Abstract
The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.
Highlights
Invasive infections caused by molds and thermally dimorphic fungi are of increasing clinical concern
Other invasive mold infections that are associated with reduced susceptibility to clinically available antifungals and poor clinical outcomes include those caused by Scedosporium species and Lomentospora prolificans, Fusarium species, as well as Microascus and Scopulariopsis species [14,15,16,17,18,19,20,21]
Following 24 h of olorofim exposure, mitosis within A. fumigatus was halted, which is consistent with cell cycle arrest, and this was postulated to be due to a decrease in cellular levels of pyrimidine, leading to an inability to fully replicate DNA [28]
Summary
Invasive infections caused by molds and thermally dimorphic fungi are of increasing clinical concern This includes those caused by Aspergillus, Scedosporium, Fusarium, and Coccidioides species, among others. There is increased recognition of azole resistance in A. fumigatus isolates, either due to clinical or environmental exposure to these agents [6,7,8,9,10,11], and studies have reported increases in cryptic Aspergillus species, including those with reduced susceptibility to clinically available antifungal agents such as A. lentulus, A. udagawae, and A. calidoustus [12,13]. This review discusses which target either ergosterol within the fungal cell membrane or its biosynthesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
