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Journal of Clinical Microbiology, January 2008, p. 150-156, Vol. 46, No. 1
0095-1137/08/$08.00+0     doi:10.1128/JCM.01901-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Susceptibility of Invasive Isolates of Candida spp. to Anidulafungin, Caspofungin, and Micafungin: Six Years of Global Surveillance{triangledown}

M. A. Pfaller,1* L. Boyken,1 R. J. Hollis,1 J. Kroeger,1 S. A. Messer,1 S. Tendolkar,1 and D. J. Diekema1,2

Departments of Pathology,1 Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa2

Received 24 September 2007/ Returned for modification 7 November 2007/ Accepted 12 November 2007


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ABSTRACT
 
The echinocandins are being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for the emergence of in vitro resistance to the echinocandins among invasive Candida sp. isolates is indicated. We determined the in vitro activities of anidulafungin, caspofungin, and micafungin against 5,346 invasive (bloodstream or sterile-site) isolates of Candida spp. collected from over 90 medical centers worldwide from 1 January 2001 to 31 December 2006. We performed susceptibility testing according to the CLSI M27-A2 method and used RPMI 1640 broth, 24-h incubation, and a prominent inhibition endpoint for determination of the MICs. Of 5,346 invasive Candida sp. isolates, species distribution was 54% C. albicans, 14% C. parapsilosis, 14% C. glabrata, 12% C. tropicalis, 3% C. krusei, 1% C. guilliermondii, and 2% other Candida spp. Overall, all three echinocandins were very active against Candida: anidulafungin (MIC50, 0.06 µg/ml; MIC90, 2 µg/ml), caspofungin (MIC50, 0.03 µg/ml; MIC90, 0.25 µg/ml), micafungin (MIC50, 0.015 µg/ml; MIC90, 1 µg/ml). More than 99% of isolates were inhibited by ≤2 µg/ml of all three agents. Results by species (expressed as the percentages of isolates inhibited by ≤2 µg/ml of anidulafungin, caspofungin, and micafungin, respectively) were as follows: for C. albicans, 99.6%, 100%, and 100%; for C. parapsilosis, 92.5%, 99.9%, and 100%; for C. glabrata, 99.9%, 99.9%, and 100%; for C. tropicalis, 100%, 99.8%, and 100%; for C. krusei, 100%, 100%, and 100%; and for C. guilliermondii, 90.2%, 95.1%, and 100%. There was no significant change in the activities of the three echinocandins over the 6-year study period and no difference in activity by geographic region. All three echinocandins have excellent in vitro activities against invasive strains of Candida isolated from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging echinocandin resistance among invasive clinical isolates of Candida spp.


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INTRODUCTION
 
The echinocandin class of antifungal agents acts by inhibition of the synthesis of 1,3-β-D-glucan in the fungal cell wall (31, 41). All three available echinocandins—anidulafungin (Pfizer), caspofungin (Merck), and micafungin (Astellas)—possess fungicidal activity against most species of Candida, including those resistant to polyenes (23) and to azoles (1, 3, 4, 7, 11, 18, 25, 26, 34-36, 41, 43). Caspofungin and anidulafungin have been approved by the U.S. Food and Drug Administration (FDA; years 2002 and 2006, respectively) for the treatment of invasive candidiasis, including candidemia (20, 40), and micafungin has been approved for the treatment of esophageal candidiasis (year 2005) (5). Although FDA approval of this drug for the treatment of candidemia is pending, micafungin has been shown to be safe and efficacious in the treatment of candidemia in recently published open-label (1, 26) and randomized (16, 28) clinical trials. These agents all provide excellent clinical efficacy coupled with low toxicity for the treatment of serious candidal infections.

Collaborative studies conducted by the Clinical and Laboratory Standards Institute (CLSI) Antifungal Subcommittee have resulted in the development of a standardized broth microdilution (BMD) method for determining echinocandin MICs for Candida spp. (24). The method employs RPMI 1640 broth medium, incubation at 35°C for 24 h, and a MIC endpoint criterion of prominent reduction in growth (≥50% inhibition relative to control growth). The CLSI method provides reproducible MIC results with good separation of the "wild-type" MIC distribution from isolates with mutations in the FKS1 gene, for which reduced susceptibility to echinocandins has been demonstrated (24, 31, 33). The availability of this standardized method has facilitated the performance of large-scale surveillance studies that have documented the potency and spectrum of echinocandin drugs against clinical isolates of Candida spp. (7, 25, 34-36). Recently, the CLSI Antifungal Subcommittee has taken into consideration the MIC distributions generated by the in vitro surveys, the mechanisms of action and of resistance known for the echinocandins, the pharmacokinetic and pharmacodynamic data available, and the clinical efficacy of each agent as it relates to the MIC for the infecting strain to arrive at a consensus MIC breakpoint for a susceptibility of ≤2 µg/ml for Candida spp. to all three echinocandins (minutes of the June 2007 meeting of the CLSI Antifungal Subcommittee; data not shown). This breakpoint encompasses more than 99% of all Candida isolates tested against each agent and reliably discriminates the susceptible wild-type strains from those with target site mutations (31, 38).

As patient exposure to echinocandins broadens, the number of infecting strains with reduced susceptibility may increase (31). Indeed, data from in vitro surveys document the presence of rare strains of otherwise highly susceptible species that exhibit unusually high MICs for one or more echinocandins (7, 34-36). Furthermore, they highlight the presence of less-susceptible species, such as C. parapsilosis and C. guilliermondii, the MICs for which may be 10- to 100-fold higher than those observed for C. albicans, C. glabrata, and C. tropicalis (2, 25, 38). Notably, sporadic treatment failures consistent with clinical resistance have been documented in association with so-called "high-MIC" isolates (i.e., MIC > 2 µg/ml) (8, 10, 12, 14, 17, 19, 21, 30, 39). In each case, the MIC of the echinocandin used in treatment was shown to increase progressively during the course of therapy, and where investigated, a mutation in FKS1 was demonstrated in the high-MIC isolate (12, 17, 19). In most (but not all) instances, resistance to all three echinocandins was demonstrated, consistent with known mechanisms of action and resistance to echinocandins in Candida (31). These observations underscore the importance of antifungal susceptibility testing of echinocandins in detecting unusual resistance profiles as these agents are used more broadly worldwide.

In the present study, we provide a unique "head-to-head" comparison of all three clinically available echinocandins by using CLSI reference BMD for a global collection of 5,346 bloodstream infection (BSI) isolates of Candida spp. We examine geographic trends in both species distribution and echinocandin activity and discuss issues of cross-resistance to the three agents.


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MATERIALS AND METHODS
 
Organisms. A total of 5,346 clinical isolates obtained internationally from 91 medical centers from 2001 to 2006 were tested. The collection included 2,869 strains of Candida albicans, 759 of Candida parapsilosis, 747 of Candida glabrata, 625 of Candida tropicalis, 136 of Candida krusei, 61 of Candida guilliermondii, 58 of Candida lusitaniae, 37 of Candida kefyr, 24 of Candida famata, 11 of Candida pelliculosa, 8 of Candida lipolytica, 6 of Candida dubliniensis, 2 of Candida rugosa, 2 of Candida zeylanoides, and 1 of Candida intermedia. All isolates were obtained from blood or other normally sterile sites and represented individual infectious episodes. The isolates were collected at individual study sites and were sent to the University of Iowa (Iowa City) for identification and susceptibility testing as described previously (33-36). The isolates were identified by standard methods (9) and stored as water suspensions until used in the study. Prior to testing, each isolate was passaged at least twice onto potato dextrose agar (Remel) and CHROMagar Candida (Becton Dickinson and Company, Sparks, MD) to ensure purity and viability.

Antifungal agents. Reference powders of anidulafungin, caspofungin, and micafungin were obtained from their respective manufacturers. Stock solutions were prepared in water (caspofungin and micafungin) or dimethyl sulfoxide (anidulafungin), and serial twofold dilutions in RPMI 1640 medium (Sigma, St. Louis, MO) buffered to pH 7.0 with 0.165 M MOPS (morpholinepropanesulfonic acid) buffer (Sigma) were made.

Antifungal susceptibility testing. BMD testing was performed in accordance with the guidelines in CLSI document M27-A2 (22) by using RPMI 1640 medium, an inoculum of 0.5 x 103 to 2.5 x 103 cells/ml, and incubation at 35°C. MICs were determined visually, after 24 h of incubation, as the lowest concentration of drug that caused a significant diminution (≥50% inhibition) of growth below control levels (18, 33-36).

Quality control. Quality control was performed by testing CLSI-recommended strains C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 (22).


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RESULTS AND DISCUSSION
 
Table 1 demonstrates the species distribution of Candida BSI isolates according to the geographic region of origin. A total of 5,346 isolates were obtained from 91 different medical centers in the Asia-Pacific region (16 sites), Latin America (15 sites), Europe (32 sites), and North America (28 sites). Consistent with previous reports (32, 35-38), the distributions of Candida species isolated from blood and other sterile sites differed considerably across the different regions. C. albicans constituted well over 50% of BSI isolates in Europe (58.42%) and the Asian-Pacific region (57.1%), whereas only 47.9% of isolates from Latin America and 50% of isolates from North America were C. albicans. Likewise, C. parapsilosis and C. tropicalis were prominent in the Asian-Pacific and Latin American regions but less so in both Europe and North America. Whereas C. glabrata was the most common species after C. albicans in both North America and Europe, it was distinctly less common than both C. parapsilosis and C. tropicalis in Latin America and the Asian-Pacific region. Finally, C. krusei was considerably more common in Europe than in the other three regions, whereas the same was true for C. guilliermondii in Latin America. These two species are especially notable for their propensity toward multidrug resistance compared to other more common species of Candida (37; M. A. Pfaller, D. J. Diekema, D. L. Gibbs, V. A. Newell, J. F. Meis, I. M. Gould, W. Fu, A. L. Colombo, E. Rodriguez-Noriega, and the Global Antifungal Surveillance Group, submitted for publication).


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  		TABLE 1. Species distribution of Candida isolates by geographic region

Table 2 summarizes that in vitro susceptibility of 5,346 isolates of Candida spp. to anidulafungin, micafungin, and caspofungin when tested in RPMI 1640 medium with 24-h incubation and the prominent reduction endpoint criteria. First of all, it should be noted that all three echinocandins demonstrate excellent potency and spectrum with 98.8 to 100% of all isolates susceptible at the MIC breakpoint of ≤2 µg/ml. The degrees of susceptibility of isolates to all three echinocandins did not change over the duration of the study (data not shown). A MIC of >4 µg/ml for any echinocandin was observed for only six (0.1%) of the 5,346 isolates tested: three isolates of C. guilliermondii (caspofungin MIC, ≥8 µg/ml), and one isolate each of C. glabrata (caspofungin MIC, ≥8 µg/ml), C. tropicalis (caspofungin MIC, ≥8 µg/ml), and C. rugosa (anidulafungin MIC, ≥8 µg/ml).


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  		TABLE 2. In vitro susceptibilities of 5,346 clinical isolates of Candida spp. to anidulafungin, caspofungin, and micafungin

As noted previously (33-36), the MIC distribution for each of the echinocandins defined two broad groups among the nine major species tested (Tables 1 and 3). C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr were all highly susceptible to each of the echinocandins (modal MIC, 0.015 to 0.06 µg/ml; MIC90, 0.015 to 0.25 µg/ml), whereas C. parapsilosis (modal MIC, 0.25 to 1 µg/ml; MIC90, 1 to 2 µg/ml), C. guilliermondii (modal MIC, 0.5 to 1 µg/ml; MIC90, 1 to 2 µg/ml), C. lusitaniae (modal MIC, 0.12 to 0.5 µg/ml; MIC90, 0.25 to 0.5 µg/ml), and C. famata (modal MIC, 0.25 to 0.5 µg/ml; MIC90, 1 to 2 µg/ml) were significantly less susceptible to all three agents. These differences may be due to differences in the sensitivities of the glucan synthesis enzyme complex to echinocandin inhibition (6, 15, 29, 31). Importantly, 90 to 100% of the isolates of the last four species listed are classified as susceptible to all three echinocandins based on the ≤2-µg/ml breakpoint. Although the reduced susceptibilities of species such as C. parapsilosis and C. guilliermondii relative to those of C. albicans, C. glabrata, and C. tropicalis have not proven to influence outcomes in the various clinical trials (13, 16, 20, 26, 40), reduced susceptibility may come into play when infections with these species involve the eye or central nervous system, where adequate free drug levels cannot be readily obtained (30, 39).


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  		TABLE 3. Variation in echinocandin MIC profiles by geographic region

The echinocandin susceptibilities of isolates stratified by geographic region and by species are shown in Table 3. Despite the differences in species distribution noted previously, the same overall and species-specific activities were observed for each echinocandin in each of the four regions.

One important observation that can be made from this large data set is that although rare, isolates of C. albicans for which anidulafungin MICs were 2 µg/ml were detected in all four geographic regions (Table 3). Although such isolates would still be considered to be "susceptible" based on the newly described CLSI breakpoints, they must be recognized as distinctly unusual, given that the modal MIC for this species is 0.03 µg/ml (Table 3). Notably, of the 12 isolates of C. albicans with this high-MIC anidulafungin phenotype, all were found to have micafungin MICs of 0.5 to 1 µg/ml (modal MIC of micafungin for C. albicans is 0.015 µg/ml) and caspofungin MICs of 0.12 to 0.25 µg/ml (modal MIC of caspofungin for C. albicans is 0.03 µg/ml). Although susceptible, these isolates are clearly outside of the normal wild-type distribution of echinocandin MICs for C. albicans. Isolates with this abnormal phenotype warrant further study, and although they may respond clinically to echinocandin treatment, they could pose problems under conditions of decreased drug penetration.

An analogous situation can be seen with C. tropicalis, of which three isolates for which anidulafungin MICs of 2 µg/ml (modal MIC of anidulafungin for C. tropicalis is 0.03 µg/ml) were detected (Table 3). The caspofungin MICs for these isolates were 0.25, 1, and 16 µg/ml (modal MIC of caspofungin for C. tropicalis is 0.03 µg/ml), and the micafungin MICs were 0.5,1, and 1 µg/ml (modal MIC of micafungin for C. tropicalis is 0.015 to 0.03 µg/ml). Again, these three strains exhibit a high-MIC phenotype for all three echinocandins relative to the wild-type MIC distribution. Similarly, one isolate of C. glabrata was noted to be nonsusceptible to both caspofungin (MIC = 8 µg/ml) and anidulafungin (MIC = 4 µg/ml), with susceptibility to micafungin, having a MIC of 1 µg/ml, but this MIC is still high compared to the modal MIC of 0.015 µg/ml.

Although C. guilliermondii is well known for its reduced susceptibility to caspofungin (33, 37), MICs for this agent are generally ≤1 µg/ml with a modal MIC of 0.5 µg/ml (Tables 2 and 3). In the present study, we detected three isolates, all from Latin America, for which the caspofungin MICs were ≥8 µg/ml (Table 3). Similar to that described for high-MIC isolates of C. albicans, C. glabrata, and C. tropicalis, these isolates were found to have anidulafungin MICs of 1, 4, and 4 µg/ml (modal MIC for anidulafungin and C. guilliermondii is 1 µg/ml) and micafungin MICs of 0.5, 1, and 2 µg/ml (the modal MIC of micafungin for C. guilliermondii is 0.5 µg/ml). Thus, although isolates of Candida with a high-echinocandin-MIC phenotype are very rare, they may be detected worldwide, exist among several different species, and generally exhibit MICs outside of the wild-type distribution for all three echinocandins. Notably, we did not detect any isolates of C. parapsilosis that exhibited the multiazole- and multiechinocandin-resistant phenotype described by Moudgal et al. (21) and by Vazquez et al. (42), suggesting that this phenotype has not spread beyond the initially reported environment.

The results of this study clearly demonstrate the comparable and excellent spectrum and potency of all three available echinocandin antifungal agents against a large collection of clinically important Candida spp. We have shown that the activities of all three agents remain consistent over time and broad geographic regions and that species-specific differences in echinocandin activities against Candida are apparent worldwide. Although slight differences in potency in vitro may be observed among the three echinocandins for a given species of Candida, such differences have been shown to be normalized by the addition of serum to the in vitro test system (27) and do not appear to be significant in vivo (31). In addition to highlighting the presence of species such as C. parapsilosis and C. guilliermondii, which exhibit decreased susceptibilities to all three echinocandins, this large survey provides additional documentation of the presence of rare strains of otherwise highly susceptible species of Candida that exhibit unusually high MICs for, but are not necessarily nonsusceptible (MIC > 2 µg/ml) to, all three echinocandins. These high-MIC strains are sufficiently rare that they have not been encountered with any frequency in clinical trials (13, 16, 20, 26, 40), although several isolates with echinocandin MICs of >2 µg/ml have recently been associated with clinical resistance to echinocandin therapy in published case reports (8, 10, 12, 14, 17, 19, 21, 30, 39). Thus far, the rare high-echinocandin-MIC phenotypes appear to exhibit a class-specific resistance profile. These observations underscore the importance of antifungal susceptibility testing of echinocandins in detecting unusual resistance profiles. Further investigation and monitoring is warranted.


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ACKNOWLEDGMENTS
 
Linda Elliot and Tara Schroder provided excellent support in the preparation of the manuscript.

This work was supported in part by grants from Pfizer and Astellas.


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FOOTNOTES
 
* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 356-8615. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu Back

{triangledown} Published ahead of print on 21 November 2007. Back


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Journal of Clinical Microbiology, January 2008, p. 150-156, Vol. 46, No. 1
0095-1137/08/$08.00+0     doi:10.1128/JCM.01901-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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