Antifungal Fluconazole Research Articles

A prospective evaluation on the interaction of fluconazole and voriconazole on serum concentrations of budesonide in patients treated for gastrointestinal GVHD.

The gastrointestinal (GI) tract is commonly affected by acute and chronic graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients developing GI GVHD, nonabsorbable corticosteroids such as budesonide may be used alone to reduce the risk of systemic corticosteroid toxicities or combined with systemic steroids to enhance clinical responses and to allow more rapid tapering of systemic corticosteroid doses. This prospective crossover study was conducted to evaluate what effect two commonly used antifungal agents, fluconazole, and voriconazole, would have on the trough (Cmin) and peak (Cmax) levels of budesonide in adult patients who had undergone allo-HSCT who subsequently developed clinical GI GVHD. Fifteen subjects were enrolled and nine completed the study and were evaluable. When coadministered with budesonide, voriconazole significantly increased the geometric mean of budesonide Cmin and Cmax levels by 8.52- and 6.63-fold, respectively. The cohort to evaluate the interaction with fluconazole did not meet accrual goals to reach definitive conclusions. In conclusion, this prospective study demonstrated that when patients with GI GVHD are treated with budesonide concurrently with voriconazole, the systemic concentrations of budesonide increase substantially which could increase the risk of steroid-associated toxicities.

Bacterial cellulose with microencapsulated antifungal essential oils: A novel double barrier release system

A double barrier release system is designed for herbal essential oils which possess tremendous anti-fungal activity, even against drug-resistant fungi. However, their utilization is limited owing to their sensitivity towards pH, temperature and light. Three essential oils (thymol, eugenol, carvacrol) are microencapsulated in polylactic acid shell with a high encapsulation efficiency of 80% in order to leverage their synergistic anti-fungal activity. These microcapsules are further incorporated in bacterial cellulose – a naturally produced nanofibrous hydrogel. This unique system offers double barrier to the release of oils – the polymeric shell and the nanofibrous matrix. The anti-fungal testing was carried out on model fungus- Candida albicans (cause of common oral, vaginal infections). In vitro transvaginal drug release study was performed to compare release from microcapsules as colloids and the composites, where the later exhibited a controlled release. Mathematical modelling was performed to understand the release, which is governed by matrix swelling, diffusion of oils and erosion of microcapsules. The time-kill curves show that the composites were able to achieve fungicidal endpoint with half the oil dosage as compared to the colloidal microcapsules and were far more effective than commercial antifungal fluconazole.

Design, Synthesis and Antimicrobial Evaluations of Novel 3,7-Disubstituted 2H-1-Benzopyran-2-ones

In present study, a novel class of 3,7-disubstituted 2H-1-benzopyran-2-one derivatives (3xa-3zc) bearing a basic ether side chain at C-7 and a substituted phenyl ring at C-3 of the coumarin ring is synthesized. These compounds have been evaluated for antimicrobial (antibacterial/antifungal) activities. Some of the compounds viz. 3xc, 3xe, 3xf, 3yb, 3yc and 3yf have shown significant antifungal activities against selective strains. Compounds 3xe, 3yb and 3yc with the MIC values of 1.56 μg/mL displayed better antifungal activity than fluconazole against Trichophyton mentagrophytes

PHOSPHATE SOLUBILIZING MICROORGANISM CONSORTIUM OF VIRGIN TIGER HILL FOREST SOIL SHOWS HIGH LEVEL TOLERANCE TO PESTICIDE, ANTIBIOTIC, ANTIFUNGAL AND HEAVY METALS

Tiger Hill, a notified reserve forest is the highest point around Darjeeling town in Eastern Himalayan Hotspot. Soil nutrition of this forest area depends on nutrient recycling where phosphate solubilising microorganisms (PSM) has crucial role to play as it solubilises insoluble phosphorus salt to soluble forms. But, with rise in use of toxic chemicals these microbes are at threat. This research initiative explores isolation of PSM from Tiger hill forest soil to detect pesticide, antibiotic, antifungal and heavy metal tolerance. Soil sample from tiger hill has moisture (18.55%), pH (3.87), organic carbon (1.187%), total Nitrogen (1.02%) and Phosphorus in P2O5 form (10ppm). Isolation and screening of PSM were conducted on Pikovskaya’s agar medium. In vitro tolerance assay was performed to detect degree of tolerance in isolated PSM-consortium (PSMC). Pesticides like Fipronil, Thiomethoxame, Emamectin benzoate, Deltamethrin, Flubendiamide, Spiromesifen, Fenazaquin and Phorate exhibited complete to high degree of tolerance. PSMC was fully tolerant to antibiotic like Augmentin, Erythromycin, Chloramphenicol, Ofloxacin, Co-Trimoxazole, Cefotaxime; antifungal Itraconazole and Fluconazole. Mild tolerance towards heavy metal salts like As2O3, SnCl2, CdCl2, CuCl2, CdSO4 and CuSO4 were detected. Synergestic effect of cells present in the isolated PSMC may also be an added advantageous property to tolerate pesticides, antibiotic, antifungal and heavy metal salts.

UPLC-MS-ESI-QTOF Analysis and Antifungal Activity of the Spondias tuberosa Arruda Leaf and Root Hydroalcoholic Extracts.

The aim of this study was to identify and evaluate the chemical compositions and effects of the S. tuberosa leaf and root hydroalcoholic extracts (HELST and HERST) against different strains of Candida. Chemical analysis was performed by Ultra-Performance Liquid Chromatography Coupled to Quadrupole/Time of Flight System (UPLC-MS-ESI-QTOF). The Inhibitory Concentration of 50% of the growth (IC50) as well as the intrinsic and combined action of the extracts with the antifungal fluconazole (FCZ) were determined by the microdilution method while the minimum fungicidal concentrations (MFCs) and the effect on fungal morphological transitions were analyzed by subculture and in humid chambers, respectively. From the preliminary phytochemical analysis, the phenols and flavonoids were the most abundant. The intrinsic IC50 values for HELST ranged from 5716.3 to 7805.8 µg/mL and from 6175.4 to 51070.9 µg/mL for the HERST, whereas the combination of the extracts with fluconazole presented IC50 values from 2.65 to 278.41 µg/mL. The MFC of the extracts, individually, for all the tested strains was ≥16384 µg/mL. When fluconazole was combined with each extract, the MFC against CA URM 5974 was reduced (HELST: 2048 and HERST: 4096 µg/mL). Synergism was observed against standard C. albicans (CA) and C. tropicalis (CT) strains and with the root extract against the CT isolate. The leaf extract inhibited the morphological transition of all strains while the root extract inhibited only CT strains.

Tinospora cordifolia Aqueous Extract Alleviates Cyclophosphamide- Induced Immune Suppression, Toxicity and Systemic Candidiasis in Immunosuppressed Mice: In vivo Study in Comparison to Antifungal Drug Fluconazole.

The present study was aimed to evaluate the effect of the aqueous extract of Tinospora cordifolia (AETC) against cyclophosphamide-induced immunosuppression and systemic Candida albicans infection in a murine model. The protective effect of AETC against cyclophosphamide-induced leukopenia was evaluated by quantitative and qualitative analysis of the leukocytes. The immune-stimulating potential of AETC on macrophages was assessed by determining the levels of secreted cytokines. To determine the direct antifungal activity, AETC or fluconazole was administered to C. albicans infected mice. The efficacy of treatment was assessed by determining the survival rate, kidney fungal burden, the organ index and liver inflammation parameters. Cyclophosphamide administration resulted in substantial depletion of leukocytes, whereas AETC treatment induced the recovery of leukocytes in cyclophosphamide-injected mice. Moreover, AETC treatment of macrophages resulted in enhanced secretion of IFN-γ, TNF-α and IL-1β. C. albicans infected mice treated with AETC at the doses of 50 and 100 mg/kg exhibited 40% and 60% survival rate, whereas the mice treated with fluconazole at a dose of 50 mg/kg showed 20% survival rate. Like survival data, the fungal load was found to be the lowest in the kidney tissues of mice treated with AETC at a dose of 100 mg/kg. Interestingly, mice infected with C. albicans demonstrated improvement in the organ indices and liver functioning after AETC treatment. These results suggest that AETC may potentially be used to rejuvenate the weakened immune system and eliminate systemic candidiasis in mice.

Diversity, Distribution, and Ecology of Fungi in the Seasonal Snow of Antarctica.

We characterized the fungal community found in the winter seasonal snow of the Antarctic Peninsula. From the samples of snow, 234 fungal isolates were obtained and could be assigned to 51 taxa of 26 genera. Eleven yeast species displayed the highest densities; among them, Phenoliferia glacialis showed a broad distribution and was detected at all sites that were sampled. Fungi known to be opportunistic in humans were subjected to antifungal minimal inhibition concentration. Debaryomyces hansenii, Rhodotorula mucilaginosa, Penicillium chrysogenum, Penicillium sp. 3, and Penicillium sp. 4 displayed resistance against the antifungals benomyl and fluconazole. Among them, R. mucilaginosa isolates were able to grow at 37 °C. Our results show that the winter seasonal snow of the Antarctic Peninsula contains a diverse fungal community dominated by cosmopolitan ubiquitous fungal species previously found in tropical, temperate, and polar ecosystems. The high densities of these cosmopolitan fungi suggest that they could be present in the air that arrives at the Antarctic Peninsula by air masses from outside Antarctica. Additionally, we detected environmental fungal isolates that were resistant to agricultural and clinical antifungals and able to grow at 37 °C. Further studies will be needed to characterize the virulence potential of these fungi in humans and animals.

Case Report: Facial mixed fungal infection in a poorly responding non-Hodgkin’s lymphoma patient with suspected immunodeficiency

A male child presented with left lacrimal gland and right submandibular masses that were diagnosed as high grade B-cell non-Hodgkin's Lymphoma. Immunodeficiency was suspected, mostly due to secondary to Epstein Barr virus infection. Chemotherapy was started and gradual regression was observed in the size of the lesions forming a central necrosis and facial wound. Cultures from this wound showed mixed gram negative growth of Pseudomonas aeruginosa, and Escherichia coli. Two days later, a follow up swab of the wound was taken and showed fungal growth of mixed Candida tropicalis and Cryptococcus laurentii which was treated with two antifungals (fluconazole and liposomal amphotericin B). After a second chemotherapy cycle, the facial necrotic lesion increased in size and the patient's general condition markedly deteriorated with multi-organ system failure secondary to septic shock by candidemia. Candida glabrata, which is non-Candida albicans fungus was the fungus that appeared in the patient's blood culture. Caspofungin was prescribed in addition to liposomal amphotericin B. two days later, the follow up blood culture revealed growth of methicillin resistant Staphylococcus aureus and the pulmonary condition of the patient then deteriorated gradually. Six days later, the patient developed multi-organ dysfunction syndrome secondary to sepsis. We conclude that we mixed fungal infection in not uncommon among immunocompromised patients, candidemia is fatal even if treated with the correct antifungals.

Study of Antifungal Susceptibility, Virulence Genes and Biofilm Formation in Candida albicans

Background: Candida albicans has emerged as an important nosocomial pathogen. The morbidity and mortality associated with this pathogen are related to the presence of virulence genes and antifungal resistance. The objective of the present study was to investigate the prevalence of antifungal resistance, biofilm formation and some virulence genes such as ALS1, PLB1, INT1, SAP1 and HWP1, among clinical isolates of Candida albicans recovered from immunocompromised patients. Methods: The study included one hundred C. albicans isolates identified phenotypically and by a molecular technique using Polymerase Chain Reaction (PCR). The identified C. albicans was further subjected to antifungal study by the microdilution method, biofilm study and molecular study for virulence genes by PCR. Results: The resistance to antifungal drugs, fluconazole, caspofungin and itraconazole was 8% for each of them and for amphotericin B, it was 9%. The prevalence of the studied virulence genes was HWP1 77%, INT1 72%, ALS1 65%, SAP1 65% and PLB1 52%. The biofilm capacity was identified by the microplate method in 58% of C. albicans. The OD was intense in 20 isolates, moderate in 21 isolates and mild in 17 isolates. There was a statistically significant increase in the prevalence of the studied virulence genes INT1, ALS1, HWP1, SAP1 and PLB1 among biofilm forming C. albicans as compared to non-biofilm forming isolates (P=0.0001). Additionally, the resistance to fluconazole, itraconazole and caspofungin was statistically, significantly higher in C. albicans with the capacity to form biofilm as compared to non-biofilm forming C. albicans. Conclusion: The present study highlights the prevalence of resistance to antifungal drugs among C. albicans which are not uncommon. Moreover, there was a high prevalence of INT1, ALS1, HWP1, SAP1 and PLB1 genes in C. albicans. The resistance to antifungal drugs was common among isolates with the capacity to form the biofilm. There was an association between the biofilm formation and virulence genes.

ROLE OF ESSENTIAL OIL FOR CONTROL OF AVIAN ASPERGILLOSIS IN EXPERIMENTALLY INFECTED CHICKENS

This study was designed to investigate the efficacy of essential oils as an alternative prophylaxis and treatment for avian aspergillosis. The in vitro susceptibility of Aspergillus fumigatus, A.flavus, and A.niger strains to antifungal drugs ( Nystatin, Amphotericin B (AMP ), Ketoconazole (KTC ), Itraconazole (ITR) and Fluconazole (FLU), and to essential oils (Garlic, thyme, cinnamon, tea tree, clove and chamomile oils) was determined using the macro diffusion methods. All fungal isolates demonstrated variable degrees of drugs resistances. All fungi showed 100% resistance to fluconazole, while ketoconazole is highly effective than itraconazol, amphotericin B and nystatin in all isolated fungi. Essential oils showed antifungal effect especially cinnamon oil followed by clove and garlic among tested EOs in vitro. Cinnamon oil showed the highest inhibition zone diameter to all fungi, so it was chosen for experimental trial based on the obtained antifungal activity results, Cinnamon oil was highly effective against A.fumigatus infection with a dose of 1 ml kg ration and could be used in the field of poultry instead of other antifungal drugs.

Comparison of the inhibitory effect of ketoconazole, voriconazole, fluconazole, and itraconazole on the pharmacokinetics of bosentan and its corresponding active metabolite hydroxy bosentan in rats

1. This study aimed to investigate the inhibitory effect of azole antifungal agents, including ketoconazole, voriconazole, fluconazole, and itraconazole, on the pharmacokinetics of bosentan (BOS) and its active metabolite hydroxy bosentan (OHBOS) in Sprague–Dawley (SD) rats.2. A total of 25 healthy male SD rats were divided into five groups and treated with various azole antifungal agents by gavage, followed by a single dose of BOS after 30 min.3. The study found that ketoconazole led to a significant increase (5.1-fold) in the AUC(0-t) of BOS, associated with a 5.8-fold elevation in the Cmax, which was greater than that for fluconazole (2.6- and 2.9-fold) and voriconazole (1.1- and 1.7-fold). Accordingly, the Vz/F and CLz/F of BOS reduced by 89.2% and 83.7%, respectively, on administering ketoconazole concomitantly. However, fluconazole caused a decrease in Vz/F and CLz/F by 77.4% and 72.2%, respectively, compared with voriconazole that exhibited a decrease in CLz/F by 51.7% with a negligible change in Vz/F. Also, obvious differences were observed in the pharmacokinetic parameters of OHBOS between the control and treated groups.4. Collectively, treatment with ketoconazole resulted in a prominent inhibitory effect on the metabolism of BOS, followed by treatment with fluconazole, voriconazole, and itraconazole. Therefore, these details of animal studies may help draw more attention to the safety of BOS while combining it with ketoconazole, voriconazole, fluconazole, or itraconazole clinically.

Unique, Diverged, and Conserved Mitochondrial Functions Influencing Candida albicans Respiration.

Candida albicans is an opportunistic fungal pathogen of major clinical concern. The virulence of this pathogen is intimately intertwined with its metabolism. Mitochondria, which have a central metabolic role, have undergone many lineage-specific adaptations in association with their eukaryotic host. A screen for lineage-specific genes identified seven such genes specific to the CTG clade of fungi, of which C. albicans is a member. Each is required for respiratory growth and is integral to expression of complex I, III, or IV of the electron transport chain. Two genes, NUO3 and NUO4, encode supernumerary subunits of complex I, whereas NUE1 and NUE2 have nonstructural roles in expression of complex I. Similarly, the other three genes have nonstructural roles in expression of complex III (QCE1) or complex IV (COE1 and COE2). In addition to these novel additions, an alternative functional assignment was found for the mitochondrial protein encoded by MNE1MNE1 was required for complex I expression in C. albicans, whereas the distantly related Saccharomyces cerevisiae ortholog participates in expression of complex III. Phenotypic analysis of deletion mutants showed that fermentative metabolism is unable to support optimal growth rates or yields of C. albicans However, yeast-hypha morphogenesis, an important virulence attribute, did not require respiratory metabolism under hypoxic conditions. The inability to respire also resulted in hypersensitivity to the antifungal fluconazole and in attenuated virulence in a Galleria mellonella infection model. The results show that lineage-specific adaptations have occurred in C. albicans mitochondria and highlight the significance of respiratory metabolism in the pathobiology of C. albicansIMPORTANCECandida albicans is an opportunistic fungal pathogen of major clinical concern. The virulence of this pathogen is intimately intertwined with its metabolic behavior, and mitochondria have a central role in that metabolism. Mitochondria have undergone many evolutionary changes, which include lineage-specific adaptations in association with their eukaryotic host. Seven lineage-specific genes required for electron transport chain function were identified in the CTG clade of fungi, of which C. albicans is a member. Additionally, examination of several highly diverged orthologs encoding mitochondrial proteins demonstrated functional reassignment for one of these. Deficits imparted by deletion of these genes revealed the critical role of respiration in virulence attributes of the fungus and highlight important evolutionary adaptations in C. albicans metabolism.

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis.

Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease.IMPORTANCECryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.

A repeated point prevalence survey of antimicrobial use in specialized cancer care hospital of Pakistan: findings and implications

ABSTRACTBackground: The extensive use of broad-spectrum antimicrobials in immunocompromised patients is inevitable in situations where culture and sensitivity testing is challenging. However, their overuse leads to an increase in antimicrobial resistance (AMR), which is a growing concern.Method: A repeated point prevalence survey (PPS) was conducted to assess the pattern of antimicrobial prescribing in a specialized cancer care hospital in Pakistan using the methodology employed by the European Centre of Disease Prevention and Control.Results: Out of 313 hospitalized patients, 156 (49.8%) were prescribed one or more antimicrobials, 82 (50.9) in 2017 and 74 (48.7) in 2018. The average bed occupancy in the hospital was 80.3%. Fever in neutropenic patients (20.2%), lower respiratory tract infections (17.8%), and sepsis (14.9%) were the three most common clinical indications. The total number of prescribed antimicrobials was 242, of whom, 41 (16.9%) were given orally and 201 (83.1%) were given parenterally. The most commonly used antimicrobials were piperacillin plus enzyme inhibitor (31.8%), meropenem (7.9%), ceftriaxone (6.2%) and vancomycin (6.2%). Of the total prescribed antimicrobials, 42 (17.3%) antimicrobials were used in surgical departments, 89 (36.8) in adult medical departments, 73 (30.1%) in pediatric medical departments and 38 (15.7) in the intensive care unit (ICU). In addition to these antibacterials, there was relatively high use of antivirals (acyclovir; 4.1%) and antifungals (fluconazole; 3.7%, amphotericin B; 2.9%).Conclusion: The study concluded that broad-spectrum antimicrobial usage in cancer hospitals in Pakistan is high, which can be a risk factor for the emergence of AMR. Repeated PPS is a fruitful way to maintain a focus on inappropriate antimicrobial use and develop pertinent intervention programs targeteing specific issues to improve future use.

Microbial melanin physiology under stress conditions and gamma radiation protection studies

Any life-threatening alteration in environmental circumstances from the optimal imposes stress on an organism. Microorganisms possess various strategies, including pigment production, to resist stress conditions in their surrounding environments. In the present study, yeast form of fungus Aureobasidium pullulans either melanized or albino was exposed to different stresses, such as salinity and antifungals (fluconazole, itraconazole, and terbinafine) as well as gamma irradiation. Results revealed that at 800 μg/ml or less of antifungal terbinafine, a positive impact was achieved on the viability of A. pullulans yeast cells, in the cultivation medium wasn't supplemented with melanin precursor (L-3,4 dihydroxyphenylalanine; L-DOPA). This enhancement in the growth yield was accompanied by increases in both internal and external melanin yields by eight and six folds, respectively. In addition, melanin is synthesized during terbinafine stress in a pathway independent from L-DOPA, but based on the excess of acetyl-CoA to tolerate squalene accumulation by feedback inhibition. Moreover, the melanized yeast cells show greater viable stability against gamma irradiation as well as pigment productivity than albino cells. The main objective of this study is to create new composites to use them as shielding materials. Theses composites based on fungal melanin's chelating activity with nanoparticles of bismuth, lead, and silver. The mass attenuation coefficient of Melanin-Bismuth composite is nearly double the mass attenuation of lead at energy = 0.662 MeV; a higher increase in mass attenuation is observed with higher gamma intensities; 1.17 and 1.33 MeV. Coupling synthesis of composites containing natural microbial products with nanotechnology is a promising field to manufacture new radiation shielding materials.

Novel mouse monoclonal antibodies specifically recognizing β-(1→3)-D-glucan antigen.

β-(1→3)-D-Glucan is an essential component of the fungal cell wall. Mouse monoclonal antibodies (mAbs) against synthetic nona-β-(1→3)-D-glucoside conjugated with bovine serum albumin (BSA) were generated using hybridoma technology. The affinity constants of two selected mAbs, 3G11 and 5H5, measured by a surface plasmon resonance biosensor assay using biotinylated nona-β-(1→3)-D-glucan as the ligand, were approximately 11 nM and 1.9 nM, respectively. The glycoarray, which included a series of synthetic oligosaccharide derivatives representing β-glucans with different lengths of oligo-β-(1→3)-D-glucoside chains, demonstrated that linear tri-, penta- and nonaglucoside, as well as a β-(1→6)-branched octasaccharide, were recognized by mAb 5H5. By contrast, only linear oligo-β-(1→3)-D-glucoside chains that were not shorter than pentaglucosides (but not the branched octaglucoside) were ligands for mAb 3G11. Immunolabelling indicated that 3G11 and 5H5 interact with both yeasts and filamentous fungi, including species from Aspergillus, Candida, Penicillium genera and Saccharomyces cerevisiae, but not bacteria. Both mAbs could inhibit the germination of Aspergillus fumigatus conidia during the initial hours and demonstrated synergy with the antifungal fluconazole in killing C. albicans in vitro. In addition, mAbs 3G11 and 5H5 demonstrated protective activity in in vivo experiments, suggesting that these β-glucan-specific mAbs could be useful in combinatorial antifungal therapy.

The impact of azole antifungal drugs on imatinib metabolism in human liver microsomes

1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism.2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole. The relevant assay was also performed to screen mechanism-based inhibitors (MBI).3. The inhibition ability of 1-OH midazolam formation from midazolam based on IC50 values was ketoconazole (0.09 µM)>itraconazole (0.31 µM)> posaconazole (0.68 µM)>voriconazole (2.10 µM) > fluconazole (8.90 µM). Similarly, the rank order of inhibitory effects on formation of N-desmethyl imatinib from imatinib was ketoconazole (4.58 µM)>itraconazole (17.45 µM)> posaconazole (31.02 µM)> voriconazole (367.9 µM) >fluconazole (1.11 mM). Posaconazole and itraconazole displayed evidence of MBI. Additionally, imatinib was also shown as a MBI of CYP3A with IC50 value of 5.40 µM against the midazolam.4. The significant difference in IC50 values of midazolam and imatinib inhibited by azole antifungal agents was observed. The role of CYP2C8 in imatinib metabolism and imatinib autoinhibits CYP3A activity may explain this difference. Our findings suggest that the azole antifungal agents might have limited impacts on imatinib exposure by CYP3A activity.

Synthesis and in vitro biological evaluation of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives as antifungal compounds fluconazole analogues

A novel series of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives was synthesized from 1-aryl-1,3-diazidopropan-2-ol derivatives and diverse alkynes using copper catalyzed azide-alkyne cycloaddition in the key step. Most of synthesized compounds showed high activity against Candida spp. strains at a 0.04–0.5 μg/mL concentration range compared to Itraconazole and Fluconazole (MIC 2.56 and 1.28 μg/mL, respectively), which were used as reference compounds. A 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivative (R1 = F and R2 = cyclopropyl) displayed an outstanding selectivity against Candida albicans and Candida krusei (MIC = 0.0075 µg/mL). Moreover, Artemia salina bioassay on 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives revealed low toxicity in this kind of compounds. In addition, molecular docking studies suggest good binding affinity of halogen atoms in some 1-aryl-1,3-diazidopropan-2-ol derivatives to HEME group present in 14-alpha demethylase (CYP51), which might explain the high antifungal activity found in these compounds.

Assessing The Knowledge and Attitudes of Group of Practicing Dentists in Saudi Arabia with Regards to Antifungal Prescriptions for The Treatment of Oral Candidiasis: A Cross-Sectional Study.

Introduction: Candida albicans is the most prevalent causative species of oral fungal infections. This study was designed to assess the knowledge of dentists who are practicing in a dental university hospital regarding antifungal prescriptions for the treatment of oral candidiasis in a Riyadh city, SA.
 Material and Methods: A self-administered questionnaire were distributed among dentists of different specialties to assess their knowledge and attitudes toward antifungal prescription for the treatment of oral candidiasis. Statistical analysis was carried out to describe the properties of the sample in terms of frequencies and distribution while chi square test was used to compare the results between groups at level of significant P value ≤0.05 using the Statistical Packages for the Social Science (SPSS) Program.
 Results: A total of 130 completed questionnaires were received. Males contributed 55.4% compared to 44.6% female counterparts. Topical antifungals were preferred by 85.4% of the participants. Topical Nystatin and oral fluconazole were the chosen antifungal agents by the dentists for the treatment of local (55.4%) and systemic (58.4%) fungal infections respectively. The challenge that was faced by most respondents (46%) is the lack of knowledge about the recommended dosage to be prescribed. Also, a significant difference in the knowledge was detected between dentists of different specialties.
 Conclusion: Most dentists will start with topical antifungal agents, nystatin suspension is the first medication of choice follow by miconazole and for the systemic antifungal agents oral fluconazole is first medication of choice. As for the adjunctive therapy most participants prescribed 0.2% chlorhexidine gluconate mouthwash.

Repurposing histone deacetylase inhibitors (HDACi) to treat Candida glabrata infections

Candida glabrata currently accounts for 25 % of all fungal cases in UK hospitals, second only to C. albicans. This number is expected to rise given the intrinsic anti-fungal resistance of this species and the difficulty in treating it. In an effort to identify novel-anti fungal targets in C. glabrata, we used comparative genomics within Saccharomycotina yeast to predict which genes are under positive selection in this species specifically. Such genes are predicted to have influenced the adaptation of C. glabrata from a free-living microbe to a human pathogen, potentially due to functional shift(s) of the proteins they encode. Our analysis predicts that histone acetylation pathways are under positive selection in C. glabrata. Thereforewe hypothesised that we could use histone deacetylase inhibitors (HDACi) to interfere with histone acetylation levels and impact C. glabrata virulence. By treating C. glabrata withbroad spectrum HDACis we show it has a reduced capacity to form biofilms, it is less well adapted to high salt conditions typically found within a human host, and most importantly, it reverts to a more anti-fungal sensitive state. RNAseq analysis indicates that HDACi treatment interferes with the C. glabrata transcriptional response to anti-fungal treatment, rendering it incapable of combating against these drugs. Furthermore, using an in vivo worm model of candidiasis, we show that HDACi treatment in conjunction with the anti-fungal fluconazole, can increase the survival rate of individuals with C. glabrata infections. Taken together our data suggest that the health threat posed by C. glabrata might be addressed by repurposing HDACi to treat this infection.