A woman puts on her gardening gloves and plunges her spade into the earth. As she digs and plants all afternoon, thousands of microscopic fungal spores are released from the soil and enter the air, where they enter her body through her nose and mouth and try to colonize her organs. If the spores succeed, an infection will take hold in her lungs. Depending on the woman’s health, she may have a 25% to 90% chance of dying.
This isn’t science fiction; this is normal life for every human being on earth. Scientists estimate we inhale between one and 10 spores with every breath. Luckily for most of us, our immune system makes quick work of the spores, neutralizing threats, and inhibiting the growth of dangerous fungus in our nasal passages and lungs.
But not everyone has a healthy immune system. If those spores do take hold, there are only 10 medicines that doctors can use to fight fungal infections, and not all of them are safe or appropriate for every case. And now, scientists around the world are sounding the alarm that five of those medicines — the first-line drug treatment for fungal infections — have stopped working for some of the most serious infections.
Discovering the source of these new drug-resistant fungi has become a global effort that could potentially implicate chemicals used by nearly every farmer on earth.
Spores are everywhere
Spores pose a serious threat to people with suppressed immune systems, like those who are organ transplant recipients, or who have diabetes, HIV, or cancer. In the U.S. alone, an estimated 10 million people are immunocompromised. And a common fungus called Aspergillus fumigatus can take root in the lungs of immunocompromised people and begin to grow, causing chest pain, shortness of breath, fever, coughing, and other respiratory symptoms. This condition, called invasive aspergillosis, was behind an estimated 15,000 hospitalizations in the U.S. in 2014 and cost the health care system $1.2 billion.
A small 2009 study, which elicited public interest after a feature story in the Atlantic, suggested that some hospital patients in the Netherlands were coming down with aspergillosis infections that were already resistant to antifungal medications. But this isn’t how drug resistance is supposed to work.
Usually, resistance develops in patients who have been taking the same medication for a long time. It can develop a few different ways. Sometimes a drug wipes out every microbe except for the fungus that is naturally resistant to the drug, which now has more room to reproduce without all that competition around. Or maybe constant exposure to a certain chemical can induce an evolutionary change in a microbe’s genome, allowing it to outwit the medication.
But the patients in the Netherlands had never taken antifungal drugs before, and yet their infections were already resistant to the medications doctors were trying. This meant that the fungus that infected these patients most likely didn’t become drug-resistant in the patients’ bodies. It had become drug-resistant after being exposed to the drug in a different way — likely via a fungicide spray. Then the fungi had traveled to the hospital grounds via soil, plants, seeds, or other gardening products, where patients unknowingly ended up inhaling its spores.
Since this discovery, drug-resistant isolates of A. fumigatus have also been found in the U.S., France, China, the U.K., Turkey, Japan, Belgium, Germany, Denmark, India, Spain, Iran, Taiwan, and Tanzania.
An emerging hypothesis
Fungal scientists theorize that agricultural fungicides known as azoles, which contain the same active ingredients as the antifungals used on human beings, maybe behind growing drug resistance.
Along with the Netherlands case, a small but growing body of global research has shown that fields that had been sprayed with azole fungicides harbored drug-resistant A. fumigatus while untreated soil did not. And in 2017, scientists for the first time found drug-resistant A. fumigatus in the U.S., in a peanut field that had been treated with azole fungicides.
While there is no conclusive, overwhelming evidence demonstrating a causal link between fungicide use and drug-resistant fungi just yet, Graham Atherton, a fungal disease researcher with the National Aspergillosis Centre in the U.K., says “Science always needs further studies. It is true to say that this is supposition at this point as we are talking about maybe 10 relatively small papers at most, however, the evidence is building up quite quickly.”
Indeed, a recent 2019 report published in the Centers for Disease Control’s Emerging Infectious Diseases journal demonstrates just how fast knowledge of this problem is evolving. Those same Netherlands researchers who initially discovered the link between fungicides and drug-resistant fungal infections continued their research, and found “hot spots” — places where the fungicide-resistant A. fumigatus is most likely to grow — in flower bulb waste, household fruit, vegetable waste, and wood chippings. These resistant fungi had the same genetic markers as fungi samples taken from patients with drug-resistant fungal infections, confirming what researchers already suspected about the way patients were contracting this illness.
But interestingly, the researchers also found that resistant fungi had only proliferated in these three places (flower bulb waste, household green waste, and wood chippings), even though many other samples they had taken (from grain, animal manure, maize, and fruit waste) had also been sprayed with azole fungicides. This suggests that it could be the way decaying plant materials are stored and composted that could be causing resistance in A. fumigatus — not necessarily just exposure to fungicides in and of themselves.
The challenges facing hospitals
As researchers get to the bottom of exactly how agricultural use may be contributing to drug-resistant fungal infections, these infections are a new and growing global threat that hospitals aren’t prepared to deal with.
Some forms of aspergillosis are mild and trigger things like allergic, asthmatic reactions to the fungus. But people with invasive aspergillosis present with respiratory symptoms that could be caused by any number of pathogens, which is why “susceptibility testing” (taking a sample of their sputum and culturing it in a petri dish) is crucial when it comes to diagnosis and treatment. Once lab workers can identify a fungus in the culture and test it to see if it’s susceptible to medications, doctors know which drugs to prescribe for patients.
Drug-resistant fungal infections are a new and growing global threat that hospitals aren’t prepared to deal with.
This week-long process is extremely delicate and time-consuming, especially for hospitals in developing countries, says Anuradha Chowdhary, a professor and clinical microbiologist at the Vallabhbhai Patel Chest Institute in Delhi, India.
There are only five azole-based antifungal medications. The medications are cheap, can be taken orally, and are the best and first line of defense for patients with fungal infections. Once those are redundant, doctors have to use more toxic and expensive types of drugs, like Amphotericin B or echinocandins, both of which need to be administered via intravenous infusion, Chowdhary explains.
Chowdhary regularly receives specimens for culture from patients with respiratory symptoms from rural areas. These patients may be uniquely susceptible to acquiring drug-resistant fungal infections because of their agricultural work. At the same time, they cannot afford to take antifungal medications, either because of cost or because of the medication’s side effects.
What’s more, many medical labs in developing countries aren’t set up to do susceptibility testing, Chowdhary says. Clinicians may not even bother requesting such tests and instead just begin treating patients with antibiotics, which only kill bacteria and not fungi. Fungal and bacterial infections often present with the same exact symptoms, and doctors can easily miss a fungal infection diagnosis without testing the patient’s specimens.
“You are dealing with a bug where detection is not done regularly in many laboratories,” she says. “And secondly, you do not have excellent alternatives, so it really increases the mortality of the patients.”
Infections with Candida auris, another drug-resistant fungus, number just 654 in the U.S. But they’re just as alarming because they are sometimes resistant to all classes of antifungal drugs, not just one. If C. auris has made it to the bloodstream, the patient suffers from fever and chills. However, it’s difficult to identify because people with the infection are usually already sick and hospitalized with a different condition. Like A. fumigatus, diagnosis is only possible with a lab test.
A New York Times article published last month explains that C. auris bedevils hospital sanitation efforts because it remains alive on surfaces even after these surfaces undergo the most extreme cleaning and renovation protocols. One hospital president in New York even described the need to rip out floor and ceiling tiles to finally eradicate C. auris from a deceased patient’s room.
Some of the scientists in the article believe that the overuse of agricultural fungicides is the probable cause for the proliferation of C. auris, too. However, there is still no clear-cut scientific evidence for this. According to the CDC, multiple cases of C. auris have also been reported in Australia, Canada, China, Colombia, France, Germany, India, Israel, Japan, Kenya, Kuwait, Oman, Pakistan, Panama, Russia, Saudi Arabia, Singapore, South Africa, South Korea, Spain, the U.K., and Venezuela.
Farmers and fungicides
If the link between agricultural fungicide use and drug-resistant fungal infections becomes firmly established, farmers in the U.S. and elsewhere worry that potential regulation may take azole fungicides away from them, devastating their harvests.
It’s almost impossible to overstate how crucial fungicides, especially azole fungicides, are to modern-day agriculture. Introduced in the 1970s, azoles now make up about one-third of all agricultural fungicides used around the world. Unlike other fungicides, azoles can both prevent and treat fungal diseases in plants. They can remain “active” in the soil and water for months, reducing the need for repeated spraying. They’re also less toxic than other fungicides, which is healthier for both the farmers and the consumers who eventually buy the food, explains Marin Talbot Brewer, a plant pathologist with the University of Georgia who studies fungicide resistance in plant pathogens.
“Farmers and other researchers that work on plant pathogens are afraid,” says Brewer. “They don’t want [azoles] to be taken away from use because they are helpful.”
Azoles are sprayed on grains, fruits, vegetables, and flowers to prevent diseases from destroying crops. Manufacturers also use azoles to inhibit fungal growth in residential products like wallpaper paste, mattresses, and paint.
In short, they’re everywhere. And in the U.S., where less than 2% of the population is tasked with growing food for the rest of the country, modern agriculture simply wouldn’t be possible without azoles, says Michelle Moyer, a viticulturist and associate professor at Washington State University. There are ways to prevent fungal disease from setting in without azoles, but they’re time-consuming and labor-intensive, she explains. These cultural practices might include more tilling in the field, or something called “canopy management” — when laborers painstakingly snip away the highest leaves of a plant to let more sun in, creating a drier and more hostile environment for fungi.
“Over the years, as we’ve gotten fewer and fewer people working in agriculture, farmers have had to rely more on the chemical approach,” she says. This is because it costs too much to hire extra laborers to tend to crops by hand or by machines that can get the job done. “If people want to pay $2.99 for their apples, this means that there are not a lot of human hands touching those apples.”
Even with azoles at farmers’ disposal, fungal diseases still destroy at least 125 million tons of rice, wheat, maize, potatoes, and soybeans every year. More than 600 million people could have been fed with the lost crops, estimate scientists from Oxford and Imperial College London. Another analysis by the same scientists at Imperial College London estimates that about 20% of all crops are lost to fungal disease, with an additional 10% lost to fungal disease after the harvest.
Moyer doesn’t believe that the world would suffer catastrophic food chain failure if azoles were no longer in the picture. Food, however, could become much more expensive, putting fresh fruits and vegetables out of reach of the poorest consumers if nothing else changes.
“We’d have to adopt more cultural practices, which will require more people for labor, mechanical techniques which might not be cost-effective yet for smaller growers, or other types of alternative or softer chemicals,” she says. “Initially, most alternative approaches effectively raise the cost of actually producing that product.”
Even doctors who are convinced about the link between agricultural fungicide overuse and drug-resistant fungal infections are skeptical that farmers will be able to scale down their use of fungicides right away.
Chowdhary, the clinical microbiologist from Delhi, is one of those doctors. She recognizes how crucial the chemicals are when it comes to feeding the world. “At present, the most important thing is that you cannot stop using these fungicides because of the loss of the crops,” she said. “So slowly and gradually, we have to move and shift to alternatives and other kinds of methods where fungicides are not used specifically in such a huge proportion.”
How to combat an airborne pathogen
Fungi researchers say that we need a multipronged approach to address growing antifungal resistance. In addition to reducing fungicide use on farms, scientists need to develop new classes of antifungal drugs, and we need to raise more awareness among immunocompromised people, says Atherton, the Aspergillosis researcher from the U.K. “We are already at the stage where we feel it is prudent to start issuing warnings to vulnerable patients when handling vegetables and when working in the garden as a precaution.”
But perhaps one of the most frightening things about drug-resistant fungi is that there isn’t much you can do to protect yourself from inhaling spores. Additionally, some people may be immunocompromised and not know it.
In recognition of the growing threat, hospitals are beginning to ban flower gifts for patients and insulate the most vulnerable from inhaling any dust that might be in the air from construction projects on the grounds. But aside from donning a surgical mask at all times, there’s no practical way for the immunocompromised to breathe more safely.
When scientists began demonstrating a causal link between antibiotic use in livestock to antibiotic resistance in human beings, the Food and Drug Administration responded by issuing new regulations banning farmers from using clinical antibiotics simply to make their animals grow bigger, faster. After the guidance was first published in 2013, it took four years for the industry to completely transition away from using antibiotics to promote livestock growth.
Before similar regulations can reform the way farmers use fungicides, scientists are going to have to learn a lot more about the mechanisms behind the evolution of fungi, and whether other misuses of fungicide may also be contributing to the problem, says Moyer.
Just as uninformed patients misuse antibiotics by requesting them without evidence of a bacterial infection, or by not following their doctor’s prescription instructions, consumers might also be misusing over-the-counter antifungals to breed resistance in fungi.
“There are a lot of fungicides that are used every day without any kind of regulation or control, like athlete’s foot spray,” Moyer says. “Most people don’t realize you can only use it for a few days before you should stop using it and seek alternative treatment.”
Brewer, the plant pathologist from Georgia, is on the forefront of learning more about fungicide resistance in the U.S. One of just a handful of researchers on the agricultural side of the equation in the United States, she is carrying out the work scientists in the Netherlands started for U.S. farms. Her research takes her to watermelon, peanut, pecan, strawberry, tomato, and grape orchards in Georgia, Florida, and South Carolina to see if she can find drug-resistant fungi. Scientists have also sent her soil samples from farms in New York, Pennsylvania, and Washington.
A farm in Oregon operated by conscientious and up-to-date owners also sent Brewer some samples, which are currently being analyzed. They wanted to open up their farm to invite the public to spend time on their grounds, but had been unsettled by the news reports linking agricultural fungicide to drug-resistant bugs.
“They just want to know if there is any risk,” Brewer says. “They don’t want people to get sick by coming into their farm.”