Background: F901318 is the most advanced candidate from a novel series of antifungal agents, the orotomides. F901318 is currently being developed for the treatment of serious systemic fungal infections, in particular invasive aspergillosis. In this study the potency of F901318 was compared with established antifungal agents against a large panel of clinical Aspergillus isolates from the UK and the Tyrol region of Austria.
Methods: A total of 221Aspergillus strains (A. fumigatus n=80, A. terreus n=45, A. flavus n=50 and A. niger n=46) were tested for susceptibility to F901318. The testing methods are outlined in CLSI document M38-A2. All strains were tested in a microdilution format. Voriconazole, posaconazole, itraconazole and amphotericin B were tested as comparators. In an inhaled model of aspergillosis, mice were infected with a L98H/TR cyp51A mutant strain and treated with posaconazole 10mg/kg/day PO or F901318 8mg/kg IV TID.
Results: All Aspergillus isolates tested were susceptible to F901318 with MICs < 0.03 mg/L. Retesting of strains at a lower drug range, (132 strains representing all four species) revealed on-scale MICs of 0.002-0.008 mg/L for all isolates except two A. niger isolates with MICs of 0.016 mg/L. Fourteen isolates of A. fumigatus were resistant to one or more azoles because of known cyp51A mutations (M220K, G54E, G138C, G54R, Y431C, H147Y/G448, G434C, M222T, G54V and L98H/TR). In these isolates the MIC for F901318 was also 0.008mg/L, indicating a lack of cross resistance with the azoles. In an inhaled model of aspergillosis, mice infected with a L98H/TR cyp51A mutant and treated with F901318 showed 80% survival 10 days post infection compared to 0% survival for posaconazole at supra-pharmacological exposures.
Conclusion: In this study F901318 was shown to have potent activity against a large collection of the commonly isolated pathogenic Aspergillus species. Activity was also demonstrated against strains with eleven well characterised cyp51A mutations resistant to one or more azoles, indicating a lack of cross-resistance. F901318 also produced a significant survival benefit in pulmonary aspergillosis caused by an azole-resistant isolate.
- ICAAC 55th (2015)