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Journal of Clinical Microbiology, July 2008, p. 2389-2392, Vol. 46, No. 7
0095-1137/08/$08.00+0     doi:10.1128/JCM.00053-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Detection of Caspofungin Resistance in Candida spp. by Etest{triangledown}

Marie Desnos-Ollivier,1 Françoise Dromer,1 and Eric Dannaoui1,2*

Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 75724 Paris Cedex 15,1 Université Paris Descartes, Faculté de Médecine, AP-HP, Hôpital Européen Georges Pompidou, Unité de Parasitologie-Mycologie, 75015 Paris, France2

Received 10 January 2008/ Returned for modification 27 February 2008/ Accepted 21 April 2008


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ABSTRACT
 
The caspofungin susceptibilities of 28 Candida sp. clinical isolates, including 8 caspofungin-resistant isolates characterized by mutations in the Fks1 protein, were determined by the Etest in RPMI and AM3 media. Good discrimination between wild-type and mutant isolates was obtained. These results suggest that the Etest is valuable for the detection of caspofungin resistance in Candida spp.


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TEXT
 
Most of the large surveillance studies on the in vitro susceptibility of Candida species isolates to caspofungin have been performed by using the reference broth microdilution techniques of the CLSI (25, 27) and AFST-EUCAST (6, 7, 9). Nevertheless, in routine clinical microbiology laboratories, alternative methods such as the commercially available agar diffusion technique Etest are commonly used. The Etest is a reproducible and reliable technique for the determination of in vitro caspofungin activity, and good agreement with reference techniques is obtained (1, 5, 13, 21, 28).

Caspofungin resistance in Candida spp. remains uncommon (27). However, several clinical case reports have been published on infections with Candida species isolates exhibiting high caspofungin MICs, some of which were associated with treatment failure (2, 8, 11, 14, 15, 18-20, 22, 23, 26, 30). In several cases, resistance was confirmed in animal models (15, 19, 26), and mutations in the fks1 gene were associated with the resistance phenotype (2, 17, 18, 20, 22, 26). It has been shown that mutations in Fks1 are sufficient to confer reduced susceptibility to caspofungin on Candida spp. (26). Even though high MICs have been recorded using the Etest on a few Candida isolates (2, 19), this technique has never been evaluated for its ability to detect caspofungin resistance. We recently characterized a collection of Candida albicans, C. tropicalis, and C. krusei isolates with decreased susceptibility to caspofungin, associated with various Fks1 mutations (10). The aim of the present study was to evaluate the Etest for its ability to discriminate between wild-type (caspofungin-susceptible) and Fks1 mutant (caspofungin-resistant) isolates of Candida spp.

The clinical isolates were collected at the French National Reference Center for Mycoses and Antifungals as part of our surveillance activities. All isolates were identified to the species level by standard mycological procedures including the assimilation patterns obtained with the commercialized ID32C strips (bioMérieux, Marcy-l'Etoile, France). For all C. albicans isolates, a specific PCR amplification (12) was performed to exclude C. dubliniensis. In a recent study (10), we sequenced and translated (to obtain the deduced protein sequence) the two hot spot (HS) regions of the fks1 gene, HS1 and HS2, for 28 clinical isolates, including Candida albicans (n = 25), C. tropicalis (n = 2), and C. krusei (n = 1), for which caspofungin MICs were determined by the AFST-EUCAST method (29). MICs of ≥0.5 µg/ml recorded in AM3 medium were associated with mutations in the deduced Fks1 sequence (6 C. albicans, 1 C. tropicalis, and 1 C. krusei isolate), while isolates with MICs of ≤0.25 µg/ml had no Fks1 mutation (19 C. albicans and 1 C. tropicalis isolate). Among the eight mutant isolates, only two (both C. albicans) had mutations in HS2. One of these two mutants also had a mutation in HS1. Thus, 8 caspofungin-resistant isolates with Fks1 protein mutations (mutant isolates) and 20 caspofungin-susceptible isolates without mutations in the Fks1 protein (wild-type isolates) were used for the present study. The 28 isolates were recovered from 24 patients. The eight resistant isolates were recovered from blood culture (n = 2), urine (n = 2), bronchoalveolar lavage (n = 1), and oropharynx (n = 3) specimens of six patients. Mutant isolates obtained from a given patient were included if they harbored different fks1 mutations.

The Etest was performed according to the manufacturer's instructions using two different media, RPMI 1640 (Sigma, Saint Quentin Fallavier, France) and AM3 (Difco, Becton Dickinson, Le Pont de Claix, France). Briefly, a stock solution of 2x-concentrated RPMI 1640 buffered with 0.165 M morpholinepropanesulfonic acid (MOPS) (Sigma) was adjusted to a pH of 7.0 and supplemented with 2% glucose. AM3 medium was also supplemented with 2% glucose. Both media were mixed with agar (volume/volume) and dispensed into petri dishes (25 ml for a 90-mm-diameter petri dish).

Isolates were cultured on Sabouraud dextrose agar plates at 35°C for 24 h. The inoculum was prepared by transferring several colonies into distilled water and adjusting the suspension spectrophotometrically at 530 nm to an optical density of 0.11 to 0.13, corresponding to an inoculum size of 1 x 106 to 5 x 106 CFU/ml. The inoculum size was checked by duplicate culture on Sabouraud agar plates. Then the petri dishes containing RPMI or AM3 medium were inoculated with the cell suspension by swabbing the entire surface of the agar in three directions. The Etest antifungal strip of caspofungin was then placed on the inoculated agar by using sterile forceps. The dishes were incubated in ambient air at 35°C for 48 h. MICs were determined after 24 and 48 h of incubation and were defined as 80% inhibition (1). The presence of microcolonies within the inhibition ellipse was ignored. Two reference strains, Candida krusei ATCC 6258 and C. parapsilosis ATCC 22019, were included in each set of determinations for quality control.

For calculation, high off-scale MICs (>32 µg/ml) were raised up to the next higher concentration (48 µg/ml). Distributions of MICs were compared by a nonparametric test (Mann-Whitney). Statistical analyses were performed using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, CA). Statistical significance was defined as a P value of ≤0.05.

Caspofungin MIC distributions for the 20 wild-type isolates and the 8 mutant isolates are presented for both media and both incubation times in Fig. 1. In RPMI and AM3 media, at both incubation times, caspofungin MICs were significantly higher for mutant isolates than for wild-type isolates (P < 0.0001), with very good discrimination between wild-type and mutant isolates. Indeed, there was no overlap: the highest MIC for all the wild-type isolates was lower than the lowest MIC for all the mutant isolates. The three mutant isolates with the lowest MICs were one C. tropicalis isolate with a mutation in HS1 and two C. albicans isolates with mutations in HS2. Nevertheless, due to the low number of C. albicans isolates with mutations in HS2 and the limited number of non-albicans Candida isolates, it is not possible to conclude that a relationship exists between the MIC level and either the site of mutation or the species. After 48 h of incubation, MICs of >0.5 µg/ml in RPMI medium and >0.25 µg/ml in AM3 medium were seen only for mutant isolates. As shown in Fig. 2, MICs determined by the Etest were readily discernible on both media. Nevertheless, at both incubation times, microcolonies were observed for some isolates within the ellipse of inhibition when RPMI medium was used. Subculture and retesting of these microcolonies showed that they were not associated with increased caspofungin resistance.


Figure 1
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  		FIG. 1. Distributions of caspofungin MICs for wild-type and Fks1 mutant clinical isolates determined in RPMI and AM3 media after 24 and 48 h of incubation. Horizontal bars, geometric mean MICs; dotted lines, lowest MICs for mutant isolates.


Figure 2
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  		FIG. 2. In vitro susceptibilities of Candida species clinical isolates to caspofungin by Etest in RPMI and AM3 media after 48 h of incubation. A susceptible wild-type isolate (isolate 14) and two resistant Fks1 mutant isolates (isolates 19 and 25) were tested.

In this study, the ability to detect caspofungin resistance in Candida albicans, C. tropicalis, and C. krusei with the Etest was evaluated by testing a collection of well-characterized wild-type and Fks1 mutant clinical isolates (10). We deliberately avoided the use of laboratory mutants, because they might not be clinically relevant. In the more comprehensive study using caspofungin-resistant laboratory mutants (3), it has been shown that fks1 mutations were located at position 645 in 93% of the cases, while a great diversity of mutations were found in our small collection of clinical mutant isolates (10). In two previously published clinical cases of caspofungin resistance, the Etest was successfully used along with broth microdilution reference techniques to detect decreased in vitro susceptibility to caspofungin (2, 19). The emergence of caspofungin resistance was documented for C. glabrata by the CLSI method performed in RPMI medium (the MIC rose from 0.5 to 8 µg/ml for the pre- and posttreatment isolates, respectively) and the Etest (MICs were 0.19 and >32 µg/ml for the same isolates) (19). In the second case report, susceptible pretreatment and resistant posttreatment C. albicans isolates were tested (2). The caspofungin MIC rose from 0.25 to 2 µg/ml when tested by AFST-EUCAST in RPMI medium and from 0.06 to 32 µg/ml by the Etest, suggesting better discrimination with the Etest.

The present study confirmed these anecdotal findings and suggests that the Etest is a valuable technique for the detection of caspofungin-resistant isolates. Due to the relatively low number of isolates included in the present study, further evaluation of the Etest with more mutant isolates exhibiting varied MICs is warranted. The influence of incubation time seems minimal, since discrimination between susceptible and resistant isolates was obtained after both 24 and 48 h of incubation. We have also compared two culture media, since previous studies have shown better discrimination between caspofungin-susceptible and -resistant Candida species isolates by using AM3 medium than by using RPMI medium with the CLSI (4, 24) or AFST-EUCAST (10) method. With the Etest, good discrimination between susceptible and resistant isolates was obtained with both media, but determination of MICs was easier in AM3 medium because of the absence of microcolonies within the inhibition ellipse. The present study was not designed for the determination of breakpoints. Further analysis including more isolates and clinical data will be necessary to define clinical breakpoints. Clinical breakpoints allow guidance of therapy, while epidemiological cutoff values permit one to categorize isolates as wild type or non-wild type, based on the detection of resistance mechanisms (16). Both wild-type and non-wild-type isolates may or may not respond clinically to the antifungal treatment. The results of the present study allowed the proposal of caspofungin epidemiological cutoff values for the Etest of >0.5 µg/ml in RPMI medium and >0.25 µg/ml in AM3 medium after 48 h of incubation.

In summary, this study suggested that the Etest is a valuable method for in vitro testing of susceptibility to caspofungin. This is best done using the strips on AM3 medium in order to detect caspofungin resistance in Candida spp. after 48 h of incubation.


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ACKNOWLEDGMENTS
 
We are grateful to Dorothée Raoux and Damien Hoinard for excellent technical assistance.


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FOOTNOTES
 
* Corresponding author. Mailing address: Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 40 61 32 50. Fax: 33 1 45 68 84 20. E-mail: dannaoui{at}pasteur.fr Back

{triangledown} Published ahead of print on 30 April 2008. Back


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Journal of Clinical Microbiology, July 2008, p. 2389-2392, Vol. 46, No. 7
0095-1137/08/$08.00+0     doi:10.1128/JCM.00053-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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