Wastewater in Asia as an evolutionary reactor: Linking environmental azoles to the emergence of clinical resistance

Antifungal resistance (AFR) has been recognised as a global health priority, with Asia reasonably identified as a critical epicentre. Several converging factors, including intensive agricultural fungicide use, inadequate wastewater infrastructure, high population density, a large burden of chronic respiratory diseases, and growing immunocompromised populations, facilitate conditions conducive to AFR emergence. This comprehensive review synthesises current evidence on environmental drivers of AFR across Asia, examining major pathways through which azole antifungals enter water resources. Wastewater treatment plants may function as evolutionary reactors where azole residues select for resistant fungal pathogens; however, direct evidence for this pathway remains limited, necessitating further empirical investigation. Molecular mechanisms of azole AFR are dominated by TR₃₄/L98H and TR₄₆/Y121F/T289A mutations in Aspergillus fumigatus and efflux pump overexpression in Candida spp. Extreme environmental contamination has been reported, with fluconazole reaching 236,950 µg/L in Indian industrial effluent, exceeding the Predicted No Effect Concentration (PNEC) thresholds by over 74,000-fold. Primary dissemination pathways, which include agricultural runoff, wastewater effluent, biosolid application, and oceanic current-mediated transboundary transport across the Bay of Bengal, are elucidated within a One Health framework. Despite the huge risk, current regulatory frameworks in many Asian countries do not consider AFR selection as an endpoint in environmental risk assessments. As a result, critical research gaps include prioritising minimal selective concentration data for Asian-relevant antifungals and enhanced water quality surveillance. We recommend that policy recommendations should be formulated to integrate AFR selection endpoints into water quality regulatory frameworks.