Search Results (344)

Invasive infections with rare yeasts are increasing worldwide and are associated with higher mortality rates due to their resistance to antifungal drugs. Accurate antifungal susceptibility testing (AFST) is crucial for proper management of rare yeast infections. We performed AFST of 74 Candida kefyr isolates by Etest, EUCAST-based MICRONAUT-AM assay (MCN-AM) and reference Clinical and Laboratory Standards Institute broth microdilution method (CLSI). Essential agreement (EA, ±1 two-fold dilution), categorical agreement (CA), major errors (MEs) and very-major errors (VmEs) were determined using epidemiological cut-off values of ≤1.0 µg/mL, ≤0.03 µg/mL, ≤0.5 µg/mL and ≤1 µg/mL, defining wild-type isolates for fluconazole, voriconazole, micafungin and amphotericin B (AMB), respectively. Results for AMB susceptibility were correlated with ERG2/ERG3 mutations and total-cell sterols. CA of ≥97% was recorded between any two methods while EA varied between 72 and 82%, 87 and 92%, and 49 and 76% for fluconazole, voriconazole and micafungin, respectively. For AMB, CAs between CLSI and Etest; CLSI and MCN-AM; MCN-AM and Etest were 95% (4 ME, 0 VmE), 96% (3 ME, 0 VmE) and 99%, respectively, while EA varied from 32% to 69%. Non-synonymous ERG2/ERG3 mutations and no ergosterol were found in seven of eight isolates of non-wild types for AMB by Etest. Our data show that Etest, CLSI and MCN-AM methods are suitable for AFST of C. kefyr for fluconazole, voriconazole and micafungin. Excellent CAs for AMB between Etest and MCN-AM with concordant sterol profiles but not with CLSI suggest that Etest is also an excellent alternative for the detection of C. kefyr isolates with reduced susceptibility to AMB. Full article

Introduction: Fungal endophthalmitis (FE) is a rare but serious intraocular inflammatory disorder, resulting from an infection of the vitreous cavity from either endogenous or exogenous components that ultimately results in blindness. This current research study aims to elucidate the histological effects of the intravitreal injection of the maximum safe dosage of voriconazole and micafungin on the retina and investigate potential histological alterations after the double and combined administration of voriconazole and micafungin. Methodology: Nine New Zealand Albino Rabbits were randomly assigned into three groups (V2, M2, and VM), and in each, voriconazole, micafungin, and a combination of the two medications were administered respectively. After the administration of the antifungal agents, the animals were sacrificed and their retinas were retrieved and studied under optical and electron microscopes. The immunohistochemical markers TNF-a and IL6 were also studied. Results: TNF-a was positive in the VM group, as it was found to be mildly positive in the presence of apoptotic cells in the ganglion cell layer. Conclusions: This study revealed voriconazole has a greater toxicity in a multi-dosage administration. However, micafungin revealed a greater toxicity than voriconazole from the extent of the lesions observed. Full article

Beach Sand Mycobiome is currently among the most important health challenges for viticulture in the world. Remarkably, the study of fungal communities in coastal beach sand and recreational waters remains underexplored despite their potential implications for human health. This research aimed to assess the prevalence of fungal species and the antifungal susceptibility profiles of fungi recovered from the beaches of the Persian Gulf and the Sea of Oman. Sand and seawater samples from 39 stations distributed within 13 beaches along the coastline were collected between May and July 2023. The grown isolates were identified at the species level based on morphological characteristics and DNA sequencing. Antifungal susceptibility testing was performed according to the Clinical Laboratory Standards Institute guidelines. Of 222 recovered isolates, 206 (92.8%) filamentous fungi and 16 (7.2%) yeast strains were identified. Sand-recovered fungi comprised 82.9%, while water-originated fungi accounted for 17.1%. The DNA sequencing technique categorized 191 isolates into 13 genera and 26 species. The most recovered genus was Aspergillus (68.9%), and Aspergillus terreus sensu stricto was the commonly identified species (26.14%). Voriconazole was the most effective antifungal drug against Aspergillus species. Research on fungal contamination levels at these locations could provide a foundation for establishing regulatory frameworks to diminish fungal risks, thereby enhancing public health protection. The ecological significance of fungal communities in sandy beaches to human infections remains to be explored, and earlier reports in the literature may motivate researchers to focus on detecting this mycobiome in natural environments where further investigation is warranted. Ultimately, our discovery serves as a reminder that much remains to be learned about pathogenic fungi and underscores the need for vigilance in areas where emerging pathogens have not yet been identified. Full article

Background: Fungal infections, particularly those caused by Candida species, pose a serious threat to immunocompromised individuals, and therapeutic options are limited due to toxicity and resistance concerns. This in vitro study aimed to explore the feasibility of using liquid fractions of autologous platelet concentrates (APCs), namely concentrated platelet-rich fibrin (c-PRF) and liquid-phase concentrated growth factor (LPCGF), as carriers for antifungal drugs. Methods: The research was conducted in two phases: first, to evaluate the inherent antifungal properties of different APCs; and second, to assess their effectiveness as drug carriers for fluconazole and voriconazole against Candida albicans, Candida glabrata, and Candida krusei. Results: Results showed that APCs alone exhibited no direct antifungal effects. However, when combined with antifungal agents, notable inhibition zones were observed—especially with voriconazole against C. krusei and fluconazole against C. glabrata using c-PRF. Both c-PRF and LPCGF were compatible with the drugs and did not hinder clot formation. Conclusions: These findings suggest that APCs can act as effective vehicles for localized antifungal drug delivery and warrant further investigation for clinical application in treating fungal-related oral diseases. Full article

Background: Exophiala spp. are dematiaceous fungi with opportunistic pathogenic potential and a widespread environmental presence. Clinical cases of Exophiala spp. fungemia are uncommon. Although rarely encountered in the general population, these organisms are increasingly reported in immunocompromised individuals or those with complex underlying health conditions. Objectives: This review seeks to examine all documented human cases of Exophiala spp. fungemia, with particular focus on aspects such as epidemiology, microbiological features, resistance patterns, therapeutic approaches and associated mortality rates. Methods: A narrative review was conducted using data sourced from the PubMed/MedLine and Scopus databases. Results: A total of 19 articles described infections in 32 patients involving Exophiala spp. fungemia. The mean patient age was 49.2 years, and 65.6% were male. Central venous catheters emerged as the leading predisposing factor (96.9%). Fever represented the most frequent clinical presentation (50%), followed by organ dysfunction (21.9%). The yeast generally demonstrated susceptibility to voriconazole and itraconazole. Voriconazole was also the most frequently administered antifungal (62.5%), followed by amphotericin (31.3%) and micafungin (28.1%). Overall mortality reached 34.4%, with 25% of deaths specifically caused by the infection. Conclusions: Given the potential of Exophiala spp. to cause severe fungemia, healthcare professionals, particularly clinicians and microbiologists, should consider this pathogen in the differential diagnosis when black yeast is detected in blood cultures, especially in patients with immunodeficiency or significant comorbidities, to ensure timely and accurate identification. 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

Background: Exophiala dermatitidis is a dematiaceous, thermotolerant, yeast-like fungus increasingly recognized as an opportunistic pathogen in chronic airway diseases. While commonly associated with cystic fibrosis, its clinical significance in non-cystic fibrosis bronchiectasis (NCFB) remains unclear. Case Presentation: We report the case of a 66-year-old immunocompetent woman with a history of breast cancer in remission and NCFB, who presented with chronic cough and dyspnea. Chest CT revealed bilateral bronchiectasis with new pseudonodular opacities. Bronchoalveolar lavage cultures identified E. dermatitidis, along with Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus. Given clinical stability and the absence of systemic signs, initial therapy included oral voriconazole, levofloxacin, doxycycline, and inhaled amikacin. Despite persistent fungal isolation on repeat bronchoscopy, the patient remained asymptomatic with stable radiologic and functional findings. Antifungal therapy was discontinued, and the patient continued under close monitoring. The patient exhibited clinical and radiological stability despite repeated fungal isolation, reinforcing the hypothesis of persistent colonization rather than active infection. Discussion: This case underscores the diagnostic challenges in distinguishing fungal colonization from true infection in structurally abnormal lungs. In NCFB, disrupted mucociliary clearance and microbial dysbiosis may facilitate fungal persistence, even in the absence of overt immunosuppression. The detection of E. dermatitidis should prompt a comprehensive evaluation, integrating clinical, radiologic, and microbiologic data to guide management. Voriconazole is currently the antifungal agent of choice, though therapeutic thresholds and duration remain undefined. Conclusions: This report highlights the potential role of E. dermatitidis as an under-recognized respiratory pathogen in NCFB and the importance of a multidisciplinary, individualized approach to diagnosis and treatment. This case underscores the need for further research on fungal colonization in NCFB and the development of evidence-based treatment guidelines. Further studies are needed to clarify the pathogenic significance, optimal management, and long-term outcomes of E. dermatitidis in non-CF chronic lung diseases. Full article

Background: Invasive aspergillosis (IA) is a severe fungal infection increasingly affecting elderly patients with chronic respiratory diseases and prolonged corticosteroid use. Methods: We evaluated clinical, biochemical, and fungal biomarkers in 45 patients over 80 years diagnosed with IA and hospitalized in a Spanish Acute Geriatric Unit. Patients received either voriconazole or isavuconazole. Mortality rates and associated risk factors were analyzed. Results: Overall mortality was 35.61%. Significant mortality risk factors included leukocytosis (p = 0.0371), neutrophilia (p = 0.0144), and lymphopenia (p = 0.0274). Deceased patients had longer hospital stays (26.6 vs. 16.8 days; p = 0.00353). Voriconazole treatment was associated with higher 30-day mortality (61.5% vs. 19.2%; p = 0.0001) and a higher incidence of adverse effects (60% vs. 5%; p = 0.0003) compared to isavuconazole. Voriconazole also showed greater pharmacokinetic variability, with 76.9% of cases outside the therapeutic range. Conclusions: Voriconazole may not be optimal for IA treatment in patients over 80 years. Isavuconazole demonstrated a more favorable safety and efficacy profile. Personalized therapeutic strategies and a multidisciplinary approach are essential to improve clinical outcomes and quality of life in this vulnerable population. Full article

Background: Invasive aspergillosis with orbital apex and intracranial involvement is rare and often misdiagnosed due to nonspecific imaging findings. Misinterpretation may lead to inappropriate therapies, such as corticosteroids, which can exacerbate fungal infections. Case Presentation: A 50-year-old immunocompetent woman with diabetes mellitus presented with right ptosis and systemic malaise. Magnetic resonance imaging (MRI) performed three months prior had shown a subtle low-signal lesion in the right orbital apex. The lesion was small and thought to represent a granulomatous process, with minimal systemic inflammation and only mild surrounding changes on imaging. Biopsy was considered too invasive at that stage, and the patient was placed under observation. Over time, her condition progressed, and repeat imaging revealed intracranial extension, including involvement of the cavernous sinus and frontal lobe. Differential diagnoses included granulomatous diseases such as sarcoidosis or tuberculosis, prompting empirical anti-tuberculosis treatment. However, the patient’s condition worsened, and biopsy of the sphenoid sinus revealed septated fungal hyphae consistent with Aspergillus species on Grocott staining. Voriconazole therapy was initiated, resulting in significant clinical and radiological improvement. Discussion: This case highlights the diagnostic challenge of identifying orbital apex aspergillosis with early MRI changes and demonstrates the risk of misdiagnosis as granulomatous disease. Differentiating fungal infections from other inflammatory etiologies based on subtle imaging features is critical, especially when considering immunosuppressive therapy. Conclusion: Clinicians should maintain a high index of suspicion for fungal infections in patients with progressive orbital apex lesions, even in the absence of classic immunosuppression. Early imaging review and biopsy are essential to prevent misdiagnosis and inappropriate treatment. Full article

Background/Objectives: Filamentous fungi, in particular the species Aspergillus, Scedosporium, and Exophiala, frequently colonize the lungs of cystic fibrosis (CF) patients. Chronic colonization is linked to hypersensitivity reactions and persistent infections leading to a significant long-term decline in lung function. Azole antifungal therapy such as voriconazole (VRC) slows disease progression, particularly in patients with advanced CF; however, excessive mucus production in CF lungs poses a diffusional barrier to effective treatment. Methods: Here, biodegradable nanohydrogels (NHGs) recently developed as nanocarriers were evaluated for formulating VRC as a platform for treating fungal infections in CF lungs. The NHGs entrapped up to about 30 μg/mg of VRC, and physicochemical properties were investigated via dynamic laser light scattering and nanoparticle tracking analysis. Diameters were 100–400 nm, and excellent colloidal stability was demonstrated in interstitial fluids, indicating potential for pulmonary delivery. Nano-formulations exhibited high in vitro cytocompatibility in A549 and HEK293T cells and were tested for the release of VRC under two different sink conditions. Results: Notably, the antifungal activity of VRC-loaded nanohydrogels was up to eight-fold greater than an aqueous suspension drug against different fungal species isolated from CF sputum, regardless of the presence of a CF artificial mucus layer. Conclusions: These findings support the development of potent VRC nano-formulations for treating fungal disorders in CF lungs. Full article

Aspergillus terreus is an opportunistic fungal pathogen and a major cause of aspergillosis. Its clinical significance is heightened by high mortality rates, dissemination, and resistance to amphotericin B, complicating treatment. The present study investigates the distribution of A. terreus in Tyrolean (Austria) soils and explores potential environmental factors influencing its uneven prevalence. Soil samples from the eastern and western parts of Tyrol were analyzed using soil extraction plating, the soil immersion tube method, and A. terreus-specific qPCR. The results revealed a significantly higher prevalence of A. terreus in the eastern region. Soil parameters, including pH, moisture, organic matter, total carbon, and nitrogen, were assessed for potential correlations with fungal distribution. The presence of A. terreus was significantly associated with lower pH, decreased total carbon and nitrogen, and lower soil density. Random sampling across Austria indicated a lower environmental frequency of A. terreus outside of Tyrol. The susceptibility profiles of amphotericin B, posaconazole, isavuconazole, and voriconazole were determined according to EUCAST guidelines, showing that 98.3% of isolates were wild type for amphotericin B, 100% wild type for voriconazole, 100% resistant to posaconazole, and 87.2% resistant to isavuconazole. Full article

Background/Objectives: Voriconazole (VRCZ) use requires accurate monitoring to avoid suboptimal drug levels and adverse effects. In addition, the appearance of resistant fungal strains is a problem that needs attention. Blood concentration measurement is the monitoring technique of choice; however, it is slow, limiting its clinical application. This study aimed to evaluate the clinical utility of rapid therapeutic drug monitoring (TDM) for VRCZ using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) compared to conventional outsourced liquid chromatography–tandem mass spectrometry (LC-MS/MS) testing in outpatient care. Methods: VRCZ blood concentrations were measured using HPLC-UV and LC-MS/MS. Reporting times, accuracy, and clinical outcomes were assessed for outpatients receiving VRCZ treatment. Safety was monitored for renal, hepatic, and visual toxicities. Results: HPLC-UV significantly reduced reporting times (0.433 h vs. 74.3 h, p < 0.001), and Deming’s regression analyses showed a strong correlation with LC-MS/MS results (Pearson’s r = 0.988). Bland–Altman analysis showed an average difference of 0.025 μg/mL between HPLC-UV and LC-MS/MS. Prospective monitoring of three outpatients revealed no adverse events, enabling safe and effective VRCZ dosing. Conclusions: Rapid VRCZ TDM using HPLC-UV is a cost-effective and feasible approach for outpatient care, significantly improving reporting times and patient safety. Further studies and cross-facility collaboration are needed to expand its application. Full article

The present investigation aimed to formulate and optimize sustained release proliposome dry powder for inhalation of Voriconazole (VZ) and its in vitro and in vivo evaluation. The proliposome-based dry powder for inhalation was formulated by spray drying technique using Phospholipon 90H and cholesterol in the lipid phase, mannitol as a carrier, and L-leucine as a dispersing agent. A face-centered central composite design was used to study the influence of factors on responses, vesicle size, VZ entrapment efficiency, and drug release. The optimized formulation was further characterized by FTIR, FESEM, DSC, XRD, and evaluated for in vitro drug release, in vitro aerosol deposition, and in vivo lung retention study in Wistar rats. For the optimized batch F-5 proliposome formulation, vesicle size was observed as 191.7 ± 0.049 nm with PDI 0.328 ± 0.009, entrapment efficiency as 72.94 ± 0.56%, and cumulative drug release after 8 h of dissolution was 82.0 ± 0.14%. The median mass aerodynamic diameter (MMAD) generated by optimized formulation F5 was significantly lower (3.85 ± 0.15 µm, p < 0.0001) as compared to spray-dried voriconazole (SD-VZ) (8.35 ± 0.23 µm). In vivo studies demonstrated a profound enhancement in lung retention (3.8-fold) compared to SD-VZ and oral VZ dispersion. Conclusively, proliposome formulation of voriconazole is a plausible and convincing approach for pulmonary fungal infections, considering its sustained release behaviour and prolonged lung retention. Full article