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1.
Medicine (Baltimore) ; 99(11): e19494, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176090

RESUMO

As detection rates of non-albicans Candida species are increasing, determining their pathogen profiles and antifungal susceptibilities is important for antifungal treatment selection. We identified the antifungal susceptibility patterns and predictive factors for mortality in candidemia.A multicenter retrospective analysis of patients with at least 1 blood culture positive for Candida species was conducted. Candida species were classified into 3 groups (group A, Candia albicans; group B, Candida tropicalis, and Candida parasilosis; group C, Candida glabrata and Candida krusei ) to analyze the susceptibility patterns, first-line antifungal administered, and mortality. Univariate and multivariate comparisons between outcomes were performed to identify mortality risk factors.In total, 317 patients were identified, and 136 (42.9%) had recorded mortality. Echinocandin susceptibility was higher for group A than group B (111/111 [100%] vs 77/94 [81.9%], P < .001). Moreover, group A demonstrated higher fluconazole susceptibility (144/149 [96.6%] vs 39/55 [70.9%], P < .001) and lower mortality (68 [45.3%] vs 34 [61.8%], P = .036) than those of group C. In the multivariate analysis, the sequential organ failure assessment score (odds ratio OR 1.351, 95% confidence interval 1.067-1.711, p = 0.013) and positive blood culture on day 7 of hospitalization (odds ratio 5.506, 95% confidence interval, 1.697-17.860, P = .004) were associated with a higher risk of mortality.Patients with higher sequential organ failure assessment scores and sustained positive blood cultures have an increased risk of mortality.


Assuntos
Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidemia/tratamento farmacológico , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Idoso , Antifúngicos/farmacologia , Candidemia/mortalidade , Feminino , Fluconazol/farmacologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Valor Preditivo dos Testes , República da Coreia , Estudos Retrospectivos , Fatores de Risco
2.
BMC Infect Dis ; 20(1): 55, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952505

RESUMO

BACKGROUND: Candidaemia is the most common form of invasive candidiasis. Resistant Candida blood stream infection (BSI) is rising, with limitations on the development of broader-spectrum antifungal agents worldwide. Our study aimed to identify the occurrence of antifungal-resistant candidaemia and the distribution of these species, determine the risk factors associated with antifungal resistance and evaluate the association of antifungal-resistant candidaemia with the length of intensive care unit (ICU) and hospital stay and with 30-day mortality. METHODS: A retrospective cohort study was conducted at King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia. Adult patients diagnosed with candidaemia from January 2006 to December 2017 were included. RESULTS: A total of 196 BSIs were identified in 94 males (49.74%) and 95 females (50.26%). C. glabrata was the most commonly isolated Candida species, with 59 (30%), followed by C. albicans with 46 (23%). Susceptibility data were available for 122/189 patients, of whom 26/122 (21%) were resistant to one or more antifungals. C. parapsilosis with available sensitivity data were found in 30/122 isolates, of which 10/30 (33%) were resistant to fluconazole. Risk factors significantly associated with antifungal-resistant candidaemia included previous echinocandin exposure (odds ratio (OR) =1.38; 95% confidence interval (CI) (1.02-1.85); P = 0.006) and invasive ventilation (OR = 1.3; 95% CI (1.08-1.57); P = 0.005). The median length of ICU stay was 29 days [range 12-49 days] in the antifungal-resistant group and 18 days [range 6.7-37.5 days] in the antifungal-sensitive group (P = 0.28). The median length of hospital stay was 51 days [range 21-138 days] in the antifungal-resistant group and 35 days [range 17-77 days] in the antifungal-sensitive group (P = 0.09). Thirty-day mortality was 15 (57.7%) and 54 (56.25%) among the antifungal-resistant and antifungal-sensitive groups, respectively (OR = 1.01; 95% CI (0.84-1.21); P = 0.89). CONCLUSIONS: Our results indicate a high frequancy of non- C. albicans candidaemia. The rise in C. parapsilosis resistance to fluconazole is alarming. Further studies are required to confirm this finding.


Assuntos
Candidemia/diagnóstico , Farmacorresistência Fúngica , Adulto , Idoso , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Candidemia/tratamento farmacológico , Candidemia/microbiologia , Feminino , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita
3.
Pol J Microbiol ; 68(4): 493-504, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880893

RESUMO

Bird fecal matter is considered a potential source of pathogenic microbes such as yeast species that contaminate the environment. Therefore, it needs to be scrutinized to assess potential environmental health risks. The aim of this study was to investigate the diversity of the yeasts in pigeon fecal droppings, their antifungal susceptibility patterns, and virulence factors. We used culturing techniques to detect the yeasts in pigeon fecal droppings. The isolates were then characterized based on colony morphologies, microscopic examinations, and biochemical reactions. The molecular identification of all yeast isolates was performed by sequencing of the amplified ITS gene. Genes encoding virulence factors CAP1, CAP59, and PLB were also detected. Antifungal susceptibility patterns were examined by the disk diffusion method. A total of 46 yeast-like isolates were recovered, and they belonged to nine different genera, namely, Cryptococcus, Saccharomyces, Rhodotorula, Candida, Meyerozyma, Cyberlindnera, Rhodosporidium, Millerozyma, and Lodderomyces. The prevalence of two genera Cryptococcus and Rhodotorula was high. None of the yeast isolates exhibited any resistance to the antifungal drugs tested; however, all pathogenic Cryptococcus species were positive for virulence determinants like urease activity, growth at 37°C, melanin production, the PLB and CAP genes. This is the first report on the molecular diversity of yeast species, particularly, Cryptococcus species and their virulence attributes in pigeon fecal droppings in Saudi Arabia.Bird fecal matter is considered a potential source of pathogenic microbes such as yeast species that contaminate the environment. Therefore, it needs to be scrutinized to assess potential environmental health risks. The aim of this study was to investigate the diversity of the yeasts in pigeon fecal droppings, their antifungal susceptibility patterns, and virulence factors. We used culturing techniques to detect the yeasts in pigeon fecal droppings. The isolates were then characterized based on colony morphologies, microscopic examinations, and biochemical reactions. The molecular identification of all yeast isolates was performed by sequencing of the amplified ITS gene. Genes encoding virulence factors CAP1, CAP59, and PLB were also detected. Antifungal susceptibility patterns were examined by the disk diffusion method. A total of 46 yeast-like isolates were recovered, and they belonged to nine different genera, namely, Cryptococcus, Saccharomyces, Rhodotorula, Candida, Meyerozyma, Cyberlindnera, Rhodosporidium, Millerozyma, and Lodderomyces. The prevalence of two genera Cryptococcus and Rhodotorula was high. None of the yeast isolates exhibited any resistance to the antifungal drugs tested; however, all pathogenic Cryptococcus species were positive for virulence determinants like urease activity, growth at 37°C, melanin production, the PLB and CAP genes. This is the first report on the molecular diversity of yeast species, particularly, Cryptococcus species and their virulence attributes in pigeon fecal droppings in Saudi Arabia.


Assuntos
Columbidae/microbiologia , Fezes/microbiologia , Fatores de Virulência/metabolismo , Leveduras/efeitos dos fármacos , Leveduras/isolamento & purificação , Animais , Antifúngicos/farmacologia , Biodiversidade , Fluconazol/farmacologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Testes de Sensibilidade Microbiana , Arábia Saudita , Fatores de Virulência/genética , Leveduras/genética , Leveduras/metabolismo
4.
Pol J Microbiol ; 68(3): 303-308, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31880875

RESUMO

The data on susceptibility to antifungals of new species within Candida glabrata complex are limited. Our study was to enrich a global knowledge of yeast epidemiology and drug resistance. The study was focused on the identification of species within clinical isolates of the C. glabrata complex and on the determination of their resistance to antifungals. Four hundred forty-five clinical C. glabrata sensu lato strains were isolated from different clinical samples at routine mycological exams at the Infant Jesus Teaching Hospital in Warsaw. The identification of the most of tested isolates to species complex level was performed using the ID 32 C system. The identification of C. nivariensis and C. bracarensis species within the C. glabrata complex was performed by DNA sequencing. The MICs of amphotericin B, fluconazole, itraconazole, posaconazole, voriconazole, caspofungin, anidulafungin, and micafungin were determined by E-test. Twenty-four isolates did not have an ITS-1 region, characteristic of C. glabrata sensu stricto and their D1/D2 regions of the 26S rRNA were 99% homologous to C. nivariensis 26S rRNA. No strains of C. bracarensis were recovered. C. nivariensis strains were very susceptible to amphotericin B, anidulafungin, micafungin, and caspofungin. Ninety-two percent of C. nivariensis were resistant to itraconazole. The halves of the strains was resistant to posaconazole. Eighty-three percent of C. nivariensis were susceptible to voriconazole. None of the tested strains were susceptible to fluconazole. In the present study, none of the C. nivariensis strains were simultaneously resistant to azoles and echinocandins. C. nivariensis should be recognized as an emerging pathogen, resistant to azoles.The data on susceptibility to antifungals of new species within Candida glabrata complex are limited. Our study was to enrich a global knowledge of yeast epidemiology and drug resistance. The study was focused on the identification of species within clinical isolates of the C. glabrata complex and on the determination of their resistance to antifungals. Four hundred forty-five clinical C. glabrata sensu lato strains were isolated from different clinical samples at routine mycological exams at the Infant Jesus Teaching Hospital in Warsaw. The identification of the most of tested isolates to species complex level was performed using the ID 32 C system. The identification of C. nivariensis and C. bracarensis species within the C. glabrata complex was performed by DNA sequencing. The MICs of amphotericin B, fluconazole, itraconazole, posaconazole, voriconazole, caspofungin, anidulafungin, and micafungin were determined by E-test. Twenty-four isolates did not have an ITS-1 region, characteristic of C. glabrata sensu stricto and their D1/D2 regions of the 26S rRNA were 99% homologous to C. nivariensis 26S rRNA. No strains of C. bracarensis were recovered. C. nivariensis strains were very susceptible to amphotericin B, anidulafungin, micafungin, and caspofungin. Ninety-two percent of C. nivariensis were resistant to itraconazole. The halves of the strains was resistant to posaconazole. Eighty-three percent of C. nivariensis were susceptible to voriconazole. None of the tested strains were susceptible to fluconazole. In the present study, none of the C. nivariensis strains were simultaneously resistant to azoles and echinocandins. C. nivariensis should be recognized as an emerging pathogen, resistant to azoles.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase/microbiologia , Anfotericina B/farmacologia , Candida/classificação , Candida/genética , Candida/isolamento & purificação , Candidíase/epidemiologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Hospitais de Ensino/estatística & dados numéricos , Humanos , Testes de Sensibilidade Microbiana , Polônia/epidemiologia , Prevalência , Triazóis/farmacologia
5.
Pharm Res ; 37(1): 15, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873806

RESUMO

PURPOSE: To explore the contribution of physiological characteristics to variability in ciclosporin pharmacokinetics in hematopoietic stem cell transplantation patients. METHODS: Clinical data from 563 patients were collected from centers in three regions. Ciclosporin concentrations were measured using immunoassays. The patients' demographics, hematological and biological indicators, coadministered drugs, region, and disease diagnosis were recorded from medical records. Data analysis was performed using NONMEM based on a one-compartment model to describe the pharmacokinetics of ciclosporin. The reliability and stability of the final model were evaluated using bootstrap resampling, goodness-of-fit plots, and prediction-corrected visual predictive checks. RESULTS: The population estimate of the clearance (CL) was 30.4 L/h, the volume of distribution (V) was 874.0 L and the bioavailability (F) was 81.1%. The between-subject variability in these parameters was 26.3, 68.0, and 110.8%, respectively. Coadministration of fluconazole, itraconazole, or voriconazole decreased CL by 17.6%, 28.4%, and 29.2%, respectively. Females' CL increased by approximately 12.0%. In addition, CL and V decreased with hematocrit, total protein, and uric acid increase, and CL also decreased with age and aspartate aminotransferase increase. However, CL increased with creatinine clearance increase. CONCLUSIONS: A multicenter-based population pharmacokinetic model of ciclosporin was established. The pharmacokinetics of ciclosporin exhibited discrepancies among different regions.


Assuntos
Ciclosporina/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Imunossupressores/farmacocinética , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Feminino , Fluconazol/farmacologia , Neoplasias Hematológicas/terapia , Humanos , Itraconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Reprodutibilidade dos Testes , Voriconazol/farmacologia
6.
Eur J Med Chem ; 183: 111660, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514064

RESUMO

This mini-review focuses on leishmanicidal drugs that were sourced from small molecules previously approved for other diseases. The mechanisms of action of these molecules are herein explored, to probe the origins of their inter-species growth inhibitory activities. It is shown how the transversal action of the azoles - fluconazole, posaconazole and itraconazole - in both fungi and Leishmania is due to the occurrence of the same target, lanosterol 14-α-demethylase, in these two groups of species. In turn, the drugs miltefosine and amphotericin B are presented as truly multi-target agents, acting on small molecules, proteins, genes and even organelles. Steps towards future leishmanicidal drug candidates based on the multi-target strategy and on drug repurposing are also briefly presented.


Assuntos
Antifúngicos , Itraconazol , Leishmaniose/tratamento farmacológico , Anfotericina B/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Humanos , Itraconazol/química , Itraconazol/farmacologia , Leishmaniose/enzimologia , Terapia de Alvo Molecular , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Esterol 14-Desmetilase/metabolismo , Triazóis/farmacologia , Voriconazol/farmacologia
7.
Eur J Med Chem ; 183: 111689, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541871

RESUMO

A series of ß-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03-1 µg/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1-8 µg/mL. Compounds with R1 = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125-4 µg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.


Assuntos
Acetona/análogos & derivados , Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Células A549 , Acetona/química , Acetona/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Azóis/química , Relação Dose-Resposta a Droga , Fluconazol/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
8.
J Med Microbiol ; 68(11): 1664-1670, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553302

RESUMO

Purpose. To assess in vitro activities of nine antifungal agents (amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, micafungin, terbinafine and 5-flucytosine) against 93 strains of rare pathogenic fungi and the combined effects of drug combinations against several multidrug-resistant fungi.Methodology. The broth microdilution method M38-A3 and M27-A4 from the Clinical and Laboratory Standards Institute and the checkerboard method were performed in this study.Results. Low MICs for fluconazole were observed in moulds including Tritirachium oryzae, Exophiala attenuata and yeasts. MICs for amphotericin B>2 µg ml-1 were found among Aspergillus nidulans, Fusarium napiforme, Trichoderma longibrachiatum, Tritirachium oryzae, Cunninghamella bertholletiae, Cunninghamella phaeospora, Conidiobolus coronatus, Exophiala attenuata, Ochroconis mirabilis and Rhinocladiella basitona. Multidrug resistance was observed in Microascus spp., Lomentospora prolificans and Pythium insidiosum.Conclusion. Our study illustrated in vitro drug susceptibilities of some rare pathogenic fungi, which provide data to guide clinical treatment of fungal infections.


Assuntos
Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Micoses/microbiologia , Anfotericina B/farmacologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Fungos/classificação , Fungos/genética , Fungos/isolamento & purificação , Humanos , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Triazóis/farmacologia , Voriconazol/farmacologia
9.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470602

RESUMO

The promising antimicrobial activity of essential oils (EOs) has led researchers to use them in combination with antimicrobial drugs in order to reduce drug toxicity, side effects, and resistance to single agents. Mentha x piperita, known worldwide as "Mentha of Pancalieri", is produced locally at Pancalieri (Turin, Italy). The EO from this Mentha species is considered as one of the best mint EOs in the world. In our research, we assessed the antifungal activity of "Mentha of Pancalieri" EO, either alone or in combination with azole drugs (fluconazole, itraconazole, ketoconazole) against a wide panel of yeast and dermatophyte clinical isolates. The EO was analyzed by GC-MS, and its antifungal properties were evaluated by minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) parameters, in accordance with the CLSI guidelines, with some modifications. The interaction of EO with azoles was evaluated through the chequerboard and isobologram methods. The results suggest that this EO exerts a fungicidal activity against yeasts and a fungistatic activity against dermatophytes. Interaction studies with azoles indicated mainly synergistic profiles between itraconazole and EO vs. Candida spp., Cryptococcus neoformans, and Trichophyton mentagrophytes. Thus, the "Mentha of Pancalieri" EO may act as a potential antifungal agent and could serve as a natural adjuvant for fungal infection treatment.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Mentha piperita/química , Monoterpenos/farmacologia , Óleos Voláteis/química , Animais , Antifúngicos/química , Antifúngicos/isolamento & purificação , Arthrodermataceae/efeitos dos fármacos , Arthrodermataceae/crescimento & desenvolvimento , Arthrodermataceae/isolamento & purificação , Candida/efeitos dos fármacos , Candida/crescimento & desenvolvimento , Candida/isolamento & purificação , Cryptococcus/efeitos dos fármacos , Cryptococcus/crescimento & desenvolvimento , Cryptococcus/isolamento & purificação , Combinação de Medicamentos , Sinergismo Farmacológico , Fluconazol/farmacologia , Guias como Assunto , Humanos , Itraconazol/farmacologia , Cetoconazol/farmacologia , Testes de Sensibilidade Microbiana , Monoterpenos/química , Monoterpenos/isolamento & purificação , Óleos Voláteis/isolamento & purificação
10.
Life Sci ; 235: 116827, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479680

RESUMO

OBJECTIVE: This study aims to evaluate the effective of azoles and MTX for patients with invasive candidiasis. METHODS: We used the disk diffusion assay and the checkerboard assay to evaluate the in vitro interactions between MTX and antifungals. In addition, we used the transmission electron microscopy to observe the ultrastructure of the effect of MTX and fluconazole on Candida albicans. RESULTS: The rates of synergy for the combination of MTX with fluconazole (FLC), itraconazole (ITC), and voriconazole (VRZ) were 91.3%, 65.2%, and 87% in checkerboard testing. No antagonism was found between methotrexate and azole antifungals in any of the strains. Furthermore, MTX treated C. albicans showed extensive cell wall vacuolations and the inhibition of blastospores growth, as observed using transmission electron microscopy. There was an apparent destruction of the cell membrane and cell wall resulting in the destruction of cytoplasm, a phenomenon observed when MTX was combined with azoles. CONCLUSION: This study provides evidence that the combination of azoles and MTX is effective for patients with invasive candidiasis, which on the other hand, will reduce the side effects of the drugs.


Assuntos
Candida albicans/efeitos dos fármacos , Sinergismo Farmacológico , Fluconazol/farmacologia , Itraconazol/farmacologia , Metotrexato/farmacologia , Voriconazol/farmacologia , Membrana Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Gástrula/efeitos dos fármacos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão
11.
Int J Nanomedicine ; 14: 5323-5338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409990

RESUMO

Background: Candida albicans as an opportunistic fungus is one of the most important causes of late-onset morbidity and mortality in patients with major burns and severely impaired immune system. In recent years, the emergence of resistance to opportunistic fungi and toxicity of antimicrobial drugs make it necessary to develop new drugs. Methods: In the present study, we investigated anticandidal effects of indolicidin, as a representative of host defense peptide, conjugated with gold nanoparticles in fluconazole-resistant clinical isolates of C. albicans. After characterizing the conjugation of indolicidin using biophysical methodologies, the cytotoxicity and hemolytic activity of the nanocomplex were examined. In addition, the expression level of ERG11, responsible for antifungal resistance, and the immunomodulatory effect of peptide-nanomaterial conjugates were assessed. Results: Our data indicated that the nanocomplex was nontoxic for the fibroblast cells and erythrocytes. Treatment with the nanocomplex significantly reduced the expression levels of the ERG11 gene in fluconazole-resistant C. albicans isolates and the iNOS gene in macrophages. Conclusion: The study data provides a chance to develop innovative therapies for the treatment of C. albicans burn infections. However, further investigation is required to examine the efficiency of the nanocomplex.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Queimaduras/microbiologia , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Fluconazol/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Animais , Peptídeos Catiônicos Antimicrobianos/química , Queimaduras/tratamento farmacológico , Candida albicans/genética , Morte Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fluconazol/química , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Fúngicos , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
12.
Emerg Infect Dis ; 25(9): 1660-1667, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31441426

RESUMO

Candida tropicalis is the leading cause of non-C. albicans candidemia in tropical Asia and Latin America. We evaluated isolates from 344 patients with an initial episode of C. tropicalis candidemia. We found that 58 (16.9%) patients were infected by fluconazole-nonsusceptible (FNS) C. tropicalis with cross resistance to itraconazole, voriconazole, and posaconazole; 55.2% (32/58) of patients were azole-naive. Multilocus sequence typing analysis revealed FNS isolates were genetically closely related, but we did not see time- or place-clustering. Among the diploid sequence types (DSTs), we noted DST225, which has been reported from fruit in Taiwan and hospitals in Beijing, China, as well as DST376 and DST505-7, which also were reported from hospitals in Shanghai, China. Our findings suggest cross-boundary expansion of FNS C. tropicalis and highlight the importance of active surveillance of clinical isolates to detect dissemination of this pathogen and explore potential sources in the community.


Assuntos
Antifúngicos/uso terapêutico , Candida tropicalis/isolamento & purificação , Candidíase Invasiva/epidemiologia , Fluconazol/uso terapêutico , Idoso , Antifúngicos/farmacologia , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/genética , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/microbiologia , Farmacorresistência Fúngica/genética , Feminino , Fluconazol/farmacologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Taiwan/epidemiologia
13.
Int J Med Microbiol ; 309(6): 151336, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31444102

RESUMO

Cryptococcosis is a fungal infection of the central nervous system predominantly caused by Cryptococcus neoformans in immunocompromised patients. In several countries worldwide, up to 50% of isolates show in vitro resistance to clinically used antifungals including fluconazole. No prospective data on susceptibility to antifungal drugs are available for Germany. In this study, we characterised all C. neoformans isolates collected from individual patients' samples at the German reference laboratory for cryptococcosis 2011 and 2017 (n = 133) by multi-locus sequence typing and phenotypic drug susceptibility testing. We identified serotype A/genotype VNI isolates belonging to clonal complexes previously described from Europe, Africa, Asia and South America as the most prevalent agents of cryptococcosis in Germany. Overall, we observed minimal inhibitory concentrations (MICs) above the epidemiological cut-offs (ECVs) in 1.6% of isolates regarding fluconazole and 2.3% of isolates regarding 5-flucytosine. Here, two C. neoformans var. grubii isolates displayed decreased drug susceptibility to fluconazole, one of them additionally to 5-flucytosine. We also found 5-flucytosine MICs above the ECV for two C. neoformans var. neoformans isolates. We identified a novel mutation in the ERG11 gene which might be associated with the elevated fluconazole MIC in one of the isolates. The clinical importance of the detected in vitro resistance is documented by patient histories showing relapsed infection or primary fatal disease. Of note, sertraline demonstrated antifungal activity comparable to previous reports. Systematic collection of susceptibility data in combination with molecular typing of C. neoformans is important to comprehensively assess the spread of isolates and to understand their drug resistance patterns.


Assuntos
Antifúngicos/farmacologia , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/genética , Criptococose/epidemiologia , Cryptococcus neoformans/classificação , DNA Fúngico/genética , Farmacorresistência Fúngica/genética , Feminino , Fluconazol/farmacologia , Flucitosina/farmacologia , Proteínas Fúngicas/genética , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Tipagem Molecular , Mutação , Técnicas de Tipagem Micológica
14.
PLoS Genet ; 15(8): e1008259, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425501

RESUMO

Drug resistance is a rapidly emerging concern, thus prompting the development of novel therapeutics or combinatorial therapy. Currently, combinatorial therapy targets are based on knowledge of drug mode of action and/or resistance mechanisms, constraining the number of target proteins. Unbiased genome-wide screens could reveal novel genetic components within interaction networks as potential targets in combination therapies. Testing this, in the context of antimicrobial resistance, we implemented an unbiased genome-wide screen, performed in Saccharomyces cerevisiae expressing a Candida glabrata PDR1+ gain-of-function allele. Gain-of-function mutations in this gene are the principal mediators of fluconazole resistance in this human fungal pathogen. Eighteen synthetically lethal S. cerevisiae genetic mutants were identified in cells expressing C. glabrata PDR1+. One mutant, lacking the histone acetyltransferase Gcn5, was investigated further. Deletion or drug-mediated inhibition of Gcn5 caused a lethal phenotype in C. glabrata cells expressing PDR1+ alleles. Moreover, deletion or drug-mediated inactivation of Gcn5, inhibited the emergence of fluconazole-resistant C. glabrata isolates in evolution experiments. Thus, taken together, the data generated in this study provides proof of concept that synthetically lethal genetic screens can identify novel candidate proteins that when therapeutically targeted could allow effective treatment of drug-resistant infections.


Assuntos
Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica/genética , Regulação Fúngica da Expressão Gênica , Antifúngicos/uso terapêutico , Candida glabrata/genética , Candidíase/microbiologia , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Mutação com Ganho de Função , Histona Acetiltransferases/genética , Humanos , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Mutações Sintéticas Letais
15.
J Mycol Med ; 29(3): 201-209, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31378442

RESUMO

Candida albicans is a polymorphic opportunistic commensal that causes both superficial and systemic fungal infections especially in immunocompromised patients. Biologically synthesized silver nanoparticles (AgNPs) have emerged as potential antifungal agents. The present work evaluates the antifungal activity of Artemisia annua synthesized AgNPs against three Candida species (C. albicans ATCC 90028, C. tropicalis ATCC 750 and C. glabrata ATCC 90030). The in vitro effect of AgNPs was investigated for fungal growth, sterol content, secretion of hydrolytic enzymes and yeast-to-hyphal transition. The green synthesized AgNPs were effective against all the three species with minimum inhibitory concentration (MIC) in the range 80-120µgml-1. Candida glabrata showed greater sensitivity for AgNPs followed by Candida tropicalis and C. albicans. AgNPs at 4MIC were as effective as fluconazole (FLC) and caused only 5% haemolysis while FLC caused 50% haemolysis at the same concentration. The secretion of hydrolytic enzymes was the lowest in case of AgNP exposed C. glabrata. Yeast-to-hyphal transition was significantly reduced in treated C. albicans cells and showed disfigured morphology in SEM images. The decrease in ergosterol content was slightly higher (94%) in both C. glabrata and C. tropicalis in comparison to C. albicans (69%). Green synthesized AgNPs thus have immense potential as an antifungal and can play a crucial role in the management of Candida infections especially those caused by C. glabrata.


Assuntos
Antifúngicos/farmacologia , Artemisia annua/química , Candida/efeitos dos fármacos , Nanopartículas Metálicas/química , Prata/farmacologia , Candida/enzimologia , Candida/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana , Peptídeo Hidrolases/metabolismo , Fosfolipases/metabolismo
16.
J Infect Chemother ; 25(10): 743-749, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31257156

RESUMO

Candida auris is a multidrug-resistant and emergent pathogen that has caused healthcare-associated infection outbreaks. Recently, C. auris has spread worldwide; nevertheless, it was unexpectedly rare before 2009. Based on the molecular epidemiological analysis, C. auris may independently emerge at specific areas at first and recently may be transmitted to other continents. As C. auris cannot be detected using conventional methods, internally transcribed spacers, D1/D2 regions of the 26S rDNA sequencing, and/or matrix-assisted laser desorption ionization time-of-flight mass spectrometry method can be selected as comparatively accessible choices. Thus, detection of C. auris using the conventional method might be underestimated. In Japan, all C. auris strains were isolated from ear specimen and not from invasive mycoses. Japan strains were classified as an East Asian clade under a single clone. Although colonization, virulence, and infection pattern are almost the same as with other Candida species, its antifungal resistance is different. Fluconazole resistance is notably common, but resistance to all three classes of antifungals (azole, polyene, and echinocandin) rarely exists. Once C. auris is detected, screening, emphasis on hand hygiene adherence, use of single-patient room isolation, contact precaution, surveillance, and eradication from the environment and patients are appropriately required for infection control.


Assuntos
Antifúngicos/farmacologia , Candida/isolamento & purificação , Candidíase/tratamento farmacológico , Antifúngicos/uso terapêutico , Azóis/farmacologia , Azóis/uso terapêutico , Candida/efeitos dos fármacos , Candida/patogenicidade , Candidíase/epidemiologia , Candidíase/microbiologia , Farmacorresistência Fúngica Múltipla , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Polienos/farmacologia , Polienos/uso terapêutico , Prevalência
17.
Artigo em Inglês | MEDLINE | ID: mdl-31281800

RESUMO

The frequent emergence of azole-resistant strains has increasingly led azoles to fail in treating candidiasis. Combination with other drugs is a good option to effectively reduce or retard its incidence of resistance. Natural products are a promising synergist source to assist azoles in treating resistant candidiasis. Eucalyptal D (ED), a formyl-phloroglucinol meroterpenoid, is one of the natural synergists, which could significantly enhance the anticandidal activity of fluconazole (FLC) in treating FLC resistant C. albicans. The checkerboard microdilution assay showed their synergistic effect. The agar disk diffusion test illustrated the key role of ED in synergy. The rhodamine 6G (R6G) efflux assay reflected ED could reduce drug efflux, but quantitative reverse transcription PCR analysis revealed the upregulation of CDR1 and CDR2 genes in ED treating group. Efflux pump-deficient strains were hyper-susceptible to ED, thus ED was speculated to be the substrate of efflux pump Cdr1p and Cdr2p to competitively inhibit the excretion of FLC or R6G, which mainly contributed to its synergistic effect.


Assuntos
Antifúngicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Triterpenos/farmacologia , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Azóis/farmacologia , Benzaldeídos , Candida albicans/genética , Candidíase/tratamento farmacológico , Sinergismo Farmacológico , Proteínas Fúngicas/genética , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Testes de Sensibilidade Microbiana , Floroglucinol/análogos & derivados , Triterpenos/química
18.
Vet Microbiol ; 235: 43-52, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282378

RESUMO

Even though it is widely known that Cryptococcus spp. may transmit cryptococcosis trough aerosol formed when dried birds (mainly pigeons) droppings are dispersed and become airborne, little is known about the role of these birds in harboring other pathogenic yeasts in their gastrointestinal tract, feathers and beaks, specifically because these animals often stay and reproduce close or even above air conditioner units. Here we evaluated the prevalence of pathogenic yeasts isolated from pigeon droppings collected in the outside area of a University Hospital in Brazil. We also aimed to investigate the pathogenic potential and antifungal susceptibility of Candida species of medical interest isolated from these samples. Therefore, we performed the evaluation of virulence factors attributes expression in vitro, including the ability to adhere to human buccal epithelial cells and biofilm formation and to produce lytic enzymes, such as phospholipases, proteinases and hemolysins. Antifungal susceptibility testing against fluconazole, itraconazole, amphotericin and micafungin was also performed. The Candida genus was the most prevalent in our study, with several medically important species being isolated. Of note, these strains were able to express several virulence factors in vitro, clearly showing their pathogenic potential. Our study was able to demonstrate that Candida spp. isolated from pigeon droppings may express virulence factors in the same manner of clinical isolates, suggesting a pathogenic potential for these yeasts. The fact these strains were collected from the outside area of a tertiary hospital may be of interest, because they may be a source of infection, specifically to immunocompromised hosts.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Columbidae/microbiologia , Farmacorresistência Fúngica , Fatores de Virulência/genética , Anfotericina B/farmacologia , Animais , Brasil , Candida/genética , Candida/isolamento & purificação , Criptococose/veterinária , Fezes/microbiologia , Fluconazol/farmacologia , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana
19.
J Med Microbiol ; 68(9): 1353-1358, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271350

RESUMO

Introduction. Candida auris is a pathogenic yeast that mainly affects immunosuppressed patients and those with implanted medical devices. This pathogen also displays elevated resistance to common antifungals and high survival and spreading capacities. Since no antifungal breakpoints have yet been defined for this pathogen, the data obtained here can be useful for further research concerning treatment or implementation of a prevention and disinfection protocol. Our aim was to study the antifungal resistance of C. auris to current antifungals in planktonic and sessile states. Using confocal laser scanning microscopy and viable biomass production, we demonstrated the ability of C. auris to develop a mature biofilm. We compared the minimal inhibitory concentration (MIC) and the minimal biofilm eradication concentration (MBEC) for the C. auris DSM 21092 strain plus two clinical isolates, and the results were compared with those obtained for Candida albicans and Candida parapsilosis, two species strongly linked to bloodstream infections and infections associated with biomaterials. We found that the clinical isolates of C. auris were resistant to fluconazole and sensitive to echinocandins and polyenes. The C. auris biofilms did not show susceptibility to any antifungal agent, showing MBECs that were up to 512-fold higher than the MICs. These findings highlight the importance of biofilm formation as a key factor underlying the resistance of this species to antifungals and suggest that the presence of implantable medical devices is one of the major risk factors in immunocompromised patients.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candida albicans/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Candidíase/microbiologia , Contagem de Colônia Microbiana , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Microscopia Confocal , Polienos/farmacologia
20.
BMC Infect Dis ; 19(1): 593, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286895

RESUMO

BACKGROUND: Current drug regimens for cutaneous leishmaniasis (CL) include toxic systemic therapies such as amphotericin B (AB) and pentavalent antimonials. Fluconazole (FZ) is a well-tolerated potential oral alternative for the management CL. To date, few objective data exist to guide clinical decision-making when selecting a therapeutic agent a priori, and standardized, clinically-approved drug susceptibility testing platforms for Leishmania spp. have yet to be established. The Sensititre™ YeastOne™ YO9 plate is a commercialized drug susceptibility plate including AB and FZ used for routine testing of non-fastidious yeast. Our objective was to adapt the readily available Sensititre™ YeastOne™ YO9 plate, to determine drug susceptibility profiles of AB and FZ in cultured isolates of Old World and New World Leishmania spp. for the treatment of CL. METHODS: Promastigotes were cultured in Tobie's medium with Locke's overlay until log phase growth was achieved, inoculated into the Sensititre™ system, and incubated over 96 H. minimum inhibitory concentrations (MICs) were determined colorimetrically, and promastigote death was assessed by conventional microscopy out to 96- h. Colour change correlated to MIC values. RESULTS: All strains tested exhibited MIC values for FZ that were ≥ 256 µg/mL. New World strains demonstrated reduced susceptibility to AB (0.25 µg/mL - 0.50 µg/mL AB) compared to Old World strains at 0.12 µg/mL AB (p = 0.02). Seventeen (61%) of 28 Viannia isolates versus 82% (27/33) of non-Viannia isolates were resistant at 0.12 µg/mL AB (p = 0.09). For L. V. braziliensis isolates, mean MIC for AB was 0.375 ± 0.14 µg/mL (range 0.25-0.50 µg/mL), while for isolates of L. V. panamensis it was 0.314 ± 0.26 µg/mL (range 0.12-1.0 µg/mL). CONCLUSIONS: We adapted the Sensititre™ YeastOne™ YO9 plate for testing of Leishmania spp. susceptibility profiles for commonly used antifungals in the treatment of CL, including AB and FZ. Given its current utility in mycology, optimization of the system for potential clinical implementation in parasitology should be pursued. However evaluation of clinically relevant amastigote-stage stages, and higher concentrations of FZ beyond the upper limit concentration of the Sensititre™ YeastOne™ Y09 plate would be required.


Assuntos
Anfotericina B/farmacologia , Fluconazol/farmacologia , Leishmania/efeitos dos fármacos , Testes de Sensibilidade Parasitária/métodos , Humanos , Leishmaniose/parasitologia , Testes de Sensibilidade Microbiana
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