsistencies. Although their databases and methods differ, current VITEK and Bruker MALDI-TOF MS systems have high concordance for identification of most common moulds isolated in clinical microbiologic laboratories, but users should be aware of performance limitations and nomenclature differences.

In recent years, the resistance of Sporothrix globosa to antifungal treatments has steadily increased, while the cure rate for sporotrichosis has declined. This growing resistance underscores the urgent need to develop novel antifungal agents with distinct mechanisms of action. Previous studies have demonstrated that phosundoxin, a biphenyl aliphatic amide that targets mitochondria, exhibits potent inhibitory effects against a broad spectrum of fungi. To further evaluate its antifungal activity, we conducted drug susceptibility testing on 112 S. globosa strains and compared the results with those of conventional antifungal agents. Phosundoxin consistently exhibited antifungal activity against all tested strains, including both mycelial forms and 32 yeast-phase strains, at concentrations ranging from 1 to 4 µg/ml. Notably, in itraconazole-resistant S. globosa strains, phosundoxin treatment led to the identification of 553 differentially expressed genes and 273 differentially expressed proteins. Integrated Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that phosundoxin exerts its antifungal effects by disrupting the mitochondrial respiratory chain and oxidative phosphorylation. This disruption triggers cellular stress responses, including the upregulation of ammonia transport and nitrogen metabolism. Additionally, phosundoxin treatment weakens cellular defense mechanisms, interferes with the cell cycle, and inhibits protein synthesis-ultimately leading to negative regulatory effects and cell death. These findings highlight phosundoxin's potential as a novel antifungal agent for treating S. globosa infections and provide critical insights into its mechanism of action against this pathogen.

Sporotrichosis is a fungal infection caused by Sporothrix species. Some of the largest outbreaks of this disease have been recorded in South Africa, and the country is considered an endemic region for the pathogen. Previous work in the 1990s considered the etiological agents of the disease, with strains stored in various culture collections. In this study, we reconsidered the identity of these strains by polymerase chain reaction amplification and sequencing of three gene regions (ITS, BenA, and CaM) and assessed their genetic diversity by microsatellite typing. The results showed that the population included four species, S. schenckii (n = 69), S. globosa (n = 1), S. pallida (n = 1), and an uncharacterised taxon (n = 2). The mating type distribution of the S. schenckii population was predominantly of the MAT1-2 idiomorph (92%). Microsatellite markers revealed only four multi-locus genotypes, of which a single genotype represented 85% of the isolates. The results provide evidence for asexual proliferation of S. schenckii lineages in South Africa, and raise questions as to how they have been dispersed. Furthermore, the results highlight uncertainties regarding the relative significance of the other species reported here.

Mucormycosis is an invasive fungal infection with very high mortality in patients with diabetic ketoacidosis, iron overload, or immune suppression. Rhizopus and Mucor are the most common etiological agents, with rhino-orbital-cerebral mucormycosis being the most frequent form of the disease. In this study, we sought to determine the activation of apoptosis, necroptosis, ferroptosis, and pyroptosis along with oxidative stress markers, in formalin-fixed paraffin embedded rhino-orbital tissues from patients with mucormycosis and COVID-19-Associated-Mucormycosis (CAM). We observed increased expression of 3-nitrotyrosine and phosphorylated Nuclear factor Erythroid 2-related factor 2, suggesting the presence of oxidative stress in these tissues. Elevated levels of CD71, phosphorylated MLKL (Mixed lineage kinase domain-like protein), and cleaved caspase 3 were detected in both mucormycosis and CAM tissues, indicating differential activation of ferroptosis, necroptosis and apoptosis during fungal infection. Notably, cleaved gasdermin D was not detected, indicating that pyroptosis does not play a significant role in mediating host lytic cell death during invasive mucormycosis. Our findings, which identify differential activation of programmed cell death pathways directly in human tissues, meet an important critical gap in the mucormycosis literature and highlight viable targets for future therapeutic interventions.