Abstract Objectives To investigate the species distribution and antifungal susceptibility profiles of clinical mould isolates from China to olorofim, manogepix, amphotericin B, triazoles and echinocandins. Methods Isolates were collected from patients at 10 tertiary hospitals across China between 2019 and 2024. Species identification was performed by sequence analysis. Antifungal susceptibility testing was performed according to the CLSI reference methods. The cyp51A, cyp51B and hmg1 genes from triazole-resistant isolates were amplified to identify mutations associated with resistance. Results Aspergillus spp. (92.02%) remained the most prevalent pathogens, followed by Fusarium spp. (4.18%) and Mucorales (1.90%). The proportion of non-A. fumigatus isolates showed an increasing trend. The majority of Aspergillus spp. were susceptible/WT to triazoles (97.52%), with posaconazole showing the highest potency. Among the triazole-resistant Aspergillus isolates, two harboured cyp51A mutations (TR46/Y121F/T289A, G441S) and one carried an hmg1 mutation (V827L). Notably, the novel antifungals olorofim and manogepix were highly potent against most tested moulds, including triazole-resistant Aspergillus isolates. For Fusarium spp., manogepix showed low MECs, whereas olorofim and triazoles showed higher and more species-specific MICs. Both novel agents showed high MIC/MECs against Mucorales isolates, and triazole MIC distributions varied markedly between species. Conclusions A. fumigatus sensu stricto remained the predominant pathogen while non-A. fumigatus moulds became increasingly prevalent. Triazole resistance among clinical Aspergillus isolates was uncommon but was associated with cross-resistance and target gene mutations. Novel antifungals olorofim and manogepix demonstrated potent in vitro activity against a broad range of clinical moulds, including triazole-resistant Aspergillus isolates.
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