The spread of resistance to antifungal medications has led to many serious infections becoming untreatable, compromising patient safety and posing a global public health threat. The World Health Organisation (WHO) will soon publish its fungal pathogen priority list, highlighting fungi that are already untreatable, and those for which treatment outcomes are poor. In this blog, Professor David Denning outlines the issue of antifungal resistance, and the approaches required to tackle its spread.

• Over 300 million people globally suffer from serious fungal infection, with 25 million at risk of death or permanent disability.
• The spread of antifungal resistance is driven by the widespread use of antifungals in humans and on crops.
• Rapid diagnosis of fungal disease and appropriate use of antifungals is crucial to prevent antifungal resistance spreading, but requires technology and expertise not often available in low income countries.
• The global problem of antifungal resistance requires action across many sectors: healthcare, public health and agriculture.

Antifungal resistance and diagnostics

Resistance to antifungal drugs is now a serious problem. With only three types of antifungal drugs available, antifungal resistance can restrict treatment of fungal diseases. Without effective antifungal drugs, serious fungal infections will become untreatable. Extensive antifungal use in humans is one driver of antifungal resistance, alongside environmental exposure to antifungals. Crops sprayed with azole-class antifungals across the world, as well their use on fish farms, has a bystander effect on human pathogenic (disease-causing) fungi present in the soil and gut, which encourages resistant strains.

In human medicine, lack of access to diagnosis of fungal disease results in broad spectrum treatment, that is often wrong. For instance, fungal infection is often misdiagnosed as tuberculosis. Empirical therapy (‘best guess’), using combinations of antibacterial and antifungal drugs to cover most infection possibilities, leads to the development of antifungal resistance. There is no certainty that empirical therapy will work as the wrong antifungal may be used, while it also unnecessarily encourages further antifungal resistance appearing.

Identifying resistant fungi could ensure that the best available antifungal treatment is used, rather than empirical, broad spectrum treatments. However, antifungal susceptibility testing requires technical expertise and is not available in all countries. Without fungal disease diagnostics and susceptibility testing, the antifungals currently used will soon become useless for many fungal diseases.

Combatting antifungal resistance will need a multi-faceted approach

To tackle the growing issue of antifungal resistance, approaches which span several sectors will need to be implemented on an international scale. Measures which promote good clinical practice of fungal infection treatment and ensure appropriate use of antifungals are critical. However, other measures such as good surveillance of antifungal resistance in the clinic, and monitoring resistance in the environment are also required to combat the spread of resistance.

Researchers from The University of Manchester have been working closely with Global Action for Fungal Infections, whose mission is to enable healthcare systems to diagnose and treat fungal infections especially in low and middle income countries. They have developed a set of recommendations to national and international public health bodies, outlined below.

Clinical care standards which should be employed include:

• Access to fungal disease diagnosis to reduce empirical treatment of suspected fungal infections.
• Culturing clinical samples to isolate fungi – this is essential to tracking antifungal resistance as recognised by the WHO.
• Antimicrobial stewardship programs should integrate rapid diagnostic testing for serious fungal disease based on best practice guidance and clinical experience.
• Healthcare systems should strive to enable speedy diagnosis including fungal disease diagnosis to decrease the use of empiricism in the clinical practice which increases the antimicrobial resistance.

To fully assess the extent of antifungal resistance in the population, all countries should accurately track antifungal resistance trends over time of major fungal pathogens. National reporting on an annual scale is recommended, allowing public health authorities, Ministries of Health, and national societies to promote awareness of such antifungal resistance and encourage good empirical antifungal prescribing.

Antifungal resistance also arises due to exposure in the environment and so measures should be implemented to reduce the use of antifungals in the agriculture sector. Azole antifungals on crops, fish farms, and non-food products should be minimized, based on international recommendations. As previously mentioned, the surveillance of antifungal resistance in clinical settings is important to reducing the spread of resistant fungi, but environmental monitoring should also be done to assess annual treads in antifungal resistance, especially for Aspergillus fumigatus. Regulation of crop or seed dressing fungicides, or new chemical classes, should require studies of their potential for resistance induction in human fungal pathogens. Alternatively, those agents which do greatly induce resistance and which cause a ‘bystander’ effect, should not be approved.

Safeguarding the future

The COVID-19 pandemic has shown how rapidly new and emerging diseases can sweep across the globe. While the coronavirus was a novel organism previously unknown to health authorities, drug-resistant strains of existing diseases pose as much, if not more, risk. The WHO has identified antimicrobial resistance as one of their ten health priorities, while the UK Government has developed a five-year plan to tackle the issue both domestically and internationally, with iterative plans to follow until 2040.

If the world is to avoid a pandemic caused by fungi, it is essential that policymakers – in the UK and around the world – build on the recommendations presented here to develop international standards for monitoring, treating, and mitigating antifungal resistance.

A full policy brief from GAFFI, on “Antifungal drug resistance – a dramatic global problem”, can be read here. This briefing note was supported by Policy@Manchester.