Novel
            <i>FKS</i>
            Mutations Associated with Echinocandin Resistance in
            <i>Candida</i>
            Species

García‐Effrón, Guillermo; Chua, Daniel Joseph; Tomada, Jon Rupert; DiPersio, Joseph R.; Perlin, David S.; Ghannoum, Mahmoud A.; Bonilla, Hector

doi:10.1128/aac.00998-09

Cited by 95 publications

(74 citation statements)

References 23 publications

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“…In addition to providing a strategy for predicting caspofungin S and R among Candida spp., these results provide further evidence for cross-resistance among the echinocandins (6,7,32,(36)(37)(38). By using a large global collection of clinically important Candida spp., including fks mutant strains, we validated concerns originating from single-center case series and provided further evidence for considering C. glabrata as the species most likely to demonstrate cross-resistance among the echinocandins.…”

Section: Resultsmentioning

confidence: 86%

Use of Anidulafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 4,290 Clinical Isolates of Candida by Using CLSI Methods and Interpretive Criteria

et al. 2014

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bThis study addressed the application of anidulafungin as a surrogate marker to predict the susceptibility of Candida to caspofungin due to unacceptably high interlaboratory variation of caspofungin MIC values. CLSI reference broth microdilution methods and species-specific interpretive criteria were used to test 4,290 strains of Candida (eight species), including 71 strains with documented fks mutations. Caspofungin MIC values were compared with those of anidulafungin to determine the percentage of categorical agreement (CA) and very major (VME), major (ME), and minor error rates, as well as the ability to detect fks mutants. For all 4,290 isolates the CA was 97.1% (0.2% VME and ME, 2.5% minor errors) using anidulafungin as the surrogate. Among the 62 isolates of Candida albicans (4 isolates), C. tropicalis (5 isolates), C. krusei (4 isolates), C. kefyr (2 isolates), and C. glabrata (47 isolates) that were nonsusceptible (NS; either intermediate [I] or resistant [R]) to both caspofungin and anidulafungin, 52 (83.8%) contained a mutation in fks1 or fks2. Eight mutants of C. glabrata, two of C. albicans, and one each of C. tropicalis and C. krusei were classified as susceptible (S) to both antifungal agents. The remaining 7 mutants (2 C. albicans and 5 C. glabrata) were susceptible to one of the agents and either intermediate or resistant to the other. Using the epidemiological cutoff value (ECV) of 0.12 g/ml for both caspofungin and anidulafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 42 of the 55 (76.4%) C. glabrata mutants were non-WT and 8 of the 55 (14.5%) were WT for both agents (90.9% concordance). Anidulafungin can accurately serve as a surrogate marker to predict S and R of Candida to caspofungin.

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Section: Resultsmentioning

confidence: 86%

Use of Anidulafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 4,290 Clinical Isolates of Candida by Using CLSI Methods and Interpretive Criteria

et al. 2014

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“…In addition to providing a strategy for predicting caspofungin susceptibility and resistance among Candida spp., these results provide strong support for concerns regarding the issue of crossresistance between micafungin and caspofungin (5,15,16,18,22,26). By using an extensive global collection of clinically important isolates, including fks mutant strains, we validate concerns originating from single-center case series and rightly focus attention on C. glabrata as the species most likely to demonstrate cross-resistance between these two studied echinocandins.…”

Section: Resultsmentioning

confidence: 93%

“…The clinical relevance of this cross-resistance has been documented in studies of the resistance mechanisms (detection of fks mutations) (15)(16)(17), in animal models of IC (18)(19)(20)(21), and in case series where clinically significant resistance to one or more echinocandins, marked by the acquisition of a resistance mutation in the fks gene, has been reported in immunocompromised patients (e.g., those in intensive care, stem cell transplant patients, and solid organ transplant patients) with a high level of prior echinocandin exposure (11,(22)(23)(24)(25)(26)(27). Although many of the resistant isolates and cases of breakthrough IC were due to Candida glabrata, a number of Candida albicans, Candida tropicalis, Candida krusei, and Candida lusitaniae isolates have also been observed to have reduced susceptibility or resistance to both micafungin and caspofungin (17, 22-24, 26, 28, 29).…”

Section: (M a Pfaller Et Al Unpublished Data)mentioning

confidence: 99%

Use of Micafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 3,764 Clinical Isolates of Candida by Use of CLSI Methods and Interpretive Criteria

et al. 2014

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bDue to unacceptably high interlaboratory variation in caspofungin MIC values, we evaluated the use of micafungin as a surrogate marker to predict the susceptibility of Candida spp. to caspofungin using reference methods and species-specific interpretive criteria. The MIC results for 3,764 strains of Candida (eight species), including 73 strains with fks mutations, were used. Caspofungin MIC values and species-specific interpretive criteria were compared with those of micafungin to determine the percent categorical agreement (%CA) and very major error (VME), major error (ME), and minor error rates as well as their ability to detect fks mutant strains of Candida albicans (11 mutants), Candida tropicalis (4 mutants), Candida krusei (3 mutants), and Candida glabrata (55 mutants). Overall, the %CA was 98.8% (0.2% VMEs and MEs, 0.8% minor errors) using micafungin as the surrogate marker. Among the 60 isolates of C. albicans (9 isolates), C. tropicalis (5 isolates), C. krusei (2 isolates), and C. glabrata (44 isolates) that were nonsusceptible (either intermediate or resistant) to both caspofungin and micafungin, 54 (90.0%) contained a mutation in fks1 or fks2. An additional 10 C. glabrata mutants, two C. albicans mutants, and one mutant each of C. tropicalis and C. krusei were classified as susceptible to both antifungal agents. Using the epidemiological cutoff values (ECVs) of 0.12 g/ml for caspofungin and 0.03 g/ml for micafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 80% of the C. glabrata mutants were non-WT for both agents (96% concordance). Micafungin may serve as an acceptable surrogate marker for the prediction of susceptibility and resistance of Candida to caspofungin.

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“…Isolates with the amino acid substitutions S629P, R631G, and D632V/G/E/Y in Fks1-HS1 and F659Y/S, S663P/F, R665G, D666V/G/E, and P667H/T in Fks2 HS1 display elevated in vitro MIC values for the echinocandins (8,13). Moreover, patients who harbor isolates with one or more of these mutations generally fail echinocandin therapy (7,9,14,15).…”

mentioning

confidence: 99%

Development of a Luminex-Based Multiplex Assay for Detection of Mutations Conferring Resistance to Echinocandins in Candida glabrata

et al. 2014

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Echinocandins are the recommended treatment for invasive candidiasis due to Candida glabrata. Resistance to echinocandins is known to be caused by nonsynonymous mutations in the hot spot-1 (HS1) regions of the FKS1 and FKS2 genes, which encode a subunit of the ␤-1,3-glucan synthase, the target of echinocandins. Here, we describe the development of a microsphere-based assay using Luminex MagPix technology to identify mutations in the FKS1 HS1 and FKS2 HS1 domains, which confer in vitro echinocandin resistance in C. glabrata isolates. The assay is rapid and can be performed with high throughput. The assay was validated using 102 isolates that had FKS1 HS1 and FKS2 HS1 domains previously characterized by DNA sequencing. The assay was 100% concordant with DNA sequencing results. The assay was then used for high-throughput screening of 1,032 C. glabrata surveillance isolates. Sixteen new isolates with mutations, including a mutation that was new to our collection (del659F), were identified. This assay provides a rapid and cost-effective way to screen C. glabrata isolates for echinocandin resistance.

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Novel FKS Mutations Associated with Echinocandin Resistance in Candida Species

Cited by 95 publications

References 23 publications

Use of Anidulafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 4,290 Clinical Isolates of Candida by Using CLSI Methods and Interpretive Criteria

Use of Anidulafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 4,290 Clinical Isolates of Candida by Using CLSI Methods and Interpretive Criteria

Use of Micafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 3,764 Clinical Isolates of Candida by Use of CLSI Methods and Interpretive Criteria

Development of a Luminex-Based Multiplex Assay for Detection of Mutations Conferring Resistance to Echinocandins in Candida glabrata

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