The rise of Candida auris: from unique traits to co-infection potential.

Candida auris is a multidrug resistant (MDR) fungal pathogen with a crude mortality rate of 30-60%. First identified in 2009, C. auris has been rapidly emerging to become a global risk in clinical settings and was declared an urgent health threat by the Centers for Disease Control and Prevention (CDC). A concerted global action is thus needed to successfully tackle the challenges created by this emerging fungal pathogen. In this brief article, we underline the importance of unique virulence traits,including its easy transformation, its persistence outside the host and its resilience against multiple cellular stresses, as well as of environmental factors that have mainly contributed to the rise of this superbug. Copyright:

The clinical use of antibiotics undoubtedly ignited a new era in modern medicine: many infectious diseases, until then, the leading cause for morbidity and mortality, became systematically treatable. At the same time, this medical breakthrough drastically changed the social and political awareness of the hazards posed by various pathogens, leading to the illusion that we are generally protected from the devastating nature of infectious diseases. However, within a few decades, antibiotic resistance has increased to a level that has left some infections de facto untreatable. In addition, nature may not provide a sufficient number of so far unexplored diverse antibiotics, as long-standing notions have suggested. Finally, novel so far less prominent infectous agents have been emergingat an unprecedented speed. In fact, the WHO already warned in its 2007 World Health Report that infectious diseases were spreading and emerging faster than at any time in history [1]. Altogether, these challenges are a serious reminder of our persisting vulnerability against infectious diseases, and certainly, we will have to face and handle comparable menaces in future. One such challenge will be the rise of fungal infections (FIs), which have long been overviewed and neglected by healthcare authorities.

Like no other fungal pathogen, Candida auris has quickly unfolded to become an acutely worrisome infective agent, reaching pandemic proportions and cementing its condition as a superbug just within a decade after its first isolation in 2009 [2, 3]. Although later retrospective studies of culture collections have revealed a much earlier occurrence of C. auris infections dated back to the mid 1990's [2, 3], it has just been in the past few years that this pathogen has turned from a sporadic infective agent to an emerging cause of nosocomial outbreaks all over the world. An astonishing aspect about the rapid emergence of C. auris is the nearly simultaneous but independent appearance of genetically distinct clades on different continents [2, 3]. Four major C. auris clades have been identified that originally clustered by geography but are now found all over the globe: the South Asian Clade (clade I), the East Asian Clade (clade II), the South African Clade (clade III), and the South American Clade (clade IV) [2, 3]. Only recently, in 2018, a potential fifth clade, which is exclusively found in Iran (Iranian Clade), was determined [4, 5].

C. auris is the first and so far only fungal pathogen categorized as an urgent health threat by the Centers for Disease Control and Prevention (CDC), a category formally reserved for drug-resistant bacteria [6]. Early after the first identification of C. auris and due to its rapid international emergence, the CDC issued a clinical alert in 2016 to healthcare facilities, making it mandatory to report infections with C. auris [2, 7] but stopped global tracking of cases in February 2021 given how widespread C. auris had become [8]. In some settings, the epidemiology of Candida infections has changed drastically: while Candida albicans continues to be the leading cause for candidiasis, the proportion of infections by non-albicans Candida (NAC) spp. has drastically shifted towards C. auris, which now surpasses other prominent NAC spp. such as Candida glabrata or Candida tropicalis [3]. The potential of C. auris to become even more prominent in overall Candida infecitons is exemplified in a recent study, in which C. auris was reported to be the most predominant causative agent of Candida bloodstream infections (candidemia) - approximately 43% of all Candida isolates - in a tertiary care multispecialty center in Western India [9]. Alarmingly, all identified C. auris isolates within this study were resistant to fluconazole and about one third also against amphotericin B (AMB) [9], two of the most important antifungal treatment options available. A crucial characteristic of many C. auris strains is antifungal resistance: 90% of the isolates are reported to be resistant to at least one class of antifungal agents, 30% to at least two different classes, and even pan-resistant isolates (isolates resistant to all antifungal classes currently used in the clinics) have been described [10, 11]. This feature is especially distressing, given the limited availability of antifungal strategies. Current treatment options are rather limited due to the eukaryotic nature of fungi and only encompasses three chemical distinct classes [12]. Resistance patterns of C. auris accompanied by the preventive subscription and excessive use of antifungals in agriculture have most likely contributed to the sudden spread of this pathogen. Thus, the appropriate treatment of C. auris infections remains challenging, and novel, innovative therapeutic options are urgently needed.

An important feature of C. auris that explains its success as a global spreader is its easy transmission. Unlike other members of the Candida family, which are often associated with the human host and for which most infections have thus an endogenous origin, C. auris is frequently transmitted from person to person through direct or indirect contact. C. auris seems to be well adapted to survive outside the human host and is thus commonly isolated from human skin or the (hospital) environment [3, 13]. Notably, C. auris is able to persist on biotic or abiotic surfaces for several weeks (or even months) and is even capable of sustaining long periods of desiccation [2]. Moreover, thermal tolerance (C. auris can grow well at 42°C) and tolerance to several common disinfectants add a further layer of difficulty, especially in hospital settings [2, 3, 7]. Indeed, recent outbreaks in healthcare facilities have been linked to individuals that were colonized with C. auris but remained asymptotic or contaminated reusable equipment such as axillary temperature probes [4, 14].

Biofilm formation is an important virulence trait of fungal pathogens, conferring protection against various extrinsic insults and serving as a reservoir for the pathogen. C. auris has been reported to form high-burden, dense multilayer biofilms on skin surface, which may explain its ability to successfully colonize and persist on human skin and spread easily among patients [7, 15]. A recent study found that C. auris gained the ability for filamentation after passage through a mammalian body and described three distinct pheno-types: yeast, filamentation-competent yeast and filamen-tous-form cells, the latter being morphologically similar to true hyphae from C. albicans [16]. Intriguingly, filamentation in filamentous-form cells was supressed at 37°C, the human physiological temperature, but was promoted at lower temperature (25°C) [16]. Notably, this might explain the ability of C. auris to form robust biofilms on human skin, a niche generally cooler than the body core temperature, and to persist in the (hospital) environment. At the same time, when using standard RPMI medium, biofilms produced by C. auris are generally thinner, less complex and not as robust as biofilms formed by C. albicans. This observation has been attributed to a lack of true hyphae in C. auris biofilms under these standardized conditions; thus, for a long time, it has been hypothesized that C. auris is not capable of forming true hyphae at all [2, 3, 15, 17] However, growing evidence suggests that hyphal growth of C. auris is possible under specific circumstances, triggered by cues that are mostly different from those known for C. albicans filamentation (e.g. high salt concentration) [2]. This dissimilarity in hyphal growth triggers might reflect the commensal versus non-commensal nature of C. albicans and C. auris, respectively. In addition, a unique feature of C. auris is the aggregative phenotype, which describes the ability to form large aggregates or so called pseudohyphal-like cells, where mother and daughter cells remain attached to each other. Compared to their non-aggregated counterparts, these cells seem to be less virulent in infection models but can evade the immune system and show reduced susceptibility to antifungal treatment [2].

In comparison to other members of the Candida family, C. auris requires a compromised host immune system and thus, comorbidities such as an immunosuppressed state, advanced age, recent surgery, diabetes, application of indwelling medical devices, or the use of broad-spectrum antibiotics or antifungals (just to name a few) are major drivers of infection [2, 3]. In line, various reports indicate that also COVID-19 may be a risk factor for fungal infections [18-20]. Indeed, candidemia incidences are comparably higher in COVID-19 patients than in non-COVID-19 patients [8][21][22]. The weakened immune system due to the underlying viral infection as well as applied antiviral therapies may thereby result in higher vulnerability of COVID-19 patients [22]. Especially in healthcare settings, this seems to provide a perfect breeding ground for prolonged C. auris outbreaks, and several case studies all over the globe document co-infection of COVID-19 and C. auris in intensive care units (ICUs), resulting in devastating outcomes with mortality rates of up to 80%, despite adequate antifungal therapy [4, 18–20]. Furthermore, breakdown of routine infection prevention protocols, limited availability as well as prolonged use and/or reuse of protective equipment such as gloves or gowns, and/or alterations in cleaning and disinfection practices during the pandemic may have contributed to the spread of hospital-acquired pathogens such as C. auris [4, 14, 22].

Besides the unique characteristics of C. auris, a number of environmental factors may have contributed to the rise of this pathogen. For instance, global warming has been suggested to be key for the rapid emergence of C. auris from a putative plant saprophyte in specialized ecosystems that was adjusted to thermal conditions below the hu-man physiological temperature to a life-threatening human pathogen that has adapted to grow at the body temperature and has developed a significant thermotolerance [3, 23, 24]. Our modern lifestyle is constantly changing the environment, creating new habitats for infective agents and facilitating the spread of new pathogenic microbes [25]. Climate change supports the adaptation of microbes to higher temperatures, and the human basal temperature, which, so far, served as a thermal restriction zone for most fungi, will no longer provide this natural antifungal barrier with the same efficacy [23]. In that sense, C. auris is only a harbinger of the challenges we will have to face in the near and far future - and a call for immediate political and economic attention to much needed investment into basic and applied research of fungal biology and antifungal therapies.