Anti-fungal Resistance: A Silent Crisis
The “Fungi’ Lacuna in AMR efforts
Antimicrobial resistance (AMR) has become a major scourge to the public health system. The WHO has declared it to be one of the top 10 global public health crisis. Between 2000 and 2015, global antibiotic use increased by 65% with India being one of the countries with the highest resistance rates in the world (1). Additionally, the COVID-19 pandemic has likely worsened the AMR situation globally (2,3). It is predicted that approximately 10 million people will die from AMR annually by 2050 and the economic cost to the world will be to the tune of 100 trillion USD (4). AMR policies and efforts have so far primarily focussed on bacterial and viral infections. Fungal diseases and resistance to antifungal drugs have not received adequate attention and coverage, although in recent years they are being recognized as a crisis in the making.
Fungi as a disease-causing organism
Fungi cause a variety of diseases, ranging from the relatively harmless athlete’s foot to life threatening invasive fungal disease (IFD), like invasive aspergillosis. They are especially dangerous to immunocompromised people like those undergoing chemotherapy or suffering from HIV (5).
Of the estimated 1.5 million fungal species, human beings are susceptible to 300 of them.
Globally, fungal diseases are responsible for the death of over 1.6 million people annually, at par with the tuberculosis death toll (6). Most deaths are caused by the fungi within the genera of Candia, Aspergillus, and Cryptococcus (7).
Life threatening fungal diseases are more prevalent in low and middle- income countries because of a lack of healthcare options, indiscriminate anti-fungal drug use and inadequate stewardship efforts. Apart from humans, fungi also destroys a third of all food crops each year and cause mass mortality in bees, bats, amphibians and other animals (9).
Anti-fungal Resistance: Hows and Whys
The eukaryotic biochemistry of fungi makes it a challenge to design new anti-fungal drugs as what is toxic to fungi may also be toxic to humans or animals. Currently, anti-fungal drugs belong to one of four classes — a) polyenes b) azoles c) echinocandins d) pyrimidine analogue 5- flucytosine (10). Resistance to even one class of drugs leads to a loss of a quarter of our therapeutic options for patients. Resistance to these drugs may occur through multiple ways — changes to the drug target binding site making it difficult to bind, elevated activity of the system that flushes out the drugs from the fungi altering effective intracellular drug concentration, or inhibition of pro-drug activation like in the case of flucytocine (10,11).
Repeated use of anti-fungal on at-risk groups; broad, non-targeted use of drugs based on prophylactic and empiric treatment strategies even in patients without fungal infections; and poor adherence to long-term treatment, are often the drivers of resistance. Also large-scale, widespread use of broad-spectrum fungicides against phytopathogenic fungi in agriculture has given rise to resistance against other environmental fungi that includes human fungal pathogens.
The rise in resistance, in both agricultural and clinical setting, is especially concerning for the antifungals in the azole class. Fungicides like difenoconazole and tebuconazole are structurally similar to first-line medical triazoles like isavuconazole and voriconazole respectively. Countries like the Netherlands have some of the highest azole resistance rates against aspergillosis infections because of the excessive use of azoles in tulip and flower farms (12,13). Similarly, multi-drug resistant fungi like C. auris have been causing difficult-to-eradicate outbreaks in hospitals of low and middle income countries like India, South Africa and Kenya (14,15). Thus, the burgeoning fungal resistance threat needs to be put into the spotlight for the broader research community, government and funding agencies and the general public to develop solutions and awareness for this global health threat.
Current Solutions and Future Directions
The treatment for fungal diseases consists of two components: a) diagnostics and surveillance (for detection and sensitivity testing), b) therapeutic options (for administering the cure).
a) Diagnostics — There are multiple ways to perform anti- fungal susceptibility testing like broth microdilution, disk diffusion and azole agar screening (16). These tests are reported in Minimum Inhibitory Concentration (MIC), the lowest concentration of anti-fungal agents that stopped the growth. These tests are both labour intensive and time consuming. Recent advances in molecular diagnostic methods have led to identifying genetic markers associated with anti-fungal resistance through real-time PCR on clinical specimens, bypassing the need for culture and improving turnaround times (17). The high sensitivity and specificity of such methods has led to more targeted pre-emptive treatment. Unfortunately, these tests require specialised labs and are not available for every strain of pathogenic fungi. More funding and research are required to create low-cost, near-bedside diagnostic tests that can be implemented in resource limited settings.
b) Therapeutics — Apart from the four existing classes of anti-fungal drugs, multiple drug candidates that represent novel anti- fungal classes with novel modes of action are in various stages of trials. Olorofim and Manogepix are two such therapeutic candidates with broad-spectrum activity that are currently in clinical trial and have shown great promise (18–20). Not only new drugs, but new modes of drug delivery system to the target are also being explored. Drugs like Opelconazole that can be administered through nebulization represent new avenues of research (21). Combination therapy strategies like those applied to bacterial, viral, and parasitic infections can also be applied to fungi to bolster the traditional anti-fungal arsenal. For example, combination of flucytosine, fluconazole, and amphotericin B have been found to accelerate infection clearance rate and reduce mortality in the case of cryptococcal meningitis (22). Investigations towards exploiting the host-directed systems through immunotherapy and fungal vaccines have shown some early promise too.(23,24)
Historically, bacteria and virus have long been the focus as pathogenic agents but with the emerging burden of fungal diseases and resistance, it is time to incentivize research in this area.
Policymaking to address Anti Fungal Resistance
In a first such global effort, WHO created a fungal priority pathogens list to drive further research and policy interventions in the field of fungal diseases and resistance in 2022. 19 fungal pathogens associated with serious risk of mortality were listed with Candida albicans, Aspergillus fumigatus, Candia auris, and Cryptococcus neoformans deemed critically important (8).
A deeper and more coordinated global effort is required to make inroads into improved diagnostics and therapies and greater understanding of the mechanisms of resistance in fungi especially as climate change and an unregulated food and agriculture ecosystem shape human-environment and host-pathogen interactions; also underlining the urgent need for a One Health approach.
Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however, this does not claim to be an exhaustive document on the subject. The mention of entities, networks, consortiums, or partnerships is merely to highlight the stakeholders working in the field and does not reflect attestations, validations or promotion of their work. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.
References
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