FKS Mutant Candida glabrata: Risk Factors and Outcomes in Patients With Candidemia

Beyda, Nicholas D.; John, Julie St.; Kılıç, Abdullah; Alam, Mohammad Jahangir; Lasco, Todd M.; Garey, Kevin W.

doi:10.1093/cid/ciu407

Cited by 146 publications

(137 citation statements)

References 15 publications

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“…In theory, such unresolved susceptible/resistant classification is a concern for directing antifungal therapy. In reality, however, it may be only trivial to the diagnostic value of this FKS genotyping method, because the frequency of T1896A mutationcaused D632E is very low (estimated as Ͻ0.5% of all FKS HS mutations) based on several large-scale epidemiological studies on FKS mutations (6,12,18,19,22,23). Nevertheless, an F625F silent mutation-specific MB probe was designed to address this susceptible/resistant uncertainty.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the stability difference of the probe-target hybrids, characteristic profiles were produced for different FKS genotypes in the subsequent melting curve analysis. Figure 1A shows melting curves of representative FKS1 HS1 genotypes, including WT, S629P, F625S, D632Y, D632E (T1896G), D632E (T1896A), I634V (just outside the hotspot region yet not associated with resistance [6,18,19]), and …”

Section: Melting Curve Analysis-based Fks1/fsk2 Hs1 Genotypingmentioning

confidence: 99%

“…a Mutation I634V is just outside the FKS1 HS1 region, and it was not yet found to be associated with echinocandin resistance in C. glabrata (6,18,19).…”

Section: Melting Curve Analysis-based Fks1/fsk2 Hs1 Genotypingmentioning

confidence: 99%

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Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

Zhao

Nagasaki

Kordalewska

et al. 2016

Antimicrob Agents Chemother

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A novel and highly accurate diagnostic assay platform was established for rapid identification of FKS mutations associated with echinocandin resistance in Candida glabrata. The assay platform uses allele-specific molecular beacon and DNA melt analysis following asymmetric PCR. A dual assay for FKS1 and FKS2 was developed to identify within 3 h the most common and clinically relevant resistance-associated mutations, including 8 FKS1 HS1 (wild type [WT], S629P, F625S, D632Y, D632E [T1896G], D632E [T1896A], I634V, and F625F) and 7 FKS2 HS1 (WT, F659del, F659S, F659V, F659L, S663P, and S663F) genotypes. A blinded panel of 188 C. glabrata clinical isolates was tested by both assays. The molecular diagnostic results from the dual assay were 100% concordant with data obtained from DNA sequencing. This platform has the potential to overcome the deficiencies of existing in vitro susceptibility-based assays to identify echinocandin-resistant C. glabrata and holds promise as a surrogate diagnostic method to better direct echinocandin therapy.C andida glabrata is the second leading cause of candidemia in the United States, as well as in northern and eastern areas of Europe (1-3). With rapidly expanded usage of echinocandins, the first-line therapy for invasive candidiasis, an alarming trend of rising echinocandin resistance in C. glabrata has posed a serious clinical challenge (4-6). Detection of echinocandin resistance can be assessed phenotypically, using either microdilution or disc diffusion MIC assays performed in accordance with guidance of the Clinical and Laboratory Standards Institute (CLSI) M27-A3 standard (7) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) Definitive Document Edef 7.2 (8). Current echinocandin clinical breakpoints for C. glabrata were established by the CLSI for all echinocandins and by EUCAST for micafungin and anidulafungin. Breakpoints were specifically developed to identify C. glabrata harboring FKS mutations by considering multiple factors, such as ␤-1,3-D-glucan synthase enzyme kinetics and echinocandin pharmacokinetic and pharmacodynamic data (6, 9). However, despite standardized methodologies, important limitations with the in vitro susceptibility testing cannot be ignored: first, the assay has a time-consuming setup and intrinsically slow turnaround time, requiring 24 to 48 h after isolate recovery; second, interlaboratory variability of caspofungin MICs has limited direct testing of this drug (10); and third, susceptible and resistant populations overlap (11).Clinical echinocandin resistance in C. glabrata is associated with amino acid substitutions caused by mutations in specific hotspot (HS) regions of FKS1 and FKS2, which encode the drug target ␤-1,3-D-glucan synthase. A recent study performed among patients with invasive candidiasis due to C. glabrata has shown that the FKS genotype is a better indicator of echinocandin therapeutic failure than MIC (12).To date, DNA sequencing is the only means to identify mutations within FKS1 and FKS2 genes. Sequence data a...

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Section: Discussionmentioning

confidence: 99%

Section: Melting Curve Analysis-based Fks1/fsk2 Hs1 Genotypingmentioning

confidence: 99%

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Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

Zhao

Nagasaki

Kordalewska

et al. 2016

Antimicrob Agents Chemother

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“…However, widespread echinocandin usage has been accompanied by reports of emerging multidrug resistance among clinical Candida isolates (Alexander et al, 2013; Fekkar et al, 2014), as well as epidemiological shifts with increased proportion of less susceptible Candida species (Lortholary et al, 2011). Resistance to echinocandins is associated with mutations in two hot spot (HS) regions in the FKS genes that correlate with clinical failure or poor response to therapy (Perlin, 2011; Shields et al, 2012; Beyda et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

CD101: a novel long‐acting echinocandin

Zhao

Perez

Jiménez‐Ortigosa

et al. 2016

Cellular Microbiology

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SummaryCD101 is a novel echinocandin drug being developed to treat severe fungal infections including invasive candidiasis. We have performed a series of studies to evaluate the antifungal properties of CD101 against both echinocandin‐susceptible and ‐resistant Candida strains. Antifungal susceptibility testing performed on a collection of 95 Candida strains including 30 caspofungin‐resistant isolates containing fks mutations demonstrated comparable antifungal potency of CD101 relative to micafungin (MCF) across different Candida species. Comparable kinetic inhibition of glucan synthase activity was also observed for CD101 and MCF on both wild‐type (WT) and resistant fks mutant Candida strains. Similarly, both drugs yielded nearly identical values for a mutant prevention concentration. In a murine model of invasive candidiasis, CD101 displayed better or at least comparable efficacy relative to MCF in treating WT or fks mutant Candida albicans. An exceptional long‐lived pharmacokinetic profile was observed in mice following a single dose of CD101. Collectively, CD101 has great potential not only in treating invasive Candida infections but also in preventing emergence of resistance to currently approved echinocandin drugs.

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“…to echinocandins is low worldwide (Perlin, 2014), secondary resistance to caspofungin at some medical centres is more substantial (Alexander et al, 2013;Beyda et al, 2014;Pappas et al, 2007;Perlin, 2014;Pfaller et al, 2012;Shields et al, 2013). In a tertiary-care cancer centre in the USA, caspofungin resistance rates of C. glabrata among patients suffering from cancer (Farmakiotis et al, 2014) and acute leukaemia (Wang et al, 2015) were 10.3% (15 out of 146 isolates) and 58.3% (7 out of 12 isolates), respectively.…”

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confidence: 99%

Dose escalation studies with caspofungin against Candida glabrata

Domán

Kovács

Perlin

et al. 2015

Journal of Medical Microbiology

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Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandinresistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were #0.03 mg l 21 but increased to 0.125-0.25 mg l 21 in RPMI 1640+50 % serum. In RPMI 1640+50 % serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l 21 showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l 21 (paradoxically decreased killing activity). In RPMI 1640+50 % serum, caspofungin at ¢1 mg l 21 was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg 21 daily) decreased the fungal tissue burdens significantly (P,0.05-0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 10 5 cells (g tissue) 21 .The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.

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FKS Mutant Candida glabrata: Risk Factors and Outcomes in Patients With Candidemia

Abstract: FKS mutations were identified in 18% of 72 patients with C. glabrata candidemia. Common risk factors for FKS mutant isolates included previous echinocandin exposure, which also influenced response rates.

Cited by 146 publications

References 15 publications

Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

CD101: a novel long‐acting echinocandin

Dose escalation studies with caspofungin against Candida glabrata

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