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Fungi are known for causing superficial infections of the nails, skin and hair, but they can also cause systemic infections that can have much more serious health implications. Indeed, over 6.5 million people are infected yearly with a life-threatening fungal infection, leading to 3.8 million deaths.
Many of the fungi we know are an essential part of nitrogen and carbon recycling in the environment through their action of decomposing complex material. As they grow, they can undergo “sporulation”, where they release tiny spores that are dispersed on air currents. These spores are breathed in but are usually cleared by the lungs.
However, this clearing is impaired in people with lung issues, such as cystic fibrosis, chronic obstructive pulmonary disease, tuberculosis and lung cancer, putting them at a significant risk of developing a fungal lung infection.
Many of the fungal pathogens are resistant to treatment with current drugs – of which only four classes are in use – or can rapidly acquire resistance during treatment or in their natural environment. As with bacteria and antibiotic resistance, so fungi can evolve to become resistant to the drugs used to treat them.
In 2022, the World Health Organization (WHO) published the fungal pathogens priority list that catalogued fungi that pose a significant risk to human health. Of critical importance are Candida albicans and auris, Aspergillus fumigatus and Cryptococcus neoformans.
The WHO list was designed to guide public health action and boost research and awareness in this field. Yet it has become clear that the desired effect of including fungal infections in the antimicrobial resistance policy debate is yet to be achieved. In a recent series of four articles in The Lancet about antimicrobial resistance (which includes resistance to bacteria, fungi, viruses and parasites), the problem of fungal disease contained just five sentences on the issue.
The second UN-hosted meeting on antimicrobial resistance took place on September 26. Aside from the wider acknowledgement of antimicrobial resistance, the meeting drew attention to the growing problem of fungal pathogens and their resistance to known treatments, globally.
Combating drug-resistant fungal infections is a complex problem. An important factor is that diagnoses of infections are often delayed – if they are even diagnosed at all. Simple tests for fungal infections are rarely available and only a few simple lateral flow tests are available.
More sensitive tests require trained personnel and expensive equipment, which is usually not available in laboratories in poorer countries.
Another issue is that antifungal drug development takes a long time and is very expensive. Fungal and human cells are more similar than bacterial and human cells, making finding antifungal targets with minimal toxicity to humans difficult.
Because of this, only several antifungals that work differently to traditional antifungals are being developed. But even after they reach the market, the development of resistance in fungi is a threat to these treatments.
Tons of fungicides are used annually to protect crops, of which some work the same way as antifungals used in humans. An example of this is an antifungal drug class called the azoles. There is strong evidence to suggest that azole resistance in the clinic can be of environmental origin due to agriculturally used azoles.
This is a particular problem in Aspergillus fumigatus, where some hospitals and research centres have reported resistance to azoles in up to 20% of fungal samples.
Over the last 25 years, a compound with a novel mechanism of action has been in development called olorofim. This compound is effective against many fungal pathogens. It is expected to be approved for use in humans soon.
But recently a fungicide for agricultural use, ipflufenoquin, has been approved in the US, that works the same way as olorofim. This makes the risk of resistance to both compounds high as they both target Aspergillus fumigatus the same way – or, in the lingo, they have the same mechanism of action. Resistance to one compound will cause resistance to the other compound.
This is not the only example of the dual-use of antifungals where compounds with the same way of working are used on farms and in hospitals and doctors’ clinics. This is a high risk for resistance development to antifungals we desperately need to treat human infections. The agricultural fungicide aminopyrifen has a similar target to the antifungal fosmanogepix, which can be used to treat humans.
Environmentally acquired resistant fungi can cause infections in patients and therefore, from the first day of treatment, can’t be treated with the desired antifungal. As food security requires antifungal protection from plant pathogens, the question arises: how do we balance human health and crop health?
The latest threat makes these issues more pressing
The rise of fungal pathogens that we have only seen more recently, such as Candida auris, make these issues even more important.
Candida auris is a yeast that was first found in 2009 and has spread globally since. It can cause life-threatening infections and has caused outbreaks in hospitals in several countries, including the UK. Unfortunately, it is resistant to many of the antifungals that are currently available.
The UN-hosted AMR meeting was a good starting point, getting fungi and antimicrobial resistance acknowledged globally. However, it is unclear what specific action will be put into place to combat fungal resistance. But having this discussion is a first step to making progress on an issue that affects so many people daily.
Norman van Rhijn receives funding from Wellcome Trust.
