Treatment of otomycosis with clotrimazole: results accordingly with the fungus isolated.

BACKGROUND: Otomycosis is usually caused by Candida spp or Aspergillus spp. While Candida is usually multissensitive to available antifungals, Aspergillus is not. Topical antifungals for otomycosis that are available in Portugal are scarce, and systemic treatments have too many interactions and contraindications. OBJECTIVES: Determine otomycosis epidemiology, microbiology and treatment results. METHODS: Observational study that included patients followed in Professor Doutor Fernando Fonseca Hospital, between 2011 and 2020. Otomycosis diagnosis was obtained through ear drainage culture, and every case was treated with 1% clotrimazole ear drops plus ear cleaning once per week. RESULTS: Aspergillus was found in ear drainage culture in 43.9% of patients and Candida in the remaining. There was a significant statistical difference between patients with otomycosis caused by Aspergillus versus Candida in treatment duration from 25.0 days (16.5-43.0) versus 14.0 days (7.0-18.5) (p < .001), respectively. CONCLUSIONS: Otomycosis was more frequently caused by Candida, and this type of otomycosis is treated faster with clotrimazole 10 mg/dL plus ear cleaning, when compared with otomycosis by Aspergillus. SIGNIFICANCE: If otomycosis causative agent is identified or suspected, a prediction of the time needed till the resolution of otomycosis can be made, when clotrimazole ear drops are used.

Echinocandins - structure, mechanism of action and use in antifungal therapy.

With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of echinocandins is based on the inhibition of ß-(1,3)-d-glucan synthesis that builds the fungal cell wall. Caspofungin, micafungin, anidulafungin and rezafungin are semi-synthetic cyclic lipopeptides. Their specific chemical structure possess a potential to obtain novel derivatives with better pharmacological properties resulting in more effective treatment, especially in infections caused by Candida and Aspergillus species. In this review we summarise information about echinocandins with closer look on their chemical structure, mechanism of action, drug resistance and usage in clinical practice. We also introduce actual trends in modification of this antifungals as well as new methods of their administration, and additional use in viral and bacterial infections.

Jerveratrum-Type Steroidal Alkaloids Inhibit ß-1,6-Glucan Biosynthesis in Fungal Cell Walls.

The limited number of available effective agents necessitates the development of new antifungals. We report that jervine, a jerveratrum-type steroidal alkaloid isolated from Veratrum californicum, has antifungal activity. Phenotypic comparisons of cell wall mutants, K1 killer toxin susceptibility testing, and quantification of cell wall components revealed that ß-1,6-glucan biosynthesis was significantly inhibited by jervine. Temperature-sensitive mutants defective in essential genes involved in ß-1,6-glucan biosynthesis, including BIG1, KEG1, KRE5, KRE9, and ROT1, were hypersensitive to jervine. In contrast, point mutations in KRE6 or its paralog SKN1 produced jervine resistance, suggesting that jervine targets Kre6 and Skn1. Jervine exhibited broad-spectrum antifungal activity and was effective against human-pathogenic fungi, including Candida parapsilosis and Candida krusei. It was also effective against phytopathogenic fungi, including Botrytis cinerea and Puccinia recondita. Jervine exerted a synergistic effect with fluconazole. Therefore, jervine, a jerveratrum-type steroidal alkaloid used in pharmaceutical products, represents a new class of antifungals active against mycoses and plant-pathogenic fungi. IMPORTANCE Non-Candida albicans Candida species (NCAC) are on the rise as a cause of mycosis. Many antifungal drugs are less effective against NCAC, limiting the available therapeutic agents. Here, we report that jervine, a jerveratrum-type steroidal alkaloid, is effective against NCAC and phytopathogenic fungi. Jervine acts on Kre6 and Skn1, which are involved in ß-1,6-glucan biosynthesis. The skeleton of jerveratrum-type steroidal alkaloids has been well studied, and more recently, their anticancer properties have been investigated. Therefore, jerveratrum-type alkaloids could potentially be applied as treatments for fungal infections and cancer.

Comparação da ação entre o antifúngico fluconazol e o óleo essencial de Melaleuca Alternifolia sobre amostras de leveduras do gênero Candida / Comparison of the action between the antifungal fluconazole and the essential oil of Melaleuca Alternifolia on samples of yeasts of the genus Candida

As onicomicoses são doenças causadas por fungos que acometem a pele, unhas e pelos, existindo diferentes formas clínicas e ocasionado por diversos agentes etiológicos. Os agentes causadores mais frequentes das onicomicoses são classificados como dermatófitos, não dermatófitos e leveduras. Dentre as leveduras destaca-se os fungos do gênero Candida, caracterizada como leveduriforme, em condições normais se apresentam como colonizantes, comensais e são consideradas oportunistas. A Candida albicans é a levedura mais comum de ser encontrada e está possui relatos de resistência ao fluconazol. A presença desta resistência representa um grande desafio terapêutico, pela escassez de alternativas no tratamento. Por conta disso muitas pessoas acabam optando por métodos alternativos para o controle deste tipo de infecção, um exemplo seria a aplicação de óleos essenciais naturais puros com ação combatente de microrganismos. O óleo essencial de Melaleuca, teve atividade antifúngica relatada por vários estudos usando diversas combinações de compostos originados da planta, mas sua aplicação mais comum é do óleo puro diluído. Porém os estudos aprofundando do quanto este composto possui de ação bactericida e antifúngica, comparados a medicamentos sintéticos, são escassos, mas sabe-se que com o uso frequente e correto do óleo ocasiona uma ação satisfatória. Objetivo geral foi descrever o efeito do óleo de Melaleuca sobre amostras de Candida albicans (ATT 90028) e Candida krusei (ATT 6258) comparando ao uso de Fluconazol.Método: Foi desenvolvida uma pesquisa qualitativa de caráter exploratório do uso tópico do óleo de Melaluca sobre Candida albicans (ATT 90028) e Candida krusei (ATT 6258) comparando com o antifúngico Fluconazol em método de difusão de disco.Os halos formados nos testes foram positivos para o Fluconazol, já para o óleo essencial de Melaleuca não constatando que a comparação por igual não é válida.

Onychomycosis are diseases caused by fungi that affect the skin, nails and hair, with different clinical forms and caused by different etiological agents. The most frequent causative agents of onychomycosis are classified as dermatophytes, non-dermatophytes and yeasts. Among the yeasts, the fungi of the genus Candida stand out, characterized as yeast, under normal conditions they present themselves as colonizers, commensals and are considered opportunistic. Candida albicans is the most common yeast to be found and has been reported to be resistant to fluconazole. The presence of this resistance represents a major therapeutic challenge, due to the scarcity of alternatives in the treatment. Because of this, many people end up opting for alternative methods to control this type of infection, an example would be the application of pure natural essential oils with microorganism-fighting action. Melaleuca essential oil has had antifungal activity reported by several studies using various combinations of compounds originating from the plant, but its most common application is as a diluted pure oil. However, the in-depth studies of how much this compound has bactericidal and antifungal action, compared to synthetic drugs, are scarce, but it is known that with the frequent and correct use of the oil it causes a satisfactory action. General objective was to describe the effect of Melaleuca oil on samples of Candida albicans (ATT 90028) and Candida krusei (ATT 6258) comparing to the use of Fluconazole. Method: A qualitative exploratory research was carried out on the topical use of Melaluca oil on Candida albicans (ATT 90028) and Candida krusei (ATT 6258) comparing it with the antifungal Fluconazole in a disc diffusion method. The halos formed in the tests were positive for Fluconazole, as for the essential oil of Melaleuca, not finding that the comparison is not valid.

In Vitro Antifungal and Antibacterial Effects of Biosynthesized Zinc Oxide Nanoparticles Against Selected Pathogenic and Non-Pathogenic Strains.

We have developed a simple, robust environment-friendly and efficient method for ZnO nanoparticles biosynthesis using Dalbergia sissoo fresh leaf extract. Before using these nanoparticles for antimicrobial assay, a detailed characterization was performed using techniques like Ultraviolet/Visible (UV/Vis) spectroscopy, Particle size analysis (PSA), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), atomic force microscopy (AFM),Transmission electron microscopy (TEM) etc. The average size of biosynthesized ZnO nanoparticles was around 30 nm and they were pure and crystalline by nature. The effectiveness of these biosynthesized nanoparticles were checked against both pathogenic and non-pathogenic microbes. A total of eight bacterial strains-Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, Klebsilla pneumoniae, Staphylococcus aureus, Streptococcus entericus, Bacillus cereus, Pantoea cypripedii and three fungal strains-Candida albicans, Aspergilus niger and Aspergilus flavus were studied to have a clear view of the spectrum of ZnO nanoparticles anti-microbial activity. The effectiveness of biosynthesized ZnO nanoparticles against the microbes was found to be better than the standard reference antibiotics used (streptomycin, chloramphenicol and rifampicin). The results seem to be very promising and can be used for some practical applications of ZnO nanoparticles in nearfuture.

Hedera rhombea inhibits the biofilm formation of Candida, thereby increases the susceptibility to antifungal agent, and reduces infection.

Candida is an opportunistic pathogen and a common cause of fungal infections worldwide. Anti-fungal use against Candida infections has resulted in the appearance of resistant strains. The limited choice of anti-fungal therapy means alternative strategies are needed to control fungal infectious diseases. The aim of this study was to evaluate the inhibition of Candida biofilm formation by Hedera rhombea (Korean name: songak) extract. Biofilm formation was assessed using the crystal violet assay which showed a dose dependent reduction in the presence of extract with the biofilm formation inhibitory concentration of C. albicans (IC50 = 12.5µg/ml), C. tropicalis var. tropicalis (IC50 = 25µg/ml), C. parapsilosis var. parapsilosis (IC50 = 6.25µg/ml), C. glabrata (IC50 = 6.25µg/ml), C. tropicalis (IC50 = 12.5µg/ml), and C. parapsilosis (IC50 = 12.5µg/ml) without directly reducing Candida growth. Treatment with 6.25µg/mL of extract increased the antifungal susceptibility to miconazole from 32% decreasing of fungal growth to 98.8% of that based on the fungal growth assay. Treatment of extract dose-dependently reduced the dimorphic transition of Candida based on the dimorphic transition assay and treatment of 3.125µg/mL of extract completely blocked the adherence of Candida to the HaCaT cells. To know the molecular mechanisms of biofilm formation inhibition by extract, qRT-PCR analysis was done, and the extract was found to dose dependently reduce the expression of hyphal-associated genes (ALS3, ECE1, HWP1, PGA50, and PBR1), extracellular matrix genes (GSC1, ZAP1, ADH5, and CSH1), Ras1-cAMP-PKA pathway genes (CYR1, EFG1, and RAS1), Cph2-Tec1 pathway gene (TEC1) and MAP kinases pathway gene (HST7). In this study, Hedera rhombea extract showed inhibition of fungal biofilm formation, activation of antifungal susceptibility, and reduction of infection. These results suggest that fungal biofilm formation is good screen for developing the antifungal adjuvant and Hedera rhombea extract should be a good candidate against biofilm-related fungal infection.

Using HPLC-DAD and GC-MS Analysis Isolation and Identification of Anticandida Compounds from Gui Zhen Cao Herbs (Genus Bidens): An Important Chinese Medicinal Formulation.

Gui Zhen Cao is an herbal formulation that has been documented in Chinese traditional medicine as a remedy for diarrhea, dysentery, inflammation, and toxicity. The sources of this formulation (Bidens pilosa L., Bidens biternata (Lour.) Merr. & Sherff, Bidens bipinnata L.) are also listed in ethnomedicinal reports all over the world. In this study, all these plants are tested for in vitro anticandida activity. A quantitative evaluation of the phytochemicals in all these plants indicated that their vegetative parts are rich in tannins, saponins, oxalates, cyanogenic glycoside and lipids; moreover, the roots have high percentages of alkaloids, flavonoids, and phenols. The results indicated significant anticandida activity, especially for the hexane extract of B. bipinnata leaves which inhibited C. albicans (42.54%), C. glabrata (46.98%), C. tropicalis (50.89%), C. krusei (40.56%), and C. orthopsilosis (50.24%). The extract was subjected to silica gel chromatography and 220 fractions were obtained. Purification by High Performance Liquid Chromatography with Diode-Array Detection (HPLC-DAD) and Gas Chromatography tandem Mass Spectrometry (GC-MS/MS) analysis led to the identification of two anticandida compounds: dehydroabietic and linoleic acid having an inhibition of 85 and 92%, respectively.

Antibacterial, antifungal and enzyme inhibitory effects of selected plants from Turkey.

In this study, antibacterial, antifungal, antihyaluronidase, anticollagenase and antielastase activity of Hypericum bithynicum, Malva neglecta, Morus alba, Rubus discolor, Sambucus ebulus and Smilax excelsa were investigated. Methanol extracts of M. neglecta and R. discolor and all extracts of H. bithynicum were more active against Staphylococcus epidermidis. Similarly, water extracts of M. alba and S. ebulus were more active against Streptococcus pneumonia. Additionally, S. ebulus and S. excelsa had prominent antifungal activity on Candida albicans. Besides, methanol extract of M. neglecta and n-hexane extract of H. bithynicum were determined to have significant antihyaluronidase activity. Only R. discolor showed significant antielastase effect.

Impact of Nutritional Assessment on the Clinical Outcomes of Patients with Non-albicans Candidemia: A Multicenter Study.

Several studies have demonstrated that malnutrition is a negative prognostic factor for clinical outcomes. However, there is limited evidence for the effect of malnutrition on clinical outcomes in patients with candidemia. We investigated the relationship between malnutrition and all-cause 28-day mortality among patients with non-albicans candidemia. Between July 2011 and June 2014, all adult patients with non-albicans candidemia, including C. tropicalis, C. glabrata, C. parapsilosis and so on, were enrolled. The Malnutrition Universal Screening Tool (MUST) scores were used to determine the patients' nutritional status before the onset of candidemia. A total of 378 patients were enrolled; 43.4% developed septic shock and 57.1% had a high risk of malnutrition (MUST ≥ 2). The all-cause 28-day mortality rate was 40.7%. The Cox proportional hazards model revealed that C. tropicalis (HR, 2.01; 95% CI, 1.24-3.26; p = 0.005), Charlson comorbidity index (HR, 1.10; 95% CI, 1.03-1.18; p = 0.007), Foley catheter use (HR, 1.68; 95% CI, 1.21-1.35; p = 0.002), concomitant bacterial infections (HR, 1.55; 95% CI, 1.11-2.17; p = 0.010), low platelet count (HR, 3.81; 95% CI, 2.45-5.91; p < 0.001), not receiving antifungals initially (HR, 4.73; 95% CI, 3.07-7.29; p < 0.001), and MUST ≥ 2 (HR, 1.54; 95% CI, 1.09-2.17; p = 0.014) were independently associated with all-cause 28-day mortality. A simple screening tool for nutritional assessment should be used for patients with non-albicans candidemia to detect early clinical deterioration, and a tailored nutritional care plan should be established for malnourished individuals, to improve their clinical outcomes.

Cytotoxicity, antimicrobial and antioxidant activities of mosses obtained from open habitats.

Mosses are mainly the object of ecological and taxonomic research. This group of plants are still underestimated by scientists in other aspects of research. Recent research has shown that these plants contain remarkable and unique substances with high biological activity. Five species of mosses from a large urban ecosystem were identified for present study. In order to determine their biological potential, multifaceted studies were carried out, including: total phenolics content, antioxidant activity, antimicrobial and antifungal study, cytotoxicity evaluation, and scratch assay to assess pro-regenerative effect in the context of their possible use as the ingredients of biologically active cosmetics. Additionally, determination of individual phenolic compounds in selected extracts of the tested mosses was made. Research showed that Ceratodon purpureus and Dryptodon pulvinatus extracts had the greatest potential as antioxidants and antimicrobial activity. The cytotoxicity assessment indicated that the extracts from Dryptodon pulvinatus and Rhytidiadelphus squarossus exerted the strongest negative effect on mouse fibroblast line L929 viability at higher concentrations. While, the extract from Tortulla muralis best stimulated human foreskin fibroblast line HFF-1 proliferation and wound healing. The research on individual phenolic compounds content in the extracts tested indicated over 20 peaks on UPLC chromatograms. The conducted study has shown that mosses, especially so far unexplored species of open ecosystems, and e.g. epilytic habitats, may be a valuable source of biologically active substances and thus may constitute important medical and cosmetic possibilities.

Glucosyl-1,2,3-triazoles derived from eugenol and analogues: Synthesis, anti-Candida activity, and molecular modeling studies in CYP-51.

This work describes the synthesis, anti-Candida, and molecular modeling studies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and correlated phenols. The new compounds were characterized by combined Fourier Transform Infrared, 1 H and 13 C nuclear magnetic resonance and spectroscopy of high-resolution mass spectrometry. The synthesized compounds did not show significant cytotoxicity against healthy fibroblast human cells (MCR-5) providing interesting selectivity indexes (SI) to active compounds. Considering the antifungal activity, nine compounds showed anti-Candida potential and the peracetylated triazoles 17 and 18 were the most promising ones. Eugenol derivative 17 was active against three species of Candida at 26.1-52.1 µM. This compound was four times more potent than fluconazole against Candida krusei and less toxic (SI > 6.6) against the MCR-5 cells than fluconazole (SI > 3.3) considering this strain. Dihydroeugenol derivative 18 showed similar activity to 17 and was four times more potent and less toxic than fluconazole against C. krusei. The deacetylated glucosides and non-glucosylated corresponding derivatives did not show considerable antifungal action, suggesting that the acetyl groups are essential for their anti-Candida activity. Molecular docking coupled with molecular dynamics showed that 14α-lanosterol demethylase is a feasible molecular target, since 17 and 18 could bind to this enzyme once deacetylated in vivo, thereby acting as prodrugs. Also, these studies demonstrated the importance of hydrophobic substituents at the phenyl ring.

Phytochemical composition, antifungal activity, in vitro and in vivo toxicity of Syzygium cumini (L) Skeels leaves extract / Composición fitoquímica, actividad antifúngica, toxicidad in vitro e in vivo del extracto de hojas de Syzygium cumini (L) Skeels

This study determined phytochemical composition, antifungal activity and toxicity in vitro and in vivo of Syzygium cumini leaves extract (Sc). Thus, was characterized by gas chromatography coupled to mass spectrometry and submitted to determination of Minimum Inhibitory (MIC) and Fungicidal concentrations (MFC) on reference and clinical strains of Candida spp. and by growth kinetics assays. Toxicity was verified using in vitro assays of hemolysis, osmotic fragility, oxidant and antioxidant activity in human erythrocytes and by in vivo acute systemic toxicity in Galleria mellonella larvae. Fourteen different compounds were identified in Sc, which showed antifungal activity (MIC between 31.25-125µg/mL) with fungistatic effect on Candida. At antifungal concentrations, it demonstrated low cytotoxicity, antioxidant activity and neglible in vivotoxicity. Thus, Sc demonstrated a promising antifungal potential, with low toxicity, indicating that this extract can be a safe and effective alternative antifungal agent.

Este estudio determinó la composición fitoquímica, la actividad antifúngica y la toxicidad in vitro e in vivo del extracto de hojas de Syzygium cumini (Sc). Así, se caracterizó mediante cromatografía de gases acoplada a espectrometría de masas y se sometió a determinación de Concentraciones Mínimas Inhibitorias (CMI) y Fungicidas (MFC) sobre cepas de referencia y clínicas de Candida spp. y mediante ensayos de cinética de crecimiento. La toxicidad se verificó mediante ensayos in vitro de hemólisis, fragilidad osmótica, actividad oxidante y antioxidante en eritrocitos humanos y por toxicidad sistémica aguda in vivo en larvas de Galleria mellonella. Se identificaron catorce compuestos diferentes en Sc, que mostraron actividad antifúngica (CMI entre 31.25-125 µg/mL) con efecto fungistático sobre Candida. En concentraciones antifúngicas, demostró baja citotoxicidad, actividad antioxidante y toxicidad in vivo insignificante. Por lo tanto, Sc demostró un potencial antifúngico prometedor, con baja toxicidad, lo que indica que este extracto puede ser un agente antifúngico alternativo seguro y eficaz.

A Natural Alternative Treatment for Urinary Tract Infections: Itxasol©, the Importance of the Formulation.

Genito-urinary tract infections have a high incidence in the general population, being more prevalent among women than men. These diseases are usually treated with antibiotics, but very frequently, they are recurrent and lead to the creation of resistance and are associated with increased morbidity and mortality. For this reason, it is necessary to develop new compounds for their treatment. In this work, our objective is to review the characteristics of the compounds of a new formulation called Itxasol© that is prescribed as an adjuvant for the treatment of UTIs and composed of ß-arbutin, umbelliferon and n-acetyl cysteine. This formulation, based on biomimetic principles, makes Itxasol© a broad-spectrum antibiotic with bactericidal, bacteriostatic and antifungal properties that is capable of destroying the biofilm and stopping its formation. It also acts as an anti-inflammatory agent, without the adverse effects associated with the recurrent use of antibiotics that leads to renal nephrotoxicity and other side effects. All these characteristics make Itxasol© an ideal candidate for the treatment of UTIs since it behaves like an antibiotic and with better characteristics than other adjuvants, such as D-mannose and cranberry extracts.

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.

Natural rubber dressing loaded with silver sulfadiazine for the treatment of burn wounds infected with Candida spp.

Millions of people are burned worldwide every year and 265,000 of the cases are fatal. The development of burn treatment cannot consist only of the administration of a single drug. Due to the infection risk, antibiotics are used in conjunction with gels and damp bandages. In this work, an inexpensive curative based on silver sulfadiazine (SS) and natural rubber latex (NRL) was developed to treat burn wounds. It was produced by the casting method. The infrared spectrum presented no interaction between drug and biopolymer. At the same time, electronic micrographs showed that the SS crystals are inserted on the polymeric dressing surface. Mechanical properties after the drug incorporation were considered suitable for dermal application. About 32.4% of loaded SS was released in 192 h by the dressings that also inhibited the growth of Candida albicans and Candida parapsilosis at 75.0 and 37.5 µg·mL-1, respectively. The curative proved to be biocompatible when applied to fibroblast cells, in addition to enhancing cellular proliferation and, in the hemocompatibility test, no hemolytic effects were observed. The good results in mechanical, antifungal and biological assays, combined with the average bandage cost of $0.10, represent an exciting alternative for treating burn wounds.

Recent progress on anti-Candida natural products.

Candida is an intractable life-threatening pathogen. Candida infection is extremely difficult to eradicate, and thus is the major cause of morbidity and mortality in immunocompromised individuals. Morevover, the rapid spread of drug-resistant fungi has led to significant decreases in the therapeutic effects of clinical drugs. New anti-Candida agents are urgently needed to solve the complicated medical problem. Natural products with intricate structures have attracted great attention of researchers who make every endeavor to discover leading compounds for antifungal agents. Their novel mechanisms and diverse modes of action expand the variety of fungistatic agents and reduce the emergence of drug resistance. In recent decades, considerable effort has been devoted to finding unique antifungal agents from nature and revealing their unusual mechanisms, which results in important progress on the development of new antifungals, such as the novel cell wall inhibitors YW3548 and SCY-078 which are being tested in clinical trials. This review will present a brief summary on the landscape of anti-Candida natural products within the last decade. We will also discuss in-depth the research progress on diverse natural fungistatic agents along with their novel mechanisms.

Biodirected Synthesis of Silver Nanoparticles Using Aqueous Honey Solutions and Evaluation of Their Antifungal Activity against Pathogenic Candida Spp.

Silver nanoparticles (AgNPs) were synthesized using aqueous honey solutions with a concentration of 2%, 10%, and 20%-AgNPs-H2, AgNPs-H10, and AgNPs-H20. The reaction was conducted at 35 °C and 70 °C. Additionally, nanoparticles obtained with the citrate method (AgNPs-C), while amphotericin B (AmB) and fluconazole were used as controls. The presence and physicochemical properties of AgNPs was affirmed by analyzing the sample with ultraviolet-visible (UV-Vis) and fluorescence spectroscopy, scanning electron microscopy (SEM), and dynamic light scattering (DLS). The 20% honey solution caused an inhibition of the synthesis of nanoparticles at 35 °C. The antifungal activity of the AgNPs was evaluated using opportunistic human fungal pathogens Candida albicans and Candida parapsilosis. The antifungal effect was determined by the minimum inhibitory concentration (MIC) and disc diffusion assay. The highest activity in the MIC tests was observed in the AgNPs-H2 variant. AgNPs-H10 and AgNPs-H20 showed no activity or even stimulated fungal growth. The results of the Kirby-Bauer disc diffusion susceptibility test for C. parapsilosis strains indicated stronger antifungal activity of AgNPs-H than fluconazole. The study demonstrated that the antifungal activity of AgNPs is closely related to the concentration of honey used for the synthesis thereof.

Antifungal Efficacy and Safety of Cycloheximide as a Supplement in Optisol-GS.

PURPOSE: The incidence of fungal infection after corneal transplant has increased significantly in recent years, especially Candida spp. This study aimed to evaluate the efficacy and safety of the addition of cycloheximide in Optisol-GS media in decreasing the growth of Candida spp. strains. METHODS: This in vitro laboratory efficacy study measured fungal colony growth in 24 vials of Optisol-GS that were divided into 6 groups of 4 vials each, as follows: (1) MIC/2 cycloheximide, (2) MIC cycloheximide, (3) MICx5 cycloheximide, (4) MICx10 cycloheximide, from MIC values obtained for each strain, (5) unsupplemented optisol-GS as a positive control (added inoculum), and (6) unsupplemented optisol-GS as a negative control (no inoculum). In each group was added Candida albicans, C. glabrata and C. parapsilosis, except in the negative control. The evaluated variables were fungal colony growth from the Optisol-GS vials, corneal endothelial cell density and endothelial cell viability at different concentrations of cycloheximide. RESULTS: In the efficacy study, all strains showed a reduction in fungal cell growth from the second day at all evaluated concentrations of optisol-GS supplemented with cycloheximide, even at subinhibitory concentrations (MIC/2). For C. glabrata, the colony count was reduced to 99%. No evidence of corneal endothelial toxicity was found at any concentration, in the safety study, compared with the paired control. CONCLUSION: The addition of cycloheximide to optisol-GS decreased the fungal growth, demonstrating fungicide action against C. glabrata and fungistatic action against C. albicans and C. parapsilosis. This drug did not demonstrate toxicity to the corneal endothelium at different concentrations.

Epidemiology, species distribution, and outcome of nosocomial Candida spp. bloodstream infection in Shanghai: an 11-year retrospective analysis in a tertiary care hospital.

BACKGROUND: The incidence of Candida bloodstream infections (BSIs), has increased over time. In this study, we aimed to describe the current epidemiology of Candida BSI in a large tertiary care hospital in Shanghai and to determine the risk factors of 28-day mortality and the impact of antifungal therapy on clinical outcomes. METHODS: All consecutive adult inpatients with Candida BSI at Ruijin Hospital between January 1, 2008, and December 31, 2018, were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and their impact on the outcomes were analyzed. RESULTS: Among the 370 inpatients with 393 consecutive episodes of Candida BSI, the incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients. Of the 393 cases, 299 (76.1%) were treated with antifungal therapy (247 and 52 were treated with early appropriate and targeted antifungal therapy, respectively). The overall 28-day mortality rate was 28.5%, which was significantly lower in those who received early appropriate (25.5%) or targeted (23.1%) antifungal therapy than in those who did not (39.4%; P = 0.012 and P = 0.046, respectively). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, and severe neutropenia were found to be independent risk factors of the 28-day mortality rate. Patients who received antifungal therapy had a lower mortality risk than did those who did not. CONCLUSIONS: The incidence of Candida BSI has increased steadily in the past 11 years at our tertiary care hospital in Shanghai. Antifungal therapy influenced short-term survival, but no significant difference in mortality was observed between patients who received early appropriate and targeted antifungal therapy.

Spectrum and Antifungal Resistance of Candidemia in Neonates With Early- and Late-Onset Sepsis in Pakistan.

BACKGROUND: Neonatal candidemia leads to high morbidity and mortality in developing countries. We studied the trends, spectrum and antifungal resistance in neonatal candidemia isolates from the year 2014 to 2019. METHODS: This was a cross-sectional study conducted at the Aga Khan University, Pakistan. Neonates with positive blood cultures with Candida species were retrospectively identified from the laboratory database (2014-2018) and prospectively in 2019 where clinical information was also collected as part of routine laboratory reporting. RESULTS: We identified 669 neonates with Candida species in blood cultures. Three hundred forty-six neonates had early-onset disease (EOD age ≤7 days) and 323 had late-onset disease (LOD age >7 days). Non-albicans Candida species (86.7%) were predominant versus C. albicans (13.3%; P-value 0.024) with Candida tropicalis being most common in both EOD and LOD. Candida pelliculosa and Candida guilliermondii were associated with EOD and C. albicans with LOD. Isolation of fluconazole nonsusceptible non-albicans Candida species was significantly higher in early-onset (5.9%) versus late-onset (2%) neonatal candidemia (P-value 0.005; crude odds ratio [COR] 2.73, 95% CI: 1.34-5.53). LOD in neonates was more likely associated with the use of vancomycin (COR 3.89, 95% CI: 1.39-10.89). EOD was more likely seen in patients with vaginal delivery (COR 4.16, 95% CI: 1.42-12.23) and in neonates with respiratory distress leading to intensive care unit admission (COR 3.31, 95% CI: 1.05-10.42). CONCLUSIONS: Non-albicans Candida species were increasingly isolated from neonates with candidemia during recent years from Pakistan. Amphotericin remains first-line option for neonatal candidemia in our setting as fluconazole nonsusceptible Candida species are commonly isolated.