Search Results (928)

Globally, invasive fungal diseases are increasing in incidence and are associated with high rates of mortality. A lack of effective diagnostic protocols, antifungal resistance and poor antifungal stewardship contribute to negative outcomes. Aspergillus, Candida, Cryptococcus, and Pneumocystis are the most common pathogens associated with fatal fungal diseases. These species are responsible for 90% of reported invasive fungal deaths globally. Fungal species employ a diverse and effective array of virulence factors to sabotage, evade, and manipulate host immune systems, allowing for colonisation and dissemination in vivo. Invasive fungal infections are clinically challenging, as they penetrate organs and deep tissues, contributing to the aetiology of respiratory tract, endocarditis, meningitis, and medical device infections and resulting in false negative diagnostic attempts. The 2025 WHO report outlines a lack of diagnostic and therapeutic options available, especially in low-to-middle-income countries. Geographical and economic factors impact fungal disease and mortality rates. There is an urgent need for new approaches to combat fungal diseases clinically with improved biocompatibility profiles. This timely review discusses the prevalent invasive fungal species, namely, Candida, Aspergillus, Cryptococcus, and Pneumocystis, which have high mortality rates, as identified by the WHO priority pathogen list, and discusses recent advances in the treatment of fungal diseases. This dissemination of information is an important aspect of the United Nations Sustainable Development Goals (SDGs) and One Health. Full article

The role of severe COVID-19 as an independent risk factor for invasive aspergillosis remains debated, with reported incidences varying widely across studies. We compared the cumulative incidence, risk factors, and outcomes of invasive pulmonary mold infection (IPMI) in intensive care unit patients with confirmed COVID-19 during the first epidemic wave and subsequent waves up to March 2021 at La Pitié-Salpêtrière Hospital, Paris, France. Patients were systematically screened for fungal infections and classified according to ECMM/ISHAM criteria and a more stringent local assessment. The study included 259 patients (n = 171, first wave and n = 88, subsequent waves). Patient characteristics were similar between periods, although short-course corticosteroid therapy increased over time. Mortality rates remained unchanged. Cumulative incidence of IPMI did not differ significantly between waves, regardless of the classification system used: 12.1% versus 15.1% with ECMM/ISHAM criteria and 4.2% versus 5.8% with local assessment. IPMI was associated with solid organ transplantation and pre-existing long-term corticosteroid therapy, whereas short-course corticosteroid therapy for COVID-19 was not associated with increased risk. IPMI was strongly associated with 90-day mortality. Classification as probable COVID-19-Associated Pulmonary Aspergillosis using the ECMM/ISHAM criteria may be partly influenced by the number of diagnostic samples collected. Overall, our findings underline that the classification system substantially influences both incidence estimates and the interpretation of survival outcomes. Full article

The global emergence of multidrug-resistant fungal pathogens, including Candida auris, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis jirovecii, poses a growing threat to public health, particularly among immunocompromised individuals. The limited number of available antifungal drug classes and the rapid evolution of resistance mechanisms, including target-site mutations, efflux pump activation, biofilm formation, metabolic adaptation, and stress-response signaling, have substantially reduced treatment efficacy. This review provides a comprehensive overview of current antifungal therapies, their limitations, and emerging molecular targets for next-generation antifungal drug discovery. We highlight promising targets involved in fungal cell wall biosynthesis, membrane integrity, mitochondrial metabolism, virulence regulation, and host–pathogen interactions, emphasizing their interconnected roles within adaptive resistance networks. Attention is given to small-molecule isothiazolone-based inhibitors, including phosphoglucomutase-targeting compounds, as novel candidates capable of disrupting multiple fungal survival pathways. We further discuss advances in combination therapies, anti-virulence approaches, nanotechnology-based delivery systems, and artificial intelligence-driven drug discovery pipelines that integrate multi-omics data, structural modeling, molecular docking, and virtual screening to accelerate therapeutic development. These advances support a transition from conventional single-target strategies toward systems-level, precision-guided antifungal therapies, providing a framework for overcoming multidrug resistance and improving clinical outcomes in invasive fungal infections. Full article

Fungal infections constitute a large portion of serious infections worldwide and are increasing, partially due to new immunomodulatory therapies, such as Sphingosine-1-Phosphate (S1P) receptor modulators, including fingolimod for the treatment of multiple sclerosis (MS). Fingolimod antagonizes multiple S1P receptors, including S1PR₁, S1PR₃, S1PR₄, and S1PR₅, resulting in immunological alterations that may increase susceptibility to invasive fungal infections (IFIs). Our PubMed-based literature search identified 43 published cases and a 60-patient case series describing invasive fungal infections in patients receiving S1P receptor modulators. Of these, cryptococcosis was the most frequently documented infection, followed by histoplasmosis and coccidioidomycosis. Most published cases involved patients on fingolimod, whereas evidence for the other medications in this class is extremely limited. Currently, there are no standardized fungal screening protocols. A baseline complete blood count with differentials should be obtained before the initiation of S1P receptor modulator therapy. Patients should also be monitored clinically for signs and symptoms of fungal infection. Primary antifungal prophylaxis and routine serum cryptococcal antigen testing are not currently recommended. Management of suspected IFIs should focus on diagnostic workup to identify the causative organism and extent of organ involvement to determine the appropriate antifungal therapy. Decisions regarding interruption or discontinuation of MS therapy should be individualized according to the clinical syndrome, infection severity, and risk of MS rebound. This narrative review synthesizes the available mechanistic and clinical evidence on invasive fungal infections in patients with multiple sclerosis receiving S1P receptor modulator therapy. Full article

Donor-derived infections (DDIs), particularly fungal DDIs, are uncommon but serious complications of solid organ transplantation. We report a case of a 52-year-old woman who underwent deceased donor kidney transplantation complicated by probable donor-derived Candida albicans candidemia with native aortic valve endocarditis, managed medically with prolonged echinocandin therapy followed by suppressive fluconazole. Approximately 14 months post-transplant, she developed progressive rhino-orbital mucormycosis due to Rhizopus oryzae, requiring extensive surgical debridement and prolonged antifungal therapy. Initial treatment with liposomal amphotericin B was limited by nephrotoxicity, prompting transition to isavuconazole for long-term management. Immunosuppression was discontinued to control infection, resulting in graft failure. This case illustrates the complex interplay between donor-derived infection, antifungal exposure, and immunosuppression in transplant recipients. It highlights the potential contribution of antifungal selective pressure to breakthrough mold infections and underscores the importance of early recognition, aggressive multidisciplinary management, and individualized antifungal strategies in this high-risk population. Full article

Invasive fungal diseases (IFDs) are a global health threat, especially among immunocompromised populations, due to their high mortality rates and the increasing prevalence of antifungal resistance. In recognition of this threat, the World Health Organization (WHO) has designated Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans as critical-priority fungal pathogens. During host infection, host-derived reactive oxygen species (ROS) function as potent antimicrobial molecules, whereas fungal-derived ROS act as intracellular signaling mediators regulating oxidative stress adaptation, metabolism, virulence, and antifungal tolerance. Although oxidative stress responses have been extensively investigated in individual fungal pathogens, a comprehensive comparative analysis of oxidative stress signaling across these critical fungal pathogens remains limited. This review systematically compares oxidative stress sensing and signaling networks in the four WHO critical-priority fungal pathogens and classifies oxidative stress-associated pathways into conserved, and species-specific regulatory mechanisms. Conserved pathways, including HOG-MAPK, calcineurin, cAMP-PKA, cell wall integrity, and thioredoxin-dependent signaling, are discussed alongside pathogen-specific adaptations that promote biofilm formation, capsule and melanin production, polarized growth, morphogenesis, immune evasion, and antifungal resistance. By integrating conserved and divergent oxidative stress signaling mechanisms, this review provides a comparative framework that advances our understanding of fungal pathogenesis and highlights potential targets for the development of broad-spectrum and species-specific antifungal therapies. Full article

Background: Subungual malignant melanoma (SMM) is an uncommon but potentially life-threatening neoplasm that frequently mimics benign nail disorders, particularly onychomycosis. Although misdiagnosis of SMM as fungal infection is well documented, laboratory-confirmed coexistence of onychomycosis and melanoma within the same nail unit is exceedingly rare and remains insufficiently characterized in the literature. Methods: A two-patient case series is presented in which both individuals underwent comprehensive clinical evaluation, nail unit biopsy, histopathologic examination with special staining, and molecular and/or mycologic testing. Longitudinal follow-up was obtained to evaluate clinical course and outcomes. Results: Both patients presented with chronic hallux nail dystrophy and laboratory-confirmed onychomycosis. In each case, fungal infection was confirmed, however, persistent symptoms prompted subsequent biopsies, that revealed malignant melanoma. In Case 1, a 71-year-old man with Candida parapsilosis onychomycosis underwent an initial nail unit biopsy demonstrating at least melanoma in situ with ulceration. Repeat biopsy confirmed invasive melanoma with an approximate Breslow thickness of 1.0 mm, while final pathology following partial hallux amputation revealed residual ulcerated melanoma with a Breslow thickness of 2.1 mm, negative margins, and negative sentinel lymph nodes, consistent with Stage IIB disease. In Case 2, an 88-year-old woman with dermatophytic onychomycosis consistent with Trichophyton species had an initial fragmented biopsy demonstrating invasive subungual melanoma with an estimated Breslow thickness of 0.6 mm. Final pathology following distal hallux amputation confirmed residual acral melanoma with a Breslow thickness of 0.6 mm, no ulceration, a mitotic rate of less than 1/mm², and negative margins, consistent with pT1a disease. Factors contributing to delayed melanoma recognition differed between cases: prior trauma, delayed intervention, and chronic ulceration complicated Case 1, whereas treatment for presumed onychomycosis without improvement delayed suspicion in Case 2. Conclusions: These findings demonstrate that positive mycologic results do not exclude concurrent melanoma and underscore the potential for diagnostic anchoring bias, supporting early biopsy consideration in refractory or atypical nail dystrophy. Full article

Background: Candida auris (C. auris) has emerged as a multidrug-resistant fungal pathogen causing healthcare-associated outbreaks worldwide, particularly in intensive care units (ICUs). Its environmental persistence, multidrug resistance, and high mortality make it a major challenge for infection prevention and clinical management. This study aimed to investigate the clinical characteristics, clinical exposures, treatment outcomes, and mortality of adult ICU patients with C. auris candidemia during the first 30 months after the opening of a tertiary care hospital. Methods: This retrospective observational study included all adult patients (≥18 years) admitted to five ICUs between 1 July 2020 and 31 December 2022 who developed culture-confirmed C. auris candidemia. Isolates were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) with the Microflex LT/SH Smart MS system (Bruker Daltonics, Bremen, Germany) according to routine microbiological laboratory procedures. Demographic characteristics, underlying diseases, invasive procedures, clinical exposures, microbiological findings, treatment, APACHE II scores, and clinical outcomes were retrospectively analyzed. Results: During the 30-month study period, 3716 adult patients were admitted to the ICUs, and candidemia developed in 432 (11.6%). Of these episodes, 22 (5.1%) were caused by C. auris. The first C. auris candidemia case occurred 184 days after hospital opening. The mean age was 55 ± 17 years, and overall ICU mortality was 77.3%. Sepsis (36.4%), malignancy (22.7%), and cerebrovascular disease (18.2%) were the most common reasons for ICU admission. All patients had received broad-spectrum antibiotics, whereas central venous catheterization and invasive mechanical ventilation were present in 77.3% of cases. The mean interval from ICU admission to candidemia was 49 ± 15 days. Caspofungin was used as first-line antifungal therapy in all patients. Non-survivors had significantly higher APACHE II scores (32.8 ± 4.9 vs. 26.4 ± 6.6, p = 0.029) and predicted mortality rates (80.1% vs. 53.3%, p = 0.012). Antifungal treatment duration was significantly shorter among non-survivors (p < 0.001), whereas no significant differences were observed in age, ICU length of stay, or time to blood culture clearance. Conclusions: C. auris candidemia was observed in critically ill patients with prolonged ICU stays and frequent invasive interventions and was associated with high all-cause ICU mortality. Higher APACHE II scores were associated with mortality in this cohort, reflecting greater baseline severity of illness. Given the small sample size and descriptive, exploratory nature of the study, these findings should be interpreted with caution. The effectiveness of specific infection-control, diagnostic, or therapeutic interventions was not evaluated. Larger multicenter prospective studies are needed to better characterize the epidemiology, clinical outcomes, and factors associated with mortality in C. auris candidemia. Full article

Invasive aspergillosis and mucormycosis are life-threatening fungal infections characterized by high early mortality, substantial toxicity, and intensive healthcare resource utilization. While multiple antifungal therapies are recommended in international guidelines, their comparative clinical and economic value remains uncertain, particularly in resource-limited settings. We developed a hybrid decision tree and Markov model to evaluate antifungal strategies, including liposomal amphotericin B, isavuconazole, voriconazole, posaconazole, and caspofungin, from the perspective of the Colombian healthcare system over a 6-month horizon. Health states included clinical response, treatment failure, toxicity, and death. Outcomes included quality-adjusted life-years (QALYs), costs, incremental cost-effectiveness ratios (ICERs), and net monetary benefit (NMB). Deterministic and probabilistic sensitivity analyses were performed. In invasive aspergillosis, isavuconazole provided a modest incremental benefit over voriconazole (+0.022 QALYs), driven primarily by improved tolerability, at an incremental cost of COP 3.4 million, yielding an ICER of COP 154.5 million/QALY. In mucormycosis, liposomal amphotericin B yielded greater survival benefits (+0.035 QALYs) but at substantially higher costs (ICER: COP 494.3 million/QALY). Across willingness-to-pay thresholds, isavuconazole and voriconazole demonstrated more favorable economic profiles, owing to lower toxicity and reduced hospitalizations. These findings highlight that the clinical–economic value of antifungal therapy is primarily determined by early survival gains, toxicity burden, and front-loaded costs. Strategies minimizing toxicity and hospitalization appear more efficient in constrained health systems, whereas survival-maximizing approaches may be justified in severe disease. This integrated analysis supports context-specific antifungal decision-making in the management of invasive fungal infections. Full article

Invasive fungal infections (IFIs) are associated with high morbidity and mortality, particularly in immunocompromised or critically ill patients and in those with complex comorbidities. Despite advances in mycological diagnosis and antifungal therapy, outcomes remain poor in a significant proportion of patients. In clinical practice, a poor response is often attributed to microbiological resistance. This interpretation may lead to empirical treatment escalation, combination therapy without a clear indication, increased toxicity, clinically relevant drug–drug interactions, and inefficient use of healthcare resources. However, therapeutic failure rarely results from a single mechanism. More often, it reflects the interaction among host vulnerability, pathogen characteristics, delayed, incomplete, or incorrect diagnosis, insufficient antifungal exposure, and inadequate source control. This narrative review presents a structured clinical approach to evaluating suboptimal responses in IFIs without attributing them solely to antifungal resistance. It examines cross-cutting determinants and specific patterns associated with invasive aspergillosis, invasive candidiasis and persistent candidemia, cryptococcal meningitis, mucormycosis, infections caused by rare filamentous fungi, and disseminated endemic mycoses. It also presents clinical algorithms, checklists, and potential quality indicators to distinguish true from apparent failure, identify modifiable factors, and support transparent clinical decision-making within antifungal stewardship programs. The proposed framework supports the assessment of non-response through systematic diagnostic and therapeutic reassessment, timely source control, and identification of modifiable gaps in care. Full article

Oil palm is a major commodity crop in Southeast Asia, particularly in Malaysia and Indonesia, but its productivity is severely threatened by basal stem rot (BSR) and upper stem rot (USR) caused by the white-rot fungus Ganoderma boninense. Infected palms can lose up to 80% yield and die within 6–24 months (young) or 2–3 years (mature). Despite extensive field management efforts, disease incidence continues to rise, especially after replanting. Understanding infection mechanisms and validating fungal virulence factors are crucial for effective control, yet functional genomics in G. boninense has been limited. Previous RNAi-based gene silencing provided initial insights but was constrained by off-target effects and transient activity. Here, we report the first successful application of CRISPR/Cas9 genome editing in G. boninense for functional gene studies. Two genes were targeted: pyrG, essential in uridine monophosphate (UMP) biosynthesis; and hyd-2, encoding a hydrophobin, a potential virulence determinant implicated in host invasion. The disruption of pyrG produced a uracil auxotroph, and the knockout was validated by screening on 5-FOA and validated our system as a functional molecular tool. Disruption of hyd-2 reduced infection capability of the fungus by ~72% to ~91% in vitro. Mutations in both gene disruptions, including insertions, deletions, and substitutions, were confirmed by sequencing. Sequencing analysis also revealed incomplete editing events, as wild-type gene sequences were detected alongside edited alleles in the mutants. Future enhancements should focus on improving editing efficiency of the system. This work establishes a robust platform for functional genetic analysis and dissecting pathogenicity in G. boninense, ultimately advancing strategies to mitigate basal stem rot disease in oil palm. Full article

Background: Invasive aspergillosis (IA) is a severe complication after solid organ transplantation, especially in patients receiving long-term immunosuppressive therapy. Pulmonary artery involvement caused by Aspergillus fumigatus is extremely rare and may mimic pulmonary artery thrombosis or malignancy, resulting in diagnostic challenges. Case Presentation: A 61-year-old male developed fatigue, intermittent fever, cough, and chest discomfort seven months after orthotopic heart transplantation. Computed tomography pulmonary angiography revealed a mass-like filling defect involving the main pulmonary artery and left pulmonary artery, which was initially suspected to represent pulmonary artery thrombosis or tumor. Whole-blood next-generation sequencing identified Aspergillus fumigatus and Streptococcus mitis. The patient was treated with voriconazole, anticoagulation therapy, and adjustment of immunosuppressive therapy. Follow-up imaging demonstrated progressive regression of pulmonary artery lesions and disappearance of pulmonary nodules without evidence of graft rejection. Conclusions: Pulmonary artery aspergillosis should be considered in heart transplant recipients presenting with pulmonary artery-occupying lesions, particularly when imaging findings are atypical. Early pathogen identification combined with appropriate antifungal therapy, individualized immunosuppression adjustment, and careful monitoring may improve clinical outcomes. Full article

Candida infections represent a major global public health challenge and remain among the most common opportunistic fungal infections worldwide. Although Candida albicans remains the predominant pathogen, the incidence of infections caused by non-albicans species, particularly Candidozyma auris, has increased substantially in recent years. Candida infections range from superficial mucocutaneous disease to invasive life-threatening infections associated with high morbidity and mortality. In addition to clinical burden, growing evidence indicates a substantial negative impact on health-related quality of life, particularly among patients with recurrent vulvovaginal candidiasis and chronic fungal infections. Full article

Invasive fungal infections, including candidemia and invasive aspergillosis, remain significant causes of morbidity and mortality in at-risk patient populations. Rapid, accurate diagnosis is critical for timely antifungal therapy and improved clinical outcomes. We evaluated two commercial molecular assays, the CandID Multiplex PCR and AspID Real-Time PCR, for detection of clinically relevant Candida and Aspergillus species, respectively, in at-risk patients in Paraguay. The CandID assay demonstrated strong agreement with blood culture in detecting candidemia. The AspID assay showed high concordance with galactomannan testing, particularly in bronchoalveolar lavage specimens, supporting its role as a complementary diagnostic tool. Our findings underscore the value of integrating molecular diagnostics into routine fungal diagnostic workflows to improve early detection of invasive fungal infections. Full article

Fragrant pear canker, caused by Cytospora pyri, is a major branch disease that reduces the productivity and longevity of Korla fragrant pear orchards in Xinjiang, China. During infection and lesion expansion in woody tissues, C. pyri must breach the host cell wall barrier, in which pectin degradation plays a central role by weakening intercellular adhesion and disrupting tissue integrity. Members of glycoside hydrolase family 28 (GH28), represented mainly by polygalacturonases and other pectin-degrading enzymes, are closely involved in fungal invasion and colonization. However, the composition and virulence-related functions of this gene family encoding for these enzymes in C. pyri remain unclear. In this study, GH28 genes were systematically identified and comparatively analyzed in C. pyri and closely related Cytospora species. Infection-stage expression profiling and functional validation were then performed to assess their roles in pathogenicity. A total of 73 GH28 genes were identified across five Cytospora species, including 15 in C. pyri. Most C. pyri GH28 proteins were predicted to be acidic, hydrophilic, extracellularly secreted proteins carrying conserved motifs. Phylogenetic analysis showed that C. pyri GH28 members were closely related to homologs from C. mali. Genomic distribution analysis revealed that these genes were dispersed across multiple scaffolds, with no obvious tandem duplication events. RT-qPCR analysis showed that all seven candidate GH28 genes were induced during infection of fragrant pear branches, with VP1G_08835 and VP1G_03209 exhibiting strong expression responses at 6 dpi. Functional validation further showed that deletion of VP1G_08835 impaired vegetative growth and reduced lesion length on detached pear branches by 26.62% compared with the wild type, whereas complementation restored these phenotypes. These findings demonstrate that GH28 genes participate in C. pyri infection and identify VP1G_08835 as an important GH28 member required for normal growth and contributing to virulence. Full article