New treatment options for critically important WHO fungal priority pathogens

BACKGROUND: Yet often overlooked in public health discourse, fungal infections pose a crucial global disease burden associated with annual mortality rates approximately equal to tuberculosis and HIV. In response, the WHO published its first global priority list of fungal pathogens in 2022 assigning Aspergillus fumigatus, Candida albicans, Candida auris, and Cryptococcus neoformans to the critical group. OBJECTIVES: This review provides succinct insights into novel antifungals in development, aiming to contribute valuable information and perspectives with a focus on recent clinical findings and new treatment approaches for critical members of the WHO fungal pathogen priority list. SOURCES: PubMed literature search using 'Aspergillus fumigatus', 'Cryptococcus neoformans', 'Candida auris', and 'Candida albicans', along with the names of novel antifungal substances, including 'fosmanogepix', 'ibrexafungerp', 'opelconazole', 'oteseconazole', 'MAT2203', 'olorofim', and 'rezafungin' was conducted. CONTENT: For each critical pathogen, current issues and global clinical data from recent trials are covered. The remarkable development of three new antifungal therapeutics recently receiving Food and Drug Administration approval (ibrexafungerp-June 2021, oteseconazole -April 2022, and rezafungin-March 2023) is outlined, with two more exciting new antifungal substances, namely, olorofim and fosmanogepix expecting approval within the next years. Ibrexafungerp, fosmanogepix, and rezafungin have additionally been granted orphan drug status by the European Medicines Agency in Europe (ibrexafungerp-November 2021, fosmanogepix-July 2022, and rezafungin-January 2024). IMPLICATIONS: Although the limited number of targets and the emergence of resistance have posed challenges to antifungal treatment, new drugs such as ibrexafungerp, rezafungin, fosmanogepix, or olorofim have shown promising clinical efficacy. These drugs not only provide alternative options for invasive fungal infections but also alleviate treatment in outpatient settings. More clinical data, implementation of stewardship programmes, and surveillance, including utilization of drugs in agriculture, are necessary to prevent resistance development and to ensure the safety and efficacy of these new agents.