COVID-19 associated candidemia: From a shift in fungal epidemiology to a rise in azole drug resistance.

Our understanding of fungal epidemiology and the burden of antifungal drug resistance in COVID-19-associated candidemia (CAC) patients is limited. Therefore, we conducted a retrospective multicenter study in Iran to explore clinical and microbiological profiles of CAC patients. Yeast isolated from blood, were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and subjected to antifungal susceptibility testing (AFST) using the broth microdilution method M27-A3 protocol. A total of 0.6% of the COVID-19 patients acquired CAC (43/6174). Fluconazole was the most widely used antifungal, and 37% of patients were not treated. Contrary to historic candidemia patients, Candida albicans and C. tropicalis were the most common species. In vitro resistance was high and only noted for azoles; 50%, 20%, and 13.6% of patients were infected with azole-non-susceptible (ANS) C. tropicalis, C. parapsilosis, and C. albicans isolates, respectively. ERG11 mutations conferring azole resistance were detected for C. parapsilosis isolates (Y132F), recovered from an azole-naïve patient. Our study revealed an unprecedented rise in ANS Candida isolates, including the first C. parapsilosis isolate carrying Y132F, among CAC patients in Iran, which potentially threatens the efficacy of fluconazole, the most widely used drug in our centers. Considering the high mortality rate and 37% of untreated CAC cases, our study underscores the importance of infection control strategies and antifungal stewardship to minimize the emergence of ANS Candida isolates during COVID-19.

[Antimicrobial peptides: A new alternative for the treatment of aspergillosis]. / Peptides antimicrobiens : une nouvelle alternative pour le traitement des aspergilloses.

Aspergillus fumigatus is the predominant fungal species causing pulmonary aspergillosis. The present-day anti-aspergillosis arsenal is limited, with a number of molecules occasioning severe side effects (amphotericin B) or provoking significant drug interactions (azole derivatives). Moreover, the recent emergence of azole-resistant A. fumigatus strains is a cause for concern. In this context, antimicrobial peptides (AMPs) are emerging as a promising therapeutic approach and alternative or complement to conventional antifungals.

Searching for Conjugates as New Structures for Antifungal Therapies.

The progressive increase in fungal infections and the decrease in the effectiveness of current therapy explain research on new drugs. The synthesis of compounds with proven antifungal activity, favorable physicochemical and pharmacokinetic properties affecting their pharmaceutical availability and bioavailability, and limiting or eliminating side effects has become the goal of many studies. The publication describes the directions of searching for new compounds with antifungal activity, focusing on conjugates. The described modifications include, among others, azoles or amphotericin B in combination with fatty acids, polysaccharides, proteins, and synthetic polymers. The benefits of these combinations in terms of activity, mechanism of action, and bioavailability were indicated. The possibilities of creating or using nanoparticles, "umbrella" conjugates, siderophores (iron-chelating compounds), and monoclonal antibodies were also presented. Taking into account the role of vaccinations in prevention, the scope of research related to developing a vaccine protecting against fungal infections was also indicated.

Clinical evaluation of antifungal de-escalation in Candida infections: A systematic review and meta-analysis.

OBJECTIVES: De-escalation (DES) from echinocandins to azoles is recommended by several medical societies in Candida infections. We summarise the evidence of DES on clinical and microbiological cure and 30-day survival and compare it with continuing the treatment with echinocandins (non-DES). METHODS: We searched MEDLINE, Embase, Web of Science and Scopus. Studies describing DES in inpatients and reporting any of the outcomes evaluated were included. Pooled estimates of the tree outcomes were calculated with a fixed or random-effects model. Heterogeneity was explored stratifying by subgroups and via meta-regression. This systematic review is registered with PROSPERO (CRD42023475486). RESULTS: Of 1853 records identified, 9 studies were included, totalling 1575 patients. Five studies stepped-down to fluconazole; one to voriconazole and three to any of azoles. The mean day of DES was 5.2 (4.6-6.5) days. The clinical cure OR was 1.29 (95% CI: 0.88-1.88); the microbiological cure 1.62 (95% CI: 0.71-3.71); and 30-day survival 2.17 (95% CI: 1.09-4.32). The 30-day survival data into subgroups showed higher effect on critically ill patients and serious-risk bias studies. Meta-regression did not identify significant effect modifiers. CONCLUSIONS: DES is a safe strategy; it showed no higher 30-day mortality and a trend towards greater clinical and microbiological cure.

Efficacy and safety of coadministration of venetoclax and anti-fungal agents under therapeutic drug monitor in unfit acute myeloid leukemia and high-risk myelodysplastic syndrome with neutropenia: a single-center retrospective study.

Unfit acute myeloid leukemia and high-risk myelodysplastic syndrome patients with prolonged neutropenia demand coadministration of venetoclax and azoles. However, venetoclax dosing under drug-drug interaction with azoles remains controversial. Therapeutic drug monitoring (TDM) is expected to guide drug dosage adjustments. We retrospectively enrolled 17 patients under this coadministration and TDM. Venetoclax dosages were interfered when inappropriate drug concentrations appeared. The primary endpoints were objective response and adverse events. Venetoclax concentration outliers were more frequently evaluated before than after dose adjustment (Cmax 60.87% vs. 0.00%, p < .0001). MRD negativity rate was higher in patients staying within reference range than those having outliers (90.91% vs. 33.33%, p = .028). Objective response rate was 100%. Hematologic adverse events included neutropenia (93.3%), febrile neutropenia (53.3%), and thrombocytopenia (81.3%). Median time to neutropenia and thrombocytopenia recovery was 20 (14-32) and 16.5 (6-34) days, respectively. No invasive fungal and other life-threatening infections were observed.

Difference in immunosuppressant dose requirement when transitioning to isavuconazole from other azoles in thoracic transplant recipients.

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant). Concentration to dosage ratios (C/D) of immunosuppressants were assessed at baseline, day 3, and weekly for 9 weeks. When starting ISAVU de novo, we observed a temporary doubling of tacrolimus exposure. Cyclosporine and sirolimus required dose decreases. Tacrolimus C/D increased by 110% at day 3 in patients started on ISAVU de novo then returned to baseline C/D ± 17% weeks 2-9 (n = 8). One cyclosporine patient started on ISAVU de novo had variable C/D, and C/D increased by 219% ± 72% in 2 sirolimus patients. When transitioning from other azoles, tacrolimus and cyclosporine required about twice the initial dose. After week 1, tacrolimus C/D decreased by 53% ± 6% in patients transitioned from posaconazole (n = 33), voriconazole (n = 14), or fluconazole (n = 2). Cyclosporine C/D decreased by 45% ± 16% in patients transitioning from other azoles (posaconazole [n = 2], voriconazole [n = 2], fluconazole [n = 1]). Sirolimus C/D decreased by 73% ± 13% in patients transitioned from posaconazole (n = 7). Aside from the initial loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in adjustments for the 4-week period after initiating antifungal therapy with ISAVU or switching from another agent.

Should ebselen be considered for the treatment of mercury intoxication? A minireview.

Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg0, Hg+ and Hg2+) and organic forms (chiefly CH3Hg+ or MeHg+). The main route of human, mammals and bird exposure occurs via predatory fish ingestion. Occupational exposure to Hg0 (and Hg2+) can also occur; furthermore, in gold mining areas the exposure to inorganic Hg can also be high. The toxicity of electrophilic forms of Hg (E+Hg) is mediated by disruption of thiol (-SH)- or selenol (-SeH)-containing proteins. The therapeutic approaches to treat methylmercury (MeHg+), Hg0 and Hg2+ are limited. Here we discuss the potential use of ebselen as a potential therapeutic agent to lower the body burden of Hg in man. Ebselen is a safe drug for humans and has been tested in clinical trials (for instance, brain ischemia, noise-induce hearing loss, diabetes complications, bipolar disorders) at doses varying from 400 to 3600 mg per day. Two clinical trials with ebselen in moderate and severe COVID are also approved. Ebselen can be metabolized to an intermediate with -SeH (selenol) functional group, which has a greater affinity to electrophilic Hg (E+Hg) forms than the available thiol-containing therapeutic agents. Accordingly, as observed in vitro and rodent models in vivo, Ebselen exhibited protective effects against MeHg+, indicating its potential as a therapeutic agent to treat MeHg+ overexposure. The combined use of ebselen with thiol-containing molecules (e.g. N-acetylcysteine and enaramide)) is also commented, because they can have synergistic protective effects against MeHg+.

Using (1,3)-ß-D-glucan concentrations in serum to monitor the response of azole therapy in patients with eumycetoma caused by Madurella mycetomatis.

INTRODUCTION: (1,3)-ß-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-ß-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-ß-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated. MATERIALS AND METHODS: In this study, we measured (1,3)-ß-D-glucan concentrations in serum with the WAKO (1,3)-ß-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-ß-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-ß-D-glucan concentrations and clinical outcome was evaluated. RESULTS: The concentration of (1,3)-ß-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-ß-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-ß-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-ß-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-ß-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-ß-D-glucan concentration was noted. CONCLUSION: Although in general (1,3)-ß-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in ß-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-ß-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.

Comparing emollient use with topical luliconazole (azole) in the maintenance of remission of chronic and recurrent dermatophytosis. An open-label, randomized prospective active-controlled non-inferiority study.

BACKGROUND: Literature on emollient use in the management of chronic and recurrent dermatophytosis is limited. OBJECTIVE: To assess the efficacy of emollient in the remission maintenance of chronic and recurrent dermatophytosis. METHODS: In this randomized open-label study with the intention to treat, 80 patients with chronic recurrent dermatophytosis were randomized into two groups, where both groups were treated adequately for 6 weeks, followed by continuation of topical azole in group A and topical emollient in group B for 6 weeks. Clinical remission was determined by disappearance signs and symptoms of tinea lesions with or without hyperpigmentation. Physician and patient global assessment scores were evaluated every 2 weeks for 6 weeks to assess remission maintenance. RESULTS: A total of 80 patients of chronic and recurrent dermatophytosis were assessed for remission maintenance. The recurrence of disease occurred in 20 patients overall, wherein 7 patients (17.5%) in group A and 13 patients (32.5%) in group B at the end of the study (18 weeks); however, the difference between the two groups was not statistically significant (p = .121). The mean physician global assessment scores of group A and group B at 12 weeks were 4.45 ± 0.74 and 4.15 ± 0.92, 4.43 ± 0.90 and 4.10 ± 0.98 at 14 weeks, 4.0 ± 1.32 and 3.98 ± 1.23 at 16 weeks, 3.85 ± 1.44 and 3.90 ± 1.35 at 18 weeks, respectively. The mean patient global assessment scores of group A and group B were 4.65 ± 0.62 and 4.25 ± 0.87 at 12 weeks, 4.40 ± 0.87 and 4.17 ± 0.98 at 14 weeks, 4.18 ± 1.15 and 4.12 ± 1.30 at 16 weeks and 3.97 ± 1.33 and 3.90 ± 1.51 at 18 weeks. CONCLUSION: The present study concludes that the efficacy of emollient was not inferior to topical luliconazole for maintaining remission in chronic and recurrent dermatophytosis.

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Antifungal Therapies for Aspergillus spp.: Present and Future.

Currently available and recommended options for the treatment of pulmonary aspergillosis include the triazoles, echinocandins, and amphotericin B products. These therapies have significant limitations. Only the azoles are available orally, but their use is often limited by toxicities, drug-drug interactions, pharmacokinetic variability, and emerging resistance. While the echinocandins are safe agents and may have a role in combination therapy, they are unproven as monotherapy. Amphotericin B preparations are toxic and require intensive monitoring. Finally, aspergillosis continues to be a disease conferring substantial morbidity and mortality, and clinical trials have not identified a therapeutic approach clearly associated with improved outcomes. As a result, there is a great need for new options in the treatment of invasive aspergillosis. Ideally, such options would be safe, have high oral bioavailability, have favorable pharmacokinetics to sequestered sites and retain activity against azole-resistant isolates. Reassuringly, there is a robust pipeline of novel therapies in development. Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same mechanism of action as echinocandins) will likely be reserved for combination therapy or refractory/intolerance scenarios with no other options. Inhaled opelconazole is an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis. Development of an oral form of amphotericin B that avoids nephrotoxicity and electrolyte disturbances is an exciting development. Finally, olorofim and fosmanogepix, two agents with novel mechanisms of action and oral formulations, hold significant potential to challenge the triazole antifungals place as preferred therapies. However, many questions remain regarding these novel agents, and at the time of this writing, none of these agents have been robustly studied in Phase III studies of aspergillosis, and so their promise remains investigational.

Chronic Pulmonary Aspergillosis: Clinical Presentation and Management.

Chronic pulmonary aspergillosis (CPA) refers to a number of clinical syndromes resulting from the presence and local proliferation of Aspergillus organisms in the lungs of patients with chronic lung disease. CPA is more common than was realized two decades ago. Recognition remains poor, despite recent studies from many countries highlighting the high prevalence in at-risk populations. In low- and middle-income countries, CPA may be misdiagnosed and treated as tuberculosis (TB). In addition, CPA may develop following successful TB treatment. The coronavirus disease pandemic has resulted in significant disruption to provision of TB care, likely leading to more extensive lung damage, which could increase the risk for CPA.Although CPA refers to various syndromes, the classic presentation is that of chronic cavitary pulmonary aspergillosis, which manifests as one or more progressive cavities with or without a fungal ball, accompanied by systemic and respiratory symptoms for at least 3 months. Diagnosis relies on Aspergillus immunoglobulin G in serum, as sputum culture lacks sensitivity. Differential diagnosis includes mycobacterial infection, bacterial lung abscess or necrotizing pneumonia, lung cancer, and endemic fungi.The aim of antifungal treatment in CPA is to improve symptoms and quality of life, and to halt progression, and possibly reverse radiological changes. Current recommendations suggest treatment for 6 months, although in practice many patients remain on long-term treatment. Improvement may manifest as weight gain and improvement of symptoms such as productive cough, hemoptysis, and fatigue. Surgical management should be considered in cases of diagnostic uncertainty, in significant hemoptysis, and when there is concern for lack of response to therapy. Itraconazole and voriconazole are the first-line azoles, with more experience now accumulating with posaconazole and isavuconazole. Side effects are frequent and careful monitoring including therapeutic drug monitoring is essential. Intravenous antifungals such as echinocandins and amphotericin B are used in cases of azole intolerance or resistance, which often develop on treatment. Relapse is seen after completion of antifungal therapy in around 20% of cases, mostly in bilateral, high-burden disease.Several research priorities have been identified, including characterization of immune defects and genetic variants linked to CPA, pathogenetic mechanisms of Aspergillus adaptation in the lung environment, the contribution of non-fumigatus Aspergillus species, and the role of new antifungal agents, immunotherapy, and combination therapy.

Candidemia Cases Caused by Candida parapsilosis Complex Species: Epidemiology and Antifungal Susceptibility of Strains.

BACKGROUND: Candida parapsilosis is a common non-albicans Candida species isolated from blood cultures. The increase in fluconazole-resistant C. parapsilosis complex isolates is worrying, especially in strains with Y132F changes in the ERG11 gene since this ultimately leads to outbreaks. This study aimed to investigate the distribution and antifungal susceptibility of C. parapsilosis complex species isolated from bloodstream, clinical characteristics of patients, prevalence of risk factors, and to determine ERG11 gene region mutations in strains that were not susceptible to fluconazole. METHODS: Between 2014 and 2018, 96 patients with C. parapsilosis candidemia were evaluated. Thermo Scientific SensititerTM YeastOneTM YO10 was used for antifungal susceptibility testing. The ERG11 gene region sequence analysis was performed for fluconazole non-susceptible isolates. RESULTS: All the strains were defined as C. parapsilosis sensu stricto. The rate of fluconazole resistance was 6.3%, and that of susceptibility to fluconazole at an increased dose was 2.1%. Two isolates showed Y132F or G458S ERG11 changes associated with azole resistance, with the most common change being identified as R398I, which was shown not to encode azole resistance. No resistance to echinocandins and amphotericin B was observed. The use of broad-spectrum antibiotics (83.3%) was the most common risk factor. CONCLUSIONS: This study highlights the importance of susceptibility testing when making a decision to use fluconazole in the treatment of C. parapsilosis candidemia. The presence of resistance associated with ERG11 Y132F changes indicated that azole resistance should be closely monitored. Increasing awareness of fluconazole-resistant C. parapsilosis candidemia will help identify strategies to overcome these infections.

Photodynamic inactivation by hypericin-P123 on azole-resistant isolates of the Trichophyton rubrum complex as planktonic cells and biofilm.

INTRODUCTION: The Trichophyton rubrum complex comprises the majority of dermatophyte fungi (DM) responsible for chronic cases of onychomycosis, which is treated with oral or topical antifungals. However, owing to antifungal resistance, alternative therapies, such as photodynamic therapy (PDT), are needed. This study investigated the frequency of the T. rubrum species complex in onychomycosis cases in the northwestern region of Paraná state, Brazil, and evaluated the efficacy of (PDT) using P123-encapsulated hypericin (Hyp-P123) on clinical isolates of T. rubrum in the planktonic cell and biofilm forms. MATERIAL AND METHODS: The frequency of the T. rubrum complex in onychomycosis cases from 2017 to 2021 was evaluated through a data survey of records from the Laboratory of Medical Mycology (LEPAC) of the State University of Maringa (UEM). To determine the effect of PDT-Hyp-P123 on planktonic cells of T. rubrum isolates, 1 × 105 conidia/mL were treated with ten different concentrations of Hyp-P123 and then irradiated with 37.8 J/cm2. Antibiofilm activity of PDT-Hyp-P123 was tested against T. rubrum biofilm in the adhesion phase (3 h), evaluated 72 h after irradiation (37.8 J/cm2), and the mature biofilm (72 h), evaluated immediately after irradiation. In this context, three different parameters were evaluated: cell viability, metabolic activity and total biomass. RESULTS: The T. rubrum species complex was the most frequently isolated DM in onychomycosis cases (approximately 80 %). A significant reduction in fungal growth was observed for 75 % of the clinical isolates tested with a concentration from 0.19 µmol/L Hyp-P123, and 56.25 % had complete inhibition of fungal growth (fungicidal action); while all isolates were azole-resistant. The biofilm of T. rubrum isolates (TR0022 and TR0870) was inactivated in both the adhesion phase and the mature biofilm. CONCLUSION: PDT-Hyp-P123 had antifungal and antibiofilm activity on T. rubrum, which is an important dermatophyte responsible for onychomycosis cases.

In-vivo efficiency of the novel azole compounds (ATTAF-1 and ATTAF-2) against systemic candidiasis in a murine model.

BACKGROUND: Antifungal resistance is the main health concern in the control of invasive fungal infections. This research was designed to further assess the antifungal activity of aryl-1,2,4-triazole-3-ylthio analogs of fluconazole (ATTAFs) against Candida albicans systemic candidiasis in the murine model. MATERIALS & METHODS: The murine model of systemic candidiasis was designed via the inoculation of 1 × 106 CFU of Candida albicans. The treatment dosages of 3.5 and 35 mg/kg per day were selected for ATTAFs and fluconazole, respectively. The median survival time (MST) was assayed for 30 days post-infection. The quantitative and qualitative (via histopathology staining) fungal burden was also assessed. Furthermore, immunohistochemistry and biochemistry assays were performed to monitor anti-inflammatory activity using the Cyclooxygenase-2 (Cox-2) marker and changes in serum protein levels. RESULTS: ATTAFs considerably improved the survival of the murine model (P < 0.003). Compared with fluconazole, the antifungal activity of ATTAFs and their MST showed no difference (P > 0.05). However, these compounds decreased the fungal burden in the kidneys, spleen, and liver. CONCLUSION: Our research indicates that ATTAF-1 and ATTAF-2 are effective therapeutic agents due to their fungal clearing and increasing the MST in the murine model of systemic candidiasis. Although we concluded that these components are novel and promising candidates for the management of invasive candidiasis, further studies are warranted to correlate these findings with clinical outcomes.

Alarming Increase of Azole-Resistant Candida Causing Blood Stream Infections in Oncology Patients in Egypt.

Candidemia is a life-threatening invasive fungal infection in immunocompromised patients. The widespread use of azoles and the shift toward non-albicans Candida (NAC) species remarkably increase azole resistance in developing countries. We aimed to study candidemia trends and associated risk factors in oncology patients since they vary geographically, and rapid and appropriate treatment improves outcomes. Vitek 2 was used to identify the Candida species, and the E-test determined their susceptibility to azoles. Candida was the cause of 3.1% (n = 53/1701) of bloodstream infections (BSIs) during a 1-year study. Candida tropicalis was the most predominant species among the 30 candidemia episodes studied (36.7%), followed by C. albicans (33.3%). However, C. krusei, C. guilliermondii, C. pelliculosa, C. parapsilosis, C. famata, and C. inconspicua accounted for 30.0% of the isolates. An increased risk of NAC BSI was significantly associated with chemotherapy and leucopenia (P = 0.036 and 0.016, respectively). However, the multivariable analysis revealed that leucopenia was the only independent risk factor (P = 0.048). Fluconazole and voriconazole resistance were 58.3% and 16.7%, with NAC species showing higher resistance rates than C. albicans. Both fluconazole and voriconazole minimum inhibitory concentration (MIC) median values were higher in NAC than in C. albicans, but only voriconazole was significantly higher (0.220 versus 0.048 µg/ml, P = 0.047). In conclusion, the increased prevalence of NAC BSIs and incredibly high fluconazole resistance rates in cancer patients emphasize the necessity of antifungal stewardship to preserve voriconazole effectiveness, continued surveillance of candidemia, and future studies into azole resistance molecular mechanisms.

Synergy In Vitro of Nikkomycin Z with Azole Against the Invasive Form of Candida albicans.

In a previous study, therapeutic activity of nikkomycin Z (NZ) in a model of invasive candidiasis did not appear to correlate with lesser activity in vitro (using classical MIC methods) with planktonic organisms. However, NZ potency was much greater assaying activity in vitro against germ tubes, the initiator of the invasive mycelial form of the fungus, as occurs in infected tissues. Synergy has been demonstrated for NZ and other drugs, notably fluconazole (the most commonly used drug against candidiasis), in planktonic testing, which correlated with results in vivo. This raised the question whether activity shown by NZ alone against germ tubes would be reflected in drug combinations, and even whether synergy testing against germ tubes might be a better correlate of synergy in future in vivo studies. We show in this study significant NZ synergy with fluconazole against germ tubes, for several C. albicans isolates, with testing in many drug ratios. This observation opens the way for further explorations of this method of susceptibility testing for synergy, and correlation with combination therapy against candidiasis.

Nanoformulation of a novel potent ebselen analog for treatment of vulvovaginal candidiasis.

Background: Vulvovaginal candidiasis is primarily caused by Candida albicans (C. albicans). Here, a novel organoselenium compound (G20) was synthesized and evaluated for anti-Candida activity. Methods: Growth-inhibition studies and medium acidification assays to assess the inhibition of the yeast plasma membrane H+-ATPase (Pma1p) were carried out in vitro using G20. A self-nanoemulsifying formulation (SNEP) of G20 was prepared and evaluated for antimycotic activity in a mouse model. Results: G20 inhibited the growth of C. albicans through a mechanism that, at least in part, involves the inhibition of Pma1p. The G20-SNEP formulation significantly reduced vaginal colonization and vaginal inflammation relative to yeast-infected but untreated control mice. Conclusion: G20-SNEP exhibits potent antimycotic activity in a mouse model of vulvovaginal candidiasis.

Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis.

The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistance-related genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound A32 demonstrated fungicidal activity against fluconazole-resistant strain 904. Most importantly, compound A32 showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound A32 represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.