High time to tackle drug-resistant fungal infections

Candida auris is a frightening yeast. It was first identified in 2009, in the inflamed ear canal of a Tokyo-based septuagenarian¹. Within a decade, researchers had found the yeast in ill people around the world. C. auris is often resistant to disinfectants and antifungal drugs, and can be difficult to kill. Between 30% and 60% of the people it infects will die.

Around 3.8 million people die each year of infections caused by C. auris and other fungi. Annual deaths caused by fungal infections have nearly doubled in the past decade.

Understanding pathogen emergence through the lens of Candida auris

Pathogenic fungi pose unique challenges, and overcoming them will require innovative approaches to both science and policy. Yet, despite the growing global threat posed by drug-resistant fungi, such infections rarely loom large in discussions of antimicrobial resistance. Two World Health Organization (WHO) reports published this month (see go.nature.com/3rniybw) — the organization’s first analyses of tests and treatments for fungal infections — highlight the result of that neglect. Only three drugs to tackle the fungi that pose the biggest threat to human health are in late-stage clinical trials. Researchers, policymakers and industry must quickly act together to bolster the treatment pipeline and also to protect the potency of the antifungal drugs already in use.

Severe fungal infections typically strike the most vulnerable, such as people with weakened immune systems or chronic respiratory conditions. Better, cheaper tests are needed to diagnose fungal infections in a timely way, and to determine whether the fungi responsible are drug-resistant. Diagnoses are often delayed, particularly in low- and middle-income countries, where fungal infections are common. This can lead to inappropriate treatment and contribute to resistance to antimicrobial drugs.

Designing such drugs is also difficult. Fungal cells are more similar to human cells than to bacteria, suggesting that an antifungal compound could also be toxic to people. And lessons learnt from bacterial antimicrobial resistance do not always apply: when drug resistance emerges in fungi, it often does so through molecular mechanisms different from those that bacteria use to overcome antibiotics.

All of this means that it is crucial to invest in basic research to better understand which cellular pathways can be targeted in fungi without harming human cells. Last month, for example, researchers reported a compound made by bacteria that targets fungal cell membranes through a new mechanism, yet is relatively non-toxic to human cells grown in culture². Studies of fungal genetics, meanwhile, will be crucial to the detection of emerging pathogenic strains and drug resistance, as well as the design of new antifungal drugs.

New antifungal breaks the mould

Drug-resistant fungal infections are fairly rare, making them difficult and expensive to study. What’s more, people who contract serious fungal infections often have other health conditions that can make it hard to determine the safety of an experimental treatment. One way to facilitate clinical trials would be to establish clinical trial networks covering many institutions. These networks could standardize protocols and diagnostic tools, as well as drawing participants from a wide geographic area.

Perhaps the biggest policy challenge will be to address a major potential source of drug resistance: agriculture. Some antifungal medicines are similar to the fungicides that farmers spray to protect crops, so the widespread use of fungicides could result in fungal resistance to similar compounds used in medicine. Overcoming this problem will require stakeholders to join together and find ways of protecting both food security and human health.

Some countries are already taking steps in this direction. India has banned two antibiotics from being used for plant protection, because alternatives that pose less danger to human antimicrobials are available. The US Environmental Protection Agency has proposed including the risks of promoting resistance to antifungals in its assessment of the potential health impacts of new fungicides.

Global warming could drive the emergence of new fungal pathogens

And, earlier this year, representatives of five European Union health and environmental agencies published a report on the threat that fungicide use in agriculture poses to a class of medicines used to treat infection with Aspergillus fungi³. The compounds these drugs contain, called azoles, are also used in fungicides, veterinary medicines, wood preservatives and cosmetics. Aspergillus species are increasingly becoming resistant to them.

The group highlighted several ways in which countries could act to preserve the utility of azoles. These included the effective management of agricultural and industrial waste, and adding fresh requirements to the approval process for azole fungicides. The agencies also advocated support for research into new fungicides that would not overlap with human treatments. Both the EU and the WHO reports have highlighted a litany of open research questions that must be addressed. It is now crucial that industry, government and philanthropic funders work together to give researchers the resources needed to fill these gaps.

So far, scientists still have not determined what pushed C. auris to appear so rapidly in hospitals around the world. Genetic studies suggest that the yeast’s ability to infect humans has evolved independently multiple times, in different regions. Some researchers worry that the conditions that encouraged this could nudge more fungi towards becoming dangerous. If so, it will be even more important to be prepared.