Recurrent Episodes of Candidemia Due to Candida glabrata with a Mutation in Hot Spot 1 of the
            <i>FKS2</i>
            Gene Developed after Prolonged Therapy with Caspofungin

Durán-Valle, María Teresa; Gago, Sara; Gómez-López, Alicia; Cuenca‐Estrella, Manuel; Díez-Canseco, Leticia Jiménez; Gómez-Garcés, José Luís; Zaragoza, Óscar

doi:10.1128/aac.06100-11

Cited by 26 publications

(28 citation statements)

References 24 publications

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“…HS1 and HS2 from the fks genes of the 5 Candida control isolates were amplified as previously described (17)(18)(19) (Table 2). The presence of fks mutations (23); the distribution of isolates was as follows: C. albicans, n ϭ 31; C. parapsilosis complex, n ϭ 27 (C. parapsilosis sensu stricto, n ϭ 24; C. orthopsilosis, n ϭ 3); C. glabrata, n ϭ 40; C. krusei, n ϭ 10; C. tropicalis, n ϭ 28; Candida spp., n ϭ 12 (C. dubliniensis, n ϭ 5; C. guilliermondii, n ϭ 4; C. kefyr, n ϭ 1; C. lusitaniae, n ϭ 1; Pichia caribbica, n ϭ 1); and other yeasts, n ϭ 12 (Rhodotorula mucilaginosa, n ϭ 7; Trichosporon spp., n ϭ 5).…”

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confidence: 99%

Comparison between the EUCAST Procedure and the Etest for Determination of the Susceptibility of Candida Species Isolates to Micafungin

Marcos-Zambrano¹,

Escribano²,

Rueda³

et al. 2013

Antimicrob Agents Chemother

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e We compared the ability of the EUCAST EDef 7.2 and the Etest to detect the susceptibility to micafungin of 160 Candida and non-Candida clinical isolates. Agreement was higher when Etest MICs were obtained after 24 h of incubation; essential agreement was 90%, and categorical agreement was >90%. False susceptibility was seen only for Candida krusei (10%), and false resistance was observed in 6% of the isolates, ranging from 2.6% (C. glabrata) to 13% (C. albicans).

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confidence: 99%

Comparison between the EUCAST Procedure and the Etest for Determination of the Susceptibility of Candida Species Isolates to Micafungin

Marcos-Zambrano¹,

Escribano²,

Rueda³

et al. 2013

Antimicrob Agents Chemother

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“…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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“…Alarmingly, C. glabrata is the first species of Candida for which measurable resistance to echinocandins has been detected (6, 10). Case reports of echinocandin-resistant C. glabrata following echinocandin therapy are becoming more common (11)(12)(13)(14)(15)(16)(17). The majority of these resistant isolates have specific mutations in one of two "hot spot" regions of the FKS1 or FKS2 genes, which encode a subunit of the 1,3-␤-D glucan synthase protein, target of the echinocandins (11,(18)(19)(20).…”

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confidence: 99%

Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

Pham

Iqbal

Bolden

et al. 2014

Antimicrob Agents Chemother

200

149

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Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted. Candida species continue to be a leading cause of bloodstream infection in U.S. hospitals, especially in intensive care units (1, 2). Although the antifungal armamentarium is limited, there are good options for the treatment of Candida species, especially with the arrival of the newest antifungal agents, the echinocandins (3, 4). The echinocandins are intravenously administered agents with a favorable safety profile. As inhibitors of 1,3-␤-D glucan synthase in the cell wall, they have a mechanism of action different from that of the older azole antifungals, which act to disrupt ergosterol (cell membrane) synthesis. This alternate mechanism of action allows the echinocandins to be effective against Candida isolates that are azole resistant. Early studies of in vitro susceptibility showed resistance to echinocandins to be extremely low for all Candida species (5, 6).Candida glabrata has recently become the second-most-frequent cause of candidemia in the United States, surpassing C. parapsilosis and C. tropicalis (6-8). While the ultimate cause for this increase in the prevalence of C. glabrata is unknown, the increase might be related to C. glabrata's higher incidence of resistance to fluconazole in comparison to most other Candida species (6-9). Because of the increased probability of fluconazole resistance, echinocandins are recommended as first-line therapy against C. glabrata (4). Alarmingly, C. glabrata is the first species of Candida for which measurable resistance to echinocandins has been detected (6, 10). Case reports of echinocandin-resistant C. glabrata following echin...

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Recurrent Episodes of Candidemia Due to Candida glabrata with a Mutation in Hot Spot 1 of the FKS2 Gene Developed after Prolonged Therapy with Caspofungin

Abstract: ABSTRACTWe report two episodes of recurrent candidemia caused by echinocandin-resistantCandida glabratain a 69-year-old patient who underwent repeated abdominal surgery. In the first episode of candidemia, an echinocandin-susceptibleCand… Show more

Cited by 26 publications

References 24 publications

Comparison between the EUCAST Procedure and the Etest for Determination of the Susceptibility of Candida Species Isolates to Micafungin

Comparison between the EUCAST Procedure and the Etest for Determination of the Susceptibility of Candida Species Isolates to Micafungin

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

Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

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