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1.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803717

RESUMO

New fluconazole-loaded, 6-Anhydro-α-l-Galacto-ß-d-Galactan hydrogels incorporated with nanohydroxyapatite were prepared and their physicochemical features (XRD, X-ray Diffraction; SEM-EDS, Scanning Electron Microscopy-Energy Dispersive X-ray Spectroscopy; ATR-FTIR, Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy), fluconazole release profiles and enzymatic degradation were determined. Antifungal activity of pure fluconazole was tested using Candida species (C. albicans, C. tropicalis, C. glabarata), Cryptococcus species (C. neoformans, C. gatti) and Rhodotorula species (R. mucilaginosa, R. rubra) reference strains and clinical isolates. Standard microdilution method was applied, and fluconazole concentrations of 2-250 µg/mL were tested. Moreover, biofilm production ability of tested isolates was tested on the polystyrene surface at 28 and 37 ± 0.5 °C and measured after crystal violet staining. Strains with the highest biofilm production ability were chosen for further analysis. Confocal microscopy photographs were taken after live/dead staining of fungal suspensions incubated with tested hydrogels (with and without fluconazole). Performed analyses confirmed that polymeric hydrogels are excellent drug carriers and, when fluconazole-loaded, they may be applied as the prevention of chronic wounds fungal infection.


Assuntos
Antifúngicos/farmacologia , Durapatita/química , Fluconazol/farmacologia , Galactanos/química , Nanopartículas/química , Cicatrização/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Doença Crônica , Fungos/efeitos dos fármacos , Hidrogéis/química , Cinética , Testes de Sensibilidade Microbiana , Muramidase/metabolismo , Nanopartículas/ultraestrutura , Plâncton/efeitos dos fármacos , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Tempo , Difração de Raios X
2.
BMC Infect Dis ; 21(1): 375, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882845

RESUMO

BACKGROUND: Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. METHOD: This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day). RESULTS: Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. CONCLUSION: Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Cryptococcus neoformans/imunologia , Ácido Desoxicólico/administração & dosagem , Fluconazol/administração & dosagem , HIV , Meningite Criptocócica/complicações , Meningite Criptocócica/tratamento farmacológico , Atenção Primária à Saúde , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Cryptococcus neoformans/isolamento & purificação , Ácido Desoxicólico/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluconazol/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Mianmar/epidemiologia , Flebite/induzido quimicamente , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
3.
Pestic Biochem Physiol ; 173: 104784, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33771264

RESUMO

Mefentrifluconazole is the first product of a new sub-class of triazoles fungicides, i.e., the isopropanol triazoles, with the broad spectrum and high activity. In this study, the potential and biochemical activities of mefentrifluconazole against Botrytis cinerea were investigated. The frequency distribution of all EC50 values of mefentrifluconazole against mycelial growth and germ tube elongation of 106 isolates formed unimodal curve, with the mean EC50 values of 0.124 ± 0.025 and 0.015 ± 0.008 µg/mL, respectively. The effect of mefentrifluconazole against gray mold was determined on detached leaves of cucumber in vivo, the treatment of mefentrifluconazole at 200 µg/mL provided 100% preventative efficacy and 72.7% curative efficacy. No evident correlation was detected between the sensitivity of B. cinerea to mefentrifluconazole and that to tebuconazole, difenoconazole, myclobutanil, hexaconazole, triadimefon, flusilazole and pyrisoxazole (P > 0.05). Mefentrifluconazole treatment resulted in the increase of mycelium branch, the decrease of ergosterol content and the changes of the permeability of cell membrane. These studies evaluated the potential of mefentrifluconazole to control gray mold and helped us to understand the possible biochemical activity of mefentrifluconazole against B.cinerea.


Assuntos
Botrytis , Fungicidas Industriais , Antifúngicos/farmacologia , Fluconazol/análogos & derivados , Fungicidas Industriais/farmacologia , Doenças das Plantas
4.
Indian J Ophthalmol ; 69(4): 987-989, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33727474

RESUMO

A 42-year-old male patient presented with profound impairment of vision in both eyes, just as he was recovering from COVID-19. A known diabetic and hypertensive, he suffered from COVID-19 pneumonia further complicated by ARDS, septicaemia and acute kidney injury. His vision on presentation was finger counting close to face bilaterally with multiple, yellowish lesions at the posterior pole. Based on the clinical findings and previous blood culture report, it was diagnosed as candida retinitis and treated with oral and intravitreal anti-fungals. The lesions were regressing at follow-up. This is a post COVID-19 presumed candida retinitis case report.


Assuntos
/diagnóstico , Candidíase/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Infecções Oportunistas/diagnóstico , Retinite/diagnóstico , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Fluconazol/uso terapêutico , Humanos , Injeções Intravítreas , Masculino , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia , Retinite/tratamento farmacológico , Retinite/microbiologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Voriconazol/uso terapêutico
5.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33688802

RESUMO

Introduction. Trichosporon asahii has been recognized as an opportunistic agent having a limited sensitivity to antifungal treatment.Hypothesis/Gap Statement. Molecular mechanisms of azole resistance have been rarely reported for Trichosproron asahii. Similar to other fungi, we hypothesized that both ERG11 gene mutation and efflux pumps genes hyper-expression were implicated.Aim. The current work aimed to study the sensitivity of clinical T. asahii isolates to different antifungal agents and to explore their resistance mechanisms by molecular methods including real-time PCR and gene sequencing.Methods. The sensitivity of T. asahii isolates to fluconazole, amphotericin B and voriconazole was estimated by the Etest method. Real-time PCR was used to measure the relative expression of Pdr11, Mdr and ERG11 genes via the ACT1 housekeeping gene. Three pairs of primers were also chosen to sequence the ERG11 gene. This exploration was followed by statistical study including the receiver operating characteristic (ROC) curve analysis to identify a relationship between gene mean expression and the sensitivity of isolates.Results. In 31 clinical isolates, the resistance frequencies were 87, 16.1 and 3.2 %, respectively, for amphotericin B, fluconazole and voriconazole. Quantitative real-time PCR demonstrated that only Mdr over-expression was significantly associated with FCZ resistance confirmed by univariate statistical study and the ROC curve analysis (P <0.05). The ERG11 sequencing revealed two mutations H380G and S381A in TN325U11 (MIC FCZ=8 µg ml-1) and H437R in TN114U09 (MIC FCZ=256 µg ml-1) in highly conserved regions (close to the haem-binding domain) but their involvement in the resistance mechanism has not yet been assigned.Conclusion. T. asahii FCZ resistance mechanisms are proven to be much more complex and gene alteration sequence and/or expression can be involved. Only Mdr gene over-expression was significantly associated with FCZ resistance and no good correlation was observed between FCZ and VCZ MIC values and relative gene expression. ERG11 sequence alteration seems to play a major role in T. asahii FCZ resistance mechanism but their involvement needs further confirmation.


Assuntos
Antifúngicos/farmacologia , Basidiomycota , Sistema Enzimático do Citocromo P-450/genética , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Tricosporonose/microbiologia , Anfotericina B/farmacologia , Basidiomycota/efeitos dos fármacos , Basidiomycota/genética , Fluconazol/farmacologia , Humanos , Voriconazol/farmacologia
6.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33669913

RESUMO

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.


Assuntos
Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Frutose/farmacologia , Proteínas Fúngicas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Candida albicans/citologia , Carbono/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Frutose/sangue , Proteínas de Fluorescência Verde/metabolismo , Frações Subcelulares/metabolismo
7.
Isr Med Assoc J ; 23(2): 116-120, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33595218

RESUMO

BACKGROUND: Extremely preterm infants are at high risk for mortality and morbidity including neurodevelopmental impairment from invasive Candida infections. Prophylactic antifungal therapy has been shown to reduce both colonization and invasive candidemia in high-risk preterm infants. Prophylactic treatment should be started in the first 48 to 72 hours after birth to extremely low birth weight (ELBW) infants (weighing ≤ 1000 grams at birth) or below 27 weeks gestation age with risk factors, or in any NICU with moderate (5-10%) or high (≥ 10%) rates of invasive candidiasis. Studies demonstrated the benefits of fluconazole prophylaxis regarding its safety of the short-term and long-term without the development of fungal resistance. Empiric antifungal therapy may lower mortality and improve outcomes.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Invasiva/prevenção & controle , Doenças do Prematuro/prevenção & controle , Antifúngicos/efeitos adversos , Candidíase Invasiva/mortalidade , Farmacorresistência Fúngica , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/microbiologia , Doenças do Prematuro/mortalidade , Unidades de Terapia Intensiva Neonatal , Seleção de Pacientes
8.
Am J Vet Res ; 82(3): 171-180, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33629900

RESUMO

OBJECTIVE: To assess the pharmacokinetics and opioid effects of methadone after administration of multiple doses by means of 2 dosing regimens of methadone-fluconazole-naltrexone. ANIMALS: 12 healthy Beagles. PROCEDURES: Dogs were randomly allocated (6 dogs/group) to receive 1 of 2 oral dosing regimens of methadone-fluconazole-naltrexone. Treatment 1 doses were administered at 0 (methadone-to-fluconazole-to-naltrexone ratio of 1:5:0.25 mg/kg), 14 (1:5:0.25), 24 (0.5:2.5:0.125), and 38 (0.5:2.5:0.125) hours. Treatment 2 doses were administered at 0 (1:5:0.25), 4 (0.5:2.5:0.125), 10 (0.5:2.5:0.125), and 24 (0.5:2.5:0.125) hours. Blood samples, rectal temperatures, and von Frey antinociceptive measurements were obtained at designated times. RESULTS: Compared with baseline, temperatures significantly decreased for treatment 1 group dogs at 2 to ≥ 4 hours and from 16 to ≥ 50 hours (12 hours after last dose) and for treatment 2 group dogs at 2 to ≥ 36 hours (12 hours after last dose), when trough methadone concentrations were ≥ 21.3 ng/mL. Antinociception occurred after the first dose but was not maintained throughout the study. Lesions were noted in some dogs at the application site of the von Frey device. Naltrexone and ß-naltrexol were sporadically detected in plasma, and naltrexone glucuronide was consistently detected. CONCLUSIONS AND CLINICAL RELEVANCE: Opioid effects were noted after oral administration of the first dose, and data suggested that administering a second dose 6 hours later and every 12 hours thereafter was necessary to maintain opioid effects. Antinociception may have been lost because dogs became averse or hyperalgesic to the von Frey device, such that the antinociception model used here may not be robust for repeated measurements in dogs.


Assuntos
Doenças do Cão , Transtornos Relacionados ao Uso de Opioides , Administração Oral , Analgésicos , Analgésicos Opioides/uso terapêutico , Animais , Doenças do Cão/tratamento farmacológico , Cães , Fluconazol , Humanos , Metadona , Naltrexona , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico
9.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33560202

RESUMO

The genus Candida spp. has been highlighted as one of the main etiological agents causing fungal infections, with Candida albicans being the most prominent, responsible for most cases of candidemia. Due to its capacity for invasion and tissue adhesion, it is associated with the formation of biofilms, mainly in the environment and hospital devices, decreasing the effectiveness of available treatments. The repositioning of drugs, which is characterized by the use of drugs already on the market for other purposes, together with molecular-docking methods can be used aiming at the faster development of new antifungals to combat micro-organisms. This study aimed to evaluate the antifungal effect of diazepam on mature C. albicans biofilms in vitro and its action on biofilm in formation, as well as its mechanism of action and interaction with structures related to the adhesion of C. albicans, ALS3 and SAP5. To determine the MIC, the broth microdilution test was used according to protocol M27-A3 (CLSI, 2008). In vitro biofilm formation tests were performed using 96-well plates, followed by molecular-docking protocols to analyse the binding agent interaction with ALS3 and SAP5 targets. The results indicate that diazepam has antimicrobial activity against planktonic cells of Candida spp. and C. albicans biofilms, interacting with important virulence factors related to biofilm formation (ALS3 and SAP5). In addition, treatment with diazepam triggered a series of events in C. albicans cells, such as loss of membrane integrity, mitochondrial depolarization and increased production of EROs, causing DNA damage and consequent cell apoptosis.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Diazepam/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , Candida/patogenicidade , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismo
10.
ABCS health sci ; 46: e021203, 09 fev. 2021. tab
Artigo em Inglês | LILACS | ID: biblio-1147180

RESUMO

INTRODUCTION: The resistance of fungal species to drugs usually used in clinics is of great interest in the medical field. OBJECTIVE: To evaluate susceptibility and in vitro response of species of Trichophyton spp. to antifungal drugs of interest in clinical medicine. METHODS: 12 samples of clinical isolates from humans were used, nine of T. mentagrophytes and three of T. tonsurans. Susceptibility tests were performed according to the agar diffusion (AD) and broth microdilution (BM) methods. RESULTS: In the AD method, the species T. tonsurans presented a percentage of sensitivity of 33% in relation to amphotericin B and 66% to itraconazole, with 100% resistance to ketoconazole and fluconazole. T. mentagrophytes also showed 100% resistance to ketoconazole in this technique, with 11% sensitivity to ketoconazole, 22% to itraconazole and 22% of samples classified as sensitive dose dependent. In the MC method, the species T. tonsurans presented a sensitivity percentage of 66%, 55% and 33% in relation to ketoconazole, fluconazole and itraconazole, respectively. The T. mentagrophytes species presented sensitivity percentages of 11%, 11%, 33% and 55% for amphotericin B, itraconazole, ketoconazole and fluconazole, respectively. CONCLUSION: There was resistance in vitro of the species of T. mentagrophytes and T. tonsurans against the antifungal fluconazole and relative resistance against ketoconazole in the AD method. In BM, however, important percentages of sensitivity were observed for the two species analyzed in relation to the antifungals fluconazole and ketoconazole when compared to itraconazole and amphotericin B.


INTRODUÇÃO: A resistência de espécies fúngicas às drogas usualmente empregadas no meio clínico é motivo de grande interesse na área médica. OBJETIVO: Avaliar susceptibilidade e resposta in vitro de espécies de Trichophyton spp. a drogas antifúngicas de interesse em clínica médica. MÉTODOS: Foram utilizadas 12 amostras de isolados clínicos de humanos, sendo nove de T. mentagrophytes e três de T. tonsurans. Foram realizados testes de susceptibilidade segundo os métodos de difusão em ágar (DA) e microdiluição em caldo (MC). RESULTADOS: No método de DA, a espécie T. tonsurans apresentou percentual de sensibilidade de 33% em relação à anfotericina B e de 66% ao itraconazol, com 100% de resistência frente ao cetoconazol e ao fluconazol. A espécie T. mentagrophytes também apresentou 100% de resistência frente ao cetoconazol nesta técnica, com 11% de sensibilidade ao cetoconazol, 22% ao itraconazol e 22% das amostras classificadas como sensível dose dependente. No método de MC, a espécie T. tonsurans apresentou percentual de sensibilidade de 66%, 55% e 33% em relação ao cetoconazol, fluconazol e itraconazol, respectivamente. A espécie T. mentagrophytes apresentou percentuais de sensibilidade de 11%, 11%, 33% e 55% para anfotericina B, itraconazol, cetoconazol e fluconazol, respectivamente. CONCLUSÃO: Houve resistência in vitro das espécies do T. mentagrophytes e T. tonsurans frente ao antifúngico fluconazol e resistência relativa frente ao cetoconazol no método de DA. Na MC, no entanto, foram observados importantes percentuais de sensibilidade das duas espécies analisadas frente aos antifúngicos fluconazol e cetoconazol quando comparadas ao itraconazol e à anfotericina B.


Assuntos
Trichophyton/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica , Suscetibilidade a Doenças/microbiologia , Antifúngicos/farmacologia , Tinha/microbiologia , Tinha/tratamento farmacológico , Contagem de Colônia Microbiana , Fluconazol/farmacologia , Anfotericina B/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia
11.
Drug Dev Ind Pharm ; 47(2): 246-258, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33416006

RESUMO

The aim of this work was to prepare and optimize mucoadhesive nanostructured lipid carrier (NLC) impregnated with fluconazole for better management of oral candidiasis. The NLCs were fabricated using an emulsification/sonication technique. The nanoparticles consisted of stearic acid, oleic acid, Pluronic F127, and lecithin. Box-Behnken design, artificial neural networking, and variable weight desirability were employed to optimize the joint effect of drug concentration in the drug/lipid mixture, solid lipid concentration in the solid/liquid lipid mixture, and surfactant concentration in the total mixture on size and entrapment. The optimized NLCs were coated with chitosan. The nanoparticles were characterized by surface charge, spectroscopic, thermal, morphological, mucoadhesion, release, histopathological, and antifungal properties. The nanoparticles are characterized by a particle size of 335 ± 13.5 nm, entrapment efficiency of 73.1 ± 4.9%, sustained release, minor histopathological effects on rabbit oral mucosa, and higher fungal inhibition efficiency for an extended period of time compared with fluconazole solution. Coating the nanoparticles with chitosan increased its adhesion to rabbit oral buccal mucosa and improved its anti-candidiasis activity. It is concluded that mucoadhesive lipid-based nanoparticles amplify the effect of fluconazole on Candida albicans in vitro. This finding warrants pre-clinical and clinical studies in oral candidiasis disease models to corroborate in vitro findings.


Assuntos
Candidíase Bucal , Fluconazol/farmacologia , Lipídeos/química , Nanopartículas , Nanoestruturas , Animais , Candidíase Bucal/tratamento farmacológico , Portadores de Fármacos , Fluconazol/administração & dosagem , Fluconazol/química , Aprendizado de Máquina , Tamanho da Partícula , Coelhos
12.
J Med Chem ; 64(2): 1116-1126, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33356256

RESUMO

Due to the evolution and development of antifungal drug resistance, limited efficacy of existing drugs has led to high mortality in patients with serious fungal infections. To develop novel antifungal therapeutic strategies, herein a series of carboline fungal histone deacetylase (HDAC) inhibitors were designed and synthesized, which had potent synergistic effects with fluconazole against resistant Candida albicans infection. In particular, compound D12 showed excellent in vitro and in vivo synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of C. albicans by blocking morphological mutual transformation and inhibiting biofilm formation. Mechanism studies revealed that the reversion of drug resistance was due to downregulation of the expression of the azole target gene ERG11 and efflux gene CDR1. Taken together, fungal HDAC inhibitor D12 offered a promising lead compound for combinational treatment of azole-resistant candidiasis.


Assuntos
Azóis/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Carbolinas/síntese química , Carbolinas/uso terapêutico , Farmacorresistência Fúngica/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Biofilmes/efeitos dos fármacos , Candida albicans/enzimologia , Candidíase/microbiologia , Carbolinas/toxicidade , Quimioterapia Combinada , Feminino , Fluconazol/farmacologia , Proteínas Fúngicas/efeitos dos fármacos , Fungos/efeitos dos fármacos , Fungos/enzimologia , Inibidores de Histona Desacetilases/toxicidade , Humanos , Fígado/patologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
13.
Artigo em Inglês | MEDLINE | ID: mdl-32942047

RESUMO

Independent studies from our group and others have provided evidence that sphingolipids (SLs) influence the antimycotic susceptibility of Candida species. We analyzed the molecular SL signatures of drug-resistant clinical isolates of Candida auris, which have emerged as a global threat over the last decade. This included Indian hospital isolates of C. auris, which were either resistant to fluconazole (FLCR) or amphotericin B (AmBR) or both drugs. Relative to Candida glabrata and Candida albicans strains, these C. auris isolates were susceptible to SL pathway inhibitors such as myriocin and aureobasidin A, suggesting that SL content may influence azole and AmB susceptibilities. Our analysis of SLs confirmed the presence of 140 SL species within nine major SL classes, namely the sphingoid bases, Cer, αOH-Cer, dhCer, PCer, αOH-PCer, αOH-GlcCer, GlcCer, and IPC. Other than for αOH-GlcCer, most of the SLs were found at higher concentrations in FLCR isolates as compared to the AmBR isolates. SLs were at intermediate levels in FLCR + AmBR isolates. The observed diversity of molecular species of SL classes based on fatty acyl composition was further reflected in their distinct specific imprint, suggesting their influence in drug resistance. Together, the presented data improves our understanding of the dynamics of SL structures, their synthesis, and link to the drug resistance in C. auris.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida/metabolismo , Farmacorresistência Fúngica Múltipla/fisiologia , Fluconazol/farmacologia , Glucosilceramidas/metabolismo , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candida albicans/metabolismo , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Candida glabrata/metabolismo , Candidíase/microbiologia , Cromatografia Líquida , Depsipeptídeos/farmacologia , Farmacorresistência Fúngica Múltipla/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Glucosilceramidas/classificação , Glucosilceramidas/isolamento & purificação , Humanos , Lipidômica/métodos , Espectrometria de Massas em Tandem
14.
Pestic Biochem Physiol ; 171: 104737, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357559

RESUMO

In the European Union (EU), regulation of sterol demethylation inhibiting (DMI) fungicides is tightened due to their suspected endocrine disrupting properties. However, the new DMI fungicide mefentrifluconazole was reported to have high fungicidal activity with minimal adverse side effects. In addition, some evidence suggests inconsistent cross resistance between mefentrifluconazole and other azoles. In this study, mefentrifluconazole and other triazoles were examined for activity to select pathogens sensitive or resistant to DMIs using mycelial growth tests on fungicide-treated culture medium or spray trials using cucumber plants. Cross-resistance was confirmed for all of the fungal species tested but activity levels varied. The sensitivity of Monilinia fructicola from peach to mefentrifluconazole was higher compared to other DMIs. In contrast, the inhibitory activity of mefentrifluconazole was equal or slightly inferior compared to difenoconazole, tebuconazole, propiconazole in Colletotrichum spp., Alternaria alternaria sp. complex and Cercospora beticola isolated from peach and sugar beet, respectively. Similar tendencies (i.e. equal or slightly inferior activity and cross-resistance) were observed for cucumber powdery mildew (Podosphaera xanthii) resistant to triflumizole, myclobutanil, and difenoconazole. Despite cross-resistance to other DMIs, mefentrifluconazole is a promising fungicide for fungal disease control on peach and other crops, with a reportedly more favorable toxicity profile.


Assuntos
Fungicidas Industriais , Ascomicetos , Farmacorresistência Fúngica , Fluconazol/análogos & derivados , Fungicidas Industriais/farmacologia
16.
Nat Commun ; 11(1): 6429, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353950

RESUMO

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.


Assuntos
Azóis/farmacologia , Candida/patogenicidade , Oxindois/farmacologia , Animais , Antifúngicos/análise , Antifúngicos/química , Antifúngicos/farmacologia , Azóis/análise , Azóis/química , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismo , Deleção de Genes , Humanos , Camundongos , Oxindois/química , Virulência/efeitos dos fármacos
17.
BMC Infect Dis ; 20(1): 827, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176724

RESUMO

BACKGROUND: Candida auris is a new pathogen called "superbug fungus" which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic review and meta-analysis was undertaken to determine the epidemic situation, drug resistance patterns and mortality of C. auris. METHODS: We systematically searched studies on the clinical report of Candida auris in Pubmed, Embase and Cochrane databases until October 6, 2019. A standardized form was used for data collection, and then statics was performed with STATA11.0. RESULTS: It showed that more than 4733 cases of C. auris were reported in over 33 countries, with more cases in South Africa, United States of America, India, Spain, United Kingdom, South Korea, Colombia and Pakistan. C. auirs exhibited a decrease in case count after 2016. Clade I and III were the most prevalent clades with more cases reported and wider geographical distribution. Blood stream infection was observed in 32% of the cases, which varied depending on the clades. Resistance to fluconazole, amphotericin B, caspofungin, micafungin and anidulafungin in C. auris were 91, 12, 12.1, 0.8 and 1.1%. The overall mortality of C. auris infection was 39%. Furthermore, subgroup analyses showed that mortality was higher in bloodstream infections (45%), and lower in Europe (20%). CONCLUSIONS: Over 4000 cases of C. auris were reported in at least 33 countries, which showed high resistance to fluconazole, moderate resistance to amphotericin B and caspofungin, high sensitivity to micafungin and anidulafungin. The crude mortality for BSI of C. auris was 45% which was similar to some drug-resistant bacteria previously reported. In conclusion, C. auris displayed similar characteristics to some drug resistance organisms. This study depicts several issues of C. auris that are most concerned, and is of great significance for the clinical management.


Assuntos
Candida/efeitos dos fármacos , Candidíase/epidemiologia , Candidíase/mortalidade , Anfotericina B/uso terapêutico , Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Candida/classificação , Candida/genética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Caspofungina/uso terapêutico , Farmacorresistência Fúngica Múltipla/efeitos dos fármacos , Fluconazol/uso terapêutico , Humanos , Micafungina/uso terapêutico , Prevalência
18.
Rev Soc Bras Med Trop ; 53: e20200249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33111910

RESUMO

INTRODUCTION: Coccidioidomycosis, a disease caused by Coccidioides immitis or Coccidioides posadasii, is endemic in arid climatic regions in Northeast Brazil. Its prevalence is higher among young adult males living in rural areas. Existing literature about this disease in Ceará, a Northeast Brazilian state, are scarce. Here, we aimed to outline the clinical and epidemiological profiles, radiological patterns, and therapeutic responses of patients with coccidioidomycosis in a reference center in Ceará, Brazil. METHODS: This is a descriptive study with quantitative analysis. Patients who underwent medical follow-up in São José Hospital of Infectious Diseases and received confirmed mycological diagnosis of coccidioidomycosis between January, 2007 and December 2017 were included. Epidemiological, clinical, radiological, and therapeutic response data were collected from medical charts. RESULTS: Thirty patients were included. The patients were males with median age of 30 years, and 73% were considered to have high-risk exposure to Coccidioides owing to professional activities. Cough (96.7%), dyspnea (63.3%), fever (86.7%), and pleuritic pain (60%) were the most prevalent clinical manifestations. Interstitial pattern (91.3%) was the most frequent pulmonary radiological finding. Fluconazole, amphotericin B, and itraconazole were administered for treatment (in 82.1%, 42.8%, and 21.4% of cases, respectively). A favorable outcome was observed in 83.8% of patients. CONCLUSIONS: Coccidioidomycosis was more prevalent in the central and southern regions of the State of Ceará. Understanding the local epidemiology and clinical manifestations of the disease, in addition to the pulmonary radiologic findings, may aid the early detection of coccidioidomycosis and facilitate early diagnosis.


Assuntos
Coccidioidomicose , Adulto , Brasil/epidemiologia , Coccidioides , Coccidioidomicose/diagnóstico por imagem , Coccidioidomicose/tratamento farmacológico , Fluconazol , Humanos , Itraconazol
19.
Am J Vet Res ; 81(9): 699-707, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33112167

RESUMO

OBJECTIVE: To determine perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. ANIMALS: 43 healthy female dogs. PROCEDURES: Dogs were randomly assigned to receive the methadone-fluconazole-naltrexone formulation at 1 of 2 dosages (0.5 mg/kg, 2.5 mg/kg, and 0.125 mg/kg, respectively, or 1.0 mg/kg, 5.0 mg/kg, and 0.25 mg/kg, respectively, PO, q 12 h, starting the evening before surgery; n = 15 each) or methadone alone (0.5 mg/kg, SC, q 4 h starting the morning of surgery; 13). Dogs were sedated with acepromazine, and anesthesia was induced with propofol and maintained with isoflurane. A standard ovariohysterectomy was performed by experienced surgeons. Sedation and pain severity (determined with the Glasgow Composite Pain Scale-short form [GCPS-SF]) were scored for 48 hours after surgery. Rescue analgesia was to be provided if the GCPS-SF score was > 6. Dogs also received carprofen starting the day after surgery. RESULTS: None of the dogs required rescue analgesia. The highest recorded GCPS-SF score was 4. A significant difference in GCPS-SF score among groups was identified at 6:30 am the day after surgery, but not at any other time. The most common adverse effect was perioperative vomiting, which occurred in 11 of the 43 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of a methadone-fluconazole-naltrexone formulation at either of 2 dosages every 12 hours (3 total doses) was as effective as SC administration of methadone alone every 4 hours (4 total doses) in dogs undergoing routine ovariohysterectomy. Incorporation of naltrexone in the novel formulation may provide a deterrent to human opioid abuse or misuse.


Assuntos
Analgesia , Doenças do Cão , Administração Oral , Analgesia/veterinária , Analgésicos Opioides/uso terapêutico , Animais , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Fluconazol , Humanos , Histerectomia/veterinária , Metadona/uso terapêutico , Naltrexona/uso terapêutico , Ovariectomia/veterinária , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/veterinária
20.
J Med Microbiol ; 69(10): 1221-1227, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32894212

RESUMO

This study evaluated the effect of etomidate against biofilms of Candida spp. and analysed through molecular docking the interaction of this drug with ALS3, an important protein for fungal adhesion. Three fluconazole-resistant fungi were used: Candida albicans, Candida parapsilosis and Candida tropicalis. Growing biofilms were exposed to etomidate at 31.25-500 µg ml-1. Then, an ALS3 adhesive protein from C. albicans was analysed through a molecular mapping technique, composed of a sequence of algorithms to perform molecular mapping simulation based on classic force field theory. Etomidate showed antifungal activity against growing biofilms of resistant C. albicans, C. parapsilosis and C. tropicalis at all concentrations used in the study. The etomidate coupling analysis revealed three interactions with the residues of interest compared to hepta-threonine, which remained at the ALS3 site. In addition, etomidate decreased the expression of mannoproteins on the surface of C. albicans. These results revealed that etomidate inhibited the growth of biofilms.


Assuntos
Candida/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Etomidato/farmacologia , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Etomidato/metabolismo , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos
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