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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
Article numbere01527-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number1
Number of pages11
ISSN0066-4804
DOIs
Publication statusPublished - 16. Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 American Society for Microbiology. All Rights Reserved.

Keywords

  • Antifungal susceptibility
  • Aspergillus
  • Azole resistance
  • Cyp51A
  • DHODH
  • EUCAST
  • F901318
  • Olorofim
  • PyrE
  • Scedosporium
  • Piperazines
  • Pyrroles
  • Aspergillus fumigatus/genetics
  • Arthrodermataceae
  • Microbial Sensitivity Tests
  • Pyrimidines/pharmacology
  • Triazoles/pharmacology
  • Antifungal Agents/pharmacology
  • Denmark
  • Acetamides
  • Drug Resistance, Fungal/genetics

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