1 / Development of echinocandin resistance after in vitro micafungin exposure in clinical isolates of Candida glabrata

2018 ◽  
Author(s):  
O. Rivero-Menendez
Keyword(s):  
Candida Glabrata ◽  
Clinical Isolates ◽  
Echinocandin Resistance

scholarly journals Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

2001 ◽  
Vol 45 (4) ◽  
pp. 1174-1183 ◽  
Author(s):  
Dominique Sanglard ◽  
Francoise Ischer ◽  
Jacques Bille
Keyword(s):  
Abc Transporter ◽  
High Frequency ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Atp Binding ◽  
Transporter Gene ◽  
Atp Binding Cassette

ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.

scholarly journals In Vitro Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
María Ángeles Bordallo-Cardona ◽  
Pilar Escribano ◽  
Elia Gómez G. de la Pedrosa ◽  
Laura Judith Marcos-Zambrano ◽  
Rafael Cantón ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Content Type ◽  
Inhibition Of Growth ◽  
Direct Exposure ◽  
In Vitro Exposure ◽  
Echinocandin Resistance

ABSTRACT We assessed the in vitro susceptibility of five echinocandin-susceptible Candida glabrata isolates after exposure to micafungin. The direct exposure to plates at different micafungin concentrations resulted in the inhibition of growth at 0.062 μg/ml. The progressive exposure was performed on plates using 0.031 μg/ml of micafungin and sequential propagation on plates containing the next 2-fold concentration; the MICs of micafungin and anidulafungin increased sequentially, and all the isolates became echinocandin resistant, showing fks2 mutations.

scholarly journals In Vitro Interaction of Posaconazole and Caspofungin against Clinical Isolates of Candida glabrata

2005 ◽  
Vol 49 (8) ◽  
pp. 3544-3545 ◽  
Author(s):  
E. R. Oliveira ◽  
A. W. Fothergill ◽  
W. R. Kirkpatrick ◽  
B. J. Coco ◽  
T. F. Patterson ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Concentration Index ◽  
Inhibitory Concentration ◽  
Clinical Isolates ◽  
Fractional Inhibitory Concentration ◽  
Fractional Inhibitory Concentration Index ◽  
Fluconazole Resistant ◽  
In Vitro Interaction

ABSTRACT Combinations of caspofungin and posaconazole were evaluated by fractional inhibitory concentration index against 119 Candida glabrata isolates. Synergy was seen in 18% of all isolates and in 4% of fluconazole-resistant isolates at 48 h without evidence of antagonism. This antifungal combination may have utility against this organism.

Impact of calmodulin inhibition by fluphenazine on susceptibility, biofilm formation and pathogenicity of caspofungin-resistant Candida glabrata

2020 ◽  
Vol 75 (5) ◽  
pp. 1187-1193 ◽  
Author(s):  
Andrés Ceballos Garzon ◽  
Daniela Amado ◽  
Estelle Robert ◽  
Claudia M Parra Giraldo ◽  
Patrice Le Pape
Keyword(s):  
Biofilm Formation ◽  
Candida Glabrata ◽  
Galleria Mellonella ◽  
Larval Survival ◽  
Clinical Isolates ◽  
Dilution Method ◽  
Life Threatening ◽  
Polyurethane Catheter ◽  
The Impact

Abstract Background In recent decades, Candida glabrata has emerged as a frequent cause of life-threatening fungal infection. In C. glabrata, echinocandin resistance is associated with mutations in FKS1/FKS2 (β-1,3-glucan synthase). The calmodulin/calcineurin pathway is implicated in response to antifungal stress and calcineurin gene disruption specifically reverses Fks2-mediated resistance of clinical isolates. Objectives We evaluated the impact of calmodulin inhibition by fluphenazine in two caspofungin-resistant C. glabrata isolates. Methods C. glabrata isolates were identified by ITS1/ITS4 (where ITS stands for internal transcribed spacer) sequencing and the echinocandin target FKS1/FKS2 genes were sequenced. Susceptibility testing of caspofungin in the presence of fluphenazine was performed by a modified CLSI microbroth dilution method. The effect of the fluphenazine/caspofungin combination on heat stress (37°C or 40°C), oxidative stress (0.2 and 0.4 mM menadione) and biofilm formation (polyurethane catheter) was analysed. A Galleria mellonella model using blastospores (1 × 109 cfu/mL) was developed to evaluate the impact of this combination on larval survival. Results F659del was found in the FKS2 gene of both resistant strains. In these clinical isolates, fluphenazine increased susceptibility to caspofungin and reduced their thermotolerance. Furthermore, the fluphenazine/caspofungin combination significantly impaired biofilm formation in an in vitro polyurethane catheter model. All these features participated in the increasing survival of infected G. mellonella after combination treatment in comparison with caspofungin alone. Conclusions In a repurposing strategy, our findings confirm that calmodulin could provide a relevant target in life-threatening fungal infectious diseases.

scholarly journals In vitro kill curves of a new semisynthetic echinocandin, LY-303366, against fluconazole-sensitive and -resistant Candida species.

1997 ◽  
Vol 41 (11) ◽  
pp. 2576-2578 ◽  
Author(s):  
J A Karlowsky ◽  
G A Harding ◽  
S A Zelenitsky ◽  
D J Hoban ◽  
A Kabani ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Candida Species ◽  
Candida Glabrata ◽  
Candida Krusei ◽  
Clinical Isolates

In vitro killing by a new semisynthetic echinocandin, LY-303366, was characterized using clinical isolates of fluconazole-sensitive (Y58) and -resistant (Y180) Candida albicans as well as Candida glabrata (Y7) and Candida krusei (Y171). The 24-h kill curves for Y58 and Y180 demonstrated dose-independent killing of between 1 and 2 log10 with LY-303366 at concentrations of 0.1, 1, 10, 50, 100, and 1,000 times the MIC. Regrowth did not occur at 24 h with either C. albicans isolate at the aforementioned LY-303366 concentrations. At their MICs, LY-303366 and amphotericin B produced similar killing kinetics in cultures of Y58, Y180, Y7, and Y171, while all cultures exposed to fluconazole at its MIC demonstrated stasis or growth over 24 h.

scholarly journals Candida glabrataMutants Demonstrating Paradoxical Reduced Caspofungin Susceptibility but Increased Micafungin Susceptibility

2011 ◽  
Vol 55 (8) ◽  
pp. 3947-3949 ◽  
Author(s):  
Kelley R. Healey ◽  
Santosh K. Katiyar ◽  
Mariana Castanheira ◽  
Michael A. Pfaller ◽  
Thomas D. Edlind
Keyword(s):  
Candida Glabrata ◽  
Gene Disruption ◽  
Rare Event ◽  
Clinical Isolates ◽  
Glucan Synthase ◽  
Highly Active ◽  
Increased Susceptibility

ABSTRACTEchinocandins, including caspofungin (CSP) and micafungin (MCF), are highly active versusCandida glabrata(MIC of ≤0.06 μg/ml). True resistance (MIC of ≥1 μg/ml) is a rare event and strictly associated with mutations in β-1,3-glucan synthase geneFKS1orFKS2. In contrast, we show here that mutants exhibiting reduced susceptibility to CSP (CRS; MICs of 0.12 to 0.5 μg/ml) are readily selectedin vitroand, paradoxically, demonstrate increased susceptibility to MCF (MIS) ranging from 4- to 32-fold. CRS-MIS mutants were generated from all 10C. glabratastrains tested and were tentatively identified within a collection of clinical isolates. Intriguingly, sequencing and gene disruption demonstrated that CRS-MIS is Fks independent.

scholarly journals The Emergence of Echinocandin-Resistant Candida glabrata Exhibiting High MICs and Related FKS Mutations in Turkey

2021 ◽  
Vol 7 (9) ◽  
pp. 691
Author(s):  
Ali Korhan Sig ◽  
Meliha Cagla Sonmezer ◽  
Dolunay Gülmez ◽  
Serhat Duyan ◽  
Ömrüm Uzun ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Venous Catheter ◽  
High Dose ◽  
High Morbidity ◽  
First Case ◽  
Hospitalization Period ◽  
Echinocandin Resistance

The frequency of invasive fungal infections shows a rising trend as well as a high morbidity and mortality. Among the causative agents, a shift toward the non-albicans Candida species including Candida glabrata species complex is being observed in several centers. Echinocandin resistance is increasingly published; however, isolates presenting with an in vitro resistance have not yet been reported from Turkey. We, herein, report the first FKS mutant and phenotypically echinocandin-resistant C. glabrata clinical strains from a single center in Turkey. In a 43-year-old female patient, several enterocutaneous fistulae developed after a long term hospitalization period and several complicated surgeries. She eventually required parenteral nutrition via a tunneled central venous catheter (CVC). Following a number of bacteremic and fungemic episodes as well as intensive antimicrobial interventions (including fluconazole, caspofungin and anidulafungin), a CVC-related candidemia caused by C. glabrata was detected. The isolated strain yielded high minimum inhibitory concentration (MIC) values for echinocandins and was categorized as resistant. A resistance-related mutation was detected in FKS2 HS1 (D666V). Blood cultures remained negative after the removal of the CVC and treatment with caspofungin and high-dose fluconazole. Following this first case, two additional C. glabrata strains with high echinocandin MICs were isolated from the urine cultures of two unrelated patients from different wards with different mutations in FKS2 HS1 (S663P and delF659). Our findings indicate that routine antifungal susceptibility testing is crucial and underlines the need for attention for the increasing trend of acquired echinocandin resistance in C. glabrata.

scholarly journals Azole Antifungal Resistance in Candida albicans and Candida glabrata Isolated from Vulvovaginal Candidiasis Patients

2021 ◽  
Vol 16 (2) ◽  
Author(s):  
Niloofar Deravi ◽  
Mobina Fathi ◽  
Seyede Nadia Tabatabaeifar ◽  
Parichehr Pooransari ◽  
Bahram Ahmadi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Candida Glabrata ◽  
Antifungal Susceptibility ◽  
Vulvovaginal Candidiasis ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Normal Women ◽  
In Vitro Antifungal Susceptibility ◽  
Iranian Patients

Background: Vulvovaginal candidiasis (VVC) is the most frequent fungal disorder in healthy and normal women. Objectives: The aim of this study was to evaluate the in vitro antifungal susceptibility of clinical isolates Candida albicans and Candida glabrata, the two most common candida species in Iranian patients with VVC. Methods: One hundred and eight clinical isolates of candida, including; C. albicans (n = 77) and C. glabrata: (n = 31) were isolated from the 108 patients with VVC. The in vitro activity of caspofungin (CAS), amphotericin B (AMB), voriconazole (VRC), itraconazole (ITC), fluconazole (FLC), and nystatin (NYS) were determined according to the CLSI M27-A3 and CLSI M27-S4. Results: Our results were shown 8 (25.8 %) and 6 (7.8 %) C. glabrata and C. albicans isolates resistance to FLU, respectively. Furthermore, resistance to VRC and ITC were observed in 8.4%, and 3.7% of all isolates, and six isolates (5.6%) had intermediate MIC to CAS. Conclusions: We reported 8 (25.8 %) and 6 (7.8 %) C. glabrata and C. albicans isolates resistance to FLU, respectively. Furthermore, resistance to VRC and ITC were observed in 8.4% and 3.7% of all isolates, respectively.

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