Invasive aspergillosis represents a serious life-threatening disease especially for immunocompromised patients and triazole therapy is frequently the first line treatment option. The emerging resistance to triazoles in the fungal pathogens causing Aspergillosis poses a growing threat to global health. Since 2001, no new classes of antifungal agents have been developed.
F901318 represents the first member of the novel orotomide antifungal class and is currently in clinical development for the treatment of serious systemic fungal infections in particular invasive aspergillosis. F901318 acts via a novel mechanism of action that is different to that of the members of the azole class which all act through inhibition of the sterol biosynthetic enzyme Cyp51. Multiple cyp51A mutations conferring azole resistance have been identified, with the most common being TR34/L98H found in Aspergillus fumigatus. The TR34/L98H mutation is associated with significantly reduced itraconazole, voriconazole, and posaconazole susceptibility.
In this study a panel of Aspergillus spp. strains, isolated in the North West of England and Tyrol, Austria, that showed resistance or elevated MICs to single or multiple azoles was tested for susceptibility to F901318. The study also included several isolates with defined cyp51A mutations.
A total of 40 Aspergillus isolates were tested for susceptibility to F901318. MICs were determined by CLSI methodology outlined in document M38-A2. All organisms were tested in microdilution format. Voriconazole, posaconazole, itraconazole and amphotericin B were tested as comparators.
All tested Aspergillus species (A. fumigatus n= 19, Aspergillus terreus n = 17 and Aspergillus flavus n=4) were highly susceptible to F901318 with all MICs < 0.03 mg/L. The F901318 MICs for these isolates were identical to those for azole susceptible ones indicating a lack of cross resistance with azole drugs.
The obtained data underline the high in vitro effectiveness of F901318 against both azole susceptible and azole resistant Aspergillus spp. The great potential of F901318 as an antifungal agent is further supported by the fact that it shows significant activity against both A. terreus and A. flavus, which are frequently found resistant to amphotericin B.