Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin.

INTRODUCTION: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. AREAS COVERED: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. EXPERT OPINION: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

Effect of Vapor-Phase Oregano Essential Oil on Resistant Candida Species Biofilms: Mechanisms of Action.

Vulvovaginal candidiasis (VVC) is one of the most prevalent vaginal infectious diseases. The increasing incidence of drug-resistant Candida strains and the limited therapeutic options make the discovery of effective alternative therapies fundamental. Essential oils (EOs) have been suggested as a promising alternative, and interestingly, vapor-phase essential oils (VP-EOs) present more advantages than their direct application. Thus, this study aims to evaluate the effect of oregano VP-EO (VP-OEO) on biofilms of antifungal-resistant vaginal isolates of Candida species (Candida albicans and Candida glabrata) and determine its mode of action. CFU, membrane integrity, and metabolic activity were evaluated. Furthermore, a reconstituted vaginal epithelium was used to mimic vaginal conditions and evaluate the effect of VP-OEO on Candida species infection, analyzed by DNA quantification, microscopy, and lactate dehydrogenase activity. The results revealed high VP-OEO antifungal activity. There was a significant reduction (>4 log CFU) in Candida species biofilms. Furthermore, the results show that the mechanisms of action of VP-OEO are related to membrane integrity and metabolic activity. The epithelium model confirms the effectiveness of VP-OEO. This study suggests that VP-EO can be considered a first approach for the development of an alternative form of VVC treatment. IMPORTANCE This work presents a new approach to the application of essential oils, exposure to the vapor phase, which can be considered a first approach for the development of a complementary or alternative form of vulvovaginal candidiasis (VVC) treatment. VVC is a significant infection caused by Candida species and remains a common disease that affects millions of women every year. The great difficulty in treating VVC and the extremely limited effective therapeutic options make the development of alternative treatments crucial. In this scope, this study aims to contribute to the development of effective, inexpensive, and nontoxic strategies for the prevention and treatment of this infectious disease, based on natural products. Moreover, this new approach has several advantages for women, such as lower costs, easy access, an easier mode of application, avoidance of skin contact, and, therefore, fewer negative impacts on women's health.

Antifungal Effect of Carrot Carotenoids on Candida Species.

BACKGROUND: Candidiasis is a serious problem in women's health that is caused by Candida species, especially Candida albicans. In this study, the effect of carotenoids in carrot extracts on Candida species including Candida albicans ATCC1677, Candida glabrata CBS2175, Candida parapsilosis ATCC2195, and Candida tropicalis CBS94 was investigated. METHODS: In this descriptive study, the carrot plant was prepared from a carrot planting site in December 2012, and then the characteristics of the plant were determined. After extracting carotenoids from carrots, the susceptibility of different Candida species to carotenoids in carrot extract was determined. Also, the minimum inhibitory concentration and the minimum lethal concentration of the extracts were measured by the macro-dilution method. Finally, the data were analyzed by SPSS software using the Kruskal-Wallis test and Mann-Whitney post-hoc test with Bonferroni adjustment. RESULTS: The highest growth inhibition zone was obtained for carrot extract at a concentration of 500 mg/ml for C. glabrata and C. tropicalis. The MFC of carrot extract on Candida species was 62.5 mg/ml for C. albicans, C. glabrata, and C. parapsilosis, and 125 mg/ml for C. tropicalis. The MFC of carrot extract on Candida species was 125 mg/ml for C. albicans, C. glabrata, and C. parapsilosis, and 250 mg/ml for C. tropicalis. CONCLUSION: The present study can be the starting point for research activities in this direction and promises new therapies based on the use of carotenoids.

Eucalyptus botryoides' resin and its new 2-O-galloyl-1,6-O-di-trans-p-coumaroyl-ß-D-glycopyranoside compound display good antimicrobial activity.

Fungal resistance to different therapeutic drugs has become a growing challenge. This crucial health problem requires new effective drug alternatives. Herein, we report the study of Eucalyptus botryoides' resin used in folk medicine as antimicrobial. Thus, E. botryoides' resin was extracted with aqueous-ethanol and fractionated using Sephadex chromatography, furnishing its major compounds. The crude extracts and the isolated compounds were evaluated for their in vitro antimicrobial activity against bacteria and yeasts. The crude extract displayed MIC of 25 µg/mL against S. salivarius, and for C. albicans, C. glabrata, and C. tropicalis the MIC were between 2.9 and 5.9 µg/mL. The 7-O-Methyl-aromadendrin was the most effective against C. glabrata and C. krusei (MIC = 1.6 µg/mL). 2-O-Galloyl-1,6-O-di-trans-p-coumaroyl-ß-D-glycopyranoside, first time reported, showed MIC of 3.1 µg/mL against C. glabrata and C. krusei. Overall, this work gave promising results, indicating that Eucalyptus botryoides' resin and its compounds have the potential for developing anti-yeast products.

Antibiofilm Potential and Exoenzyme Inhibition by Elattaria cardamomum Essential Oil in Candida spp. Strains.

Fungal infections caused by Candida species have attracted great interest due to their resistance to commercial antifungal agents. Essential oils from aromatic and medicinal plants have many bioactive compounds that are known for their important biological activities, mainly their antimicrobial effects. In the present study, we aimed to evaluate the antifungal ability of Elettaria cardamomum essential oil (EO) against different clinical Candida isolates. Then, we investigated the anti-phospholipase, anti-protease, and anti-biofilm activity of E. cardamomum EO against the selected isolates. Twenty-four Candida strains (clinical and reference) were tested for virulence factors such as biofilm formation, protease, and phospholipase activity. The minimum inhibitory (MIC) and fungicidal (MFC) concentrations of E. cardamomum were determined, and their effects were tested against all Candida strains. Our results revealed that E. cardamomum EO was rich in α-terpinyl acetate (56.5%), limonene (12.6%), and mentha-2.4(8)-diene (7.65%). The tested EO showed activity against all tested Candida strains in their planktonic form and against exoenzymes and biofilm production. Based on our findings, we promote the use of E. cardamomum EO as a treatment against clinical Candida isolates active on the virulence factors of this fungus.

Ethnobotanical study of medicinal plants utilized in the management of candidiasis in Northern Uganda.

BACKGROUND: The emergence of resistant Candida species to antifungal drugs has led to resurgence in herbal usage globally. However, little is known about anti-candida plants. This study explored ethnomedicinal plants as treatment option for candidiasis in Pader, Northern Uganda. METHODS: A cross-sectional survey of potential anti-candida plants was conducted using questionnaires, focus group discussions and field observations in March 2022. Sixty-three respondents were selected by snowball technique. The frequencies of respondents/responses were analyzed, associations of respondents' socio-demographics with indigenous knowledge of herbal usage established by Chi-square (χ2) test using SPSS 27. Informant Consensus Factor was computed to establish level of agreement on herbal usage, and thematic analysis done for focus group discussions. RESULTS: Candidiasis is still common and troublesome in Pader. All herbalist had equal chances of receiving and treating candidiasis patients irrespective of herbalist's gender, age, education level, occupation, marital status and religion (p > 0.05). About 39.7% of herbalists received candidiasis patients weekly (p < 0.01). All herbalists had knowledge on candidiasis. Death (56.8%) and discomfort (36.8%) were the major health risks of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC), respectively. A total of 32 potential anti-candida plant species in 18 families were identified. Families of Fabaceae (9 species) and Asteraceae (5 species) had most plant species. Trees (50.0%) and herbs (43.8%) were the dominant life forms. The commonest plants by frequency of mention were: Momordica foetida (26), Sansevieria dawei (20), Khaya anthotheca (15), Piliostigma thonningii (10), Clerodendrum umbellatum (7), Hallea rubrostipulata (5) and unidentified plant, 'Agaba/daa layata' in Acholi dialect (5). Plant parts mainly used were roots (56.3%) and stem barks (15.6%) harvested majorly by cutting (46.9%) and uprooting (12.5%). Most respondents (females, 95%) preferred herbal to western medication (p < 0.01) due to its perceived effectiveness. There was high consensus among herbalists on herbal remedies for OPC and VVC (FIC = 0.9). CONCLUSIONS:  Pader communities have diverse indigenous knowledge on candidiasis and prefer herbal medicines to orthodox treatment for candidiasis. However, the herbalists use unsustainable harvesting techniques like uprooting whole plants and cutting main roots. Hence, the need to document such indigenous knowledge before being lost for community usage and scientific validation.

Characterization of Cervus timorensis velvet antler and its effect on biofilm formation of Candida species.

Oral biofilms comprise extracellular polysaccharides and polymicrobial microorganisms. The objectives of the study were to characterize the deer velvet antler (DVA) compounds and their effect on Candida species biofilm formation with the hypothesis that DVA inhibits the biofilm of Candida spp. Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry (LC-QTOF-MS) was conducted to characterize the DVA compounds. To study the effect of DVA on biofilm, Candida albicans ATCC MYA-4901 (ALT5), AIDS isolate (ALC2), oral cancer isolate (ALC3), C. dubliniensis ATCC MYA-2975, C. glabrata ATCC 90030, C. krusei 14 243, C. lusitaniae ATCC 34449, C. parapsilosis ATCC 22019, and C. tropicalis ATCC 13803 were inoculated with DVA in separate wells of a 96-well plate containing RPMI-1640 followed by 72 h incubation. A total of 45 compounds were detected in the DVA extract. C. lusitaniae exhibited a higher percentage of biofilm biomass reduction when treated with DVA extract (66.10% ± 5.33), followed by ALC3 (44.12% ± 6.24). However, C. glabrata, C. krusei, and C. parapsilosis showed no reduction in biofilm biomass after being treated with DVA extract. Most Candida strains also exhibited decreased total cell count when treated with DVA extract, except for ALC3 and C. krusei. ALT5 had the lowest total cell count (0.17 × 105 cells/ml) when cultured with DVA extract. In conclusion, DVA extract inhibits Candida spp. biofilm formation except for C. glabrata, C. krusei, and C. parapsilosis.

The study determines deer velvet antler (DVA) compounds and their effect on Candida species biofilm formation. A total of 45 compounds were detected in the DVA extract. Most Candida spp. exhibited a higher percentage of biofilm reduction and decreased total cell count when treated with DVA extract.

Eugenol: A novel therapeutic agent for the inhibition of Candida species infection.

The high occurrence and mortality rates related to candidiasis emphasize the urgent need to introduce new therapeutic approaches to treat this infection. Eugenol, the main phenolic component of Clove and Cinnamomum essential oil, has been used to inhibit growth and different virulence factors of Candida, including strains with decreased susceptibility to antifungals, particularly fluconazole. The results showed that this compound could bind to Candida membrane and decrease ergosterol biosynthesis, consequently leading to cell wall and membrane damage. Additionally, eugenol not only reduced germ tube formation, which reduces nutrient absorption from host tissues, but it also increased the levels of lipid peroxidation and reactive oxygen species, which induces oxidative stress and causes high permeability in the fungal cell membrane. Eugenol inhibited Candida cells' adhesion capacity; additionally, this compound inhibited the formation of biofilms and eliminated established Candida biofilms on a variety of surfaces. Furthermore, by disrupting fungal cell integrity, eugenol could boost the entry of the antifungal drugs into the Candida cell, improving treatment efficacy. Therefore, eugenol could be used in the clinical management of various presentations of candidiasis, especially mucocutaneous presentations such as oral and vulvovaginal infections. However, further investigations, including in vivo and animal studies, toxicology studies and clinical trials, as well as molecular analysis, are needed to improve formulations and develop novel antifungal agents based on eugenol.

Synbiotic Musa acuminata skin extract and Streptococcus salivarius K12 inhibit candida species biofilm formation.

This study aimed to determine the effect of synbiotic Musa acuminata skin extract (MASE) and Streptococcus salivarius K12 (K12) on Candida species biofilm formation. Liquid chromatography quadrupole time-of-flight (LC-Q-TOF-MS) was conducted to characterize MASE. To determine the effect of synbiotic on Candida biofilm, 200 µL of RPMI-1640 containing Candida, K12, and MASE were pipetted into the same well and incubated at 37 °C for 72 h. A similar protocol was repeated with K12 or MASE to determine the probiotic and prebiotic effects, respectively. Dimorphism, biofilm biomass, and Candida total cell count (TCC) were determined. A total of 60 compounds were detected in MASE. C. albicans (ALT5) and Candida lusitaniae exhibited the highest reduction in biofilm biomass when co-cultured with prebiotic (77.70 ± 7.67%) and synbiotic (97.73 ± 0.28%), respectively. All Candida spp. had decreased TCC and hyphae when co-cultured with synbiotic. In conclusion, MASE and K12 inhibit Candida biofilm formation.

Chemical composition, antifungal activity, antifungal mechanism and interaction manner of the fatty acid of Prunus mahaleb L. with fluconazole.

The interaction manner of Prunus mahaleb L. (P. mahaleb) seed oil (MSO) and fluconazole (FLC: antimycotic) combinations (MSO*FLC) against C. albicans and C. parapsilosis were evaluated using the microdilution technique. The most representative compounds of mahaleb oil were found to be conjugated linolenic acid (34.39%), oleic acid (31.76%), and linoleic acid (25.54%) by GC-MS. In antimicrobial activity study, P. mahaleb had an inhibition zone (IZ) of C. albicans and C. parapsilosis with 6.89 mm and 11.39 mm and a minimum inhibitory concentration (MIC) with 35.3 µgmL-1 and 23.9 µgmL-1, respectively. The strongest indifferent effect was observed as 57.14% for C. albicans and 100% for C. parapsilosis in fluconazole-mahaleb oil combinations. An increase in DNA and protein leakage was observed when yeast was exposed to the FA. The destruction on the cell surface was visualized using Scanning Electron Microscopy (SEM) analysis.

The antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy.

INTRODUCTION: Candida species have been regarded as global health threats due to their ability to cause invasive infections. It is challenging to treat Candida bloodstream infections, which are associated with high mortality levels. Monotherapy with antifungals is sometimes not effective against severe Candida infections, and combination therapy is needed in clinical practice. AREAS COVERED: This review was undertaken based on data from a PubMed search for English language reports published before March 2021 by using the terms 'caspofungin,' 'Candida species,' 'combination therapy,' 'antifungal effect,' and 'novel antifungal agent.' EXPERT OPINION: Combination therapy is an empirical strategy for treating refractory Candida infections. Caspofungin has been recommended to treat candidaemia. Caspofungin in combination therapy has some applications, while the efficacy of combination therapy in the treatment of refractory Candida infections needs more study, such as randomized controlled trials. In addition, novel compounds or drugs with potential antifungal activities have been examined, and some of them exhibit synergistic interactions with caspofungin. Thus, the antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy is summarized.

Antibiofilm and Anti-Candidal Activities of the Extract of the Marine Sponge Agelas dispar.

This study aimed to determine the antifungal and antibiofilm activities of Agelas dispar on biofilm-producing Candida species. The methanolic extract of A. dispar was obtained and the fraction Ag2 showed inhibitory activity for all 13 Candida strains tested, in concentrations ranging from 2.5 to 0.15625 mg/mL. Antifungal activity of fungicidal nature was seen between 5.0 and 0.3125 mg/mL of extract against the strains. All the strains were classified as biofilm producers. The methanolic extract Ag2 was tested at concentrations of 2.5 and 1.25 mg/mL for antibiofilm activity against the biofilm formation and maturation in all the strains of the genus Candida. Treated and untreated biofilm samples were selected for visualization using scanning electron microscopy (SEM). SEM allowed the visualization of the quantitative decrease in the microbial community, alterations of structural morphology, and destruction of both the formation and maturation of biofilms, at the cellular level. The mechanism of action of this fraction is suggested to be at the plasma membrane and/or cell wall alteration level. Therefore, the use of the methanolic extract of A. dispar may be a promising antifungal and antibiofilm therapeutic strategy against different species of the genus Candida.

The Inhibition of Non-albicans Candida Species and Uncommon Yeast Pathogens by Selected Essential Oils and Their Major Compounds.

The epidemiology of yeast infections and resistance to available antifungal drugs are rapidly increasing, and non-albicans Candida species and rare yeast species are increasingly emerging as major opportunistic pathogens. In order to identify new strategies to counter the threat of antimicrobial resistant microorganisms, essential oils (EOs) have become an important potential in the treatment of fungal infections. EOs and their bioactive pure compounds have been found to exhibit a wide range of remarkable biological activities. We investigated the in vitro antifungal activity of nine commercial EOs such as Thymus vulgaris (thyme red), Origanum vulgare (oregano), Lavandula vera (lavender), Pinus sylvestris (pine), Foeniculum vulgare (fennel), Melissa officinalis (lemon balm), Salvia officinalis (sage), Eugenia caryophyllata (clove) and Pelargonium asperum (geranium), and some of their main components (α-pinene, carvacrol, citronellal, eugenol, γ-terpinene, linalool, linalylacetate, terpinen-4-ol, thymol) against non-albicans Candida strains and uncommon yeasts. The EOs were analyzed by GC-MS, and their antifungal properties were evaluated by minimum inhibitory concentration and minimum fungicidal concentration parameters, in accordance with CLSI guidelines, with some modifications for EOs. Pine exhibited strong antifungal activity against the selected non-albicans Candida isolates and uncommon yeasts. In addition, lemon balm EOs and α-pinene exhibited strong antifungal activity against the selected non-albicans Candida yeasts. Thymol inhibited the growth of all uncommon yeasts. These data showed a promising potential application of EOs as natural adjuvant for management of infections by emerging non-albicans Candida species and uncommon pathogenic yeasts.

Portuguese honeys as antimicrobial agents against Candida species.

BACKGROUND AND AIM: Honey has been recognized worldwide for its antioxidant, anti-tumor, anti-inflammatory and antimicrobial properties. Among them, the antifungal properties associated to honey make it an attractive alternative treatment for Candida-associated infections, particularly for topical application to the mucous membranes and skin. In this sense, the main purpose of this work was to evaluate physicochemical properties of five Portuguese honeys and Manuka honey (an Australian honey with well recognized medical proprieties, used as control) and to evaluate the antifungal activity in Candida species planktonic and biofilm assays. EXPERIMENTAL PROCEDURE: Pollen analysis, pH determination, color, concentration of protein and methylglyoxal, conductivity, total phenolics and flavonoids, hydrogen peroxide concentration, and characterization by differential scanning calorimetry in honey samples were determined. Additionally, the effect of honeys on planktonic growth of Candida was initially evaluated by determination of the minimum inhibitory concentrations. Then, the same effect of those honeys was evaluated in biofilms, by Colony Forming Units enumeration. RESULTS AND CONCLUSION: It has been shown that Portuguese heather (Erica cinereal) honey presented the most similar physicochemical properties to manuka honey (specially phenolic and flavonoids contents). The five Portuguese honeys under study, presented in general a potent activity against planktonic multi-resistant yeast pathogens (several clinical isolates and reference strains of Candida species) and S. aureus and P. aeruginosa bacteria cultures. Additionally, it was also concluded that Portuguese heather honey (50% and 75% (w/v)) can also act as a good Candida species biofilm reducer, namely for C. tropicalis.

The use of nanoparticles as alternative therapeutic agents against Candida infections: an up-to-date overview and future perspectives.

Candida spp. are opportunistic fungi that can cause severe infections especially in immunocompromised patients. Candidiasis is currently the most frequent fungal disease affecting humans globally. This rise is attributed to the vast increase in resistance to antifungal agents. In recent years, the epidemiological and clinical relevance of fungal infections caused by Candida species have attracted a lot of interest with increasing reports of intrinsic and acquired resistance among Candida species. Thus, the formulation of novel, and efficient therapy for Candida infection persists as a critical challenge in modern medicine. The use of nanoparticle as a potential biomaterial to achieve this feat has gained global attention. Nanoparticles have shown promising antifungal activity, and thus, could be seen as the next generation antifungal agents. This review concisely discussed Candida infection with emphasis on anti-candida resistance mechanisms and the use of nanoparticles as potential therapeutic agents against Candida species. Moreover, the mechanisms of activity of nanoparticles against Candida species, recent findings on the anti-candida potentials of nanoparticles and future perspectives are also presented.

Potent In Vitro Activity of Citrus aurantium Essential Oil and Vitis vinifera Hydrolate Against Gut Yeast Isolates from Irritable Bowel Syndrome Patients-The Right Mix for Potential Therapeutic Use.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder without any pathological alteration, in which the alterations of the Candida/Saccharomyces ratio of the gut microbiota, the balance of pro and anti-inflammatory cytokines and the brain-gut-microbiome axis are important for the development and progression of IBS. The aim of the study was to identify natural products, including essential oils or hydrolates, which were contextually harmless for the gut beneficial strains (e.g. Saccharomyces spp.) but inhibitory for the pathogenic ones (Candida spp.). METHODS: The effectiveness of 6 essential oils and 2 hydrolates was evaluated using microbiological tests, carried out on 50 clinical isolates (Candida, Saccharomyces and Galattomyces species) and 9 probiotic strains (Saccharomyces cerevisiae, Lactobacillus species, Akkermansia muciniphila and Faecalibacterium prausnitzii) and immunological and antioxidant assays. RESULTS: The study led to a mixture based on a 1/100 ratio of Citrus aurantium var. amara essential oil / Vitis vinifera cv Italia hydrolate able to contextually reduce, in a concentration-dependent manner, the ability of Candida species to form hyphal filaments and have an interesting immunomodulatory and anti-oxidant action. This mixture can potentially be useful in the IBS treatment promoting the restoration of the intestinal microbial and immunological balance.

Original Research Article (Experimental): Targeting fungal menace through copper nanoparticles and Tamrajal.

BACKGROUND: WHO reports, an escalation of antibiotic resistance in opportunistic pathogens like Candida. Tamrajal, i.e., water stored in copper vessels has been proclaimed as health elixir by ancient Ayurveda. Vis-a-Vis the use of copper contact surfaces and nanoparticles has gained significance for their antimicrobial effects. It thus seems imperative to examine copper nanoparticles and tamrajal as promising alternatives to existing antifungals. OBJECTIVE: This study not only assessed the influence of Tamrajal and copper nanoparticles on the morphological alterations of the Candida and its biofilm forming ability, but also on their ability to destroy preformed biofilms. MATERIALS AND METHODS: Copper oxide nanoparticles as well as Tamrajal were evaluated as complementary as well as stand-alone antimicrobial agents. 'Time kill assay' and 'germ tube inhibition test' were performed as end-point analysis for pathogenesis, while biofilm quantification, performed to assess the colonizing capability of Candida. Scanning Electron Microscope was used for visualizing the cells, whilst ICP-AES to determine the copper concentration. RESULTS: 92-100% cytotoxicity to the fluconazole resistant Candida species was observed with copper oxide nanoparticles as well as tamrajal during 24hr time kill assay. The study also confirmed complete germ tube inhibition by copper in both its forms in addition to the reduction in the biofilm production. CONCLUSION: Compared to the classes of antifungals like azoles, echinocandins etc, copper based anti-candidal agents highlight a potential way to combat resistant candidiasis. The possibility of accumulation of NP resulting in cytotoxicity puts tamrajal as the choice due to its efficacy as well as non-toxicity as per the EPA.

Antifungal activity of Mongolian medicinal plant extracts.

The in vitro antifungal activity of extracts obtained from 14 medicinal plants of the mongolian flora were investigated by measuring their minimal inhibitory concentration (MIC) against fungi cause of cutaneous diseases such as Candida species, dermatophytes and Malassezia furfur. Among the species examined, Stellaria dichotoma L., Scutellaria scordifolia L. Aquilegia sibirica Fisch. Et Schrenk. and Hyoscyamus niger L. extracts demonstrated antifungal activity against all studied fungi. In particular, S. scordifolia L. methanol extract, obtained at room temperature, showed the best activity against Candida spp., Malassezia furfur and dermatophytes with GMMIC50 values of 22 µg/mL, 64 µg/mL and 32 µg/mL, respectively. The flavones, luteolin and apigenin, identified in S. scordifolia extracts, and rutin identified in S. dichotoma and Hyoscyamus niger L. extracts, could be responsible of the observed antifungal activity.

Repurposing of Ribavirin as an Adjunct Therapy against Invasive Candida Strains in an In Vitro Study.

The use of antifungal agents in clinical settings is limited by the appearance of drug resistance and adverse side effects. There is, therefore, an urgent need to develop new drugs to strengthen the treatment of invasive fungal diseases. The aim of this study is to describe the potential repurposing of ribavirin as an adjunct therapy against Candida spp. Primary screening of a Prestwick Chemical library against Candida albicans ATCC 90028 and fluconazole-resistant Candida albicans strains was performed. Subsequently, we evaluated the responses of 100 Candida sp. strains to ribavirin, an antiviral agent, using the broth microdilution method as recommended by CLSI. We checked the involvement of efflux pump activity in the development of ribavirin resistance. We studied time-kill curves and performed a checkerboard assay for a ribavirin-antifungal combination study. Twenty-one nonstandard antifungal compounds were identified, including ribavirin. Ribavirin had antifungal activity in vitro against 63 Candida strains, including strains of C. albicans, C. parapsilosis, and C. tropicalis, with MICs ranging from 0.37 to 3.02 µg/ml, while MICs for C. krusei, C. glabrata, C. lusitaniae, and some C. albicans strains remained high (≥24.16 µg/ml). No relation was observed between efflux pump activity and ribavirin resistance. Ribavirin exhibited fungistatic activity against multidrug-resistant (MDR) C. albicans and fungicidal activity against a C. parapsilosis strain. In addition, ribavirin acted synergistically with azoles against Candida strains for which ribavirin MICs were <24.4 µg/ml. This study highlights the potential clinical application of ribavirin, alone or in association with other antifungal agents, as an adjunct anti-Candida drug.

Development and validation of mathematical models for testing antifungal activity of different essential oils against Candida species.

OBJECTIVE: The upward trend in using plant materials introduced essential oils (EOs) as a valuable, novel, bioactive antifungal agent and as an alternative to standard treatment protocol of denture stomatitis caused by Candida species. Therefore, the aim was to evaluate the antifungal activity of different EOs and to present the response surface methodology (RSM) and artificial neural network (ANN) as possible tools for optimizing and predicting EOs antifungal activity. METHODS: Minimum inhibitory concentration (MIC) and Minimum fungicidal concentration (MFC) of the EOs against 3 species Candida spp. (C. albicans, C. tropicalis, C. glabrata) isolated in patients with DS were determined, together with optimization and prediction based on non-terpene and terpene content in EOs, using two mathematical models RSM and ANN-GA. RESULTS: The highest concentrations of EO M. alternifolia inhibited (1.6-2.8 µg/ml) and fungicided (3.5-6.0 µg/ml) all three investigated Candida spp. while the lowest concentrations of EO C. limon inhibited (0.2 - 0.5 µg/ml) and fungicided (0.6-1.1 µg/ml). Among the three types of Candida, C. glabrata was the most sensitive. The RSM modelling proved that MICs and MFCs statistically depend on non-terpene and terpene content in different EOs (<0.0001). Both models showed that a citrus oil (EO C. limon) with 89% content of terpenes and limonene as major constituent was more antifungal efficient. CONCLUSIONS: The investigated EOs showed a broad spectrum of anticandidal activity, also confirmed using the RSM and ANN-GA models. Since EOs can be cytotoxic in higher concentrations, models may be used for qualitative and quantitative dosage predictions of the antifungal activity of EOs.