Improving detection and diagnosis of antimicrobial resistance in Aspergillus fumigatus
( IMPROVE-ASP )

Surveillance

Research Project: 2024-04-01 - 2027-03-31
Total sum awarded: €1 154 996

Azole resistance is an emerging concern in Aspergillus fumigatus, a fungus that may cause life-threatening infections in humans and animals. A. fumigatus is listed as one of 4 fungal pathogens in the 2022 WHO critical priority pathogen group, which is the first global effort to systematically prioritize fungal pathogens, considering their unmet research needs and perceived public health importance. Resistance in A. fumigatus is mainly caused by mutations in the Cyp51A-gene, which commonly causes a pan-azole-resistant phenotype. Alternative treatment options to azoles are very limited although new compounds are under development, most notably olorofim (OLO). Detection of azole resistance is challenging as current tests have limited sensitivity. In addition, the variation in Cyp51A resistance genotypes that impact on azole MIC is increasing and a large subset of 20% of isolates with high azoles MICs have unknown resistance mechanisms. Our proposal aims to IMPROVE current diagnostic tools by developing reverse complement (RC)-PCR, characterising critical single nucleotide polymorphisms (SNPs) and identifying new resistance mechanisms in azole-resistant A. fumigatus. In addition, we will IMPROVE current agar-based screening tools to allow rapid screening for azole resistance and adding OLO resistance screening. Our studies will provide improved reference diagnostics as well as low cost screening tools benefiting patients with Aspergillus diseases. These tools and insights will also benefit international One Health resistance surveillance programs.

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  • Paul Verweij, Radboud University Medical Centre, Netherlands (Coordinator)
  • Paul Dyer, University of Nottingham, United Kingdom (Partner)
  • Sarah Delliere, Publique Hôpitaux de Paris, France (Partner)
  • Lewis White, Public Health Wales, United Kingdom (Observer)
  • Bii Christine, Kenya Medical Research Institute, Kenya (Partner)
  • Michael Voetz, Xebios Diagnostic Group GmbH, Germany (Partner)

Aspergillus fumigatus is a very useful mould that breaks down decaying plant material. However, A. fumigatus may cause life-threatening infections in humans who have certain immune defects. We can treat patients with azole drugs, but increasingly these drugs have become less effective due to resistance. Resistance usually does not develop during therapy, but is already present in the fungus before infection is established. Researchers have found that the fungus becomes resistant in the environment, when it grows in organic waste that contains residues of azole fungicides. Resistance is caused by DNA changes in the fungus, which need to be detected when the fungus has caused an infection because treatment can then be changed to other drugs. There are a limited number of drugs we can use to treat Aspergillus infections, but fortunately new drugs are being developed. An important problem is that it is very difficult to determine if a patient has a resistant infection because the current tests are not very good. This is caused by more and more DNA changes that may cause resistance, while in 20% of resistant fungi the DNA changes are unknown. In this proposal we aim to find new DNA changes that cause resistance and use this knowledge to develop better diagnostic tests. We will also improve a screening test by enabling the test to detect resistance against the newly developed drug. The development of better tests will benefit patients, but will also help to study how often patients are infected with resistant A. fumigatus and to better understand how patients become infected.

Call

2023 - Development of innovative strategies, tools, technologies, and methods for diagnostics and surveillance of antimicrobial resistance