Positions and Numbers of
 FKS
 Mutations in Candida albicans Selectively Influence
 In Vitro
 and
 In Vivo
 Susceptibilities to Echinocandin Treatment

Lackner, Michaela; Tscherner, Michael; Schaller, Martin; Kuchler, Karl; Mair, Christian; Sartori, Bettina; Istel, Fabian; Arendrup, Maiken Cavling; Lass‐Flörl, Cornelia

doi:10.1128/aac.00123-14

Cited by 64 publications

(47 citation statements)

References 37 publications

(42 reference statements)

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“…Echinocandin resistance is conferred by characteristic amino acid substitutions in Fks subunits [7], which induce elevated MIC values (10–100 fold) and reduce the sensitivity of glucan synthase (IC 50 ) to drug by 50- to 3000-fold [26, 45, 66]. Characteristic mutations in FKS genes are prominently associated with reduced clinical response [67, 68]. In a recent study of patients with invasive candidiasis, the presence of an FKS mutation was the only independent risk factor associated with echinocandin failure and among C. glabrata isolates, and the presence of an FKS mutation was superior to MIC in predicting echinocandin therapeutic responses among patients [68].…”

Section: Mechanism Of Acquired Resistancementioning

confidence: 99%

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Perlin

2014

Drugs

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This article addresses the emergence of echinocandin resistance among Candida species, mechanisms of resistance, factors that promote resistance and confounding issues surrounding standard susceptibility testing. Fungal infections remain a significant cause of global morbidity and mortality, especially among patients with underlying immunosupression. Antifungal therapy is a critical component of patient management for acute and chronic diseases. Yet, therapeutic choices are limited due to only a few drug classes available to treat systemic disease. Moreover, the problem is exacerbated by the emergence of antifungal resistance, which has resulted in difficult to manage multidrug resistant strains. Echinocandin drugs are now the preferred choice to treat a range of candidiasis. These drugs target and inhibit the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a key cell wall polymer. Therapeutic failures involving acquisition of resistance among susceptible organisms like Candida albicans is largely a rare event. However, in recent years, there is an alarming trend of increased resistance among strains of Candida glabrata, which in many cases are also resistant to azole drugs. Echinocandin resistance is always acquired during therapy and the mechanism of resistance is well established to involve amino acid changes in “hot-spot regions of the Fks subunits carrying the catalytic portion of glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values. A range of drug responses, from complete to partial refractory response, is observed depending on the nature of the amino acid substitution, and clinical responses are recapitulated in pharmacodynamic models of infection. The cellular processes promoting the formation of resistant Fks strains involve complex stress response pathways, which yield a variety of adaptive compensatory genetic responses. Stress-adapted cells become drug tolerant and can form stable drug resistant FKS mutations with continued drug exposure. A major concern for resistance detection is that classical broth microdilution techniques show significant variability among clinical microbiology laboratories for certain echinocandin drugs and Candida species. The consequence is that susceptible strains are misclassified according to established clinical breakpoints, and this has led to confusion in the field. Clinical factors that appear to promote echinocandin resistance include the expanding use of antifungal agents for empiric therapy and prophylaxis. Furthermore, host reservoirs such as biofilms in the gastrointestinal tract or intra-abdominal infections can seed development of resistant organisms during therapy. A fundamental understanding of the primary molecular resistance mechanism, along with cellular and clinical factors that promote resistance emergence, is critical to develop better diagnostic tools and therapeutic strategies to overcome and prevent echinocandin resistance.

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Section: Mechanism Of Acquired Resistancementioning

confidence: 99%

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Perlin

2014

Drugs

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“…It has been demonstrated, however, that substitutions at different amino acids, even within the same hotspots, can have different impacts on resistance profiles in terms of which echinocandins are effected, and the extent of the decrease in susceptibility [11, 12]. Furthermore, more than one of these mutations can occur in the same isolate, producing a less susceptible phenotype than would result from either mutation singularly [13, 12]. …”

Section: Echinocandin Resistancementioning

confidence: 99%

Epidemiology of Echinocandin Resistance in Candida

Grossman

Chiller

Lockhart

2014

Curr Fungal Infect Rep

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Echinocandins are the newest antifungal agents approved for use in treating Candida infections in the US. They act by interfering with 1,3-β-D-glucan synthase and therefore disrupt cell wall production and lead to Candida cell death. There is no intrinsic resistance to echinocandins among Candida species, and isolates from historic collections archived before the release of the echinocandins show no resistance. Resistance to the echinocandins remains low among most Candida species and ranges overall from 0–1%. Among isolates of Candida glabrata, the proportion of resistant isolates is higher and has been reported to be as high as 13.5% in at least one hospital. Antifungal resistance is due to specific amino acid mutations in the Fksp subunit(s) of the 1,3-β-D-glucan synthase protein which are localized to one of two hotspots. These mutations are being recognized in isolates from patients who have failed echinocandin therapy, and often lead to a poor outcome. While the future looks bright for the echinocandins against most Candida species, C. glabrata remains a species of concern and resistance rates of C. glabrata to the echinocandins should be monitored closely.

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“…A lag in regrowth was tested by monitoring the germination from NCT-pretreated conidia by time-lapse microscopy (BioStation live cell imaging; Nikon, Tokyo, Japan), which allows an exact documentation of fungal outgrowth (31). Conidia (1 ϫ 10 5 /ml) were incubated in 0.5 ml of 1.0% NCT in PBS at 37°C under rotation for 1 min, 10 min, 30 min, and 60 min (controls without NCT for 60 min).…”

Section: Methodsmentioning

confidence: 99%

N -Chlorotaurine Exhibits Fungicidal Activity against Therapy-Refractory Scedosporium Species and Lomentospora prolificans

Lackner

Binder

Reindl

et al. 2015

Antimicrob Agents Chemother

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N-Chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as an antiseptic, was tested on its fungicidal activity against Scedosporium and Lomentospora, opportunistic fungi that cause severe infections with limited treatment options, mainly in immunocompromised patients. In quantitative killing assays, both hyphae and conidia of Scedosporium apiospermum, Scedosporium boydii, and Lomentospora prolificans (formerly Scedosporium prolificans) were killed by 55 mM (1.0%) NCT at pH 7.1 and 37°C, with a 1-to 4-log 10 reduction in CFU after 4 h and a 4-to >6-log 10 reduction after 24 h. The addition of ammonium chloride to NCT markedly increased this activity. LIVE/DEAD staining of conidia treated with 1.0% NCT for 0.5 to 3 h increased the permeability of the cell wall and membrane. Preincubation of the test fungi in 1.0% NCT for 10 to 60 min delayed the time to germination of conidia by 2 h to >12 h and reduced their germination rate by 10.0 to 100.0%. Larvae of Galleria mellonella infected with 1.0 ؋ 10 7 conidia of S. apiospermum and S. boydii died at a rate of 90.0 to 100% after 8 to 12 days. The mortality rate was reduced to 20 to 50.0% if conidia were preincubated in 1.0% NCT for 0.5 h or if heat-inactivated conidia were used. Our study demonstrates the fungicidal activity of NCT against different Scedosporium and Lomentospora species. A postantifungal effect connected with a loss of virulence occurs after sublethal incubation times. The augmenting effect of ammonium chloride can be explained by the formation of monochloramine.

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Positions and Numbers of FKS Mutations in Candida albicans Selectively Influence In Vitro and In Vivo Susceptibilities to Echinocandin Treatment

Abstract: Candidemia is the fourth most common kind of microbial bloodstream infection, with

Cited by 64 publications

References 37 publications

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Epidemiology of Echinocandin Resistance in Candida

N -Chlorotaurine Exhibits Fungicidal Activity against Therapy-Refractory Scedosporium Species and Lomentospora prolificans

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