Mycoses最新文献

Background: Dermatophytes are the most common agents of superficial mycoses in humans and animals. In a model of Trichophyton benhamiae dermatophytosis in its natural host (guinea pig), the most overexpressed gene was subtilisin 6 (SUB6). Given the availability of powerful genetic and immunological tools in mice, murine models of dermatophytosis should be developed using strains that can mimic natural infections.

Objective: The aim of this study was to test a strain of Trichophyton mentagrophytes isolated from a rodent in a murine skin infection model, to characterise the expression of key host and fungal genes and investigate the role of SUB6 in virulence by mimicking a natural infection as closely as possible.

Results: A phylogenetic tree was generated to better discriminate the T. mentagrophytes strains isolated from animals. The T. mentagrophytes TIMM 2789 strain used in this study is genotype IV, specific to rodents. Infection induced symptoms and lesions, including hair follicle invasion, typical of acute superficial dermatophytosis. Early overexpression of genes encoding specific cytokines revealed the involvement of the Th1, Th2 and Th17 responses by the host, and the overexpression of the fungal SIDC gene underscores the importance of iron acquisition during infection. The use of deleted and complemented SUB6 strains revealed that SUB6 does not appear to be necessary for fungal virulence, while SUB5 overexpression suggests a compensatory mechanism.

Conclusion: This study demonstrates the crucial importance of carefully selecting the most appropriate dermatophyte strain for the animal species in the experimental model used.

Invasive pulmonary aspergillosis (IPA) is increasingly recognised in intensive care units (ICU) affecting not only patients with classical immunosuppressive conditions but also other severely ill patients, including those with respiratory viral infections (influenza, COVID-19), advanced chronic obstructive pulmonary disease or acute and chronic liver diseases. Several expert panels have proposed definitions of IPA in different ICU settings. However, practical recommendations for its diagnostic and therapeutic approaches are scarce. Moreover, these approaches can be influenced by different parameters that may vary across countries including the case mix of ICU patients, the incidence of IPA, the prevalence of azole resistance and the availability of diagnostic tests and antifungal drugs. For these reasons, the Fungal Infection Network of Switzerland (FUNGINOS) has appointed a panel of different specialists to develop a practical guideline for the management of IPA in ICU. This article provides the executive summary of the panel conclusions and recommendations regarding the epidemiology, diagnosis, definitions and therapy of IPA in ICU.

Background: Dermatomycoses, superficial fungal infections of the skin, hair and nails, are among the most common dermatological conditions worldwide. Rapid and accurate diagnosis is essential, particularly in light of emerging antifungal resistance. Conventional diagnostic methods are limited by long turnaround times and lack of species-level specificity; hence the use of modern DNA-based tools should be expedient.

Objectives: The aim of this study was to evaluate the diagnostic performance of a pan-dermatophyte PCR-based workflow for dermatomycosis in routine diagnostics and to describe the epidemiological landscape in Tyrol, Austria.

Methods: In this retrospective study, 4483 patient specimens (skin, hair and nails) submitted to the Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, between 2018 and 2024 were analysed. The workflow included initial pan-dermatophyte PCR, followed by microscopy and fungal culture for PCR-negative or inconclusive cases. Species identification was performed by Matrix-assisted Laser-Desorption Ionisation Time-of-Flight mass spectrometry or, if unsuccessful, by sequencing.

Results: Of all specimens, 1170 (26.1%) were PCR-positive, predominantly with Trichophyton rubrum (76.4%), or members of the T. mentagrophytes-interdigitale complex (15.4%). In PCR-negative but microscopy-positive samples, 67 dermatophytes were identified by culture. The PCR-based workflow demonstrated a sensitivity of 94.6%, a negative predictive value of 98.0%, and an overall diagnostic accuracy of 98.5%. Among 335 non-dermatophyte fungi, Aspergillus spp. were most frequent.

Conclusion: The proposed workflow demonstrated high sensitivity and accuracy, supporting its suitability for routine diagnostics. It reduced the need for microscopy and culture while enabling reliable species-level identification, facilitated epidemiological surveillance, revealing a predominance of T. rubrum.

Background: The prevalence of onychomycosis among children is suspected to be increasing. The current global prevalence of paediatric onychomycosis ranges from 0% to 7.7%. Clinical observations in Denmark suggest the same but to our knowledge no study exists estimating the prevalence of onychomycosis among Danish children.

Objective: The aim of the study was therefore to estimate this prevalence.

Methods: Children and their siblings were included upon visiting the Paediatric Department, Zealand University Hospital, Roskilde, Denmark. The children and their legal guardian, if under the age of 15 years, were asked to answer a questionnaire, and the children had their finger- and toenails photographed. Children with nail abnormalities suggestive of onychomycosis were offered a referral to the Department of Dermatology, Zealand University Hospital, Roskilde, Denmark for clinical and mycological examination.

Results: A total of 170 children with a mean age of 6.9 years were included. Ninety-seven (57.1%) were boys and a total of 46.5% of the children were healthy. Twenty-nine children had nail abnormalities, and 23 accepted a referral to the Department of Dermatology. Four children had onychomycosis, all caused by T. rubrum, resulting in an estimated prevalence of 2.4% (CI 0.6%-5.9%).

Conclusion: The estimated prevalence (2.4%) of onychomycosis among Danish children is higher than expected compared to other European countries, but larger studies are needed to validate these findings. This supports the suggestion of an increasing prevalence of paediatric onychomycosis.

Objectives: This study reports the first isolation of a multidrug-resistant Trichophyton rubrum strain in China, characterizing its drug resistance profile and mechanisms.

Methods: The isolate was identified by internal transcribed spacer (ITS) sequencing and phylogenetic analysis. In vitro antifungal susceptibility testing (AFST) was performed according to the M38-A3 CLSI guideline to determine minimum inhibitory concentrations (MICs) against eight antifungals (terbinafine, itraconazole, fluconazole, amorolfine, griseofulvin, voriconazole, luliconazole and amphotericin B). Whole genome sequencing (WGS), transcriptome sequencing and qRT-PCR were performed to explore the resistance mechanism.

Results: The multidrug-resistant T. rubrum strain L-6424 was isolated from a Chinese patient with generalised tinea corporis/cruris, tinea unguium and tinea manuum. It exhibited elevated MICs to terbinafine (2 mg/L), itraconazole (0.5 mg/L), and amorolfine (0.5 mg/L). The phylogenetic tree based on genome-wide single nucleotide polymorphisms (SNPs) showed L-6424 is not a novel genotype of T. rubrum, with high genetic similarity (99.94%) with the reference strain (CBS 139224). There were three amino acid substitutions in the squalene epoxidase (SQLE), including the previously reported F397L and H440Y, as well as a newly discovered V105M, and one amino acid substitution in the CYP51A (R239C) was identified. Also, significant differences at the transcriptome level between the drug-resistant and sensitive strains were observed, and it was screened and found that CYP51A, TruMDR5 and TERG_08139 may be related to azole resistance.

Conclusions: Drug-resistant T. rubrum has emerged in China, indicating the possibly increasing severity of antifungal resistance. The complex mechanism of multidrug-resistant dermophytes poses challenges to clinical treatment, needing more attention.

Background: Nitroxoline is an old antibiotic currently approved for the treatment of uncomplicated urinary tract infections. Its mode of action is based on the chelation of bivalent cations, such as zinc.

Objectives: As zinc plays a central role in the metabolism of Aspergillus spp., we performed antifungal susceptibility testing against Nitroxoline using broth microdilution.

Methods: Overall, 13 Aspergillus isolates were tested according to the EUCAST guidance document (Guinea et al. EUCAST, def. doc. 9.4, 2022) including two genetically proven Azole-resistant strains.

Results: The overall Minimal Inhibitory Concentration (MIC)_50/90 was 0.5 mg/L.

Conclusions: These results correspond to excellent in vitro activity against Aspergillus spp.

Background: The global double-blind, randomised, Phase 3 ReSTORE trial (NCT03667690) demonstrated noninferiority of rezafungin versus caspofungin for all-cause mortality at Day 30 and global cure at Day 14 in patients with candidemia and/or invasive candidiasis.

Objectives: We report outcomes for patients from China (ReSTORE China), comprising participants enrolled in the original ReSTORE trial (n = 11) and from an extended, China-only phase (n = 47) implemented to fulfill Chinese regulatory requirements.

Methods: Patients with candidemia/invasive candidiasis were randomised 1:1 to intravenous rezafungin (400 mg loading, then 200 mg once weekly) or caspofungin (70 mg loading, then 50 mg once daily) for ≤ 4 weeks. Primary endpoints were all-cause mortality at Day 30 and global cure at Day 14 in the modified intent-to-treat population. Between October 2018 and March 2024, 58 patients were randomised and received study treatment (rezafungin n = 28 [modified intent-to-treat n = 27], caspofungin n = 30 [modified intent-to-treat n = 28]).

Results: All-cause mortality at Day 30 was 33.3% (9/27) for rezafungin versus 35.7% (10/28) for caspofungin (difference -2.4% [95% confidence interval -27.0-22.6]). Global cure at Day 14 was 48.1% (13/27) versus 46.4% (13/28), respectively (weighted difference 0.3% [95% confidence interval -25.4-26.3]). Day 5 and 14 mycological eradication rates were 70.4% and 63.0% for rezafungin versus 71.4% and 67.9% for caspofungin, respectively. Safety and tolerability profiles were similar between groups.

Conclusions: Rezafungin demonstrated similar efficacy and safety to caspofungin in the ReSTORE China cohort. These findings support the primary ReSTORE analysis and suggest that rezafungin could provide a new treatment option for candidemia/invasive candidiasis in China.

Trial registration: ClinicalTrials.gov identifier: NCT03667690.

Background: Atopic dermatitis (AD) is a common chronic skin disorder characterised by a highly inflamed local environment and elevated epidermal proteolytic activity. Changes in the skin mycobiome have been observed in this disease, specifically Candida albicans colonization positively correlating with AD severity, yet the mechanisms by which this fungus contributes to disease features remain elusive.

Objectives: This study aimed to elucidate how C. albicans can influence AD pathogenesis through its influence on keratinocyte (KC) proteolytic activity, inflammatory cytokine secretion and epidermal barrier integrity, as well as define the signaling pathways mediating these effects.

Methods: Immortalized human KC were co-cultured with C. albicans and changes in KC protease expression and activity, along with the secretion of the pro-inflammatory cytokine IL-1β were assessed. Additionally, the impact of IL-1β on KC barrier formation was determined using transepithelial electrical resistance. To identify signalling pathways mediating Candida-induced phenotypes, CRISPR/Cas9 was used to establish cell lines deficient in myeloid differentiation primary response protein 88 (MyD88) or matrix metalloprotease-9 (MMP-9).

Results: C. albicans induced proteolytic activity from KC through fungal secreted aspartyl proteases (Sap4-6) and promoted IL-1β secretion via MyD88 signalling. This response increased expression and activation of host MMP-9 and led to impaired barrier function. Genetic deletion of either MYD88 or MMP9 restored barrier function in IL-1β treated cells, suggesting MMP-9 serves as a downstream effector of IL-1β/MyD88 signalling.

Conclusion: These findings establish a mechanistic link between skin resident fungi and epidermal barrier dysfunction. We demonstrate a pathway linking fungal colonization to innate immune responses by skin cells, providing insight into how the commensal fungus C. albicans may contribute to AD pathogenesis.

Background: The global prevalence and incidence of fungal skin diseases continue to rise due to population ageing, urbanisation and environmental changes, posing a significant public health challenge. These infections are particularly severe in immunocompromised individuals, potentially leading to deep-seated infections and life-threatening complications. However, comprehensive data on the global burden of fungal skin diseases remain limited, especially in low- and middle-income countries (LMICs) with constrained resources.

Methods: Using Global Burden of Disease (GBD) data from 1990 to 2021, this study analysed trends in incidence, prevalence and disability-adjusted life years (DALYs) across 204 countries and territories. Joinpoint regression was employed to identify temporal trend changes, while the Age-Period-Cohort (APC) model was used to disentangle age, period and cohort effects. Additionally, the Bayesian Age-Period-Cohort (BAPC) model was applied to project disease burden from 2022 to 2036.

Results: In 2021, the global age-standardised incidence rate (ASIR) was 21,668.4 per 100,000 population, showing a slight increase compared to 1990 (Estimated annual percentage change [EAPC] = 0.11). The burden exhibited marked disparities by Socio-demographic Index (SDI): low-SDI countries had the highest ASIR and DALYs (e.g., Ethiopia's ASIR reached 45,535.04 per 100,000), whereas high-SDI countries demonstrated a declining trend. Joinpoint regression revealed pronounced fluctuations in low-SDI nations, contrasting with sustained declines in high-SDI regions. APC analysis indicated elevated risks among older populations and younger birth cohorts. BAPC projections suggested a continued rise in global incidence by 2030, with females likely facing a higher burden than males.

Conclusion: The burden of fungal skin diseases is closely linked to socioeconomic development, with resource-limited regions bearing the highest risks. The projected upward trend underscores the urgent need for targeted public health interventions, particularly in strengthening prevention and management systems in low-SDI countries. This study provides critical evidence to inform global strategies for mitigating the impact of fungal skin diseases.

Background: Posaconazole (POS) prophylaxis is recommended for the prevention of invasive mould infections among patients with haematologic cancer and prolonged neutropenia or following allogeneic haematopoietic cell transplantation. Albeit rare, breakthrough invasive mould infections (bIMI) are associated with high mortality rates.

Objectives: To assess the epidemiology, causes and outcomes of bIMI under POS prophylaxis.

Patients/methods: Haematologic cancer patients with a diagnosis of proven/probable bIMI while receiving POS prophylaxis for ≥ 7 days were retrospectively included in five hospitals (Switzerland and Germany). For each bIMI case, one to two non-bIMI controls receiving POS prophylaxis for the same haematologic condition were included.

Results: A total of 29 bIMI episodes and 46 controls were included. Baseline characteristics and median POS trough concentrations did not significantly differ between the two groups. Invasive aspergillosis was the most frequent bIMI (52%), followed by invasive mucormycosis (31%). POS non-susceptible pathogens were the causes of bIMI in 14% of cases. While insufficient POS exposure was observed in 39% of bIMI cases, this proportion was similar in the control group. Most bIMI were treated with liposomal amphotericin B first-line therapy and received multiple antifungal therapies. Overall mortality was significantly higher among bIMI compared to controls (52% vs. 20%, p = 0.005). Surgery was the only parameter significantly associated with survival.

Conclusions: This case-control study shows that bIMI is associated with a significant impact on mortality. Most bIMI were attributed to presumably POS-susceptible pathogens without a clear association with POS underexposure. The causes of bIMI remain unclear and may be the conjunction of multiple parameters.