PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

Antifungal resistance is occurring increasingly often in the most important human pathogenic fungi, such as Candida spp and Aspergillus fumigatus. Usually, resistance development in the fungus takes place inside patients during long periods of treatment or prophylaxis with antifungal drugs. However, drug-resistant fungi can also be isolated from naïve patients who have no previous history of antifungal treatment^1,2. This suggests that drug-resistant isolates can infect the patient before any treatment is applied. A possible explanation for this observation would be the transmission of a drug-resistant fungal isolate from one patient to another. However, it is very unlikely that fungi such as A. fumigatus, a filamentous fungus that causes a set of diseases called aspergillosis could be transmitted between patients. Instead, transmission occurs when the individual inhales asexual spores from the environment, and the fungus then grows inside the lungs. Thus, the question that remains is whether these fungi have become drug-resistant in the environment and what causes or selects for drug resistance?

Clearly, the use of fungicides and other pesticides is essential for the world’s food production. However, it is not plausible to justify maintaining food ‘quality’ and ‘productivity’ over human health.

Is resistance fungicide-driven?

Clinically relevant drug resistance in A. fumigatus to azoles, the first drug class of choice to treat aspergillosis, varies enormously when taking into consideration the location and type of patient from which the fungus was isolated³. However, as many as 30% of patients can have drug-resistant infections⁴. Of these drug-resistant isolates, it is estimated that only a third develop resistance within the host⁵, the others probably acquire it in the environment, before infection. A. fumigatus is easily found in decaying plant matter, and soils, where it grows saprophytically and plays an important global role in carbon and nitrogen recycling. It is also commonly isolated from agricultural environments and on plant-based agricultural products⁶. Therefore, it is possible that the fungus may come into contact with substances that are used to treat or prevent plant diseases, such as fungicides. This is particularly true for azoles, a group of fungicides that are vastly used in both agriculture and medical settings. Furthermore, some of the azole fungicides share chemical structural similarities to medical azoles⁷. Thus, when coming into contact with the fungicide, drug-resistant mutants can be selected, and the mechanisms can concomitantly confer drug resistance to antifungal azoles used to treat patients. Indeed, azole-resistant A. fumigatus from patients are also cross-resistant to environmental azoles (and vice versa)⁷, and exposure to environmental azoles may also select resistant variants with the same mutations as the drug-resistant isolates coming from patients⁸. Despite this, the literature has shown controversial results about the predominance of resistant A. fumigatus strains in azole-contaminated or fungicide-sprayed soil^9–11. This opposing data can be explained by the hypothesis that resistance does not arise in the soil by itself but instead, heaps of waste material gathered during crop cultivation may be a more likely environment for the emergence of azole resistance. A. fumigatus is very common in compost piles, decomposing plant material, and municipal waste treatment plants⁶. This would also explain why many authors have demonstrated the prevalence of drug-resistant strains in compost¹⁰ instead of farmable soil¹². Therefore, studies that failed to demonstrate the presence of resistant isolates in contaminated soils assumed that the soil is a hotspot for the emergence of resistance when, in fact, it may not play a major role.

The question that remains is whether these fungi have become drug-resistant in the environment and what causes or selects for drug resistance?

The problem with the development of drug resistance in the environment and consequent infection by such strains means that the tools used to prevent and control the emergence of drug-resistant strains in clinical practice, such as the rational use of drugs, may not control resistance. Thus, other approaches, such as infection prevention and control strategies, need to be used in order to avoid such a problem.

A One Health approach is the solution

The One Health Commission defines¹³ One Health as: “a collaborative, multisectoral, and trans-disciplinary approach – working at local, regional, national, and global levels – to achieve optimal health and well-being outcomes recognizing the interconnections between people, animals, plants and their shared environment.” A One Health approach is recognised as being part of resolving the problem of antibiotic resistance transmission from animals to humans, where the use of these drugs as growth promoters for animals has been perceived as a source of drug-resistant bacteria. Thus, there is a great international effort and pressure for the rational use of antibiotics in animal medicine and restriction of their use as growth promoters. Antifungal resistance should also be viewed from the One Health perspective, since the origin of this problem may lie beyond the hospital, in the environment. Clearly, the use of fungicides and other pesticides is essential for the world’s food production. However, it is not plausible to justify maintaining food ‘quality’ and ‘productivity’ over human health. Therefore, discussions about the rational use of fungicides that have been proven to select for drug resistance to clinically useful drugs for human infections must be urgently conducted.

References

1. Verweij PE, Mellado E, Melchers WJG (2007) Multiple-Triazole–Resistant Aspergillosis. New England Journal of Medicine. 356(14):1481-3
2. Mellado E, Garcia-Effron G, Alcázar-Fuoli L, Melchers WJG, Verweij PE, Cuenca-Estrella M, et al. (2007) A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrobial Agents and Chemotherapy.51(6):1897–904
3. Sharpe AR, Lagrou K, Meis JF, Chowdhary A, Lockhart SR, Verweij PE (2018) Triazole resistance surveillance in Aspergillus fumigatus. Medical Mycology. 56(suppl_1):83-92
4. Van der Linden JWM, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, et al. (2015) Prospective Multicenter International Surveillance of Azole Resistance in Aspergillus fumigatus. Emerging Infectious Diseases. 21(6) 1041-1044
5. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, et al. (2009) Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerging Infectious Diseases. 15(7):1068–76
6. Burks C, Darby A, Londoño LG, Momany M, Brewer MT. (2021) Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance. PLoS Pathogens. 17(7):e1009711
7. Snelders E, Camps SMT, Karawajczyk A, Schaftenaar G, Kema GHJ, van der Lee HA, et al. (2012) Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS ONE.7(3)
8. Ren J, Jin X, Zhang Q, Zheng Y, Lin D, Yu Y. (2017) Fungicides induced triazoleresistance in Aspergillus fumigatus associated with mutations of TR46/Y121F/T289A and its appearance in agricultural fields. Journal of Hazardous Materials.326:54–60
9. Barber AE, Riedel J, Sae-Ong T, Kang K, Brabetz W, Panagiotou G, et al. (2020) Effects of Agricultural Fungicide Use on Aspergillus fumigatus Abundance, Antifungal Susceptibility, and Population Structure. mBio. 11(6)
10. Zhang J, Snelders E, Zwaan BJ, Schoustra SE, Meis JF, van Dijk K, et al. (2017) A novel environmental azole resistance mutation in Aspergillus fumigatus and a possible role of sexual reproduction in its emergence. mBio. 8(3)
11. Alvarez-Moreno C, Lavergne RA, Hagen F, Morio F, Meis JF, le Pape P. (2017) Azole-resistant Aspergillus fumigatus harboring TR 34 /L98H, TR 46 /Y121F/T289A and TR 53 mutations related to flower fields in Colombia. Scientific Reports. 7:45631
12. Fraaije B, Atkins S, Hanley S, Macdonald A, Lucas J. (2020) The Multi-Fungicide Resistance Status of Aspergillus fumigatus Populations in Arable Soils and the Wider European Environment. Frontiers in Microbiology. 11:599233
13. One Heatlh Comission. (2021). What is One Health?