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In the intensive care ward of Radboud University Medical Center, a sprawling hospital in the southeastern Netherlands, Paul Verweij was worried. The physician-scientist was accustomed to dealing with very sick patients; as chair of medical microbiology, his job was to identify dire pathogens so the right treatments could be prescribed.
One group of patients had the kind of grave illnesses that are frequent in an ICU: blood cancers, immune disorders, end-stage lung disease. But layered on top of those, they all were suffering from a fast-growing, life-threatening invasion of an environmental fungus called Aspergillus fumigatus. In the past, a class of drugs called azoles had reliably cured Aspergillus, but these fungal infections were strangely drug-resistant. Five out of every six patients were dying.
Those deaths were tragic, but they were also odd. It’s common for organisms to become resistant to drugs that a patient has taken for a long time. But these patients hadn’t been prescribed azoles; the fungus was already resistant when it infected them. In his lab, Verweij could see an explanation: Their Aspergillus had novel mutations, ones he’d never seen in decades as a microbiologist. With the help of the Dutch public health system, he looked beyond his own hospital—and discovered an identical pattern in deathly ill patients nationwide, an unrecognized outbreak scattered across a dozen ICUs.
Verweij realized that no single hospital could be the source. There had to be something outside the medical system, something present throughout the Netherlands and exerting as much mutational pressure as a prescription drug would. With the help of other investigators, he identified it: a class of agricultural chemicals, functionally identical to azole drugs, that are critical for food and flower growing. Famous for tulips, the Netherlands is the world’s leading producer of flowers. While protecting their plants from diseases, Dutch farmers had unknowingly endangered their neighbors’ health.
“We created a niche,” Verweij says, “where these super-resistant bugs can emerge.”
That realization happened more than a decade ago, an episode well known in a narrow slice of medicine but little reported outside it. Since then, that pattern of resistance has spread to more than 40 countries, including the United States and the United Kingdom; three out of five patients who contract azole-resistant Aspergillus die from it. Disease specialists and plant pathologists hoped that the parallel development of azoles in medicine and agriculture had been a one-time thing. If they kept an eye on each other’s research, they felt, surely this would not happen again.
Except it has. Experts now fear that medicine may be at risk of losing a critically needed new drug because agricultural chemistry has once again deployed a similar compound first.
The looming conflict arises from the emergence of two compounds, one pharmaceutical and one agricultural, that share a novel mechanism for killing fungi: a drug, olorofim, that is moving through human clinical trials, and a fungicide, ipflufenoquin (trade name Kinoprol), that was registered by the US Environmental Protection Agency last year. Ipflufenoquin, made by Nisso America, is intended to combat diseases of important tree crops, including almonds, apples, and pears. Olorofim, developed by the British firm F2G, is a desperately needed new treatment for Aspergillus and valley fever, which affects up to 150,000 people in the US each year—and occurs most densely in the part of California where most almonds are grown.
