Thirty years of research shows increased resistance in fungi Combination of fungal strains complicates infection treatment

Fungi are increasingly resistant to antifungals, and the variation in resistance has significantly increased. This is evident from the analysis of more than 12,000 lung samples collected over thirty years in Dutch hospitals. In addition, a resistant infection in a patient almost always consists of different fungal strains, making treatment more challenging. This study by Radboud university medical center and public health institute RIVM has been published in The Lancet Microbe.

When consultant microbiologist Paul Verweij and his team began collecting Aspergillus fumigatus isolates from patients’ lungs in 1994, they did not find any fungi that were resistant to antifungals. In 2000, the team discovered a mutation, a change in DNA, that caused resistance. Another important mutation was found in 2009. To date, there are more than 12,000 isolates of A. fumigatus stored in the freezers at Radboudumc. These samples show a clear increase in resistance.

Waste heaps

In addition to the two major mutations found, various smaller DNA changes in this fungus occurred over the thirty years, which can appear in different combinations. ‘We now have collected about two thousand resistant fungal strains, 17% of which show variations in resistance mutations’, says Verweij. It has now been found that these different strains almost always appear in a mixed form in patients, which makes treatment increasingly challenging.

The primary medications for treating fungal infections are the so-called azoles. But resistance is developing against these drugs. This does not occur in humans during therapy but in agriculture. ‘Azoles are also used in food production and flower cultivation, and are aimed at fungi that make plants sick, such as Fusarium’, explains Verweij. ‘These azoles end up in waste heaps from certain production lines, where A. fumigatus thrives. There, the fungus becomes resistant to azoles, especially when these waste heaps are left for a while.’

Useful fungus

A. fumigatus thrives in such piles of plant waste because the fungus breaks down dead plants. It is therefore a very useful fungus that actually appears everywhere. We breathe in spores of this fungus daily, which spread through the air. For healthy people, this is not a problem; their lungs clear the spores. However, in vulnerable people with an underlying lung condition, the fungus can cause an infection called aspergillosis.

‘We see such fungal infections, for example, in people who are in the intensive care unit with severe flu or COVID-19’, says Verweij. ‘Their risk of death doubles when they contract an infection with A. fumigatus. Other vulnerable patients are also at risk, such as people with COPD, leukemia, or organ transplant recipients.’ The fungal spores then grow in the lungs, which can lead to shortness of breath, fatigue, and lung bleeding. In severe cases, the fungus enters the bloodstream and reaches the brain.

Attractive climate

Due to the rise in resistance variations against azoles, it is becoming more difficult to combat this fungus. Guidelines were therefore adjusted in 2017. Verweij: ‘If we now culture A. fumigatus in a patient in the ICU with flu or COVID-19, we immediately start combination therapy.’

Although resistant fungi are found worldwide, infections are relatively common in the Netherlands. ‘We don’t entirely know why this is’, Verweij explains. ‘We live in a small area where antifungal agents are used intensively. This leads to a lot of exposure. Additionally, our climate is attractive for fungi, with high humidity. These factors may play a role.’

About the publication

This research has been published in The Lancet Microbe: Characteristics and dynamics of triazole-resistant Aspergillus fumigatus variants emerging over a 29-year period in The Netherlands. Yinggai Song, Jochem B Buil, Johanna Rhodes, Jan Zoll, Marlou Tehupeiory-Kooreman, Mehmet Ergün, Jianhua Zhang, Ruoyu Li, Thijs Bosch, Willem J G Melchers, Paul E Verweij. DOI: 10.1016/j.lanmic.2025.101114.

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