The main topics of discussion when it comes to antimicrobial resistance (AMR) are bacterial infections and the declining effectiveness of antibiotics in the last few years. In 2017, WHO issued a bacterial priority pathogen list in the public interest that included 12 families of bacteria that pose a great risk to human health. This great risk comes from the area of the dynamic process of antimicrobial resistance.  The fungal realm, which is the minuscule analogue of bacteria but biologically more organized, has gained public attention due to a notable string of events in recent years and requires rapid attention. This article focuses on the chaos that these tiny "frenemies" of humanity are currently causing.

However, how might the fungi cause a rise in mortality? Fungi are prevalent creatures in the environment that have long been known to have benefits for agriculture, food, medicine, and industry. Over the last few decades, fungi-caused superficial infections like ringworm and athlete's foot have received unwarranted attention. However, it has become increasingly clear from epidemiological studies and evidence-based research that fungal illnesses play a major role in the death rate associated with infectious diseases. This is especially true for patients with impaired immune systems, patients with terminal cancer, recipients of organ transplants, long-term hospital stays, and HIV/AIDS patients. Most of this scientific literature suggests that antifungal resistance is the common cause.

Antifungal resistance has been a persistent issue that has been under the radar. A few groups of antifungal medications that have been used consistently to treat fungal infections are to blame for this. The fact that most fungal species are well-known enough to evade detection by conventional diagnostic methods is another likely explanation. Regretfully, sensitive diagnostics are rather expensive and not readily available everywhere. During the COVID-19 pandemic, when the purported "black fungus" outbreak occurred in India and accounted for 71% of new cases of mucormycosis worldwide, this covert pandemonium gained widespread notice.

The rise of multidrug-resistant species such as Candida auris, which have caused life-threatening epidemics in healthcare settings globally, has also been linked to high mortality rates in invasive fungal infections. Infections brought on by the fungus Cryptococcus neoformans, which primarily affects HIV patients, are an analogous example. Just one fungus alone causes roughly 181,000 deaths and 250,000 cases of illness per year.

According to recent research by Dr. David Denning, Professor of Infectious Diseases in Global Health at the University of Manchester, Senior Advisor, and former Chief Executive of Global Action for Fungal Infection, there has been a drastic increase in death rates from fungal infections. This epidemiological research shows that the annual incidence of affected individuals has increased to 6.5 million and about 3.7 million resultant deaths. This research has placed a lot of emphasis on timely diagnosis.

When MedBound Times contacted Dr. Juan Luis Rodriguez Tudela—Vice President, Board of Trustees, Co-founder of GAFFI, Interim CEO, and Director of LATAM programs—in this regard, he kindly gave MedBound Times permission to use the GAFFI literary material as an extra reading resource (https://gaffi.org/). In one of the literary resources he has explained his own perspective, stating the need for prompt diagnosis to prevent fatalities from fungal diseases in the resource that is linked. He says,

The World Health Organization (WHO) was alerted to all this information and preliminary research, and on October 25, 2022, the WHO released the first-ever fungal priority pathogen list (FPPL) to fortify the international response to the high mortality rate caused by fungal infections and the underlying antifungal resistance.

It is regrettable, however, that despite mounting evidence linking antifungal resistance to increased death rates, the issue is not given the proper attention and resources to address the root cause. Consequently, the precise prevalence of fungal infections, resistance to antifungals, and corresponding death rates. As a result, the illness response is still compromised.

The WHO started the process of developing FPPL by adding 19 new fungus and classifying them as critical, high, or medium priority. Based on the impact on public health and the prevalence of growing antifungal resistance, each category was created. To control the much predictable "fungal pandemic of future," FPPL claims that it is necessary to strengthen public intervention, improve the fungal pathogen surveillance network, and provide adequate funding for research and development as well as creative activities. Lastly, the FPPL offers suggestions for management, preventive actions, and policy initiatives in the interest of public health.

All things considered, it is projected that the FPPL will hasten the creation of a global gene surveillance system for antifungal drug resistance, consequently offering efficient preventive and therapeutic approaches.

One of the key drivers of antifungal resistance is the overuse and misuse of antifungal medications. Inadequate dosing, inappropriate prescribing practices, and the widespread use of antifungal agents in agriculture and food production contribute to the emergence and spread of resistant fungi. Additionally, factors such as the globalization of travel and trade facilitate the rapid dissemination of resistant strains across geographic regions.

Like bacterial resistance, antifungal resistance arises when fungi evolve mechanisms to evade the effects of antifungal drugs, rendering them ineffective. This can occur through various mechanisms, including alterations in drug targets, increased efflux of drugs from fungal cells, and the development of biofilms—complex communities of fungi that are highly resistant to antifungal agents.

The consequences of antifungal resistance are far-reaching and pose significant challenges for patient care and public health. Infections caused by resistant fungi are associated with higher mortality rates, longer hospital stays, and increased healthcare costs. Moreover, the lack of effective treatment options for resistant infections can lead to treatment failures and exacerbate the spread of drug-resistant strains.

The problem of antifungal resistance calls for a multimodal strategy that includes stewardship, research, and surveillance. To track the occurrence and spread of resistant fungus and spot new resistance trends, increased surveillance is required. Programs for antifungal stewardship can reduce the emergence of resistance, encourage acceptable prescribing practices, and maximize the use of antifungal drugs.

Research funding is also desperately needed to create new antifungal medications with unique modes of action, and increased potency against resistant fungi. Furthermore, the creation of focused treatments and treatment plans and the use of combination therapy depend on our ability to comprehend the underlying mechanisms of antifungal resistance, including the genetic and molecular components involved.

More importantly, a lot of focus is being placed on the idea of therapeutic drug monitoring, which entails the treating physician keeping a careful watch to make sure the medication is accomplishing its intended function while maintaining the patient's health.

Incorporating a segment from an interview featuring renowned Experimental Mycology specialist Professor Michaela Lackner of the Medical University of Innsbruck, Austria, would offer significant perspectives on state-of-the-art investigations and advancements within the discipline. Professor Lackner is a well-known authority in the field of microbiology, and her knowledgeable advice could clarify everything from host-pathogen interactions and microbial ecology to cutting-edge treatment strategies and newly developing infectious diseases. Her views are priceless for readers looking for reliable and current information on microbiological discoveries and their consequences for public health and healthcare due to her vast experience and scholarly contributions.

Could you please introduce yourself to our readers and tell us about your background, your expertise, and your journey in the field of antifungal resistance research?

"Hello, I'm Michaela Lackner, full Professor of experimental mycology at the Medical University in Innsbruck. My background is in biology, specializing in microbiology and molecular biology. During my PhD training, conducted partly in Germany and the Netherlands, I focused on rare fungal pathogens such as Scedosporium and Lomentospora prolificans. Dealing with these multidrug-resistant pathogens highlighted the challenges in handling and treating them effectively. Consequently, I worked on clarifying their taxonomic position and renaming them to reflect their clinical significance and resistance patterns accurately. I've also contributed to international guidelines for organizations like ECMM (European Confederation of Medical Mycology) and ISHAM (International Society of Human and Animal Mycology). My research has two main focuses: developing diagnostic assays to enhance fungal diagnosis, especially for multidrug-resistant fungal pathogens, and investigating the molecular mechanisms of resistance, particularly in azole-resistant fungi."

Additionally, she tried to explain how exactly the antifungal azole resistance mechanism works

"We aim to understand how fungi develop resistance, focusing on their primary target binding site, Lanosterol 14α-demethylase. This binding site functions like a lock and key mechanism. When the fungus mutates this 'lock', the key treatment no longer fits perfectly. Our goal is to identify the specific amino acids and protein residues involved in this lock. Just like modifying a key, it's crucial to ensure that the key still fits even after alterations."

When talking about this process of antifungal azole resistance, she frequently stressed the concept of "One Health".

She said, "We don't only want to look isolated in the medical field, but we also want to see this problem from a bigger perspective. And then try to understand what the azole burden is on the general population because this has not been widely investigated."

She additionally highlighted examples from her own comparative studies, such as preliminary data from blackbirds indicating disparities in blood levels between groups living next to vineyards and those living in cities, which could affect reproduction. In aquacultures, such as salmon farms, azole resistance hinders fish reproduction and biodiversity by influencing the spread of fungal infections. A great deal of evidence suggests that fish hormones are affected by azole pollution, which lowers fish reproduction rates in wild fish populations. It is noted that the azole-resistant population is causing a decline in biodiversity, and research is being done to determine the effects of azole resistance.

"And we want to understand the impact of azole pollution in the general population either because azoles can be absorbed by inhalation, also skin to skin contact, and then also by the intake of food and drinks."

Preliminary studies indicate that apples, and other fruit products may contain up to four different azoles. Additionally, strawberries and bananas, where azole-containing agricultural chemicals are used, may have heightened levels of azole contamination. The azole contamination of the general population is being investigated, including potential variations between summer and winter diets due to differences in the availability of fresh fruits and vegetables. The significance of this azole burden for human health is also being examined.

As a major step in order to deal with this problem of azole antifungal resistance, Professor Lackner has established PhD positions to address the major issue, and is currently seeking innovative and talented researchers, who will be trained under the supervision of well established principal investigators coming from various disciplines. Through the direction of professionals from diverse sectors, these roles seek to attract students and promote an interdisciplinary approach to the problem of azole resistance. Clinical specialties include surgery, internal medicine, and infectiology are among these fields, along with other scientific disciplines like bioinformatics, public health, biology, biochemistry, chemistry, and toxicology.

Are there any notable trends of global antifungal resistance or antifungal developments that you find particularly concerning or promising?

"Yes, there are a few drugs in development, but they face the same issue of being used in agriculture or being on the brink of legalization for agricultural purposes. We haven't learned from the azole situation despite strong evidence. I've given talks internationally to raise awareness of the problem. It's crucial to reserve certain drug classes for medical use, but I understand food security is a concern too. We need global stakeholders like the WHO, veterinary medicine, and agricultural organizations to come together and lead discussions. There's a lack of awareness in agriculture and veterinary fields about the impact of azole contamination on public health. We're seeing rising trends in rare mold infections like mucormycosis and azole-resistant Aspergillus fumigatus. We also want to explore the emergence of Candida auris, potentially linked to global warming and azole contamination. We must be prepared for future epidemics and multi-drug-resistant organisms that could emerge from agriculture. There's speculation that Candida auris originated from agriculture, but we need to consider other animal reservoirs too. We need to raise awareness, communicate from a One Health perspective, and find solutions to mitigate improper usage of drugs and preserve future drug candidates for better infection treatment."

Could you please elaborate on the potential impact of antifungal resistance specially in the terms of diagnosis, treatment and prevention? And how do these challenges affect the healthcare systems and the patient outputs?

"Dealing with multi-drug resistant pathogens like Aspergillus fumigatus poses significant challenges. While we have good diagnostic tests for Aspergillus, they're mainly available in high-resource countries, leaving most of the global population with a diagnostic gap. Expertise in fungal pathogens is limited to a handful of international centers, hindering both diagnosis and treatment. Many centers rely on culture positivity, which isn't very reliable, especially for rare pathogens. Limited expertise often leads to resorting to costly and sometimes ineffective combination therapies out of desperation. Additionally, not all countries have access to the full range of antifungal treatments, further restricting options. Access to proper diagnostics and treatment is crucial for patients with fungal infections, especially those caused by multi-drug resistant pathogens."

How can collaboration between healthcare professionals, policymakers and researchers help mitigate the impact of antifungal resistance?

"We aim to foster discussion and collaboration among key stakeholders and various disciplines to address the global emergence of resistance. Each person brings a unique perspective shaped by their training background. In addition to health economics, we need involvement from public health specialists, global health experts, and agriculture professionals to ensure a comprehensive approach. Balancing regulations with food security is crucial to prevent unintended consequences such as crop loss and starvation. We must carefully consider all variables and potential impacts before implementing measures. In agriculture, we must assess available alternatives to azoles and establish consistent monitoring of environmental concentrations. Achieving food security is paramount, especially considering unequal access to safe drinking water and food resources globally. By raising awareness and working collaboratively with experts, we can find solutions beneficial to our global community."

To sum up, antifungal resistance poses a serious risk to the health of the world and calls for quick attention and coordinated action. We can lessen the effects of antifungal resistance and preserve the efficacy of antifungal drugs for future generations by increasing awareness, bolstering surveillance systems, encouraging antimicrobial stewardship, and boosting research efforts. Now is the moment to act before the silent threat grows into an overwhelming obstacle. An interdisciplinary approach, training and looking at the bigger picture can easily tackle this new threat and maintain the effectiveness of our antifungal arsenal.

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(By Dr. Pallavi Saxena)

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