From crops to clinic: the impact of dual azole use on antifungal resistance in Candida and Candida associated yeasts

Abstract

Invasive fungal infections caused by pathogenic yeasts are an escalating global health crisis that demands urgent attention within a One Health framework. This review critically examines mounting evidence that widespread agricultural azole fungicide use is a key driver accelerating antifungal resistance in pathogenic yeast. We dissect the shared molecular targets and resistance pathways that underpin dangerous cross-resistance between environmental fungicides and clinical azoles. Traditionally viewed as human commensals, we provide a comprehensive account of the evidenced environmental reservoirs of yeast pathogens, including agricultural soils, wastewater, and the food chain. Ecosystems burdened by persistent azole contamination that create hotspots for resistance evolution and amplification. With antifungal treatment options rapidly diminishing and resistant infections causing rising morbidity and mortality worldwide, we identify vulnerabilities in our shared environment and consider integrated surveillance, stewardship, and environmental interventions to help preserve the efficacy of life-saving antifungals and mitigate the growing threat of fungal disease.

Keywords: Candida; antifungal resistance; azoles; cross-resistance; one health.

Figure 1

Chemical structures of short-tailed (fluconazole, voriconazole, propiconazole, and tebuconazole), and long-tailed (itraconazole, posaconazole, difenoconazole, and prochloraz) ergosterol biosynthesis inhibitors. The common structure is highlighted by a yellow box, featuring a nitrogen-containing ring with two adjacent CH or N ring members. *imidazole-based DMIs, ^†fungicides which are classified as long-tailed based on potency, not length.

Figure 2

Resistance profiles in fungal pathogens. The image illustrates the potential resistance profiles of pathogenic yeast to antifungal drugs.

Figure 3

One Health perspective of Candida azole resistance. This diagram illustrates the non-clinical reservoirs of Candida species, the environmental contamination of clinical azoles and DMIs, as well as the potential routes of transmission of cross-resistant strains (Figure generated using Biorender.com).