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1.
Antimicrob Agents Chemother ; 66(11): e0088922, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36226945

RESUMO

We investigated the evolution of fluconazole resistance mechanisms and clonal types of Candida parapsilosis isolates from a tertiary care hospital in South Korea. A total of 45 clinical isolates, including 42 collected between 2017 and 2021 and 3 collected between 2012 and 2013, were subjected to antifungal susceptibility testing, sequencing of fluconazole resistance genes (ERG11, CDR1, TAC1, and MRR1), and microsatellite typing. Twenty-two isolates carried Y132F (n = 21; fluconazole MIC = 2 to >256 mg/L) or Y132F+R398I (n = 1; fluconazole MIC = 64 mg/L) in ERG11 and four isolates harbored N1132D in CDR1 (fluconazole MIC = 16 to 64 mg/L). All 21 Y132F isolates exhibited similar microsatellite profiles and formed a distinct group in the dendrogram. All four N1132D isolates displayed identical microsatellite profiles. Fluconazole MIC values of the Y132F isolates varied depending on their MRR1 mutation status (number of isolates, year of isolation, and MIC): K177N (n = 8, 2012 to 2020, 2 to 8 mg/L); K177N + heterozygous G982R (n = 1, 2017, 64 mg/L); K177N + heterozygous S614P (n = 2, 2019 to 2020, 16 mg/L); and K177N + homozygous S614P (n = 10, 2020 to 2021, 64 to > 256 mg/L). Our study revealed that Y132F in ERG11 and N1132D in CDR1 were the major mechanisms of fluconazole resistance in C. parapsilosis isolates. Furthermore, our results suggested that the clonal evolution of Y132F isolates persisting and spreading in hospital settings for several years occurred with the acquisition of heterozygous or homozygous MRR1 mutations associated with a gradual increase in fluconazole resistance.


Assuntos
Candida parapsilosis , Fluconazol , Fluconazol/farmacologia , Candida parapsilosis/genética , Farmacorresistência Fúngica/genética , Centros de Atenção Terciária , Antifúngicos/farmacologia , Proteínas Fúngicas/genética , Testes de Sensibilidade Microbiana
2.
Braz J Microbiol ; 53(4): 1761-1779, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306113

RESUMO

Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a saprophyte detected on human mucosa and skin. It can lead to serious infections in patients with risk factors like chemotherapy, immunodeficiency, gastrointestinal or cardiovascular surgery, and oncology disorders. Most deaths related to M. guilliermondii infections occur in individuals with malignancy. In recent decades, incidence of M. guilliermondii infections is increased. Sensitivity of this microorganism to conventional antifungals (e.g., amphotericin B, fluconazole, micafungin and anidulafungin) was reduced. Prophylactic and empirical uses of these drugs are linked to elevated minimal inhibitory concentrations (MICs) of M. guilliermondii. Drug resistance has concerned many researchers across the world. They are attempting to discover appropriate solution to combat this challenge. This study reviews the most important mechanisms of resistance to antifungals developed by in M. guilliermondii species complex.


Assuntos
Antifúngicos , Farmacorresistência Fúngica , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fluconazol/farmacologia , Anfotericina B/farmacologia , Testes de Sensibilidade Microbiana
3.
Antimicrob Agents Chemother ; 66(11): e0102822, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36286491

RESUMO

We evaluated the in vitro activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, and Latin America during 2020. Of the isolates tested, 74.7% were Candida spp.; 3.7% were non-Candida yeasts, including 27 Cryptococcus neoformans var. grubii (1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC90 values, manogepix (MIC50/MIC90, 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against Candida spp. isolates and the most active agent tested. Similarly, manogepix (MIC50/MIC90, 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Based on minimum effective concentration for 90% of the isolates tested (MEC90) and MIC90 values, manogepix (MEC90, 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC90s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Candida auris (MIC50/MIC90, 0.004/0.015 mg/liter) and 12 isolates of Scedosporium spp. (MEC50/MEC90, 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.


Assuntos
Cryptococcus neoformans , Fluconazol , Anidulafungina/farmacologia , Micafungina/farmacologia , Fluconazol/farmacologia , Voriconazol/farmacologia , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Candida , Aspergillus , Farmacorresistência Fúngica
4.
Antimicrob Agents Chemother ; 66(11): e0072522, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36286552

RESUMO

The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal pathogen is Candida albicans. Fluconazole (FLC) is the common drug for treating C. albicans infections, but increasing drug resistance has limited its clinical use. Currently, combination therapy is being investigated as a treatment to overcome the resistance of C. albicans. This report investigated the synergistic properties of deferoxamine (DFO) and FLC combination therapy in vitro and in vivo against drug-resistant C. albicans. The results showed that the combination of DFO and FLC had a great synergistic antifungal effect against C. albicans, an FLC-resistant strain, with a fractional inhibition concentration index (FICI) of 0.25 by the broth microdilution checkerboard assay. Furthermore, the combination of DFO and FLC significantly inhibited the activity of C. glabrata cells (approximately 30% of C. glabrata cells are azole-resistant). The time-growth curves confirmed that the combination of DFO and FLC have a potent synergistic antifungal effect. Hyphal formation assays confirmed that DFO inhibited the hyphal induction of C. albicans. In addition, the combination of DFO and FLC significantly inhibited the expression of the adhesion gene (ALS1). In vivo experiments showed that the combination of DFO and FLC significantly reduced pustules, CFU counts and inflammatory cell infiltration in skin tissue. These results suggest that the combination of DFO and FLC inhibits yeast-hyphae transformation, reduces C. albicans infectivity and resistance in vitro and in vivo, and affects Cek1 MAPK signaling. This may offer a new option for the treatment of cutaneous candidiasis.


Assuntos
Candida , Fluconazol , Humanos , Fluconazol/farmacologia , Antifúngicos/farmacologia , Desferroxamina/farmacologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Candida albicans , Candida glabrata
5.
Int J Biol Macromol ; 222(Pt B): 2785-2795, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36240895

RESUMO

Bacterial and fungal co-infection leads to polymicrobial keratitis (PMK). The current study produced swellable mucoadhesive biopolymeric films composed of chitosan, HPMC, and glycerol using cast drying method. The film was dual-loaded with fluconazole (FCZ) and ofloxacin (OFX) to treat PMK. The prepared film exhibited excellent thickness, folding endurance, surface pH, tensile strength, and stability characteristics. In addition, it also exhibited good in vitro antimicrobial activity, ex-vivo mucoadhesion, and corneal permeation. AUC (0-∞) and MRT were 6.5 and 5.2-fold higher for a film containing FCZ and 22.5 and 2.5-fold higher for a film containing OFX than their marketed formulations. PK-PD simulation study supports desired efficacy of the proposed dosage form. Thus, the film exhibits longer pre-corneal drug residence time and enhanced ocular bioavailability, most likely resulting in high patient compliance. The proposed film could be a prominent replacement for the existing dosage form and may present a viable alternative for the treatment of PMK.


Assuntos
Quitosana , Ceratite , Humanos , Quitosana/uso terapêutico , Ofloxacino , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Ceratite/tratamento farmacológico , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos
6.
Microbiol Spectr ; 10(5): e0253622, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36190417

RESUMO

Candida albicans is an opportunistic pathogenic fungus responsible for candidiasis. The pathogen readily forms antifungal agent-resistant biofilms on implanted medical devices or human tissue. Morphologic transition from yeast to filamentous cells and subsequent biofilm formation is a key virulence factor and a prerequisite for biofilm development by C. albicans. We investigated the antibiofilm and antifungal activities of 18 hydroquinones against fluconazole-resistant C. albicans. Tetrachlorohydroquinone (TCHQ) at subinhibitory concentrations (2 to 10 µg/mL) significantly inhibited C. albicans biofilm formation with an MIC of 50 µg/mL, whereas the backbone hydroquinone did not (MIC > 400 µg/mL), and it markedly inhibited cell aggregation and hyphal formation. Transcriptomic analyses showed that TCHQ downregulated the expressions of several hyphae-forming and biofilm-related genes (ALS3, ECE1, HWP1, RBT5, and UME6) but upregulated hyphae- and biofilm-inhibitory genes (IFD6 and YWP1). Furthermore, it prevented C. albicans biofilm development on porcine skin and at concentrations of 20 to 50 µg/mL was nontoxic to the nematode Caenorhabditis elegans and did not adversely affect Brassica rapa seed germination and growth. This study indicates that hydroquinones, particularly TCHQ, diminish the virulence, biofilm formation, and animal tissue adhesion of C. albicans, which suggests hydroquinones should be considered potential candidate antifungal agents against drug-resistant C. albicans strains. IMPORTANCE Persistence in chronic infections by Candida albicans is due to its ability of biofilm formation that endures conventional antifungals and host immune systems. Hence, the inhibition of biofilm formation and virulence characteristics is another mean of addressing infections. This study is a distinctive one since 18 hydroquinone analogues were screened and TCHQ efficiently inhibited the biofilm formation by C. albicans with significantly changed expressional profile of hyphae-forming and biofilm-related genes. The antibiofilm efficacy was confirmed using a porcine skin model and chemical toxicity was investigated using plant seed germination and nematode models. Our findings reveal that TCHQ can efficiently control the C. albicans biofilms and virulence characteristics.


Assuntos
Candida albicans , Hifas , Animais , Humanos , Candida albicans/genética , Hifas/genética , Antifúngicos/farmacologia , Hidroquinonas/farmacologia , Fluconazol/farmacologia , Biofilmes , Fatores de Virulência/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiologia
7.
Egypt J Immunol ; 29(4): 134-147, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36208042

RESUMO

Candida species resistant to fluconazole and voriconazole were screened for the presence of ERG11gene by polymerase chain reaction (PCR). Also, the association of this gene with the demonstration of Candida virulence factors; biofilm formation, phospholipase and proteinases activities were studied. A total of 61 Candida isolates were collected from urine specimens. Candida species were identified by API 20 C Aux test. Extracellular phospholipase, secretory aspartyl proteinase and biofilm formation were determined. ERG11 gene was detected by PCR. C. albicans was identified in 34.5%, C. glabrata in 29.5% and C. tropicalis and C. krusei in 18% each. Candida species was resistant to fluconazole and voriconazole in 55.7% and 27.9%, respectively. Seventeen (50%) of fluconazole resistant Candida isolates were sensitive to voriconazole. The most frequently Candida species revealed fluconazole resistance were C. glabrata (47.1%), C. krusei (29.4%), and C. tropicalis and C. albicans (11.8% each). Biofilm formation, phospholipase and proteinase activity were determined in 41.2%, 67.6% and 35.3% of fluconazole resistant Candida isolates, respectively. Erg 11 gene was determined in 82.4% of fluconazole resistant Candida isolates and prominent in C. glabrata (93.75%), followed by C. krusei (90%), C. tropicalis (75%) and C. albicans (25%). Erg 11 gene was detected in 64.7% (11/17) of fluconazole resistant-voriconazole sensitive Candida isolates. Regarding, correlation of Erg11 gene positivity and virulence factors among fluconazole resistant Candida isolates, 34.5% exhibited biofilm formation and 62.1% and 31% showed phospholipase and proteinase activities, respectively. There were statistically significant difference concerning the association of proteinase activities and Erg 11 gene expression among fluconazole resistance Candida isolates (P=0.04). The study emphasizes the high prevalence of Erg11 gene among fluconazole resistant Candida species. There was association between the proteinase activity, fluconazole resistance and the presence of Erg11 among Candida species. Voriconazole maintains better activity towards Candida species and represent an alternative therapy.


Assuntos
Ácido Aspártico Proteases , Sistema Enzimático do Citocromo P-450/genética , Fluconazol , Proteínas Fúngicas/genética , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/genética , Candida albicans/genética , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Peptídeo Hidrolases , Fosfolipases , Fatores de Virulência/genética , Voriconazol/farmacologia
8.
Curr Microbiol ; 79(11): 338, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36201048

RESUMO

Owing to the resistance of nosocomial pathogens to antibiotics, the need for herbal medicines is felt. The aim of this study was to identify the chemical composition of bark essential oils of Campsis radicans and the effect of its free and encapsulated form on resistant nosocomial pathogens. This plant is a native of Northern Iran. The Bark essential oils of Campsis radicans was first extracted and its antimicrobial effects were investigated. Then, its phytochemical compounds were determined using Gas Chromatography-Mass Spectrometry (GC/MS). Guaiacol (2-methoxy phenol) was selected as the active ingredient among 32 compounds (2.40%). It was encapsulated and the encapsulation efficiency (EE), the particle size, polydispersity index (pdi), Fourier transform infrared (FTIR), release, and stability were determined. Then, the antimicrobial effect of both free and encapsulated forms was evaluated on cotrimoxazole-resistant Pseudomonas aeruginosa, cefixime-resistant Escherichia coli, and fluconazole-resistant Candida albicans. It was observed that both free and encapsulated forms of Guaiacol had an antimicrobial effect on the studied resistant strains, but the encapsulated form had a more antimicrobial effect due to more stability and a more targeted effect. MBC (MFC) ranged from 0.270 to 0.439 µg/ml in the free form and from 0.055 to 0.133 µg/ml in the encapsulated form, EE was 86%, particle size, and pdi were 138 nm and 0.26, respectively. This study showed that this plant can be a suitable alternative to chemical drugs due to its antimicrobial effects.


Assuntos
Anti-Infecciosos , Infecção Hospitalar , Óleos Voláteis , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias , Cefixima/farmacologia , Fluconazol/farmacologia , Guaiacol , Humanos , Testes de Sensibilidade Microbiana , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Óleos Vegetais/farmacologia , Combinação Trimetoprima e Sulfametoxazol/farmacologia
9.
Bioorg Chem ; 129: 106216, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36283177

RESUMO

In order to develop new triazole derivatives, we optimized the lead compound a6 by structural modifications to obtain a series of (2R,3R)-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compounds 5-36. Most of the target compounds exhibited excellent in vitro antifungal activity against Candida albicans 10231 and Candida glabrata 537 with MIC ≤ 0.125 µg/mL. Of particular note, compounds 6, 22, 28, 30 and 36 were highly active against Candida neoformans 32609 with MIC ≤ 0.125 µg/mL and showed broad-spectrum antifungal activity including against fluconazole-resistant Candida auris 891. In addition, compounds 6 and 22 demonstrated inhibitory effects on filamentation in the azole-resistant C. albicans isolate. Moreover, compounds 6 and 22 were minimally toxic to HUVECs and possessed weak inhibitory effects on the human CYP3A4 and CYP2D6. SARs and docking study further indicated that ortho-substituted groups in the terminal phenyl ring can promote the compounds to improve their antifungal activity.


Assuntos
Antifúngicos , Triazóis , Humanos , Antifúngicos/química , Triazóis/química , Testes de Sensibilidade Microbiana , Fluconazol/farmacologia , Candida albicans , Relação Estrutura-Atividade
10.
BMC Complement Med Ther ; 22(1): 264, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224581

RESUMO

BACKGROUND: The development of multidrug resistance (MDR) associated with the overexpression of the efflux transporters Mdr1 and Cdr1 in Candida species impedes antifungal therapies. The urgent need for novel agents able to inhibit the function of both pumps, led us to evaluate this property in 137 extracts obtained from Argentinian plants. METHODS: The ability of the extracts to reverse efflux pump-mediated MDR was determined with an agar chemosensitization assay using fluconazole (FCZ) resistant Mdr1- and Cdr1-overexpressing clinical isolates of Candida albicans and Candida glabrata as well as Saccharomyces cerevisiae strains selectively expressing Mdr1 (AD/CaMDR1) or Cdr1 (AD/CaCDR1). The resistance-reversing activity of the most potent extracts was further confirmed using a Nile Red accumulation assay. RESULTS: Fifteen plant extracts overcame the FCZ resistance of Candida albicans 1114, which overexpresses CaMdr1 and CaCdr1, and AD/CaMDR1, with those from Acalypha communis and Solanum atriplicifolium being the most effective showing 4- to 16-fold reversal of resistance at concentrations ≥ 25 µg/mL. Both extracts, and to a lesser extent that from Pterocaulon alopecuroides, also restored FCZ sensitivity in CgCdr1-overexpressing C. glabrata 109 and in AD/CaCDR1 with fold reversal values ranging from 4 to 32 and therefore demonstrating a dual effect against Mdr1 and Cdr1. Both, A. communis and S. atriplicifolium extracts at concentrations ≥ 12.5 and ≥ 25 µg/mL, respectively, increased the intracellular Nile Red accumulation in all yeast strains overexpressing efflux pumps. CONCLUSIONS: The non-toxic and highly active extracts from A. communis and S. atripicifolium, provide promising sources of compounds for potentiating the antifungal effect of FCZ by blocking the efflux function of Mdr1 and Cdr1 transporters.


Assuntos
Candida , Fluconazol , Ágar/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans , Farmacorresistência Fúngica , Fluconazol/farmacologia , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae
11.
Molecules ; 27(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36234837

RESUMO

The aim of our study was to determine the susceptibility of 15 Candida albicans sputum isolates on fluconazole and caspofungin, as well as the antifungal potential of Lavandula angustifolia essential oil (LAEO). The commercial LAEO was analyzed using gas chromatography-mass spectrometry. The antifungal activity was evaluated using EUCAST protocol. A killing assay was performed to evaluate kinetics of 2% LAEO within 30 min treatment. LAEO with major constituents' linalool (33.4%) and linalyl acetate (30.5%) effective inhibited grows of C. albicans in concentration range 0.5-2%. Fluconazole activity was noted in 67% of the isolates with MICs in range 0.06-1 µg/mL. Surprisingly, 40% of isolates were non-wild-type (non-WT), while MICs for WT ranged between 0.125-0.25 µg/mL. There were no significant differences in the LAEO MICs among fluconazole-resistant and fluconazole-susceptible sputum strains (p = 0.31) and neither among caspofungin non-WT and WT isolates (p = 0.79). The 2% LAEO rapidly achieved 50% growth reduction in all tested strains between 0.2 and 3.5 min. Within 30 min, the same LAEO concentration exhibited a 99.9% reduction in 27% isolates. This study demonstrated that 2% solution of LAEO showed a significant antifungal activity which is equally effective against fluconazole and caspofungin susceptible and less-susceptible strains.


Assuntos
Lavandula , Óleos Voláteis , Antifúngicos/farmacologia , Candida , Candida albicans , Caspofungina/farmacologia , Criança , Farmacorresistência Fúngica , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Óleos Voláteis/farmacologia , Escarro
12.
Molecules ; 27(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36235041

RESUMO

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10-4 to 1.98 × 10-3 mol·L-1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.


Assuntos
Antifúngicos , Fluconazol , 1-Octanol/química , Antifúngicos/farmacologia , Fluconazol/farmacologia , Octanóis , Solubilidade , Solventes/química , Termodinâmica , Água/química
13.
Future Microbiol ; 17: 1325-1333, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36111728

RESUMO

Aim: To evaluate the antifungal activity of chelerythrine in combination with fluconazole against planktonic Candida albicans strains and preformed biofilm. Materials & methods: A broth microdilution assay was used to reveal the antifungal activity of chelerythrine combined with fluconazole against C. albicans and the preformed biofilm. A fractional inhibitory concentration index model was used to evaluate the interaction. Results: Chelerythrine strongly synergized with fluconazole against fluconazole-resistant C. albicans and the biofilm preformed for less than 12 h. In addition, chelerythrine combined with fluconazole exhibited a synergistic effect against C. albicans morphogenesis. Conclusion: Chelerythrine could reverse the drug resistance of resistant C. albicans and its biofilm to fluconazole, providing new insights for overcoming the drug resistance of C. albicans.


Assuntos
Candida albicans , Fluconazol , Antifúngicos/farmacologia , Benzofenantridinas , Biofilmes , Resistência a Medicamentos , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana
14.
Emerg Microbes Infect ; 11(1): 2405-2411, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36154919

RESUMO

Candida auris has emerged globally as a multidrug-resistant pathogen causing outbreaks in health care facilities. Whole genome sequencing (WGS) analysis has identified four major clades, while earlier WGS data from a single Iranian isolate suggested the existence of a potential fifth clade. Here, we confirm the existence of this fifth clade by providing WGS data of another four Iranian isolates. These clade V isolates differed less than 100 single-nucleotide polymorphisms (SNPs) between each other, while they were separated from the other clades by more than 200,000 SNPs. Two of these isolates were resistant to fluconazole and were found to harbour mutations in the TAC1b and ERG11 genes.


Assuntos
Candida , Candidíase , Humanos , Antifúngicos/farmacologia , Candida/genética , Candida auris , Candidíase/epidemiologia , Fluconazol/farmacologia , Irã (Geográfico) , Testes de Sensibilidade Microbiana , Sequenciamento Completo do Genoma , Polimorfismo de Nucleotídeo Único
15.
J Med Microbiol ; 71(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36126092

RESUMO

Introduction. Candida spp. may cause opportunistic infections called vulvovaginal candidiasis (VVC), which is estimated to be the second most common cause of vaginitis worldwide.Gap Statement. Under various circumstances, VVC could compromise pregnancy outcomes. Emerging data suggests that VVC during pregnancy may be associated with increased risk of complications and congenital cutaneous candidiasis.Aim. To assess the prevalence of Candida spp. in asymptomatic pregnant women and determine the susceptibility of the isolates to antifungal drugs.Methodology. In a prospective cohort, 65 high vaginal swab samples of consented pregnant women. Candida isolates were identified using both microbiological and molecular tools and drug susceptibilities were profiled.Results. The prevalence of VVC among our study participants was 37 %, 24 of the 65 asymptomatic pregnant women show Candida spp. colonization. C. albicans was the most common species 61 %, followed by C. glabrata 39 %. In addition, a significant fraction of the isolated colonies showed resistance to Fluconazole, with a ratio of 63 % for C. albicans isolates and 16 % for Candida glabrata isolates. Moreover, relative quantification of genes related to resistance to fluconazole, CDR1, ERG11 as well as HWP1, showed a significant change compared to controls.Conclusion. Monitoring of vaginal Candida colonization before the third trimester of pregnancy, that could reduce congenital Candida colonization and risk of pregnancy complications.


Assuntos
Candida , Candidíase Vulvovaginal , Antifúngicos/farmacologia , Candida albicans/genética , Candidíase Vulvovaginal/epidemiologia , Candidíase Vulvovaginal/microbiologia , Feminino , Fluconazol/farmacologia , Humanos , Recém-Nascido , Gravidez , Gestantes , Estudos Prospectivos , Vagina/microbiologia
16.
Emerg Microbes Infect ; 11(1): 2264-2274, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36066554

RESUMO

Patients presenting with severe COVID-19 are predisposed to acquire secondary fungal infections such as COVID-19-associated candidemia (CAC), which are associated with poor clinical outcomes despite antifungal treatment. The extreme burden imposed on clinical facilities during the COVID-19 pandemic has provided a permissive environment for the emergence of clonal outbreaks of multiple Candida species, including C. auris and C. parapsilosis. Here we report the largest clonal CAC outbreak to date caused by fluconazole resistant (FLZR) and echinocandin tolerant (ECT) C. parapsilosis. Sixty C. parapsilosis strains were obtained from 57 patients at a tertiary care hospital in Brazil, 90% of them were FLZR and ECT. Although only 35.8% of FLZR isolates contained an ERG11 mutation, all of them contained the TAC1L518F mutation and significantly overexpressed CDR1. Introduction of TAC1L518F into a susceptible background increased the MIC of fluconazole and voriconazole 8-fold and resulted in significant basal overexpression of CDR1. Additionally, FLZR isolates exclusively harboured E1939G outside of Fks1 hotspot-2, which did not confer echinocandin resistance, but significantly increased ECT. Multilocus microsatellite typing showed that 51/60 (85%) of the FLZR isolates belonged to the same cluster, while the susceptible isolates each represented a distinct lineage. Finally, biofilm production in FLZR isolates was significantly lower than in susceptible counterparts Suggesting that it may not be an outbreak determinant. In summary, we show that TAC1L518F and FKS1E1393G confer FLZR and ECT, respectively, in CAC-associated C. parapsilosis. Our study underscores the importance of antifungal stewardship and effective infection control strategies to mitigate clonal C. parapsilosis outbreaks.


Assuntos
COVID-19 , Candidemia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Brasil/epidemiologia , COVID-19/epidemiologia , Candida parapsilosis/genética , Candidemia/tratamento farmacológico , Candidemia/epidemiologia , Candidemia/microbiologia , Surtos de Doenças , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Pandemias , Voriconazol/uso terapêutico
17.
Pediatr Endocrinol Diabetes Metab ; 28(3): 226-232, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36134674

RESUMO

The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including glucocorticosteroids, immune checkpoint inhibitors, mitotane, metyrapone, aminoglutetimide, etomidate, ketoconazole, fluconazole), but also radiation therapy on the functioning of the hypothalamic-pituitary-adrenal axis in children and adolescent during and after oncological treatment. The most common pediatric cancers, where complications of adrenal insufficiency occur, are presented. Moreover, current recommendations how to diagnose the function of the adrenal axis in oncological pediatric patients, as well during oncological treatment as after it, including patients treated with steroids and also patients in severe stages, are reported. The rules of the treatment of adrenal dysfunction in those patients are presented. This understanding is of key importance for oncologists and endocrinologists in the process of diagnosing, treating and developing patient health care, as well as during therapy as after it, offering safety and improving the quality of life.


Assuntos
Etomidato , Sistema Hipófise-Suprarrenal , Adolescente , Glândulas Suprarrenais , Criança , Etomidato/farmacologia , Fluconazol/farmacologia , Humanos , Sistema Hipotálamo-Hipofisário , Inibidores de Checkpoint Imunológico , Cetoconazol/farmacologia , Cetoconazol/uso terapêutico , Metirapona/farmacologia , Metirapona/uso terapêutico , Mitotano/farmacologia , Mitotano/uso terapêutico , Qualidade de Vida
18.
Virulence ; 13(1): 1573-1589, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36120738

RESUMO

Antifungal resistance to Candida pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the Candida prevalence and antifungal susceptibility pattern is necessary to control and treat candidiasis. We aimed to systematically analyse the susceptibility profiles of Candida species published in the last ten years (December 2011 to December 2021) from mainland China. The studies were collected from PubMed, Google Scholar, and Science Direct search engines. Out of 89 included studies, a total of 44,716 Candida isolates were collected, mainly comprising C. albicans (49.36%), C. tropicalis (21.89%), C. parapsilosis (13.92%), and C. glabrata (11.37%). The lowest susceptibility was detected for azole group; fluconazole susceptibilities against C. parapsilosis, C. albicans, C. glabrata, C. tropicalis, C. guilliermondii, C. pelliculosa, and C. auris were 93.25%, 91.6%, 79.4%, 77.95%, 76%, 50%, and 0% respectively. Amphotericin B and anidulafungin were the most susceptible drugs for all Candida species. Resistance to azole was mainly linked with mutations in ERG11, ERG3, ERG4, MRR1-2, MSH-2, and PDR-1 genes. Mutation in FKS-1 and FKS-2 in C. auris and C. glabrata causing resistance to echinocandins was stated in two studies. Gaps in the studies' characteristics were detected, such as 79.77%, 47.19 %, 26.97%, 7.86%, and 4.49% studies did not mention the mortality rates, age, gender, breakpoint reference guidelines, and fungal identification method, respectively. The current study demonstrates the overall antifungal susceptibility pattern of Candida species, gaps in surveillance studies and risk-reduction strategies that could be supportive in candidiasis therapy and for the researchers in their future studies.


Assuntos
Candida , Candidíase , Anfotericina B , Anidulafungina , Antifúngicos/farmacologia , Azóis , Candida albicans , Candida glabrata , Candida parapsilosis , Candida tropicalis , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Candidíase/microbiologia , Equinocandinas , Fluconazol/farmacologia , Humanos , Hormônios Estimuladores de Melanócitos , Testes de Sensibilidade Microbiana
19.
Med Mycol ; 60(9)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36055797

RESUMO

Baicalein could inhibit the growth and biofilm formation of Candida albicans, the most common clinical fungal pathogen. However, the antifungal mechanism of baicalein has not been elucidated. In this study, isobaric tags for relative and absolute quantification (iTRAQ) was used to verify the mechanism of antifungal fluconazole and baicalein. A total of 58 common proteins were detected in cells treated with fluconazole. These proteins encompassed fluconazole-targeted sterol synthesis pathway, including Erg11p, Erg6p, Erg3p, Erg25p, Erg5p, Erg10p, and Ncp1p. Next, iTRAQ was applied to the comparison of baicalein-treated C. albicans proteins, which detected 16 common proteins. The putative NADH dehydrogenase Cpd2p and the ATP-binding cassette transporter Snq2p were the most upregulated proteins with the treatment of baicalein. Our results showed that CPD2 disruption elevated C. albicans resistance to baicalein significantly both in vitro and in vivo. Further in-depth studies revealed that CPD2 disruption reduced the activation of C. albicans metacaspase and partially restored the mitochondrial membrane potential reduction caused by the treatment of baicalein, which indicated that CPD2 was involved in the apoptosis induced by baicalein. Consistently, under the treatment of baicalein, CPD2Δ/Δ mutant produced lower reactive oxygen species that was critical in causing oxidative damage and apoptosis in C. albicans. These results indicated that baicalein could increase intracellular oxidative damage by upregulating the expression of Cpd2p so as to inhibit the growth of C. albicans, which provides new insights for investigating the antifungal target of baicalein.


In our study, isobaric tags for relative and absolute quantification (iTRAQ) was used to study the antifungal mechanisms of fluconazole and baicalein. Baicalein could enhance the oxidative stress of Candida albicans by upregulating CPD2 expression.


Assuntos
Candida albicans , Fluconazol , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Farmacorresistência Fúngica , Flavanonas , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana/veterinária , Estresse Oxidativo , Proteômica
20.
J Pak Med Assoc ; 72(7): 1330-1334, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36156555

RESUMO

OBJECTIVE: To examine the in vitro antifungal effects of water-soluble pure elemental boron with an alkaline solution against Candida species, Trichophyton species, and Aspergillus fumigatus that cause superficial mycosis. METHODS: The study was conducted at the microbiology laboratory of Kahramanmaras Sutcu Imam University Hospital, Kahramanmaras, Turkey, from June to December 2018, and comprised fungal strains isolated from patients with superficial mycosis who visited the dermatology clinic. The in vitro antifungal effects of the boron solution at various concentrations were determined using the microbroth dilution method. Candida albicans ATTC 90028 and Candida albicans MYA 274 served as the quality control strains, while fluconazole and amphotericin B were used as comparator antifungal agents. Data was analysed using SPSS 22. RESULTS: Of the 58 strains, 28(48.3%) were Candida albicans, 9(15.5%) non-Candida albicans, 12(20.7%) Trichophyton rubrum, 4(6.9%) Trichophyton mentagrophytes, 2(3.4%) Trichophyton species and 3(5.2%) were Aspergillus fumigates. Boron at a concentration of 78.125 µg/mL inhibited the growth of Candida albicans. The 50% and 90% minimum inhibitory concentrations of the solution in non-Candida albicanswere 78.125 and 312.5 µg/mL, respectively, whereas those in Trichophyton rubrum were 312.5 and 625 µg/mL, respectively. The 50% minimum inhibitory concentration of the solution in Aspergillus fumigatus was 625 µg/mL, whereas the 90% minimum inhibitory concentration could not be determined. CONCLUSIONS: Boron is an inexpensive, non-antibiotic element with potential uses as an antifungal agent.


Assuntos
Antifúngicos , Fluconazol , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Arthrodermataceae , Boro/farmacologia , Candida , Candida albicans , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Trichophyton , Água
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