PLS: Azole resistance in Aspergillus spp.

Disclaimer

• This plain language summary (PLS) is a simplified communication of the report on the Impact of the use of azole fungicides, other than as human medicines, on the development of azole-resistant Aspergillus spp. The full report can be found here.
• The purpose of the PLS is to enhance transparency and inform interested parties on the work of EU agencies on the topic using simplified language to present a summary of the main findings.

Background

• Azole substances are used against fungi (moulds). They are regulated in the EU for use as human and veterinary medicines, plant protection products (‘pesticides’), biocides and industrial chemicals.
• Aspergillus species (spp.) like A.fumigatus, A.flavus, A.terreus and A.niger are fungi commonly found in the environment. They can cause severe respiratory diseases in humans, like invasive aspergillosis (IA), chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA). In the EU, A. fumigatus is the leading cause of these diseases.
• Aspergillosis is primarily treated with azole medications like itraconazole and voriconazole, with few effective alternatives available.
• Aspergillus spp. can develop resistance to azole fungicides, reducing the effectiveness of azole medications. This resistance may result from prolonged medical treatment or environmental exposure to azoles.
• In 2013, the European Centre for Disease Prevention and Control (ECDC) published a report assessing the impact of environmental triazole use on resistance development in Aspergillus spp. to medical triazoles.

What did the European Commission request?

• The European Commission (EC) requested ECDC, the European Chemicals Agency (ECHA), the European Environment Agency (EEA), the European Food Safety Agency (EFSA) and the European Medicines Agency (EMA), with the support of the EC’s Joint Research Centre (JRC), to assess the impact of non-medical azole fungicides on the development of azole-resistant Aspergillus spp. This is the first mandate involving all five EU agencies and the JRC.
• The request included the following key tasks:
  • investigatingthe types and amounts of non-medical azole fungicides used in the EU;
  • assessing the link between non-medical use of azoles and the development of azole resistance in Aspergillus spp. and related risks to human health;
  • identifying the ‘environmental hotspots’ for the development of azole resistance in Aspergillus spp.;
  • identifying risk management measures for preventing and controlling the development and spread of azole resistance in the environment and its spread to humans;
  • identifying the current data gaps and recommendations for future research;
  • recommending data requirements for future applications for approval of azole fungicides.

How was the work conducted and what data were used?

• Following a One Health approach, and bringing together the widest scientific and technical knowledge, the agencies collaborated on this joint scientific report, each contributing their expertise.
• The agencies collected relevant information through specific surveys, gathered data from relevant EU databases, performed extensive literature searches to identify and review scientific papers, carried out a systematic collection of expert opinion, and developed new methods to identify and prioritise environmental hotspots for resistance development.

What were the outcomes and their implications?

• Between 2010 and 2021, approximately 120 000 tonnes of azoles were sold in the EU/EEA (European Economic Area) for non-medical purposes. Over 119 000 tonnes of these azoles were used for plant protection, with a stable annual average of 10 000 tonnes.
• Substantial evidence supports a link between environmental azole fungicide exposure, azole resistance selection in Aspergillus spp. and cross-resistance to medical azoles (environmental resistance route). This link has been demonstrated for A.fumigatus but is less clear for other Aspergillus spp.
• Non-medical use of azoles likely contributes to the environmental selection of azole-resistant A.fumigatus, potentially leading to infections caused by azole-resistant A. fumigatus. However, further research is required to estimate the extent of this contribution.
• Based on ecological selection dynamics, identified environmental hotspots for selection of azole resistance include:
  • agriculture: stockpiled agricultural waste used to improve and fertilise soil for various crops (indoor fruiting vegetables, wine grape, corn, sugar beet, olives, pome fruit, citrus fruit and field heaps);
  • biocides: freshly-cut wood.
• The reported prevalence of human azole-resistant A. fumigatus infections among all A.fumigatus infections varies by the type of aspergillosis disease and the geographic region (IA: 0.7–63.6 %, CPA: 5.9–59.2 %, APA: 2.3–42.8 %).
• Azole resistance has significant clinical implications, especially for azole-resistant A.fumigatus IA, with mortality rates reaching 36–100 %. The clinical implications of CPA and ABPA are less documented.

What were the uncertainties/limitations?

The uncertainties and limitations affecting the assessment originate from, for example:

• agriculture:
  • possible overestimation in the identification of hotspots;
  • uncertainties about actual residue levels in crop waste;
  • incomplete information on disposal of food and agricultural waste;
  • limited data on Aspergillus spp. growth in field waste under no-till conditions.
• biocides:
  • uncertainties regarding A.fumigatus growth on wood, the volume of wood treated and effective azole concentrations in wood;
  • limited data on the quantity of azole-containing biocidal products.

The report suggests additional research, data collection and field studies to resolve data gaps and the identified uncertainties. This will lead to a more comprehensive understanding of azole-related risks, enabling the development of effective mitigation strategies.

What are the key recommendations?

To combat azole resistance in Aspergillus spp. (mainly A. fumigatus), a comprehensive strategy is recommended:

• In agriculture: thoughtful use of azole fungicides, promoting best practices for waste management and soil fertilisation, as well as further research;
• In medicine: enhanced disease diagnostics, surveillance and increased awareness of this topic;
• For research: focus on developing new antifungals with novel mechanisms of action;
• For biocide use: optimise concentrations of azole fungicides when treating wood, and ensure proper wood waste management;
• For EU approval of fungicides: assess potential for cross-resistance with antifungals used in human medicine before approving new fungicides.

Glossary

Antifungals: Substances used to treat or prevent fungal infections.

Biocides: Products that protect people and animals against harmful organisms, like pests or bacteria. Each biocidal product contains one or several active substances that are designed to control viruses, fungi and other microbes before they cause harm.

Cross-resistance: The development of resistance to one substance that leads to resistance to one or more other substances with a similar mechanism of action.

Ecological selection dynamics: The interplay of factors that drive the development of resistance, in this case, in A. fumigatus (see Figures 1 & 2).

Fungicides: Pesticides (both chemical compounds and biological organisms) that kill or prevent the growth of fungi and their spores.

One Health: An integrated, unifying approach that aims to sustainably balance and optimise the health of people, animals and ecosystems.

References

Impact of the use of azole fungicides, other than as human medicines, on the development of azole-resistant Aspergillus spp. DOI: https://doi.org/10.2903/j.efsa.2025.9200