<i>In vitro</i> activity of novel antifungals, natamycin, and terbinafine against <i>Fusarium</i>

The genus <i>Fusarium</i> includes several trans-kingdom pathogens, infecting plants, animals, and humans, with widespread occurrence. Invasive <i>Fusarium</i> infections are often destructive due to their prevalence in critically ill patients. Furthermore, severe superficial infections, like keratitis or endophthalmitis with potential loss of vision, are rising in incidence globally. Infections are difficult to treat due to the intrinsic resistance of <i>Fusarium</i> against echinocandins and often high minimal inhibitory concentrations (MICs) for azoles. In this article, we assessed the <i>in vitro</i> activity of the novel antifungals olorofim, manogepix, rezafungin, and ibrexafungerp, as well as the established but nonstandard drugs, natamycin and terbinafine, against a large set of molecularly identified clinical <i>Fusarium</i> isolates via EUCAST microdilution. The tested isolates represent the clinically most relevant species of the <i>F. solani</i> (FSSC), <i>F. oxysporum</i> (FOSC), <i>F. fujikuroi</i> (FFSC), <i>F. incarnatum-equiseti</i> (FIESC), <i>F. dimerum</i> (FDSC), and <i>F. redolens</i> (FRSC) species complexes. While rezafungin and ibrexafungerp showed no effect on the <i>Fusarium</i> spp. tested, a general antifungal susceptibility of <i>Fusarium</i> against natamycin and manogepix was found. Specific profiles were detailed for terbinafine and olorofim. While species from the FDSC, FSSC, and FIESC show high MICs for olorofim, specific susceptibility rates were found for species of the FFSC and FOSC. Furthermore, we report specific susceptibilities for terbinafine against FDSC, FFSC, and FOSC species. These findings of complex- and species-specific olorofim and terbinafine <i>in vitro</i> susceptibilities highlight the need for diagnostics below genus level.