Summary

Candida auris was first isolated in Japan in 2009. It has since been reported in more than 25 countries worldwide. This species, which can cause invasive infections with high mortality rates, is difficult to identify with traditional biochemical methods. C. auris can be transmitted among hospitalized patients by colonizing the skin. Resistance to fluconazole and amphotericin B is common in this species, and resistance to echinocandins, which are preferred in the treatment in some countries, is seen to develop. Studies have shown that resistance to antifungals is acquired, not intrinsic, and primary resistance mechanisms against echinocandins and azoles have been identified. This species is difficult to control because of its multidrug resistance, even the emergence of pan-resistant strains, misidentification with conventional methods in clinical microbiology laboratories, and long-term persistence in the hospital environment. In order to prevent infections with infection control measures, advanced laboratory methods that allow accurate diagnosis is needed. In addition, new antifungal agents should be researched and included in practice in order to ensure success in treatment. In this short review, current information about the epidemiology, infections, microbiological features and laboratory diagnosis of C. auris is mentioned.

Keywords:

Candida auris, diagnosis, antifungal drug resistance, Candida

Introduction

Invasive fungal infections increase the mortality rate in hospitalized patients with underlying diseases and especially in immunocompromised patients^[1-4]. Candida spp. is the most frequently isolated species among invasive fungal infections. These yeasts are commensal in healthy humans and can cause systemic infections in case of immunosuppression due to their ability to adapt easily to different hosts. The genus Candida includes approximately 500 species, and at least 30 species infect humans. More than 90% of invasive infections are caused by C. albicans, C. glabrata, C. parapsilosis, C. dubliniensis, C. tropicalis and C. krusei. However, C. auris, which has been resistant to multiple drugs in recent years, also poses a threat to public health^[5-7]. Studies on the sequencing of the 28S D1/D2 and 18S ITS regions show that C. auris belongs to the Metscnikowiaceae family. C. auris is a member of the CTG lineage, such as C. albicans, C. tropicalis, C. haemulonii and C. lusitaniae species of the genus Candida/Clavispora^[8]. C. auris was first isolated from the outer eardrum of a patient in Japan in 2009 and was named C. auris because of the Latin word “auris” meaning “ear”^[9]. After a long process, the second patient was detected in Japan in 2017 and five more C. auris strains were isolated in 2018^{[10, 11]}.

Although initially assumed to be a rare pathogen, less than 10 years after its initial isolation, it has begun to be detected in increasing numbers all over the world. However, since this species is difficult to identify using conventional and biochemical methods, data on its incidence and prevalence are not yet clear^{[12, 13]}. This review aimed to provide information about the epidemiology, infections, laboratory diagnosis and antifungal drug sensitivity of C. auris.

Epidemiology and Risk Factors

C. auris was first isolated from the ear secretion of a 70-year-old patient in Japan in 2009. However, in a retrospective study of Candida strains in South Korea, it was reported that the oldest known C. auris strain was isolated from the blood of a child in South Korea in 1996 and was initially misidentified as C. haemulonii^{[8, 14, 5]}. As of August 2016, the CDC began collecting epidemic data in the United States, and seven new patients were registered within the first month. In the latest CDC report, as of 2020, one patient with C. auris was reported from Austria, Belgium, Chile, Costa Rica, Egypt, Greece, Italy, Iran, Norway, Poland, Switzerland, Taiwan, Thailand and the United Arab Emirates; while multiple patients with C. auris were reported from Australia, Bangladesh, Canada, China, Colombia, France, Germany, India, Israel, Japan, Kenya, Kuwait, Malaysia, Netherlands, Oman, Pakistan, Panama, Russia, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sudan, the United Kingdom, the United States, and Venezuela. In Turkey, Kurt et al.^[16] reported the first C. auris isolation from an 81-year-old patient with fungemia, Bölükbaşı et al.^[17] reported the first C. auris isolation from a Coronavirus disease-2019 positive patient, and Kömeç et al.^[18] reported three patients with C. auris in another study.

In genome analysis studies to determine the clonal link between C. auris strains in epidemic and sporadic patients, it has been observed that the strains are clonally close but have slight differences from each other, and therefore the emergence of C. auris is independent and each one spreads locally^[19].

Based on the genomic information and the regions where the first strains were isolated, four main clades of C. auris were identified as South Asia (I), East Asia (II), South Africa (III), and South America (IV). There are very few single nucleotide polymorphisms (SNPs) in each segment. Recently, a new
C. auris line (Clade V) has been reported in Iran and this clade differs from the others by more than 200 000 SNPs. Whole genome sequencing (WGS) analyzes revealed that the first four genetically distinct clades of C. auris appear independently and almost simultaneously in different regions on three continents^{[8, 20]}. While the East Asian clade is seen to infect only the ear, other clades are known to cause invasive infections, hospital-acquired infections and epidemics^[20].

Although C. auris is closely related to other Candida species in nature, its isolation from environmental sources has not been found. In a study conducted in the Netherlands, it was reported that C. auris was isolated from swimming pools, but it was reported that this situation was caused by pool visitors. On the other hand, some studies have suggested that the emergence of C. auris may have resulted from climate change, especially global warming, and that wetlands may have natural ecological niches due to their resistance to high temperature and salt concentration^{[8, 20]}.

The risk factors for infections due to C. auris are generally similar to those of infections with the genus Candida. Suppression of the immune system, use of broad-spectrum antibiotics and antifungal drugs, presence of important medical comorbidities (diabetes mellitus, lung disease, cardiovascular disease, chronic kidney disease, presence of malignancy), presence of central venous catheter/urinary catheter/post-operative drain, parenteral nutrition, bacteremia, candiduria, chemotherapy, blood transfusions, hemodialysis, bone marrow suppression, prolonged stay in the intensive care unit are among these risk factors^[21-25]. Intensive care patients, premature newborns and elderly patients are risky groups. Candidemias due to C. auris typically occur several weeks after hospitalization. Mortality rates due to infection range from 30% to 72%. Variability in mortality rates depends on the extent of infection, age and age-related risk factors, and various factors such as comorbid conditions. Studies have shown that the increase in C. auris colonization or infection is associated with diarrhea and the use of tetracycline, a broad-spectrum antibiotic, and the use of minocycline and tigecycline, which are second-generation tetracycline derivatives, and that infections are more common in males^{[8, 24, 26]}.

Its Virulence Factors and Infections it Causes

C. auris has many virulence features similar to C. albicans. Pathways involved in enzyme secretion, nutrient uptake, siderophore-based iron uptake, tissue invasion, the bicomponent histidine kinase system, and cell wall modeling are some of these similarities. Virulence factors may vary depending on the strain. Studies have shown that different C. auris strains secrete different levels of phospholipase and proteinase, can evade the attack of neutrophils and innate immunity, and have a lower ability to stimulate cytokine release and phagocytosis compared to C. albicans. Although it can form a biofilm that allows it to adhere to various surfaces, this feature varies depending on the strain. Due to the rarity of pseudohyphae formation, its ability to form biofilms and adhere to tissue is less than C. albicans. C. auris is divided into two groups according to its aggregation feature. As a result of the inability of the daughter cells to separate from the mother cell after budding, a large cell aggregation occurs, which is difficult to break down with disinfectants. Non-clustered strains have been shown to be more pathogenic than aggregates and C. albicans. Aggregation, thermotolerance and osmotolerance are the properties of C. auris that contribute to its longevity and viability on biotic and abiotic surfaces. Its persistence on surfaces is important because it is one of the factors leading to in-hospital contamination^{[8, 25]}.

The clinic of C. auris infections is similar to that of other Candida infections. C. auris is isolated from body parts such as nose, pharynx, lung, pleural cavity, heart, liver, abdominal cavity, ear, vagina, armpit, bone, groin, brain, and clinical specimens such as blood, sputum, feces, urine, surgical tissue. Studies have shown that strains isolated from the genitourinary system, skin, soft tissue and lungs are the representatives of the colonized group rather than the actual infection^{[12, 27-30]}.

Complications of invasive C. auris infections vary depending on the extent of infection, host comorbidities, and resistance patterns^[25]. C. auris can cause fungemia, myocarditis, vulvovaginitis, urinary tract infection, surgical wound infections, burn infections, skin abscesses, malignant otitis, meningitis, complicated intra-abdominal infections, pericarditis and bone infections^{[15, 31-33]}.

C. auris, which most commonly causes fungemia, spreads to different organs by hematogenous route and causes multi-organ dysfunction. On the contrary, dissemination of a localized infection causes multi-organ system failure and death^[25].

C. auris can be easily transmitted from person to person. Patients colonized with this strain are a source of contamination for other patients. Colonization occurs a few hours to several days after contact with the microorganism, while invasive infection occurs within days or months after colonization. Colonization with C. auris can continue for months or even indefinitely. Therefore, identifying asymptomatic colonized patients is very important in terms of taking additional precautions during surgical interventions in these patients^[34-36]. C. auris can also be spread from infected or colonized patients by contact with contaminated surfaces. Studies have shown that C. auris is isolated from patient rooms, corridors outside patient rooms, chairs, beds, windowsills, benches, electrocardiogram cables, infusion pumps and ventilators. Common patient equipment such as thermometer, sphygmomanometer and oximeter also act as a reservoir for C. auris. It has been shown that the persistence of C. auris on moist and dry surfaces is between seven days and four weeks^[37-39]. In hospitals, patients colonized by or infected with C. auris should be placed in single rooms. If single rooms are not available, cohorts should be performed. Disposable equipment should be used. Disinfection of contacted areas and surfaces should be done using both detergent and disinfectant. Substances with sporicidal properties (peracetic acid or hydrogen peroxide) should be used for disinfection. In addition, disinfection techniques that do not require contact, such as UV and hydrogen peroxide vapor, are also suitable. Patient rooms should be disinfected at least once a day. Healthcare workers who come into contact with the patient should provide appropriate hand hygiene. Routine screening of healthcare workers and the environment for C. auris is not recommended. However, based on epidemiological evidence, screening may be considered in cases where there is a relationship between health workers and the environment with transmission or where transmission is detected despite recommended precautions^[24]. For this reason, it is of great importance to take the necessary precautions to prevent transmission.

Identification

C. auris is phylogenetically closely related to C. krusei,
C. haemulonii and C. lusitaniae^[40]. It is a haploid yeast. The genome size ranges between 12.1 and 12.7 Mb and it has seven chromosomes. Based on genomic and RNA sequencing information, it is estimated to have approximately 5,500 genes^{[8, 20]}.

They can be seen singly, in pairs or in groups in microscopic examination and reproduce by budding like other species. It is oval shaped and 2.5-5.0 µm in size. The germ tube test is negative and does not produce pseudohyphae. However, pseudohyphae can form in environments with high salt concentrations and in the case of heat shock protein depletion, suggesting that this morphological change may also occur under stress conditions^{[8, 41]}. While they grow as smooth-edged, white/cream colonies on sabouraud dextrose agar, they form beige, pink, pale rose or pale purple colored colonies on commercial chromogenic media including CHROMagar Candida, BBL CHROMagar Candida, CAN2 chromogenic, Candida ID and Brilliance Candida agar (Figure 1)^{[37, 42]}. Chromogenic agars are not used for primary identification, but can help differentiate C. auris strains, especially from mixed cultures^[24]. C. auris grows well at 38 °C or 42 °C and its growth is inhibited in the presence of 0.01% or 0.1% cycloheximide^[43].

Figure 1: Colony morphologies of C. auris on different media; A) Saboraud dextrose agar (white-cream colony), B) BrillianceTM Candida agar (beige-pink colony), C) CHROMagar^TM Candida (pale pink colony), D) CHROMIDR Candida agar (pale pink colony), E) CHROMagar^TM

Candida Plus (blue colony)^[37]

The carbohydrate assimilation characteristics of C. auris are shown in Table 1^[44].

Table 1: Carbohydrate assimilation characteristics of C. auris ^[44]

C. auris cannot be identified phenotypically accurately with automated systems such as API 20C (bioMerieux, France), API ID 32C (bioMerieux, France), API Candida (bioMerieux, France) BD Phoenix (Becton, Dickinson and Company, USA), Microscan (Beckman Coulter, USA), RapID Yeast Plus (Remel, USA) and Vitek-2 YST ID (bioMerieux, France) as with conventional methods, and it is misidentified as C. haemulonii, C. sake, C. famata, C. catenulata, Saccharomyces kluyveri and Rhodotorula mucilaginosa (Table 2)^[45-47].

Table 2: Results of C. auris in automated systems^[48]

Another method, matrix-assisted laser desorption ionization-time of flight mass spectro-metry (MALDI-TOF MS), is a fast and reliable method for the identification of C. auris from pure culture. C. auris strains can be identified at species level with 100% sensitivity and specificity using updated commercial MALDI-TOF MS database libraries. However, if the databases used are not sufficient for reliable identification, the result should be verified with other identification methods^{[13, 24]}.

Molecular methods based on the sequencing of the D1-D2 region of 28S rDNA and the internally transcribed spacergen gene regions allow the accurate identification of C. auris and the establishment of its phylogenetic structure. Since DNA sequencing methods, which are time-consuming and expensive, cannot be found in all diagnostic laboratories, their applicability has been limited to developed countries. Polymerase chain reaction (PCR)-based methods have been developed to overcome this limitation. Polymerase chain reaction-based methods are generally divided into three groups. Methods in the first group are based on end-point PCR and range from a single PCR specific to C. auris only to multiplex PCR, which simultaneously identifies closely related and unrelated species. Since applications in this group require less equipment, their applicability is more possible in developing countries^[49]. The second group is based on real-time PCR, which can only detect C. auris or species closely related to C. auris^{[50, 51]}. These methods are highly sensitive and advantageous as some can detect directly from clinical and environmental samples. However, its use is limited in countries with limited resources due to its high cost and requiring more equipment. The third group includes methods based on other technologies such as PCR-RFLP, loop-mediated isothermal amplification and T2 magnetic resonance system^{[42, 52]}.

Methods such as amplified fragment length polymorphism analysis, multilocus sequence typing and variable area gel electrophoresis (pulsed-field gel electrophoresis) give successful results in distinguishing epidemic strains. However, WGS has a superior distinguishing feature between species. It is also preferred for simultaneous identification and genotyping of strains. While the WGS method gives results in a short time like 8-72 hours compared to other typing methods, it requires bioinformatics expertise and is more costly for laboratories^[24].

Resistance to Antifungal Drugs

Liquid microdilution, E-test or VITEK2 methods are mostly used to determine the sensitivity of C. auris to antifungal drugs in clinical microbiology laboratories. While these methods are standard, they have some limitations such as the application steps are time consuming and at least 24 hours are required to read the results. However, the developed molecular methods allow accurate and rapid detection of antifungal susceptibility results^[53].

To date, no clinical threshold has been defined for C. auris in reference antifungal susceptibility testing methods. However, epidemiological threshold values have been proposed tentatively in some publications. In the studies performed, the limit values for fluconazole, voriconazole, flucytosine, amphotericin B, anidulafungin, micafungin and caspofungin were 32 mg/L, 2 mg/L, 128 mg/L, 2 mg/L, 4 mg/ L, 4 mg/L, and 2 mg/L^{[12, 40]}. Minimum inhibitory concentration (MIC) values determined for amphotericin B and caspofungin in VITEK2 YST AST and E-test method differ when compared to Clinical and Laboratory Standards Institute Standards. The MIC values determined by these methods need to be verified using the reference method^[24].

One of the reasons why the emergence of C. auris is of such concern is that this strain is resistant to or has the potential to develop resistance to multiple antifungal drugs^[54]. It has been reported that the sensitivity of C. auris to azole group antifungal agents, including voriconazole, posaconazole, itraconazole and isavuconazole, is decreased^{[40, 54-57]}. The widespread prevalence of reduced sensitivity to azole drugs is extremely worrying. Because azoles are the mainstay in the treatment of Candida infections. As a result of the studies, the idea has appeared about fluconazole resistance is acquired resistance^[19]. Although it is known that resistance to fluconazole in C. auris is caused by mutations in ERG11, different mechanisms have been described that contribute to the formation of resistance. In addition, C. auris strains also show a variable susceptibility profile to amphotericin B. Concerns about developing resistance to azoles and amphotericin B led to the recommendation to use echinocandins as first-line therapy. However, the detection of high MIC values for one or more echinocandins in studies with C. auris strains was found to be alarming^{[58, 59]}.

Whole genome sequencing studies have shown that C. auris possesses both ATP-binding cassette and major facilitator superfamily proteins. These proteins have a very similar homologue to MDR1 and CDR1/CDR2, as well as CDR4 and two SNQ2 homologs. Mutations in Hotspot1 S639 in FKS1 are responsible for echinocandin resistance. In addition, two different regions, called S639P and S639F, have been identified in C. auris. These regions cause a 4- to 8-fold increase in the MIC value of echinocandins. The molecular mechanism of resistance to amphotericin B has not been clarified yet^{[60, 61]}. In addition, mutations of F126T in the South African clade, Y132F in the South American clade, and Y132F and K143R mutations in the South Asian clade caused azole resistance. In addition, Y132F and K143R mutations were found to increase resistance to fluconazole^[20].

The problem of resistance to antifungals has revealed the need to find new drugs that can be effective in treatment. Currently, there are publications on four new antifungal drugs whose efficacy against C. auris has been determined. The first of these drugs is ibrexafungerp (formerly SCY-078 or MK-3118). Ibrexafungerp is a triterpenoid antifungal drug that acts fungicidally by inhibiting 1,3-ß-D-glucan synthase, an important component of the fungal cell wall, similar to echinocandins. It shows broad-spectrum in vitro activity against various Candida species, including C. auris strains with the FKS mutation. It is also the first oral drug that is not included in the azole group in the treatment of vaginal candidiasis^[62-64]. Another newly developed drug is rezafungin. Rezafungin (formerly CD101) is a new b-glucan synthase inhibitor chemically related to anidulafungin. Phase 3 clinical trials of the drug have been initiated. It has a low MIC for some echinocandin-resistant C. auris strains and a long half-life that allows once-weekly dosing^[65]. Manogepix (APX0011A), on the other hand, is another broad-spectrum antifungal that inhibits a protein that plays an important role in fungal cell wall integrity, such as Gwt1p, and has been found to be effective against multi-drug resistant C. auris strains^[66]. VT-1598 is a tetra-azole inhibitor of Cyp51, just like tri-azole-based Cyp51 inhibitors, they inhibit the conversion from lanosterol to ergosterol, disrupting the pathway of ergosterol biosynthesis. Due to its unique chemical structure, this antifungal agent is more specific to Cyp51 in the fungal cell compared to mammalian cytochrome P450 enzymes. In this way, drug-drug interactions that may be clinically important for triazoles such as fluconazole, voriconazole, posaconazole and isavuconazole can be avoided^[67].

Conclusion

C. auris infections have high morbidity and mortality worldwide. Accurate and timely identification of the agent in clinical microbiology laboratories is critical for effective treatment and prevention of infection. In order to control the spread of C. auris, it is necessary to understand its epidemiology and to pay attention to infection control methods to minimize transmission between patients. The emergence of pan-resistant strains after multidrug-resistant strains is a signal to worry about the agent. For this reason, it is of great importance to investigate the effects of natural compounds, semi-synthetic and synthetic compounds, nanoparticles, and peptides with reported antifungal activities on C. auris, in terms of increasing treatment options.

Ethics

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: E.Y.S., M.U., Design: E.Y.S., M.U., Data Collection or Processing: E.Y.S., M.U., Analysis or Interpretation: E.Y.S., M.U., Literature Search: E.Y.S., M.U., Writing: E.Y.S.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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Candida auris: Microbiological Characteristics and Laboratory Diagnosis of the Hidden Pathogen

Summary

Introduction

Conclusion

References