Search Results (184)

Aspergillus spp. are common environmental molds worldwide and mostly cause infections in immunocompromised individuals. We have previously shown that black aspergilli (Aspergillus section Nigri) isolates are the most common aspergilli in indoor and outdoor hospital environments in Kuwait. This study reports on the relative prevalence of different Aspergillus section Nigri complex species among clinical isolates and their susceptibility to antifungal drugs. Black aspergilli isolated from clinical (n = 34) and environmental (n = 2) sources were studied. The isolates were initially identified as Aspergillus section Nigri complex members based on morphological characteristics. Species-specific identification was carried out by PCR-sequencing of the β-tubulin gene fragment and sequence comparisons with the GenBank database. The phylogenetic analysis was performed by using the Maximum Likelihood method in MEGA (version 11) software. Antifungal susceptibility testing was performed by Etest. The phylogenetic analysis based on β-tubulin gene sequences identified only three species: A. niger sensu stricto (A. niger) (n = 26), A. tubingensis (n = 7), and A. luchuensis (n = 1) among 34 clinical Aspergillus section Nigri isolates in Kuwait. All seven otomycoses cases were due to A. niger. The two environmental isolates were identified as A. niger and A. tubingensis. All isolates appeared susceptible to all five (amphotericin B, itraconazole, voriconazole, posaconazole, and caspofungin) antifungal drugs tested. In conclusion, our study shows that A. niger predominates among phenotypically identified clinical isolates of the Aspergillus section Nigri complex, and that A. niger is also the main agent in otomycosis cases in Kuwait. The detection of only three species within the Aspergillus section Nigri complex in Kuwait could be due to the limited number (n = 34) of clinical isolates analyzed in this study. Full article

Imaging of infections has the potential to improve clinical outcomes, but pathogen-specific imaging strategies are currently unavailable. Given their target specificity, antimicrobials may be useful as molecular imaging ligands to target infections. Despite substantial development efforts, no antimicrobial-based ligands are approved for clinical use. This scoping review comprehensively surveys radiolabeled antimicrobials across antibacterial, antimycobacterial, antiviral, and antifungal drug classes, examining their progression through the translational pipeline. The review utilized PubMed and Google Scholar databases (1970–2025), following PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. Two reviewers independently screened titles, abstracts, and full-text articles; data were extracted, and content duplicates were removed. In total, 143 preclinical and 25 clinical articles met the selection criteria. In clinical studies, most tracers showed suboptimal specificity for infections, while some proved useful for pharmacokinetic characterization. Among preclinical studies, radiolabeled plazomicin and echinocandins (caspofungin and anidulafungin) exhibited the greatest number of preferred characteristics. In conclusion, ideal antimicrobial pharmacologic properties can be counterproductive for imaging, where rapid background clearance and a high target-to-non-target ratio (T/NT) are essential. Many radioligands demonstrate good tissue penetration but suboptimal washout, limiting their diagnostic value. In vivo pharmacokinetic applications during active infections are promising, though significant challenges remain for infection imaging. Full article

Objectives: Recurrent vulvovaginal candidiasis (RVVC) is a difficult-to-treat infection, most likely due to the growth of Candida biofilms on the human vaginal epithelium. We assessed in vitro efficacy of conventional antifungals and complementary and alternative medicine (CAM) used in clinical settings, and sought for Candida biofilm-effective single or combination therapies. Methods: Standard broth microdilution assay and XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) assay were used for antifungal and anti-biofilm efficacies of three conventional antifungals, and selected CAM including boric acid, povidone-iodine, and allicin (garlic extract), against Candida clinical isolates grown at neutral and acidic pHs respectively. Fractional inhibitory concentration (FIC) indices were assessed to evaluate interactions between fluconazole and different CAM. Viable count-based cell enumeration and confocal laser scanning microscopy (CLSM) were performed to confirm the efficacy of single or combination therapies against Candida biofilms. Results: All selected conventional antifungals and CAM showed efficacies against planktonic Candida cells. Acidic vaginal microenvironments provided agent-specific protection to Candida cells against conventional antifungals and the CAM. Synergistic or additive interactions were observed between fluconazole at serum achievable concentrations and povidone-iodide at topically achievable concentrations against all tested Candida strains. Most antifungal agents except caspofungin had very limited activities against Candida biofilms. Combining fluconazole at 8 mg/L with povidone-iodine at 2048 mg/L effectively killed Candida biofilms in an acidic vaginal microenvironment to a level that is comparable to that of caspofungin. Conclusions: We provided robust in vitro evidence supporting the combinational use of oral fluconazole and topical CAM povidone-iodine against Candida biofilms in managing RVVC. Full article

Candida species, particularly Candida albicans (C. albicans), are the leading cause of vulvovaginal candidosis (VVC) among women of reproductive age. In recent years, the epidemiology of VVC has shifted toward non-albicans Candida (NAC) species, accompanied by increasing antifungal resistance. This retrospective study evaluated the epidemiological profile of VVC and antifungal susceptibility patterns in Greece between 2020 and 2024 at a tertiary maternity and gynecological hospital. Species identification was performed using the VITEK^® 2 system, and antifungal susceptibility followed EUCAST guidelines. A total of 526 vaginal swab samples were analyzed, comprising C. albicans (57.9%) and NAC species (42.1%). The median age was 36.3 years (range: 18–92). Among NAC isolates, Nakaseomyces glabratus (26.4%) predominated, followed by Pichia kudriavzevii (7.6%), Candida parapsilosis (5.1%), and Candida tropicalis (3.0%). Resistance rates among C. albicans isolates increased from 9.3% in 2020 to 22.3% (fluconazole) and 20.9% (itraconazole) in 2024. Voriconazole resistance was not detected until 2023 and 2024, when rates rose to 3.2% and 15.2%. Fluconazole resistance was observed in C. parapsilosis (3.5%) and C. tropicalis (12.5%). Echinocandin resistance remained low overall, except for N. glabratus, which demonstrated a 13.8% resistance rate to caspofungin. These findings highlight the need for surveillance, improved diagnostics and antifungal stewardship. Full article

Genetic diversity and antifungal susceptibility profiles of Aspergillus fumigatus are critical for understanding the evolution of resistance in clinical and environmental settings. We performed comprehensive genomic characterization of A. fumigatus isolates using whole-genome sequencing combined with phenotypic susceptibility assays. SnpEff-based variant annotation identified 76,079 single-nucleotide polymorphisms, revealing a high proportion of mutations (78.8%) in upstream and downstream regulatory regions, whereas high-impact coding variants remained rare (0.083%). Several key mutations were identified, including the well-established cyp51A M220V and HMG1 S212P/Y564H mutations. Moreover, a diverse array of peripheral cyp51A polymorphisms (M39I, E402D, N248K, and K372N) was detected, although these variants did not correlate with the resistant phenotypes. Our comparative genomic analysis identified a novel A586T substitution in the FKS1 gene in an isolate with an elevated minimum effective concentration of caspofungin, suggesting its possible association with reduced susceptibility, although functional validation is required. In isolates lacking canonical target-site mutations, the high frequency of regulatory-region variants indicated the involvement of non–target-site mechanisms. This study provides a detailed map of the genomic landscape of A. fumigatus and identifies candidate loci for future functional validation. Our results demonstrate the utility of high-throughput genomic surveillance for monitoring emerging resistance trends and characterizing the genetic background of clinical fungal pathogens. Full article

Candidozyma auris is an emerging multidrug-resistant fungal pathogen associated with severe invasive infections and high mortality, particularly in healthcare environments. Its rapid global expansion and resistance to multiple antifungal classes pose major challenges to treatment and containment. Extracellular vesicles (EVs) have recently been recognized as important mediators of fungal communication, virulence, and stress adaptation. Here, we examine how caspofungin, a frontline echinocandin, reshapes the EV metabolome of C. auris. Caspofungin exposure drives pronounced remodeling of EV size distributions, yielding a predominance of smaller, more uniform EVs alongside a minor population of larger subtypes. Metabolomic profiling of EVs revealed marked enrichment of metabolites involved in nucleotide salvage and recycling, along with altered amino acid abundances, including increases in amino acids associated with stress responses and redox regulation. These changes are consistent with altered nucleotide turnover and amino acid metabolism under antifungal stress. Importantly, these metabolic alterations reflect caspofungin-induced changes in cellular metabolism that are selectively exported via extracellular vesicles, rather than metabolic activity occurring within the vesicles themselves. Export of these metabolites via EVs may support population-level coordination, biofilm remodeling, and modulation of host immune responses, contributing to echinocandin tolerance. Together, our findings highlight nucleotide- and amino acid-associated metabolic features of EVs as informative readouts of caspofungin exposure and highlight the EV metabolome as a promising source of non-invasive biomarkers for monitoring drug exposure and resistance. This work advances understanding of C. auris adaptation under antifungal stress and reveals new opportunities for therapeutic and diagnostic innovation against this high-priority pathogen. Full article

(1) Background: Meyerozyma guilliermondii is a yeast species widely distributed in the natural environment and one of the rare emerging pathogens capable of causing difficult to treat, severe infections. The species’ susceptibility profile is not fully defined; however, the species could be more prone to develop resistance than other Candida species. The objective of this research was to determine the susceptibility of a local collection of Meyerozyma guilliermondii clinical isolates to classical antifungal drugs as well as a new one—manogepix. (2) Methods: The study included 20 clinical isolates identified using the MALDI–TOF method followed with sequencing of ITS1-2 region of DNA. Overall, the susceptibility to 12 antifungal drugs was tested. Nine drugs (amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin) were assessed using the MICRONAUT–AT test. The susceptibility to the new drug, manogepix, as well as isavuconazole, clotrimazole and anidulafungin, was determined using the microdilution method recommended by EUCAST. Additionally, anidulafungin and voriconazole MIC was also examined with commercial gradient tests. (3) Results: Overall, the isolates showed low MIC values for amphotericin B (0.125 to 1 mg/L) and for flucytosine (≤0.06 to 32 mg/L), with the exception of one isolate with a high MIC value. The MIC ranges for azoles were 2–64 mg/L (fluconazole), 0.008–0.5 mg/L (voriconazole), ≤0.03–≥4 mg/L (itraconazole) and 0.008–0.5 mg/L (posaconazole). One isolate showed non-WT phenotype to all tested azoles. For anidulafungin, the MIC values ranged from ≤0.06 to 0.25 mg/L; however, in the reference method, higher values were observed, but they did not exceed 2 mg/L (ECOFF value). For manogepix, the MIC values ranged from 0.002 to 0.125 mg/L. Finally, the comparison of the obtained and published susceptibility data was conducted. (4) Conclusions: The data obtained in this study are consistent with reports by other authors and indicate that resistance to azoles or 5-fluorocytosine among clinical isolates of Meyerozyma guilliermondii should be considered. The low MIC values of manogepix suggest the potentially good efficacy of this drug against Meyerozyma guilliermondii species. Full article

Background/Objectives: Certain yeast species are recognized as significant opportunistic pathogens, capable of causing severe systemic infections, particularly in immunocompromised individuals or those with disrupted physiological barriers. The rising incidence of invasive candidiasis associated with vascular infections poses a significant clinical challenge due to the high mortality rates and the limited efficacy of conventional antifungal therapies. The formation of resilient biofilms on vascular catheters by species such as Candida albicans and Nakaseomyces glabratus further complicates treatment, often leading to persistent fungemia and necessitating device removal. With the emergence of multidrug-resistant (MDR) strains, there is a critical need for new therapeutic agents like rezafungin—a novel, long-acting echinocandin with potential enhanced antibiofilm activity. Methods: This study tested susceptibility to antimycotics available in Poland (fluconazole, voriconazole, posaconazole, amphotericin B, anidulafungin, caspofungin, and micafungin) using the commercial Micronaut-AM test (Bruker, Bremen, Germany). Susceptibility to rezafungin (Angene Chemical, Great Britain) was determined using the microdilution method in RPMI medium, recommended by European Committee on Antimicrobial Susceptibility Testing (EUCAST), with amphotericin B as a control compound. We evaluated the biofilm-forming capacity and the in vitro activity of rezafungin against 42 clinical isolates of Candida albicans and Nakaseomyces glabratus recovered from positive blood cultures. Results: The obtained minimum inhibitory concentration (MIC) values suggest rezafungin activity against all the tested isolates, with different susceptibility to echinocandins and other antifungal drugs (azoles, amphotericin B) currently registered and used in Poland. The MIC readings for rezafungin were in the range of 0.008–0.5, with MIC₅₀ = 0.016 and MIC₉₀ = 0.25. The isolates were categorized as low, moderate, or strong biofilm producers according to established Stepanović criteria (cut-off values OD₆₃₀ < 0.019, 0.19–0.38, >0.38, respectively). Furthermore, the higher minimum biofilm eradication concentrations (MBECs) compared to the minimum inhibitory concentrations (MICs) of planktonic cells confirm the reduced activity of rezafungin against biofilms. Conclusions: Critically, the high antibiofilm efficacy at clinically achievable concentrations suggests that rezafungin shows promise as a potential therapeutic option for catheter-related candidemia, though further clinical studies are needed. Furthermore, the high susceptibility of N. glabratus isolates—a species frequently associated with azole resistance—suggests rezafungin may be a valuable addition to the existing antifungal arsenal of multidrug-resistant (MDR) fungal infections in hospital settings. Future research should focus on in vivo models to confirm if these in vitro results translate into accelerated clearance of vascular biofilms. Full article

Candida albicans, a commensal and opportunistic fungal pathogen, is a major clinical concern due to its ability to cause infections ranging from mild mucosal conditions to life-threatening systemic diseases, particularly in immunocompromised patients. Its capacity to form biofilms on medical devices further complicates treatment by enhancing antifungal resistance and immune evasion. In the search for novel therapeutic strategies, the lysine-enriched amphibian-derived temporin B analog, TB_KKG6K, has emerged as a promising antifungal agent. This study demonstrates that TB_KKG6K exhibits potent fungicidal activity against planktonic C. albicans cells, with a low potential to induce adaptation or resistance. TB_KKG6K has no adverse impact on the anti-Candida efficacy of standard antifungal drugs when applied in combination, interacting additively with amphotericin B and caspofungin in a fungicidal mode of action. Additionally, TB_KKG6K effectively reduces biofilm maturation on silicone elastomers, a material commonly used in medical devices, further highlighting its therapeutic potential. These data together with our previous documentation of minimal cytotoxicity and irritation potential in human cells makes TB_KKG6K a strong candidate for combating both planktonic and biofilm-associated C. albicans infections. These findings underscore the dual efficacy of TB_KKG6K and its potential to address the challenges posed by C. albicans in clinical settings. Full article

This study evaluated the in vitro interaction of 5-fluorouridine (5-FUrd) with antifungal drugs and examined the role of efflux pumps in 5-FUrd resistance. Eleven reference Candida strains and twenty-three clinical C. albicans isolates from gynecological patients were tested. The antifungal activity of 5-FUrd alone and in combination with amphotericin B, fluconazole, voriconazole, caspofungin, and flucytosine was assessed using the checkerboard microdilution method. Efflux pump activity was evaluated using two inhibitors: carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and verapamil. 5-FUrd exhibited antifungal activity against both the reference and clinical Candida strains, with MIC values ranging from 0.1 µg/mL to 409.6 µg/mL. The checkerboard assays revealed primarily no interactions in the reference Candida strains, whereas the reference C. albicans and clinical C. albicans isolates showed notable synergy between 5-FUrd and fluconazole, voriconazole, or caspofungin. The efflux pump inhibitors reduced the MICs of 5-FUrd in the resistant strains of C. lusitaniae, C. kefyr, and particularly C. krusei, suggesting efflux-mediated resistance mechanisms. This study highlights the potential of 5-FUrd, alone or combined with azoles or caspofungin, as an adjunct therapy against Candida infections. It also suggests that reduced susceptibility may be linked to efflux pump activity in certain strains. Full article

Purpureocillium lilacinum is an emerging pathogen that can cause severe ocular infections. This study aimed to investigate the risk factors, clinical manifestations, antifungal susceptibilities, and outcomes of ocular infections caused by P. lilacinum at a large ophthalmic center in Southern China. This retrospective study reviewed the medical records of 34 patients with culture-proven P. lilacinum oculomycosis treated at the Zhongshan Ophthalmic Center from January 2020 to December 2024. The study included 34 patients (17 males, 17 females). The most common risk factor was ocular trauma (38.2%). In vitro susceptibility testing revealed high resistance to fluconazole and caspofungin, but general susceptibility to voriconazole (median MIC 0.25 mg/L). Despite 97.1% of patients receiving voriconazole therapy, outcomes were generally poor, with 54.5% of patients experiencing a poor outcome (vision worse than counting fingers). A significantly shorter time to microbiological diagnosis was associated with a favorable outcome (median 26 days vs. 65 days, p = 0.007). In conclusion, the visual outcomes of this infection remain generally poor, with the major clinical challenge being the delay in diagnosis. Therefore, prompt microbiological investigation is recommended for patients with suspected intraocular infection. Voriconazole remains the first-line therapeutic choice, the therapeutic potential of newer triazoles warrants further investigation. Full article

Cryptococcus neoformans is a fungal pathogen commonly found in the environment. It mainly infects immunocompromised individuals, causing cryptococcal pneumonia and meningitis, which result in hundreds of thousands of deaths each year. Zinc finger proteins, with zinc finger domains, are common across organisms and serve many biological functions. In this study, we identified and characterized Zfp2, a C₃HC₄-type zinc finger protein, which regulates cell fusion and virulence in C. neoformans. Stress tests showed that the zfp2Δ mutant is hypersensitive to SDS, Congo red, NaCl, KCl, caspofungin, and fluconazole, suggesting that Zfp2 helps maintain cell membrane or wall integrity in C. neoformans. Notably, deleting ZFP2 reduced capsule size, while its overexpression led to capsule enlargement. The zfp2Δ mutants also demonstrated a growth defect at 37 °C. Cell fusion assay showed that Zfp2 is essential for cell fusion during sexual reproduction, as zfp2Δ mutants could not fuse during bilateral mating. To understand why the zfp2Δ mutants failed to fuse, we examined key genes in the pheromone response pathway and found that Zfp2 may affect cell fusion by regulating this pathway. Finally, a virulence test in mice showed that both ZFP2 deletion and overexpression significantly reduced C. neoformans’ virulence. Overall, our research suggests that the zinc finger protein Zfp2 is vital for cell fusion and virulence in C. neoformans. Full article

Background: Community-onset fungemia is a clinically significant syndrome frequently linked to recent healthcare exposure and significant morbidity and mortality. Methods: We performed a 21-year, single-centre retrospective cohort of consecutive yeast bloodstream infections diagnosed at the Emergency Department (2004–2024). Clinical/epidemiological data, species identification (MALDI-TOF MS), antifungal susceptibility (CLSI M27; Sensititre YO10), and whole-genome sequencing (WGS) were analyzed. Results: Forty-eight episodes (51 isolates) were included; 56.3% were male, median age 74 years (IQR 63–82). Acquisition was healthcare-associated in 38/48 (79.2%). Sources were unknown (36.7%), abdominal (22.4%), urological (22.4%), catheter-related (14.3%), and 2.1% was attributed to a cardiovascular and a joint focus; 18.8% were polymicrobial. Crude mortality was 20.8% at 7 days (10/48) and 29.2% at 30 days (14/48). Species distribution: Candida albicans 41.2%, Nakaseomyces glabratus 27.5%, Candida parapsilosis 11.8%, Candida tropicalis 11.8%, Pichia kudriavzevii 3.9%, Clavispora lusitaniae 1.9%, and Candida orthopsilosis 1.9%. No isolate was resistant to anidulafungin, micafungin, or amphotericin B; one N. glabratus showed reduced susceptibility to caspofungin. Azole resistance was observed in one C. albicans and one N. glabratus isolate. WGS (44 isolates) confirmed MALDI-TOF identifications and characterized resistance markers. All 12 sequenced N. glabratus carried ERG2 I207V, PDR15/PDH1 E839D, and PDR1 V91I/L98S. Notable cases included one N. glabratus caspofungin-intermediate with FKS2 F659C, N. glabratus fluconazole-resistant with multiple PDR1 substitutions including a unique novel G857V, and C. albicans fluconazole-resistant harbouring alterations in MRR1/MRR2, CDR1, and ERG11. Conclusions: In this 21-year cohort, community-onset fungemia was predominantly healthcare-associated, with C. albicans as the predominant species, followed by N. glabratus. Crude mortality reached 29.2% at 30 days. Echinocandin resistance was not observed; azole resistance was uncommon. WGS provided precise speciation and actionable insight into resistance mechanisms, including a putatively novel PDR1 G857V in N. glabratus. Full article

Extracorporeal membrane oxygenation (ECMO) is increasingly used to support critically ill adults with severe cardiac or respiratory failure, but ECMO circuits and the physiological disturbances of critical illness significantly alter drug pharmacokinetics (PK) and pharmacodynamics (PD), complicating dosing and monitoring. This narrative review synthesizes current clinical evidence on ECMO-related PK/PD alterations and provides practical guidance for optimizing pharmacotherapy in adult intensive care. A structured literature search (January–May 2025) was conducted across PubMed/MEDLINE, EMBASE, Scopus, Cochrane Library, Sage Journals, ScienceDirect, Taylor & Francis Online, SpringerLink, and specialized databases, focusing on seven therapeutic classes commonly used in ECMO patients. Eligible studies included clinical trials, observational studies, systematic reviews, and practice guidelines in adults, while pediatric and preclinical data were excluded. Evidence quality varied substantially across drug classes. Hydrophilic, low-protein-bound agents such as β-lactams, aminoglycosides, fluconazole, and caspofungin generally showed minimal ECMO-specific PK alterations, with dose adjustment mainly driven by renal function. Conversely, lipophilic and highly protein-bound drugs including fentanyl, midazolam, propofol, voriconazole, and liposomal amphotericin B exhibited substantial circuit adsorption and variability, often requiring higher loading doses, prolonged infusions, and rigorous therapeutic drug monitoring. No ECMO-specific data were identified for certain neuromuscular blockers, antivirals, and electrolytes. Overall, individualized dosing guided by therapeutic drug monitoring (TDM), organ function, and validated PK principles remains essential to optimize therapy in this complex population. Full article

Candida krusei empyema is a rare but serious manifestation of invasive candidiasis, characterized by intrinsic resistance to fluconazole, biofilm formation, and high mortality, with limited case-level data to inform management. This review aims to systematically identify and synthesize all reported English-language cases of Candida krusei empyema from January 2005 to June 2025 using PubMed, ScienceDirect, OVID MEDLINE, and Gale OneFile and perform descriptive analysis on them. Screening, data extraction, and eligibility assessment were performed, and those articles not clearly meeting eligibility criteria were reviewed by additional reviewers with consensus resolution. Seven publications (six individual cases and two cohorts) were included. We additionally describe the clinical course, management, and outcome of a 70-year-old bilateral lung transplant patient who developed persistent C. krusei empyema despite optimized antifungal therapy. Patients ranged from 11 to 74 years of age (median 62.5 years). Predisposing factors included esophageal perforation (n = 4), post-transplant hemorrhage (n = 1), community-acquired empyema (n = 1), and thoracic surgery (n = 1). Empiric fluconazole was switched to caspofungin (3/4), with others receiving amphotericin B, voriconazole, or combination therapy. Source control varied: chest tube drainage (n = 3), percutaneous catheter (n = 3), and surgical decortication (n = 2). Mortality was 14.3% (1/7). In the absence of clear guidelines and robust literature, the management approach remains heterogeneous. Optimal care requires early recognition, aggressive multimodal antifungal therapy, and effective source control tailored to patient risk. Standardized antifungal protocols and larger case series are needed to guide clinicians in managing this challenging infection. Full article