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The invasion of Candida albicans is one of the most common fungal infections seen in clinical practice, and serious drug resistance has been reported in recent years. Therefore, new anti- C. albicans drugs must be introduced. In this research, it was demonstrated that cinnamaldehyde (CA) shows strong antimicrobial activity, with 0.26 mg/mL CA being the minimum inhibitory concentration to manage C. albicans . Extraordinarily, we detected that CA accumulated the intracellular reactive oxygen species (ROS) and enhanced the calcium concentration in the cytoplasm and mitochondria through flow cytometry. In addition, we observed that C. albicans cells released Cytochrome c from the mitochondria to the cytoplasm, depolarized the mitochondrial membrane potential, and activated the metacaspase when exposed to 0.065, 0.13, 0.26, and 0.52 mg/mL CA. Furthermore, to confirm that CA introduces the C. albicans apoptosis, we discovered that when the phosphatidylserine was exposed, DNA damage and chromatin condensation occurred, which were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 4′,6-diamidino-2-phenylindole (DAPI) staining. Finally, demonstrations of phenotype investigation, colony-forming unit (CFU) counts, and periodic acid–Schiff (PAS) staining were conducted to prove that CA possessed the ability to treat oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC). From the above, our research indicates that CA is a promising antifungal candidate when applied to C. albicans infections.

The main objective of the proposed work was the development of a thermosensitive gel (containing clove and tea tree oil) for the management of vaginal candidiasis. Both oils have been recommended to be used separately in a topical formulation for vaginal candidiasis. Incorporating two natural ingredients (clove and tea tree oil) into a product give it a broad antimicrobial spectrum and analgesic properties. The two oils were mixed together at a 3:1 ratio and converted into o/w nanoemulsion using the aqueous titration method and plotting pseudo ternary phase diagrams. Further transformations resulted in a gel with thermosensitive properties. To determine the final formulation's potential for further clinical investigation, in vitro analyses (viscosity measurement, MTT assay, mucoadhesion, ex vivo permeation) and in vivo studies (fungal clearance kinetics in an animal model) were conducted. The current effort leveraged the potential of tea tree and clove oils as formulation ingredients and natural therapeutic agents for vaginal infections. Its synergy generated a stable and effective thermosensitive gel that can be utilized for recurrent candidiasis and other infections.

Introduction For decades, clinicians dealing with immunocompromised and critically ill patients have perceived a link between Candida colonization and subsequent infection. However, the pathophysiological progression from colonization to infection was clearly established only through the formal description of the colonization index (CI) in critically ill patients. Unfortunately, the literature reflects intense confusion about the pathophysiology of invasive candidiasis and specific associated risk factors. Methods We review the contribution of the CI in the field of Candida infection and its development in the 20 years following its original description in 1994. The development of the CI enabled an improved understanding of the pathogenesis of invasive candidiasis and the use of targeted empirical antifungal therapy in subgroups of patients at increased risk for infection. Results The recognition of specific characteristics among underlying conditions, such as neutropenia, solid organ transplantation, and surgical and nonsurgical critical illness, has enabled the description of distinct epidemiological patterns in the development of invasive candidiasis. Conclusions Despite its limited bedside practicality and before confirmation of potentially more accurate predictors, such as specific biomarkers, the CI remains an important way to characterize the dynamics of colonization, which increases early in patients who develop invasive candidiasis.

Despite advances in antifungal therapy, the mortality associated with invasive candidiasis remains as high as 40%. This review summarizes recent trends and current strategies, including early treatment and the emergence of resistance against triazoles and echinocandins. Invasive candidiasis is the most common fungal disease among hospitalized patients in the developed world. Invasive candidiasis comprises both candidemia and deep-seated tissue candidiasis. Candidemia is generally viewed as the more common type of the disease, and it accounts for the majority of cases included in clinical trials. Deep-seated candidiasis arises from either hematogenous dissemination or direct inoculation of candida species to a sterile site, such as the peritoneal cavity (Figure 1). Mortality among patients with invasive candidiasis is as high as 40%, even when patients receive antifungal therapy. In addition, the global shift in favor of nonalbicans candida species . . .

We investigated the spectrum of infection and risk factors for invasive fungal disease due to Candida auris (CA) in Qatar. We performed structured chart reviews on individuals with any positive CA culture between May 2019 and December 2022 at three tertiary care hospitals in Qatar. Invasive CA disease (ICAD) was defined as a positive sterile site culture, or any positive culture for CA with appropriate antifungal prescription. Main outcomes included proportion of individuals who developed ICAD among those with positive cultures, and 30-day/in-hospital mortality. Among 331 eligible individuals, median age was 56 years, 83.1% were male, 70.7% were non-Qataris, and 37.5% had ≥ 3 comorbidities at baseline. Overall, 86.4% were deemed to have colonization and 13.6% developed ICAD. Those with ICAD were more likely to have invasive central venous or urinary catheterization and mechanical ventilation. Individuals with ICAD had longer prior ICU stay (16 vs 26 days, P = 0.002), and longer hospital length of stay (63 vs. 43 days; P = 0.003), and higher 30-day mortality (38% vs. 14%; P<0.001). In multivariable regression analysis, only mechanical ventilation was associated with a higher risk of ICAD (OR 3.33, 95% CI 1.09-10.17). Invasive Candida auris Disease is associated with longer hospital stay and higher mortality. Severely ill persons on mechanical ventilation should be especially monitored for development of ICAD.

Candida albicans is a commensal fungal microbe of the human orogastrointestinal tract and skin. C. albicans causes multiple forms of disease in immunocompromised patients, including oral, vaginal, dermal and disseminated candidiasis. The cytokine IL-17 (IL-17A) and its receptor subunits, IL-17RA and IL-17RC, are required for protection to most forms of candidiasis. The importance of the IL-17R pathway has been observed not only in knockout mouse models, but also in humans with rare genetic mutations that impact generation of Th17 cells or the IL-17 signaling pathway, including Hyper-IgE Syndrome (STAT3 or TYK2 mutations) or IL17RA or ACT1 gene deficiency. The IL-17 family of cytokines is a distinct subclass of cytokines with unique structural and signaling properties. IL-17A is the best-characterized member of the IL-17 family to date, but far less is known about other IL-17-related cytokines. In this study, we sought to determine the role of a related IL-17 cytokine, IL-17C, in protection against oral, dermal and disseminated forms of C. albicans infection. IL-17C signals through a heterodimeric receptor composed of the IL-17RA and IL-17RE subunits. We observed that IL-17C mRNA was induced following oral C. albicans infection. However, mice lacking IL-17C or IL-17RE cleared C. albicans infections in the oral mucosa, skin and bloodstream at rates similar to WT littermate controls. Moreover, these mice demonstrated similar gene transcription profiles and recovery kinetics as WT animals. These findings indicate that IL-17C and IL-17RE are dispensable for immunity to the forms of candidiasis evaluated, and illustrate a surprisingly limited specificity of the IL-17 family of cytokines with respect to systemic, oral and cutaneous Candida infections.

Autosomal recessive CARD9 deficiency underlies life-threatening, invasive fungal infections in otherwise healthy individuals normally resistant to other infectious agents. In less than 10 years, 58 patients from 39 kindreds have been reported in 14 countries from four continents. The patients are homozygous (n = 49; 31 kindreds) or compound heterozygous (n = 9; 8 kindreds) for 22 different CARD9 mutations. Six mutations are recurrent, probably due to founder effects. Paradoxically, none of the mutant alleles has been experimentally demonstrated to be loss-of-function. CARD9 is expressed principally in myeloid cells, downstream from C-type lectin receptors that can recognize fungal components. Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo. The proportion of Th17 cells is low in most, but not all, patients tested. Up to 52 patients suffering from invasive fungal diseases (IFD) have been reported, with ages at onset of 3.5 to 52 years. Twenty of these patients also displayed superficial fungal infections. Six patients had only mucocutaneous candidiasis or superficial dermatophytosis at their last follow-up visit, at the age of 19 to 50 years. Remarkably, for 50 of the 52 patients with IFD, a single fungus was involved; only two patients had IFDs due to two different fungi. IFD recurred in 44 of 45 patients who responded to treatment, and a different fungal infection occurred in the remaining patient. Ten patients died from IFD, between the ages of 12 and 39 years, whereas another patient died at the age of 91 years, from an unrelated cause. At the most recent scheduled follow-up visit, 81% of the patients were still alive and aged from 6.5 to 75 years. Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora, Exophiala, Corynesprora, Aureobasidium, and Ochroconis. Human CARD9 is essential for protective systemic immunity to a subset of fungi from this phylum but seems to be otherwise redundant. Previously healthy patients with unexplained invasive fungal infection, at any age, should be tested for inherited CARD9 deficiency.Key Points• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state.• CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands.• Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein).• The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity.• The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis.• The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned.• Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease.• All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed.• The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

Chronic disseminated candidiasis (CDC) is an invasive fungal infection typically affecting patients with hematological diseases and severe neutropenia, associated with increased mortality. However, there is a global shortage of clinical evidence on CDC. We retrospectively analyzed clinical data from 49 CDC patients over the past decade. Clinical characteristics of primary hematological diseases, CDC diagnosis, treatment and response evaluations were included. Clinical factors associated with CDC remission and patients’ survival were analyzed. The majority of patients had hematological malignancies (n = 43, 87.8%), and 27 patients (55.1%) had persistent severe neutropenia for more than 10 days prior to CDC. CT scans revealed liver lesions in 44 patients, spleen lesions in 34 patients, and kidney lesions in 9 patients. Proven, probable and possible CDC was diagnosed in 5 (10.2%), 3 (6.1%) and 41 patients (83.7%), respectively, and treatment outcomes at 3 months included 5 complete response (CR, 10.2%), 34 partial response (PR, 69.4%) and 10 treatment failure (20.4%). Caspofungin treatment showed a trend towards improving CR/PR rate, while severe neutropenia > 20 days and proven diagnosis were significantly associated with 3-month treatment failure. Kaplan–Meier curve showed achieving CR/PR within 3 months did not significantly prolong OS compared to treatment failure patients (1197.6 days vs. 564.8 days, P  = 0.074). Additionally, no patient deaths were directly attributed to CDC infection. Age > 45 years old and malignancy non-remission were prognostic factors of overall survival (OS). Furthermore, a prediction model identified severe neutropenia > 20 days, proven/probable diagnosis and concomitant bacteremia as risk factors to effectively predict treatment failure. Also, patients with a risk score < 0.203 in the model exhibited more rapid treatment response. After CDC symptoms onset, lymphocyte levels remained consistently higher in treatment failure patients, while the neutrophil-to-lymphocyte ratio was persistently higher in CR/PR patients. Our findings recommend CT scans for diagnosis and caspofungin as first-line therapy while continuing scheduled chemotherapy or bone marrow transplantation. Notably, risk factors identified by the prediction model could be used to predict treatment response.