Candida auris infection

# Overview
Candida auris is a fungus, recently described as a rare cause of fungal infection with significant resistance to antifungal medications. It was first described in the year 2009 in Japan, and since then, reports of C. auris infection has been published from several countries. However, retrospective testing of collected isolates show the earliest known infection with C. auris occurred in South Korea in 1996. Serious and prolonged outbreaks have been documented with data showing an innate resilience of C. auris for survival, persistence in the clinical environment with the ability to rapidly colonize the skin of patients, and high transmissibility within the healthcare system. The first reported case in Europe involved over fifty cases in a span of more than sixteen months in a cardiothoracic center in London, and it is the largest outbreak in Europe. The precise mode of transmission within the healthcare facility is unknown. The high rate of therapeutic failure noted in cases of Candida auris fungemia poses significant concerns. Misidentification of C. auris with related Candida species such as Candida haemulonii by commercially available biochemical-based tests poses a challenge. C. auris is recognized as a globally emerging fungal pathogen and it requires reproducible laboratory methods for identification and typing. Institution of key infection prevention and control measures, correct identification and standardized antifungal susceptibility testing for optimal management strategies of patients with invasive infections can hardly be overemphasized.

# Historical Perspective
- C. auris was first described in 2009 after being isolated from the external ear canal discharge of a patient in Japan.
- The first report of blood stream infection by C. auris was in 2011 from Korea.
- C. auris was incidentally found by molecular identification of bloodstream isolates of unidentified yeasts recovered in 1996, suggesting the paucity of isolation of C. auris may partly reflect the difficulty in identifying the species.
- The occurrence of C. auris in at least nine countries on four continents since 2009 has been reported.
- C. auris infections have most commonly been hospital-acquired and occurred several weeks into a patients hospital stay.
- It has been documented to cause infection in patients of all ages.

# Causes
Candida auris infection is caused by C. auris; an ascomycetous yeast species belonging to the genus Candida, and it has a high potential for nosocomial horizontal transmission.

# Pathophysiology

## Pathogenesis
- C. auris cases have been identified from clinical sites such as wound swabs, urine samples, vascular devices tips, blood cultures as well as skin screening samples (including nose, oropharynx, axilla, groin and stool samples).
- C. auris has been reported to cause bloodstream infections, wound infections, and otitis media.
- The occurrence of candidemia attributed to C. auris appears increasingly common.
- Evidence of distinct geographic clustering of Candida auris isolates has been established.
- C. auris has been isolated from the blood culture of a patient who was already on antifungals for C. albicans candidemia.
- C. auris optimally grows at 3740C and remains viable till 42C, exhibiting the thermotolerance necessary to infect humans.
- Clinical information from three continents revealed a median time of 19 days from admission to C. auris infection.
- The exact mode of transmission is unknown.

## Genetics
- C. auris has a complex genome.
- It is phylogenetically closely related to C. haemulonii.
- Analysis of selected isolates from the affected hospital in the UK using Amplified Fragment Length Polymorphism (AFLP) suggested distinct clustering of the London isolates when compared to other global isolates. The AFLP dendrogram is suggestive of the introduction of a single infecting genotype into the hospital. There is still ongoing analysis of whole-genome sequences to confirm this preliminary observation.
- Detailed information regarding genotypes/clonal strains endemic to specific geographical locations is lacking.

## Microscopic Pathology
- C. auris cannot be distinguished from most other Candida species on microscopy.
- It is a germ tube test negative budding yeast.
- It has a pale purple/pink color on chromogenic agar.

# Epidemiology and Demographics

## Incidence
- Higher incidence in public sector hospitals in India when compared to the private sector hospitals.
- Thirteen reported  cases in the US, the first seven cases occurred between May 2013 - August 2016.
- Over fifty cases in the UK between April 2015 - July 2016.
First outbreak of C. auris in the UK

## Age
- C. auris infection has been documented in both pediatric and adult population.

## Gender
- No known gender predilection.

## Race
- No known racial predilection.

## Geographical Distribution
Countries with documented isolation of C. auris :
- Japan
- South Korea
- India
- Kuwait
- South Africa
- Venezuela
- USA
- UK
- Colombia
- Pakistan
- Israel
- Kenya

## Geographical Distribution in the US
- First seven reported cases in the US (May 2013 - August 2016) .

# Risk Factors
- Stay in the Intensive Care Unit is a major risk factor for C. auris infection.
- Patients who had a prolonged hospital stay.
- Multiple invasive medical procedures.
- Similar risk factors for infections with other Candida spp including diabetes mellitus, recent surgery, recent antibiotics, presence of central venous catheters.
- Serious underlying medical conditions such as hematologic malignancies, respiratory failure requiring high dose steroids, short gut syndrome requiring total parenteral nutrition, paraplegia with a chronic urinary catheter, etc.
- Co-infection with other Candida spp.

# Screening
Screening is advised for patients coming from other affected hospitals / units in the UK and abroad.

# Natural History, Complications, and Prognosis

## Natural History
- Persistent colonization of patients reported from affected hospitals around the world.
- Colonization with C. auris is difficult to eradicate.
- Recurrence of C. auris  candidemia three to four months after an initial episode has been reported in at least two patients.

## Complications
- Invasive wound infections
- Otitis media
- Candidemia with high mortality
- Septic shock

## Prognosis
- Candidemia  attributed to C auris is associated with mortality of up to 50 % in some countries.

# Diagnosis

## History and Symptoms

### History
Patients with Candida auris infection often present with underlying risk factors, such as:
- An underlying serious medical condition.
- A history of a prolonged hospital stay.
- A history of admission into the ICU.

### Symptoms
C. auris infection can present like Candida infection caused by other Candida species. However, unlike the other Candida species, C. auris  has been noted to persistently colonize the healthcare environment. Presenting symptoms depend on the affected part of the body and can include the following:
- Ear discharge
- Vaginal discharge
- Vaginal itching
Symptoms of Candida auris blood infection can include:
- Fever
- Septic shock
- Multiorgan failure

## Physical Examination
The physical examination findings in C. auris infection is not well documented.

## Laboratory Findings
Microscopy
- C. auris is indistinguishable from most other Candida species.
- It is a germ tube test negative budding yeast, however some strains can form rudimentary pseudohyphae on cornmeal agar.
- Most C. auris isolates are a pale purple or pink colour on the chromogenic agar; CHROMagar Candida, in common with several other non-C. albicans species. Growth on this and other chromogenic agars (which may display a different colour) cannot be used as a primary identification method.
- Chromogenic agars are useful to identify mixed cultures including the presence of C. albicans.
- When there is evidence of non-C. albicans on chromogenic agar, these should be sub-cultured on Sabourauds agar and identified according to local laboratory protocols.
Biochemical-based test
- Laboratories are advised to check the databases provided for their current methods.
- Currently available biochemical-based tests highly unlikely to include C. auris in their database as it is a newly recognized species.
- Commercially available biochemical-based tests, including API AUX 20C and VITEK-2 YST, used in many front line diagnostic laboratories can misidentify C. auris as Candida haemulonii, Saccharomyces cerevisiae, Rhodotorula glutinis. 
- Candida spp associated with invasive infections and isolates from superficial sites in patients from high intensity settings, and those transferred from an affected hospital should be analysed to species level.
Molecular-based test
- If Candida haemulonii, Candida famata, Candida sake or Saccharomyces cerevisiae are identified, it is pertinent to ensure that they are not C. auris. This would involve either molecular sequencing of the D1/D2 domain or MALDI-TOF(matrix-assisted laser desorption ionization time-of-flight mass spectrometry) Biotyper analysis with C. auris either already present or added to the database.

# Differentiating Candida auris from other non-Candida albicans species
- C.auris can be differentiated from other non-Candida albicans species via reliable methods for speciation that are molecular-based such as PCR, AFLP(amplified fragment length polymorphism) fingerprinting, sequencing analysis, and MALDI-TOF biotyping.

# Treatment

## Medical Therapy
- Early identification of Candida species to ensure appropriate use of antifungal medication and also for prompt implementation of infection control measures.
- Antifungal susceptibility testing: Candida auris isolates from north and south Indian hospitals, Japan and Korea were all found to be resistant to the antifungal medication fluconazole. Some isolates were also noted to be resistant to antifungal medications such as flucytosine and voriconazole.There are no established minimum inhibitory concentration (MIC) breakpoints at present for C. auris. Using breakpoints for other Candida spp, the Centers for Disease Control and Prevention (CDC) demonstrated that nearly all isolates from the global outbreaks being investigated are highly resistant to fluconazole. In their analysis, more than half of C. auris isolates were resistant to voriconazole, one- third were resistant to amphotericin B (MIC 2 mg/L), and a few were resistant to echinocandins. Some isolates have demonstrated elevated MICs to all three major antifungal classes, including azoles, echinocandins, and polyenes, indicating that treatment options would be limited. Whole genome sequencing of the organism has found resistant determinants to a variety of antifungal agents.
- First-line therapy is an echinocandin pending specific susceptibility testing which should be undertaken as soon as possible. There is evidence that resistance can evolve quite rapidly in this species and ongoing vigilance for evolving resistance is advised in patients found to be infected or colonized with C. auris.
- Combination therapy: Evidence supporting combination therapy in invasive infections with C. auris  is lacking and clinicians are advised to make decisions on a case by case basis.

## Primary Prevention
- Isolation of colonized or infected patients with en suite facilities wherever possible.
- Adherence to strict infection prevention and control precautions, including hand hygiene using soap and water followed by alcohol hand rub, use of personal protective equipment in the form of gloves and aprons (or gowns if there is a high risk of soiling with blood or body fluids).
- A chlorine releasing agent is currently recommended for cleaning of the environment at 1000 ppm of available chlorine.
- A terminal clean should be undertaken once the patient has left the environment preferably using hydrogen peroxide vapour. All equipment should be cleaned in accordance with manufacturers instructions and where relevant, returned to the company for cleaning. Particular attention should be paid to cleaning of multiple-use equipment (such as  BP cuffs, thermometers, computers on wheels, ultrasound machines) from the bed spaces of infected/colonized patient.