The in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as Bipolaris spicifera and Veronaea botryosa, remain more susceptible to other triazoles or to echinocandins.
KEYWORDS: antifungal susceptibility, dematiaceous fungi, isavuconazole, ravuconazole
ABSTRACT
The in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as Bipolaris spicifera and Veronaea botryosa, remain more susceptible to other triazoles or to echinocandins.
INTRODUCTION
The huge diversity of dematiaceous fungi and wide range of symptoms make it impossible to adopt a uniform approach for the treatment of these fungal infections (1–5). Typically, Cladophialophora carrionii, Fonsecaea pedrosoi, and Phialophora verrucosa are commonly found in chromoblastomycosis (2), and Exophiala jeanselmei is known to produce black granules form eumycotic mycetoma (5). Some black fungi have been extensively reported in phaeohyphomycosis cases, such as cerebral infections caused by Exophiala dermatitidis in East Asia, fungal endophthalmitis caused by Curvularia lunata (6), and subcutaneous disease caused by Veronaea botryosa in heart and liver transplant recipients (3, 7). The involvement of Bipolaris spp. and Curvularia spp. in allergic fungal sinusitis and allergic bronchopulmonary mycosis has been documented as well (1).
To date, guidelines for infections caused by dematiaceous fungi are still lacking (5). Systematic antifungal treatment, sometimes combined with surgical debridement, is often required. Even today, the challenge for antifungal treatment remains because of the limited number of effective antifungal drugs and the various sensitivities of different fungi to each of those drugs (8). In light of these issues, persistent efforts to develop more efficacious and safer drugs against fungi, including dematiaceous fungi, are continuing. As a result, two novel azole members were recently introduced into the market.
Ravuconazole, intended to work as an oral treatment for onychomycosis, was developed in Japan in 2018 (9, 10). Ravuconazole is an extended-spectrum triazole agent that is highly active in vitro against Candida spp., Cryptococcus neoformans, and other yeast species, including most fluconazole-resistant yeast isolates (11–13). It also inhibits in vitro growth of Aspergillus spp., Trichophyton spp., and some dematiaceous fungi, such as Fonsecaea spp., Madurella spp., and Alternaria spp. (9, 14–16). Data derived from animals and clinical treatment indicated a fungicidal effect and favorable pharmacokinetics (17). Isavuconazole and the water-soluble prodrug isavuconazonium sulfate are also broad-spectrum antifungal agents. In March 2015, isavuconazonium sulfate was approved by the FDA for treatment of invasive aspergillosis and invasive mucormycosis (18). The tolerability profile of isavuconazole was similar to that of fluconazole and had fewer drug interactions than voriconazole and itraconazole. Although antifungal activities have been demonstrated in vitro and in animal models with invasive aspergillosis, mucormycosis, candidiasis, certain endemic mycoses, and other invasive fungal diseases (19–23), clinical data for isavuconazole on the treatment of phaeohyphomycosis are still lacking, and in vitro data for susceptibility to dematiaceous fungi are incomplete (1, 24).
This study aims to determine the in vitro activity of ravuconazole and isavuconazole against a broad spectrum of dematiaceous fungi in comparison with other antifungal agents. A total of 84 clinical isolates of dematiaceous fungi were obtained from the Institute of Dermatology, Chinese Academy of Medical Sciences. All clinical strains were identified by morphological methods and sequencing of the conserved ribosomal internal transcribed spacer (ITS) region and large subunit region. Candida krusei ATCC 6258, Candida parapsilosis ATCC 22019, and Aspergillus fumigatus ATCC MYA-3626 were included in the study for quality control.
Ravuconazole, isavuconazole, anidulafungin, micafungin, caspofungin, 5-flucytosine, posaconazole, voriconazole, itraconazole, fluconazole, and amphotericin B were purchased from Sigma-Aldrich Co. LLC (USA). We performed all antifungal susceptibility tests in triplicate for each isolate to estimate the MIC or minimum effective concentration (MEC) value individually as outlined by CLSI (25, 26). Geometric means of related MICs or MECs were calculated as GMIC or GMEC for each test drug. The susceptibility of species to each drug was also calculated at levels of MIC50/MEC50 and MIC90/MEC90.
Results for the nonechinocandins are summarized in Table 1, and results from the three echinocandins are shown in Table 2. In terms of GMIC, ravuconazole and isavuconazole showed a better inhibitory effect than itraconazole, voriconazole, and posaconazole on most dematiaceous species, especially F. pedrosoi, P. verrucosa, C. carrionii, and C. lunata (Table 1).
TABLE 1.
In vitro susceptibilities of dematiaceous fungi isolates to 5-flucytosine, posaconazole, voriconazole, itraconazole, fluconazole, amphotericin B, ravuconazole, and isavuconazole, determined by CLSI methodology
| Species (no. of strains) | Test agent | MIC (μg/ml) |
|||
|---|---|---|---|---|---|
| Range | MIC50 | MIC90 | GMIC | ||
| Fonsecaea pedrosoi (16) | 5-Flucytosine | 1–8 | 8 | 8 | 2.48 |
| Posaconazole | 0.03–1 | 0.25 | 1 | 0.17 | |
| Voriconazole | 0.03–0.5 | 0.5 | 0.25 | 0.09 | |
| Itraconazole | 0.125–1 | 0.5 | 1 | 0.41 | |
| Fluconazole | 4–16 | 8 | 8 | 9.11 | |
| Amphotericin B | 0.5–2 | 1 | 2 | 1.21 | |
| Ravuconazole | 0.03–0.06 | 0.03 | 0.03 | 0.03 | |
| Isavuconazole | 0.03–0.125 | 0.03 | 0.06 | 0.04 | |
| Exophiala dermatitidis (12) | 5-Flucytosine | 16–32 | 16 | 32 | 13.20 |
| Posaconazole | 0.125–1 | 0.25 | 1 | 0.40 | |
| Voriconazole | 0.125–1 | 0.5 | 0.5 | 0.37 | |
| Itraconazole | 0.125–2 | 0.5 | 1 | 0.54 | |
| Fluconazole | 8–32 | 16 | 32 | 15.69 | |
| Amphotericin B | 1–4 | 2 | 4 | 1.82 | |
| Ravuconazole | 0.03–1 | 0.5 | 1 | 0.37 | |
| Isavuconazole | 0.06–2 | 1 | 2 | 0.75 | |
| Exophiala jeanselmei (9) | 5-Flucytosine | 0.06–0.5 | |||
| Posaconazole | 0.125–1 | ||||
| Voriconazole | 0.125–1 | ||||
| Itraconazole | 0.125–1 | ||||
| Fluconazole | 8–64 | ||||
| Amphotericin B | 1–4 | ||||
| Ravuconazole | 0.03–1 | ||||
| Isavuconazole | 0.03–2 | ||||
| Exophiala spinifera (10) | 5-Flucytosine | 0.06–1 | 0.125 | 0.5 | 0.18 |
| Posaconazole | 0.06–0.5 | 0.25 | 0.5 | 0.18 | |
| Voriconazole | 0.06–0.5 | 0.25 | 0.5 | 0.18 | |
| Itraconazole | 0.125–1 | 0.25 | 0.5 | 0.24 | |
| Fluconazole | 8–32 | 16 | 32 | 14.93 | |
| Amphotericin B | 1–8 | 2 | 4 | 2.4 | |
| Ravuconazole | 0.03–2 | 0.125 | 1 | 0.14 | |
| Isavuconazole | 0.03–4 | 0.25 | 2 | 0.25 | |
| Phialophora verrucosa (11) | 5-Flucytosine | 1–8 | 2 | 4 | 2.04 |
| Posaconazole | 0.03–2 | 0.125 | 0.5 | 0.18 | |
| Voriconazole | 0.06–1 | 0.125 | 0.5 | 0.17 | |
| Itraconazole | 0.125–1 | 0.5 | 1 | 0.34 | |
| Fluconazole | 1–16 | 8 | 16 | 6.35 | |
| Amphotericin B | 0.5–4 | 1 | 2 | 1.11 | |
| Ravuconazole | 0.03–0.125 | 0.03 | 0.125 | 0.04 | |
| Isavuconazole | 0.03–0.5 | 0.03 | 0.5 | 0.06 | |
| Phialophora richardsiae (4) | 5-Flucytosine | >64 | |||
| Posaconazole | 0.5–1 | ||||
| Voriconazole | 0.5–1 | ||||
| Itraconazole | 0.25–1 | ||||
| Fluconazole | 16–64 | ||||
| Amphotericin B | 1–4 | ||||
| Ravuconazole | 0.25–1 | ||||
| Isavuconazole | 1–2 | ||||
| Cladophialophora. carrionii (9) | 5-Flucytosine | 0.03–0.5 | |||
| Posaconazole | 0.06–0.5 | ||||
| Voriconazole | 0.06–0.5 | ||||
| Itraconazole | 0.06–0.5 | ||||
| Fluconazole | 4–32 | ||||
| Amphotericin B | 0.5–2 | ||||
| Ravuconazole | 0.03–0.03 | ||||
| Isavuconazole | 0.03–0.06 | ||||
| Bipolaris spicifera (5) | 5-Flucytosine | >64 | >64 | >64 | >64 |
| Posaconazole | 0.125–1 | ||||
| Voriconazole | 0.25–0.5 | ||||
| Itraconazole | 0.125–1 | ||||
| Fluconazole | 8–64 | ||||
| Amphotericin B | 1–4 | ||||
| Ravuconazole | 0.25–4 | ||||
| Isavuconazole | 1–4 | ||||
| Curvularia lunata (4) | 5-Flucytosine | >64 | |||
| Posaconazole | 0.03–0.125 | ||||
| Voriconazole | 0.06–0.25 | ||||
| Itraconazole | 0.06–0.25 | ||||
| Fluconazole | 2–8 | ||||
| Amphotericin B | 1–4 | ||||
| Ravuconazole | 0.03–0.06 | ||||
| Isavuconazole | 0.06–0.125 | ||||
| Veronaea botryosa (4) | 5-Flucytosine | 8–32 | |||
| Posaconazole | 0.125–1 | ||||
| Voriconazole | 0.5–2 | ||||
| Itraconazole | 0.5–2 | ||||
| Fluconazole | >64 | ||||
| Amphotericin B | 0.5–2 | ||||
| Ravuconazole | 1–4 | ||||
| Isavuconazole | 1–8 | ||||
TABLE 2.
In vitro susceptibilities of dematiaceous fungi isolates to anidulafungin, micafungin, and caspofungin as determined by the CLSI methods
| Species (no. of strains) | Test agent | MEC (μg/ml) |
|||
|---|---|---|---|---|---|
| Range | MEC50 | MEC90 | GMEC | ||
| Fonsecaea pedrosoi (16) | Anidulafungin | 0.5–4 | 2 | 4 | 1.43 |
| Micafungin | 0.25–4 | 2 | 4 | 1.31 | |
| Caspofungin | 0.125–4 | 2 | 4 | 1.03 | |
| Exophiala dermatitidis (12) | Anidulafungin | >4 | >4 | >4 | >4 |
| Micafungin | >4 | >4 | >4 | >4 | |
| Caspofungin | >4 | >4 | >4 | >4 | |
| Exophiala jeanselmei (9) | Anidulafungin | 0.5–4 | |||
| Micafungin | 0.5–4 | ||||
| Caspofungin | 1–4 | ||||
| Exophiala spinifera (10) | Anidulafungin | 0.25–2 | 0.5 | 1 | 0.68 |
| Micafungin | 0.03–0.25 | 0.125 | 0.25 | 0.11 | |
| Caspofungin | 0.125–1 | 0.25 | 0.5 | 0.26 | |
| Phialophora verrucosa (11) | Anidulafungin | 0.125–4 | 1 | 2 | 1.02 |
| Micafungin | 0.06–2 | 0.5 | 1 | 0.53 | |
| Caspofungin | 0.06–4 | 1 | 2 | 0.88 | |
| Phialophora richardsiae (4) | Anidulafungin | 0.5–2 | |||
| Micafungin | 0.5–1 | ||||
| Caspofungin | 0.25–1 | ||||
| Cladophialophora. carrionii (9) | Anidulafungin | 0.5–4 | |||
| Micafungin | 0.5–2 | ||||
| Caspofungin | 0.5–2 | ||||
| Bipolaris spicifera (5) | Anidulafungin | 0.03–0.25 | |||
| Micafungin | 0.06–0.25 | ||||
| Caspofungin | 0.125–0.5 | ||||
| Curvularia lunata (4) | Anidulafungin | 0.06–0.25 | |||
| Micafungin | 0.015–0.125 | ||||
| Caspofungin | 0.125–0.5 | ||||
| Veronaea botryosa (4) | Anidulafungin | >4 | |||
| Micafungin | >4 | ||||
| Caspofungin | >4 | ||||
Generally, the MIC values for the other four azoles were consistent with published data (27–30). In this study, the MICs of fluconazole for most tested fungi, except for V. botryosa, were <64 μg/ml. The MICs of amphotericin B on these dematiaceous fungi were slightly higher than those of itraconazole, voriconazole, and posaconazole but much lower than those of fluconazole and 5-flucytosine. Finally, the MICs of 5-flucytosine were significantly varied with the tested species.
The antifungal activities of the three echinocandins (β-glucan inhibitors) were evaluated by MEC and GMEC values (Table 2). We found that echinocandin MECs for most tested fungi ranged from 0.03 to 4 μg/ml but were >4 μg/ml against E. dermatitidis and V. botryosa.
This study represented the first research on these two new triazoles together with nine other antifungal agents for testing the in vitro susceptibility of a broad spectrum of dematiaceous fungi. Antifungal activities of two novel azoles, i.e., ravuconazole and isavuconazole, have not been widely tested beyond a few reports on Exophiala spp., Alternata spp., and Fonsecaea spp. (11, 24). In our study, ravuconazole and isavuconazole showed better antifungal activity than itraconazole, voriconazole, and posaconazole to most tested fungi. However, both novel drugs had only limited antifungal activities against Bipolaris spicifera and V. botryosa. We therefore recommend alternatives to these two drugs in the treatment of mycosis caused by B. spicifera and V. botryosa.
Accession number(s).
All sequences were submitted to GenBank under accession numbers MH010901 to MH010967 and MT023596 to MT023612 for ITS and MH012056 to MH012122 and MT023613 to MT023629 for the large subunit.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of China (no. 81972949), the scientific and technological innovation projects of medicine and health of the Chinese Academy of Medical Sciences (no. 2016-I2M-3-021), the basic scientific research fund projects of the Chinese Academy of Medical Sciences (no. 2018PT31013 and Young Teacher Foundation no.3332018121), and the National Science and Technology Major Project (no. 2018ZX10734404).
We have no conflicts of interest to declare.
X.L. and W.L. conceived the ideas. H.Z., H.M., and J.D. collected the data. H.Z. and N.S. analyzed the data. H.Z. and D.L. led the writing.
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