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Susceptibility

Olorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum Activity

Karen Marie Thyssen Astvad, Karin Meinike Jørgensen, Rasmus Krøger Hare, Raluca Datcu, Maiken Cavling Arendrup
Karen Marie Thyssen Astvad
aUnit of Mycology, Statens Serum Institut, Copenhagen, Denmark
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Karin Meinike Jørgensen
aUnit of Mycology, Statens Serum Institut, Copenhagen, Denmark
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Rasmus Krøger Hare
aUnit of Mycology, Statens Serum Institut, Copenhagen, Denmark
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Raluca Datcu
aUnit of Mycology, Statens Serum Institut, Copenhagen, Denmark
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Maiken Cavling Arendrup
aUnit of Mycology, Statens Serum Institut, Copenhagen, Denmark
bDepartment of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
cDepartment of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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DOI: 10.1128/AAC.01527-20
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ABSTRACT

Olorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus. Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates, as population data are needed for future epidemiological cutoff (ECOFF) settings. Fifteen A. fumigatus isolates previously found with low/medium/high MICs (≤0.002 to 0.25 mg/liter) were tested repeatedly and EUCAST MICs read in a blinded fashion by three observers. pyrE, encoding the olorofim target enzyme dihydroorotate dehydrogenase (DHODH), was sequenced. A total of 1,423 mold isolates (10 Aspergillus species complexes [including 1,032 A. fumigatus isolates] and 105 other mold/dermatophyte isolates) were examined. Olorofim susceptibility (modal MIC, MIC50, MIC90, and wild-type upper limits [WT-ULs] [species complexes with ≥15 isolates]) was determined and compared to that of four comparators. MICs (mg/liter) were within two 2-fold dilutions (0.016 to 0.03) for 473/476 determinations. The MIC range spanned four dilutions (0.008 to 0.06). No significant pyrE mutations were found. Modal MIC/WT-UL97.5 (mg/liter) values were 0.03/0.06 (A. terreus and A. flavus), 0.06/0.125 (A. fumigatus and Trichophyton rubrum), and 0.06/0.25 (A. niger and A. nidulans). The MIC range for Scedosporium spp. was 0.008 to 0.25. Olorofim susceptibility was similar for azole-resistant and -susceptible isolates of A. fumigatus but reduced for A. montevidensis and A. chevalieri (MICs of >1). With experience, olorofim susceptibility testing is robust. The testing of isolates from our center showed uniform and broad-spectrum activity. Single-center WT-ULs are suggested.

FOOTNOTES

    • Received 17 July 2020.
    • Returned for modification 29 August 2020.
    • Accepted 1 October 2020.
    • Accepted manuscript posted online 5 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Olorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum Activity
Karen Marie Thyssen Astvad, Karin Meinike Jørgensen, Rasmus Krøger Hare, Raluca Datcu, Maiken Cavling Arendrup
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01527-20; DOI: 10.1128/AAC.01527-20

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Olorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum Activity
Karen Marie Thyssen Astvad, Karin Meinike Jørgensen, Rasmus Krøger Hare, Raluca Datcu, Maiken Cavling Arendrup
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01527-20; DOI: 10.1128/AAC.01527-20
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KEYWORDS

olorofim
F901318
Aspergillus
Scedosporium
EUCAST
antifungal susceptibility
DHODH
pyrE
cyp51A
azole resistance

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