Understanding the clinical and environmental drivers of antifungal resistance in the One Health context

Abstract

Antifungal drugs have had a tremendous impact on human health and the yields of crops. However, in recent years, due to usage both in a health setting and in agriculture, there has been a rapid emergence of antifungal drug resistance that has outpaced novel compound discovery. It is now globally recognized that new strategies to tackle fungal infection are urgently needed, with such approaches requiring the cooperation of both sectors and the development of robust antifungal stewardship rationales. In this review, we examine the current antifungal regimes in clinical and agricultural settings, focusing on two pathogens of importance, Candida auris and Aspergillus fumigatus, examining their drivers of antifungal resistance, the impact of dual-use azoles and the impact agricultural practices have on driving the emergence of resistance. Finally, we postulate that a One Health approach could offer a viable alternative to prolonging the efficacy of current antifungal agents.

Keywords: AFR; AMR; Aspergillus; Candida; One Health; azoles; resistance.

Fig. 1.. Antifungal drug development and resistance emergence timeline, separating antifungals into clinical or agricultural use. Coloured points refer to their antifungal drug class: polyenes (red), pyrimidine analogues (blue), azoles (green), echinocandins (yellow), quinolines (pink) and orotomides (orange). Dashed lines refer to the first reported case of resistance to the drug class either in the clinical or agricultural settings [199202]. Point borders refer to drug development status: approved/in use (full/closed) and in development (dotted/broken). AMB, amphotericin B; BDZ, benzimidazole; 5-FC, 5-flucytosine; MCZ, miconazole; TMF, triadimefon; TMN, triadimenol; CLZ, clotrimaconazole; PPZ, propiconazole (expired regulatory status); HXZ, hexaconazole (expired regulatory status); TBZ, tebuconazole; DFZ, difenoconazole; FLC, fluconazole; ITC, itraconazole; EPZ, epoxiconazole; MTZ, metconazole; CSF, caspofungin; VOR, voriconazole; PRO, prothioconazole; MCF, micafungin; POS, posaconazole; ANF, anidulafungin; ISV, isavuconazole; MFT, mefentrifluconazole; IFQ, ipflufenoquin; OLF, olorofim. Created with BioRender.com.

Fig. 2.. The One Health drivers of AFR. Drivers in solid blue represent clinical drivers of resistance alone. Indwelling medical devices allow for increased biofilm formation, which is associated with resistant and recurrent infections. Increasing immunosuppression due to medical advances increases the population of individuals at risk of a fungal infection. Additionally, their impaired immune system can result in prolonged infection and, therefore, long-course treatment, which creates strong selection pressures for resistance. Drivers of environmental resistance alone are represented in solid green. Wastewater treatment plants (WWTPs) often cannot efficiently clear antifungals from water due to long antifungal half-lives; this introduces antifungal residues into the environment, which creates an indirect selection pressure. Agricultural practices such as monocultures, composting, sludge application, etc. are all practices that increase the selection pressure for AFR. Drivers of AFR in both the clinic and environment are represented in half-blue and half-green. These include dual antifungal use in the clinic and environment (causing increased selection pressures), climate change (increasing fungal thermotolerance), increased globalization (introduction of pathogens to novel environments), overuse of antifungals (increased selection pressures) and lack of rapid diagnostics (delays in selection of effective treatment). The five main strategies to tackle increasing AFR, as proposed by this review, are represented in the larger circles on the outermost edges of the figure. These strategies include increased AFS (in purple), development of novel therapeutics (in pink), improved diagnostics (in orange), increased surveillance (in teal) and integrated disease management (in red). Colour-coordinated arrows indicate which main strategies we propose could decrease the contribution of a particular driver to increasing AFR. Created with BioRender.com.