Low and constant micafungin concentrations may be sufficient to lead to resistance mutations in FKS2 gene of Candida glabrata

Bordallo-Cardona, María Ángeles; Escribano, Pilar; Marcos-Zambrano, Laura Judith; Díaz-García, Judith; Pedrosa, Elia Gómez de la; Bouza, Emilio; Guinea, Jesús

doi:10.1093/mmy/myx124

Cited by 14 publications

(12 citation statements)

References 18 publications

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“…Among clinical isolates, MSH2 polymorphisms did not correlate with echinocandin resistance in low-resistance settings (20). MSH2 polymorphisms were not evaluated in the present study; however, a prior report did not find a correlation with selection of micafungin resistance and MSH2 genotype (21). In patients, resistance is most commonly encountered following echinocandin exposure, which can serve as a useful Bayesian indicator for clinical decision making before susceptibility test results are available (4).…”

Section: Discussionmentioning

confidence: 58%

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Shields

Kline

Healey

et al. 2019

Antimicrob Agents Chemother

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Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in Candida mutational frequency of resistance or propensity to develop FKS mutations. The objective of this study was to measure spontaneous and FKS mutation rates among Candida glabrata strains. Twenty bloodstream isolates from patients with or without prior echinocandin exposure were included. Minimum inhibitory concentrations (MICs), minimum fungicidal concentrations (MFCs), and mutation prevention concentrations were higher for caspofungin than for anidulafungin (P < 0.0001) and micafungin (P < 0.0001). Mutational frequencies of resistance at 3× the baseline MIC were highest for caspofungin and lowest for micafungin. A total of 247 isolates were recovered at or above the MFC for caspofungin (n = 159), anidulafungin (n = 74), or micafungin (n = 14). Agent-specific MIC increases were noted for anidulafungin and caspofungin, but not micafungin. Thirty-three percent of isolates harbored hot spot mutations in FKS1 (n = 6) or FKS2 (n = 76). Mutations at the Ser629 (Fks1) or Ser663 (Fks2) loci were more common after selection with anidulafungin or micafungin than with caspofungin (P = 0.003). Four isolates demonstrated >4-fold increases in MICs without FKS hot spot mutations; three of these harbored Fks2 mutations upstream of hot spot 1. The final isolate was FKS1 and FKS2 wild-type, but the 50% inhibitory concentrations of caspofungin and micafungin were increased 2.7- and 8-fold, respectively. In conclusion, micafungin may be superior in vitro to the other agents in limiting the emergence of resistance among C. glabrata. Caspofungin exposure may be most likely to promote resistance development. These data provide a foundation for future investigations of newly developed echinocandin agents.

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Section: Discussionmentioning

confidence: 58%

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Shields

Kline

Healey

et al. 2019

Antimicrob Agents Chemother

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“…Very recently, Bordallo-Cardona et al . investigated the ability of five echinocandin-susceptible C. glabrata isolates to acquire in vitro resistance to anidulafungin and micafungin and, remarkably, all isolates acquired resistance after 2–4 days of exposure to low and constant micafungin concentrations and mutations in FKS2 were found in all of them [88]. This study highlights the idea that the constant exposure to low doses of echinocandins promotes the development of resistance.…”

Section: Candida Evolution Towards Drug Resistancementioning

confidence: 80%

Microevolution of the pathogenic yeasts Candida albicans and Candida glabrata during antifungal therapy and host infection

Pais¹,

Galocha²,

Viana³

et al. 2019

Microb Cell

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Infections by the pathogenic yeasts Candida albicans and Candida glabrata are among the most common fungal diseases. The success of these species as human pathogens is contingent on their ability to resist antifungal therapy and thrive within the human host. C. glabrata is especially resilient to azole antifungal treatment, while C. albicans is best known for its wide array of virulence features. The core mechanisms that underlie antifungal resistance and virulence in these pathogens has been continuously addressed, but the investigation on how such mechanisms evolve according to each environment is scarcer. This review aims to explore current knowledge on micro-evolution experiments to several treatment and host-associated conditions in C. albicans and C. glabrata . The analysis of adaptation strategies that evolve over time will allow to better understand the mechanisms by which Candida species are able to achieve stable phenotypes in real-life scenarios, which are the ones that should constitute the most interesting drug targets.

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“…Recent studies indicate that echinocandin resistance rates among C. glabrata clinical isolates have risen worldwide (Kiraz et al, 2010; Bourgeois et al, 2014; Guinea et al, 2014; Orasch et al, 2014; Klotz et al, 2016; Chapman et al, 2017; Hou et al, 2017). Resistance has been reported to easily develop in vitro (Bordallo-Cardona et al, 2017, 2018a,c; Shields et al, 2019) and in patients after echinocandin exposure (Dannaoui et al, 2012; Shields et al, 2012; Alexander et al, 2013; Bizerra et al, 2014; Sasso et al, 2017), being conferred by the presence of point mutations in hot-spot regions of FKS1 and FKS2 genes (Castanheira et al, 2014; Pham et al, 2014) that have been associated with higher MICs and therapeutic failure (Shields et al, 2012). Our study provides a new insight into the development of echinocandin resistance of C. glabrata strains both sequentially isolated from several patients and after in vitro exposure to growing concentrations of micafungin and anidulafungin.…”

Section: Discussionmentioning

confidence: 99%

“…FKS mutations have been reported to correlate with elevated in vitro minimal inhibitory concentrations (MICs) and clinical failure (Alexander et al, 2013), yet an explanation for this increase in echinocandin resistant strains has not been proved. Several possibilities are being studied, such as strains proneness to acquire resistance as an answer to echinocandin exposure (Bordallo-Cardona et al, 2017, 2018a,c; Shields et al, 2019), the existence of hidden reservoirs in the human body of echinocandin resistant C. glabrata isolates (Shields et al, 2014; Grau et al, 2015; Jensen et al, 2015; Healey et al, 2017) or molecular mechanisms like MSH2 mutator phenotype (Delliere et al, 2016; Healey et al, 2016b; Byun et al, 2018; Hou et al, 2018; Singh et al, 2018; Bordallo-Cardona et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization

et al. 2019

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The pathogenic yeast Candida glabrata has become a public health issue due to the increasing number of echinocandin resistant clinical strains reported. In this study, acquisition and development of resistance to this antifungal class were studied in serial C. glabrata isolates from five patients admitted in two Spanish hospitals with a resistant profile against echinocandins associated with different mutations in hot-spot 1 of FKS2 gene. For two of these patients susceptible FKS wild-type isolates obtained prior to resistant ones were also investigated. Isolates were genotyped using multilocus sequence typing and microsatellite length polymorphism techniques, which yielded comparable results. Susceptible and resistant isolates from the same patient had the same genotype, being sequence type (ST) 3 the most prevalent among them. Isolates with different FKS mutations but the same ST were present in the same patient. MSH2 gene alterations were also studied to investigate their correlation with antifungal resistance acquisition but no association was found with antifungal resistance nor with specific genotypes. In vitro exposure to increasing concentrations of micafungin to susceptible isolates developed colonies carrying FKS mutations in agar plates containing a minimum concentration of 0.06 mg/L of micafungin after less than 48 h of exposure. We investigated the correlation between development of resistance and genotype in a set of susceptible strains after being in vitro exposed to micafungin and anidulafungin but no correlation was found. Mutant prevention concentration values and spontaneous growth frequencies after selection with both echinocandins were statistically similar, although FKS mutant colonies were more abundant after micafungin exposure ( p < 0.001). Mutation S663P and F659 deletion were the most common ones found after selection with both echinocandins.

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Low and constant micafungin concentrations may be sufficient to lead to resistance mutations in FKS2 gene of Candida glabrata

Cited by 14 publications

References 18 publications

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Microevolution of the pathogenic yeasts Candida albicans and Candida glabrata during antifungal therapy and host infection

Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization

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