Abstract
The in vitro susceptibilities of 24 worldwide Exserohilum isolates belonging to 10 species from human and environmental sources were determined for eight antifungal drugs. The strains were characterized by internal transcribed spacer (ITS) sequencing and amplified fragment length polymorphism fingerprinting. Posaconazole had the lowest geometric mean MIC (0.16 μg/ml), followed by micafungin (0.21 μg/ml), amphotericin B (0.24 μg/ml), itraconazole (0.33 μg/ml), voriconazole (0.8 μg/ml), caspofungin (1.05 μg/ml), isavuconazole (1.38 μg/ml), and fluconazole (15.6 μg/ml).
TEXT
The anamorphic genus Exserohilum (teleomorph Setosphaeria, family Pleosporaceae, order Pleosporales) comprises approximately 35 species, which are common saprobic fungi on plant debris worldwide (1). Until recently, Exserohilum species were considered to be rare opportunistic pathogens reported sporadically from cases of keratitis, cutaneous and subcutaneous phaeohyphomycosis, and invasive infections, especially in immunosuppressed patients (2, 3). However, at the end of 2012, the meningitis outbreak in the United States due to Exserohilum demonstrated this fungus to be an agent of severe life-threatening infections (4, 5). Although several fungi were implicated in the outbreak, the vast majority of infections were caused by Exserohilum rostratum, which was traced to contaminated steroid injections as the source (4–8). Previously, Exserohilum rostratum, Exserohilum longirostratum, and Exserohilum mcginnisii were reported as opportunistic human pathogens. However, molecular studies have demonstrated that these species are conspecific, with E. rostratum being the accepted species (1).
The pathobiology of this melanized mold, including infections in the immunocompromised host, is not clearly understood. A recent report (9) suggested that methylprednisolone-induced suppression of phagocytosis by polymorphonuclear leukocytes was responsible for the rapid development of an E. rostratum outbreak in the United States. The therapeutic approach to combat this pathogen has not yet been established; therefore, knowledge regarding its pathogenic potential and antifungal susceptibility is of paramount importance (8, 10, 11). The large majority of patients in the recent outbreak were administered voriconazole with or without amphotericin B; this was based on a small case series, personal experience, and the favorable pharmacokinetic profile of voriconazole with regard to cerebral infections (10). Clinical outcomes with voriconazole seemed to be satisfactory, although a recent case showed failure after 4.5 months of voriconazole therapy, with excellent trough levels (12); therefore, its upfront use has been challenged (13, 14). In vitro antifungal susceptibility (AFS) data for Exserohilum species are scarce. Three studies reported AFS data on E. rostratum (1, 4, 15). Given the fact that E. rostratum is a coincidental opportunist, there is no a priori reason to believe that this will be the only Exserohilum species with this ability. Therefore, we aimed to study the potential activity of isavuconazole, a new triazole recently approved by the FDA for the treatment of invasive aspergillosis and mucormycosis, against E. rostratum (n = 10) and 9 other species of Exserohilum (n = 14) made available by the Centraalbureau Schimmelcultures (CBS)-KNAW Fungal Biodiversity Centre (Utrecht, The Netherlands) and the Vallabhbhai Patel Chest Institute (Delhi, India) (Table 1).
TABLE 1.
Origin, source, and MIC/MEC data of all Exserohilum isolates tested
| Species | Country of origin | CBS no./source | GenBank accession no. | MIC/MEC (μg/ml) ofa: |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| AMB | ISA | POS | ITC | VRC | FLU | CASb | MFGb | ||||
| E. rostratum (E. mcginnisii) | USA | CBS 120308/clinical | KT265236 | 0.125 | 2 | 0.063 | 0.25 | 0.5 | 32 | 1 | 0.125 |
| CBS 325.87T/clinical | KT265237 | 0.25 | 4 | 0.125 | 0.25 | 1 | 16 | 2 | 0.5 | ||
| E. rostratum | Canada | CBS 112815/clinical | KT265238 | 1 | 1 | 0.125 | 0.5 | 1 | >64 | 4 | 8 |
| CBS 128063/clinical | KT265239 | 0.25 | 8 | 0.25 | 0.5 | 2 | 32 | 1 | <0.008 | ||
| CBS 128061/clinical | KT265240 | 0.063 | 1 | 0.125 | 0.125 | 0.5 | 32 | 0.5 | <0.008 | ||
| CBS 128060/clinical | KT265245 | 0.125 | 2 | 0.125 | 0.25 | 1 | 8 | 0.5 | 0.25 | ||
| CBS 131565/clinical | KT265242 | 0.25 | 4 | 0.125 | 0.25 | 1 | 16 | 1 | 0.125 | ||
| CBS 128062/clinical | KT265247 | 0.5 | 4 | 0.25 | 0.5 | 2 | 32 | 2 | 0.25 | ||
| India | CBS 134641/clinical | KT265248 | 0.5 | 8 | 0.25 | 0.5 | 2 | 32 | 0.5 | 0.25 | |
| CBS 134640/clinical | KT265241 | 0.125 | 4 | 0.5 | 0.25 | 2 | 32 | 1 | 0.25 | ||
| E. gedarefense | Sudan | CBS 504.90/environment | KT265243 | 0.25 | 1 | 0.063 | 0.063 | 1 | 8 | 1 | 0.5 |
| CBS 297.80T/environment | KT265244 | 0.25 | 1 | 0.125 | 0.5 | 2 | 16 | 1 | 0.063 | ||
| E. neoregeliae IM201-D | Japan | CBS 132832T/environment | KT265254 | 0.25 | 2 | 0.125 | 0.25 | 1 | 16 | 1 | 0.125 |
| E. neoregeliae IM201-E | CBS 132833/environment | KT265255 | 0.125 | 2 | 0.125 | 0.125 | 0.5 | 32 | 1 | 0.063 | |
| E. pedicellatum | USA | CBS 322.64/environment | KT265258 | 0.25 | 0.5 | 0.125 | 0.063 | 0.25 | 1 | 1 | 0.25 |
| Turkey | CBS 375.76/environment | KT265259 | 0.5 | 0.25 | 0.125 | 0.25 | 0.5 | 2 | 0.5 | 0.125 | |
| E. protrudens | Australia | CBS 132710T/environment | KT265256 | 0.125 | 2 | 0.5 | 0.25 | 2 | 8 | 2 | 0.5 |
| E. fusiforme | CBS 132709T/environment | KT265257 | 0.031 | 0.125 | 0.031 | 0.031 | 0.063 | 1 | 1 | 0.25 | |
| E. antillanum | Cuba | CBS 412.93T/environment | KT265246 | 1 | 4 | 0.25 | 0.25 | 2 | >64 | 4 | 8 |
| E. curvatum | Venezuela | CBS 505.90T/environment | KT265252 | 0.25 | 2 | 1 | >16 | 2 | 32 | 1 | 2 |
| E. prolatum | Unknown | CBS 128058/unknown | KT265249 | 1 | 1 | 0.125 | 0.25 | 0.5 | >64 | 2 | 4 |
| Unknown | CBS 128059/unknown | KT265250 | 0.25 | 1 | 0.25 | 0.5 | 1 | 8 | 4 | 1 | |
| E. holmii | Unknown | CBS 128053/unknown | KT265253 | 0.25 | 1 | 1 | >16 | 1 | 64 | 1 | 0.125 |
| Exserohilum sp. | Unknown | CBS 128064/unknown | KT265251 | 0.25 | 8 | 2 | >16 | 4 | >64 | 1 | 0.125 |
AMB, amphotericin B; ISA, isavuconazole; POS, posaconazole; ITC, itraconazole; VRC, voriconazole; FLU, fluconazole; CAS, caspofungin; MFG, micafungin.
For echinocandins, MECs were defined as lowest drug concentrations that allowed the growth of small, rounded, and degenerated hyphae vis-à-vis the growth in the control well.
(Portions of this work were presented previously at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO [16].)
The Exserohilum isolates were analyzed by amplified fragment length polymorphism (AFLP) genotyping (see Fig. S1 in the supplemental material), as described previously (17, 18), and subjected to sequencing of the internal transcribed spacer (ITS) region (see Fig. S2 in the supplemental material). The MICs of amphotericin B (Bristol Myers Squibb, Woerden, The Netherlands), fluconazole, voriconazole (Pfizer Central Research, Sandwich, Kent, United Kingdom), itraconazole (Janssen Cilag, Tilburg, The Netherlands), posaconazole (Merck, Whitehouse Station, NJ), isavuconazole (Basilea Pharmaceutica, Basel, Switzerland), caspofungin (Merck), and micafungin (Astellas, Toyama, Japan) were determined using the microdilution method, in accordance with the guidelines of the CLSI document M38-A2 (19).
E. rostratum isolates (n = 8) clustered together in AFLP, along with 2 isolates that were previously identified by conventional methods as E. mcginnisii (CBS 325.87T and CBS 120308), confirming their synonymy (see Fig. S1 in the supplemental material) (1). Also, two isolates each of Exserohilum prolatum (CBS 128058 and CBS 128059 [no type strain]) and Exserohilum antillanum (CBS 412.93T) clustered with E. rostratum; E. antillanum can thus be regarded as another synonym of E. rostratum. Notably, in the ITS phylogenetic tree, E. antillanum also could not be discriminated from E. rostratum (see Fig. S2 in the supplemental material). E. rostratum isolates exhibited somewhat variable banding patterns, suggesting genotypic diversity in this complex. Two isolates of Exserohilum pedicellatum, neither of which was a type strain, clustered together (see Fig. S1). Further, two isolates for each of the species Exserohilum gedarefense (CBS 297.80T) and Exserohilum neoregeliae (CBS 132832T) and a solitary isolate each of Exserohilum fusiforme (CBS 132709T) and Exserohilum protrudens (CBS 132710T), all type strains, represented four different species. Overall, ITS sequencing could not discriminate E. rostratum, E. gedarefense, E. antillanum, and E. mcginnisii. Also, similar but not identical AFLP profiles were observed for Exserohilum holmii (no type strain) and Exserohilum curvatum (CBS 505.90T) representing two different species, which was in conformity with ITS phylogeny.
The MIC ranges, MIC50s/MIC90s, and geometric mean MICs of all isolates are presented in Table 2, along with data from the three previously published studies for comparison (1, 4, 15). Table 1 summarizes the origins and sources of the isolates. They originated from the United States (n = 3), Australia (n = 2), Canada (n = 6), Cuba (n = 1), India (n = 2), Japan (n = 2), Sudan (n = 2), Turkey (n = 1), and Venezuela (n = 1). Of these, 10 were environmental and 10 clinical isolates, whereas 4 isolates were of unknown origin and source. Posaconazole, itraconazole, and amphotericin B had the lowest MIC90s across all Exserohilum isolates, whereas fluconazole had no activity. The MIC ranges of 10 E. rostratum isolates (inclusive of E. mcginnisii) for isavuconazole spread over 2 to 3 twofold dilutions (1 to 8 μg/ml) and were similar to those of posaconazole (0.06 to 0.5 μg/ml), voriconazole (0.5 to 2 μg/ml), itraconazole (0.125 to 0.5 μg/ml), caspofungin (0.5 to 4 μg/ml), amphotericin B (0.06 to 1 μg/ml), and micafungin (0.008 to 8 μg/ml). The geometric mean (GM) MIC of isavuconazole for E. rostratum was 3 μg/ml, compared to 1.15 μg/ml for voriconazole and 0.16 μg/ml for posaconazole. Notably, the geometric mean (GM) MICs of isavuconazole for all Exserohilum spp. (1.38 μg/ml) were lower than that of E. rostratum (3.03 μg/ml). In the present study, isavuconazole had the lowest in vitro activity among azoles, which was in conformity with the data of the U.S. meningitis outbreak caused by E. rostratum strains (4). Further, the E. rostratum outbreak strains exhibited equivalent susceptibility against itraconazole, posaconazole, amphotericin B, and to a lesser extent, voriconazole (4). Notably, in the present study, for all Exserohilum species, the GM minimum effective concentration (MEC) of caspofungin (1.18 μg/ml) was 3-fold higher than that of micafungin (0.36 μg/ml). Further, in contrast to previous findings with Candida, all tested isolates had reproducible MECs for caspofungin when performed on two occasions.
TABLE 2.
Comparison of present and previously published in vitro antifungal susceptibility profiles of Exserohilum species and E. rostratum, according to CLSI M38-A2
| Species tested (n) | MIC parameter | MIC (μg/ml) ofa: |
Reference (yr) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| AMB | ISA | POS | ITC | VRC | FLU | CASb | MFGb | AFGb | |||
| All Exserohilum spp. (24) | GM | 0.24 | 1.38 | 0.19 | 0.38 | 0.97 | 17.4 | 1.18 | 0.36 | Present study (2015) | |
| MIC50 | 0.25 | 1 | 0.125 | 0.25 | 1 | 32 | 1 | 0.25 | |||
| MIC90 | 1 | 4 | 1 | 16 | 2 | 64 | 4 | 8 | |||
| Range | 0.03 to 1 | 0.125 to 8 | 0.03 to 2 | 0.03 to 16 | 0.06 to 2 | 1 to >64 | 0.5 to 4 | <0.008 to 8 | |||
| E. rostratum (10) | GM | 0.23 | 3.03 | 0.16 | 0.30 | 1.14 | 25.9 | 1.07 | 0.16 | ||
| MIC50 | 0.25 | 4 | 0.125 | 0.25 | 1 | 32 | 1 | 0.25 | |||
| MIC90 | 1 | 8 | 0.5 | 0.5 | 2 | 64 | 4 | 8 | |||
| Range | 0.06 to 1 | 1 to 8 | 0.06 to 0.5 | 0.125 to 0.5 | 0.5 to 2 | 8 to 64 | 0.5 to 4 | 0.008 to 8 | |||
| Exserohilum spp. other than E. rostratum (14) | GM | 0.24 | 1.16 | 0.21 | 0.45 | 0.86 | 13.1 | 1.28 | 0.37 | ||
| MIC50 | 0.25 | 1 | 0.125 | 0.25 | 1 | 16 | 1 | 0.25 | |||
| MIC90 | 1 | 8 | 2 | 16 | 4 | 64 | 4 | 8 | |||
| Range | 0.03 to 1 | 0.125 to 8 | 0.03 to 2 | 0.03 to 16 | 0.06 to 4 | 1 to 64 | 0.5 to 4 | 0.06 to 8 | |||
| E. rostratum (6) | Range | 2 to 4 | 0.5 to 1 | 1 to 2 | 2 | 4 | 15 (2014) | ||||
| E. rostratum (50) | MIC50 | 0.25 | 4 | 0.5 | 0.5 | 1 | 4 (2013) | ||||
| MIC90 | 0.5 | 4 | 1 | 1 | 2 | ||||||
| Range | 0.03 to 2 | 2 to 4 | 0.25 to 1 | 0.25 to 4 | 1 to 2 | ||||||
| E. rostratum (34) | GM | 0.02 | 0.03 | 0.02 | 0.1 | 0.06 | 0.27 | 0.06 | 1 (2012) | ||
| MIC90 | 0.03 | 0.03 | 0.03 | 0.25 | 0.125 | 0.05 | 0.125 | ||||
| Range | <0.03 to 0.125 | <0.03 to 0.125 | <0.03 to 0.125 | <0.03 to 1 | <0.03 to >16 | <0.03 to >16 | <0.03 to 1 | ||||
AMB, amphotericin B; ISA, isavuconazole; POS, posaconazole; ITC, itraconazole; VRC, voriconazole; FLU, fluconazole; CAS, caspofungin; MFG, micafungin; AFG, anidulafungin.
For echinocandins, MECs were defined as lowest drug concentrations that allowed the growth of small, rounded, and degenerated hyphae vis-à-vis the growth in the control well.
Regarding the published reviews of the therapeutic outcomes of cases of sinusitis and cutaneous infections with Exserohilum, successful outcomes with amphotericin B and more recently with itraconazole and voriconazole have been reported (2, 11, 20). The expert panel for the U.S. outbreak recommended voriconazole for treatment of meningitis in patients with less severe disease and the lipid formulation of amphotericin B for those with severe extraneural disease or refractory infections (10). The present study showed low amphotericin B MICs against E. rostratum, while voriconazole had geometric mean MICs of >1 μg/ml. In contrast, da Cunha et al. (1) reported low geometric mean MICs of voriconazole (0.1 μg/ml) for 34 E. rostratum isolates originating from the United States. The different susceptibilities to voriconazole in the present study could be attributed to strains tested from various geographical locations. Recently, using whole-genome analysis, significant genomic variability has been reported among E. rostratum strains unrelated to the outbreak strains (21).
Although the clinical relevance of MIC data for Exserohilum has not been established, we conclude that amphotericin B, itraconazole, and posaconazole are the most active drugs in vitro, exhibiting MICs of <1 μg/ml, with both isavuconazole and voriconazole showing MICs below achievable serum trough levels.
The accession numbers for the Exserohilum isolates tested in this study are listed in Table 1.
Nucleotide sequence accession numbers.
The ITS nucleotide sequences of all 24 Exserohilum species have been deposited in GenBank under accession numbers KT265236 and KT265259 (Table 1).
Supplementary Material
ACKNOWLEDGMENTS
This work was partially funded by Astellas, USA. A.C. was supported by the Indian Council of Medical Research, New Delhi, India (reference no. 5/3/3/26/200-ECD-I), and H.M. was funded by the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Chile, project no. 11140562.
J.F.M. received grants from Astellas, Basilea, and Merck. He has been a consultant to Astellas, Basilea, and Merck and received speaker's fees from Merck and Gilead.
Footnotes
Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.01218-15.
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