Candida auris: an emerging multi-resistant fungus

Introduction

Candida auris is a pathogen that has emerged as a global threat in recent years. It is the first human pathogenic fungus subject to international health alerts. The reason behind these concerns are –

• It is multi-resistant
• It isn't easy to identify – often misidentified in standard laboratories
• It has been known to cause outbreaks in healthcare settings
• It colonises the skin and the hospital environment

Public Health England reported in 2017 that almost all the C auris in the UK are fluconazole-resistant. There is also cross-resistance with other azoles like voriconazole.

The resistance to echinocandins is about 10%, and polyenes (amphotericin B), 20%.

There have been reports where C auris was resistant to all three classes of antifungal – pan-resistant.

Epidemiology

Candida auris was first reported in 2009 in Japan from the external ear canal of a patient. However, a retrospective review of microbiology cases in South Korea identified Candida auris from a case dating back to 1996.

Following this, many countries reported cases of C auris. As per CDC, up till February 2021, 49 countries have reported cases of C auris.

Here is a video showing when a country first reported a case of C auris [Forsberg 2019,  Hu 2021]

UK National Mycology Reference Laboratory (MRL) found evidence of C. auris in the UK in 2013. It was first identified as the cause of a hospital outbreak in England in 2015. Borman reported that by mid-2019, PHE had recorded approximately 270 cases of C. auris in England, including at least 35 cases of candidemia. PHE reported in 2017 that over 35 additional hospitals in the United Kingdom had received patients with a known C. auris detection.

Whole-genome sequencing (WGS) identified Candida auris have 4 different clades:

• Clade I (Southern Asia),
• Clade II (East Asia),
• Clade III (South Africa), and
• Clade IV (South America).

A potential fifth clade has been reported from Iran [Chow 2019].

There is very little difference between the strains in each clade, but vast differences exist between the clades – suggesting they emerged independently of each other.

Of these, three clades have been reported in the UK.

Ref: Borman AM, Johnson EM (2020) Candida auris in the UK: Introduction, dissemination, and control. PLoS Pathog 16(7): e1008563. https://doi.org/10.1371/journal.ppat.1008563

Clinical features

C auris was first reported from an ear sample, and many early cases were from chronic otitis media. It received its name from this association. Since then, it has been isolated from various other infections.

C auris bloodstream infection is associated with 30–60% mortality rates.

The risk factors associated with Candida auris infections are:

Risk factors	Risk factors	Risk factors
Urinary catheters	Mechanical ventilation	Diabetes mellitus
Arterial line, central venous access	Hospital and intensive care unit (ICU) stays	HIV
Parenteral nutrition	Prior or continual exposure to broad-spectrum antifungal or antibiotic therapy, especially tetracycline, minocycline and tigecycline.	Elderly age
Invasive medical procedures (surgeries) and devices	Chronic renal disease	Immunosuppressed state. Neutropenia

[Sekiyere 2018; Han Du, PLOS, 2020 ]

Colonisation:

Isolation of Candida auris from a non-sterile site does not always suggest infection. It is known to colonise the skin and, in rare instances, the gut, oral, and oesophagal mucosa. A salivary antimicrobial peptide histatin 5 has a potent antifungal effect on C. auris, making it difficult for this organism to colonise this area. [Han Du, PLOS, 2020]

Virulence factors:

• Tolerance to high temp (42 degrees C), high salt concentration and osmotolerance – able to colonise and persist in various environments.
• Ability to form biofilms.
• Lipases to degrade and invade host tissues
• Morphological transformation may form an aggregate of cells, which are less susceptible to antifungals (however, they are also less virulent).
• Resistance to multiple antifungal classes –

Class	Mechanism
Azoles	Mutation in ERG11 (ERG11 encodes for the lanosterol demethylase – the target of azole class) MFS efflux pump. Upregulated ABC efflux pump.
Echinocandin	Mutation in Fks1 (FKS1 encodes the catalytic subunit of 1,3-beta-D-glucan synthase that is critical for cell wall synthesis. 1,3-beta-D-glucan synthase is the target of echinocandins)
Polyenes	single nucleotide polymorphisms in multiple loci

[Chabaane 2019]

Diagnosis

Candida auris is often misidentified as another organism by commercial systems.

As per PHE, any Candida spp. isolates associated with invasive infections and isolates from superficial sites in patients from high-intensity/augmented care settings and those transferred from an affected hospital (the UK or abroad) should be analysed to species level.

Microscopy:

• C auris is indistinguishable from most other Candida species.
• Germ tube test - negative budding yeast; some strains can form rudimentary pseudohyphae on cornmeal agar.

Culture:

• C. auris grows well at 40–42º C. Growth at 42 – 45⁰C may be useful to help differentiate it from many other Candida species, especially C haemolounii, with which it is frequently confused.
• Colonies on CHROMagar may appear white, pink, red, or purple. Although it can be used for screening purposes, it cannot be used as the sole method of identification.

• CHROMagar Candida Plus:
  Developed specifically to facilitate the detection and identification of C. auris.
  Performs well as a primary isolation medium and permits C. auris to be differentiated from over 50 other yeast species in Candida and related genera

Automated commercial system:

Automated commercial systems often misidentify C auris. CDC has presented a list of common misidentifications.

System	Misidentification
Vitek 2 YST	Candida haemulonii Candida duobushaemulonii
API 20C	Rhodotorula glutinis (characteristic red colour not present) Candida sake
API ID 32C	Candida intermedia Candida sake Saccharomyces kluyveri
BD Phoenix yeast identification system	Candida haemulonii Candida catenulata
MicroScan	Candida famata Candida guilliermondii Candida lusitaniae Candida parapsilosis
RapID Yeast Plus	Candida parapsilosis

So, if these organisms are identified from the respective platform – the possibility of a C auris should be considered.

MALDI-ToF and molecular tests:

MALDI-ToF and molecular methods are considered the best identification methods.

MALDI-ToF: Bruker Biotyper and BioMérieux VITEK (MALDI-TOF) MS can identify C auris but the lab must ensure that the database is updated and contains C auris in it.

Molecular methods: sequencing the D1-D2 region of the 28s rDNA or the Internal Transcribed Region (ITS) of rDNA – are some methods that can be used. [Ref: CDC]

Susceptibility test

There are currently no established C. auris-specific susceptibility breakpoints. Tentative breakpoint from CDC

Antifungal	MIC µg/mL
Fluconazole	≥32
Voriconazole and other second generation triazoles	NA	Consider using fluconazole susceptibility as a surrogate; however, isolates that are resistant to fluconazole may respond to other triazoles occasionally
Amphotericin B	≥2	a MIC of 1.5 is determined; that value should be rounded up to 2
Anidulafungin	≥ 4
Caspofungin	≥ 2
Micafungin	≥ 4

Treatment

• Echinocandins (caspofungin, anidulafungin, micafungin) are considered as the first line therapy pending susceptibility test.
• However, resistance may develop quickly while a patient is receiving therapy and strains resistant to echinocandins have been reported. Clinical monitoring and repeat susceptibility testing from new isolates should be considered.
• As per CDC, liposomal amphotericin B (5 mg/kg daily) could be considered if the patient is clinically unresponsive to echinocandin treatment or has persistent fungemia for >5 days.
• Combination therapy has not been evaluated in clinical settings (CDC). PHE suggest if the urinary tract or central nervous system (CNS) is involved, dual therapy may be necessary, and some antifungal classes do not have bio-availability in either urine or CNS.
• Terbinafine: Currently, UK strains remain susceptible to the topical agents' nystatin and terbinafine, and it is possible that for the treatment of any future multi-drug resistant strains, a regimen incorporating oral terbinafine could be considered [PHE].
• Multiple new drugs are being evaluated with potential activity against C auris. Novel antifungals ibrexafungerp have activity against C auris. [de Oliveira 2019, Billamboz 2021]