Candida auris and COVID-19: A health threatening combination

Since its first emergence in December 2019, due to its fast distribution throughout the world, SARS-COV-2 become a global concern. With the extremely increased number of hospitalized patients, this situation provided a potential basis for the transmission of nosocomial infections. Candida auris is a multidrug-resistant pathogen with improved transmission dynamics and resistance traits. During the worldwide spread of COVID-19, cases or outbreaks of C. auris colonization or infection have been reported. Resistance to antifungal drugs has been observed in the causative agents of the majority of such cases. The focus in this review is on COVID-19-associated C. auris infections (case studies/outbreaks) and the pandemic's potential effect on antifungal drug resistance.


Introduction
evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the most significant global health event since Spanish influenza in the early 20th century, is alarmingly on the rising and threatens human health and public safety [1,2]. Unlike influenza outbreaks, coronavirus disease 2019  has spread fast all over the world, and over 100 countries have reported cases of this disease [1,3,4]. SARS-CoV-2 ranks third among members of the Coronavirus family regarding its pathogenicity; however, due to its rapid spreading, it has posed the severest threat to global health in this century [1].
The hospital mortality of COVID-19 is estimated to range from 15% to 20% and increases to 40% among patients requiring intensive care unit (ICU) admission [5]. Meanwhile, early estimates suggested that the true burden of disease and an actual number of deaths may be as much as 10 times higher than reported cases [4,6,7]. Patients with severe COVID-19 need intensive care, including mechanical ventilation, extracorporeal membrane oxygenation, continuous renal replacement therapy, glucocorticoids, and intravenous immuneglobulin therapy. These interventions could predispose patients to co-infections by different microorganisms including fungi (both filamentous fungi and yeasts) [8][9][10]. Co-infections by Candida auris, due to its persistence on hospital surfaces and high resistance to antifungal drugs, are of significant value, and COVID-19 has provided a potential bed for these infections [11,12]. Patients admitted to ICU have the greatest risk factors for such infections [11,13]. Antimicrobial resistance (AMR) as another threat to global health and the economy is likely to be overshadowed by the COVID-19 pandemic [2]. Currently, infections caused by antimicrobial-resistant pathogens are responsible for nearly 700,000 deaths every year worldwide. It can be anticipated that AMRrelated deaths due to the catastrophe status of the COVID-19 pandemic can reach up to 10 million deaths per year by 2050 if the world could not tackle these current states [14,15]. So far, cases or outbreaks of C. auris infection/colonization among COVID-19 patients have been reported [16][17][18]. In this study, we have a particular focus on the C. auris infection/colonization in patients with COVID-19 and the potential impact of this viral pandemic on antifungal drug resistance.

Candida auris in the era of COVID-19
C. auris, first isolated in Japan in 2009, is an emerging member of the Metschnikowiaceae family within the Candida/Clavispora clade [19]. To date, C. auris has been reported from at least 40 countries; therefore, it has a global distribution [11,20,21]. C. auris has been isolated as an infecting or colonizing agent from various specimens or parts of the human body including blood, urine, wounds, bile, the nares, the skin, the axilla, and the rectum of patients [22,23]. Furthermore, this fungus can survive on environmental surfaces and human skin for several weeks and can even tolerate some frequently used disinfectants [24][25][26]. These traits can be associated with intrahospital transmission of C. auris, leading to outbreaks [27,28]. In the past decade, C. auris has led to several outbreaks in hospitals worldwide and become a global health threat [29]. Invasive infections by this pathogen are usually observed in critically ill patients in ICUs and are related to high mortality rates [30].
COVID-19-associated C. auris infections (cases/outbreaks) are not limited to a specific geographical region. As shown in Figure 1, they have been reported from American, European, and Asian countries. Lack of reports from other parts of the world does not necessarily mean a lack of such infections, but Figure 1. Global distribution of COVID-19-associated C. auris infections (cases/outbreaks) (data for Panama is extracted from the WHO epidemiological alert [35]). a lack of sufficient data, which indicates the need for further studies.
Inter-clade difference in susceptibility pattern of C. auris is reported in some studies [48]. Results of the present review confirm the inter-clade difference. While all isolates of clades III and IV were resistant to at least one antifungal drug, 11 out of 18 isolates of clade I were susceptible to antifungal agents. As the available data might be still scarce to make a firm conclusion, special attention to genetic characterization of C. auris isolates in different studies would be beneficial in this regard and is recommended.
Due to some features, C. auris is more likely to cause a hospital outbreak than other Candida species [27,49,50]. Biofilm formation is one of these pathogenesis traits that lead to withstanding desiccation and persistence in environments and health care settings [51]. Elongated survival on environmental surfaces and healthcare-mediated exogenous transmission between patients are other facilitating factor for this fungus. As a result, outbreaks, which continue for several months and sometimes lead to the closing of intensive care units, continuously have been described [33,52]. During the current pandemic, the overload of ICUs has been a breeding ground for the emergence and expansion of C. auris [12,17,34,38]. Based on our literature review, 9 COVID-19-associated C. auris outbreaks have been reported [12, 17, 32-34, 38, 40, 47, 53]. It is noteworthy that in some of these countries including Lebanon, Brazil, Mexico, and Peru, no isolates of this pathogen had been noted prior to this period [12,32,35,38]. Details of the outbreaks are presented in Table 2.

The impact of COVID-19 on AMR
One of the unforeseen and unavoidable consequences of the COVID-19 pandemic is the appearance of antimicrobial resistance [54]. It is anticipated that too much and inappropriate use of antibiotics, disinfectants, and biocides during this pandemic may raise devastating effects on antifungal resistance control and antibiotic stewardship programs [15].
In the current pandemic, hospitalized patients with COVID-19 are more predisposed to superinfections with bacterial and/or fungal pathogens which is likely to impact the mortality rates [55]. This phenomenon is especially important in the case of emerging resistant species, such as C. auris [55]. An association between antibiotic use and the emergence of candidemia by Candida species with high minimum inhibitory concentration and/or intrinsic resistance to fluconazole has been reported [56,57]. Along the same line, up to 94% of COVID-19 hospitalized patients receive antimicrobial agents [58,59], which may increase the colonization rate of Candida species, such as C. auris [60]. In our literature review, results of antifungal susceptibility testing showed that 59 out of 70 (84.29%) isolates with available data were resistant to at least one antifungal drug. Among them, 31 (44.29%) isolates were multidrug resistant, which is 14.29% higher than the CDC report (30%) [61]. As shown in Table 2, in all reported COVID-19-associated C. auris outbreaks, drug-resistant isolates play a key role, and it makes the management more complicated.

Conclusion
With the increased hospital stay and the higher need for intensive care, COVID-19 patients are at risk for C. auris infections. Regarding the specific features of this fungus, it can circulate within clinical settings and cause outbreaks. Moreover, due to the different conditions in COVID-19 patients which are in favor of the selection of drug-resistant organisms, these patients are at risk for coinfections by single or multi-drug resistant C. auris. Accordingly, attempts for timely diagnosis and targeted treatment of such infections in COVID-19 patients should be made.