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Antimicrobial Agents and Chemotherapy, March 2008, p. 1062-1065, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01016-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Reliability of the WIDERYST Susceptibility Testing System for Detection of In Vitro Antifungal Resistance in Yeasts

Manuel Cuenca-Estrella,^* Alicia Gomez-Lopez, M. Olga Gutierrez, M. Jose Buitrago, and Juan L. Rodriguez-Tudela

Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, España

Received 2 August 2007/ Returned for modification 18 October 2007/ Accepted 24 December 2007

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study evaluated the WIDERYST system, a commercially available computer-assisted image-processing device for the antifungal susceptibility testing of yeasts. A collection of 90 clinical isolates selected to represent ranges of susceptibilities in vitro as broad as possible was tested. An evaluation compared the results obtained by the new system with those achieved by both the Clinical and Laboratory Standards Institute (CLSI) microdilution reference procedure and the antifungal susceptibility standard of the European Committee for Antimicrobial Susceptibility Testing (EUCAST). Overall, the agreement and the correlation index between results obtained by the EUCAST method and the WIDERYST system were 89% and 0.84 (P < 0.01), respectively, and agreement and correlation index between data obtained by the CLSI procedure and the WIDERYST system were 90% and 0.86 (P < 0.01), respectively. The system was able to detect amphotericin B-resistant isolates. All Candida sp. isolates with resistance in vitro to azole agents were detected as well. The system misclassified some isolates belonging to the slowly growing genera Dipodascus and Pichia. A total of 2.7% very major errors were detected for fluconazole. The WIDERYST system is an alternative to reference procedures for antifungal susceptibility testing of clinical isolates of yeasts, particularly for Candida and Cryptococcus species.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The development and standardization of reference procedures for antifungal susceptibility testing (AST) have represented a breakthrough in the field of medical mycology (7, 11). The detection of strains and species exhibiting resistance in vitro to antifungal agents has become clinically significant since several therapeutic alternatives are available.

The main utility of yeast AST is the detection of fluconazole (FLC) resistance (5, 13). Reference procedures are reliable techniques to detect strains with resistance in vitro to FLC. However, the standard reference procedures are impractical and hardly affordable for clinical laboratories since they recommend complex methods based on in-house dilution procedures with intricate quality control methodologies. Many microbiologists prefer to use other systems which have particular advantages such as ease of performance, economy, or more-rapid results. For this reason, several automated or semiautomated commercial systems have been developed for AST. These systems are specifically designed to allow reliable and more accessible MIC determination (3, 5, 12, 15).

The WIDER system (Francisco Soria Melguizo S.A., Madrid, Spain) is a commercially available computer-assisted image-processing system that was designed originally for bacterial identification and susceptibility testing (2). It has been adapted now to read microdilution trays for AST of yeasts (WIDERYST) against amphotericin B (AMB), FLC, itraconazole (ITC), voriconazole (VRC), ketoconazole (KTC), and flucytosine (5FC). The image of the panel is digitized by a video camera (Hitachi KP-D50 color; Hitachi, Crofton, MD) and analyzed by the software included. The susceptibility profile is generated automatically depending on the analysis and the interpretation of growth parameters in the susceptibility testing wells. Inoculation, incubation, and reading conditions are based on the reference procedures of the Clinical and Laboratory Standards Institute (CLSI) and the Antifungal Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST), but the automation makes the MIC determination easier.

We report here an evaluation of the accuracy of the WIDERYST system to detect antifungal resistance in vitro. The evaluation compared the AST results obtained by the new system with those achieved by both the CLSI microdilution reference procedure and the EUCAST standard.

(This study was presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005.)

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Fungi. A collection of 90 clinical isolates was tested. The majority of isolates (n = 49) were obtained from blood cultures and the remainder from specimens of deep site (n = 18) or from oropharyngeal exudates (n = 23). Species distribution was as follows: 15 Candida albicans isolates, 15 Candida tropicalis isolates, 10 Candida parapsilosis isolates, 10 Candida glabrata isolates, 10 Candida krusei isolates, 11 Candida lusitaniae isolates, three Candida guilliermondii isolates, two Candida famata isolates, one Candida pelliculosa isolate, one Candida haemulonii isolate, three Cryptococcus neoformans isolates, three Rhodotorula mucilaginosa isolates, three Dipodascus capitatus isolates, two Pichia membranifaciens isolates, and one Saccharomyces cerevisiae isolate. The isolates were selected to represent ranges of susceptibilities in vitro as broad as possible, including organisms resistant in vitro to antifungal agents (5-7). A total of six isolates had an AMB MIC of >1 µg/ml, nine a 5FC MIC of >4 µg/ml, 44 an FLC MIC of >8 µg/ml (15 strains with a MIC of 16 µg/ml, 12 with a MIC of 32 µg/ml, and 17 with a MIC of 64 µg/ml), 14 an ITC MIC of >0.5 µg/ml, 11 a VRC MIC of >1 µg/ml, and 12 a KTC MIC of >1 µg/ml by both reference AST procedures. Each strain represented a unique isolate from a patient and was sent to our laboratory for identification or AST. Isolates were identified by morphological and physiological techniques and were maintained at –70°C (8, 10). C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were incorporated as quality control strains in each set of experiments (1, 6, 7). Table 1 displays MIC ranges and susceptibility data for quality control strains per susceptibility testing method.

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TABLE 1. MIC ranges of susceptibility results for quality control strains per susceptibility testing methoda

Reference susceptibility testing procedures. The antifungal agents used in the study were AMB (Sigma-Aldrich Química S.A., Madrid, Spain), 5FC (Sigma-Aldrich), FLC (Pfizer S.A., Madrid, Spain), ITC (Janssen Pharmaceutica, Madrid, Spain), VRC (Pfizer Ltd., Sandwich, United Kingdom), and KTC (Janssen Pharmaceutica). The MICs for all isolates were determined by strictly following the reference microdilution procedure M27-A2 of the CLSI (11). AMB MICs were determined using RPMI as the assay medium.

In addition, AST was performed using the standard of the AFST-EUCAST for testing fermentative yeasts (document 7.1) (7, 11, 16). This second reference procedure is a microdilution technique with RPMI 1640 medium supplemented with 2% glucose as the assay medium, an inoculum size of 10⁵ CFU/ml, and flat-bottomed microdilution plates. For Cryptococcus neoformans and other species of nonfermentative yeasts, susceptibility testing was also performed by the EUCAST standard but a minor modification was done: microdilution plates were sealed to limit evaporation, attached to an electrically driven wheel inside the incubator, and agitated at 350 rpm at 30°C for 48 h (14). MIC endpoints were determined spectrophotometrically at 24 and 48 h. For AMB, the MIC endpoint was defined as the lowest drug concentration that resulted in a reduction in growth of 90% or more compared with that of a drug-free growth control well. For 5FC and azoles, the MIC endpoint was defined as a 50% reduction in optical density.

WIDERYST system. Susceptibility testing, reading, and interpretations of the WIDERYST system results were performed in accordance with the manufacturer's instructions. Susceptibility testing was repeated three times on three separate days in order to reduce changeable experiment conditions.

The WIDER system is basically composed of a reader module assisted by a data analysis module. The reader module is an illuminated chamber with a digitizing video camera that completely reflects the image of a commercial tray used for susceptibility testing. The digitized image is analyzed by the WIDER system's software in the data analysis module. The software automatically detects the panel, and growth parameters in wells are analyzed in comparison with those in positive- and negative-control wells. The MIC is defined as the lowest concentration exhibiting a reduction in growth parameters of 90% for AMB or of 50% for the other compounds compared with those of the positive control (2).

WIDERYST panels with 96 wells containing lyophilized antifungal agents were used. The panel was manufactured by TREK Diagnostic Systems, Inc. (Cleveland, OH). Concentrations of the antifungal agents used in the panels were as follows: FLC and 5FC concentrations between 128 and 0.06 µg/ml and AMB, ITC, VRC, and KTC concentrations from 8 to 0.004 µg/ml. The panels were inoculated with a standardized inoculum (1 x 10⁵ to 5 x 10⁵ CFU/ml) by using the disposable WIDERYST inoculator according to the manufacturer's recommendations. Trays were incubated at 35°C for 24 h in a non-CO₂ incubator. If the wells had no growth, trays were incubated for a further 24 h. Cryptococcus and other nonfermentative species had to be incubated for 48 to 72 h.

Data analysis. Both on-scale and off-scale results obtained by AST procedures were included in the analysis. The low off-scale MICs were left unchanged and the high off-scale MICs were converted to the next-highest concentration. The levels of reproducibility of the results obtained by reference techniques and by the WIDERYST system were calculated by determining the percentage of agreement between MICs. Agreement was defined as discrepancies in MIC results of no more than ±1 twofold dilution. In addition, the correlation between the results was evaluated using the intraclass correlation coefficient (ICC), which was expressed to a maximum value of 1 and with a 95% confidence interval. In order to approximate a normal distribution, the MICs were transformed to log₂ values. A P value of <0.01 was considered statistically significant. The ICC is a reverse measurement of the variability of the counting values. The ICC was calculated using the formula ICC = (group mean square – error mean square)/(group mean square + error mean square) and thus has a maximum value of 1 if there is a perfect correlation and a minimum value of –1 if there is complete absence of correlation. The ICC evaluates the correlation between values offering a statistical significance since it takes into account number of cases and absolute value of the counting. The ICC is a scale analysis and exhibits the highest statistical power for correlation studies.

Categorical agreement and percentage of discrepancies were also evaluated. Categories were defined depending on the existence of interpretative breakpoints. The CLSI has defined breakpoints for 5FC, FLC, ITC, and VRC. However, the EUCAST has not still defined interpretive breakpoints for antifungal agents and the CLSI has not proposed breakpoints for AMB and KTC. In the case of antifungal agents whose breakpoints have been set, categorical agreement was defined as the percentage of isolates classified in the same category by the reference procedures and the WIDERYST system, and discrepancies between methods were considered very major errors if an isolate classified as showing resistance in vitro by the reference method was categorized as susceptible by the WIDERYST method. Discrepancies were considered major errors if an isolate categorized as susceptible by the reference method was classified as resistant by the commercial technique. Minor errors were considered when a susceptible isolate was classified as intermediate or susceptible-dose dependent (S-DD), when a resistant organism was grouped with intermediate or S-DD isolates, when intermediate or S-DD strains were considered susceptible, or when intermediate or S-DD isolates were classified as resistant organisms (5, 9).

If breakpoints were not defined, discrepancies were classified as insubstantial or substantial differences. Insubstantial differences were defined as discrepancies in MIC results of 3 or 4 twofold dilutions and substantial differences as discrepancies of more than 4 twofold dilutions. All statistical analyses were done with the Statistical Package for the Social Sciences (version 15.0; SPSS, S.L., Madrid, Spain).

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Table 1 displays the susceptibility results for reference strains per antifungal agent tested and per susceptibility method. The MICs of the two quality control strains were consistent within 3 twofold dilutions. These values agreed with those described in the discussion document 7.1 by EUCAST and the CLSI document M27-A2 (1, 6, 7, 9, 11). The table shows MIC data calculated after nine repetitions.

A total of 4,860 MICs were included in the survey, including 1,620 by the AST method and 270 per antifungal agent. Table 2 shows percentages of agreement and correlation indexes (ICCs) between reference method (CLSI and EUCAST) results and MICs obtained by the WIDERYST system, sorted by yeast species. Table 3 displays results per antifungal agent.

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TABLE 2. Agreement values and correlation coefficients between results obtained by reference susceptibility testing methods and the WIDERYST system, with data classified per Candida species

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TABLE 3. Agreement values and correlation coefficients between results obtained by reference susceptibility testing methods and the WIDERYST system, with data classified per antifungal agent

Overall, the agreement and the ICC between results obtained by the EUCAST method and the WIDERYST system were 89% and 0.84 (P < 0.01), respectively, and agreement and ICC between data obtained by the CLSI procedure and the WIDERYST system were 90% and 0.86 (P < 0.01), respectively. Per species, the percentages of agreement and correlation indexes of Candida spp. were very high and statistically significant. Average agreement and ICC were above 90% and 0.90, respectively. Lower figures were observed for non-Candida species, although correlation indexes between the reference procedures and the WIDERYST system also had statistical significance (ICCs of >0.80 [P < 0.01]). The lowest agreement and correlation rates were detected for the three D. capitatus isolates and the two P. membranifaciens isolates, with an agreement of 67% and ICC of 0.70 (P < 0.01). These isolates exhibited slow growth in wells of AST trays, and the WIDERYST system had trouble detecting the growth.

When the analysis was done by antifungal agent, the highest reproducibility values were observed for 5FC, FLC, and VRC, with agreement rates around 90% and significant ICCs between both reference methods (CLSI and EUCAST) and the WIDERYST system. Agreement percentages for AMB, ITC, and KTC were over 84%, with ICCs statistically significant as well.

With regard to categorical analysis (Table 4), the WIDERYST system was able to identify the six strains with AMB MICs of >1 µg/ml. In addition, the WIDERYST system detected 43 out of 44 strains with FLC MICs of 8, 16, 32, and 64 µg/ml. The commercial method identified all isolates of Candida spp. and C. neoformans with resistance in vitro to FLC. Only an FLC-resistant strain of P. membranifaciens was classified as susceptible by the WIDERYST system (2.7% of very major errors according to CLSI criteria and 2.7% of substantial differences by EUCAST definitions). Similar figures were observed for the other antifungal agents, although rates of very major errors and substantial discrepancies were slightly higher for ITC and KTC. As for VRC, the percentage of substantial differences was 4.8% and that of very major errors was 1%. The WIDERYST system was able to classify as resistant all Candida and Cryptococcus species exhibiting resistance to ITC, VRC, or KTC. Some isolates belonging to slowly growing species such as Dipodascus capitatus and Pichia membranifaciens were misidentified as susceptible organisms.

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TABLE 4. Categorical agreement between results obtained by reference susceptibility testing methods and the WIDERYST systema

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Commercial semiautomated techniques for AST usually show some advantages over the reference methods. On a general basis, they are easier to perform, are more economical, and can be performed readily in clinical laboratories. However, some commercial techniques can be less accurate in detecting resistance in vitro to AMB and azole agents, providing AST results in total disagreement with those obtained by reference methods (5).

We have previously evaluated the WIDER system, a semiautomatic device that was validated for bacterial identification and susceptibility testing years ago (2). The major attractions of this technology are the image-processing technology and the image-assisted analysis that facilitate reading of the results. The method is a microdilution test which uses a tray containing antifungals at different concentrations. The organism to be studied is inoculated in the tray by use of the disposable WIDERYST inoculator and incubated for 24 h. The panel is then read with the image-processing system. Reading at 24 h should not be undertaken if the control wells are not clearly positive.

A comparison between results obtained by reference methods and those achieved with the device was done. A collection of 90 strains, susceptible and resistant in vitro to antifungal agents, was tested. The WIDERYST system exhibited high rates of agreement and correlation indexes, which indicates that it is a reliable technique for susceptibility testing of antifungal agents. The concordances between the EUCAST and WIDERYST methods and the CLSI and WIDERYST methods were 89% and 90%, respectively. Regarding resistances, the WIDERYST system was able to identify all AMB-resistant isolates and the great majority of azole-resistant organisms. The device has trouble detecting resistant strains belonging to uncommon species such as Dipodascus capitatus and Pichia membranifaciens, which usually do not grow luxuriantly in RPMI, the assay medium recommended for testing the activity of antifungal compounds (4).

In conclusion, AST results obtained by the WIDERYST method were comparable to those achieved by both EUCAST and CLSI procedures, with correlation indexes being statistically significant. Most AMB- and azole-resistant strains were identified correctly by the device, but some isolates were misclassified. A total of 2.7% very major errors and 2.3% substantial differences were detected for FLC. The WIDERYST system is an alternative to reference procedures for AST of clinical isolates of yeasts, particularly for Candida and Cryptococcus species. These results are preliminary, and higher numbers of isolates for rare species should be tested. The system should include newly licensed antifungal agents such as caspofungin, posaconazole, micafungin, and anidulafungin in order to make its clinical utility better.

 
This study was supported by a nonrestrictive research grant from Francisco Soria Melguizo S.A. A. Gomez-Lopez has a research contract from the Fondo de Investigaciones Sanitarias (grant CM05/00184).

 
* Corresponding author. Mailing address: Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo Km 2, 28220 Majadahonda (Madrid), Spain. Phone: 34-91-8223661. Fax: 34-91-5097966. E-mail: mcuenca-estrella{at}isciii.es

Published ahead of print on 14 January 2008.

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Antimicrobial Agents and Chemotherapy, March 2008, p. 1062-1065, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01016-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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