In vitro evaluation of olorofim and antifungal combinations against Aspergillus and Candida species.

Background and objectives: Aspergillus and Candida spp. are important causes of systemic fungal infections. Although various therapies are available, resistance to current antifungal treatments, particularly azoles, is increasing. Combinations of antifungals can be used to treat infections with resistant pathogens. In a recent in vitro study, antagonism was reported in a single A. fumigatus isolate between olorofim and voriconazole. Available clinical data are limited but do not reflect this phenomenon. The in vitro interactions of olorofim with current antifungal agents (voriconazole, posaconazole, isavuconazole, fluconazole, amphotericin B, terbinafine and caspofungin) were evaluated against various Aspergillus and three Candida species.

Methods: In vitro interactions were evaluated by the EUCAST microdilution broth technique modified for checkerboard assay.

Results: Olorofim demonstrated different interaction patterns when tested in combination with various classes of antifungal. Unidirectional antagonism was seen between olorofim and the mould-active azoles with the strongest effect seen in A. niger: azole MIC values were unaffected but olorofim MIC values increased, although remained within wild-type distributions. Olorofim antagonized amphotericin B activity in the single A. niger strain tested. There was indifference between olorofim and fluconazole, terbinafine and caspofungin for all isolates. Finally, olorofim showed indifference with fluconazole or voriconazole against three Candida species.

Conclusions: Mould-active azoles antagonize olorofim activity against Aspergillus spp. combination MICs remain within wild-type distributions for Aspergillus spp., other than for A. niger. In addition, olorofim does not affect the anti-Candida effect of fluconazole and could be co-dosed where necessary without loss of the effect of the azole against the yeast.