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Antimicrob Agents Chemother. 2016 November; 60(11): 6890–6891.
Published online 2016 October 21. Prepublished online 2016 August 15. doi:  10.1128/AAC.00742-16
PMCID: PMC5075100

In Vitro Activity of Isavuconazole against Rasamsonia Species

Abstract

The in vitro susceptibilities to the novel triazole isavuconazole and six other antifungal agents of a large collection of Rasamsonia isolates (n = 47) belonging to seven species were determined. Isavuconazole and voriconazole had no in vitro activity (MIC, >32 mg/liter) against isolates of the Rasamsonia argillacea species complex. The echinocandins were the most potent antifungal drugs against all of the isolates tested (minimum effective concentration, ≤0.19 mg/liter).

TEXT

On the basis of phenotypic, physiological, and molecular data, the genus Rasamsonia was introduced to accommodate thermotolerant and thermophilic Penicillium-like species that produce cylindrical phialides that usually gradually taper toward the apices, distinctly rough-walled stipes and metulae, olive-brown conidia, and ascomata, if present, with a scanty covering (1). In 2013, the Rasamsonia argillacea species complex was investigated and currently consists of four species: R. argillacea sensu lato, R. eburnea, R. piperina, and R. aegroticola (2). R. cylindrospora and R. brevistipitata were shown to be phenotypically similar but genetically more distant (1).

Rasamsonia can be isolated from hot environments and clinical samples, and species belonging to the R. argillacea complex were described as an emerging fungus in immunocompromised hosts and cystic fibrosis patients (3). In particular, this pathogen was reported to cause invasive, disseminated infections in patients with chronic granulomatous diseases or hemato-oncological malignancies (4,7).

Isavuconazole, a novel triazole with broad-spectrum antifungal activity, showed noninferiority to voriconazole for the primary treatment of suspected invasive mold disease (8). In addition, isavuconazole showed activity against mucormycosis with efficacy similar to that of amphotericin B (9) and demonstrated clinical activity against Cryptococcus spp. and dimorphic fungi (10).

The objective of this study was to analyze the in vitro activity of isavuconazole and other antifungal agents against isolates from the R. argillacea species complex and those closely related to them.

A collection of 47 clinical and reference isolates were included in this study. A detailed description of 35 isolates and the method used for identification was published previously (11). The additional 12 isolates were patient isolates from the University Hospital Essen, Essen, Germany.

Susceptibility testing was performed with EUCAST E.Def 9.3 as recently described (12). All of the isolates were cultured on malt agar (Oxoid, Wesel, Germany) before testing. The drug concentrations used ranged from 0.0625 to 32 mg/liter for isavuconazole (Basilea, Basel Switzerland), voriconazole (Sigma-Aldrich, Munich, Germany), and amphotericin B (Sigma-Aldrich); from 0.03125 to 16 mg/liter for posaconazole (Hycultec, Beutelsbach, Germany) and itraconazole (Sigma-Aldrich); and from 0.0078 to 4 mg/liter for micafungin (Hycultec) and caspofungin (Sigma-Aldrich). A stock isavuconazole solution (Basila, Basel, Switzerland) was dissolved in dimethyl sulfoxide (Sigma-Aldrich) in accordance with the manufacturer's instructions. After inoculation, the prepared plates were incubated at 36°C for 2 days and visually assessed. The minimum effective concentrations (MECs) of micafungin and caspofungin were determined microscopically as the lowest concentrations of the drugs promoting abnormal, short, and branched hyphal clusters (12). For calculation of the geometric mean (GM), MICs of >16 mg/liter were set at 32 mg/liter. A clinical Aspergillus fumigatus isolate and a Candida parapsilosis reference strain (ATCC 22019) recommended by EUCAST were used as controls. Isavuconazole breakpoints are defined for A. fumigatus (≤1 mg/liter for susceptible, >1 mg/liter for resistant) by EUCAST version 8.0 (valid from 16 November 2015).

The in vitro susceptibilities (the GM and range of the MIC) of the different Rasamsonia isolates to isavuconazole and the other antifungals are shown in Table 1. The isavuconazole MICs for all of the isolates in the R. argillacea species complex (R. argillacea, R. aegroticola, R. eburnea, and R. piperina) were high (>32 mg/liter). Voriconazole had also no activity against isolates in the R. argillacea species complex. The GMs of the MICs of amphotericin B, posaconazole, and itraconazole were variable. The MECs of micafungin and caspofungin for all of the Rasamsonia isolates were low. For R. cyclindrospora and R. brevistipitata, the overall MICs/MECs of all of the antifungals tested were low.

TABLE 1
In vitro susceptibilities of Rasamsonia species to seven antifungal agents, including isavuconazole

Here, we show for the first time that the isavuconazole MICs for the emerging pathogenic R. aergillacea species complex in vitro are high, suggesting no meaningful activity.

It was shown that isavuconazole has potent in vitro activity against most common Aspergillus species, Purpureocillium lilacinum (= Paecilomyces lilacinus), and Scedosporium apiospermum (13, 14). The MICs for fungi of the family Mucoraceae varied between the genera (15).

The finding that the MICs of voriconazole were high and the MECs of echinocandins were low for R. aergillacea is consistent with a previous report in which susceptibility testing was performed by the broth microdilution method of the CLSI (M38-A2) (2). R. cyclindrospora and R. brevistipitata, both exhibiting low isavuconazole MICs, were mostly isolated from the environment and have so far not been described as pathogens causing invasive fungal infections.

In summary, we found high isavuconazole MICs for isolates of the R. argillacea species complex, indicating that this agent may not be a viable treatment option for invasive infections with this emerging fungus. However, future in vivo studies are warranted to verify the in vitro data obtained in the present study.

ACKNOWLEDGMENTS

We thank Axel Hamprecht and Ludwig Sedlacek for providing some of the clinical isolates.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

REFERENCES

1. Houbraken J, Spierenburg H, Frisvad JC 2012. Rasamsonia, a new genus comprising thermotolerant and thermophilic Talaromyces and Geosmithia species. Antonie Van Leeuwenhoek 101:403–421. doi:.10.1007/s10482-011-9647-1 [PMC free article] [PubMed] [Cross Ref]
2. Houbraken J, Giraud S, Meijer M, Bertout S, Frisvad JC, Meis JF, Bouchara JP, Samson RA 2013. Taxonomy and antifungal susceptibility of clinically important Rasamsonia species. J Clin Microbiol 51:22–30. doi:.10.1128/JCM.02147-12 [PMC free article] [PubMed] [Cross Ref]
3. Giraud S, Bougnoux ME, Bouchara JP 2013. Rasamsonia argillacea species complex: taxonomy, pathogenesis and clinical relevance. Future Microbiol 8:967–978. doi:.10.2217/fmb.13.63 [PubMed] [Cross Ref]
4. De Ravin SS, Challipalli M, Anderson V, Shea YR, Marciano B, Hilligoss D, Marquesen M, Decastro R, Liu YC, Sutton DA, Wickes BL, Kammeyer PL, Sigler L, Sullivan K, Kang EM, Malech HL, Holland SM, Zelazny AM 2011. Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease. Clin Infect Dis 52:e136–143. doi:.10.1093/cid/ciq250 [PMC free article] [PubMed] [Cross Ref]
5. Machouart M, Garcia-Hermoso D, Rivier A, Hassouni N, Catherinot E, Salmon A, Debourgogne A, Coignard H, Lecuit M, Bougnoux ME, Blanche S, Lortholary O 2011. Emergence of disseminated infections due to Geosmithia argillacea in patients with chronic granulomatous disease receiving long-term azole antifungal prophylaxis. J Clin Microbiol 49:1681–1683. doi:.10.1128/JCM.02456-10 [PMC free article] [PubMed] [Cross Ref]
6. Valentin T, Neumeister P, Pichler M, Rohn A, Koidl C, Haas D, Heiling B, Asslaber M, Zollner-Schwetz I, Hoenigl M, Salzer HJ, Krause R, Buzina W 2012. Disseminated Geosmithia argillacea infection in a patient with gastrointestinal GvHD. Bone Marrow Transplant 47:734–736. doi:.10.1038/bmt.2011.149 [PubMed] [Cross Ref]
7. Corzo-León DE., Satlin MJ, Soave R, Shore TB, Schuetz AN, Jacobs SE, Walsh TJ. 2015. Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens. Mycoses 58:325–336. doi:.10.1111/myc.12318 [PubMed] [Cross Ref]
8. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR III, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ 2016. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 387:760–769. doi:.10.1016/S0140-6736(15)01159-9 [PubMed] [Cross Ref]
9. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR III, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Ráčil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JH, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild MJ, VITAL and FungiScope Mucormycosis Investigators 2016. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 16:828–837. doi:.10.1016/S1473-3099(16)00071-2 [PubMed] [Cross Ref]
10. Thompson GR III, Rendon A, Ribeiro Dos Santos R, Queiroz-Telles F, Ostrosky-Zeichner L, Azie N, Maher R, Lee M, Kovanda L, Engelhardt M, Vazquez JA, Cornely OA, Perfect JR 2016. Isavuconazole treatment of cryptococcosis and dimorphic mycoses. Clin Infect Dis 60:3533–3539. doi:.10.1093/cid/ciw305 [PMC free article] [PubMed] [Cross Ref]
11. Steinmann J, Giraud S, Schmidt D, Sedlacek L, Hamprecht A, Houbraken J, Meis JF, Bouchara JP, Buer J, Rath P-M 2014. Validation of a novel real-time PCR for detecting Rasamsonia argillacea species complex in respiratory secretions from cystic fibrosis patients. New Microbe New Infect 2:72–78. doi:.10.1002/nmi2.44 [PMC free article] [PubMed] [Cross Ref]
12. Arendrup MC, Meletiadis J, Mouton JW, Guinea J, Cuenca-Estrella M, Lagrou K, Howard SJ, Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). 2016. EUCAST technical note on isavuconazole breakpoints for Aspergillus, itraconazole breakpoints for Candida and updates for the antifungal susceptibility testing method documents. Clin Microbiol Infect 22:571.e1-4. doi:.10.1016/j.cmi.2016.01.017 [PubMed] [Cross Ref]
13. Miceli MH, Kauffman CA 2015. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis 61:1558–1565. doi:.10.1093/cid/civ571 [PubMed] [Cross Ref]
14. Lackner M, de Hoog GS, Verweij P, Najafzadeh MJ, Curfs-Breuker I, Klassen CH, Meis JF 2012. Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species. Antimicrob Agents Chemother 56:2635–2642. doi:.10.1128/AAC.05910-11 [PMC free article] [PubMed] [Cross Ref]
15. Chowdhary A, Kathuria S, Singh PK, Sharma B, Dolatabadi S, Hagen F, Meis JF 2014. Molecular characterization and in vitro antifungal susceptibility of 80 clinical isolates of mucormycetes in Delhi, India. Mycoses 57(Suppl 3):97–107. doi:.10.1111/myc.12234 [PubMed] [Cross Ref]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)