Flucytosine and its clinical usage.

Flucytosine is an antifungal agent first licensed in the 1970's. However, its clinical value has long been overlooked and its availability across the globe is limited. This review highlights the important clinical and pharmacological aspects of flucytosine. This a narrative review of the clinical and in vitro susceptibility literature, with a focus on clinical uses for flucytosine. Detailed literature review including early literature related to primary and acquired resistance to flucytosine. Flucytosine has good antifungal activity against Cryptococcus species, Candida species, and dematiaceous fungi. Its water solubility enables good penetration into the eye, urinary tract, central nervous system (CNS), cardiac vegetations and fungal biofilms. In combination with amphotericin B, it shows early fungicidal activity against Cryptococcus species, and this translates to ~20% improved survival in cryptococcal meningitis. Combination therapy also reduces the mortality of Candida meningitis, and should be used in neonatal candidiasis because of the high frequency of CNS infection. Monotherapy for urinary candidiasis is under-studied, but is usually effective. It is probably valuable in the treatment of Candida endocarditis and endophthalmitis: there are few data. It is not effective for aspergillosis or mucormycosis. Flucytosine monotherapy of urinary candidiasis resulted in 22% developing resistance on therapy and failing therapy, and in 29% of 21 patients with cryptococcosis. Certain regions of the world still do not have access to flucytosine compromising the management of certain severe fungal infections. Flucytosine has an important role in combination therapy for yeast and dematiaceous infections and probably as monotherapy for urinary candidiasis, with a modest risk of resistance emergence. Facilitating access to flucytosine in those regions (especially low-income countries) might alleviate the mortality of invasive fungal diseases.
Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr D.W.D. and family hold Founder shares in F2G Ltd, a University of Manchester spin-out antifungal discovery company, and share options in TFF Pharma. He acts or has recently acted as a consultant to Pulmatrix, Pulmocide, Biosergen, TFF Pharmaceuticals, Pfizer, Omega, Novacyt, Rostra Thereaputics, MucPharm, and Cipla. He sat on the DSMB for a SARS-CoV-2 vaccine trial and chairs a Data Review Committee for Pulmocide. In the last 3 years, he has been paid for talks on behalf of Hikma, Gilead, BioRad, Basilea, Mylan, and Pfizer. He is a long-standing member of the Infectious Disease Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines group and recently joined the One World Guideline for Aspergillosis. Dr L.S.M.S. declares that she has no conflict of interest.
(© The Author(s), 2023.)