Mycology
Wild-type minimum effective concentration distributions and epidemiologic cutoff values for caspofungin and Aspergillus spp. as determined by Clinical and Laboratory Standards Institute broth microdilution methods

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Abstract

Antifungal susceptibility testing of Aspergillus spp. against caspofungin has been standardized by the Clinical and Laboratory Standards Institute (CLSI). Recent studies have documented breakthrough infections with Aspergillus spp. for which the minimum effective concentration (MEC) for caspofungin ranged from 0.25 to 8 μg/mL. We tested a collection of 1590 clinical isolates of Aspergillus spp. (188 Aspergillus flavus, 1187 Aspergillus fumigatus, 114 Aspergillus niger, 71 Aspergillus terreus, and 30 Aspergillus versicolor) against caspofungin using the CLSI broth microdilution method. An epidemiologic cutoff value (ECV) of ≤0.06 μg/mL encompassed the wild-type (WT) MEC distribution (percentage of MECs) of A. flavus (99.5%), A. fumigatus (98.7%), A. niger (100%), and A. terreus (97.2%), and an ECV of ≤0.12 μg/mL encompassed the WT distribution of A. versicolor (96.7%). A total of 20 strains showed MECs that were outside the ECVs: 1 A. flavus (0.12 μg/mL), 16 A. fumigatus (0.12 μg/mL [13], 1 μg/mL [1], 2 μg/mL [2]), 2 A. terreus (0.12 [1] and >8 μg/mL [1]), and 1 A. versicolor (4 μg/mL). The establishment of the WT MEC distributions and ECVs for caspofungin and the major species of Aspergillus will be useful in resistance surveillance and is an important step toward the development of clinical breakpoints.

Introduction

Caspofungin is used clinically in the treatment of invasive candidiasis and in salvage therapy for invasive aspergillosis (IA) (Maertens et al., 2004, Pappas et al., 2009, Walsh et al., 2008). Although breakthrough IA has been reported among patients receiving caspofungin therapy/prophylaxis, thus far, no clinical isolates of Aspergillus spp. have been shown to have acquired the FKS1 mutations considered necessary for echinocandin resistance (Arendrup et al., 2008, Madureira et al., 2007, Rocha et al., 2007). Despite standardization of a broth microdilution (BMD) method for testing caspofungin against Aspergillus spp. (Clinical and Laboratory Standards Institute, 2008, Odds et al., 2004), clinical minimum effective concentration (MEC) breakpoints have not yet been established. Given the increased use of caspofungin and other echinocandins clinically (Arendrup et al., 2008, Neofytos et al., 2009), coupled with the emergence of azole-resistant Aspergillus spp. (Arendrup et al., 2008, Pfaller et al., 2008, Rodriquez-Tudela et al., 2008, Snelders et al., 2008, van der Linder et al., 2009), in vitro surveillance for the emergence of decreased susceptibility to caspofungin among Aspergillus spp. is warranted (Madureira et al., 2007, Rocha et al., 2007). As such, we have conducted global surveillance of Aspergillus spp. using CLSI M38-A2 BMD methods to ascertain the wild-type (WT) MEC distribution for caspofungin and Aspergillus spp. and to establish epidemiologic cutoff values (ECVs) that may be used to assess the emergence of strains with decreased susceptibility to this agent.

Section snippets

Organisms

Between January 2001 and December 2007, 1590 unique patient isolates of Aspergillus spp. (188 Aspergillus flavus, 1187 A. fumigatus, 114 Aspergillus niger, 71 Aspergillus terreus, and 30 Aspergillus versicolor) were obtained from more than 80 medical centers in 24 countries worldwide. Of the submitted isolates, 49% were from centers in North America, 12% from Latin America, 25% from Europe, and 13% from the Asia-Pacific region. The isolates were obtained from a variety of specimen sources,

Results and discussion

The WT MEC distributions for caspofungin and each of the 5 species of Aspergillus are shown in Fig. 1. The modal MECs (percentage of MECs) for caspofungin and each species are as follows (Table 1): A. flavus, 0.015 μg/mL (39.4% of all values); A. fumigatus, 0.015 μg/mL (48.5% of all values); A. niger, 0.007 μg/mL (50.0% of all values); A. terreus, 0.015 μg/mL (38.0% of all values); and A. versicolor, 0.03 μg/mL (33.3% of all values). The modal MEC ± one 2-fold dilution encompassed 92.6% of all

Acknowledgments

The authors thank Caitlin Howard for excellent secretarial support.

This study was supported in part by research and educational grants from Astellas US (Deerfield, IL), Merck (Whitehouse Station, NJ), and Pfizer Pharmaceuticals (New York, NY).

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