Farming and human medicine initially seem to have as much in common as air conditioning in Antarctica.

Yet, there’s an unsettling link between triazole fungicides that farmers use to manage crop diseases and resistance to azole drugs that physicians use to treat human fungal diseases. Due to similar chemical structures, scientists find azole-resistant fungi can leap from agricultural settings into medical ones.

The link

If human “azole” drugs sound familiar, it’s because they are akin to triazole fungicides.

“They are in a similar class and have a similar mechanism of action,” says Kathryn Dalton, an assistant professor in the University of Iowa College of Public Health.

“If the fungus develops resistance to tebuconazole [fungicide], it can be cross-resistant to the azole drug voriconazole,” says Marin Brewer, a University of Georgia plant pathologist. “What’s really scary is that if patients have invasive Aspergillus [fumigatus] that is azole-resistant, mortality [from resulting lung infections] is very high. It’s almost 100%.”

As a result, federal regulators are starting to evaluate the relationship between triazole fungicides and azole antifungal drugs.

“Azoles are commonly used in human medicine as a first line of treatment against fungal infections,” Dalton says. “There are few fungal medications in human health, so it’s important to protect and preserve the ones that we do have. That is why we are so concerned about the use of triazole fungicides in agriculture.”

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What triazole fungicides do

“Triazole fungicides are the backbone of many fungicide products,” says Carl Bradley, a University of Kentucky Extension plant pathologist. If a product label lists a FRAC Group 3 component, it contains a triazole fungicide. Such active ingredients include propiconazole, metconazole or tebuconazole. Companies include triazoles in branded products such as:

Depending on the label, farmers apply fungicides to control or suppress corn diseases such as tar spot and soybean diseases that include frogeye leaf spot. Triazoles also help farmers manage mycotoxins, such as deoxynivalenol (DON) fungi that cause Fusarium head blight in wheat.

“Levels of DON and some of the other mycotoxins produced by these fungi are regulated by the [Food and Drug Administration] to protect human and livestock health,” Bradley says. “Without triazole fungicides, food safety becomes a big concern.”

The medical arena

Farming isn’t the only place where this chemistry shines. A. fumigatus fungi thrive in environments such as compost and crop debris that warm due to microbial activity. These fungi find a similar warm home inside human bodies when people breathe in the infectious spores. A. fumigatus annually causes 300,000 life-threatening infections in susceptible humans, according to a February 2022 article in the scientific journal G3. 

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Fortunately, physicians use azole drugs to treat these infections. However, the U.S. Centers for Disease Control and Prevention in 2019 estimated that 18 superbugs — both drug-resistant fungi and bacteria —annually cause at least 2.8 million drug-resistant infections in the U.S., spurring more than 35,000 deaths.

“What we’re finding is that A. fumigatus is already resistant to azoles used in patients who have never been treated with azole drugs,” Brewer says. “These types of mutations [that spur azole resistance] are called pan-azole-resistant, meaning [A. fumigatus fungi] are cross-resistant to many types of azole drugs.”

European exposure

Cross-resistance first surfaced in Europe. An analysis of 52 published scientific journal articles by Caroline Burks, a UGA plant pathology graduate student, showed cross-resistance often appeared around European hospitals.

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“There was a connection between the application of agricultural fungicides inadvertently selecting for azole-resistant fungi [A. fumigatus] in soil and plant debris,” says Steve Harris, an Iowa State University fungal biologist. “As the fungi sporulated, people breathed in the spores, got sick and went to the hospital, where they were treated with azole antifungals. They didn’t respond because [the fungi] was already resistant through previous exposure to the [triazole] fungicide application.”

By finding a specific genetic signature, scientists were able to link fungal resistance to triazole fungicides used in flower beds surrounding the hospitals.

This cross-resistance wasn’t just limited to hospitals. Burks’ analysis also showed 35% of azole-resistant fungi developed from agricultural settings, with most being flower farms.

“In general, farmers in western Europe apply a lot of fungicides on horticultural crops and small grains,” Harris says. “There are a lot of inadvertent exposures because fungicides are applied more frequently.”

The U.S. scene

This raised concerns about whether a similar pattern was occurring in the U.S.

In 2017 and 2018, UGA researchers collected about 700 A. fumigatus isolates from 50 Georgia and Florida sites containing soil and plant debris from peanuts and fruits. In 2018 and 2019, they gathered 727 A. fumigatus isolates from 52 East and West Coast sites in soil and plant debris where farmers grew flowers, wheat, peanuts, corn, soybeans, herbs, brassicas and fruits. They screened 350 of the isolates for resistance to both tebuconazole fungicide and azole antifungal drugs.

The good news is UGA researchers found a minority of isolates were cross-resistant. They found 12 of the isolates in Georgia and Florida compost and pecan debris sites resisted both triazole fungicides and antifungal drugs. Only 20 cross-resistant isolates occurred in the East and West Coast areas.

“Hot spots seem to be flower gardens and flower farms and in retail compost and retail flower beds,” Brewer says. “We found that a lot of retail products, such as lawn products and compost, had a lot of [triazole and azole]-resistant Aspergillus fumigatus.”

ISU scientists have found little evidence of triazole-resistant A. fumigatus in field surveys. They sampled soil and residue from corn and soybean fields where farmers applied triazole fungicides and where they had not. Sampling for triazole-resistant A. fumigatus also included hay and silage fields and in animals tested at the ISU veterinary diagnostic laboratory.

“We tested several hundred samples, and level of resistance is low — 0.1% to 0.2%,” Harris says.

Still, farmers shouldn’t let down their guard.

“We see certain hints of azole resistance in some fungi to a higher degree than what we see with Aspergillis [fumigatus], but they are not yet clinically common,” Harris says. “It's inevitable that at some point we will see a greater frequency of these resistant fungi here.”

For now, individuals who work around hay and silage are most at risk of illness, Harris says. He advises farmers who work around hay and silage in enclosed areas to wear N95 masks.

“You don’t want to inhale clouds of spores and be subject to fungal diseases like farmer’s lung,” he says.

What’s next

These developments have garnered the attention of the Environmental Protection Agency. In October, the EPA finalized its framework to expand federal collaboration for a review of both antibacterial and antifungal pesticides.

“It will develop a working group [of various government agencies] that will put together a risk assessment that can help address needs with regard to regulation and future research priorities,” Dalton says.

For now, no move exists to ban or further regulate the use of triazole fungicides.

“We need these [triazole fungicides] to produce food,” Brewer says. “They’re effective, inexpensive and broad spectrum against a lot of different plant pathogenic fungi.”

She adds another benefit to triazoles is that fungi don’t resist them as quickly as they do other fungicide classes, such as strobilurins.

Brian Lill, a Le Mars, Iowa, farmer, agrees.

“[A curtailment or ban] would have a pretty drastic effect, that’s for sure,” he says. “I run trials, and every year, fungicide pays. In a 2023 trial, I ran short [of fungicide], so that served as my check strip. It was a day-and-night difference between where I applied the fungicide and where I didn’t.”

Dalton concurs.

“These pesticides are very important not just for the farmers who use them to produce reliable and productive crops, but also for our overall food system,” she adds. “But we also know that these fungal organisms can be harmful to people as well. It’s important to control fungal infections in crops, but it needs to be done in a cognizant way to help minimize the risk of these organisms developing resistance [to azole drugs].”

Editor’s note: Companies that market triazole fungicides including BASF, Bayer, Corteva, FMC, Syngenta and UPL and the industry trade group CropLife America did not provide comment upon requests made by Wallaces Farmer for this story.