Abstract
A collection of 2,278 isolates belonging to 86 different fungal species was tested with micafungin and eight other drugs using the EUCAST procedures. Micafungin was active against species of Candida and Aspergillus (even azole-resistant species) as well as Penicillium spp., Scedosporium apiospermum, and Acremonium spp. It was inactive for species of Basidiomycota and Mucorales and for multiresistant species such as those of Fusarium.
Micafungin is a new drug that belongs to the echinocandin class of antifungal agents. Its mechanism of action is by means of the inhibition of 1,3-β-d-glucan synthesis in the fungal cell wall (10).
Micafungin has been recently approved in Europe and the United States for the treatment of candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, esophageal candidiasis, and recently for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.
The in vitro activity of micafungin against most common species of Candida is well known (4, 11-13). However, information is limited for uncommon species of yeasts as well as for molds.
The aim of this study is to analyze the in vitro activity of micafungin and eight other antifungal agents against a collection of clinical isolates of yeasts and molds from human beings using the methods approved by AFST-EUCAST.
The strains were recovered from 115 Spanish hospitals through a period of 3 years, from 2005 to 2007. A total of 2,278 clinical isolates were included in the analysis. Isolates were identified by morphological and biochemical methods and sequencing of DNA targets if necessary. They belonged to 86 different species of common and emerging fungal pathogens. The isolates were obtained from blood (559; 24.5%), biopsies and other deep sites (217; 9.5%), respiratory tract specimens (751; 33%), skin samples (180; 7.9%), and other locations (707; 25.1%).
The following drugs were used: amphotericin B (range, 16.0 to 0.03 μg/ml; Sigma-Aldrich Quimica S.A., Madrid, Spain), flucytosine (64.0 to 0.12 μg/ml; Sigma-Aldrich), fluconazole (64.0 to 0.12 μg/ml; Pfizer S.A. Madrid, Spain), itraconazole (8.0 to 0.015 μg/ml; Janssen S.A., Madrid, Spain), voriconazole (8.0 to 0.015 μg/ml; Pfizer S.A.), posaconazole (8.0 to 0.015 μg/ml; Schering-Plough, Kenilworth, NJ), caspofungin (16.0 to 0.03 μg/ml; Merck & Co., Inc., Rahway, NJ), micafungin (16.0 to 0.03 μg/ml; Astellas Pharma Inc., Tokyo, Japan), and anidulafungin (16.0 to 0.03 μg/ml; Pfizer S.A.).
Susceptibility testing was performed by using broth microdilution. For Candida species, MICs were determined using the reference procedure for testing fermentative yeasts described by AFST-EUCAST (7, 17). For Cryptococcus neoformans and other species of nonfermentative yeasts, such as Trichosporon and Rhodotorula spp., susceptibility testing strictly followed the recommendations by the EUCAST with a minor modification in order to improve the growth of microorganisms (3). For filamentous fungi, broth microdilution testing was performed following the AFST-EUCAST reference method (18). For testing echinocandins against molds, the MIC was defined as the lowest drug concentration resulting in aberrant hyphal growth by examination with an inverted microscope, that is, the minimum effective concentration (MEC) (2).
Tables 1 and 2 display the susceptibility results obtained when the collection of clinical isolates was tested.
TABLE 1.
Summary of susceptibility results of antifungal agents tested in vitro against yeast speciesa
| Species | n | Amphotericin B
|
Flucytosine
|
Fluconazole
|
Itraconazole
|
Voriconazole
|
Posaconazole
|
Caspofungin
|
Anidulafungin
|
Micafungin
|
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | ||
| Candida species | |||||||||||||||||||
| Candida albicans | 393 | 0.06 | 0.12 | 0.12 | 0.50 | 0.12 | 0.25 | 0.02 | 0.03 | 0.02 | 0.02 | 0.02 | 0.02 | 0.06 | 0.12 | 0.03 | 0.03 | 0.03 | 0.03 |
| Candida parapsilosis | 225 | 0.12 | 0.25 | 0.12 | 0.25 | 0.50 | 1.0 | 0.02 | 0.03 | 0.02 | 0.02 | 0.02 | 0.03 | 1.0 | 1.0 | 1.0 | 2.0 | 0.5 | 1.0 |
| Candida tropicalis | 105 | 0.12 | 0.25 | 0.12 | 0.25 | 0.25 | 2.0 | 0.02 | 0.06 | 0.03 | 0.12 | 0.02 | 0.03 | 0.12 | 0.25 | 0.03 | 0.03 | 0.03 | 0.03 |
| Candida glabrata | 182 | 0.12 | 0.25 | 0.12 | 0.25 | 4.0 | 32.0 | 0.25 | 1.0 | 0.12 | 1.0 | 0.25 | 1.0 | 0.12 | 0.25 | 0.03 | 0.03 | 0.03 | 0.03 |
| Candida krusei | 53 | 0.50 | 0.50 | 4.0 | 8.0 | 32.0 | >64.0 | 0.25 | 0.25 | 0.25 | 0.50 | 0.12 | 0.25 | 0.25 | 0.50 | 0.03 | 0.06 | 0.03 | 0.06 |
| Candida guilliermondii | 20 | 0.06 | 0.50 | 0.12 | 0.25 | 4.0 | >64.0 | 0.25 | >8.0 | 0.12 | >8.0 | 0.12 | >8.0 | 0.50 | 1.0 | 1.0 | 8.0 | 0.12 | 1.0 |
| Candida lusitaniae | 21 | 0.06 | 0.12 | 0.12 | 16.0 | 0.25 | 1.0 | 0.02 | 0.03 | 0.02 | 0.02 | 0.02 | 0.02 | 0.50 | 1.0 | 0.03 | 0.12 | 0.03 | 0.03 |
| Candida kefyr | 15 | 0.25 | 0.50 | 0.50 | 4.0 | 0.25 | 0.50 | 0.02 | 0.06 | 0.02 | 0.02 | 0.03 | 0.06 | 0.06 | 0.12 | 0.03 | 0.03 | 0.03 | 0.03 |
| Other Candida spp.b | 29 | 0.12 | 1.0 | 0.25 | 16.0 | 8.0 | >64.0 | 0.12 | >8.0 | 0.12 | >8.0 | 0.03 | >8.0 | 0.06 | 0.50 | 0.06 | 0.25 | 0.03 | 0.12 |
| Other Ascomycota yeasts | |||||||||||||||||||
| Dipodascus capitatus | 30 | 0.50 | 0.50 | 0.12 | 1.0 | 16.0 | 32.0 | 0.25 | 0.50 | 0.50 | 1.0 | 0.50 | 0.50 | >16.0 | >16.0 | 2.0 | 4.0 | >16.0 | >16.0 |
| Saccharomyces cerevisiae | 25 | 0.12 | 0.25 | 0.12 | 0.50 | 4.0 | >64.0 | 0.50 | 2.0 | 0.06 | 0.50 | 0.25 | 0.50 | 0.50 | 1.0 | 0.12 | 0.25 | 0.03 | 0.06 |
| Yarrowia lipolytica | 10 | 0.50 | 0.50 | >64.0 | >64.0 | 8.0 | >64.0 | 0.50 | >8.0 | 0.50 | 2.0 | 0.25 | 2.0 | 0.50 | 1.0 | 0.06 | 0.12 | 0.03 | 1.0 |
| Galactomyces geotrichum | 10 | 0.25 | 0.50 | 0.12 | 0.25 | 64.0 | >64.0 | 0.50 | 2.0 | 0.50 | 1.0 | 0.50 | 0.50 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Basidiomycota yeasts | |||||||||||||||||||
| C. neoformans var. neoformans | 35 | 0.12 | 2.0 | 16.0 | 32.0 | 16.0 | >64.0 | 0.12 | 0.50 | 0.12 | 0.50 | 0.12 | 0.50 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Trichosporon asahii | 13 | 8.0 | >16.0 | 32.0 | >64.0 | 16.0 | >64.0 | 0.50 | >8.0 | 0.25 | >8.0 | 0.25 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Rhodotorula mucilaginosa | 11 | 0.12 | 0.50 | 0.25 | 1.0 | >64.0 | >64.0 | 8.0 | >8.0 | 4.0 | >8.0 | 2.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Trichosporon inkin | 10 | 0.12 | 1.0 | 64.0 | >64.0 | 4.0 | 4.0 | 0.12 | 0.25 | 0.06 | 0.12 | 0.06 | 0.12 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Other Basidiomycota yeastsc | 35 | 0.50 | 8.0 | 16.0 | >64.0 | 16.0 | >64.0 | 0.50 | >8.0 | 0.50 | >8.0 | 0.25 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
MIC50 and MIC90 values (μg/ml) were calculated for those species with 10 or more isolates.
“Other Candida species” includes the following species with less than 10 isolates: Candida rugosa (4), Candida famata (4), Candida pelliculosa (4), Candida colliculosa (3), Candida norvegensis (2), Candida intermedia (2), Candida inconspicua (2), Candida metapsilosis (2), Candida orthopsilosis (2), Candida pintolopesii (2), and Candida zeylanoides (2).
“Other Basidiomycota yeasts” includes the following species with less than 10 isolates: Trichosporon ovoides (5), Trichosporon dermatis (5), Trichosporon jirovecii (4), Cryptococcus albidus (3), Ustilago spp. (3), Rhodotorula glutinis (3), Cryptococcus laurentii (2), Trichosporon domesticum (2), Trichosporon mycotoxinivorans (2), and Trichosporon spp. (6).
TABLE 2.
Summary of susceptibility results of antifungal agents tested in vitro against mold speciesa
| Species | n | Amphotericin B
|
Itraconazole
|
Voriconazole
|
Posaconazole
|
Caspofungin
|
Anidulafungin
|
Micafungin
|
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | ||
| Aspergillus spp. | |||||||||||||||
| Aspergillus fumigatus | 299 | 0.25 | 0.50 | 0.25 | 0.50 | 0.50 | 1.0 | 0.06 | 0.25 | 0.25 | 0.50 | 0.03 | 0.03 | 0.03 | 0.03 |
| Aspergillus terreus | 155 | 1.0 | 4.0 | 0.25 | 0.50 | 1.0 | 2.0 | 0.06 | 0.12 | 1.0 | 2.0 | 0.03 | 0.03 | 0.03 | 0.03 |
| Aspergillus flavus | 81 | 1.0 | 2.0 | 0.25 | 0.50 | 1.0 | 2.0 | 0.12 | 0.25 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Aspergillus niger | 83 | 0.25 | 0.25 | 1.0 | >8.0 | 1.0 | 2.0 | 0.25 | 0.50 | 0.25 | 0.50 | 0.03 | 0.03 | 0.03 | 0.06 |
| Aspergillus nidulans | 29 | 1.0 | 4.0 | 0.25 | 0.50 | 0.25 | 1.0 | 0.06 | 0.25 | 0.50 | >16.0 | 0.03 | 0.25 | 0.03 | >16.0 |
| Aspergillus sydowii | 28 | 1.0 | 2.0 | 0.50 | >8.0 | 1.0 | 2.0 | 0.25 | 0.50 | 0.25 | 1.0 | 0.03 | 0.03 | 0.03 | 0.03 |
| Aspergillus versicolor | 12 | 1.0 | 2.0 | 0.50 | 1.0 | 1.0 | 2.0 | 0.25 | 0.50 | 0.25 | 2.0 | 0.03 | 0.03 | 0.03 | 0.06 |
| Other Aspergillus spp.b | 18 | 0.50 | >16.0 | 0.50 | >8.0 | 0.25 | >8.0 | 0.12 | >8.0 | 0.12 | 0.50 | 0.06 | 0.25 | 0.06 | 0.25 |
| Other hyaline fungi | |||||||||||||||
| Penicillium spp. | 72 | 0.50 | 2.0 | 0.50 | >8.0 | 2.0 | >8.0 | 0.25 | 4.0 | 0.25 | 8.0 | 0.03 | 0.03 | 0.03 | 0.06 |
| Fusarium solani | 32 | 1.0 | 2.0 | >8.0 | >8.0 | >8.0 | >8.0 | >8.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Fusarium proliferatum | 19 | 2.0 | 4.0 | >8.0 | >8.0 | 8.0 | >8.0 | >8.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Fusarium oxysporum | 17 | 1.0 | 2.0 | >8.0 | >8.0 | 4.0 | >8.0 | 4.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Fusarium verticillioides | 11 | 2.0 | 4.0 | >8.0 | >8.0 | 8.0 | >8.0 | 2.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Paecilomyces variotii | 17 | 0.03 | 0.50 | 0.06 | 0.25 | 1.0 | 8.0 | 0.03 | 0.25 | 0.50 | 4.0 | 0.03 | 0.03 | 0.03 | 0.03 |
| Paecilomyces lilacinus | 10 | >16.0 | >16.0 | >8.0 | >8.0 | 0.50 | 4.0 | 0.25 | 0.50 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Acremonium spp. | 10 | 4.0 | >16.0 | >8.0 | >8.0 | 4.0 | 8.0 | 8.0 | >16.0 | 0.50 | 1.0 | 0.03 | 0.03 | 0.12 | 0.25 |
| Other hyaline fungic | 26 | 0.50 | >16.0 | >8.0 | >8.0 | 4.0 | >8.0 | 4.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Black fungi | |||||||||||||||
| Scedosporium apiospermum | 36 | 4.0 | >16.0 | 1.0 | >8.0 | 0.50 | 2.0 | 1.0 | 8.0 | 2.0 | >16.0 | 0.50 | 4.0 | 0.03 | >16.0 |
| Scedosporium prolificans | 17 | >16.0 | >16.0 | >8.0 | >8.0 | >8.0 | >8.0 | >8.0 | >8.0 | 8 | >16.0 | 4.0 | >16.0 | 8.0 | >16.0 |
| Alternaria alternata | 11 | 0.50 | >16.0 | 0.50 | >8.0 | 4.0 | >8.0 | 1.0 | >8.0 | 4.0 | >16.0 | 0.06 | >16.0 | 0.25 | >16.0 |
| Alternaria infectoria | 10 | 0.06 | >16.0 | 2.0 | >8.0 | 2.0 | >8.0 | 0.50 | >8.0 | >16.0 | >16.0 | 2.0 | >16.0 | >16.0 | >16.0 |
| Other black fungid | 14 | 0.25 | 1.0 | 0.12 | >8.0 | 0.06 | >8.0 | 0.06 | >8.0 | 0.25 | 1.0 | 0.03 | 0.06 | 0.03 | 0.06 |
| Mucorales | |||||||||||||||
| Mycocladus corymbiferus | 16 | 0.12 | 0.25 | 1 | >8.0 | >8.0 | >8.0 | 0.50 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Rhizopus oryzae | 11 | 0.50 | 2.0 | 4.0 | >8.0 | >8.0 | >8.0 | 2.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Mucor spp. | 11 | 0.12 | 1.0 | >8.0 | >8.0 | >8.0 | >8.0 | 4.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
| Other Mucorales speciese | 11 | 2.0 | >16.0 | >8.0 | >8.0 | >8.0 | >8.0 | 4.0 | >8.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 | >16.0 |
MIC50 and MIC90 values (μg/ml) were calculated for those species with 10 or more isolates.
“Other Aspergillus spp.” includes the following species with less than 10 isolates: Aspergillus ochraceus (5), Aspergillus ustus (4), Aspergillus niveus (3), Aspergillus sclerotiorum (2), Aspergillus glaucus (2), and Aspergillus spp. (2).
“Other hyaline fungi” includes the following species with less than 10 isolates: Scopulariopsis brevicaulis (6), Trichoderma spp. (5), Phialemonium curvatum (5), Hormographiella aspergillata (3), Fusarium equiseti (2), Fusarium reticulatum (2), Hormographiella verticillata (1), Chrysonilia sitophila (1), and Beauveria bassiana (1).
“Other black fungi” includes the following species with less than 10 isolates: Exophiala dermatitidis (4), Exophiala jeanselmei (3), Aureobasidium pullulans (2), Hortae werneckii (1), Cladosporium spp. (1), Cladophialophora bantiana (1), Scytalidium hyalinum (1), and Lecythophora hoffmannii (1).
“Other Mucorales species” includes the following species with less than 10 isolates: Cunninghamella bertholletiae (6), Rhizopus microsporus (2), Rhizomucor spp. (2), and Saksenaea vasiformis (1).
Micafungin exhibited a potent activity in vitro against Candida spp. That activity was somehow better than the in vitro activity of caspofungin and similar to that of anidulafungin. AFST-EUCAST has not yet proposed breakpoints to read the susceptibility testing of echinocandins. CLSI and others have published that Candida isolates exhibiting MICs of echinocandins of >2 μg/ml can be considered nonsusceptible in vitro (14). Following that criterion, only one isolate out of 20 Candida guilliermondii clinical isolates tested (1/20; 5%) had a MIC of micafungin of >2 μg/ml. That isolate exhibited cross-resistance in vitro to both caspofungin and anidulafungin.
A total of 15.3% of the Candida isolates analyzed (160/1,043; 61 Candida glabrata, 53 Candida krusei, 25 Candida albicans, 8 Candida tropicalis, 7 C. guilliermondii, 3 Candida parapsilosis, 1 Candida lusitaniae, 1 Candida norvegensis, and 1 Candida rugosa) were resistant in vitro to fluconazole according to AFST-EUCAST criteria (fluconazole MIC, >4 μg/ml) (19). In addition, 7.9% of the isolates (82/1,043; 36 C. glabrata, 18 C. krusei, 16 C. albicans, 7 C. tropicalis, 4 C. guilliermondii, and 1 C. parapsilosis) were also resistant in vitro to voriconazole (MIC, >0.12 μg/ml by EUCAST criteria) (20). All azole-resistant Candida strains exhibited low MICs of micafungin and other echinocandins.
Micafungin and the other echinocandins were inactive in vitro against Dipodascus capitatus and Galactomyces geotrichum and against species of all genera belonging to Basidiomycota, such as Cryptococcus, Trichosporon, and Rhodotorula. The echinocandins were active in vitro against some non-Candida Ascomycota species, such as Saccharomyces cerevisiae and Yarrowia lipolytica.
Regarding Aspergillus spp., micafungin exhibited a good activity in vitro against most of the Aspergillus isolates. Notably, the echinocandin seemed to be inactive in vitro against Aspergillus flavus and a number of Aspergillus nidulans clinical isolates as others have reported before (1, 9). Micafungin and the other echinocandins were active in vitro (MEC, ≤ 2μg/ml) against 11 strains of Aspergillus spp. (1.6%; 11/705; 7 Aspergillus niger, 2 Aspergillus fumigatus, and 2 Aspergillus ustus) that had MICs of itraconazole of ≥8 μg/ml.
Micafungin also inhibited in vitro some other species of hyaline fungi, such as Penicillium spp., Paecilomyces variotii, and Acremonium spp. In addition, it exhibited activity against some isolates of black fungi as the echinocandin had low MEC values (MEC, ≤ 2μg/ml) for 32 out of 36 (88.9%) isolates of Scedosporium apiospermum, 7/11 (63.6%) isolates of Alternaria alternata, and for most of the Exophiala strains tested.
On the contrary, micafungin and the other two echinocandins were inactive in vitro against some species of molds, such Fusarium spp., Paecilomyces lilacinus, Scopulariopsis spp., and Trichoderma spp. which are characterized by their resistance to other antifungal families. The echinocandins were inactive against Mucorales species as well.
These results of in vitro activity match published data by other authors for Candida and Aspergillus species (5, 6, 8, 9, 21), including the good activities of the three echinocandins against azole-resistant isolates (15, 16). There again, this study collects susceptibility data on species of fungal pathogens that have not been published before, such as non-Candida Ascomycota yeasts and some species of hyaline and black molds. Notably, micafungin showed activity in vitro against most of the strains of S. apiospermum tested. Zeng et al. reported that that species is resistant in vitro to echinocandins when the MIC is defined as total inhibition of growth (22). However, as a criterion of the MIC definition, we use the lowest drug concentration resulting in aberrant hyphal growth by examination with an inverted microscope (MEC). Following that, micafungin exhibited activity in vitro against 89% of the clinical isolates analyzed.
In summary, micafungin is a broad-spectrum antifungal agent with a good profile of activity in vitro which is comparable to those of caspofungin and anidulafungin. It exhibits activity against Candida and Aspergillus spp. except for A. flavus. The echinocandin also inhibits Candida isolates with resistance to both fluconazole and voriconazole and Aspergillus strains with resistance in vitro to itraconazole. It must be noted that micafungin and the other echinocandins are inactive in vitro against Basidiomycota spp., Mucorales spp., and some species of multiresistant fungi, such as Fusarium spp.
Acknowledgments
A potential conflict of interest for all authors is that this study was supported by a nonrestrictive research grant from Astellas Pharma S.A.
In the past 5 years, M.C.-E. has received grant support from Astellas Pharma, bioMerieux, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, Soria Melguizo S.A., the European Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III, the Ramon Areces Foundation, and the Mutua Madrileña Foundation. M.C.-E. has been an advisor/consultant to the Panamerican Health Organization, Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Schering Plough. He has been paid for talks on behalf of Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Schering Plough. In the past 5 years, J.L.R.-T. has received grant support from Astellas Pharma, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, Soria Melguizo S.A., the European Union, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III, the Ramon Areces Foundation, and the Mutua Madrileña Foundation. J.L.R.-T. has been an advisor/consultant to the Panamerican Health Organization, Gilead Sciences, Merck Sharp and Dohme, Mycognostica, Pfizer, and Schering Plough. He has been paid for talks on behalf of Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Schering Plough.
Footnotes
Published ahead of print on 17 February 2009.
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