OBJECTIVE: To evaluate the clinical outcomes of anidulafungin for candidemia treatment in critically ill obese patients.
METHODS: A multicenter, retrospective cohort study was conducted in Saudi Arabia for critically ill adults with candidemia who received anidulafungin. Patients with obesity have a body mass index ≥ 30 kg/m2. The primary outcome was the clinical cure rate.
RESULTS: 146 patients were included, 64 of whom were obese. There were no statistically significant differences in the clinical cure rate (P=0.63), microbiological cure rate (P=0.27), or the median time for a clinical cure (P=0.13) for patients with obesity compared to non-obese. The median time for a microbiological cure was longer in non-obese patients than in patients with obesity (P=0.04). The median hospital length of stay (LOS) and the median mechanical ventilation (MV) durations were numerically longer in obese patients.
CONCLUSIONS: Clinical and microbiological cure rates and time for clinical cure were statistically similar for both groups. Considering the study\'s limitations (especially with a small sample size), it is uncertain if patients with obesity have similar effectiveness to non-obese patients. Future studies with larger sample sizes are warranted to evaluate if obesity negatively impacts anidulafungin\'s clinical outcomes for candidemia.

BACKGROUND: Echinocandins belong to the fourth generation of antifungals, and there are no systematic studies on their risk in coagulation dysfunction; this study will predict the risk of coagulation dysfunction of echinocandins using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.
METHODS: Data from January 2004 to March 2024 were obtained from FAERS. We examined the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare echinocandins with the full database.
RESULTS: There were 313 reports of coagulation dysfunction related to echinocandins as the primary suspect (PS) drug. The median time to incident for coagulation dysfunction was 3 (interquartile range [IQR] 1-9) days. Compared to triazoles and polyenes, echinocandins have a stronger signal (ROR 3.18, 95%CI 2.81-3.51, p < 0.01) of coagulation dysfunction. Compared to caspofungin and micafungin, anidulafungin has a stronger signal (ROR 6.84, 95%CI 4.83-9.70, p < 0.01). The strongest signal corresponding to disseminated intravascular coagulation (DIC), platelet count decreased, thrombocytopenia, gastrointestinal haemorrhage, cerebral haemorrhage, pulmonary haemorrhage and thrombotic thrombocytopenic purpura (TTP) is micafungin (ROR 27.19, 95%CI 18.49-39.98), micafungin (ROR 3.50, 95%CI 2.36-5.19), anidulafungin (ROR 9.75, 95%CI 5.22-18.19), micafungin (ROR 3.17, 95%CI 2.02-4.97), micafungin (ROR 4.95, 95%CI 2.81-8.72), caspofungin (ROR 20.76, 95%CI 11.77-36.59), micafungin (ROR 20.43, 95%CI 8.49-49.14), respectively.
CONCLUSIONS: For coagulation dysfunction, we found stronger signals for echinocandins than triazoles and polyenes, and stronger signals for anidulafungin than micafungin and caspofungin. Coagulation parameters should be closely monitored while using the respective drugs.

The misfolding and aggregation of beta-amyloid (Aβ) peptides have been implicated as key pathogenic events in the early stages of Alzheimer\'s disease (AD). Inhibiting Aβ aggregation represents a potential disease-modifying therapeutic approach to AD treatment. Previous studies have identified various molecules that inhibit Aβ aggregation, some of which share common chemical substructures (fragments) that may be key to their inhibitory activity. Employing fragment-based drug discovery (FBDD) methods may facilitate the identification of these fragments, which can subsequently be used to screen new inhibitors and provide leads for further drug development. In this study, we used an in silico FBDD approach to identify 17 fragment clusters that are significantly enriched among Aβ aggregation inhibitors. These fragments were then used to screen anti-infective agents, a promising drug class for repurposing against amyloid aggregation. This screening process identified 16 anti-infective drugs, 5 of which were chosen for further investigation. Among the 5 candidates, anidulafungin, an antifungal compound, showed high efficacy in inhibiting Aβ aggregation in vitro. Kinetic analysis revealed that anidulafungin selectively blocks the primary nucleation step of Aβ aggregation, substantially delaying Aβ fibril formation. Cell viability assays demonstrated that anidulafungin can reduce the toxicity of oligomeric Aβ on BV2 microglia cells. Molecular docking simulations predicted that anidulafungin interacted with various Aβ species, including monomers, oligomers, and fibrils, potentially explaining its activity against Aβ aggregation and toxicity. This study suggests that anidulafungin is a potential drug to be repurposed for AD, and FBDD is a promising approach for discovering drugs to combat Aβ aggregation.

The limited number of available antifungal drugs and the increasing number of fungal isolates that show drug or multidrug resistance pose a serious medical threat. Several yeast pathogens, such as Nakaseomyces glabratus (Candida glabrata), show a remarkable ability to develop drug resistance during treatment through the acquisition of genetic mutations. However, how stable this resistance and the underlying mutations are in non-selective conditions remains poorly characterized. The stability of acquired drug resistance has fundamental implications for our understanding of the appearance and spread of drug-resistant outbreaks and for defining efficient strategies to combat them. Here, we used an in vitro evolution approach to assess the stability under optimal growth conditions of resistance phenotypes and resistance-associated mutations that were previously acquired under exposure to antifungals. Our results reveal a remarkable stability of the resistant phenotype and the underlying mutations in a significant number of evolved populations, which conserved their phenotype for at least two months in the absence of drug-selective pressure. We observed a higher stability of anidulafungin resistance over fluconazole resistance, and of resistance-conferring point mutations as compared with aneuploidies. In addition, we detected accumulation of novel mutations in previously altered resistance-associated genes in non-selective conditions, which suggest a possible compensatory role. We conclude that acquired resistance, particularly to anidulafungin, is a long-lasting phenotype, which has important implications for the persistence and propagation of drug-resistant clinical outbreaks.

The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical Candida isolates (including 400 C. albicans, 200 C. glabrata, 200 C. parapsilosis, 150 C. tropicalis and 50 C. krusei) and 150 Aspergillus isolates (100 A. fumigatus and 50 A. flavus) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against C. albicans that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common Candida species. C. tropicalis exhibited higher resistance rates (about 8.67-40.67% in different antifungals) than the other four Candida species. Through the sequencing of FKS genes, we searched for mutations in echinocandin-resistant C. tropicalis isolates and found that all displayed alterations in FKS1 S654P. The determined MEC (minimal effective concentration) values against A. fumigatus and A. flavus for rezafungin (0.116 μg/mL, 0.110 μg/mL) are comparable to those of caspofungin (0.122 μg/mL, 0.142 μg/mL) but higher than for anidulafungin (0.064 μg/mL, 0.059 μg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common Candida and Aspergillus species. Rezafungin showed higher susceptibility rates against C. glabrata. Rezafungin indicates its potent activity for potential clinical application.

暂无摘要。

Introduction. The increasing prevalence and growing resistance of fungi present a significant peril to public health. There are only four classes of antifungal medicines available today, and few candidates are in clinical trials.Hypothesis/Gap Statement. Rapid and sensitive diagnostic techniques are lacking for most fungal pathogens, and those that do exist are expensive or hard to obtain.Aim. This study aimed to evaluate the feasibility of a novel automated antifungal susceptibility testing system, Fungus AST, in comparison to the broth microdilution method (BMD) recommended by the Clinical and Laboratory Standards Institute (CLSI).Methodology. A total of 101 clinical Candida spp. isolates were collected from the Zengcheng Branch of Nanfang Hospital and subjected to antifungal susceptibility testing. Antifungal susceptibility was assessed using the Fungus AST method and the BMD.Results. In this study, we introduce a novel automated antifungal susceptibility testing system, Fungus AST, which detects the turbidity and/or colour intensity of microdilution wells using a four-wavelength detection technology in real time and is designed to match the growth characteristics of strains over time. Based on our analysis, all reportable ranges of Fungus AST were suitable for clinical fungal isolates in PR China. Within ±twofold dilutions, reproducibility was 100 %. Considering the BMD as a referenced method, ten antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B, 5-flucytosine and nystatin) showed an essential agreement of >95 %. The category agreement of five antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole and voriconazole) was excellent at >90 %. One Candida albicans isolate and voriconazole showed a major error (ME) (1.7 %), and no other ME or very ME agents were found.Conclusion. Given the above, it can be argued that the utilization of Fungus AST is a discretionary automated approach. More improvements are needed in Fungus AST compared to the BMD system for a wider range of clinical isolates, including different types of fungi.

BACKGROUND: Fluconazole-resistant Candida parapsilosis is a matter of concern.
OBJECTIVE: To describe fluconazole-resistant C. parapsilosis genotypes circulating across hospitals in Spain and Rome and to study their azole-resistance profile associated with ERG11p substitutions.
METHODS: We selected fluconazole-resistant C. parapsilosis isolates (n = 528 from 2019 to 2023; MIC ≥8 mg/L according to EUCAST) from patients admitted to 13 hospitals located in five Spanish cities and Rome. Additionally, we tested voriconazole, posaconazole, isavuconazole, amphotericin B, micafungin, anidulafungin and ibrexafungerp susceptibility.
RESULTS: Of the 53 genotypes found, 49 harboured the Y132F substitution, five of which were dominating city-specific genotypes involving almost half the isolates. Another genotype involved isolates harbouring the G458S substitution. Finally, we found two genotypes with the wild-type ERG11 gene sequence and one with the R398I substitution. All isolates were fully susceptible/wild-type to amphotericin B, anidulafungin, micafungin and ibrexafungerp. The azole-resistance patterns found were: voriconazole-resistant (74.1%) or voriconazole-intermediate (25.2%), posaconazole-resistant (10%) and isavuconazole non-wild-type (47.5%). Fluconazole-resistant and voriconazole non-wild-type isolates were likely to harbour substitution Y132F if posaconazole was wild type; however, if posaconazole was non-wild type, substitution G458S was indicated if isavuconazole MIC was >0.125 mg/L or substitution Y132F if isavuconazole MIC was ≤0.125 mg/L.
CONCLUSIONS: We detected a recent clonal spread of fluconazole-resistant C. parapsilosis across some cities in Spain, mostly driven by dominating city-specific genotypes, which involved a large number of isolates harbouring the Y132F ERG11p substitution. Isolates harbouring substitution Y132F can be suspected because they are non-susceptible to voriconazole and rarely posaconazole-resistant.

Candida glabrata is the most common non-albicans Candida species that causes vulvovaginal candidiasis (VVC). Given the intrinsically low susceptibility of C. glabrata to azole drugs, investigations into C. glabrata prevalence, fungal susceptibility profile, and molecular epidemiology are necessary to optimise the treatment of VVC. This molecular epidemiological study was conducted to determine antifungal drug profile, single nucleotide polymorphisms (SNPs) associated with phenotypic antifungal resistance and epidemic diversity of C. glabrata isolates from women with VVC in Namibia. Candida glabrata isolates were identified using phenotypic and molecular methods. Antifungal susceptibility of strains was determined for fluconazole, itraconazole, amphotericin B, and anidulafungin. Whole genome sequencing was used to determine SNPs in antifungal resistance genes and sequence type (ST) allocation. Among C. glabrata isolates, all (20/20; 100%) exhibited phenotypic resistance to the azole class antifungal drug, (fluconazole), and phenotypic susceptibility to the polyene class (amphotericin B), and the echinocandins (anidulafungin). Non-synonymous SNPs were identified in antifungal resistance genes of all fluconazole-resistant C. glabrata isolates including ERG6 (15%), ERG7 (15%), CgCDR1 (25%), CgPDR1 (60%), SNQ2 (10%), FKS1 (5.0%), FKS2 (5.0%), CgFPS1 (5.0%), and MSH2 (15%). ST15 (n = 8/20, 40%) was predominant. This study provides important insight into phenotypic and genotypic antifungal resistance across C. glabrata isolates from women with VVC in Namibia. In this study, azole resistance is determined by an extensive range of SNPs, while the observed polyene and echinocandin resistance-associated SNPs despite phenotypic susceptibility require further investigation.
Candida glabrata is inherently resistant to azole drugs. In this study, we identified a clone that was predominant in women with vulvovaginal candidiasis in Namibia, and that harboured various mutations in resistance-associated genes. This study provides important insight into antifungal resistance across C. glabrata isolates in a sub-Sahara African setting.

Invasive candidiasis is a major hospital-acquired infection. Usually, echinocandins are considered first-line treatment. However, resistant phenotypes have emerged. Ibrexafungerp (IBX) is a new antifungal substance with potent anti-Candida activity. We challenged IBX with a library of 192 pheno-/genotypically echinocandin-resistant Candida isolates, focusing on the substance susceptibility, its activity on certain FKS hotspot (HS) mutated strains, and applying WTULs (wild-type upper limits). Therefore, a 9-year-old strain and patient data collection provided by the German National Reference Center for Invasive Fungal Infections were analyzed. Species identification was confirmed through ITS-sequencing. Molecular susceptibility testing was performed by sequencing HS of the FKS gene. Anidulafungin (AND) and IBX EUCAST-broth-microdilution was conducted. The four most common echinocandin-resistance mediating mutations were found in Candida glabrata [112/192 isolates; F659-(43×) and S663-(48×)] and Candida albicans [63/192 isolates; F641-(15×) and S645-(39×)]. Mutations at the HS-start sequence were associated with higher IBX MIC-values (F659 and F641 (MIC 50/90 mg/L: >4/>4 and 2/4 mg/L) in comparison to AND (F659 and F641 (MIC 50/90: 1/4 and 0.25/1 mg/L). MIC-values in HS-center mutations were almost equal [MIC50/90 in S663: 2/4 (AND and IBX); in S645: 0.5/1 (AND) and 0.25/1 (IBX) mg/L]. In total, 61 vs 78 of 192 echinocandin-resistant isolates may be classified as IBX wild type by applying WTULs, whereas the most prominent effect was seen in C. albicans [48% (30/63) vs 70% (44/63)]. IBX shows in vitro activity against echinocandin-resistant Candida and thus is an addition to the antifungal armory. However, our data suggest that this effect is more pronounced in C. albicans and strains harboring mutations, affecting the HS-center.