Review Article | Volume: 9, Issue: 1, Jan-Feb, 2021

Multidrug-resistant Candida auris: A global challenge

Hardeep Kaur Khushbu Wadhwa Kusum Jain Anamika Yadav   

Open Access   

Published:  Jan 17, 2021

DOI: 10.7324/JABB.2021.9114
Abstract

Candida auris is an emerging fungal pathogen showing resistance to most of the currently available antifungal drugs. The pathogen is spreading rapidly worldwide. It mainly affects immunocompromised individuals such as intensive care unit patients, adults, and newborns who are treated in health care facilities. The isolates can be recovered from a variety of specimens, including mucocutaneous swabs, urine, respiratory specimens, and body fluids; however, bloodstream infections are the most commonly observed invasive infections. The advent of C. auris as a human fungal pathogen has been directly linked to the occurrence of new virulence traits and its ability to adhere to various surfaces to form a multidrug-resistant biofilm. With the lack of distinctive traits in C. auris, its identification has been problematic. The commercially available biochemical tests often misdiagnose the pathogen to phylogenetically related Candida haemulonii species making it difficult for clinicians to initiate proper antifungal treatment in patients. Emergence of resistant isolates has further posed a new challenge to the limited therapeutic options. This review highlights the risk factors involved in infection, virulence traits of C. auris, diagnostic methods, and mechanism of drug resistance along with novel antifungal drugs against this fungal pathogen which could provide direction for future work on it.


Keyword:     Azoles Echinocandins Pseudohyphae Multidrug resistance.


Citation:

Kaur H, Wadhwa K, Jain K, Yadav A. Multidrug-resistant Candida auris: A global challenge. J App Biol Biotech. 2021;9(1):104-113. DOI: 10.7324/JABB.2021.9114

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

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1. INTRODUCTION

The invasive candidemia is predominantly caused by Candida albicans and is defined as the most common nosocomial infection in the world. However, the paradigm has changed in the last few years with more incidence of candidiasis due to non-albicans Candida species (NACS) [1].

Candida auris, an emerging fungal species, has changed the basic insights about candidemia. Unlike other Candida species which are abundantly present in the gastrointestinal tract, C. auris is a good colonizer of the skin and is also responsible for invasive infections. It belongs to the order Saccharomycetales which are mainly ascomycetous yeasts that reproduce by budding. It was first identified in 2009 in an old Japanese lady suffering from ear infection (Latin: auris means “ear”) [2]. Fungemia due to C. auris is accompanied by a high mortality rate and the key factor behind this is treatment failure due to recalcitrant nature of the pathogen against most of the antifungal drugs [3]. The situation gets critical as scientists are still struggling to quickly and correctly identify this pathogen with the standard laboratory method. There is ample news of its incidence ranging from cases of C. auris infections in Venezuela in 2012 [4] to its occurrence in 2013 in the US [5], its emergence in a cardio-thoracic center in London in 2015-2016 [6] and in South Africa in 2016-2017 [7]. In the last 5 years, the pathogen has gained a worldwide presence in India, Pakistan, South Africa, Norway, Japan, Korea, Kuwait, Kenya, Israel, Canada, Venezuela, Spain, Germany, and many other countries [Figure 1] [8-12]. In the US, C. auris started spreading around 2015, and in the year 2018, there was about 318% increase in the number of reported cases [13]. As per the Centers for Disease Control and Prevention (CDC), the number of people afflicted by C. auris (only clinical case count) till September 22, 2020 in the US alone has risen to 1302 [13]. Candidiasis due to C. auris is not confined to any specific age group, affecting preterm infants as well as elderly patients. The report also highlights that majority of C. auris infections (more than 90%) are resistant to at least one antifungal and since there are limited antifungal drugs available, this becomes a frightening situation. The propensity with which this pathogen is spreading has indeed alarmed the world and made C. auris a worldwide menace.

Figure 1: Countries from which C. auris cases have been reported as of July 31, 2020. Source: https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html.



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1.1. Characteristics of C. auris

C. auris produces smooth white cream-colored colonies on Sabouraud’s agar and pink to beige colonies on CHROM agar. It forms oval or elongated shaped yeast cells that can be singly present or in pairs or groups and do not have the ability to form pseudohyphae, chlamydospores, and germ tube [14,15]. However, it has been found that under high stress and saline conditions, C. auris can form pseudohyphae [3]. It is able to grow at 37°C but exhibits thermotolerance (can grow even at 40°C–42°C) and is also able to grow on high saline conditions. This characteristic helps to differentiate C. auris from related species C. haemulonii and C. pseudohaemulonii that are not able to grow under these conditions. C. auris can ferment glucose, sucrose, and trehalose but does not have the capacity to ferment galactose, maltose, lactose, and raffinose. It does not have the ability to grow in the presence of 0.01% and 0.1% of cyclohexidine [16]. The haploid genomic size of C. auris is about 12.3 Mb with a 45.3% GC content [17]. Its genome analysis has established that there are 6500–8500 protein-coding sequences present; most of these genes encode for the virulence factors in Candida species. The sequence comparison of 285bp D1–D2 domain of the large ribosomal subunit of 28S ribosomal DNA gene of C. auris has shown that there is a significant variance of C. auris from other Candida species. In fact, a genetic analysis has further established that C. auris is more closely related to C. haemulonii and C. lusitaniae than to other Candida species [18] [Table 1]. Single nucleotide polymorphism (SNP) has been found in different isolates of C. auris gathered from different geographical regions, leading to its categorization into four clades [16,19-21].

Table 1: Percentage identity of C. auris with other Candida species using D1-D2 region of rDNA (Source: Jeffery-Smith et al. 2017 [18]).

OrganismPercentage
Identity
Candida auris (South Asian clade)100
Candida lusitaniae82
Candida haemulonii82
Candida tropicalis79
Candida famata75
Candida parapsilosis70
Candida albicans43
Candida krusei43
Candida glabrata42
Candida rugosa39

1.2. Identification of C. auris

The genetic variation of C. auris from other Candida species has led to a major problem of non-identification or misidentification of this pathogen in hospitalized patients using conventional biochemical typing [22]. This has led to inappropriate treatment which has resulted in the arrival of new resistant isolates. Therefore, newer methods of identifying and isolating C. auris from human and environmental sites that are rich in diverse microbes have been devised. Culture-based identification of C. auris has led to the development of enrichment broth assay that has been designed to screen out C. auris from the clinical and environmental samples. The method shows high sensitivity and specificity and has a very low cost. It facilitates easy detection of C. auris by exploiting its property to grow under high saline and high-temperature conditions. The broth consists of 10% salt, gentamicin, chloramphenicol, and either dulcitol, mannitol, or dextrose in Sabouraud broth or Yeast Nitrogen Base (YNB) Broth. All four clades of C. auris are able to grow under elevated temperature and salt conditions, but the closely related C. haemulonii, C. duobushaemulonii, C. pseudohaemulonii, and other Candida species (that are not closely related to C. auris) are not able to grow under these conditions [23].

The failure of commercially available biochemical identification test such as VITEK2 YST, API 20C AUX, BD Phoenix, and MicroScan in distinctly identifying C. auris from other related species is due to a lack of the relevant C. auris database in the identification system [Table 2]. However, for phenotypic yeast identification, BioMerieux has now updated the VITEK2 identification to software version 8.01 which is able to identify C. auris [24]. However, this updated software is not very competent in identifying C. auris isolates from African and East Asian clade but is able to identify isolates from South American clade [25].

Table 2: Misidentification of C. auris by commercial identification methods.

Method of IdentificationC. auris misidentified as
VITEK 2 YSTC. haemulonii,
C. duobushaemulonii
API 20CRhodotorula glutinis
C. sake
BD Phoenix yeast identification systemC. haemulonii
C. catenulata
MicroScanC. famata
C. guilliermondii
C. lusitaniae
C. parapsilosis
API ID32CC. sake
Saccharomyces kluyveri
RapID Yeast PlusC. parapsilosis

Source: Mizusawa et al., 2017, Desoubeaux et al., 2018, Forsberg et al., 2018, Iguchi et al., 2019 [91,92,39,35]

Matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry assay is the most reliable method for the identification of C. auris [26,27]. This method can provide the correct and consistent method of identification of C. auris, provided the spectral library contains the updated and validated reference spectra for all the clades and closely related species of C. auris. It is a proteome based low-cost technology. The mass spectrum provides a fingerprint for the particular fungal pathogen. The generated spectrum is very unique to every microorganism, with each peak specific to genera, species, and even strains. The MALDI-TOF MS approach is commercially provided by two manufacturers, Bruker Biotyper (Bruker Daltonics, Berman, Germany) and VITEK MS (BioMerieux). The Bruker Biotyper 3.1 software contains spectra of three C. auris strains: Two isolates from Korea and one from Japan. Both Bruker Biotyper and VITEK MS include C. auris in their research-use-only (RUO) library and FDA approved system databases [22,25,28]. In association with Biotyper, MicrobeNet recently has released the Biotyper Classification Module. The MicrobeNet database contains spectral libraries of all C. auris strains and its clades and provides the accurate identification of C. auris at species level [29,30].

Accurate identification of C. auris can also be done by sequencing of internal transcribed spacer (ITS) regions and D1/D2 region of 28S large ribosomal subunits. The development of PCR specific assay provides the easy identification of C. auris and its related species. The culture independent assay includes a TaqMan quantitative PCR (qPCR), a SYBR green qPCR, T2 magnetic resonance assay, and loop-mediated isothermal amplification (LAMP) [31]. These molecular-based methods also help to detect the resistance mutation in C. auris [32]. Both Fungiplex C. auris RUO real-time PCR assay (Bruker Daltonics) and the GPS™ MONODOSE dtec-qPCR test have also been found to be very useful in the correct identification of this pathogen [33,34]. However, C. auris identification is still a big challenge, especially in resource deficit countries and its misidentification often results in a treatment failure in most cases.

1.3. C. auris Infection and its Associated Risk Factors

Candidiasis due to C. auris includes both superficial infections as well as invasive diseases; however, bloodstream infections (BSI) cause significant mortality in intensive care unit (ICU) patients. The primary concerns of healthcare workers associated with C. auris are: Misidentification of the pathogen, its resistance to multiple antifungals, and its colonization to human body and environment that can result into outbreak like conditions in health care settings [23,35]. The situation gets aggravated by the fact that C. auris also has the ability to survive on biotic and abiotic surfaces for weeks and even for months resulting in further spread. Patient to patient transmission has been found to cause skin colonization and increased risk for candidemia. The hospital environment, therefore, serves as a reservoir for the nosocomial transmission of C. auris [36]. The risk factors that are significant for C. auris infections are almost same as with any other Candida species, as these are opportunistic fungal pathogens. These risk factors are related to severe underlying diseases and immunosuppression (such as bone marrow transplantation and HIV), long stay of patients in ICU, chronic kidney disease, malignancy, neutropenia, recent surgery, corticosteroid therapy, parenteral nutrition, blood transfusions, hemodialysis, diabetes mellitus, use of a broad-spectrum antibiotics or antifungals, prior or concomitant bacterial infections, use of central nervous and urinary catheters, and prolonged hospitalization [37]. Among these, patients suffering from diabetes mellitus and having a long stay in ICU are at major risk to develop C. auris fungemia.

1.4. Emergence of C. auris

The rapid emergence of C. auris around the world has led to some extensive research to understand its cause and pattern of transmission. Whole Genome Sequencing (WGS) of C. auris isolates demonstrated the independent emergence of four different clades in different geographical locations, thus dispelling all doubts of the spread of one clone from a single source to different regions of the world [17,20]. These geographically specific clades have been described as: South Asian (India, Pakistan), East Asian (Japan), South African, South American (Venezuela), and each is separated by around thousands of single nucleotide polymorphism (SNP) [38]. Isolates belonging to the same clade are highly related to each other or nearly clonal and have very less genetic variation. Further, WGS studies on C. auris isolates from four different Indian hospitals found them to be highly related or exhibits less genetic diversity and confirmed the clonal transmission of the isolates [17]. The results were also similar from Pakistan, South Africa, and Venezuela [20]. This further confirmed that isolates within each country or same clade are highly related to each other and differ by less than a hundred SNP as compared to isolates from different regions that differed by thousands of SNP [20,39]. All major clades except for the East Asian clade have been linked to outbreaks causing invasive infections [40]. It has been found that isolates from East Asian clade are involved in causing ear colonization and external otitis. It also shows higher genetic diversity as compared to other clades which often indicates an older natural population and therefore it can be the ancestor of C. auris [40]. Recently, another fifth clade has appeared in Iran, where the patient has never travelled abroad and the fungal isolate of this clade was found to be susceptible to the antifungal drugs [41]. The clade is genetically very different from all the other clades with >200,000 SNPs compared with the other four clades.

Many factors are considered to be responsible for the emergence of new C. auris strains. Changes in the ecological niche of this fungus and its tolerance to divergent environment conditions such as high temperature and salt conditions might contribute in the development of various virulence traits [40,42]. As the temperature on earth and atmosphere increases, the difference between optimal temperature of the environment and mammalian body temperature will become lesser and lesser; and the emergence of new invasive fungal pathogen can take place [40,43]. This further raises a pertinent question that if this is true, then how will the scientific community ensure that other fungal pathogens do not follow C. auris in adapting to non-ambient temperatures in a similar manner.

1.5. Antifungal Drug Resistance

The key to the right treatment with an antifungal agent depends on the accurate identification of the type of C. auris strain involved in the infection [44]. The pathogen develops resistance very rapidly while the patient is still undergoing treatment, that’s why it is very essential to use the antifungals at the right time and in the correct dosage [18]. Unfortunately, the antifungals against Candida infections are limited to three basic drugs – azoles, echinocandins, and polyenes (Amphotericin B). C. auris shows resistance to antifungal drugs such as fluconazole (FLC) and amphotericin B [29]. Most of the C. auris isolates show susceptibility toward the echinocandin class of antifungals. However, at present, no antifungal can be defined as the absolute drug of choice to combat C. auris.

Azole resistance in C. auris: The C. auris isolates that show resistance to azole class of antifungals are found to have increased expression of ABC (ATP-binding cassette) and MFS (Major facilitator superfamily) transporters. These transporters help in the efflux of azole compounds from the fungal cell [45] [Figure 2]. Inside the yeast cells, these azole compounds work by inhibiting the enzyme 14a-lanosterol demethylase that mainly functions in the biosynthesis of ergosterol in the cell membrane of the yeast by removing the methyl group from the lanosterol. Ergosterol is an important component of cell membrane which helps in maintaining the integrity of the cell and the inhibition of enzyme leads to the accumulation of toxic precursors in a cell which can inhibit the growth of a fungal cell. Point mutation in ERG11 gene that encodes 14a-lanosterol demethylase enzyme leads to altered protein structure, reduced binding of azole drugs to the target molecule, decreased susceptibility of the pathogen to azole that will exhibit elevated Minimum Inhibitory Concentration (MIC) to azole [Figure 3]. Whole-genome sequencing (WGS) has identified three different types of amino acid substitution in ERG11 gene that are associated with azole resistance in C. auris. These mutations in ERG11 gene are found to be very specifically associated with the geographical clade. Isolates from South Africa and South America (Venezuela) share F126L alterations, while Indian isolates harbor Y132F and K143R substitutions [20,31,46,47]. The association between each mutation and geographical clade shows that resistance to fluconazole is acquired independently and is not intrinsic in nature [48]. However, based on antifungal susceptibility testing, it has been reported that isolate from East Asian clade shows less resistance to antifungal drug as compared to isolates from other three clades [49].

Figure 2: Overexpression of (a) ABC efflux pump and (b) MFS efflux pump in azole-resistant C. auris. Source: Adapted from Whaley et al., 2017 [90].



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Figure 3: Mutation in ERG11 leads to expression of proteins with reduced affinity for fluconazole binding. Source: Adapted from Whaley et al., 2017 [90].



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Echinocandin resistance in C. auris: Most of the C. auris isolates exhibits elevated MIC and reduced susceptibility to triazole and amphotericin B class of antifungal agent. This has led to a recommendation for the use of echinocandins in the treatment of invasive candidiasis. Micafungin, a promising echinocandin, proved to be more useful in treating invasive candidemia as compared to fluconazole and amphotericin B. However, due to extensive and indiscriminate use of echinocandins, many of the C. auris isolates are increasingly becoming resistant to this drug [50,51]. Draft genome sequencing of C. auris has established that it contains single copy of ERG3, ERG11, FKS1, FKS2, FKS3, and a substantial portion encodes for the ABC and MFS transporters that demonstrate multidrug resistance in this emerging pathogen [17,19,51]. FKS1 gene encodes b-1,3-D-glucan synthase enzyme and represents the potential target for echinocandin class of antifungal. This enzyme plays a crucial role in the biosynthesis of b-1,3-D glucan, a major component of the Candida cell wall. It is composed of two subunits named as FKS1p (encoded by FKS1, FKS2, FKS3) and Rho1p. FKS1p is a catalytic subunit of the enzyme, while Rho1p is a regulatory protein involved in cellular processes, one being the synthesis of b-1,3-D glucan. Inhibition of glucan synthase enzyme by echinocandin results in cell wall lysis and osmotic instability in a cell. Reduced susceptibility to echinocandin mainly occurs through three main mechanisms (a) acquired FKS resistance mutation which results in reduced glucan synthase enzymatic activity and elevated MIC to Echinocandins, (b) intrinsic FKS mutations, (c) and adaptive stress response that results in increased chitin content in the cell wall of fungi. In most of the Candida species, there are mainly two hotspot regions in FKS gene, named as Hotspot-1 (HS1) and Hotspot-2 (HS2) at which amino acid substitution can decrease the echinocandin susceptibility [52-54]. However, in C. auris, mutation responsible for resistance occurs as a single amino acid substitution S639Y in FKS1, in Hotspot 1 (HS1) region. This amino acid substitution is equivalent to S645 and S629 in C. albicans and C. glabrata, respectively.

In general, two different substitutions have been identified in C. auris, S639F and S639P [55,56]. In C. albicans and C. glabrata, the substitution of a phenylalanine (F) results in only a moderate increase in MIC while substitution of proline (P) results in dramatic increase in MIC to echinocandin. For C. auris, these both amino acid substitutions result in about 4–8 fold increase in echinocandin MIC values [56]. In response to inhibition of glucan synthase enzyme by echinocandins, there is activation of compensatory pathways, which results in the increased synthesis of chitin in the fungal cell wall. The biosynthesis of chitin occurs through the protein kinase C (PKC), high osmolarity glycerol kinase (HOG Kinase), and by Ca2+ calcineurin signaling pathways. Echinocandins are mainly excreted through feces rather than the urine, so very little active drug can be recovered from the urine. The site of infection plays a crucial role in the choice of antifungal agent for the treatment of invasive infections. Echinocandins have high molecular weight; hence, these drugs have inadequate penetration into many sites, including cerebrospinal fluid (CSF). Treatment with this drug in infants and neonates is considered only when the central nervous system (CNS) is not affected. Hence, other medications (amphotericin B with 5-Flourocytosine/ 5-Flucytosine) should be used for CNS and renal tract infections [18,56,57]. Further, CDC recommends amphotericin B deoxycholate (1mg/kg daily) as the first-line treatment in neonates [39].

C) Polyene (Amphotericin-B) resistance in C. auris: Several C. auris isolates have been found to be resistant to amphotericin B [16]. In almost all cases, it is the modification of the membrane viz a viz its sterol composition that seems to be the cause of resistance to this family of antifungal agents.

The role of molecular chaperone Hsp90 in maintaining resistance toward antifungal drugs in various fungal species has also been recently established in C. auris. Hsp90 was found to be very important for growth in C. auris. It helps clinical isolates to develop tolerance to azoles, thus leading to the development of drug resistance in susceptible strains and this further inhibits biosynthesis of the membrane ergosterol [58]. It was also established that deletion of HSP90 gene leads to morphogenetic transformation of C. auris from yeast to filamentous growth.

Another mechanism of drug resistance takes advantage of morphological plasticity of Candida that is dependent on changing environmental factors. These morphological changes in C. albicans include yeast-filament transition and white-opaque colony transition [59,60]. It is well documented that filamentous Candida has high virulence and leads to systemic infections and is mostly associated with drug resistance. Furthermore, the white cells are more virulent than the opaque ones and are more common in systemic infections. It was a common belief that C. auris lacks pseudohyphae or hyphal morphology and therefore does not actively form any biofilms. However, contrary to this, it has been found that certain strains of C. auris undergo morphological switching under certain temperature fluctuations and this is further aided by passage of C. auris through mammalian system [60]. One significant difference that was found in this study was that unlike change of morphogenesis from yeast to hyphal form that ensued at high temperature in C. albicans [59], reverse was true for C. auris [60]. The characteristic biofilm formation by C. albicans with an intricate network of hyphae embedded in the extracellular matrix (ECM) was, however, not well developed in C. auris where there is mere adherence or clumping of yeast cells to surfaces. However, despite this very elementary biofilm architecture of C. auris, it still is found to be resistant to all major antifungals [61].

1.6. Biofilm Formation in C. auris

Biofilm can be defined as microbial community sticking to each other and to the surface. The growth of a microorganism in association with the surface is called as a biofilm. In biofilm, organism grows as a community rather than separate surface adherent cells. The cells of a biofilm have a capacity to produce their own extracellular matrix and show specific phenotypes that are different from the phenotypes of a cell growing in suspension called as planktonic cells. The use of devices such as central venous catheters, urinary bladder catheters, and mechanical heart valves are the major risk factors to develop infections that are mainly caused by Candida species. These infections arise due to the ability of fungal cells to adhere to devices and their growth occurs in the form of a biofilm [62]. There are mainly three stages involved in the formation and development of biofilm in C. auris (i) attachment or adherence of yeast cells to the surface, (ii) proliferation of yeast cells by the process of budding, and (iii) maturation into a structural biofilm [63]. The biofilm consists of yeast cell and hyphae embedded in matrix. ECM is composed of various kinds of polysaccharides, protein, and lipids [64], and it provides a surface for adhesion and helps in maintaining the structure of a biofilm. It also helps in the absorption of nutrients and retention of water. ECM is degraded during the nutrient limiting conditions to provide the carbon and nitrogen source to fungal cells [62]. The polysaccharide, glucan, and mannose component of ECM helps in sequestration of the antifungal drugs. The production of a matrix in biofilm is associated with the stress response regulatory pathways such as calcium/calcineurin signaling pathways. The molecular chaperone Hsp90 is required for the production of a mature biofilm. Many of the transcriptional factors are also involved in the biosynthesis of ECM matrix. Zinc sensing transcription factor negatively regulates the production of matrix, while RLM1 (transcription factor involved in cell wall integrity) acts as a positive regulator for the formation of matrix [64]. The ECM contributes in the pathogenicity by promoting the immune evasion.

Biofilm formation is very important for pathogenicity in Candida species. C. auris exhibits minimal adherence to silicone elastomer material as compared to C. albicans; hence, it plays much less role in catheter-associated candidiasis as compared to C. albicans that is generally known to cause such type of infections [65]. Phenotypic observation of biofilm has further revealed that C. auris biofilm is intermediate to C. albicans and C. glabrata [61]. C. auris exhibits more propensities to survive on a wide range of surfaces, including dry, moist, and plastic surfaces as compared to C. albicans [23,66].

Experiments have been done to determine the pathogenicity and virulence of C. auris viz a viz other Candida species by using invertebrate Galleria mellonella insect model. C. auris shows two patterns of cellular morphology, one forming aggregates while the other is non-aggregating type. Non-aggregating form of C. auris was found to have more biofilm-forming capacity compared to aggregating strains of C. auris. It also exhibited greater pathogenicity as compared to aggregate forming isolates as well as C. albicans, and resulted into a significantly higher larval death of G. mellonella with much less inoculum concentration [63]. Dissection of larva inoculated with C. albicans was found to have more hyphal proliferation in the hemolymph. However, larva infected with C. auris strains on dissection did not show any such hyphal or pseudohyphal growth. Larvae that had received non-aggregate strains of C. auris exhibited large number of budding yeast cells in hemolymph, while larva infected with aggregate forming strains of C. auris exhibited fewer single yeast cells and contained large aggregates of yeast cells. These aggregate isolates are formed due to the inability of C. auris to separate out its daughter cell after the budding and they were resilient to separation even by physical disruption methods [3].

During formation of biofilm in Candida species, several genes are upregulated. Transcriptomic analysis shows that adhesion-related glycosylphosphatidylinositol (GPI) anchored cell wall genes (CSA1, PGA26, PGA52) are expressed much earlier when the biofilm formation has just started. As the formation of biofilm enters into intermediate and mature stages, the expression of genes coding for ABC (SNQ2, CDR1) and MFS (YHD3, MDR1) and MFS (YHD3, MDR1) transporters is also increased. These genes control the efflux pump activity of the transporters and are found to be more upregulated in mature biofilm in C. auris [44,67]. The upregulation of these genes seems to occur more in sessile cells as compared to planktonic cells and also confirms that formation of biofilm promotes antifungal drug resistance and virulence in the fungi.

1.7. Antifungal Drug Resistance in Biofilm

A study has been done to determine the effect of various antifungals on the sessile and planktonic cells of the biofilm. It has been found that both sessile and planktonic cells exhibit enhanced resistance to fluconazole (FLC) and voriconazole (VRC). Both sessile and planktonic cells were found to exhibit increased MIC against the FLC (MIC > 32 mg/L) and VRC [61]. The resistance to FLC and VRC is the result of overexpression of efflux pump transporters in cells. Both sessile and planktonic cells exhibit susceptibility to liposomal amphotericin B, but sessile cells require about 16 mg/L of amphotericin B as compared to planktonic cells which require 4 mg/L. Echinocandins are ineffective to sessile cells, but planktonic cells are susceptible to it. Micafungin is the most effective echinocandin that requires <0.5 mg/L to inhibit planktonic cells, while caspofungin requires 2–32 mg/L to inhibit planktonic cells. To inhibit sessile cells, both micafungin and caspofungin requires >32 mg/L [18,61].

1.8. Hog1 Regulates Stress Tolerance and Virulence in C. auris

Despite having genetic divergence, C. auris has been found to exhibit much higher virulence and pathogenicity as compared to the other pathogenic Candida species. However, C. auris is incapable to show phenotypic switching from yeast to filamentous growth; hence, it must be using different strategies to infect and colonize the host. An important feature that is essential for the virulence and pathogenicity of an organism is its ability to survive in different kinds of divergent environments. The cellular stress response plays a pivotal role in tolerating various stress conditions imposed by host during the infection. The niches colonized by fungi in the human host are dynamic. These niches show fluctuations in the osmolarity, pH, and the availability of nutrients [68]. To cope up with various stress conditions, C. auris has been found to contain stress sensing pathways in which Hog1 related stress-activated protein kinase (SAPK) plays an important role. The Hog1 SAPK is the most conserved fungal protein that helps in stress sensing and signaling. To determine the role of Hog1 SAPK in C. auris, the Hog1-deleted strains of C. auris were exposed to various kinds of diverse environments and results were examined. Cells deficient in Hog1 were found to be very sensitive to the high concentration of NaCl and KCl. Hog1 was also found to be important for the growth of C. auris in highly acidic environments [69].

1.9. Novel Antifungal Used against C. auris

The rising incidence of resistance in C. auris to triazole drugs and amphotericin B has led to use of echinocandins as the first line of treatment [70-72]. Micafungin has also been found to have higher efficacy as compared to fluconazole and amphotericin B in a PK/PD (pharmacokinetics/pharmacodynamic) study of C. auris candidemia in mice [73]. However, with the alarming rise of antifungal resistance, there is an urgent need to develop new antifungal therapies for the control of C. auris infection. The new antifungal compounds that have been developed show promising results against C. auris. These new compounds have various drug targets such as b-glucan synthase inhibitors, enzymes involved in chitin synthesis, and GPI anchored protein [63].

Ibrexafungerp (commonly called as SCY-078) is the new antifungal drug and is currently in a phase III trial for invasive infections caused by C. auris. SCY-078 is a triterpene [65], orally available glucan synthase inhibitor that has been shown to exhibit anti-biofilm activity against most Candida species. It leads to cellular deformation, pore formation in fungal cells, and inhibits cell division [36]. When C. auris strains are treated with the SCY-078, it reduces the thickness of biofilm and also decreases the metabolic activity of the fungal cells in the biofilm [65].

Isavuconazole sulfate is the new second-generation triazoles which demonstrate better results in vitro against the fluconazole-resistant C. auris strains [65,74]. The new antifungal rezafungin (CD101) is a novel semisynthetic echinocandin with long-acting chemical stability and shows activity against the C. auris strains [63,75]. The other new antifungal with a novel mechanism of action is APX001 which has currently completed the second clinical trial. This antifungal targets the glycosylphosphatidylinositol (GPI) synthesis by inhibiting the cell wall transfer protein GWT1 (glycosylphosphatidylinositol-anchored wall transfer protein 1) and can prove effective against C. auris [76]. Another new antifungal VT-1598 targets the lanosterol demethylase enzyme and has been found to have in vitro activity against C. auris [77]. In addition to these new antifungal drugs, research is going on to characterize new antifungal with a drug target mechanism which includes molecular chaperone Hsp90 and calcium calcineurin signaling pathways. Continued research, evaluation, and clinical studies are required to check the potential of existing compounds and new compounds against multi drug-resistant C. auris isolates.

1.10. Role of Anti-CR3-RP Polyclonal Antibody against C. auris Biofilm

Candida sp. exhibits virulence-associated surface antigen called as complement receptor-3 related protein (CR3-RP). C. auris also possess this cell surface protein that plays an important role in adhesion during the formation of biofilm. It has been found that polyclonal antibody anti-CR3-RP antibody directed against this surface antigen can be used to reduce the adherence and biofilm formation in C. auris [78]. It was further seen that these antibodies also demonstrated activity against C. auris 24 h pre-formed biofilms almost to the same level as achieved with conventionally used antifungals.

1.11. Role of NDA-3V Vaccine against the Multidrug-resistant C. auris

C. auris has been found to possess an evolutionarily conserved adhesion protein Als3p, which is very essential for the early stages of a biofilm in fungi [79]. Anti-Als3p antibodies have been generated by vaccinating the mice with a NDA-3V vaccine which is formed from N-terminus of the Als3p protein [80]. The vaccine induces the formation of antibody and cell-mediated immune responses in a host cell. These anti-als3p antibodies act as opsonins and increase the sensitivity of C. auris to macrophage killing by the process of phagocytosis [80]. The vaccine has shown high efficacy in a clinical trial that has been done against vulvovaginal candidiasis.

1.12. Infection Control and Prevention

The emergence of C. auris has grown to the proportion of an outbreak in many countries, with the situation becoming grave due to the persistence of the pathogen in the face of regular antifungals [28,81-84]. An exhaustive study of 350 isolates of C. auris from 10 hospitals in India has found about 90% of the strains resistant to azoles [85]. However, the degree of azole resistance has been found to be highly variable with isolates collected from different geographical regions, further suggesting the rate of resistance to be a localized phenomenon and place dependent [85-87]. It has further been seen that the minimum time needed to acquire infection from a patient suffering with C. auris infection or from his immediate environment is about 4h or less [6]. Being predominantly a nosocomial infection, there exists a direct correlation of usage of contaminated central venous catheter (CVC), urethral catheters, and long hospital stay with the occurrence of C. auris cases, especially in ICUs. In fact method of containment of this fungal infection is largely dependent on understanding its mode of transmission.

The proper implementation of infection control practices is very essential to prevent C. auris outbreak like conditions in hospitals. To prevent C. auris transmission through patients and medical equipment, its presence in the environment must be recognized and effective control measures should be taken up. Thorough hand cleaning with soap or alcohol-based sanitizer should be done before and after coming in contact with the patient or contaminated environment. Patients suffering from C. auris infection should be kept in a separate single room or in isolation and use of personal protective equipment (PPE) should be made mandatory for caregivers to such patients. Disinfectants must be used to completely destroy C. auris from the patient room, mobile devices such as temperature probes, glucometers, and ultrasound probes. The quaternary ammonium compounds (QAC) are the most widely used disinfectant in healthcare settings, but they are found to be ineffective against C. auris [25]. Disinfectant such as chlorhexidine gluconate, iodinated povidone, and chlorine-based disinfectant should be used. CDC recommends that patients should be screened by taking swab samples from the regions of groin and axilla (these sites are considered to be the most persistently positive sites). C. auris has the ability to survive on plastic surfaces where it can survive up to 14 days. For the efficient removal of C. auris from these surfaces, sodium hypochlorite (NaOCl) and per-acetic acid should be used. These disinfectants have the ability to kill C. auris from all surfaces. Despite all these treatments, some viable cells of C. auris are found to remain on non-porous surfaces like stainless steels [88]. Therefore, higher concentration of this disinfectant with a longer period of exposure time helps to reduce the regrowth of C. auris. Ultraviolet light also seems to show good result for the surface disinfection, but the density of C. auris, time of exposure of UV-C to C. auris, and distance to UV source plays an important role in the effective treatment [89]. However, persistence of C. auris in a hospital environment despite proper disinfection highlights the tenacity of this pathogen and its strong interaction with surfaces poses a continuous threat, especially in health care facilities.


2. CONCLUSION

The emergence of C. auris as pathogenic fungi is a major concern among clinical microbiologists. This is the first species in the actinomycetes that can rapidly develop antifungal resistance mechanism and also maintains these mechanisms throughout its generations. The development of novel diagnostic and treatment methods holds a promise for the control of infection by these pathogenic fungi. A close collaboration should be needed between the various clinical laboratories and medical teams to control the nosocomial transmission of C. auris.

Accurate identification of this species is very essential to prevent its outbreak. Till date, the scientific community is perplexed with its sudden emergence, the propensity with which it is affecting immunocompromised individuals, its transmission dynamics, its evolving antibiotic resistance, and its eventual impact on mortality of patients. Clearly, it is not a simple ear infection as its name suggests but could lead to invasive fatal infection. There are many unanswered questions regarding C. auris and continued research into the matter has the potential to reveal solutions to these puzzling queries.


3. AUTHORS’ CONTRIBUTIONS STATEMENT

The authors declare that there are no competing interests. The article was conceived by HK; written by HK and KW; and reviewed by KJ and AY.


4. ACKNOWLEDGMENT

The authors express gratitude to Principal, Ramjas College, University of Delhi, for his constant encouragement. Thanks are also due to Professor Anuradha Chowdhary, Department of Mycology at VP Chest Institute, for her never-ending support and guidance. KW, KJ, and AY also wish to acknowledge Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC) for financial support in the form of Junior Research fellowships.


5. CONFLICTS OF INTEREST

Authors declared that they do not have any conflicts of interest.


6. FUNDING

None.

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