Multifocal Candidiasis can be considered a form of Invasive Candidiasis in critically non neutropenic patients.

INTRODUCTION: Candida infections can be serious in ICU patients, as Candida is an organism that specially colonizes the digestive system. In immunocompromised patients, treatment is protocolized but in non-neutropenic patients it is not well established. On the other hand, the treatment of this type of infection is not absent of adverse effects. DISSEMINATED VERSUS INVASIVE CANDIDIASIS: The prevalence of fungal infections, especially Candidiasis and its mortality in the ICU is high, mainly due to the lack of diagnosis and absence of treatment criteria, because they are often detected in the Disseminated Candidiasis phase, such as candidemia. One of the indicators of the progression of the disease is the presence of Candida in more than two different foci, named Candida Multifocality, within the concept of Invasive Candidiasis. In fact, Fundicu Project was created to optimize the management of Candidiasis. APPROACH TO THE CLINICAL MANAGEMENT OF CANDIDIASIS: The management of Candidiasis in ICU patients first requires the identification of patients at high risk of Candidiasis, which must be performed based on the evidence of immune dysregulation, higher severity index (APACHE, MODS), long ICU stays or other factors such as mechanical ventilation or use of broad-spectrum antibiotics. In order to increase detection and dispense the appropriate anti-fungal at an early stage, it is necessary to include the concept of Multifocality in Invasive Candidiasis with screening of different foci. Anti-fungal treatment reduces mortality both overall and attributable to Candida. CONCLUSIONS: Detecting a high Invasive Candidiasis risk is a patient safety concept and should be treated as such. Identifying patients (critically non-neutropenic adult patients with severe MODS and the first isolation of Candida species in a study sample of possible secondary infection) and demonstrating Invasive Candidiasis (Multifocal or Disseminated) require urgent initiation of anti-fungal treatment to minimize mortality attributable to Invasive Candidiasis in ICU and eliminate mortality rates above 50%.

Case report: Successful combination therapy with isavuconazole and amphotericin B in treatment of disseminated Candida tropicalis infection.

Disseminated candidiasis is a severe complication in patients with hematological malignancies who have undergone chemotherapy or hematopoietic stem cell transplantation. It has a high mortality rate. When disseminated candidiasis caused by Candida tropicalis involves either the brain or heart, the prognosis is extremely poor. Traditional methods such as cultures are limited in diagnosing disseminated candidiasis. We describe a case report of a 55-year-old man with acute myeloid leukemia who developed candidemia caused by Candida tropicalis after chemotherapy, which disseminated extensively to the heart, brain, skin, liver, spleen and kidneys. In this instance, the patient was rapidly diagnosed with candida infection by metagenomic next generation sequencing, and successfully treated with combination therapy of isavuconazole and amphotericin B. The patient continued with treatment of leukemia while simultaneously receiving antifungal therapy, and both leukemia and disseminated candidiasis were effectively controlled. This case report provides real-world experience for treatment of patients with leukemia complicated by disseminated candidiasis.

Prognostic value of serial (1,3)-ß-D-glucan measurements in ICU patients with invasive candidiasis.

BACKGROUND: To determine whether a decrease in serum (1,3)-ß-D-glucan (BDG) was associated with reduced mortality and to investigate the performance of BDG downslope in predicting clinical outcome in invasive candidiasis. METHODS: Observational cohort study in ICU patients over a ten-year period (2012-2022) in Italy. Proven invasive candidiasis with at least 2 BDG determinations were considered. RESULTS: In the study population of 103 patients (age 47 [35-62] years, SAPS II score 67 [52-77]) 68 bloodstream and 35 intrabdominal infections were recorded. Serial measurements showed that in 54 patients BDG decreased over time (BDG downslope group) while in 49 did not (N-BDG downslope group). Candida albicans was the pathogen most frequently isolated (61%) followed by C. parapsilosis (17%) and C. glabrata (12%), in absence of any inter-group difference. Invasive candidiasis related mortality was lower in BDG downslope than in N-BDG downslope group (17% vs 53%, p < 0.01). The multivariate Cox regression analysis showed the association of septic shock at infection occurrence and chronic liver disease with invasive candidiasis mortality (HR [95% CI] 3.24 [1.25-8.44] p = 0.02 and 7.27 [2.33-22.66] p < 0.01, respectively) while a BDG downslope was the only predictor of survival (HR [95% CI] 0.19 [0.09-0.43] p < 0.01). The area under the receiver operator characteristic curve for the performance of BDG downslope as predictor of good clinical outcome was 0.74 (p = 0.02) and our model showed that a BDG downslope > 70% predicted survival with both specificity and positive predictive value of 100%. CONCLUSIONS: A decrease in serum BDG was associated with reduced mortality and a steep downslope predicted survival with high specificity in invasive candidiasis.

Causal relationship between type 1 diabetes mellitus and mycoses: a Mendelian randomization study.

Background: Type 1 diabetes mellitus (T1DM) is frequently associated with various infections, including mycoses; however, the direct link between T1DM and fungal infections remains under-researched. This study utilizes a Mendelian randomization (MR) approach to investigate the potential causal relationship between T1DM and mycoses. Methods: Genetic variants associated with T1DM were sourced from the European Bioinformatics Institute database, while those related to fungal infections such as candidiasis, pneumocystosis, and aspergillosis were obtained from the Finngen database, focusing on European populations. The primary analysis was conducted using the inverse variance weighted (IVW) method, with additional insight from Mendelian randomization Egger regression (MR-Egger). Extensive sensitivity analyses assessed the robustness, diversity, and potential horizontal pleiotropy of our findings. Multivariable Mendelian randomization (MVMR) was employed to adjust for confounders, using both MVMR-IVW and MVMR-Egger to evaluate heterogeneity and pleiotropy. Results: Genetically, the odds of developing candidiasis increased by 5% in individuals with T1DM, as determined by the IVW method (OR = 1.05; 95% CI 1.02-1.07, p = 0.0001), with a Bonferroni-adjusted p-value of 0.008. Sensitivity analyses indicated no significant issues with heterogeneity or pleiotropy. Adjustments for confounders such as body mass index, glycated hemoglobin levels, and white blood cell counts further supported these findings (OR = 1.08; 95% CI:1.03-1.13, p = 0.0006). Additional adjustments for immune cell counts, including CD4 and CD8 T cells and natural killer cells, also demonstrated significant results (OR = 1.04; 95% CI: 1.02-1.06, p = 0.0002). No causal associations were found between T1DM and other fungal infections like aspergillosis or pneumocystosis. Conclusion: This MR study suggests a genetic predisposition for increased susceptibility to candidiasis in individuals with T1DM. However, no causal links were established between T1DM and other mycoses, including aspergillosis and pneumocystosis.

Treatment Outcomes Among Patients With a Positive Candida Culture Close to Randomization Receiving Rezafungin or Caspofungin in the ReSTORE Study.

BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was non-inferior to caspofungin for Day 30 all-cause mortality (ACM) and Day 14 global cure in the Phase 3 ReSTORE trial (NCT03667690). We conducted pre-planned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization, or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included Day 30 ACM, Day 14 global cure rate, and Day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively: Day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval] 4.6% [-13.7, 23.5]); Day 14 global response was 55.3% and 50.0% (between-group difference 5.3% [-16.1, 26.0]); and Day 5 mycological eradication was 71.1% and 50.0% (between-group difference 21.1% [-0.2, 40.2]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Expert Panel Recommendations on the Clinical Practice Guidelines for the Diagnosis and Management of Invasive Candidiasis in Indonesia.

Invasive candidiasis (IC) ranks among the primary causes of deadly fungal infections. The frequency of IC rises alongside increasing number of patients with altered immune systems, critically ill, chronic diseases, and various medical procedures. The disease causes high morbidity and mortality, as well as prolonged stay and increases hospital costs. The diagnosis and management of IC in Indonesia is still a challenge. Laboratory facilities in identifying pathogenic fungi and susceptibility tests to antifungals are still limited. Clinical awareness and financial support from health policymakers are also insufficient. Early diagnosis is essential for proper treatment to reduce morbidity and mortality rates. Initiated by the Indonesian Pulmonary Mycoses Centre (IPMC), several expert representatives from six medical professional organizations in Indonesia have agreed to set up a meeting series to prepare a joint draft on the diagnosis and management of IC. The expert panel aimed to achieve a consensus on the clinical practice guidelines for diagnosing and treating IC in Indonesia.

A novel quantitative double antigen sandwich ELISA for detecting total antibodies against Candida albicans enolase 1.

PURPOSE: This study aimed to develop a double antigen sandwich ELISA (DAgS-ELISA) method for more efficient, accurate, and quantitative detection of total antibodies against Candida albicans enolase1 (CaEno1) for diagnosing invasive candidiasis (IC). METHODS: DAgS-ELISA was developed using recombinant CaEno1 and a monoclonal antibody as the standard. Performance evaluation included limit of detection, accuracy, and repeatability. Dynamic changes in antibody levels against CaEno1 in serum from systemic candidiasis mice were analyzed using DAgS-ELISA. Patient serum samples from IC, Candida colonization, bacterial infections, and healthy controls were analyzed with DAgS-ELISA and indirect ELISA. RESULTS: DAgS-ELISA outperformed indirect ELISA in terms of linear range and test background. In systemic candidiasis mice, a distinctive 'double-peak' pattern in dynamic antibody levels was observed. Additionally, there was a high level of consistency in the positive rates of CaEno1 antibodies detected by both DAgS-ELISA and indirect ELISA. While the positivity rates differed among patient groups, no significant variations in antibody levels were detected among the various positive patient groups. CONCLUSIONS: DAgS-ELISA offers a reliable novel approach for IC diagnosis, enabling rapid, accurate, and quantitative detection of CaEno1 antibodies. Further validation and optimization are needed for its clinical application and effectiveness.

Might photobiomodulation therapy interfere with the frequency of severe mucositis and oral candidiasis? A retrospective analysis in patients with head and neck carcinoma.

PURPOSE: Considering the tumor in the oral cavity or the oropharynx and nasopharynx region might be an aggravating factor for oral mucositis (OM) manifestation, the present study aimed to evaluate whether the location of the tumor and the use of photobiomodulation therapy (PBMT) might affect the frequency of oral candidiasis (OC) during radiotherapy (RT) and/or chemotherapy (CT) treatments. METHODS: The medial records of seventy-four patients with head and neck cancer treated in a public service from 2016 to 2019 were evaluated. All these patients were submitted to RT in an accumulated dose of 48 to 70 Gy of radiation. Data about OM and OC were collected and presented according to the application of a therapeutic protocol with laser photobiomodulation (PBMT) to control oral mucositis, or not (No-PBM), and the location of tumor (head and neck or oral cavity). In the PBMT group patients, a low-power laser device composed of InGaAlP diode (maximum output power of 86.7 mW, active tip area of 0.1256 cm2, and continuous wavelength of 660 nm), was applied to the lips (three points each), right and left jugal mucosa (three points each), the limit between hard and soft palate (three points), buccal floor/sublingual gland (one point), lateral edge of the tongue (three points on each side), and back of the tongue (six points), three times weekly, for 5 weeks. The dosimetry used in each application was 2 J for 3 s, thus totaling 56 J. The correlation between clinical characteristics such as age, tumor size (T), metastatic lymph node (N), number of RT and CT sessions, candidiasis, and OM were analyzed. RESULTS: Mucositis grades 1 and 2 were the most common among all patients, especially before the 12th radiotherapy session, regardless of the treatment with PBM (p > 0.05). Additionally, no difference in the grade of OM and OC was significantly observed when comparing the two laser therapy groups. OC was more frequent after the 12th radiotherapy session in all groups. Nonetheless, OM and OC had a different correlation regarding to tumor location (head and neck and oral cavity) being PBMT a positive therapy to delay OM. It was observed a positive and statistically significant correlation between tumors at oral cavity and OM, regardless PBMT (R = 0.84, p < 0.05 to PBMT and R = 0.13, p < 0.05 to No-PBM). Otherwise, OC was positively correlated to local metastasis in patients with oral tumors undergoing PBMT (R = 0.84, p < 0.05). CONCLUSION: Patients with oral cavity tumor presented more OM, especially high grades, then patients with tumors in other regions of the head and neck, which seems to be related to the irradiation parameters of radiotherapy and/or with the limitation of conduction of PBMT in tumor areas. OM and OC were not changed by PBMT, although it helped to reduce the incidence of severe cases of OM.

A prospective observational study on species differentiation and antifungal susceptibility pattern in patients with genital candidiasis.

Background: Candidial balanitis, balanoposthitis and vulvovaginitis can be diagnosed by direct microscopy, culture and treated with antifungals. Resistance to antifungals is emerging. Hence, we conducted a study to identify the causative species and antifungal susceptibility. Aim: To observe the species differentiation and antifungal susceptibility pattern in patients with genital candidiasis. Materials and Methods: A prospective observational study was carried out that included 54 patients of age group (18-60 years) diagnosed clinically and direct microscopically (KOH) for genital candidiasis. Culture was done using Sabouraud dextrose agar. Species identification and antifungal susceptibility were tested. Descriptive data were expressed in the form of frequency and percentage. Results: Out of 54 patients, 41 had culture positive candidiasis. Among the isolated species, 68.3% were Candida albicans (28/41) and 31.7% were non- albicans Candida spp. Among non-albicans Candida species (13/41), Candida glabrata (19.5%), Candida tropicalis (7.3%), Candida guilliermondii (2.4%), Candida parapsilosis (2.4%) were identified. Antifungal susceptibility was tested for fluconazole (FLU), clotrimazole (CLTZ), itraconazole (ITZ), ketoconazole (KTZ), voriconazole (VOR), amphotericin-B (AMPH-B). Except C. glabrata and C.parapsilosis, all other species were sensitive to all tested antifungals. All isolated species were sensitive to KTZ, VOR, AMPH-B, and CLTZ. Nearly 22% of isolates were resistant to fluconazole. Conclusion: C. glabrata causes complicated, severe recurrent vulvovaginitis which is fluconazole resistant. Drug sensitivity prior prescribing antifungal agent identifies appropriate drug, decreases patient's disease morbidity and cross resistance.

Vulvovaginal candidiasis and type 2 diabetes: A nationwide retrospective cohort study.

AIMS: To examine whether vulvovaginal candidiasis (VVC) precedes type 2 diabetes and to quantify the possible time period between VVC and subsequent diabetes. MATERIAL AND METHODS: We conducted a nationwide retrospective primary healthcare study including 1 838 929 women aged 35-65 years in Sweden (2007-2018). Cox regression models were used to examine associations between VVC and type 2 diabetes, while controlling for possible confounders. Propensity-score-weighted analysis was also conducted. RESULTS: The incidence rate of diabetes per 1000 person-years was 3.06 (95% confidence interval [CI] 3.05-3.08) in women without preceding VVC and 4.05 (95% CI 3.86-4.24) in women with preceding VVC. The incidence rate was particularly high in women aged 55 years and older with VVC: 9.56 (95% CI 8.01-11.11). Women with VVC had a hazard ratio (HR) of 1.41 (95% CI 1.28-1.55) for diabetes compared to women without VVC in the multivariable-adjusted model. The corresponding HR was 1.63 (95% CI 1.53-1.74) in propensity-score-weighted analysis. Women with prior VVC also seemed to have a stronger risk of diabetes with older age, particularly after the age of 55 years. The mean (range) time between VVC and subsequent diabetes was 0.57 (0-2) years, depending on the age of the woman. CONCLUSION: We found temporal associations between VVC and diabetes. The findings demonstrate that the presence of VVC may indicate a future diagnosis of diabetes, especially in women aged 55 years and older. This knowledge could be valuable for clinicians when treating women with VVC.

Clinical features and risk factors for Sjogren's syndrome patients suffering from oral candidiasis in Shanxi, China.

OBJECTIVES: To investigate the clinical features and risk factors of Sjogren's Syndrome (SS) patients suffering from oral candidiasis and to provide a foundation for the prevention and treatment of oral candidiasis in SS patients. METHODS: The medical records of 479 SS patients admitted to the Second Hospital of Shanxi Medical University from 2018 to 2020 were analysed to determine the clinical characteristics and risk factors that influence the occurrence of oral candidiasis infection in SS patients. RESULTS: Patients with oral candidiasis were older than those without oral candidiasis (P < 0.05). Male SS patients had greater oral candidiasis rates (P < 0.05). Unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were both shown to be adversely associated with oral Candida infections (P < 0.001). Logistic regression revealed that a low UWS was an independent risk factor for oral Candida infections in SS patients (OR: 0.004, P = 0.023). Greater WBC counts (OR: 1.22, P < 0.001), lower haemoglobin levels (OR: 0.97, P = 0.007), lower serum albumin levels (OR: 0.88, P < 0.001), lower IgG levels (OR: 0.91, P = 0.011), lower IgA levels (OR: 0.75, P = 0.011), and lower IgM levels (OR: 0.91, P = 0.015) were found in patients with oral Candida infections. Patients on immunosuppressive medications (OR: 0.32, P = 0.011), particularly rapamycin (P < 0.001), had a decreased rate of oral Candida infections. CONCLUSIONS: Patients with oral candidiasis were older than those without oral candidiasis. Male SS patients are more likely to have oral candidiasis. Individuals with lower UWS and SWS are more susceptible to oral Candida infection. Oral Candida infections in SS patients depend on their immunological status. Rapamycin may increase the abundance of Treg cells to reduce oral Candida infection in SS patients.

Changing Paradigm of Yeast Isolates in HIV-Seropositive Patients with Oropharyngeal Candidiasis (OPC).

Background Oropharyngeal candidiasis (OPC) is a common fungal infection in HIV-seropositive patients. Understanding the spectrum of yeast isolates and their antifungal susceptibility patterns is crucial for effective management. This study aimed to determine the yeast isolates, antifungal susceptibility patterns, and associated factors in HIV-seropositive patients with OPC. Material and methods A prospective observational study was conducted on 350 HIV-seropositive patients attending an Integrated Counselling and Testing Centre (ICTC) at the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar. Yeast isolates from oropharyngeal lesions were identified, and their antifungal susceptibility was determined by automated method VITEK 2. Demographic characteristics, highly active antiretroviral therapy (HAART) status, and CD4+ cell count categories were analyzed for associations. Results This study of 350 HIV-seropositive patients revealed that 100 tested positive for Candida, with distinct differences between HAART (n=67) and non-HAART (n=33) groups. HAART patients had a younger age distribution and higher median CD4+ cell counts (350 vs. 250 cells/mm³, U = 175, p < 0.05) compared to non-HAART patients. Candida albicans was the most common species in both groups, but significant variations in species distribution (χ² = 9.23, p < 0.05) and antifungal susceptibility were noted. Specifically, susceptibility differences were significant for flucytosine (χ² = 7.21, p = 0.027) and voriconazole (χ² = 8.64, p = 0.013), emphasizing the influence of HAART on managing immune function and antifungal resistance in HIV patients. Conclusion This study provides insights into the spectrum of yeast isolates and their antifungal susceptibility patterns in HIV-seropositive patients with OPC. The findings emphasize the importance of considering multiple factors, such as Candida species, HAART status, and individual patient characteristics, in treatment decisions. The results will aid in the development of evidence-based management protocols for this vulnerable population. Further research is warranted to explore additional factors influencing antifungal susceptibility and optimize treatment strategies for this patient population.

Mechanism of Vaginal Epithelial Cell Pyroptosis Induced by the NLRP3 Inflammasome in Vulvovaginal Candidiasis.

PROBLEM: Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. METHOD OF STUDY: Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1ß and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. RESULTS: In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. CONCLUSION: C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.

Infectious Aspects of Chronic Wounds.

The treatment, maintenance, and suppression of infection in chronic wounds remain a challenge to all practitioners. From an infectious disease standpoint, knowing when a chronic wound has progressed from colonized to infected, when to use systemic antimicrobial therapy and when and how to culture such wounds can be daunting. With few standardized clinical guidelines for infections in chronic wounds, caring for them is an art form. However, there have been notable advances in the diagnosis, treatment, and management of infected wounds. This article will discuss the pathophysiology of infection in older adults, including specific infections such as cutaneous candidiasis, necrotizing soft tissue infection, osteomyelitis, and infections involving hardware.

Candida Isolation During COVID-19: Microbiological Findings of a Prospective Study in a Regional Hospital.

BACKGROUND: Prolonged hospitalization due to the COVID-19 pandemic gathered risk factors for developing invasive candidiasis. AIM: To describe Candida spp. isolated from patients with clinical suspicion of COVID treated in a public hospital specialized in COVID-19 during the pandemic, considering the susceptibility profiles and the risk factors related to the species detected in a positive yeast culture. METHODS: From different samples of 33 patients with comorbidities, 42 clinical isolates were identified by VITEKⓇ MS Plus. Antifungal susceptibility testing was performed using VITEKⓇ 2 Compact with the AST-YS08 card. RESULTS: The most frequently identified species were C. albicans and C. glabrata, which were also the most common co-infections, Saprochaete capitata, an uncommon yeast was isolated in one patient. 85% of the co-infections were COVID positive and 100% of patients with a co-infection required mechanical ventilation (MV) which has been described as one of the major predisposing factors to candidiasis. Candida species vary in their response to treatment. In this study, 44% of isolates identified as C. glabrata were fluconazole-resistant, which were also immediately susceptible to caspofungin; this profile limits therapeutic options and emphasizes the importance of evaluating the susceptibility profile. CONCLUSIONS: This work highlights the increase in isolation of different Candida species during COVID-19 and the importance of establishing criteria to declare Candida colonization or infection and the correct etiological identification to establish an agent-based antifungal treatment, to reduce the spreading risk of Candida spp. in the hospital environment, mortality, time, and cost of hospitalization.

Naringenin-Zinc Oxide Nanocomposites Amalgamated Polymeric Gel Augmented Drug Delivery and Attenuated Experimental Cutaneous Candidiasis in Balb/c Mice: In Vitro and In Vivo Studies.

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.

Ibrexafungerp: A narrative overview.

Ibrexafungerp (IBX) is a new antifungal drug that recently entered the antifungal landscape. It disrupts fungal cell wall synthesis by non-competitive inhibition of the ß-(1,3)-D-glucan (BDG) synthase enzyme. It has demonstrated activity against a range of pathogens including Candida and Aspergillus spp., as well as retaining its activity against azole-resistant and echinocandin-resistant strains. It also exhibits anti-biofilm properties. Pharmacokinetic (PK) studies revealed favorable bioavailability, high protein binding, and extensive tissue distribution with a low potential for CYP-mediated drug interactions. It is characterized by the same mechanism of action of echinocandins with limited cross-resistance with other antifungal agents. Resistance to this drug can arise from mutations in the FKS genes, primarily FKS2 mutations in Nakaseomyces glabrata. In vivo, IBX was found to be effective in murine models of invasive candidiasis (IC) and invasive pulmonary aspergillosis (IPA). It also showed promising results in preventing and treating Pneumocystis jirovecii infections. Clinical trials showed that IBX was effective and non-inferior to fluconazole in treating vulvovaginal candidiasis (VVC), including complicated cases, as well as in preventing its recurrence. These trials positioned it as a Food and Drug Administration (FDA)-approved option for the treatment and prophylaxis of VVC. Trials showed comparable responses to standard-of-care in IC, with favorable preliminary results in C. auris infections in terms of efficacy and tolerability as well as in refractory cases of IC. Mild adverse reactions have been reported including gastrointestinal symptoms. Overall, IBX represents a significant addition to the antifungal armamentarium, with its unique action, spectrum of activity, and encouraging clinical trial results warranting further investigation.

Optimizing the Treatment of Invasive Candidiasis-A Case for Combination Therapy.

Invasive candidiasis is a rising global health threat with increasing incidence, persistently high mortality, and diminishing treatment options. Antifungal resistance has rapidly emerged and spread, with multidrug-resistant species deemed an urgent and serious threat. While acknowledging the key role of antifungal stewardship and infection control in curbing spread, we examine the role of antifungal monotherapy in driving resistance and the potential for combination therapy to prevent stress adaptation and emergence of drug resistance. In addition to its role in mitigating resistance, combination treatment may improve drug penetration, expedite fungal clearance, and allow lower, less toxic doses of individual drugs to be used. A growing body of laboratory-based evidence suggests that antifungal combinations can yield synergistic activity against Candida spp., including against frequently multidrug-resistant Candida auris. It is imperative to test these combinations in clinical trials, incorporating resistance end points as a marker of success.

Antifungal Plant Defensins as an Alternative Tool to Combat Candidiasis.

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.