Potential pandemic pathogens series: Candida auris, an imposter among us?
Nederstigt1,2, L.G. Bakker3, D.J. van Westerloo1 and J. van Paassen1
1Department of Intensive Care, Leiden University Medical Center, Leiden, the Netherlands
2Department of Intensive Care, Tergooi Medical Center, Hilversum, the Netherlands
3Department of Medical Microbiology, Tergooi Medical Center, Hilversum, the Netherlands
Judith van Paassen, email@example.com
Potential pandemic pathogens series: Candida auris, an imposter among us?
The last two years we have experienced the effects of the COVID-19 pandemic. Since pandemics have been a part of the history of humanity, we can be certain of new pandemics to appear, even more frequently than in the past, due to growth in the human population, increased travel, global warming and increasing spillover events due to decreased barriers between animals and humans. In this series, each edition we highlight a different potential pandemic pathogen and describe its characteristics, history and potential for global pandemics. This time we discuss Candida auris.
Introduction of Candida auris
Candida auris derives its name from the ear of a Japanese woman (Auris means ear in Latin), from where the yeast was first sampled, isolated and sequenced in 2009 . After that, in 2011 in South Korea three patients had positive blood cultures with C. auris of two patients deceased despite treatment . In the years to follow retrospective studies revealed that C. auris was already cultured in clinical samples since 1996 . Furthermore it was discovered in other continents, its incidence was increasing, its resistance to antifungal medication was imminent and its pathogenicity in the seriously ill was a serious burden. Therefore C. auris is expected to become an increasing threat to our health care system. Do we have to be prepared?
The clinical picture is not that different from other Candida species, although C. auris colonizes preferably the skin, which may be an explanation for the high capacity for person-to-person spread (BRON EIX). It has also been isolated from invasive locations including urine, bile, blood and the gut and is generally hospital acquired. It is considered as an opportunistic pathogen, and invasive infections are associated with health care exposures and underlying conditions , such as polytrauma, cardiovascular disease, sepsis, diabetes and cancer [5, 6] and several outbreaks were reported from ICU COVID-19 units . Long-stay at a health care facility is probably one of the strongest predictors of C. auris colonization and infection [8, 9], especially for bloodstream infections .
In particular, the use of medical devices is associated with colonization including tracheostomy, mechanical ventilation, percutaneous gastrostomy or jejunostomy tubes and indwelling urinary catheters. [5, 9]. Broad spectrum antimicrobial treatment (carbapenems) and antifungal treatment are other predisposing factors for colonization. .
After its discovery, it soon became clear that C. auris was remarkable for its resistance to widely used antifungal regimens. Of C. auris isolates ninety percent is resistant to a least one antifungal medication and 30 percent to at least two  and it is shown that C. auris acquires further multidrug resistance rapidly in vitro . In some areas the estimated resistance to fluconazole is over ninety percent and resistance to amphotericin B, voriconazol and caspofungin is generally over twelve percent [13, 14], although percentages and MICs (minimal inhibitory concentrations of antimicrobials) vary widely among different geographic regions [13, 15]. Contrary, the susceptibility for micafungin and anidulafungin, is around 99 percent  and are recommended as initial therapy . Pan resistant isolates are emerging, especially in areas where patients have been treated with antifungal drugs [9, 17, 18]. In case of reduced susceptibility to echinocandins, liposomal amphotericin B can be considered if tested susceptible. For treatment of pan-resistant C. auris infections several forms of combination therapies are proposed but efficacy is varying and clade- and isolate specific . Treatment of colonization is not recommended and undesirable, since C. auris is difficult to irradicate and only adds to resistance . Besides antifungal therapy, replacement of medical devices (if possible) is necessary because of biofilm formation, which is an important mechanism for longstanding colonization of catheters and devices in Candida species [20, 21]. C. auris biofilms, though in some clades less effective compared to C. albicans biofilms, have been shown to be more resistant to antifungals than their planktonic equivalents [22, 23] and one study showed significant biofilm formation in specific conditions mimicking the (axillary) skin .
Globally, around 400 000 blood stream infections caused by Candida species occur annually with a mortality of 30-40 percent . From the limited studies available we learn that mortality from C. auris bloodstream infection is 30-45 percent but highly variable [13, 14, 26]. Furthermore, C. auris infection is relatively frequent complicated by distant septic metastases (as spondylodiscitis and endocarditis) in twelve percent of the patients . Because yeast infections occur most frequent in patients with compromised immune status, a long-standing serious illness, and serious pre- or coexistent extensive disease, it is difficult to distinguish whether mortality has a (partial) causal relationship to C. auris infections or C. auris is being the marker for poor prognosis at baseline.
Pandemic threat potential
Epidemiology and spread
As Candida auris is difficult to distinguish by macroscopic characteristics and traditional phenotypical methods
Done from other Candida species and misidentification was common, several surveillance studies researched old samples of Candida infections throughout the past decades that were stored [3, 26, 28, 29]. Then, it became clear that C. auris was already amongst us since 1996 and incidence was rapidly increasing. From 2013 an increasing incidence of C. auris was reported worldwide, peaking in 2016 and decreasing thereafter  (Figure 1) with currently continuous outbreaks in the Americas [30, 31] and Europe .
To date, five genetically diverse clades have been discovered . Although, spread of C. auris mainly occurs in health care facilities , reservoirs are also found in natural environments and on apples (handled by human) [34, 35]. Three clades of C. auris emerged on three different continents including Asia, Africa and South America. Sequencing analysis suggests near-simultaneous emergence of C. auris rather than recent spread from a single source [26, 36]. Various hypotheses are described explaining this mechanism, including the increased thermal resistance of fungi following global warming as this reduces the difference between ambient temperatures in which fungi preferably grow and mammalian basal temperatures. This mechanism would make human an increasingly suitable host [37, 38]. As isolates in the Unites States and Europe include multiple clades of C. auris, it is thought that repatriation of colonized patients and healthy travelers are the most plausible explanation for the occurrence of C. auris in these parts of the world [26, 39].
After discharge, clearance of C. auris is 62 percent in colonized patients, with clearance rates of 5.1 percent per 100 person-months  but the exact prevalence of C. auris in a healthy population is unknown. Epidemiological outpatient studies on Candida species in urinary tract infections and vaginal flora may be the best surrogates and generally find no C. auris among the isolates [41, 42] but, as C. auris has a history of misidentification in the past, these studies may be not representative.
After retyping stored Candida species, the first European case of C. auris occurred in 2007 in a patient that was repatriated from India to France . Thereafter several large outbreaks have been reported in the United Kingdom (50 cases, during 2015–2017) [44, 45], Spain (203 cases, during 2017–2019) , Italy (277 cases, from 2019) [32, 47] and Greece (74 cases, 2019-2021) . As isolates of patients during a local outbreak generally form a single genetic cluster [44, 45], it is likely that the admission of one colonized patient can be the starting point of a significant outbreak.
In 2018, in two different Dutch hospitals, two separate cases of C. auris were found. Both patients were of treated in a healthcare facility in India prior to admission . No further cases have been described since then. However, quality assessment to evaluate the ability of Dutch clinical microbiological laboratories to identify C. auris from 2019 showed that only 74 percent of the laboratories were able to identify C. auris correctly in the past. At present, widely used MALDI-TOF databases contain several C. auris spectra and it is likely that C. auris is correctly identified in the majority of the Dutch laboratories .
To date, several strategies to contain C. auris transmission in health care facilities are proposed and have been more or less successful . Based on these experiences, several guidelines and recommendations are developed with as agreement that early detection forms a corner-stone [6, 32] including prehospital screening of patients transferred from other healthcare facilities. Patients who are colonized or infected with C. auris should be isolated during their entire hospital stay and direct contacts should be screened including patients that are already discharged .
Detection of colonized patients is reliably done by rectal and skin swabs  and further surveillance is essential as C. auris specifically tends to colonize not only the human host but also its environment. Compared to other Candida species, C. auris shows higher resistance against various environmental stresses including long-term starvation and higher temperatures  and stays viable on plastic surfaces for weeks . In several studies during a local outbreak C. auris was isolated from sphygmomanometer cuffs, patient tables, keyboards, temperature probes and infusion pumps, indicating that C. auris spreads and dwells on surfaces in patient rooms [27, 44] and despite strict measures, new cases continue to appear including medical staff . Eradication from a health care facility usually takes a long standing joint effort including adherence to isolation and hygiene measures. C. auris is for example resistant to some common eradication methods such as ammonia and UV light, used in hospital cleaning [56, 57].
Although not frequently reported in the Dutch health care facilities yet, C. auris is among the most threatening nosocomial infections to date. Colonization of the environment persists for weeks and once a health care facility is contaminated, it is very difficult to eradicate C. auris permanently. Furthermore, C. auris colonizes and infects our most vulnerable patients, is increasingly resistant to antifungal drugs, and is associated with a high mortality. Carefully mounted protocols including guidelines on infection prevention, detection, treatment and eradication are needed to prevent further spread and outbreaks. Increased awareness of this treat to our healthcare system is essential.
All authors declare no conflict of interest. No funding or financial support was received.
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