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The first commercially-available antibiotics, the sulphonamides, were discovered through a trial-and-error approach screening various coal-tar dyes and serendipity played a major role in the discovery of penicillin in the late 1920s. Since then, strategies to discover new antimicrobials have significantly diversified, although there have been few truly novel breakthroughs in recent decades. Research has also led to the development of new anti-viral drugs for the treatment of previously impossible to treat or undiscovered viruses and rapidly emerging diseases such as AIDS and COVID-19, amongst others. Similarly, antifungal agents (also known as antimycotics) have emerged as important tools to combat infection, especially for immunocompromised patients.

Antifungal resistance is a cause for high morbidity and mortality

Human diseases caused by different types of microbes are often perceived and conveyed in quite different ways. The recent and still ongoing COVID-19 pandemic has led to dire health and economic consequences. Everyone is now talking about viruses and yet while mortality from COVID-19 remains high, total numbers (~6 million deaths to date world-wide)¹ are likely far inferior to those observed due to life-threatening bacterial or fungal infections. Resistance to antifungals leads to high morbidity and moderate to severely high mortality^2,3. Yet, we don’t hear much about this in the news or on social media – an exception is the incidence of ‘black fungus’ in the lungs of hospitalised COVID-19 patients (more about this later).

There have also been numerous reports of opportunistic fungal infections, many highlighted in national and international news. A concerning example of this are COVID-19 patients in India who succumbed to a secondary infection by the fungus Mucor – duly named the “black fungus.”

There are many species of fungi that cause infections. These range from yeasts which include different Candida species, such as the drug-resistant C. auris, to filamentous fungi such as Aspergillus spp. and Mucor spp.. Many of these species can be “carried” by their human host in their microbiome without causing disease. However, given the opportunity fungi can cause diseases ranging from common and mild to moderate dermatophyte infections to severe and, in many cases, fatal diseases such as invasive Aspergillosis.

The need for antifungal resistance monitoring

Considering that there are hundreds of such fungal species, understanding the characteristics of such organisms is paramount. An appreciation of any changes in clonal dominance and spreading, dissemination within and between human populations as well as antifungal susceptibility are all incredibly important. In a nutshell, there is a need for “antifungal surveillance monitoring” and sharing such surveillance data is essential in educating scientific, medical and laypeople. It is fundamental that these studies have a global reach, especially to avoid yet another public health crisis lurking around the corner. Notably, such monitoring is encouraged by the United States Centers for Disease Control (CDC)⁴ and the World Health Organisation⁵.

Antifungal resistance monitoring is conducted by various groups working nationally, regionally or even globally. Most studies are sponsored by governments or research institutions and although they are not standardised (because they may just collect local data or generate centralised data for example), they all tend to share one aspect: the monitoring of antifungal activity (or lack thereof) of antifungal agents against key target pathogens isolated from various infections, geographies and other patient demographics. The monitoring of antifungal resistance is best done using longitudinal studies over many years to be able to discover trends rather than one-off snap-shot studies. For example, the Funginos study group recently published clinical and antifungal susceptibility data from a 15-year analysis of candidaemia in Switzerland.⁵ Other centralised laboratory studies include China Hospital Invasive Fungal Surveillance Net (CHIF-NET), which has been running since 2009. Alternative approaches are based on the collation of clinical data rather than centralised testing, such as Fungiscope⁶. Although these studies are very well run and important, they do not readily lend themselves to the assessment of new antifungals because these agents are generally not available for testing in clinical laboratories until after market approval. These activities are supported by commercially-run global antifungal surveillance studies such as SENTRY Antimicrobial Surveillance Program (JMI labs in the USA) and the Antimicrobial Resistance in Antifungals (ARIA) program (IHMA Europe, Switzerland).

Everyone is now talking about viruses and yet while mortality from COVID-19 remains high, total numbers (~6 million deaths to date world-wide) are likely far inferior to those observed due to life-threatening bacterial or fungal infections.

As mentioned earlier, COVID-19 has had and continues to have a highly negative impact worldwide. It is important to note that the cause of mortality in many patients is not COVID-19 itself but sepsis and multi-organ failure⁷. There have also been numerous reports of opportunistic fungal infections, many highlighted in national and international news. A concerning example of this is COVID-19 patients in India who succumbed to a secondary infection by the fungus Mucor – duly named the “black fungus⁸.” This is still is a highly relevant public health issue, especially considering that this pathogen can be difficult to diagnose and treat and that mortality can be very high^9,10.

Current antifungal resistance monitoring needs to cover a multitude of fungal pathogens with the testing of as many antifungal classes to be performed in longitudinal studies. The more monitoring is performed, the better, and the sooner we grasp such resistance trends, our awareness will be enriched, and action can be taken. In this rapidly evolving world of antimicrobial resistance, often a direct or indirect consequence of other human diseases, being aware and prepared to combat antifungal resistance is crucial.

References

1. WHO Coronavirus (COVID-19) Dashboard (2021) Home page.
2. Hoenigl M (2020) Invasive Fungal Disease complicating COVID-19: when it rains it pours. Clinical Infectious Diseases. 73(7): e1645–e1648.
3. Jenks JD, Cornely OA, Chen SC, Thompson GR 3rd, Hoenigl M (2020) Breakthrough invasive fungal infections: Who is at risk? Mycoses. ;63(10):1021-1032.
4. Centers for Disease Control (2021) CDC actions to prevent the spread of antifungal resistance. 
5. WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) (2021) Home page. 
6. Adam K-M, Osthoff M, Lamoth F, Conen A, Erard V, Boggian K et al. (2021) Trends of the Epidemiology of Candidemia in Switzerland: A 15-Year FUNGINOS Survey. Open Forum Infectious Diseases. 8(10): ofab471.
7. Elezkurtaj S, Greuel S, Ihlow J, Michaelis EG, Bischoff P, Kunze CA et al (2021) Causes of death and comorbidities in hospitalized patients with COVID-19. Scientific Reports 11: 4263
8. Fungiscope (2021) Home page. 
9. BBC News (2021) Mucormycosis: The “black fungus” maiming Covid patients in India.  
10. Gupta A, Sharma A, Chakrabarti A. (2021) The emergence of post-COVID-19 mucormycosis in India: Can we prevent it? Indian J Ophthalmol. 69: 1645-1649.