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.

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.

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.

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.

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.

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.

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.

Contemporary Insights Into HIV Esophagitis: Pathogenesis, Therapeutic Strategies, and Prognostic Outcomes.

Opportunistic infections caused by various bacteria, viruses, fungi, or parasites can cause esophagitis. The fungus Candida albicans is often believed to be the thief behind this disorder. This condition's distinctive signs include the process of inflammation and the development of esophageal ulcers. The underlying immunodeficiency condition in HIV/AIDS patients, especially those in the late stages of the disease, may lead to severe illness or even death if the lowered immune system can no longer combat common infections. These individuals are, therefore, more at risk of contracting diseases like Candidiasis since they already have weakened immune systems. Furthermore, bacteria and mycobacteria can cause esophagitis in the same way that viruses can. Tobacco use, alcohol drinking, and nutritional deficiency are three additional problems that can lead to an HIV esophagitis infection. Complaints of inability to swallow, suffocating feeling or discomfort behind the breastbone, and painful swallowing are the primary symptoms of the patients. White plaques or ulcers observed in the esophagus during an endoscopy can be biopsied for further examination. The presence of C. albicans hyphae and inflammatory infiltrates in these samples confirms the diagnosis of HIV-associated esophagitis. Treatment involves the use of antifungal medications and addressing any underlying causes of esophagitis, which is linked to AIDS. For superficial to moderate infections, fluconazole is typically used first. If the disease is severe or recurs after treatment, intravenous amphotericin B may be necessary. Patients with recurring oral symptoms of HIV esophagitis might also need to take antifungal drugs as a preventative measure.

Antileishmanial and Antifungal Activities of Volatile Oils from Cinnamomum cassia Bark and Schinus molle Leaves.

This study reports on the chemical composition and antileishmanial and anticandidal activities of volatile oils of Schinus molle dried leaves (SM), Cinnamomum cassia branch bark (CC) and their blends. Major constituents of SM were spathulenol (26.93%), ß-caryophyllene (19.90%), and caryophyllene oxide (12.69%), whereas (E)-cinnamaldehyde (60.11%), cinnamyl acetate (20.90%) and cis-2-methoxycinnamic acid (10.37%) were predominant in CC. SM (IC50 = 21.45 µg/mL) and CC (IC50 = 23.27 µg/mL) displayed good activity against L. amazonensis promastigotes, besides having good or moderate activity against nine Candida strains, with Minimum Inhibitory Concentration (MIC) values ranging from 31.25 to 250 µg/mL. While the three SM and CC blends were not more active than the EOs tested individually, they exhibited remarkably high antileishmanial activity, with IC50 values ranging between 3.12 and 7.04 µg/mL, which is very similar to the IC50 of amphotericin B (positive control).

Candida albicans skin infection in diabetic patients: An updated review of pathogenesis and management.

Candida species, commensal residents of human skin, are recognized as the cause of cutaneous candidiasis across various body surfaces. Individuals with weakened immune systems, particularly those with immunosuppressive conditions, are significantly more susceptible to this infection. Diabetes mellitus, a major metabolic disorder, has emerged as a critical factor inducing immunosuppression, thereby facilitating Candida colonization and subsequent skin infections. This comprehensive review examines the prevalence of different types of Candida albicans-induced cutaneous candidiasis in diabetic patients. It explores the underlying mechanisms of pathogenicity and offers insights into recommended preventive measures and treatment strategies. Diabetes notably increases vulnerability to oral and oesophageal candidiasis. Additionally, it can precipitate vulvovaginal candidiasis in females, Candida balanitis in males, and diaper candidiasis in young children with diabetes. Diabetic individuals may also experience candidal infections on their nails, hands and feet. Notably, diabetes appears to be a risk factor for intertrigo syndrome in obese individuals and periodontal disorders in denture wearers. In conclusion, the intricate relationship between diabetes and cutaneous candidiasis necessitates a comprehensive understanding to strategize effective management planning. Further investigation and interdisciplinary collaborative efforts are crucial to address this multifaceted challenge and uncover novel approaches for the treatment, management and prevention of both health conditions, including the development of safer and more effective antifungal agents.

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.

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.

Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs.

Background: Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. Methods: A PubMed search was conducted with Clinical Queries using the key terms "antifungal", "children", "critical care" AND "paediatric intensive care unit" OR "PICU". The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Results: Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5-3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Conclusions: Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment.This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Liposomal Fba and Met6 peptide vaccination protects mice from disseminated candidiasis.

Epitopes from the Candida cell surface proteins Fba and Met6 are putative vaccine targets for invasive candidiasis. Here, we describe a Candida vaccine approach in which short peptides derived from Fba and Met6 are used in spontaneous nanoliposome antigen particle (SNAP) format. SNAP was enabled by the interaction of cobalt porphyrin phospholipid in liposomes with three histidine residues on the N-terminus of synthetic short peptide immunogens from Fba (F-SNAP), Met6 (M-SNAP), or bivalent Fba and Met6 (FM-SNAP). Liposomes were adjuvanted with synthetic monophosphoryl lipid and QS-21. In mice, immunization with F-SNAP, M-SNAP, or FM-SNAP induced antigen-specific IgG responses and mixed Th1/Th2 immunity. The duplex FM-SNAP vaccine elicited stronger antibody responses against each peptide, even at order-of-magnitude lower peptide dosing than a comparable adjuvanted, conjugate vaccine. Enzyme-linked immunosorbent spot analysis revealed the induction of antigen-specific, cytokine-producing T cells. Compared to F-SNAP or M-SNAP, higher production of TNFα, IL-2, and IFNγ was observed with re-stimulation of splenocytes from bivalent FM-SNAP-immunized mice. When vaccinated BALB/c mice were challenged with Candida auris, analysis of the fungal burden in the kidneys showed that SNAP vaccination protected from disseminated candidiasis. In a lethal fungal exposure model in A/J mice, F-SNAP, M-SNAP, and FM-SNAP vaccination protected mice from candidiasis challenge. Together, these results show that further investigation into the SNAP adjuvant platform is warranted using Fba and Met6 epitopes for a pan-Candida peptide vaccine that provides multifaceted protective immune responses. IMPORTANCE: This study introduces a promising vaccine strategy against invasive candidiasis, a severe fungal infection, by targeting specific peptides on the surface of Candida. Using a novel approach called spontaneous nanoliposome antigen particle (SNAP), we combined peptides from two key Candida proteins, Fba and Met6, into a vaccine. This vaccine induced robust immune responses in mice, including the production of protective antibodies and the activation of immune cells. Importantly, mice vaccinated with SNAP were shielded from disseminated candidiasis in experiments. These findings highlight a potential avenue for developing a broad-spectrum vaccine against Candida infections, which could significantly improve outcomes for patients at risk of these often deadly fungal diseases.

A novel inherited CARD9 deficiency in an otherwise healthy woman with CNS candidiasis.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

Clinical and epidemiological aspects of Candida yeast infections and rational use of antifungals.

Aim: The objective of this study was to evaluate the clinical and epidemiological aspects of Candida infections. Methods: The study relied on the analysis of electronic medical records. Results: Among 183 patients with positive fungal infections, 57 were from the community and 126 from hospitals. Females predominated in both groups (82.4% in the community, 54.7% in hospitals). Non-albicans Candida spp. accounted for 62.8% of cases. Antifungal therapy was prescribed for 67 patients, with a 55.6% mortality rate. Conclusion: The increasing prevalence of non-albicans Candida species highlights the need for better candidiasis monitoring and control, especially concerning antifungal use amidst rising antimicrobial resistance, particularly in empirical therapy scenarios.

Fungal infections, particularly those caused by a group of yeasts called Candida, are a major concern. This study looks at clinical laboratory and medical records. We found that certain species of Candida not previously associated with human disease are common. We also noted the inappropriate use of antifungal medication, highlighting the need for healthcare workers to carefully diagnose patients and make appropriate decisions when treating fungal infections.

Median Rhomboid Glossitis: A Case Study.

A smooth, red, oval, or rhomboid patch on the dorsal midline is the classic presentation of median rhomboid glossitis (MRG), a rare and benign lesion of the tongue. MRG is still not fully understood, which presents diagnostic hurdles and calls for additional clinical investigation. It is frequently associated with candidal infections. We describe a case of a 42-year-old man who initially appeared to have either mechanical irritation or thermal injury related to a painless patch on the dorsum surface of the tongue. We document a case of MRG that was consulted for a standard dental examination in this case report. This article also highlights a dentist's need to identify the lesion and provide appropriate education for the patient.