Continuing Education Activity

Candida auris is an emerging fungal pathogen that is associated with nosocomial infections and is considered a serious global health threat. It has numerous virulence qualities and shows multi-drug resistance patterns to common antifungal therapy used for other invasive Candida infections. Yeast identification methods employed by laboratories typically misidentify C. auris as other yeasts making the detection and control of this pathogen difficult. The transmission of Candida auris occurs in nosocomial settings, even in those implementing infection prevention and control measures. In the United States, it is a nationally notifiable pathogen that allows for public health tracking and containing its spread. This activity reviews the evaluation, treatment, and management of Candida auris and explains the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of Candida auris infection.
• Review the appropriate evaluation of Candida auris.
• Outline the management options available for Candida auris.
• Summarize interprofessional team strategies for improving care coordination and communication to reduce Candida auris infections and improve outcomes.

Introduction

Candida auris is an emerging pathogen that results in nosocomial infections and is considered a serious global health problem. It was first observed as a novel Candida species in 2009 and has been isolated in 35 countries, except Antarctica.[1][2]

C. auris may cause invasive infections associated with high mortality. It is considered a multi-drug resistant species, having variable resistance patterns to many typical antifungal agents used to treat other Candida infections. In recent years, the rising prevalence of infection and colonization with non-albicans Candida species is thought to be due to the excessive use of prophylactic antifungals such as fluconazole.[3] Yeast identification methods employed by laboratories typically misidentify C. auris as other yeasts making the detection and control of this pathogen difficult. The transmission of Candida auris occurs in nosocomial settings, even in those implementing infection prevention and control measures. In the United States, it is a nationally notifiable pathogen that allows for public health tracking and containing its spread.

Etiology

Candida auris is a yeast species belonging to the genus Candida. It is so named because it was first isolated from the external ear canal of a patient in a Japanese hospital.[1] Analysis of the yeast genomic DNA showed a distinct species with close phylogenetic profiles to Candida ruelliae, Candida haemulonii, C. duobushaemulonii, and C. pseudohaemulonii.[1][4]

C. auris is a budding yeast with cells that may be single, in pairs, or in groups. The cells are ovoid, ellipsoidal to elongate, and 2.5-5.0 micrometers in size. C. auris rarely forms hyphae or pseudohyphae, nor does it form germ tubes.[5] However, growth under high-salt stress, such as on YTD (yeast extract, tryptone, and dextrose) plus 10% NaCl, and depletion of heat-shock proteins (HSP) can induce pseudohyphae-like forms.[6][7] C. auris strain grows well at 40 degrees Celcius but shows slow growth at 42 degrees Celcius.[1] The colonial growth of C. auris in culture medium varies depending on the medium. On Sabouraud agar, C. auris will produce smooth and white to cream-colored colonies.[8] On CHROMagar, colonies of C. auris may display multiple color morphs ranging from pale to dark pink and rarely beige.

Epidemiology

Genetic analysis of C. auris isolates has demonstrated four distinct geographical clades: South Asian, East Asian, South African, and South American, with a possible fifth clade originating from Iran.[9] Genetic differences between the clades are suggestive that C. auris emerged independently in the aforementioned geographic locations.

The prevalence of Candida auris infection globally is unknown and likely underreported due to the lack of commercially available diagnostic methods and resemblance to other phenotypically related Candida species.[10] Since its original description in Japan in 2009, it has become widespread across all continents except Antarctica. A study queried the international SENTRY Antifungal Surveillance Program that sought to identify 15,271 candidemia isolates collected between 2004 to 2015 from 152 international medical centers (Asia, Europe, Latin America, and North America). It showed that no Candida auris isolates were identified before 2009 and that the prevalence of C. auris was rare before 2009.[11] Further surveillance studies of misidentified samples recovered from South Korea in 1996, 2004, and 2006, and Pakistan in 2008 later detected C. auris.[12] 

These studies suggest that C. auris emerged before 2009; however, the rapid global spread occurred afterward. By 2018, there were cases reported in the United States, Canada, Panama, Colombia, Venezuela, United Kingdom, Germany, Switzerland, Netherlands, France, Spain, Belgium, Norway, Russia, India, Pakistan, Bangladesh, Malaysia, China, Thailand, Singapore, Isreal, Kuwait, Oman, United Arab Emirates, Saudi Arabia, Iran, South Africa, Kenya, and Australia.[13][14][15][16][17] As of March 2020, the Center for Disease Control and Prevention (CDC) has reported C. auris isolates in 41 countries. C. auris typically occurs in outbreaks in the nosocomial setting; however, sporadic cases have also been reported.

In the United States, the CDC has recorded 1092 cases of C. auris as of March 2020, with most cases occurring in New York City, New Jersey, and Illinois.[8] Epidemiologic information from these cases suggests that most strains were introduced from abroad and that these strains belonged to the clades of C. auris originating from South America and South Asia.[18] While the isolates belong to distinct clades that originated abroad, most cases acquired the infection in the United States in the healthcare setting, demonstrating clonal nosocomial transmission.[19]

Pathophysiology

Transmission

Candida auris is efficiently transmitted person-to-person.[20] The transmission of C. auris is different from most other Candida species in that most cases of candidiasis arise from the host's microflora rather than acquisition from another person. C. auris is not considered a resident commensal organism and is not typically present within the human gastrointestinal tract, as are many other Candida species.[21] C. auris has a particular predilection for skin, particularly the axilla and groin. It has the potential to colonize hosts within days to weeks of exposure, and invasive infections may occur within days to months after colonization.[22] Colonization with C. auris may persist for many months and possibly indefinitely.[23] Therefore, it is essential to identify asymptomatic colonized patients to take additional precautions when they undergo placement of indwelling devices or surgical intervention. These patients may also be a source of transmission to other patients and environmental contamination.

C. auris can spread through contact with contaminated surfaces and fomites when shed from infected or colonized patients. Studies have found that C. auris may be found in patients' rooms and outside the patient's rooms in hallways, chairs, beds, windowsills, counters, electrocardiogram leads, blood pressure cuffs, infusion pumps, and ventilators.[23] Shared multi-use patient equipment such as temperature probes and pulse oximeters may act as reservoirs of C. auris.[24] Laboratory studies of C. auris persistence show that it may survive on moist or dry surfaces for seven days.[25] Another study showed that C. auris cells might remain viable for up to 4 weeks and culturable for two weeks.[26] Isolation and contact precautions should prevent nosocomial transmission of C. auris.

Virulence Factors

Genetic studies of Candida auris have shown that a significant percentage of its genes are involved in central metabolism, a common trait among pathogenic Candida species that allows for adaptation in divergent environments.[27] Candida auris has numerous virulence attributes that resemble C. albicans, such as enzyme secretion, nutrient acquisition, siderophore-based iron acquisition, tissue invasion, two-component histidine kinase system, and pathways involved in cell wall modeling.[28][29] Virulence factors may be strain-dependent. A study of 16 isolates of C. auris showed different levels of phospholipase and proteinase production.[30]

C. auris has also demonstrated the ability to evade the immune response. In a comparison study between Candida albicans and Candida auris, neutrophils preferentially targeted and killed C. albicans.[31] This same study showed that C. auris evaded the neutrophil attack and the innate immune response, which is in line with another study showing that recognition and ability to stimulate cytokine release and phagocytosis were greater in C. albicans versus C. auris.[32]

C. auris also form biofilms allowing for adherence to surfaces and plastic materials. Biofilm formation is also strain-dependent, and C. auris shows a reduced ability to adhere and form biofilms compared to Candida albicans due to the rarity of pseudohyphae.[30][33]

In vitro studies have shown C. auris isolates may be aggregating or non-aggregating. The failure of C. auris to release daughter cells after budding results in a large aggregation of cells that is difficult to disrupt by detergent vortexing or detergent.[34] The property of aggregating strains is thought to promote survival in hospital environments. However, in vivo models have shown that the non-aggregating isolates exhibit more pathogenicity than aggregating isolates and have greater pathogenicity than C. albicans.[30][34] The thermotolerance of C. auris, growing optimally in temperatures of 37 degrees Celcius and surviving in temperatures up to 42 degrees Celcius, also helps certain strains persist in hospital environments.

Resistance Factors

Although C. auris can express the virulence mentioned above factors, the expression is weaker than other Candida species. The primary factor contributing to its high mortality rates is its ability to develop resistance to multiple antifungal agents.[30] Biofilm formation allows for drug sequestration within the extracellular matrix, which confers antifungal tolerance observed in many Candida species.[35] A recent study showed that matrix sequesters nearly 70% of the available triazole antifungal due to its rich mannan-glucan polysaccharides.[36]

Another study found that C. auris isolates with biofilms did not show susceptibility to any antifungal agent, including fluconazole, echinocandins, and polyenes, compared to planktonic C. auris isolates, which were only resistant to fluconazole.[37] Genetic studies of Candida auris have shown expansions of genes linked to drug resistance and multidrug efflux.[4] Resistance to azoles and echinocandins is mediated by mutations in the genes encoding the lanosterol 14-alpha-demethylase (ERG11) gene and drug target 1,3-beta-glucan synthase (FSK1), respectively.[38] Efflux pumps such as the ATP-binding cassette (ABC) and major facilitator superfamily (MFS) also play a role in azole resistance.[29][39]

History and Physical

The clinical presentation of Candida auris infection is similar to that of other Candida species. C. auris has been isolated from different body sites, including the nose, pharynx, sputum, lungs, pleural cavity, heart, blood, liver, abdominal cavity (peritoneal fluid), rectal or stool culture, urine, vagina, bone, axilla, groin, wounds/surgical tissue, pus, ear, and brain.[13][40]

Isolates from non-sterile body sites such as the genitourinary tract, skin and soft tissues, and lungs likely represent colonization rather than actual infection.[8] Any indwelling devices, such as venous catheters, ports, urinary catheters, and prosthetic devices, should be examined for erythema, tenderness, and purulent material.

Clinical conditions reported include bloodstream infections (fungemia), myocarditis, urinary tract infection, surgical wound infections, burn infections, skin abscesses (related to catheter insertion), otitis, meningitis, and bone infections.[1][12][41][42][5][43][44][45]

Compared to other Candida species, which are typical commensals of the gastrointestinal tract and not typically associated with nosocomial transmission, C. auris has been shown to thrive on the skin.[22] C. auris forms a multilayer biofilm that proliferates best in the milieu that mimics sweaty axillary skin conditions.[46] Colonized patients are a source of transmission to other patients. Colonization may occur within a few hours to days of exposure, and invasive infections may occur within days to months after initial colonization.[22]

Risk factors associated with Candida auris infections are similar to those of other Candida species.[40] These risk factors include:

• Presence of a central venous catheter
• Indwelling urinary catheter
• Immunosuppressive state (human immunodeficiency virus, hematologic malignancy, solid tumors, transplant recipients, neutropenia, chemotherapy, corticosteroid therapy)
• Diabetes mellitus
• Chronic kidney disease
• Exposure to broad-spectrum antibiotics or previous exposure to antifungal agents within 30 days
• Concomitant bacteremia or candiduria
• Parenteral nutrition
• Blood transfusion
• Hemodialysis
• Surgery within 30 days
• Admission to intensive care units

Evaluation

The evaluation of suspected Candida auris infection starts with obtaining a clinical specimen from the site of infection. Specimens may be obtained from blood, urine, nose, pharynx, sputum, pleural cavity, heart, bile, peritoneal fluid, stool, vagina, bone, axilla, groin, wounds/surgical tissue, pus, ear, and cerebrospinal fluid and sent for culture, staining, and/or histopathologic evaluation. It is important to establish whether there is clinical evidence of a true infection, especially in the setting of cultures obtained from non-sterile sites, which may represent colonization. Growth of Candida species in blood culture systems typically takes 1 to 3 days and another 1 to 2 days for identification after subculture onto agar medium.

The identification of Candida auris has presented challenges for laboratories, and it is commonly misidentified using clinical microbiology methods. While the aforementioned phenotypic characteristics of Candida auris colonies in culture may be useful in identifying it, they cannot be used for definitive diagnosis. Many biochemical methods and automated testing methods commonly misidentify C. auris for other Candida species, notably C. haemulonii and other yeast species.[47]

The most accurate identification is made with devices using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with appropriate reference databases, which can differentiate C. auris from other Candida species.[48] Accurate identification relies on the spectra for the sample organisms. This results in misidentifying C. auris as C. albicans and C. haemulonii by MALDI-TOF MS.[49] Once spectra are added to the MALDI-TOF MS database, the labeling of C. auris to the species level becomes accurate, although the distinction between geographic strains depends on the number of spectra for each clade in the library.[50] Other molecular methods have also been developed and are based on sequencing the D1-D2 region of the 28s rDNA or the internal transcribed region (ITS) of the rDNA.[10][51][51]

An automated molecular test using competitive DNA hybridization and electrochemical detection can rapidly distinguish 15 fungal pathogens, including C. auris. A multi-center study showed that this testing method has a 100% sensitivity and specificity for C. auris, C. dubliniensis, C. famata, and C. krusei and was able to distinguish between other Candida species, including C. glabrata, C. lusitaniae, C. albicans, C. tropicalis, and C. parapsilosis.[52] The more accurate, reliable, and rapid forms of molecular tests are not always available in all facilities, which makes the diagnosis, management, and infection control efforts challenging.

A range of molecular techniques, including amplified fragment length polymorphism (AFLP), have been utilized for the typing of Candida auris isolates. The role of AFLP analysis in the demarcation of the geographical clusters has been demonstrated.[53][53]

Treatment / Management

The most challenging aspect of managing invasive Candida auris infections is the level of drug resistance and the ability to develop drug resistance to the three main classes of antifungals, as previously discussed. A study from India investigated the susceptibility patterns of 350 C. auris isolates and showed that 90% were resistant to azoles (fluconazole), 8% were resistant to polyene (amphotericin B), and 2% were resistant to echinocandins (anidulafungin and micafungin).[38] The study showed that overall, 25% of isolates were multidrug-resistant, and 13% of the isolates were multi-azole-resistant.[38] The Centers for Disease Control and Prevention breakpoint analysis of isolates in the United States showed exceptionally high minimal inhibitory concentration (MIC) for azoles, echinocandins, polyenes, and nucleoside analogs.[54]

In vitro investigations reveal that the synergistic use of antifungals has shown initial promising results for the use of combination treatment of voriconazole and micafungin for multiresistant isolates. However, this was not observed in other combinations of echinocandins and azole.[55]

There is no concrete documentation for therapeutic options for C. auris infection. Most cases are managed on a case-by-case basis with the guidance of susceptibility testing. It is highly recommended that consultation from an infectious disease specialist is obtained. Treatment of C. auris should be started only in the presence of clinical disease and should be avoided in patients colonized with C. auris when isolated from non-invasive sites (respiratory tract, urine, and skin).[13]

The CDC has published tentative guidelines for initial therapy.[13] The concern about resistance to triazole antifungal agents and amphotericin B has led to the recommendation for using echinocandins as an empirical treatment prior to the availability of specific susceptibility testing results.[56][57] Adults and children greater than two months of age may be started on echinocandin therapy with caspofungin or micafungin. Anidulafungin may be used in adults but is not approved for use in children and should be avoided in this age category. Monitoring for clinical improvement, repeat blood culture to ensure clearance of fungemia, and repeat susceptibility testing should be conducted as resistance to echinocandins may develop. In clinically unresponsive patients, liposomal amphotericin B may be considered. In neonates and infants less than two months of age, the initial choice of antifungal therapy is amphotericin B deoxycholate, followed by liposomal amphotericin B. Echinocandins may be used with caution if central nervous system involvement is ruled out.

Apart from timely antifungal therapy, the management of candidemia involves the removal of central venous catheters or other indwelling devices and draining collections as soon as possible. In the setting of repeated positive blood cultures, a search for a metastatic focus should be done to rule out endocarditis, suppurative thrombophlebitis, or abscess formation. Nonneutropenic patients with candidemia should undergo a dilated ophthalmologic eye examination within the first week of diagnosis and one week after recovery from neutropenia in neutropenic patients to evaluate for endophthalmitis, chorioretinitis, and vitritis. Repeat blood cultures should be performed daily or every other day to establish clearance of candidemia. The Infectious Disease Society of America recommends continuing antifungal therapy for two weeks after the blood cultures remain negative in patients without obvious metastatic complications.[58]

Prevention of invasive infection in colonized individuals involves minimizing the entry of the organism into sterile body sites. Ensuring appropriate use of medical devices, such as central venous catheters, indwelling urinary catheters, and maintenance of tracheostomy sites is needed. Continuous assessment of the need for such invasive lines and tubes followed by prompt removal are basic strategies to mitigate the risk of introducing organisms to sterile sites. Patients undergoing surgical procedures should have meticulous skin preparation with an alcohol-based agent.[13]

The site of infection plays a crucial role in the choice of antifungals for invasive infections. Echinocandins do not have adequate penetration into many sites, such as cerebrospinal fluid, because of their high molecular weight, and the very less active drug could be recovered from urine.[59] The use of amphotericin B with the potential addition of 5-flucytosine has been recommended for urinary tract infections.[59] For central nervous system disease, as with other candidal infections, empirical amphotericin B and 5-flucytosine combination has had some success, with the tailoring of therapy as guided by sensitivity testing.[60]

Differential Diagnosis

The differential diagnoses of Candida auris include invasive fungal infections caused by other species of Candida and comprise 95% of all invasive fungal infections:[2]

• Candida albicans
• Candida glabrata
• Candida tropicalis
• Candida paratropicalis
• Pichia kudriavzevii

Other differentials are:

• Aspergillosis
• Bacterial sepsis
• Cryptococcosis
• Septic shock 

While these pathogens are more common, infections with Candida auris occur at a higher incidence in primary and acquired immunosuppression than other fungal pathogens. However, infection in immunocompetent hosts also occurs, and the mere clinical presentation is insufficient to distinguish among Candida species.

The phenotypic characterization, such as the appearance and color of C. auris colonies in culture, high tolerance to growth in high heat (up to 42C), and saline environments, helps distinguish it from other Candida species but should not be used as the sole method for identification. Phenotypic platforms typically mistake C. auris for C. haemulonii and different yeasts (C. famata, C. guilliermondii, C. lusitaniae, C. parapsilosis, C. sake, Saccharomyces cerevisiae, and Rhodotorula glutinis).[61] Molecular identification methods are the standard-of-care testing for a definitive diagnosis of C. auris.

Prognosis

The mortality rate of invasive infections associated with C. auris is comparatively higher than that of other Candida species. The crude mortality rate associated with C. auris infections ranges from 30% to 72%.[11][62][63][64] The variable mortality rate data may be due to several factors, including the extent of the infection, age, associated risk factors, and co-morbid conditions. Infections have been reported in preterm infants to the elderly.[40] Pediatric populations showed a higher likelihood of survival.[65] Early identification of Candida auris and prompt treatment with appropriate anti-fungal regimens are associated with higher survival.[12]

Complications

The complications of invasive Candida auris infection vary depending on the extent of the infection, host co-morbidities, and resistance patterns. While the most common presentation of Candida auris infection occurs as bloodstream infection (fungemia), it may spread hematogenously to seed different organs and cause multi-organ dysfunction. Conversely, a localized infection may eventually become an overwhelming bloodstream infection and have further complications such as sepsis, multi-organ system failure involving the kidneys, heart, lungs, eyes, brain, liver, and spleen, and ultimately death.

Deterrence and Patient Education

Given the high rates of transmissibility and antifungal resistance patterns, C. auris was declared a public threat by the Centers for Disease Control and Prevention (CDC). In June 2016, the CDC announced to general providers, infection control providers, laboratories, and public health authorities about Candida auris, making all cases in the United States reportable to the authorities and the CDC.[8] The CDC has outlined various aspects of infection control and prevention of C. auris.

Hand hygiene is the basic component of infection control. Healthcare personnel should follow standard hand hygiene principles to control the spread of C. auris.[23] The preferred alcohol-based hand rubs are effective against C. auris, as are chlorhexidine hand rubs when hands are not visibly soiled.[66] Visibly soiled hands should be washed with soap and water. Contact precautions with gowns and gloves should be worn. Gloves do not substitute for hand hygiene.

The recommendations for infection control of C. auris are adapted from infection control strategies for Clostridium difficile infections and other multidrug-resistant organisms, showing swift nosocomial spread. Infection control is applied to both infected and colonized individuals since both pose a risk of transmission.

Transmission-based precautions are implemented in acute care hospitals, long-term acute care hospitals, and nursing homes, including skilled nursing facilities with ventilator units. In the acute care setting, contact precautions are recommended, and in skilled nursing facilities, either contact precautions or enhanced barrier precautions are used. Contact precautions include using gloves and gowns for healthcare personnel, single room placement, and placing patients in cohorts of patients with only C. auris infection or colonization in non-single occupancy rooms or specific wings of a hospital.[18] 

Of note, patients with C. auris should not be in a cohort with patients having other multidrug-resistant organisms besides C. auris. Patients may remain colonized with C. auris for months, even after the treatment and resolution of an acute infection. It is recommended that the patient stays on contact precautions for their hospitalization. The CDC does not recommend routine assessment for colonization. However, patients with a prolonged hospital stay or residing in nursing homes may be screened three months after the last C. auris-positive test and if no longer on antifungal therapy for at least one week or receiving topical antiseptic for 48 hours. Contact precautions may be discontinued if the patient has had two negative colonization tests at least one week apart.

C. auris may persist in the healthcare environment on a variety of surfaces.[25] Environmental disinfection of the patient’s room and other areas where care is received should be performed daily. Equipment that is being shared between patients should be thoroughly cleaned and disinfected. Fungicidal products that are effective against other Candida species and quaternary ammonia compounds may not necessarily be effective against C. auris.[67] Ultraviolet light, commonly used for environmental disinfection, does not appear effective against C. auris.[68] In vitro studies have shown sodium hypochlorite and hydrogen peroxide to be effective against C. auris.[66][67][69] Environmental studies have found that rooms cleaned with sodium hypochlorite and hydrogen peroxide vapor were effective.[18][70]

Enhancing Healthcare Team Outcomes

Candida auris is an emerging fungal pathogen associated with nosocomial infections and a serious global health threat. An interprofessional healthcare team that includes epidemiologists, both globally and in healthcare settings, is crucial for monitoring the spread of this pathogen. C. auris has numerous virulence qualities, shows multi-drug resistance patterns to common antifungal therapy used for other invasive Candida infections, and has been challenging for microbiology laboratories to diagnose. All interprofessional team members, including clinicians, nurses, medical technicians, pharmacists, and laboratory technicians, should be aware of the seriousness of this pathogen.

All care team members must engage in open communication and accurate record-keeping at every step of the case; this includes nurses, pharmacists, lab techs, clinicians, and specialists. Open communication channels are vital to success; this involves not only the patient but population-wide protocols to prevent outbreaks or containment of outbreaks in the community. This is where interprofessional care coordination, information sharing, and communication will help drive the best possible outcomes. [Level 5]

Staff should be educated on the recommendations for disinfecting patient rooms and contaminated environments. Infectious disease specialists should collaborate with microbiology technicians in diagnosing patients and obtaining appropriate antibiogram information to manage infected patients effectively; this may involve a consult with an infectious disease specialized pharmacist. C. auris tends to occur in cluster breakouts in the healthcare setting and carries a high mortality. The infection prevention and control officer of the healthcare facility should be immediately notified and guide staff for appropriate infection control techniques and prevention of spread. C. auris is a reportable pathogen and should be reported to the Centers for Disease Control and Prevention.