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1.
Mycoses ; 67(4): e13727, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38650397

RESUMO

BACKGROUND: Candidaemia is a life-threatening disease that is associated with high mortality, especially in intensive care units (ICUs). The number of comprehensive studies dealing with the epidemiologic characteristics of biofilm-related properties is limited. OBJECTIVE: This study evaluated the clinical characteristics of candidaemia, to assess the biofilm-forming properties of isolates, and to identify the risk factors of mortality. PATIENTS AND METHODS: A total of 149 candidaemia episodes from the University of Debrecen, Clinical Centre, between January 2020 and December 2023 were investigated retrospectively. The susceptibility of Candida isolates to fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin was evaluated and compared to the susceptibility of 1-day-old biofilms. Multivariate logistic regression analysis was applied to identify the independent predictors of 30-day mortality rate. RESULTS: The most common Candida species was Candida albicans (41%), followed by C. parapsilosis (20%), C. glabrata (14%), C. tropicalis (13%), rare Candida species (7%), and C. krusei (5%). Sixty-six percent of Candida isolates were biofilm formers and 44% had high metabolic activity. The 30-day mortality rate was 52%, which was higher in ICUs (65%). The logistic regression analysis revealed several factors significantly influencing mortality including ICU admission (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.17-8.04, p = 0.025), fluconazole treatment (OR 4.12, 95% CI 1.62-11.42, p = .004), and pneumonia (OR 0.261, 95% CI 0.1-0.67, p = .006). CONCLUSIONS: This comprehensive analysis supports the better characterisation of candidaemia in healthcare settings, which ultimately may reduce mortality among patients.


Assuntos
Antifúngicos , Biofilmes , Candida , Candidemia , Humanos , Candidemia/microbiologia , Candidemia/epidemiologia , Candidemia/mortalidade , Candidemia/tratamento farmacológico , Biofilmes/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , Estudos Retrospectivos , Feminino , Masculino , Hungria/epidemiologia , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candida/classificação , Candida/fisiologia , Pessoa de Meia-Idade , Idoso , Testes de Sensibilidade Microbiana , Adulto , Fatores de Risco , Unidades de Terapia Intensiva/estatística & dados numéricos , Idoso de 80 Anos ou mais , Fluconazol/uso terapêutico , Fluconazol/farmacologia
2.
Mycopathologia ; 188(1-2): 111-118, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36399230

RESUMO

Until recently, little was known about the susceptibility pattern of Cyberlindnera fabianii (Cy. fabianii) planktonic cells and biofilms regarding the most frequently administered systemic antifungals, despite the high mortality rate and its potential role in catheter-related infections. In the current study, the activity of fluconazole, amphotericin B and echinocandins (anidulafungin, caspofungin and micafungin) was determined against planktonic and sessile cells of Cy. fabianii clinical isolates (n = 8). Planktonic minimum inhibitory concentrations (MICs) ranged from 1 to 2, from 0.25 to 1, from 0.015 to 0.06, from 0.03 to 0.12 and from 0.25 to 0.5 mg/l for fluconazole, amphotericin B, anidulafungin, caspofungin and micafungin, respectively. One-day-old biofilms were highly resistant to fluconazole (MIC ranged from 512 to > 512) compared to planktonic counterparts, but not to amphotericin B (MIC ranged from 0.25 to 2 mg/l) and echinocandins (MIC ranged from 0.06 to 2 mg/l). Based on the calculated planktonic killing rates, the highest activity was observed in the case of anidulafungin (k values ranged from 0.37 to 2.09), while micafungin, caspofungin, amphotericin B and fluconazole exerted 0.46-1.47, 0.14-0.86, -0.03 to 2.08 and -0.15 to 0.09 killing rate value ranges, respectively. The obtained in vitro planktonic and sessile susceptibility patterns suggest that echinocandins and amphotericin B may be the most reliable treatment option for the treatment of Cy. fabianii infections.


Assuntos
Anfotericina B , Equinocandinas , Equinocandinas/farmacologia , Anfotericina B/farmacologia , Fluconazol/farmacologia , Anidulafungina/farmacologia , Caspofungina , Micafungina , Biofilmes
3.
Med Mycol ; 59(10): 1015-1023, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34021571

RESUMO

The in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug-drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2 mg/l and between 0.015 and 4 mg/l for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2-128-fold and 2-256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03-0.5; Bliss cumulative synergy volume range 0-4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32 mg/l and between 0.5 and >2 mg/l for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0-128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023-0.5; Bliss cumulative synergy volume range 0.13-234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than three log volumes in mice treated with combination of 1 mg/kg caspofungin and 20 mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (P < 0.001). Despite the favorable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.


Candida auris poses a continuous therapeutic challenge. We demonstrate an approach where the combination of caspofungin and isavuconazole showed a potent activity against planktonic cells and biofilms. This synergism helps to expand the therapeutic options against C. auris.


Assuntos
Candida auris , Candida , Animais , Antifúngicos/farmacologia , Biofilmes , Caspofungina , Camundongos , Testes de Sensibilidade Microbiana/veterinária , Nitrilas , Plâncton , Piridinas , Triazóis
4.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466640

RESUMO

Candida auris is a potential multidrug-resistant pathogen able to persist on indwelling devices as a biofilm, which serve as a source of catheter-associated infections. Neosartorya fischeri antifungal protein 2 (NFAP2) is a cysteine-rich, cationic protein with potent anti-Candida activity. We studied the in vitro activity of NFAP2 alone and in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin against C. auris biofilms. The nature of interactions was assessed utilizing the fractional inhibitory concentration index (FICI), a Bliss independence model, and LIVE/DEAD viability assay. NFAP2 exerted synergy with all tested antifungals with FICIs ranging between 0.312-0.5, 0.155-0.5, 0.037-0.375, 0.064-0.375, and 0.064-0.375 for fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. These results were confirmed using a Bliss model, where NFAP2 produced 17.54 µM2%, 2.16 µM2%, 33.31 µM2%, 10.72 µM2%, and 111.19 µM2% cumulative synergy log volume in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. In addition, biofilms exposed to echinocandins (32 mg/L) showed significant cell death in the presence of NFAP2 (128 mg/L). Our study shows that NFAP2 displays strong potential as a novel antifungal compound in alternative therapies to combat C. auris biofilms.


Assuntos
Antifúngicos/metabolismo , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Proteínas Fúngicas/metabolismo , Neosartorya/metabolismo , Antifúngicos/farmacologia , Candida/fisiologia , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Proteínas Fúngicas/farmacologia , Humanos
5.
Med Mycol ; 58(3): 404-407, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127836

RESUMO

Candida auris biofilms exhibit decreased susceptibility to echinocandins, which is associated with poorer clinical outcomes. Farnesol is a quorum-sensing molecule enhancing the activity of antifungals; therefore, we evaluated the in vitro effect of farnesol with anidulafungin, caspofungin, or micafungin against biofilms using fractional inhibitory concentration indexes (FICI), Bliss independence model, LIVE/DEAD-assay and scanning electron microscopy. Based on mathematical models, farnesol caused synergism in eleven out of twelve cases (FICIs range 0.133-0.507; Bliss synergy volume range 70.39-204.6 µM2%). This was confirmed by microscope images of combination-exposed biofilms. Our study showed the prominent effect of farnesol with echinocandins against C. auris biofilms.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Equinocandinas/farmacologia , Farneseno Álcool/farmacologia , Caspofungina/farmacologia , Sinergismo Farmacológico , Micafungina/farmacologia , Testes de Sensibilidade Microbiana , Modelos Teóricos
6.
Mycoses ; 63(4): 352-360, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31943428

RESUMO

BACKGROUND: Candidaemia is a common life-threatening disease among hospitalised patients, but the effect of the Candida biofilm-forming ability on the clinical outcome remains controversial. OBJECTIVE: The aim was to determine the impact of biofilms, specifically focusing on biofilm mass and metabolic activity, on the mortality in candidaemia. PATIENTS/METHODS: The clinical data of patients (n = 127) treated at the University of Debrecen, Clinical Centre, between January 2013 and December 2018, were investigated retrospectively. Biofilm formation was assessed using the crystal violet and XTT assays, measuring the biofilm mass and metabolic activity, respectively. Isolates were classified as low, intermediate and high biofilm producers both regarding biofilm mass and metabolic activity. The susceptibility of one-day-old biofilms to fluconazole, amphotericin B, anidulafungin, caspofungin and micafungin was evaluated and compared to planktonic susceptibility. RESULTS: Intermediate/high biofilm mass was associated with significantly higher mortality (61%). All Candida tropicalis, Candida parapsilosis and Candida glabrata isolates originating from fatal infections were intermediate/high biofilm producers, whereas this ratio was 85% for Candida albicans. Solid malignancy was associated with intermediate/high biofilm producers (P = .043). The mortality was significantly higher in infections caused by Candida strains producing biofilms with intermediate/high metabolic activity (62% vs. 33%, P = .010). The ratio of concomitant bacteraemia was higher for isolates forming biofilms with low metabolic activity (53% vs 28%, P = .015). CONCLUSIONS: This study provides evidence that the Candida biofilms especially with intermediate/high metabolic activity are related to higher mortality in candidaemia.


Assuntos
Biofilmes/crescimento & desenvolvimento , Candida , Candidemia/sangue , Mortalidade , Candida/isolamento & purificação , Candida/metabolismo , Candida albicans/isolamento & purificação , Candida albicans/metabolismo , Candida glabrata/isolamento & purificação , Candida glabrata/metabolismo , Candida parapsilosis/isolamento & purificação , Candida parapsilosis/metabolismo , Candida tropicalis/isolamento & purificação , Candida tropicalis/metabolismo , Feminino , Humanos , Masculino , Estudos Retrospectivos
7.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085460

RESUMO

: Multiple drug resistant fungi pose a serious threat to human health, therefore the development of completely new antimycotics is of paramount importance. The in vitro antifungal activity of the original, 1-amino-5-isocyanonaphthalenes (ICANs) was evaluated against reference strains of clinically important Candida species. Structure-activity studies revealed that the naphthalene core and the isocyano- together with the amino moieties are all necessary to exert antifungal activity. 1,1-N-dimethylamino-5-isocyanonaphthalene (DIMICAN), the most promising candidate, was tested further in vitro against clinical isolates of Candida species, yielding a minimum inhibitory concentration (MIC) of 0.04-1.25 µg/mL. DIMICAN was found to be effective against intrinsically fluconazole resistant Candida krusei isolates, too. In vivo experiments were performed in a severly neutropenic murine model inoculated with a clinical strain of Candida albicans. Daily administration of 5 mg/kg DIMICAN intraperitoneally resulted in 80% survival even at day 13, whereas 100% of the control group died within six days. Based on these results, ICANs may become an effective clinical lead compound family against fungal pathogens.


Assuntos
Antifúngicos/farmacologia , Naftalenos/farmacologia , Animais , Antifúngicos/química , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Naftalenos/química , Naftalenos/uso terapêutico , Relação Estrutura-Atividade
8.
Clin Infect Dis ; 69(8): 1410-1421, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30561543

RESUMO

BACKGROUND: Increasing antibiotic resistance may reciprocally affect consumption and lead to use of broader-spectrum alternatives; a vicious cycle that may gradually limit therapeutic options. Our aim in this study was to demonstrate this vicious cycle in gram-negative bacteria and show the utility of vector autoregressive (VAR) models for time-series analysis in explanatory and dependent roles simultaneously. METHODS: Monthly drug consumption data in defined daily doses per 100 bed-days and incidence densities of gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii) resistant to cephalosporins or to carbapenems were analyzed using VAR models. These were compared to linear transfer models used earlier. RESULTS: In case of all gram-negative bacteria, cephalosporin consumption led to increasing cephalosporin resistance, which provoked carbapenem use and consequent carbapenem resistance and finally increased colistin consumption, exemplifying the vicious cycle. Different species were involved in different ways. For example, cephalosporin-resistant Klebsiella spp. provoked carbapenem use less than E. coli, and the association between carbapenem resistance of P. aeruginosa and colistin use was weaker than that of A. baumannii. Colistin use led to decreased carbapenem use and decreased carbapenem resistance of P. aeruginosa but not of A. baumannii. CONCLUSIONS: VAR models allow analysis of consumption and resistance series in a bidirectional manner. The reconstructed resistance spiral involved cephalosporin use augmenting cephalosporin resistance primarily in E. coli. This led to increased carbapenem use, provoking spread of carbapenem-resistant A. baumannii and consequent colistin use. Emergence of panresistance is fueled by such antibiotic-resistance spirals.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Colistina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Acinetobacter baumannii/efeitos dos fármacos , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Humanos , Hungria , Klebsiella pneumoniae/efeitos dos fármacos , Modelos Estatísticos , Pseudomonas aeruginosa/efeitos dos fármacos
9.
Artigo em Inglês | MEDLINE | ID: mdl-30478163

RESUMO

As a consequence of emerging numbers of vulvovaginitis cases caused by azole-resistant and biofilm-forming Candida species, fast and efficient treatment of this infection has become challenging. The problem is further exacerbated by the severe side effects of azoles as long-term-use medications in the recurrent form. There is therefore an increasing demand for novel and safely applicable effective antifungal therapeutic strategies. The small, cysteine-rich, and cationic antifungal proteins from filamentous ascomycetes are potential candidates, as they inhibit the growth of several Candida spp. in vitro; however, no information is available about their in vivo antifungal potency against yeasts. In the present study, we investigated the possible therapeutic application of one of their representatives in the treatment of vulvovaginal candidiasis, Neosartorya fischeri antifungal protein 2 (NFAP2). NFAP2 inhibited the growth of a fluconazole (FLC)-resistant Candida albicans strain isolated from a vulvovaginal infection, and it was effective against both planktonic cells and biofilm in vitro We observed that the fungal cell-killing activity of NFAP2 is connected to its pore-forming ability in the cell membrane. NFAP2 did not exert cytotoxic effects on primary human keratinocytes and dermal fibroblasts at the MIC in vitro. In vivo murine vulvovaginitis model experiments showed that NFAP2 significantly decreases the number of FLC-resistant C. albicans cells, and combined application with FLC enhances the efficacy. These results suggest that NFAP2 provides a feasible base for the development of a fundamental new, safely applicable mono- or polytherapeutic topical agent for the treatment of superficial candidiasis.


Assuntos
Antifúngicos/metabolismo , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Neosartorya/metabolismo , Animais , Candidíase Vulvovaginal/microbiologia , Farmacorresistência Fúngica , Feminino , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana
10.
J Antimicrob Chemother ; 74(12): 3505-3510, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539426

RESUMO

BACKGROUND: Rezafungin is a novel echinocandin with excellent activity against common Candida species; however, limited data are available regarding rare Candida species. METHODS: We determined the in vitro susceptibility of 689 clinical isolates of 5 common and 19 rare Candida species, as well as Saccharomyces cerevisiae. The activity of rezafungin was compared with that of anidulafungin, caspofungin, micafungin, amphotericin B and fluconazole, using CLSI broth microdilution methodology (Fourth Edition: M27). RESULTS: Rezafungin MIC90 values were 0.06 mg/L for Candida albicans (n=125), Candida tropicalis (n=51), Candida dubliniensis (n=22), Candida inconspicua (n=41), Candida sojae (n=10), Candida lipolytica (n=10) and Candida pulcherrima (n=10), 0.12 mg/L for Candida glabrata (n=81), Candida krusei (n=53), Candida kefyr (n=52) and Candida fabianii (n=15), 0.25 mg/L for Candida lusitaniae (n=46) and Candida auris (n=19), 0.5 mg/L for Candida metapsilosis (n=15) and S. cerevisiae (n=21), 1 mg/L for Candida orthopsilosis (n=15) and Candida guilliermondii (n=27) and 2 mg/L for Candida parapsilosis sensu stricto (n=59). Caspofungin MIC90 values were 0.25-2 mg/L for all species, while micafungin and anidulafungin MIC90 values were similar to those of rezafungin. Fluconazole resistance was found in C. albicans (5.6%) and C. glabrata (4.9%); rezafungin was effective against these isolates as well. Amphotericin B MIC values did not exceed 2 mg/L. CONCLUSIONS: Rezafungin showed excellent in vitro activity against both WT and azole-resistant Candida species, as well as against S. cerevisiae. Rezafungin had similar activity to other echinocandins (excluding caspofungin) against common Candida species and, notably, against clinically relevant uncommon Candida species.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Equinocandinas/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Candida/classificação , Candida glabrata/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana
11.
Appl Environ Microbiol ; 85(20)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31399405

RESUMO

Tyrosol plays a key role in fungal morphogenesis and biofilm development. Also, it has a remarkable antifungal effect at supraphysiological concentrations. However, the background of the antifungal effect remains unknown, especially in the case of non-albicans Candida species such as Candida parapsilosis We examined the effect of tyrosol on growth, adhesion, redox homeostasis, virulence, as well as fluconazole susceptibility. To gain further insights into the physiological consequences of tyrosol treatment, we also determined genome-wide gene expression changes using transcriptome sequencing (RNA-Seq). A concentration of 15 mM tyrosol caused significant growth inhibition within 2 h of the addition of tyrosol, while the adhesion of yeast cells was not affected. Tyrosol increased the production of reactive oxygen species remarkably, as revealed by a dichlorofluorescein test, and it was associated with elevated superoxide dismutase, glutathione peroxidase, and catalase activities. The interaction between fluconazole and tyrosol was antagonistic. Tyrosol exposure resulted in 261 and 181 differentially expressed genes with at least a 1.5-fold increase or decrease in expression, respectively, which were selected for further study. Genes involved in ribosome biogenesis showed downregulation, while genes related to the oxidative stress response and ethanol fermentation were upregulated. In addition, tyrosol treatment upregulated the expression of efflux pump genes, including MDR1 and CDR1, and downregulated the expression of the FAD2 and FAD3 virulence genes involved in desaturated fatty acid formation. Our data demonstrate that exogenous tyrosol significantly affects the physiology and gene expression of C. parapsilosis, which could contribute to the development of treatments targeting quorum sensing in the future.IMPORTANCECandida-secreted quorum-sensing molecules (i.e., farnesol and tyrosol) are key regulators in fungal physiology, which induce phenotypic adaptations, including morphological changes, altered biofilm formation, and synchronized expression of virulence factors. Moreover, they have a remarkable antifungal activity at supraphysiological concentrations. Limited data are available concerning the tyrosol-induced molecular and physiological effects on non-albicans Candida species such as C. parapsilosis In addition, the background of the previously observed antifungal effect caused by tyrosol remains unknown. This study reveals that tyrosol exposure enhanced the oxidative stress response and the expression of efflux pump genes, while it inhibited growth and ribosome biogenesis as well as several virulence-related genes. Metabolism was changed toward glycolysis and ethanol fermentation. Furthermore, the initial adherence was not influenced significantly in the presence of tyrosol. Our results provide several potential explanations for the previously observed antifungal effect.


Assuntos
Antifúngicos/farmacologia , Candida parapsilosis/efeitos dos fármacos , Candida parapsilosis/genética , Candida parapsilosis/fisiologia , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Biofilmes/efeitos dos fármacos , Células CACO-2 , Catalase/metabolismo , Antagonismo de Drogas , Fluconazol/farmacologia , Glutationa Peroxidase/metabolismo , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Testes de Sensibilidade Microbiana , Estresse Oxidativo , Álcool Feniletílico/análogos & derivados , Percepção de Quorum , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ativação Transcricional/efeitos dos fármacos , Transcriptoma , Virulência/efeitos dos fármacos , Virulência/genética , Fatores de Virulência/genética
12.
Med Mycol ; 57(5): 573-581, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339227

RESUMO

Biofilm formation is a relevant risk factor for mortality in candidemia. Data about serum-based susceptibility testing against Candida biofilms are scant; therefore, the activity of fluconazole, amphotericin B, caspofungin and micafungin was determined against Candida albicans and C. parapsilosis biofilms with or without 50% human serum using XTT-based assays. Serum caused a remarkable adverse effect regarding biofilm structure for both species. Additionally, the ratio of nonviable cells increased for C. parapsilosis biofilms, as confirmed by fluorescent microscopy and flow cytometry. Despite impaired biofilm development, traditionally biofilm-active antifungals, surprisingly, showed decreased activity against C. albicans biofilms in serum at concentrations ranging from 0.5 to 1 mg/l and from 0.015 to 1 mg/l for amphotericin B and echinocandins, respectively (P < .01-.05). However, C. parapsilosis showed higher susceptibility to these antifungals due to reduced biofilm mass and the fungicidal effect of serum at concentrations ranging from 0.015 to 1 mg/l and from 0.015 to 512 mg/l for amphotericin B and echinocandins, respectively (P < .01-.05). Fluconazole exerted better antifungal activity in serum than traditionally biofilm-active antifungals against both examined biofilms. For fluconazole, significant differences were observed in susceptibility between serum-treated and serum-free biofilms at concentrations ranging from 0.015 to 8 mg/l and from 0.03 to 512 mg/l for C. albicans and C. parapsilosis isolates, respectively (P < .01-.05). The high antifungal activity of fluconazole in 50% serum both against C. albicans and C. parapsilosis biofilms supports the utility of fluconazole prophylaxis to reduce the risk of catheter-associated fungal infections.

13.
Med Mycol ; 56(4): 493-500, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28992253

RESUMO

The activity of fluconazole, amphotericin B, caspofungin and micafungin was determined using XTT-based fungal damage assays against planktonic cells, early and mature biofilms of Candida kefyr. Median MICs of planktonic cells were 0.25 mg/l, 0.25 mg/l, 0.5 mg/l, and 0.06 mg/l for fluconazole, amphotericin B, caspofungin, and micafungin, respectively. Fluconazole showed at least 50% fungal damage at ≥4 mg/l (51.5% ± 6.63% to 78.38% ± 1.44%) and at ≥128 mg/l (57.88% ± 9.2% to 67.25% ± 9.59%), while amphotericin B produced an even higher anti-biofilm effect at ≥0.5 mg/l (64.63% ± 6.79% to 79.5% ± 5.9%) and at ≥0.12 mg/l (77.63% ± 8.43% to 92.75% ± 1.89%) against early and mature biofilms, respectively. In case of micafungin, 50% fungal damage was observed at ≥0.06 mg/l (66.88% ± 10.16% to 98.63% ± 1.24%) and ≥0.25 mg/l (74.13% ± 10.77% to 99.38% ± 0.38%) for early and mature biofilms, respectively. Caspofungin-exposed cells showed an unexpected susceptibility pattern, that is, planktonic cells showed significantly decreased susceptibility at concentrations ranging from 0.015 mg/l to 1 mg/l compared to biofilms (P < .05-.01). The damage in planktonic cells and biofilms was comparable at higher concentrations. For planktonic cells and biofilms, 50% fungal damage was observed first at 0.5 mg/l (59.75% ± 3.16%) and at 0.06 mg/l (70.25% ± 10.95%), respectively. This unexpected pattern was confirmed using scanning electron microscopy. The unusual susceptibility pattern observed at lower caspofungin concentrations may explain the poorer outcome of caspofungin-treated C. kefyr infections documented in certain patient populations. As this phenomenon was markedly less apparent in case of micafungin, these data suggest that micafungin may be a more reliable option than caspofungin for the treatment of C. kefyr infections.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida/crescimento & desenvolvimento , Candida/ultraestrutura , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/microbiologia , Humanos , Testes de Sensibilidade Microbiana
14.
Mycopathologia ; 183(6): 905-912, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30382508

RESUMO

Currently echinocandins are recommended in Candida peritonitis and pleuritis. We determined micafungin killing rates (k values) at therapeutic concentrations (0.25-2 mg/L) in RPMI-1640 with and without 10 and 30% serum mimicking in vivo conditions against six Candida species isolated from peritoneal and pleural fluid. In RPMI-1640, micafungin was fungicidal against C. glabrata, C. krusei and C. kefyr within 2.27 ± 10.68, 2.69 ± 10.29 and 3.10 ± 4.41 h, respectively, while was fungistatic against C. albicans, C. tropicalis and C. parapsilosis. In 10% serum, ≥ 0.25, ≥ 0.5, ≥ 0.5 and ≥ 1 mg/L micafungin produced positive k values (killing) for all C. albicans, C. glabrata, C. kefyr and C. krusei, respectively. In 30% serum, 2 mg/L micafungin produced killing against all C. albicans, C. glabrata and C. kefyr isolates, but was ineffective against C. krusei, C. parapsilosis and 2 of 3 C. tropicalis. Micafungin exposure should be increased against non-albicans species to eradicate fungi from peritoneal and pleural cavities.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase Invasiva/microbiologia , Micafungina/farmacologia , Testes de Sensibilidade Microbiana/métodos , Cavidade Peritoneal/microbiologia , Cavidade Pleural/microbiologia , Candida/isolamento & purificação , Humanos , Viabilidade Microbiana/efeitos dos fármacos
15.
Anal Chem ; 89(4): 2514-2521, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28219247

RESUMO

In the context of supporting the EU Member States in the implementation of the EU Water Framework Directive (WFD), a project for the production of a fish reference material (ERM-CE100) certified for its content of the two priority substances hexachlorobenzene (HCB) and hexachlorobutadiene (HCBD) was carried out at the Joint Research Centre (JRC) of the European Commission. The starting material was naturally contaminated Wels catfish (Silurus glanis), caught in the Ebro River (Spain). A novel approach for the processing of the fish was tested that resulted in a homogeneous and stable reference material in the form of a wet paste. The fresh-like texture of the matrix enhances the comparability of this material toward routinely analyzed environmental biota samples and facilitates its use as a quality assurance tool given that the WFD environmental quality standards (EQS) for biota are expressed as wet weight. Certified values for the mass fractions of HCB and HCBD were assigned with 120 ± 8 and 36 ± 4 µg/kg, respectively. The related interlaboratory comparison involved 13 expert laboratories applying a range of analytical methodologies. It is the first biota CRM ever available for HCBD. ERM-CE100 can be used to assess the performance of analytical methods employed in the mandatory monitoring of water bodies under the WFD, thus, providing a benchmark for establishing comparability among measurement results.

16.
New Microbiol ; 40(4): 286-288, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28994449

RESUMO

We compared the micafungin killing rate and postantifungal effect (PAFE) at 4, 16 and 32 mg/L in RPMI- 1640 and in 50% serum against the C. albicans complex. In RPMI-1640 PAFEs were 1.5 - >19.4, 9.7 - >20.1 and 15.9 - >18.5 hours for C. albicans, C. africana and C. dubliniensis, respectively. In 50% serum PAFEs decreased sharply to 0-1.7 hours for all three species; killing rates were always negative. Short growth inhibition without killing in 50% serum suggests that micafungin PAFE has a limited role in the eradication of the C. albicans complex from the bloodstream.


Assuntos
Antifúngicos/farmacologia , Equinocandinas/farmacocinética , Lipopeptídeos/farmacocinética , Candida/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Humanos , Micafungina , Testes de Sensibilidade Microbiana , Fatores de Tempo
17.
Mycopathologia ; 182(11-12): 979-987, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28699056

RESUMO

We compared killing activity of micafungin in time-kill experiments in RPMI-1640 with and without 50% serum against Candida albicans, Candida dubliniensis and Candida africana reference strains and clinical isolates. Killing rates (k values) were determined for each strain and concentration. In RPMI-1640 MIC ranges were 0.015-0.03, 0.015-0.03 and 0.015 mg/L against C. albicans, C. dubliniensis and C. africana, respectively. In 50% serum MIC values for the three species increased 16- to 64-fold. In RPMI-1640 micafungin was fungicidal against two of three C. albicans isolates at 16 and 32 mg/L within 14.54 h and fungistatic against all C. africana and C. dubliniensis. Fifty per cent serum significantly decreased the growth rate of C. africana, but not of the other two species; weak in vivo replication ability of C. africana was confirmed in murine model. In 50% serum micafungin at 0.25 and 1 mg/L did not inhibit any of the three species (k values were always negative). Micafungin killing rate in 50% serum at 4, 16 and 32 mg/L was significantly decreased for C. albicans, but increased for C. dubliniensis compared to RPMI-1640. Killing activity of micafungin against C. africana was comparable or higher in 50% serum than in RPMI-1640. Although micafungin is a highly protein-bound drug, it was equally effective against the species of the C. albicans complex in 50% serum at therapeutic trough concentration (4 mg/L). Both in vitro and in vivo data confirmed the low virulence of C. africana compared to the two sibling species.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Equinocandinas/farmacologia , Lipopeptídeos/farmacologia , Soro/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Candida albicans/classificação , Candida albicans/isolamento & purificação , Equinocandinas/metabolismo , Humanos , Rim/microbiologia , Lipopeptídeos/metabolismo , Masculino , Micafungina , Camundongos , Testes de Sensibilidade Microbiana , Ligação Proteica/fisiologia
18.
J Basic Microbiol ; 57(11): 910-921, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28891112

RESUMO

Candida albicans is the best-studied opportunistic human pathogenic yeast species, and its virulence factors, susceptibility to antimycotics, the diversity of its physiological properties and the determinative factors of these traits are interesting from a clinical as well as from an evolutionary perspective. By applying statistical modeling for the phenotypical differences observed among a collection of 63 C. albicans isolates originating from different clinical care units, from a diverse group of patients with or without mycosis, collected in a Hungarian clinic, we found that (i) host-related aspects like anatomical source, care unit of isolation, patients' age, sex, and disease severity, or ABC genotypes of the isolates had less effect on the phenotypic features of this opportunistic pathogen than host-independent aspects, for example, year or month of isolation; (ii) different phenotypic traits did not show any significant correlations with each other; and (iii) different genotypes displayed no anatomical specialization and rarely showed any significant correlation with parameters of isolation either. These results shed light on the dynamic nature and low specialization of the C. albicans populations observable in a narrow geographic range, namely in the patients hospitalized in the different care units of the clinic.


Assuntos
Candida albicans/genética , Candida albicans/isolamento & purificação , Candidíase/microbiologia , Genótipo , Fenótipo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Criança , Pré-Escolar , Feminino , Hospitais , Humanos , Hungria , Hifas/crescimento & desenvolvimento , Lactente , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Peptídeo Hidrolases/metabolismo , Fosfolipases/metabolismo , Fatores Sexuais , Virulência , Fatores de Virulência , Adulto Jovem
19.
Microbiol Immunol ; 60(5): 285-94, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26959958

RESUMO

Because asymptomatic carriage of extended-spectrum beta-lactamase (ESBL) producers is a risk factor for infection, data on colonization dynamics are important when planning infection control. This study investigated fecal colonization with ESBL producers among inpatients, outpatients and medical students and compares the characteristics of ESBL producers among these groups. Carriage rates were investigated in 5581 fecal samples; 4343 from inpatients (330, 1397, 619 and 1864 from adult ICUs [intensive care units], adult non-ICUs, pediatric ICUs and pediatric non-ICUs, respectively), 814 from outpatients and 424 from screening of medical students. ESBL producers were characterized by co-resistance, integrons carried, and aminoglycoside resistance and ESBL genes. Dynamic regression models were built to identify relationships between combinations of time series of monthly antibiotic consumption, prevalence of carriers and infected subjects. Inpatients, ICU patients and adults showed higher prevalence than outpatients, non-ICU patients or children (7.4%, 9.3% and 12.0% vs. 3.1%, 6.1% and 4.1%, respectively). Klebsiella pneumoniae was more frequent in ICU patients; dominance of CTX-M-15 producers was more marked in adult than in pediatric inpatients. ESBL carriage was shown to be a consequence of infection in adults in the time-series analysis; antibiotic consumption had little effect. The epidemiology of colonization with ESBL producers differed between pediatric ICU, adult ICU and adult non-ICU patients. In adults, carriage of ESBL producers seems to be the consequence of infection, especially in ICU patients; the main source of colonization is nosocomial acquisition. In contrast, children are less likely to acquire colonizer strains in hospitals; importation of ESBL producers by colonized children seems to be significant.


Assuntos
Portador Sadio/epidemiologia , Infecções por Enterobacteriaceae/epidemiologia , Enterobacteriaceae/enzimologia , Fezes/microbiologia , beta-Lactamases/análise , Antibacterianos/uso terapêutico , Portador Sadio/microbiologia , Uso de Medicamentos , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Humanos , Pacientes Internados , Integrons , Testes de Sensibilidade Microbiana , Pacientes Ambulatoriais , Prevalência , Estudantes de Medicina
20.
J Basic Microbiol ; 55(8): 973-81, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25707543

RESUMO

The fluorinated glucocorticoid betamethasone stimulated both the extracellular phospholipase production and hypha formation of the opportunistic human pathogen Candida albicans and also decreased the efficiency of the polyene antimycotics amphotericin B and nystatin against C. albicans in a dose-dependent manner. Importantly, betamethasone increased synergistically the anti-Candida activity of the oxidative stress generating agent menadione, which may be exploited in future combination therapies to prevent or cure C. albicans infections, in the field of dermatology.


Assuntos
Antifúngicos/farmacologia , Betametasona/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Vitamina K 3/farmacologia , Anfotericina B/farmacologia , Candida albicans/patogenicidade , Candida albicans/fisiologia , Candidíase/microbiologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Nistatina/farmacologia , Estresse Oxidativo
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