Wild-type MIC distributions and epidemiological cut-off values for ibrexafungerp, manogepix, and rezafungin against WHO fungal priority pathogens

Objective This study gathered public data regarding the in vitro activity of three novel antifungal agents, ibrexafungerp, manogepix, and rezafungin, against the fungi listed in the WHO fungal priority pathogens list. Methods Epidemiological cut-off values (ECVs/ECOFFs) were established for species with sufficient data (≥100 MIC values) and when distributions met further essential criteria. For pathogens in which data did not fulfil one or more essential criteria, tentative ECVs (T-ECVs/T-ECOFFs) were proposed. The values were determined by a comprehensive analysis that included visual inspection of histograms and the calculation of ECOFFinder-based values (95% and 97.5%), as well as the Mode + 2 and MIC50 + 2 dilutions. Results A total of 34,736 MIC values were collected from studies using standardised CLSI (25,027) or EUCAST (9,709) methodologies: ibrexafungerp (5,388), manogepix (10,610), and rezafungin (18,738). The analysis successfully defined ECVs for a core group of clinically relevant yeasts, including Candida albicans, Candidozyma auris , and Nakaseomyces glabratus . Tentative ECVs were proposed for data-limited pathogens such as Cryptococcus neoformans, Lomentospora prolificans , and Talaromyces marneffei , among others. For Aspergillus fumigatus , a CLSI ECV was also established with rezafungin. Conclusions The ECVs and T-ECVs derived herein provide crucial reference points to guide future resistance surveillance and inform the foundational epidemiology needed for clinical breakpoint setting. Importantly, the data gaps identified for dimorphic and filamentous fungi underscore the urgent need for standardised susceptibility testing methods and targeted research efforts for these neglected priority pathogens.