Multicenter Study of Epidemiological Cutoff Values and Detection of Resistance in Candida spp. to Anidulafungin, Caspofungin, and Micafungin Using the Sensititre YeastOne Colorimetric Method

Espinel-Ingroff, Ana; Álvarez-Fernández, Maximiliano; Cantón, Emilia; Carver, Peggy L.; Chen, S. C.A.; Eschenauer, Gregory A.; Getsinger, D. L.; González, Gloria M.; Govender, Nelesh P.; Grancini, Anna; Hanson, Kimberly E.; Kidd, Sarah; Klinker, Kenneth P.; Kubin, Christine J.; Kus, Julianne V.; Lockhart, Shawn R.; Meletiadis, Joseph; Morris, Arthur J.; Peláez, Teresa; Quindós, Guillermo; Rodríguez-Iglesias, Manuel; Sánchez-Reus, Ferran; Shoham, Shmuel; Wengenack, Nancy L.; Solé, N. Borrell; Echeverría, J.M. Alústiza; Esperalba, Juliana; Pedrosa, Elia Gómez G. de la; García, Inmaculada García; Linares, María José Pedraja; Marco, Francesc; Merino, Paloma; Pemán, Javier; Molino, Luisa Pérez del; Mayans, E. Roselló; Calvo, Carmen Rubio; Pipaón, Maite Ruiz Pérez de; Yagüe, Genoveva; García‐Effrón, Guillermo; Guinea, Jesús; Perlin, David S.; Sanguinetti, Maurizio; Shields, Ryan K.; Turnidge, John

doi:10.1128/aac.01250-15

Cited by 56 publications

(69 citation statements)

References 28 publications

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“…The recently reported YeastOne caspofungin epidemiological cutoff values (ECVs) were used to classify isolates as wild-type or non-wild-type isolates in this colorimetric assay (9). The rates of very major errors (VME), major errors (ME), and minor errors (mE) were also determined according to accepted definitions (10,11).…”

Section: Discussionmentioning

confidence: 99%

Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species

et al. 2016

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Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of >0.5 g/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others. Significant interlaboratory variability has been reported for caspofungin susceptibility testing, with some laboratories reporting MIC values elevated above the revised CLSI clinical breakpoints (1). The interlaboratory variability is not without consequences, as it may result in major errors for caspofungin use (i.e., falsely interpreting an isolate as resistant to this echinocandin). In a retrospective review of our antifungal susceptibility database using data from 2008 to 2012, we found that 95.6% of C. glabrata and 74.3% of C. krusei isolates would be classified as resistant to caspofungin on the basis of the revised CLSI echinocandin clinical breakpoints (2). Other laboratories have reported similar results (3). As the factors that lead to interlaboratory variability are unknown, we sought to determine if the choice of plastic used in the microtiter trays, either treated or untreated polystyrene, could affect caspofungin MIC values. These trays are designed for cell cultures, and treatment of the plastic, either by coating or corona discharge to impart an electrical charge to the plastic, allows the cells to adhere. Our laboratory has historically used 96-well microtiter trays made of treated polystyrene, while other laboratories have used those made of untreated plastic. The CLSI M27-A3 standard for yeast antifungal susceptibility testing has not addressed plastic type or recomm...

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Section: Discussionmentioning

confidence: 99%

Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species

et al. 2016

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“…As defined in the introduction, the WT is the population of strains in a species-drug combination with no detectable acquired resistance mechanisms. The ECV (or WT cutoff value [CO WT ]) is the highest MIC that would categorize an isolate as WT (without known mechanisms of resistance) or, alternatively, the critical drug concentration value that may identify those strains that have decreased susceptibility to the agent being evaluated (non-WT isolates) or are potentially resistant (26,27,35).…”

Section: Methodsmentioning

confidence: 99%

“…The data were analyzed as reported previously in various studies, by following the CLSI guidelines set forth for this purpose (26,27,35; CLSI documents on ECVs under development). Briefly, after the MIC distributions for each combination of an antifungal agent and a species or species complex from each laboratory were listed in an Excel spreadsheet, they were reviewed for skewed/abnormal distributions (e.g., the mode at the lowest concentration tested and/or bimodal [two modes in the same distribution]), which were not included in the statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…However, it is still possible to define ECVs. These are calculated on the basis of MIC distributions (Ն100 MIC results per species and antifungal agent) from multiple (Ն3) independent laboratories (26,27; CLSI documents on ECVs under development). ECVs can identify non-wild-type (non-WT [often harboring molecular mechanisms of resistance]) isolates or isolates that are less susceptible to the antifungal agent being evaluated.…”

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International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method

Espinel-Ingroff

Colombo

Córdoba

et al. 2016

Antimicrob Agents Chemother

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rThe CLSI epidemiological cutoff values (ECVs) of antifungal agents are available for various Candida spp., Aspergillus spp., and the Mucorales. However, those categorical endpoints have not been established for Fusarium spp., mostly due to the difficulties associated with collecting sufficient CLSI MICs for clinical isolates identified according to the currently recommended molecular DNA-PCR-based identification methodologies. CLSI MIC distributions were established for 53 Fusarium dimerum species complex (SC), 10 F. fujikuroi, 82 F. proliferatum, 20 F. incarnatum-F. equiseti SC, 226 F. oxysporum SC, 608 F. solani SC, and 151 F. verticillioides isolates originating in 17 laboratories (in Argentina, Australia, Brazil, Canada, Europe, Mexico, and the United States). According to the CLSI guidelines for ECV setting, ECVs encompassing >97.5% of pooled statistically modeled MIC distributions were as follows: for amphotericin B, 4 g/ml (F. verticillioides) and 8 g/ml (F. oxysporum SC and F. solani SC); for posaconazole, 2 g/ml (F. verticillioides), 8 g/ml (F. oxysporum SC), and 32 g/ml (F. solani SC); for voriconazole, 4 g/ml (F. verticillioides), 16 g/ml (F. oxysporum SC), and 32 g/ml (F. solani SC); and for itraconazole, 32 g/ml (F. oxysporum SC and F. solani SC). Insufficient data precluded ECV definition for the other species. Although these ECVs could aid in detecting nonwild-type isolates with reduced susceptibility to the agents evaluated, the relationship between molecular mechanisms of resistance (gene mutations) and MICs still needs to be investigated for Fusarium spp.

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“…and echinocandins (22), which prompted the establishment of method-dependent echinocandin SYO ECVs for Candida spp. (23). Another commercial and frequently used method for antifungal susceptibility testing is the gradient agar diffusion-based Etest assay (bioMérieux, Marcy l'Etoile, France) (24).…”

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Multicenter Study of Method-Dependent Epidemiological Cutoff Values for Detection of Resistance in Candida spp. and Aspergillus spp. to Amphotericin B and Echinocandins for the Etest Agar Diffusion Method

Espinel-Ingroff

Arendrup

Cantón

et al. 2017

Antimicrob Agents Chemother

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Method-dependent Etest epidemiological cutoff values (ECVs) are not available for susceptibility testing of either Candida or Aspergillus species with amphotericin B or echinocandins. In addition, reference caspofungin MICs for Candida spp. are unreliable. Candida and Aspergillus species wild-type (WT) Etest MIC distributions (microorganisms in a species-drug combination with no detectable phenotypic resistance) were established for 4,341 Candida albicans, 113 C. dubliniensis, 1,683 C. glabrata species complex (SC), 709 C. krusei, 767 C. parapsilosis SC, 796 C. tropicalis, 1,637 Aspergillus fumigatus SC, 238 A. flavus SC, 321 A. niger SC, and 247 A. terreus SC isolates. Etest MICs from 15 laboratories (in Argentina, Europe, Mexico, South Africa, and the United States) were pooled to establish Etest ECVs. Anidulafungin, caspofungin, micafungin, and amphotericin B ECVs (in micrograms per milliliter) encompassing Ն97.5% of the statistically modeled population were 0.016, 0.5, 0.03, and 1 for C. albicans; 0.03, 1, 0.03, and 2 for C. glabrata SC; 0.06, 1, 0.25, and 4 for C. krusei; 8, 4, 2, and 2 for C. parapsilosis SC; and 0.03, 1, 0.12, and 2 for C. tropicalis. The amphotericin B ECV was 0.25 g/ml for C. dubliniensis and 2, 8, 2, and 16 g/ml for the complexes of A. fumigatus, A. flavus, A. niger, and A. terreus, respectively. While anidulafungin Etest ECVs classified 92% of the Candida fks mutants evaluated as non-WT, the performance was lower for caspofungin (75%) and micafungin (84%) cutoffs. Finally, although anidulafungin (as an echinocandin surrogate susceptibility

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Multicenter Study of Epidemiological Cutoff Values and Detection of Resistance in Candida spp. to Anidulafungin, Caspofungin, and Micafungin Using the Sensititre YeastOne Colorimetric Method

Cited by 56 publications

References 28 publications

Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species

Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species

International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method

Multicenter Study of Method-Dependent Epidemiological Cutoff Values for Detection of Resistance in Candida spp. and Aspergillus spp. to Amphotericin B and Echinocandins for the Etest Agar Diffusion Method

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