Background and Purpose: Fluconazole resistance in Candida species is on the rise, posing a significant clinical challenge. There is a growing interest in using complementary therapies, especially those from natural sources. This study aimed to evaluate the synergistic and apoptotic effects of Bunium persicum essential oil (BPEO) and its two pure components,cuminaldehyde (CA) and γ-terpinene (γ-TPN), combined with fluconazole (FLC) on susceptible and resistant C. albicans isolates. Moreover, molecular docking was used to study the interactions between lanosterol 14-alpha-demethylase and each agent.Materials and Methods: The BPEO was prepared using the Clevenger apparatus and the hydro-distillation method. The in vitro antifungal activity was evaluated according to the Clinical andLaboratory Standards Institute guideline (M60). The checkerboard and isobologram assays assessed the interaction between BPEO, CA, γ-TPN, and FLC.The necrotic and apoptotic effects of different agents were analyzed using a flow cytometry assay. An in-silico study was performed to examine the receptor-ligand interaction.Results: The CA showed the lowest minimum inhibitory concentrations and minimum fungicidal concentrations, compared to BPEO and γ-TPN. Statistical analyses indicated significant differences betweenresistant and sensitive C. albicans isolates regarding minimum inhibitory concentration values of BPEO, CA, and γ-TPN. The most synergistic effect wasobtained for FLC combined with CA (n=7, 63.6%), followed by BPEO (n=6, 54.5%), and γ-TPN (n=3, 27.2%). Statistical analyses indicated the synergistic effect of FLC incombination with CA was more than γ-TPN (p=0.023). Apoptotic indicators confirmed that the tested compounds could cause cell death in yeast cells.Combination of each natural component with FLC resulted in a greater apoptosis effect than each tested agent alone. The docking study indicated that both pure compounds haveinteractivity with the protein residue of 14α-demethylase.Conclusion: The results indicated that the synergistic properties of natural products combined with synthetic antifungal agents available in the market could contribute to developing effective therapeutic strategies, particularly in resistant fungal species.

Background and Purpose: Fungal endometritis, an uncommon yet severe condition affecting the uterine lining, typically manifests with abnormal uterine bleeding (AUB), pelvic discomfort, and vaginal discharge. This investigation aimed to present a pioneering study focused on fungal endometritis in women presenting with these clinical symptoms.Materials and Methods: A cohort of 43 female patients experiencing abnormal uterine bleeding was comprehensively evaluated at Babol University of Medical Sciences in Babol, Iran, between March 21, 2023, and March 19, 2024. Diagnostic procedures encompassed ultrasound imaging, a range of laboratory tests, hysteroscopy for direct visualization and tissue sampling, microscopic examination, fungal culture with subsequent colony count, and polymerase chain reaction for enhanced accuracy in fungal identification. Additionally, drug susceptibility patterns were assessed for all isolated fungal species.Results: Among the 43 patients, five (11.62%) received a definitive diagnosis of fungal endometritis.The identified species included two isolates of Candida albicans, two isolates of Nakaseomyces glabratus (previously known as C. glabrata),and one isolate of Candida orthopsilosis. A notable diagnostic observation was that all confirmed cases yielded negative results from vaginal discharge cultures,emphasizing the necessity of direct endometrial sampling. Antifungal susceptibility testing revealed varying minimum inhibitory concentrations among the isolates,though all responded effectively to the combined treatment of voriconazole and surgical debridement.Conclusion: This study highlighted the critical importance of prompt evaluation and precise diagnosis, including comprehensive antifungal susceptibility testing, in individuals presentingwith acute endometritis and AUB. Such rigorous considerations are essential for guiding clinical management and mitigating the risk of adverse outcomes, particularly giventhe increasing antifungal resistance and the emergence of non-albicans Candida species as significant pathogens.

Background and Purpose: Incidence of candiduria attributed to Candida species has been increasing, with a notable rise in cases involving antifungal-resistant non-albicans Candida (NAC) species.This investigation aimed to assess both the prevalence and antifungal susceptibility patterns of Candida isolates obtained from patients diagnosed with candiduria. Materials and Methods: In total, 100 urine specimens were collected from patients diagnosed with candiduria and subjected to analysis. Subsequent to the preliminary identification, a 21-plex polymerase chain reaction (PCR) assay was employed for species characterization. Antifungal susceptibility testing was conducted using the broth microdilution technique, which aimed to determine the minimum inhibitory concentrations (MICs) of fluconazole, amphotericin B, and caspofungin. Results: Among the 100 analyzed patients, Candida albicans was the predominant species, accounting for 70% of isolates, followed by C. tropicalis (11%), C. glabrata (9%),and C. parapsilosis (5%). Resistance to fluconazole was observed in 2.86% of C. albicans isolates, whereas 29.41% of the NAC species exhibited resistance to this antifungal agent. Conclusion: The fluconazole resistance rate was notably higher among NAC species, compared to that of C. albicans. To deepen current understanding, it is recommended that future molecular investigations employ advanced and diverse methodologies, along with larger and more representative patient cohorts.

Background and Purpose: Candidemia is a prevalent nosocomial bloodstream infection with a high mortality rate. Involvement of heart valves by Candida spp. after candidemia can result in native and prosthetic valve endocarditis as biofilm-related infections.Case Report: This report aimed to introduce a case of a 13-year-old male with bloodstream infection and prosthetic valve endocarditis, caused by itraconazole-resistant Candida glabrata (Nakaseomyces glabratus). Despite undergoing itraconazole for 4 weeks, the patient did not improve. White colonies were identified as C. glabrata (N. glabratus) by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction. The isolate was resistant to itraconazole (MIC=8 µg/mL) but susceptible to amphotericin B and caspofungin. Based on concerns about biofilm-related resistance, treatment was switched to caspofungin for 5 weeks. He continued to do well and showed no signs of relapse during his 6-month follow-up. Conclusion: This study explored the importance of antifungal susceptibility testing in handling complicated infections, as well as the potential of caspofungin in the treatment of cases of fungal bloodstream infections and endocarditis.

Background and Purpose: Traumatic fungal diseases are relatively less common and present significant challenges in treatment. In some cases, there is progressive spread and deep soft tissue colonization, especially in immunocompromised patients and those showing neglect and non-compliance with treatment. This pattern is common in patients from rural settings who are unaware of the consequences of delaying medical care and the resulting complications.Case Report: This study reported a case of Basidiobolomycosis manifesting as deep necrotizing myositis of the left thigh complicated by secondary bacterial sepsis in a 46-year-old immunocompetent man. Basidiobolus ranarum, was morphologically identified, isolated in culture and supported by wet mount microscopy and histopathology. It was treated with a multipronged strategy due to a refractory infection showing an unsatisfactory response to fungal monotherapy.Conclusion: The diagnosis was evasive due to the clinical picture of overt soft-tissue necrosis resembling a highly virulent bacterial infection showing antibiotic resistance. Broad aseptate hyphae in potassium hydroxide mount (KOH 10%) preparation led us to suspect the Entomophthorales organism and initiate prompt antifungal chemotherapy.

Background and Purpose: The current study aimed to assess the demographic features, clinical characteristics, species diversity, and contributing factors among patients with severe acute respiratory syndrome coronavirus-2 pneumonia-associated mucormycosis in northwestern Iran.Materials and Methods: This cross-sectional descriptive study was performed on patients who tested positive for COVID-19 via reverse-transcriptase-polymerase chain reaction and were suspected of having invasive fungal infection. Mucormycosis was confirmed by histopathology of biopsy samples and species identification was performed using morphological and internal transcribed spacer-rDNA sequencing methods.Results: Mucormycosis was observed in 63 COVID-19 patients. Mean age of patients was 56.65±14.49 years (range of 22-85 years) and 63.5% of the involved patients were male.The most common involvement site of patients with mucormycosis was the sinus (63.5%). Among all participants, 84% of patients (n=53) had received intravenous dexamethasone, and 25.4% of themhad diabetes mellitus. All patients with proven invasive mucormycosis received intravenous amphotericin B. In total, 21 (33%) positive cultureswere identified and Rhizopus arrhizus was the main causative agent.Conclusion: Awareness among physicians should be raised that corticosteroid therapy not only causes dysfunction of the immune system but may also lead to the development of this neglected mycosis through corticosteroid-induced diabetes in vulnerable patients.

Nano-graphene oxide is a promising Candidate for therapeutic applications, particularly due to its notable antifungal and antibacterial properties, which stem from the uniquephysicochemical characteristics of this innovative nanocarrier. Antifungal efficacy of nano-graphene oxide is increasingly attracting attention, particularly in light of the risingresistance of pathogens to conventional drug therapies. Upon exposure to graphene oxide, fungal cells generate reactive oxygen species, a key indicator of cellular oxidative stress.This mechanism accounts for the apoptotic-like cell death observed in the presence of graphene oxide. This nano-drug delivery system holds the potential to achieve therapeutic efficacyat reduced doses, minimize side effects, enable controlled drug release, prolong circulation time, reduce toxicity, and enhance the stability of the nano-formulation, particularlywhen administered as an inhaled dry powder. However, the factors influencing the antifungal activity of nano-graphene oxide and the underlying mechanisms remain poorly understood.This article aimed to review the anti-pathogenic properties of nano-graphene oxide, focusing on its antifungal mechanisms and its role in biofilm formation associated with pulmonary fungal infections.

Background and Purpose: Histoplasmosis, caused by Histoplasma capsulatum, typically presents as a pulmonary infection but can disseminate, with oral lesions being common among immunocompromised individuals. However, this is rare among immunocompetent patients. Preferred treatments include itraconazole for mild cases and liposomal amphotericin B for severe forms.Case presentation: This study aimed to report a 28-year-old female who developed disseminated histoplasmosis following a right oroantral fistula after dental surgery. It was initially misdiagnosed asActinomycosis; however, a positive urinary Histoplasma antigen test confirmed histoplasmosis. Despite itraconazole therapy (200 mg twice daily, later increased to 600 mg),her condition continued to deteriorate, with disease progression seen on imaging. Switching to six weeks of intravenous liposomal amphotericin B led to marked improvement,resolution of lung nodules, and negative antigen testing. She was discharged with a 12-month course of itraconazole therapy.Conclusion: This case highlights the importance of timely recognition and adjustment of treatment in non-severe histoplasmosis, particularly for patients who do not respond adequately to itraconazole therapy.

Background and Purpose: One of the most severe mycotic infections caused by Candida spp. is invasive candidiasis. According to the literature, among all healthcare- associated infections, it has the highest mortality rate. This study aimed to assess 30-day and overall mortality in invasive candidiasis and candidemia patients depending on the antifungal therapy (AFT) regimens.Materials and Methods: This single-center retrospective study of 30-day survival was conducted at Clinical City Hospital No. 52, Moscow Healthcare Department in Moscow, Russia.The participants were 169 patients aged 19-94 years who had verified invasive candidiasis with candidemia during hospitalization in 2020–2023.This study included patients with Candida spp. isolated from blood culture using matrix-assisted laser desorption/ionization with time-of-flight mass spectrometry, and proven invasivecandidiasis according to EORTC/MSG criteria. Patient survival analysis was performed using the Kaplan-Meier method, which is a nonparametric approach for estimating time- to-event.Risk of death was compared between the group of patients receiving AFT after pathogen verification and the group of patients receiving AFT before and after blood culture results.Results: Based on the findings, the likelihood of death was lower in the group of patients who received AFT both after and before blood culture results compared to the group of patients who receivedit after verification of the diagnosis. By day 50 of hospitalization, the risks of death were comparable between the two groups. However, when analyzing the overall mortality,the odds of death in patients with AFT before and after receiving blood culture results were 2.56 times higher (OR=0.391; 95% CI: 0.177–0.865; p=0.019) compared with patients to whom antifungal therapy was prescribed only after blood culture results. Conclusion: This study provided the first data regarding the assessment of 30-day mortality and risk factors for death. Risk of 30-day mortality was lower in the group of patients receiving AFT both before and after the blood culture, but overall mortality in this group was higher, compared to patients who received AFT after the blood culture.

Background and Purpose: The high morbidity and mortality caused by invasive mold infections require new and effective treatment strategies. Heat shock proteins, which are found in all living organisms, play a role in the homeostatic control of the cell and the stress response mediated by calcineurin. Their release increases especially under stress conditions, and they play a role in ensuring the stability of cellular proteins. Therefore, inhibition of Hsp90 or calcineurin may be an effective method in antifungal therapy.This study aimed to evaluate the in vitro activity of four different antifungal agents (caspofungin, amphotericin B, itraconazole, and voriconazole) in combination with fungal stressresponse regulators, Hsp90 inhibitors, and calcineurin inhibitors, against clinical isolates of Aspergillus, Rhizopus, and Fusarium.Materials and Methods: In this study, the effectiveness of Hsp90 inhibitors geldanamycin, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), radicicol, novobiocin (NOV), and calcineurin inhibitors cyclosporine,tacrolimus (TAC), and rapamycin (RAP) combined with common antifungals itraconazole (ITRA), voriconazole (VOR), caspofungin (CAS), and amphotericin B (AMB) wereinvestigated against four Aspergillus, three Rhizopus, and three Fusarium isolates using checkerboard method.Results: The minimum inhibitory concentration (MIC)/minimum effective concentration (MEC) values of ITRA, VOR, CAS, and AMB were ≤ 0.25, ≤ 0.06-0.125, ≤ 0.03-> 4,and 1-4 µg/mL for Aspergillus spp.; 2-8, > 4, > 4, and 2 µg/mL for Rhizopus spp.; 8- > 16, 1-4, > 4, and 2-4 µg/mL for Fusarium spp., respectively.Although tacrolimus was found to have generally low MIC values (≤0.03 µg/mL) for Aspergillus and Rhizopus isolates, NOV, and 17-AAG did not exhibitantifungal activity (MICs>128 and ≥16 µg/mL, respectively) against almost all of the isolates.In combination testing against Aspergillus and Rhizopus spp., synergistic interactions were prevalent (≥75%) for thecombinations of ITRA and all inhibitory substances, except for TAC.The effects of CAS and TAC in combination tests were weak. Moreover, synergistic interactions were not frequent in all combinations against Fusarium spp. However,antagonistic interaction was observed only in one ITRA and RAP combination throughout this study.Conclusion: The Hsp90 and calcineurin inhibitors did not have significant antifungal activity alone. Moreover, they did not show a significant antagonistic effect in combination and even increased the efficacy of antifungals at some concentrations.