Search Results (408)

Invasive infections caused by rare moulds (RM) are increasingly reported and often exhibit resistance to antifungal agents. Their epidemiology varies regionally, yet data from Greece are scarce. To address this gap, we conducted a 15-year retrospective study of RM fungaemia at a tertiary academic hospital in Athens, Greece. All microbiologically confirmed cases in hospitalised patients between 2010 and 2024 were reviewed. Demographic and clinical data were retrieved from medical records. Incidence rates were calculated per 1000 admissions and 10,000 bed-days. Isolates were morphologically identified and, when available, molecularly characterised and tested for antifungal susceptibility according to EUCAST guidelines. Eight RM fungaemia episodes (0.8% of total fungaemias) were identified, with an incidence of 0.01/1000 admissions and 0.03/10,000 bed-days, without bacterial co-infections. Haematological malignancies (62%) were the most common underlying condition. Fusarium spp. were the predominant pathogens (6/8), followed by single cases due to Lomentospora prolificans and Acremonium spp. Amphotericin B showed the highest in vitro activity against Fusarium isolates (MIC 0.5–1 mg/L), followed by voriconazole (MICs 2–8 mg/L) whereas other azoles showed no in vitro activity (MICs ≥ 8 mg/L). Half of the infections were breakthrough, whereas in 3/8 cases, the diagnosis was established post-mortem (n = 2) or post-discharge. Among the five patients who received treatment, the crude mortality rate was 60%. This first epidemiological report on RM fungaemia in Greece highlights the predominance of Fusarium spp., the frequency of breakthrough infections, and the challenges in early diagnosis and management. Increased clinical awareness and regional surveillance are essential for optimising outcomes. Full article

Background: Oral candidiasis is a prevalent opportunistic infection, predominantly caused by Candida albicans (CA), though non-albicans Candida (NAC) species are increasing worldwide. This study aimed to characterize the prevalence of Candida species, evaluate antifungal susceptibility, and identify predisposing risk factors in patients with oral mucosal candidiasis. Methods: A retrospective review of 1286 electronic patient medical records (788 women, 498 men) from 2018 to 2022 was conducted at the Department of Periodontal and Oral Mucosa Diseases, Medical University of Silesia. Swabs from the oral cavity were processed to identify Candida strains by mass spectrometry, followed by drug susceptibility testing for amphotericin B, nystatin, flucytosine, econazole, ketoconazole, miconazole, and fluconazole. Relevant local and systemic predisposing factors were recorded and analyzed statistically. Results: Among 958 patients with positive fungal cultures, CA accounted for 66.79% of isolates, while NAC constituted 33.21%. Multi-strain infections were detected in 8.46% of patients. CA showed lower resistance (<10%) to amphotericin B, nystatin, and flucytosine, but up to 30% resistance to azoles. NAC strains demonstrated elevated resistance rates (>40% for most azoles), with C. krusei exhibiting the highest resistance to the previously mentioned antifungal agents. Key risk factors included wearing removable dentures (p = 0.042) and uncontrolled diabetes mellitus (p = 0.0431). Additional factors, including poor oral hygiene, reduced salivary flow, and immunosuppressive conditions, further increased infection risk. Patients presenting with multiple risk factors were more likely to have multi-strain infections and more severe disease courses. Conclusions: This retrospective analysis highlights the growing prevalence of NAC, rising antifungal resistance (particularly to azoles), and the importance of identifying risk factors, especially denture use and poor glycemic control. Enhanced preventive strategies, robust diagnostic approaches, and optimized antifungal regimens are essential to address this evolving clinical challenge. Full article

Candida albicans is the primary etiological agent of vulvovaginal candidiasis (VVC), a widespread fungal infection affecting millions of women worldwide. Although often self-limiting, VVC can become recurrent or severe, significantly impacting quality of life. The pathogenesis of C. albicans is driven by key virulence factors, including hyphal transformation, biofilm formation, and immune evasion, which all facilitate persistence and resistance to host defenses. Epidemiological data indicate that up to 75% of women experience at least one episode of VVC, with 5–10% developing recurrent vulvovaginal candidiasis. The condition typically presents with vaginal itching, burning, erythema, edema, and an abnormal discharge. Diagnosis relies on both clinical presentation and microbiological confirmation; however, misdiagnosis remains common due to symptom overlap with other vaginal infections and conditions in general. Azole antifungals remain the cornerstone of treatment; however, increasing resistance (particularly in non-albicans Candida species) poses substantial therapeutic challenges. Consequently, the emergence of antifungal-resistant strains underscores the need for novel treatment strategies, including probiotics and natural antifungal agents. Preventive measures—including maintaining vaginal microbiota balance, avoiding unnecessary antibiotic usage, and improving hygiene practices—play a pivotal role in reducing disease burden due to C. albicans. Given the rising incidence of VVC and the burden of recurrent cases, further research is essential to develop targeted therapeutic interventions. This comprehensive review highlights the evolving epidemiology, pathogenesis, and clinical challenges of C. albicans-associated VVC, emphasizing the need for improved diagnostic strategies, alternative therapeutic approaches, and targeted preventive measures to reduce disease burden and enhance patient outcomes. Full article

The research aimed to study the genome of Cryptococcus neoformans isolated from bird excreta. Thirteen isolates were cultured, colony stained, and underwent biochemical testing confirmation by nested polymerase chain reaction using ITS1-ITS4 and CN4-CN5 primers, respectively. Antifungal susceptibility testing and whole-genomic sequencing were analyzed. The results determined that all isolates were susceptible to amphotericin B (100%), fluconazole, and itraconazole (92.3%). One isolate (DOP3) showed resistance to fluconazole and itraconazole (MIC >64 and >8 µg/mL, respectively). A phylogenetic tree showed the identity of C. neoformans (serotype A). The genome of resistant (DOP3) and non-resistant isolates (DOP3.1) had 14 chromosomes. DOP3 consisted of 38 candidate antifungal resistance genes, which were the most active against azoles (14). The annotated genes in the azole group mostly were in the ATP-binding cassette transporter transmembrane superfamily. Resistance genes against FCZ were in the transcription factors (HAP2, HAP5), zinc finger (NRG1), cytochrome P450 (ERG11), and Myb-like DNA-binding domain (REB1). The most frequent resistance genes against ITZ were cytochrome P450 (ERG5 and ERG11) and a transcription factor (HAP5). DOP3.1 also consisted of 26 candidate resistance genes against azoles. Resistance genes against the azole group belong to the ABC transporter transmembrane superfamily. Resistance genes against FCZ belong to cytochrome P450 (ERG11), the zinc finger (NRG1), and the CCAAT binding transcription factor (HAP2). Resistance genes belonging to cytochrome P450 (ERG5) were found against ITZ. This research provides the first report of C. neoformans (serotype A) in zebra dove excreta, drug susceptibility to a resistant strain, and identification of resistance genes. Farm sanitation should be strictly applied, and immunocompetent people should avoid contact with zebra dove excreta. Full article

The genus Aspergillus, widely distributed across natural and urban environments, may cause allergies and opportunistic infections such as chronic or invasive pulmonary aspergillosis. Its high pathogenic potential for immunocompromised patients, together with the alarming increase of azole resistance reported in clinical and environmental isolates, claims urgent actions to assess and control the Aspergillus community in hospital environments. To contribute to that, here, we combine a large environmental survey covering numerous air and surface samples from different zones of three hospitals in Spain, with an integrated approach including general and selective culture- and eDNA-based analyses. Despite the high prevalence of Aspergillus observed, present in almost all indoor zones (mostly in air but also on surfaces) of the three hospitals, its relative abundance in the whole fungal community was limited and dependent on the used methods, with median values ranging from 1.4% (eDNA data) and 6.8% (cultivation at 28 °C) to 28.3% (cultivation at 37 °C). Remarkably, the most protected zones (intensive care units) showed the highest proportion of Aspergillus eDNA sequences. A total of 32 species belonging to 10 Aspergillus sections were molecularly identified, including well-known causal agents of invasive pulmonary infections such as A. fumigatus, A. flavus, A. terreus, A. niger, A. oryzae, A. sydowii, and A. tubingensis. This highlights the importance of such environmental assessments for monitoring and controlling the fungal burden in hospitals. Full article

Invasive candidiasis (IC) in Latin America is undergoing a significant epidemiological shift, increasingly driven by non-albicans strains such as Candida tropicalis, Candida parapsilosis, and Candidozyma auris. These pathogens often exhibit multidrug resistance, which complicates treatment and increases mortality. Diagnostic limitations, particularly in rural and public hospitals, delay detection and hinder the provision of rapid care. Environmental pressures, such as climate change and the widespread use of azoles in agriculture, appear to favor the selection of resistant and thermotolerant strains. Migratory birds may also play a role in the environmental transmission of pathogenic fungi. These factors are amplified by socioeconomic inequalities that restrict access to diagnostics and first-line antifungals. To help mitigate this emerging challenge, a One Health-oriented framework combining integrated environmental surveillance, robust antifungal-stewardship programmers, broader diagnostic access, and coordinated cross-sector public health actions should be developed. Reinforcing these pillars could lessen the regional burden of IC and slow the advance of antifungal resistance. Full article

Invasive fungal infections (IFIs) are one of the most significant public health challenges worldwide. Yet, research and communication thereof were left behind for a long time, until the WHO published a priority pathogens list to guide research, development, and public health action in October 2022. Indeed, due to the rising number of immunocompromised patients at risk and the high level of morbidity, mortality, and economic burden they entail, especially in low- and middle-income countries, IFIs are a serious public health threat. Fungal infections due to dimorphic fungi face additional challenges such as limited knowledge outside of endemic areas and restricted availability of antifungal molecules in areas affected by these infections. The number of related deaths per year is estimated at 2.5 million, but non-governmental organisations make a wider estimation, due to the difficulties in early in vitro diagnostic and troublesome collection and analysis of epidemiological data. Despite this fact, the therapeutic toolbox addressing these infections remains limited, with only four main families of molecules available so far. The antifungal therapeutic supply is composed of very toxic polyenes, the weakly selective and nearly unused 5-fluorocytosine, and azoles, some of which are becoming increasingly inefficient against IFIs. In the 2000–2020s, the fourth arising family consisted of safer semisynthetic echinocandins. Unfortunately, nowadays, more and more fungal isolates encountered in intensive care units exhibit a low susceptibility to echinocandins or are even multiresistant. In this review, we expose the current treatments available to fight against invasive fungal infections. We recall the discovery and physico-chemical aspects of these substances leading to structure/activity and structure/properties relationships. We particularly focus on the to-date resistances and their molecular mechanisms. We finally list some of the most relevant antifungal drug candidates, as they were freshly overviewed by the World Health Organization in April 2025, highlighting the importance of the molecular dimension of this pursuit toward the expansion of the antifungal therapeutic toolbox. Full article

Considering the clinical relevance of commensal yeasts (Malassezia and Candida) and zoophilic dermatophytes (Microsporum canis and Trichophyton mentagrophytes) in dogs and cats, this study determines the prevalence of fungal species involved in ear and superficial skin infections in dogs and cats in Grenada and examines their antifungal susceptibility. The etiological agents were isolated from ear, skin, and hair samples of suspected clinical fungal cases using Sabouraud Dextrose Agar (SAB). The isolates’ identification comprised morphological, biochemical, and molecular methods encompassing micro-/macroscopy analysis. Biochemically, yeast isolates were identified by the BD Phoenix M50 microbial identification system, and additional validation of all fungal isolates was performed by polymerase chain reaction (PCR) and sequencing of the ITS region. Furthermore, the E-Test (Epsilometer Test) was used to determine the susceptibility patterns for four azole drugs: ketoconazole, itraconazole, fluconazole, and voriconazole. A total of 405 samples (266 ear, 61 skin, and 78 hair) were collected from 136 dogs and 43 cats. The identified species were Malassezia pachydermatis, Candida tropicalis, and Trichophyton spp. All isolates demonstrated (100%) resistant activity to fluconazole. Importantly, this knowledge will significantly contribute to our understanding of the epidemiology of fungal infections as well as provide guidelines for preventive measures against fungal infections in Grenada. Full article

In this study, a series of novel β-phenylalanine derivatives were synthesised and evaluated for their anticancer activity. The 3-(4-methylbenzene-1-sulfonamido)-3-phenylpropanoic acid (2) was prepared using β-phenylalanine as a core scaffold. The β-amino acid derivative 2 was converted to the corresponding hydrazide 4, which enabled the development of structurally diverse heterocyclic derivatives including pyrrole 5, pyrazole 6, thiadiazole 8, oxadiazole 11, triazoles 9 and 12 with Schiff base analogues 13 and series1,2,4-triazolo [3,4-b][1,3,4]thiadiazines 14. These modifications were designed to enhance chemical stability, solubility, and biological activity. All compounds were initially screened for cytotoxicity against the A549 human lung adenocarcinoma cell line, identifying N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxo-1-phenylpropyl]-4-methylbenzenesulfonamide (5) and (E)-N-{2-[4-[(4-chlorobenzylidene)amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-phenylethyl}-4-methylbenzenesulfonamide (13b) as the most active. The two lead candidates were further evaluated in H69 and H69AR small cell lung cancer lines to assess activity in drug-sensitive and multidrug-resistant models. Schiff base 13b containing a 4-chlorophenyl moiety, retained potent antiproliferative activity in both H69 and H69AR cells, comparable to cisplatin, while compound 5 lost efficacy in the resistant phenotype. These findings suggest Schiff base derivative 13b may overcome drug resistance mechanisms, a limitation commonly encountered with standard chemotherapeutics such as doxorubicin. These results demonstrate the potential role of β-phenylalanine derivatives, azole-containing sulphonamides, as promising scaffolds for the development of novel anticancer agents, particularly in the context of lung cancer and drug-resistant tumours. Full article

Background/Objectives: The diminished efficacy of azoles in treating fungal infections is attributed to the emergence of resistance among pathogenic fungi. Employing a synergistic approach with other compounds to enhance the antifungal activity of azoles has shown promise, yet the availability of clinically valuable adjuvants for azoles and allylamines remains limited. Studies have demonstrated that the human host environment provides multiple carbon sources, which can influence the susceptibility of C. albicans to antifungal agents. Therefore, a comprehensive investigation into the mechanisms by which carbon sources modulate the susceptibility of C. albicans to azoles may uncover a novel pathway for enhancing the antifungal efficacy of azoles. Methods: This study explored the impact of various carbon sources on the antifungal efficacy of azoles through methodologies including minimum inhibitory concentration (MIC) assessments, super-MIC growth (SMG) assays, disk diffusion tests, and spot assays. Additionally, the mechanism by which galactose augments the antifungal activity of azoles was investigated using a range of experimental approaches, such as gene knockout and overexpression techniques, quantitative real-time PCR (qRT-PCR), Western blot analysis, and cycloheximide (CHX) chase experiments. Results: This study observed that galactose enhances the efficacy of azoles against C. albicans by inhibiting the translation of Erg1. This results in the suppression of Erg1 protein levels and subsequent inhibition of ergosterol biosynthesis in C. albicans. Conclusions: In C. albicans, the translation of Erg1 is inhibited when galactose is utilized as a carbon source instead of glucose. This novel discovery of galactose’s inhibitory effect on Erg1 translation is expected to enhance the antifungal efficacy of azoles. Full article

Invasive fungal infections (IFIs) represent a growing global health threat, particularly for immunocompromised populations, with mortality exceeding 1.5 million deaths annually. Despite their clinical and economic burden—costing billions in healthcare expenditures—fungal infections remain underprioritized in public health agendas. This review examines the current landscape of antifungal therapy, focusing on advances, challenges, and future directions. Key drug classes (polyenes, azoles, echinocandins, and novel agents) are analyzed for their mechanisms of action, pharmacokinetics, and clinical applications, alongside emerging resistance patterns in pathogens like Candida auris and azole-resistant Aspergillus fumigatus. The rise of resistance, driven by agricultural fungicide use and nosocomial transmission, underscores the need for innovative antifungals, rapid diagnostics, and stewardship programs. Promising developments include next-generation echinocandins (e.g., rezafungin), triterpenoids (ibrexafungerp), and orotomides (olorofim), which target resistant strains and offer improved safety profiles. The review also highlights the critical role of “One Health” strategies to mitigate environmental and clinical resistance. Future success hinges on multidisciplinary collaboration, enhanced surveillance, and accelerated drug development to address unmet needs in antifungal therapy. Full article

Azole resistance in dermatophytes, particularly Trichophyton indotineae, has become a growing global concern. Current antifungal susceptibility testing protocols (EUCAST, CLSI) have limitations in reproducibility and sensitivity. This study aimed to evaluate how medium composition, incubation temperature, and spore concentration influence itraconazole susceptibility testing across various dermatophyte species. Thirty-eight clinical isolates representing Trichophyton, Microsporum, and Epidermophyton species were tested using a microplate laser nephelometry system (MLN). IC₅₀ values for itraconazole were determined in three different media (Sabouraud glucose (SG), RPMI-based (RG), and RG supplemented with casein (RGC)) at 28 °C and 34 °C. Effects of spore concentration on growth dynamics and lag phase were also analyzed. SG medium provided clear phenotypic separation between resistant and sensitive isolates. In contrast, RG and RGC showed overlapping IC₅₀ values. Lower spore concentrations revealed underlying growth differences, which were masked at higher inoculum levels. Temperature and media composition significantly affected IC₅₀ outcomes. Genotypic analysis confirmed resistance-associated Erg11B point mutations and genomic amplifications in T. indotineae, particularly in combination with Erg1 mutations, forming distinct subpopulations. SG medium combined with reduced spore concentrations offered improved differentiation of resistant versus sensitive strains. These findings support the development of more accurate susceptibility testing protocols and highlight the need to establish species-specific ECOFF values for dermatophytes. Full article

Background: Oral candidiasis (OC) and vulvovaginal candidiasis (VVC) are infections caused by species belonging to the genus Candida. In Chile, epidemiological studies on OC/VVC are scarce, leading to an overestimation of the prevalence of C. albicans. Additionally, awareness of the prevalence of species phenotypically and genotypically similar to C. albicans is lacking. The clinical impact of non-albicans species in cases of OC/VVC is also often underestimated. This study aims to determine the distribution of Candida species, their phenotypic and molecular characteristics, and their antifungal susceptibility patterns in incidents of oral and vulvovaginal candidiasis in Chile. Methods: A descriptive analysis was conducted on 101 isolates of Candida spp. obtained from OC/VVC cases. The identification of Candida species was performed using both phenotypic and molecular techniques. Antifungal susceptibility testing was carried out using the Sensititre YeastOne system. Results: Among the analyzed isolates, 89.1% were identified as C. albicans, while 10.9% were categorized as non-albicans species, including C. dubliniensis, C. glabrata sensu stricto, C. bracarensis, C. tropicalis, C. lusitaniae, and C. parapsilosis sensu stricto. The susceptibility pattern was predominantly susceptible, with only 10.9% of the total strains demonstrating resistance, and low antifungal activity in vitro was observed for Fluconazole, Voriconazole, and Posaconazole. Conclusions: The most prevalent species causing OC/VVC in Chile is C. albicans. This study also presents the first report of C. lusitaniae as a causal agent of VVC in the country. The identification of azole-resistant strains emphasizes the critical role of laboratory diagnosis in VVC cases, thereby preventing potential treatment failures. No resistance was observed in the strains associated with OC. Full article

The increasing emergence of antifungal resistance poses potential clinical challenges, particularly among immunocompromised patients with cancer at risk of invasive mold infections, but data on antifungal susceptibility trends specific to this population are few. We evaluated distributions of minimal inhibitory concentrations (MIC), including minimal effective concentrations (MEC) for echinocandins, of 11 antifungal agents for 523 mold isolates (395 Aspergillus spp.) from cancer patients. Based on published Clinical and Laboratory Standards Institute guidelines, isavuconazole had notably high rates of non-wild-type MICs for A. fumigatus (19.6%), A. flavus/oryzae (34.8%), A. niger complex (26.1%), and A. terreus complex (8.33%). Persistent low baseline resistance of A. fumigatus to voriconazole was observed across multiple years (2.4–11.5% per year, average 8.41%) without significant trends in MIC change over time. Itraconazole and posaconazole demonstrated the lowest MIC distributions (MIC₅₀ ≤ 0.06–0.5 µg/mL) of the azoles against Aspergillus spp. Amongst the A. niger complex, 29.4% (27/92) demonstrated non-wild-type MICs to itraconazole. While the A. nidulans group was less frequent (n = 24), bimodal peaks in MIC/MEC were noted for caspofungin (≤0.06 and 1 µg/mL). Non-Aspergillus molds of significance (Zygomycetes, Fusarium spp., Scedosporium spp., and Lomentospora prolificans) demonstrated variable but increased MICs to antifungal agents as previously described. Our results highlight increased rates of non-wild type MICs for Aspergillus spp. to isavuconazole and voriconazole, which are commonly used antifungal agents in cancer patients. Such AST trends should be closely monitored in populations with frequent antifungal use and encourage increased antifungal stewardship efforts. Full article

The emergence of antifungal-resistant Aspergillus fumigatus (A. fumigatus) became a serious public health concern, underscoring the need for new effective antifungal agents. Here, we present a strategy based on the in situ generation of radical species that are toxic to the pathogen. The synthesis of an alkoxyamine linked to a peptide substrate recognized by A. fumigatus-secreted dipeptidyl peptidase is described. Kinetic experiments show a stable prodrug prior to enzymatic activation. Ensuing peptide cleavage and spontaneous homolysis resulted in the generation of a stable nitroxide and a reactive alkyl radical moiety. Next, the exposure of A. fumigatus spores to the prodrug lead to pathogen growth inhibition in a compound concentration-dependent fashion (e.g., 42% inhibition at 10 µg/L). Importantly, the designed alkoxyamine inhibited not only the growth of a clinical voriconazole-susceptible A. fumigatus strain, but also the growth of a strain resistant to this azole. To determine the antifungal importance of the reactive alkyl radical, its substitution with a non-radical structure did not prevent A. fumigatus growth. Furthermore, the introduction of succinic group in the peptide substrate resulted in the loss of alkoxyamine antifungal properties. Our work reports a novel chemical strategy for antifungal therapy against A. fumigatus based on the pathogen enzyme-mediated generation of toxic radicals. Significantly, these findings are timely since they could overcome the emerged resistance to conventional drugs that are known to target defined pathogen biologic mechanisms such as ergosterol synthesis. Full article