Candida Biology

Candida is a genus of yeasts in the Ascomycota (order Saccharomycetales). About 200 species are described and roughly 15 cause human disease. Five species account for over 90 percent of invasive infections: Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei. Candida auris has joined them as a healthcare associated pathogen.

Candida species are commensals of mucosal surfaces and skin. Disease follows loss of competing bacteria, breach of a barrier, or failure of immunity, and the source of an invasive isolate is usually the patient's own gut or skin. This is the reason a Candida isolate must always be interpreted against the site, the host and the clinical picture.

The genus produces three groups of disease:

• Mucosal and cutaneous infection: oral, oesophageal, vaginal, intertriginous, nail and chronic mucocutaneous candidiasis.
• Bloodstream infection (candidaemia) and invasive disease of deep organs.
• Device associated and urinary infection.

Regional patterns: Candida albicans accounts for about 40 to 50 percent of candidaemia in many centres, and is falling. Candida glabrata is relatively more frequent in North America and northern Europe. Candida parapsilosis is more frequent in southern Europe, Latin America, Asia and neonatal units. Candida tropicalis is more frequent in Asia and Latin America. Candida auris is established in South Asia, southern Africa, the Middle East and Latin America and has spread to many other countries.

• Cells are ovoid, 3 to 6 micrometres, and multiply by narrow based budding. They are Gram positive and stain with periodic acid Schiff and Grocott methenamine silver.
• Candida albicans is polymorphic and exists as budding yeast (blastoconidia), pseudohyphae, true hyphae and thick walled chlamydoconidia. Candida glabrata grows only as small budding yeasts, which can be mistaken for Histoplasma in tissue and for Cryptococcus when capsule is absent, and its lack of filamentation is a clue to the species.
• Colonies on Sabouraud dextrose agar at 25 to 37 degrees Celsius are cream, smooth, pasty and glistening, and appear within 24 to 48 hours.
• Candida species are facultative anaerobes, ferment sugars, and are urease negative.

Identification points:

• Germ tube test: formation of a hyphal outgrowth with no constriction at its origin within 2 to 3 hours in serum at 37 degrees Celsius. It identifies Candida albicans and Candida dubliniensis. Prolonged incubation causes false positives from Candida tropicalis.
• Chlamydoconidia: thick walled terminal spores on cornmeal Tween 80 agar.
• Chromogenic agar: presumptive identification of common species, which is not reliable for Candida auris or rare species.
• MALDI TOF mass spectrometry and sequencing: the reliable methods, dependent on database content. Older biochemical platforms commonly misidentify Candida auris as Candida haemulonii, Candida sake or Rhodotorula glutinis.

Candida albicans is diploid and heterozygous, with a genome of about 14 megabases in 8 chromosome pairs. The CUG codon encodes serine, not leucine, in the CTG clade (Candida albicans, Candida tropicalis, Candida parapsilosis, Candida auris). Candida glabrata and Candida krusei lie outside this clade, and Candida glabrata is haploid.

Features that generate diversity and resistance:

• Parasexual cycle: mating needs loss of heterozygosity at the mating type locus and switching from the white to the opaque cell type, followed by return to diploidy through chromosome loss, with no meiosis. Opaque cells are mating competent and are favoured on skin.
• Loss of heterozygosity and aneuploidy: duplication of chromosome 5 left arm amplifies ERG11 and TAC1 and produces azole resistance, and homozygosity for gain of function alleles of TAC1, MRR1 and UPC2 increases efflux and ergosterol synthesis.
• Haploid species: a single resistance mutation is expressed immediately, as in FKS mutations in Candida glabrata, and a mutator phenotype from MSH2 mutations increases drug resistance in some Candida glabrata isolates.

• Colonisation of newborns begins at birth, through the maternal vagina, and through hospital hands.
• Candida isolated from respiratory secretions, urine from catheterised patients, wounds and drains is usually colonisation. Heavy, multisite colonisation in critically ill patients raises the risk of invasive disease, but has a poor positive predictive value, so it does not justify therapy.
• Candida from a blood culture is never regarded as a contaminant.
• Endogenous infection from the gut and skin is the usual route. Exogenous routes, through hands, devices and contaminated solutions, are important for Candida parapsilosis and Candida auris.

• Direct microscopy: Gram stain, potassium hydroxide or calcofluor white shows budding yeasts with pseudohyphae in mucosal and skin samples. Pseudohyphae and hyphae in a clinical sample from a mucosal surface support invasion, while yeasts alone may be colonisation.
• Blood culture: positivity in 24 to 48 hours, and sensitivity of only about 50 to 70 percent in invasive disease, so a negative culture does not exclude deep infection.
• Beta D glucan: raised in invasive candidiasis, and a negative result has a good negative predictive value. False positives follow intravenous immunoglobulin, albumin, haemodialysis with cellulose membranes, surgical gauze, bacteraemia and some antibacterials. Results are not species specific.
• Molecular and rapid methods: polymerase chain reaction panels and T2 magnetic resonance detect Candida in whole blood within hours, with limited availability.
• Histopathology: yeasts with pseudohyphae and true hyphae on periodic acid Schiff or Grocott methenamine silver. Candida glabrata shows yeasts only.
• Species level identification: needed for every invasive isolate, because species predicts the antifungal choice.

Susceptibility testing standards:

• Fluconazole clinical breakpoints for Candida albicans, Candida tropicalis and Candida parapsilosis are susceptible at an MIC of 2 micrograms per mL or lower, susceptible dose dependent at 4, and resistant at 8 or higher. Candida glabrata is susceptible dose dependent at 32 or lower and resistant at 64 or higher.
• Echinocandin breakpoints differ by species. Caspofungin testing is variable between laboratories, so micafungin or anidulafungin results, or FKS sequencing, are used to detect resistance.
• Amphotericin B has no species specific clinical breakpoints, and an MIC above 1 microgram per mL is regarded as resistant in practice.

Treatment dose, route and duration depend on the site and the host. The species determines the drug class.

Colonisation alone is not treated.