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Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45-91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p-r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC 50  = 0.6 μM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC 50  = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC 50  = 1.2 μM and SI = 20.2); compound 14h, with IC 50  = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH 3 group, with IC 50  = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Cryptococcosis is an opportunistic disease with a worldwide distribution. This disease is caused by fungi of the genus Cryptococcus , and its treatment is limited to several antifungals. In this study, the antifungal, cytotoxic and mutagenic properties of ethanol extracts from the bark and leaves of Annona coriacea were evaluated against the standard Cryptococcus species and clinical yeast specimens. Both extracts of A. coriacea showed inhibitory activity of 1.5 mg/mL for all of the yeasts tested. The number of viable cells at the lowest tested concentration was 0.187 mg/mL. The extracts that were tested showed inhibitory activity and reduced the fungal growth of the Cryptococcus gattii species and Cryptococcus neoformans species complexes, suggesting that this plant may be an effective alternative treatment for cryptococcosis.

Objective: To evaluate the treatment compliance of patients with paracoccidioidomycosis., Methods: We studied 188 patients with paracoccidioidomycosis admitted to a tertiary referral hospital in the Central-West Region of Brazil from 2000 to 2010, to assess their compliance to treatment. In order to be considered compliant, patients needed to present two established criteria: (1) receive medicines from the pharmacy, and (2) achieve a self-reported utilization of at least 80% of the dispensed antifungal compounds prescribed since their previous appointment., Results: Most patients were male (95.7%), had the chronic form of the disease (94.2%), and were treated with cotrimoxazole (86.2%). Only 44.6% of patients were treatment compliant. The highest loss to follow-up was observed in the first 4 months of treatment (p < 0.02). Treatment compliance was higher for patients with than for those without pulmonary involvement (OR: 2.986; 95%CI 1.351-6.599), and higher for patients with than without tuberculosis as co-morbidity (OR: 2.763; 95%CI 1.004-7.604)., Conclusions: Compliance to paracoccidioidomycosis treatment was low, and the period with the highest loss to follow-up corresponds to the first four months. Pulmonary paracoccidioidal involvement or tuberculosis comorbidity predicts a higher compliance to paracoccidioidomycosis therapy.

We describe the characterization of IETI, the first trypsin inhibitor purified from Inga edulis, a tree widely distributed in Brazil. Two-step chromatography was used to purify IETI, a protein composed of a single peptide chain of 19,685.10 Da. Amino-terminal sequencing revealed that IETI shows homology with the Kunitz family, as substantiated by its physical-chemical features, such as its thermal (up to 70 °C) and wide-range pH stability (from 2 to 10), and the value of its dissociation constant (6.2 nM). IETI contains a single reactive site for trypsin, maintained by a disulfide bridge; in the presence of DTT, its inhibitory activity was reduced in a time- and concentration-dependent manner. IETI presented activity against Candida ssp., including C. buinensis and C. tropicalis. IETI inhibitory activity triggered yeast membrane permeability, affecting cell viability, thus providing support for the use of IETI in further studies for the control of fungal infections.

Introduction: We describe the clinical and laboratorial features of oral candidiasis in 66 HIV-positive patients., Methods: Polymerase chain reaction-based techniques were performed for differentiation of Candida spp. isolated from patients at a public teaching hospital in Midwest Brazil., Results: Oral lesions, mainly pseudomembranous, were significantly related to higher levels of immunosuppression. Of 45 Candida isolates, 66.7% were C. albicans. Most of the isolates were susceptible to the antifungal drugs tested., Conclusions: Oral lesions were associated with higher immunosuppression levels. Lower susceptibility to antifungals by non-albicans isolates supports the importance of surveillance studies using susceptibility tests to aid in the treatment.

The aim of this study was to identify Candida spp. isolated from candiduria episodes at a tertiary hospital in the Midwest region of Brazil, and to determine their susceptibility profiles to antifungal compounds. From May 2011 to April 2012, Candida spp. isolated from 106 adult patients with candiduria admitted to the University Hospital of the Federal University of Mato Grosso do Sul were evaluated. Both, species identification and susceptibility testing with fluconazole-FLC, voriconazole-VRC, and amphotericin B-AmB were carried out using the Vitek 2. To discriminate species of the C. parapsilosis complex, a RAPD-PCR technique using the RPO2 primer was performed. From the total of 106 isolates, 42 (39.6%) C. albicans and 64 (60.4%) Candida non-albicans (CNA) - 33 C. tropicalis, 18 C. glabrata, 5 C. krusei, 4 C. parapsilosis sensu stricto, 2 C. kefyr, 1 C. lusitaniae, and 1 C. guilliermondii were identified. All isolates were susceptible to AmB and VRC, whereas all C. glabrata isolates presented either resistance (5.6%) or dose-dependent susceptibility (94.4%) to FLC. The study of Candida spp. and their resistance profiles may help in tailoring more efficient therapeutic strategies for candiduria.

Introduction: Incidence and antifungal susceptibility of Candida spp. from two teaching public hospitals are described., Methods: The minimum inhibitory concentrations of fluconazole, voriconazole, itraconazole, and amphotericin B were determined using Clinical Laboratory Standard Institute broth microdilution and genomic differentiation using PCR., Results: Of 221 Candida isolates, 50.2% were obtained from intensive care unit patients; 71.5% were recovered from urine and 9.1% from bloodstream samples. Candida parapsilosis sensu stricto was the most common candidemia agent., Conclusions: We observed variations in Candida species distribution in hospitals in the same geographic region and documented the emergence of non-C. albicans species resistant to azoles.

Background: Recent decades have seen a global emergence of candidaemia caused by non-Candida albicans Candida species, particularly the Candida parapsilosis complex., Aims: To evaluate the clinical features and antifungal susceptibility profiles of isolates belonging to the C. parapsilosis species complex in patients with candidaemia in a midwestern Brazilian tertiary-care teaching hospital., Methods: Yeast identification was performed using an automated Vitek 2 Compact system. PCR-RFLP was employed for species differentiation., Results: Five cases of infection by C. parapsilosis sensu stricto and two by Candida orthopsilosis were found. Of the seven cases, five were adult patients undergoing haemodialysis. The only isolate of C. parapsilosis sensu stricto resistant to fluconazole (MIC=8μg/ml) was obtained from a patient on a long-term regimen with this drug. This was the only patient who evolved to death., Conclusions: Resistance to antifungal agents poses a therapeutic challenge, especially for non-C. albicans Candida species, and requires continuous monitoring using susceptibility tests because resistance in vitro can be predictive of treatment failure. In the present study, in vitro antifungal susceptibility proved consistent with clinical outcome., (Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

We evaluated the antimicrobial activity of Aspilia latissima - an abundant plant from the Brazilian Pantanal region - against Candida albicans, Candida parapsilosis, Candida krusei, Candida tropicalis, Pseudomonas aeruginosa, Enterococcus faecalis, Escherichia coli and Staphylococcus aureus. The crude extracts and fractions showed activity in all tested microorganisms. The chloroform fraction of the leaves and roots showed the most antimicrobial activity against S. aureus, with an MIC of 500 μg/mL. This fraction was submitted to bioautographic assays to characterize the activity of the compounds. Two bands from the leaves (L-A and L-B) and three bands from the roots (R-C, R-D and R-E) were bioactive. Within the root-derived bands, the terpene derivatives stigmasterol, kaurenoic acid and kaura-9(11), 16-dien-18-oic acid were identified. Antibiotic activity of A. latissima is reported for the first time.

To describe the incidence and susceptibility profile of Candida bloodstream infections in a tertiary-care hospital, we performed a retrospective observational study from 1998 to 2007. Comorbidities and risk factors were compiled from all cases. In vitro susceptibility testing to fluconazole, itraconazole, voriconazole, and amphotericin B was performed for 100 isolates, and caspofungin was tested for C. parapsilosis complex. In a ten-year evaluation of candidemias, 44 % were caused by C. albicans, and species of the C. parapsilosis complex were the second most frequent agents (37 %). Other species presented lower incidences (C. tropicalis, 13 %, C. glabrata, 5 %, and C. krusei, 1 %). Neither C. dubliniensis nor C. metapsilosis were observed in this study. C. orthopsilosis (3 %) and C. parapsilosis stricto sensu (34 %) were also found. Species distribution was independent of catheterization, mechanical ventilation, or previous use of antifungals or corticoids. Parenteral nutrition administration was strongly related to C. glabrata infection, and the highest mortality (80 %) was observed in patients infected by this species. All C. albicans isolates showed high susceptibility to all tested drugs. However, two C. parapsilosis stricto sensu isolates presented high minimum inhibitory concentration (MIC) (4 mg/L each) to fluconazole, and one exhibited voriconazole MIC of 0.25 mg/L, highlighting the cross-resistance to these azoles. All isolates of C. tropicalis and C. glabrata showed no resistance to any drug tested. No difference was noted between C. parapsilosis and C. orthopsilosis susceptibilities to caspofungin. Our results suggest that resistance to amphotericin B, fluconazole, voriconazole, itraconazole, and caspofungin in Brazilian Candida bloodstream isolates is still uncommon.

The therapeutic efficacy of amphotericin B and voriconazole alone and in combination with one another were evaluated in immunodeficient mice (BALB/c-SCID) infected with a fluconazole-resistant strain of Cryptococcus neoformans var. grubii. The animals were infected intravenously with 3 × 10(5) cells and intraperitoneally treated with amphotericin B (1.5 mg/kg/day) in combination with voriconazole (40 mg/kg/days). Treatment began 1 day after inoculation and continued for 7 and 15 days post-inoculation. The treatments were evaluated by survival curves and yeast quantification (CFUs) in brain and lung tissues. Treatments for 15 days significantly promoted the survival of the animals compared to the control groups. Our results indicated that amphotericin B was effective in assuring longest-term survival of infected animals, but these animals still harbored the highest CFU of C. neoformans in lungs and brain at the end of the experiment. Voriconazole was not as effective alone, but in combination with amphotericin B, it prolonged survival for the second-longest time period and provided the lowest colonization of target organs by the fungus. None of the treatments were effective in complete eradication of the fungus in mice lungs and brain at the end of the experiment.

The aim of our study was to perform molecular typing on 25 clinical samples of Candida spp that were isolated from children with candidemia who were hospitalized in the neonatal intensive care unit of a university hospital between 1998 and 2006. Demographic and clinical data were obtained from the medical records to ascertain the clinical and epidemiological characteristics. Yeast identification was done using conventional methods and susceptibility to antifungals was assessed using a microdilution method. The genetic profile was determined using the RAPD-PCR technique. Candida albicans (11; 44%) and Candida parapsilosis (10; 40%) were the species most frequently isolated. Seventeen (68%) of the newborns weighed less than 1,500 g. Prematurity (92%) and use of a central venous catheter (100%) were the risk conditions with greatest association. Nineteen patients (76%) died. Only one strain of Candida parapsilosis showed dose-dependent sensitivity to fluconazole. Molecular analysis showed 11 distinct genetic patterns. An epidemiological relationship was seen in only two cases, thus suggesting the same source of infection.