Ibrexafungerp Citrate

Periodic surveillance of antifungal susceptibility among Aspergillus isolates is essential to guide effective treatment. This multicenter study analyzed 550 clinical Aspergillus isolates collected in Taiwan from 2021 to 2023, primarily from the respiratory tract (69.6%) and ear (12.9%). Calmodulin-based sequencing identified 24 species across six Aspergillus sections: Flavi (28.7%), Fumigati (28.5%), Nigri (21.6%), Terrei (15.8%), Nidulantes (5.1%), and Circumdati (0.2%). The major sections were represented by Aspergillus fumigatus (99.4%), Aspergillus flavus (91.8%), and Aspergillus terreus (100%), while section Nigri comprised nine species, with Aspergillus welwitschiae (57.1%) predominant. Using Clinical Laboratory Standards Institute (CLSI) M38-A3 protocols, reduced susceptibility to amphotericin B (MIC > 1 µg/mL) was observed in A. flavus (8.3%), A. terreus (22.7%), and section Nidulantes (32.1%). Acquired voriconazole resistance was found in 5.8% (9/156) of A. fumigatus isolates, including eight with cyp51A mutations (3 TR 34 /L98H, 4 TR 34 /L98H/S297T/F495I, and 1 TR 46 /Y121F/T289A). Voriconazole non-wild-type phenotypes were identified in 2.1% (3/158) of A. flavus isolates, including one carrying a novel P214L mutation (orthologous to A. fumigatus P216L). Members of the Aspergillus niger clade exhibited reduced susceptibility to itraconazole and isavuconazole. Anidulafungin, along with novel antifungals including orolofim, manogepix, and rezafungin, demonstrated broad activity across Aspergillus species, including those with intrinsic or acquired azole resistance. Ibrexafungerp also showed efficacy against azole-resistant A. fumigatus and A. flavus . In contrast, opelconazole exhibited limited activity against A. flavus , the A. niger clade, Aspergillus sydowii , and voriconazole-resistant A. fumigatus . These findings underscore the need for species-level identification, susceptibility testing of causative isolates, and continued surveillance to detect emerging resistance and support the use of novel non-azole antifungals for azole-resistant aspergillosis.

Timely and effective antifungal therapy is essential for aspergillosis. This multicenter surveillance study provides comprehensive insights into the species distribution and antifungal susceptibility of 550 clinical Aspergillus isolates in Taiwan, with intrinsic reduced susceptibility to amphotericin B, itraconazole, or isavuconazole noted in certain species. Regarding acquired resistance, a novel cyp51A mutation, P214L, was identified in an azole-resistant Aspergillus flavus , orthologous to Aspergillus fumigatus P216L. Recovery of azole-resistant A. fumigatus harboring TR34/L98H or TR46/Y121F/T289A mutations remains a concern and emphasizes the need for antifungal stewardship in the environment. Novel antifungals, including orolofim, manogepix, rezafungin, and ibrexafungerp, demonstrated broad activity across Aspergillus species, including resistant isolates. Nevertheless, the inhaled agent opelconazole exhibited limited activity against A. flavus regardless of voriconazole susceptibility and against other species showing reduced susceptibility to itraconazole. These findings highlight the importance of species-level identification, susceptibility testing, and continued surveillance and support the use of novel antifungals for aspergillosis.