In vitro activity of olorofim against 507 filamentous fungi including antifungal drug-resistant strains at a tertiary laboratory in Australia: 2020-2023

J Antimicrob Chemother. 2024 Oct 1;79(10):2611-2621. doi: 10.1093/jac/dkae267.

Abstract

Background: New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non-Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data.

Objectives: Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital.

Materials and methods: Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific).

Results: A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25-0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4->8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species.

Conclusions: Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava.

MeSH terms

  • Acetamides
  • Antifungal Agents* / pharmacology
  • Australia
  • Drug Resistance, Fungal*
  • Fungi* / drug effects
  • Fungi* / isolation & purification
  • Humans
  • Microbial Sensitivity Tests*
  • Mycoses / drug therapy
  • Mycoses / microbiology
  • Nitriles
  • Piperazines
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Triazoles / pharmacology

Substances

  • Antifungal Agents
  • olorofim
  • isavuconazole
  • Triazoles
  • Pyrroles
  • Pyridines
  • Piperazines
  • Nitriles
  • Acetamides
  • Pyrimidines

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