Fungal infections can be superficial or subcutaneous, affecting the skin layers or mucous membranes, or systemic, reaching the bloodstream and deeper tissues. While superficial infections can seriously affect a patient’s quality of life, both diagnosis and treatment are often straightforward. Systemic infections, on the other hand, are a serious health concern as diagnosis is difficult and they are associated with high morbidity and mortality rates, especially in vulnerable populations. New estimates show annual incidences of 6.5 million people affected by severe fungal diseases and 3.8 million deaths.
From beach to bloodstream
The WHO fungal priority pathogens list categorizes the pathogens as critical, high, and medium priority, based on 10 predefined criteria, including mortality, incidence, global distribution, and resistance. Three of the four critical priority pathogens, Cryptococcus neoformans, Aspergillus fumigatus, and Candida albicans are relatively well-known and studied organisms. A new kid on the fungal block, with its first case of detection only dating back to 2009, is Candida auris. Due to its rapid global emergence, mortality rates of 30-60%, and multidrug resistance, this fungus poses a significant health concern and was pre-selected for prioritization by the WHO. Moreover, since 2019, the Centers for Disease Control and Prevention (CDC) included Candida auris as the first-ever fungus in the Antimicrobial Resistance Threats List.
It remains unclear where C. auris originated from. We do know that it was first identified in 2009, when a 70-year-old Japanese woman sought medical attention for her ear complaint. In the external ear canal of the patient, C. auris was isolated for the first time. Since then, C. auris has been isolated from all continents, except Antarctica. Remarkably, the fungus appears to have emerged independently and near simultaneously in different parts of the world, as suggested by genomic and epidemiological analyses. So far six major clades of isolates have been discovered based on phylogenetic clustering, with each clade corresponding to a certain geographic region – clade I (South Asia), clade II (East Asia), clade III (South Africa), clade IV (South America), clade V (Iran), and clade VI (Bangladesh). As C. auris was also isolated from natural habitats relatively untouched by human activity, such as the beaches of the Andaman islands in the Indian Ocean, it is believed to have evolved in the wild before interacting with humans. Some of the key pathogenic characteristics of the fungus, such as its high stress – and drug – resistance, might actually originate from its presence in natural habitats with high salt concentrations and elevated temperatures, such as oceans.
The greatest danger lies in the unknown
Wherever C. auris may originate from, it is currently on the rise. The number of infections and victims increases at a staggering pace. In 2023, the CDC reported 4,514 new cases in the US alone, several of which were associated with hospital outbreaks. “A worrying aspect of C. auris is that it spreads easily in healthcare facilities and often causes substantial outbreaks,” confirms Hans Carolus, postdoctoral researcher studying C. auris at KU Leuven (Belgium) and Université Laval (Québec, Canada). Both patients who are infected and those colonized yet asymptomatic can spread the fungus. Since it can persist on surfaces and skin for extended periods and many disinfectants are ineffective against it, C. auris spreads easily and can cause outbreaks. C. auris mainly affects patients with underlying medical conditions. “Significant risk factors for C. auris infection and related mortality include the presence of invasive medical devices—such as breathing tubes or catheters—and a weakened immune system. However, even relatively healthy individuals of advanced age or those having milder conditions, such as diabetes, can be affected,” warns Carolus.
The number of people affected and killed by serious fungal infections has long been underestimated. The primary reason for this underestimation is the absence of sufficient data. “For a long time, C. auris cases went unreported,” explains Carolus. “It’s only in recent years that some countries have begun implementing surveillance programs to accurately track the presence of C. auris and its resistance to drugs.” Apart from monitoring, also diagnosis and treatment could be optimized. Currently, diagnosis mainly happens through elimination of other suspects. “As initial symptoms are comparable to infections caused by bacteria and time is of the essence, clinicians often initialize broad-spectrum antibiotics,” says Carolus. “Once these show to be ineffective, other routes are investigated.” That’s why Carolus advocates for greater awareness among healthcare professionals. “Outbreaks tend to occur more frequently in regions where hospital surveillance and containment programs are less developed,” he adds. “Raising awareness will help clinicians recognize C. auris as a potential cause of infection, improving the chances of containing it before it leads to an outbreak.”
Drug cycling rather than combining
When pathogens become resistant to several drugs, clinicians often turn to combination therapy, administering multiple drugs at the same time, hoping for a better outcome. Mixing drugs, however, could also select for multidrug resistance. “As there are no standardized protocols present on how to best combat C. auris infections and prevent resistance in the clinic, procedures differ greatly between hospitals and physicians,” says Carolus. “When the patient doesn’t react to a first type of antifungal, multiple drugs are typically combined, potentially leading to onset of pan resistance.” This is especially dangerous in fungal pathogens, as only four major classes of antifungal drugs are available.
A more effective approach than combining therapies is drug cycling, which involves periodically rotating different drugs instead of administering them simultaneously. This strategy is based on the concept of collateral sensitivity, a principle first established in the 1960s, describing the evolutionary trade-off between antibiotic resistance mechanisms in bacteria. This means that resistance to one antibiotic confers increased susceptibility to another. Using experimental evolution, Carolus and coworkers recently showed that cycling clinically available drugs can effectively prevent the onset of resistance in C. auris. “Our data suggests that collateral sensitivity trends could prevent the establishment of resistance by cycling drugs, or it can guide therapeutic decisions when resistance emerges in monotherapy. Although the effect of such treatment strategies on established resistant populations remains to be further investigated in a clinical context”, says Carolus. The researchers also investigated cross resistance, in which one drug resistance mechanism reduces susceptibility to multiple drugs, and by doing so they could also make recommendations for which drugs not to use consecutively. Collaborations with hospitals and healthcare providers will be crucial for identifying clinically relevant patterns and developing practical protocols. Achieving this requires strong awareness efforts. “Educating clinicians about the real threat of C. auris and emphasizing the importance of well-considered treatment strategies remains a key priority,” Carolus concludes.
Overall, more research is urgently needed. While the threat of antibiotic-resistant bacteria is widely acknowledged by the public and actively addressed by governments and healthcare systems, fungal infections continue to be severely underestimated and neglected both in fundamental research and within the pharmaceutical industry. Acknowledging the urgent need for greater awareness among researchers, clinicians, and the public is the first step needed to move from ignorance to understanding.
