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Tackling the emerging threat of antifungal resistance to human health

Nature Reviews Microbiology volume 20, pages 557–571 (2022)Cite this article

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Abstract

Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.

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Fig. 1: Major routes to acquiring antifungal drug resistance and/or tolerance in key invasive human fungal pathogens.
Fig. 2: Emerging antifungal resistance and environment–One Health drivers.
Fig. 3: Resistance detection, tracking and surveillance.
Fig. 4: Interventions for invasive fungal infections within the landscape of antifungal resistance.

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Acknowledgements

M.C.F., D.C.S. and S.J.G. are fellows in the Canadian Institute for Advanced Research (CIFAR) ‘Fungal Kingdom’ programme. M.C.F. acknowledges funding from the Natural Environment Research Council (NERC) and the Medical Research Council (MRC) Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK MRC and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement, and is also part of the EDCTP2 programme supported by the European Union. J.B. is supported by the Israel Science Foundation (#997/18) and European Research Council (ERC) Synergy Fungal Tolerance (#951475). A.W. and E.M.B. are supported by the MRC Centre for Medical Mycology (grant MR/N006364/2). S.J.G. is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (grant no. BB/PO18335) and the Bill and Melinda Gates Foundation. The contribution of B.Z. and P.E.V. is supported by the project ‘One health consequences of circularity. What lessons to learn from the saprophytic and human pathogenic fungus Aspergillus fumigatus?’ (project number GROEN.2019.002), which is financed by the Dutch Research Council (NWO). The authors thank L. Schouls, Centre for Infectious Diseases Research, National Institute for Public Health and the Environment (RIVM), for comments. This Review was conceived as a result of the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) Strategic Research and Innovation Agenda (SRIA) update consultation.

Author information

Authors and Affiliations

  1. MRC Centre for Global Infectious Disease Outbreak Analysis, Imperial College London, London, UK

    Matthew C. Fisher & Johanna Rhodes

  2. Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    Ana Alastruey-Izquierdo

  3. Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel

    Judith Berman

  4. Institute of Infection and Immunity, St George’s University London, London, UK

    Tihana Bicanic & Thomas S. Harrison

  5. MRC Centre for Medical Mycology, University of Exeter, Exeter, UK

    Elaine M. Bignell, Thomas S. Harrison & Adilia Warris

  6. Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Paul Bowyer & Michael Bromley

  7. Department of Pharmacy, Radboudumc Institute for Health Sciences and Radboudumc — CWZ Centre of Expertise for Mycology, Radboud University Medical Centre, Nijmegen, Netherlands

    Roger Brüggemann

  8. Department of Medicine and the School of Public Health and Epidemiology, University of Ottawa, Ottawa, Ontario, Canada

    Gary Garber

  9. University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Cologne, Germany

    Oliver A. Cornely

  10. Biosciences, University of Exeter, Exeter, UK

    Sarah. J. Gurr

  11. Centre for Infectious Diseases Research, Diagnostics and Laboratory Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands

    Ed Kuijper & Paul E. Verweij

  12. Infectious Disease in Global Health Program and McGill Interdisciplinary Initiative in Infection and Immunity, McGill University Health Centre, Montreal, Québec, Canada

    Donald C. Sheppard

  13. Public Health Wales Mycology Reference Laboratory, University Hospital of Wales, Cardiff, UK

    P. Lewis White

  14. Department of Biology, McMaster University, Hamilton, Ontario, Canada

    Jianping Xu

  15. Department of Plant Science, Laboratory of Genetics, Wageningen University & Research, Wageningen, Netherlands

    Bas Zwaan

  16. Department of Medical Microbiology and Radboudumc — CWZ Centre of Expertise for Mycology, Radboud University Medical Centre, Nijmegen, Netherlands

    Paul E. Verweij

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  1. Matthew C. Fisher
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Matthew C. Fisher or Paul E. Verweij.

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Competing interests

M.C.F. and P.E.V. receive speaker fees from Gilead Scientific. O.A.C. reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G Ltd, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer and Scynexis; consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis and Seres; honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan and Pfizer; payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI and Shionogi; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); and other interests from DGHO, DGI, ECMM), ISHAM, MSG-ERC and Wiley. The other authors declare no competing interests.

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Glossary

Antifungal tolerance

A characteristic of drug-susceptible genotypes to grow slowly at or above inhibitory drug concentrations. Characteristically, only a proportion of cells manifest tolerance.

Antifungal resistance

Defined as the ability to grow at antifungal drug concentrations above a defined antifungal susceptibility break point, normally (but not exclusively) owing to a defined causal molecular change following adaptation to drug exposure. It is expressed as a minimum inhibitory concentration (MIC).

Minimum inhibitory concentration

(MIC). The lowest concentration of an antifungal drug that inhibits fungal growth and, in the context of defined susceptibility break points, defines resistance.

Fungicides

Antifungal compounds used in the environment to inhibit fungal growth; widely used in agriculture, horticulture and timber industries as well as components of antifouling agents and paints.

Saprotrophic decay

Heterotrophic nutrition provided by extracellular digestion of organic matter in the environment.

Intrinsic resistance

Species of fungi that have not obviously evolved resistance in response to drug pressure.

Acquired resistance

Species of fungi that have evolved resistance in response to drug pressure.

Aneuploidies

Increase in the numbers of copies of chromosomes, often resulting in phenotypic changes to drug resistance and/or tolerance profiles.

Hypermutator

Genotypes that manifest accelerated mutation rates because of mutations to genes involved in nucleic acid repair mechanisms.

Fungistatic

Exposure to a chemical that halts the growth of, but does not kill, the fungus.

Antifungal susceptibility testing

An in vitro measure of susceptibility and resistance to the drug concentrations required to inhibit fungal growth, measured by the minimum inhibitory concentration (MIC).

Loop-mediated isothermal amplification

Enzymatic nucleic acid amplification at a single temperature.

Therapeutic drug monitoring

The pharmacological practice of measuring drug concentrations at specific intervals in order to optimize individual dosage regimens.

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Fisher, M.C., Alastruey-Izquierdo, A., Berman, J. et al. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol 20, 557–571 (2022). https://doi.org/10.1038/s41579-022-00720-1

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