Emergence of azole resistant Aspergillus fumigatus and One Health: time to implement environmental stewardship

Abstract

At present, the treatment of mycotic infections is becoming increasingly complicated because fungi are developing resistance to antifungal agents worldwide (Chowdhary et al., 2017; Perlin et al., 2017). Although originally considered only a problem of human health, containment of emerging antifungal resistance requires a multisectorial approach involving experts in human, animal and environmental health. Emergence of resistance towards the azoles, which are critically important for human therapy, are the most worrisome (Chowdhary et al., 2013). The study from Taiwan by Wang and colleagues, published in Environmental Microbiology, reports results of a nationwide surveillance of azole resistance of the human pathogenic fungus Aspergillus fumigatus in the environment. In addition, in this study, the authors included clinical isolates with azole resistance (Wu et al., 2015) from Taiwan. The findings were compared to and explained by an increasing azole fungicide use in agriculture in Taiwan. Even though most of the available fungicide compounds are exclusively designed for agricultural use (Brent and Hollomon, 2007), several belong to the same structural class as those used in human medicine with identical or very similar structures. These fungicides, with a similar structure as human azole antifungals, such as propiconazole, difenoconazole (in use since 1987 and 1993 respectively) and tebuconazole, bromuconazole and epoxiconazole (used since 1999) are particularly implicated in selection of azole resistance in A. fumigatus (Snelders et al., 2009; Verweij et al., 2009; Chowdhary et al., 2012; Alvarez‐Moreno et al., 2017;) and their usage coincide with the emerging increase of clinical azole resistant A. fumigatus (Meis et al., 2016). The above‐mentioned five azole fungicides from the triazole class are highly active against wild‐type A. fumigatus, but show no activity against resistant isolates with TR34/L98H mutations (Chowdhary et al., 2012). The study by Wang and colleagues (2018) demonstrates that A. fumigatus exhibit resistance to azole fungicides and cross‐resistance to medical azoles in the environment of Taiwan and the study reinforces much needed attention to the ‘One health approach in antimicrobial resistance (AMR)’ regarding antifungal drugs. It clearly shows that agricultural AMR, a largely neglected area, is the missing one third niche in the ‘One Health concept’, next to human AMR and veterinary AMR. Fungicides are an essential component in the armamentarium against fungal plant diseases with sterol demethylation inhibitor (DMI) compounds, such as triazoles and imidazoles, representing a large class of fungicides that are used in agriculture. These compounds are widely deployed for crop protection with, for instance, over 250 000 kg being used to protect UK crops each year and the global usage being in the thousands of tonnes (Kleinkauf et al., 2013). However, the dual‐use of DMIs in both clinical and agricultural settings will come at a considerable human cost as in recent years' multiazole resistance in fungi that infect humans has been observed as a widely emerging phenomenon across the globe.