Non Albicans Candida
Also known as: Non-Albicans Candida, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei
Non-albicans Candida species cause more than half of candidaemia in many regions and a rising share of mucosal and deep infection. They differ from Candida albicans in their epidemiology, intrinsic and acquired antifungal resistance, and in the host groups they affect, which is why species level identification and susceptibility data change therapy.
Current taxonomy places several of the best known species in other genera: Candida glabrata is Nakaseomyces glabratus, Candida krusei is Pichia kudriavzevii, Candida lusitaniae is Clavispora lusitaniae, Candida guilliermondii is Meyerozyma guilliermondii, and Candida kefyr is Kluyveromyces marxianus. Clinical laboratories still report the older names, and the guideline literature uses them.
| Species | Hosts and settings | Typical morphology and clues | Antifungal susceptibility |
|---|---|---|---|
| Candida glabrata | Older adults, diabetes, azole exposure, abdominal surgery, urinary tract | Small (2 to 4 micrometres) yeasts without pseudohyphae; germ tube negative; cream or pink to purple on chromogenic media; ferments only glucose and trehalose | Fluconazole susceptible dose dependent or resistant; azole cross resistance; echinocandin resistance in 5 to 10 percent in some centres |
| Candida parapsilosis complex | Neonates, parenteral nutrition, catheters, hand carriage | Pseudohyphae with "crossed sticks" or giant cell forms; cream or pale on chromogenic media | Reduced echinocandin susceptibility, usually susceptible; fluconazole resistance clones |
| Candida tropicalis | Neutropenia, haematological malignancy, Asia, Latin America | Pseudohyphae and blastoconidia; metallic blue on chromogenic media; produces gas; strongly invades gut and skin | Rising azole resistance; usually echinocandin and amphotericin susceptible |
| Candida krusei | Haematological malignancy, fluconazole prophylaxis | Elongated cells, "rice grain" or matchstick pseudohyphae; rough, flat, pink fuzzy colonies on chromogenic medium | Intrinsically fluconazole resistant; reduced amphotericin B susceptibility in some isolates; echinocandin susceptible |
| Candida lusitaniae | Haematological malignancy, intensive care | Small oval yeasts; ascospores; rapid growth | Amphotericin B resistance arises in some isolates |
| Candida guilliermondii | Cancer, central line | Small yeasts; pseudohyphae | Higher echinocandin MICs; fluconazole variable |
| Candida kefyr | Haematological malignancy, dairy exposure | Gas from lactose; pseudohyphae | Mostly susceptible |
| Candida dubliniensis | HIV oral candidiasis | Germ tube and chlamydospore positive, like Candida albicans; dark green on chromogenic media; fails to grow at 45 degrees Celsius | Fluconazole resistance develops during repeated exposure |
| Candida haemulonii complex (Candida haemulonii, Candida duobushaemulonii, Candida pseudohaemulonii) | Intensive care, diabetes foot disease, tropical regions | Misidentified on biochemical panels; MALDI-TOF mass spectrometry or sequencing identifies | Amphotericin B resistance in a large share, fluconazole resistance, variable echinocandin susceptibility |
| Candida rugosa, Candida famata, Candida inconspicua, Candida norvegensis | Rare, sporadic | Variable | Variable, with reduced azole or polyene susceptibility |
The balance between species depends on region, patient group, and drug exposure. Candida glabrata leads in North America, northern Europe, and Australia, and Candida parapsilosis is first or second in southern Europe, Latin America, and Asia. Candida tropicalis is more frequent in Asia and Latin America and in haematological patients, and Candida krusei occurs where fluconazole prophylaxis is widespread. Regional surveillance and local antibiograms guide empirical therapy.
Prior fluconazole use selects Candida glabrata and Candida krusei, and prior echinocandin use selects echinocandin resistant Candida glabrata and increases Candida parapsilosis.
| Species | Azoles | Echinocandins | Amphotericin B |
|---|---|---|---|
| Candida glabrata | PDR1 gain of function raises efflux pump (CDR1, CDR2, SNQ2) expression; no stable ERG11 mutations because the species is haploid | FKS1 and FKS2 hot spot mutations (for example FKS2 S663P), found in 5 to 10 percent in high prevalence settings, often together with azole resistance and mismatch repair gene (MSH2) mutations that raise mutation rate | Rare, from ERG gene mutations |
| Candida parapsilosis | ERG11 Y132F with MRR1 gain of function, outbreaks of fluconazole resistant clones | Natural FKS1 P660A polymorphism gives MICs 1 to 2 log2 higher than for other species | Rare |
| Candida tropicalis | ERG11 substitutions and UPC2, TAC1 changes with efflux | Rare | Rare |
| Candida krusei | Intrinsic resistance through altered azole binding and efflux | Rare | Reduced susceptibility in some isolates |
| Candida lusitaniae | Variable | Rare | Acquired resistance through sterol changes |
| Candida haemulonii complex | ERG11 alterations, intrinsic fluconazole resistance | Variable | Intrinsic or acquired resistance in many isolates |
Species level identification is required for blood and sterile site isolates. Methods:
- Chromogenic agar: presumptive separation (green for Candida albicans, metallic blue for Candida tropicalis, pink and fuzzy for Candida krusei, cream or white to purple for Candida glabrata).
- Germ tube test at 37 degrees Celsius in serum for 3 hours: positive for Candida albicans and Candida dubliniensis only.
- Matrix assisted laser desorption ionisation time of flight mass spectrometry: species level identification from colonies, with the right database for rare species.
- Rapid multiplex panels from positive blood cultures: identify Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, and Candida auris in about an hour.
- Sequencing: the large subunit D1/D2 domains and the internal transcribed spacer region identify unusual species and complexes, for example the Candida parapsilosis complex and the Candida haemulonii complex.
- Susceptibility testing: broth microdilution with species specific breakpoints. Reference thresholds are fluconazole susceptible at 2 micrograms per mL or less and resistant at 8 or more for Candida albicans, Candida tropicalis, and Candida parapsilosis; for Candida glabrata susceptible dose dependent at 32 or less and resistant at 64 or more. Echinocandin breakpoints are species and agent specific (micafungin for Candida glabrata is 0.06 micrograms per mL or less for susceptible and 0.25 or more for resistant), and FKS sequencing resolves discordant results. Thresholds should be confirmed against the current standard in use.
| Species | First choice | Alternatives and notes |
|---|---|---|
| Candida glabrata | Echinocandin (caspofungin 70 mg then 50 mg daily, micafungin 100 mg daily, or anidulafungin 200 mg then 100 mg daily) | Fluconazole 800 mg (12 mg per kg) daily only for susceptible dose dependent isolates with confirmed susceptibility, after clearance; voriconazole where susceptible; liposomal amphotericin B 3 to 5 mg per kg daily for echinocandin resistance; flucytosine 25 mg per kg every 6 hours with amphotericin B in refractory disease |
| Candida parapsilosis | Fluconazole 800 mg then 400 mg daily, or liposomal amphotericin B 3 to 5 mg per kg daily | Echinocandins are acceptable if the patient has responded; remove catheters; neonates are given fluconazole 12 mg per kg daily |
| Candida tropicalis | Echinocandin, with step down to fluconazole if susceptible | Test for azole resistance before step down |
| Candida krusei | Echinocandin | Liposomal amphotericin B 3 to 5 mg per kg daily, or voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours; fluconazole is never used |
| Candida lusitaniae | Echinocandin or fluconazole | Avoid amphotericin B |
| Candida guilliermondii | Fluconazole or liposomal amphotericin B | Echinocandin MICs are higher; confirm susceptibility |
| Candida kefyr, Candida dubliniensis | Fluconazole or echinocandin | Test Candida dubliniensis after azole exposure |
| Candida haemulonii complex | Echinocandin, with liposomal amphotericin B or combination in refractory disease | Test amphotericin B and fluconazole susceptibility |
| Candida rugosa, rare species | Echinocandin or liposomal amphotericin B guided by susceptibility testing | Few data |
Common to all species are removal of central venous catheters, repeated blood cultures to document clearance, a fundoscopic examination, and treatment for 14 days after the first negative culture when there is no metastatic infection. Susceptibility data are reviewed at day 3 to 5, and any rising MIC on therapy raises the question of acquired resistance.
- Neutropenia: an echinocandin or liposomal amphotericin B is first line, and breakthrough infection during azole prophylaxis points to Candida glabrata, Candida krusei, or fluconazole resistant Candida parapsilosis or Candida tropicalis.
- Urinary tract: echinocandins reach low urinary concentrations, so fluconazole resistant Candida glabrata in urine is treated with amphotericin B deoxycholate 0.3 to 0.6 mg per kg daily or flucytosine 25 mg per kg every 6 hours.
- Prophylaxis and stewardship: fluconazole prophylaxis shifts the flora toward Candida glabrata and Candida krusei, so prophylactic agents are chosen using local epidemiology, and posaconazole, an echinocandin, or an alternative azole is used where species shift is a problem.
- Outbreaks: clusters of Candida parapsilosis (hand carriage and contaminated infusates) and Candida tropicalis need molecular typing and infection control response.
