The emergence of Candida auris, a recently known fungus causing fevers and illness, often resistant to medicine, raises red flags about the overuse of antibiotics making bacteria and fungi harder to kill and potentially deadly to humans. In early April, a New York Times investigation revealed that simultaneous infection outbreaks of C. auris in more than a dozen countries had been kept out of the public eye. Researchers are still unable to pin down its causes, linking C. auris’ unbreakability to antifungals’ abuse in healthcare and agriculture, the article shows.
Discovered in 2009 in the ear of an elderly Japanese woman, C. auris can wreak havoc among people with compromised immune systems; among infected patients, its ability to spread quickly through medical environments and its resilience to drugs used for treating common Candida yeasts―antifungals―caused death rates between 30-60 percent, according to the Center for Disease Control and Prevention (CDC).
This unresponsiveness to treatment, known as antimicrobial resistance (AMR), occurs when microorganisms suffer changes in order to go around the drugs meant to destroy them; in response to stress, they develop more resistant genes by natural selection and pass the trait to the next generation, which can be fully resistant. While AMR can occur naturally, microorganisms can also become resistant if overexposed to medication, in the case of C. auris, to antifungals.
In 2015, a European Union review on antimicrobial resistance stated that azoles, a particular class of fungicides, appeared to threaten people’s health by making them more resistant to antifungals used in medical care. Experts highlighted the example of the Netherlands, where tulip production relies heavily on azole-based fungicides, to point to an increasingly strong link between azoles’ use and high rates of antifungal resistance in humans.
Azoles help protect cereals, vegetables, fruits, and vineyards from diseases and also control mildews and rust; their multiple uses make them “indispensable for efficient and large-scale crop production,” says a study from researchers at the University of Porto.
Farmers favor azoles because they’re cheap, a review in the American Society of Microbiology shows. EU agriculture sprays them on half of the Union’s cereal crops and grapevine acreage, a 2015 study shows. By comparison, in the United States that happens annually on less than 5 percent of its total area, though there are no differences in resistance prevalence in people, according to the EU.
Although they sequenced C.auris’ genome, experts have not identified clear links between almost simultaneous outbreaks of multidrug-resistant C. auris in eastern and southern Asia, southern Africa, and South America. A CDC-led study asked earlier in 2019 whether food and environmental factors might be behind the highly resistant fungus.
“An animal or environmental reservoir for C. auris has not yet been identified,” the experts state. “However, closely related Candida species have been isolated from several animals, food, and environmental sources, including fish, cassava roots, and seawater.” In 2013, researchers linked resistance of another fungus, Aspergillus fumigatus, to high usage of fungicides across Dutch agriculture; but scientists still lack data to match fungicide use outside medical care to human resistance.
How much people are exposed to azoles in the environment might be a cause of AMR in humans. Azoles molecules are very stable, many studies point out, so they can stay for several months in soils and water, as well as in some fruits and vegetables. A review of azoles’ use in plant protection shows biological processes in soils, for example, take between 110-375 days to halve the amount of a primary product of triadimefon, an azole-based fungicide sprayed on barley, corn, cotton, oats, rye, sorghum, and wheat. The review further detects azole residues in foods such as strawberries, grapes or peppermint. But researchers are still investigating their toxicity and accumulation in the environment.
The way azoles work might also nurture resistant fungi, suggests a study from the University of Kansas-Missouri. As azoles do not kill fungal cells, but only inhibit growth, azoles’ prolonged use favors the selection of resistant strains, the researchers explain. And most fungicides target a single aspect in the fungus’ metabolism, the Pesticide Environmental Stewardship says―meaning one gene mutation is enough for the yeast to survive. The experts from the University of Porto warn that single-target fungicides―heavily used in the last few decades―can trigger resistance within the first few years of use and that antifungal mixtures and rotation of highly efficient products might help block resistance development.
More and more patients require antifungal-based treatments, but so do crops. Given the similarities between substances used, the EU recommends that “new classes of clinical antifungals developed in the future should be banned from use in food production.” But some scientists are looking at creating more efficient substances for both humans and food systems. A team of researchers led by the Centre for Research in Agricultural Genomics (CRAG) has developed a biotechnological tool that can harness plants to produce proteins with antifungal effect in humans and plants; this can pave the way to more alternative, sustainable, non-toxic antifungals.
Moving away from substances that might cause AMR yet remain critical to crop yields has yet to happen. “Countries should adopt targets for reducing antimicrobial resistance in animals and agriculture, at 50 mg of antibiotic/kilogram,” says Jim O’Neill, Chair of the Review on Antimicrobial Resistance.
Though not specific to antifungals, O’Neill says agriculture has made “reasonably encouraging progress” in tackling AMR since the 2015 review, as G20 countries plan to ban antibiotics stimulating animals’ growth and the EU is moving towards prohibiting so-called last-resort antibiotics in agriculture. “But perhaps most importantly, major Western food producers including some supermarkets, are starting to realize consumers want to eat things with less or no antibiotics. This is happening in the U.S. and the UK; it is a beginning and a long way to go, but it’s a start.”