Candida

Background

• Most common medically-important genus of yeast

Microbiology

• Budding yeast
• Human pathogens include:
  • Candida albicans
  • Candida dubliniensis
  • Candida glabrata
  • Candida tropicalis
  • Candida parapsilosis
  • Candida krusei
  • Candida guilliermondii
  • Candida auris
• Species that only rarely cause disease in humans include: Candida albidus, Candida catenulate, Candida chiropterorum, Candida ciferrii, Candida famata, Candida haemulonii, Candida humicola, Candida inconspicua, Candida kefyr, Candida lambica, Candida lipolytica, Candida norvegensis, Candida pelliculosa, Candida pintolopesii, Candida pulcherrima, Candida rugosa, Candida utilis and Candida zeylanoides

Identification

• Any yeast that has growth on culture (blood, fluid, tissue) or seen on Gram stain gets subcultured to SAB-CG at 35º C.
• Do wet mount to confirm features of Candida.
• Microscopy for chlamydospores, pseudohyphae, hyphae, arthroconidia, blastoconidia formation, budding, capsules, pigmentation.
  • C. glabrata is smaller, does not produce hyphae or pseudohyphae, produces blastoconidia, and grows as creamy yeast colonies.
  • Non-glabrata spp. usually exhibit single buddings and can have pseudohyphae (rarely true septate hyphae). Cannot identify species based on microscopy alone.
• MALDI-ToF (Vitek MS) provides a species. If C. haemolunii or C. famata identified on Vitek, need to rule out C. auris.
  • If Vitek not ≥95% match, or identifies one of the two species above, then repeat the MALDI-ToF and set up Dalmau on cornmeal agar.
• Dalmau technique: growth in adverse conditions (bile oxgall and corn meal) to help identify differences between species of yeast.
  • Light inoculum of single colony in a #-sign pattern with lines 1 inch apart. Cover streaks with coverslip and tamp down gently. Incubate at room temperature 18-72 hours.
  • Examine after 18-24 hours. Look for thick-walled chlamydospores (terminal refractory circles), blastoconidia morphology, and presence of pseudohyphae. Then continue incubating, examining daily.
• Old-school enzymatic tests and assimilation assays.
• Temperature tolerance test at 35-37º C, 42º C, and 45º C
• Germ tube test: if positive, either C. albicans or C. dubliniensis

Species	Colony	Conidia	Pseudohyphae	Other	Other Tests
C. albicans	White to creamy, raised, pasty, smooth and soft, shiny and moist. May produce mycelial growth called “feet” or “roots”.	Blastoconidia globose to oval.	Well-developed, abundant with blastoconidia in clusters or grape-like arrangement at septa.	Chlamydospores: round, large, thick-walled, usually single and mostly terminal forming on the tip of pseudohyphae, but some may be sessile. True hyphae may be present in older cultures.	Growth at 42-45º C.
C. dubliniensis	Cream-coloured, glistening, waxy, usually smooth.	Blastoconidia subspherical, identical to C. albicans.	Well-developed with blastoconidia in grape-like arrangement.	Chlamydospores: round, large, thick-walled, usually in pairs, triplets, and clusters of 1-3 and mostly terminal. True hyphae may be present, especially in older culture.	Usually no growth at 42-45º C.
C. glabrata	Small, white to cream-coloured, shiny, pasty, and smooth.	Terminal single budding, oval, and small. Typically arranged in dense groups.	Absent, or rudimentary if present
C. krusei	Cream-coloured to tannish-white. Flat, dry, ground-glass appearance. Spreading edge with a delicate feathery periphery.	Elongate, ellipsoidal to cylindrical. Cells are liberated and arranged parallel to the main axis appearing like logs on the stream.	Initially sparse, often present on prolonged incubation. Elondated and slender, with blastoconidia forming a cross-matchstick or treelike branching appearance at the septa.
C. parapsilosis	White to creamy, shiny, moist, slightly flat, mostly smooth or partly or entirely wrinkled.	Ovoid, single or in small clusters.	Usually abundant, but may be slow to grow. Crooked or curved, relatively short, branched chains of pseudohyphae with clusters of blastoconidia at or between septa. Christmas-tree-like arrangement.	Occasional presence of large hyphal elements called giant cells.
C. tropicalis	Cream-coloured to semiwhite, dull, dry, soft, smooth and creamy. May be wrinkled or have a mycelial fringe near the edge. Can have feet (root mycelium) similar to C. albicans.	Oval. Single or in small groups or short chains at or between septa of pseudohyphae.	Very active growth. Abundant, long and branched. Blastoconidia produced in verticils from the pseudohyphae.	True hyphae may be present.
C. famata	White to cream coloured.	Ellipsoidal.	Absent.		Weak growth at 40º C. Does not grow at 42º C.
C. auris	White to cream-coloured. Pink to beige on chromogenic agar (depending on the agar).	Oval or elongated yeast cells, singly or in pairs or groups.	Absent.		Grows well at 42º C. Variable growth at 45º C. Cycloheximide-susceptible. Usually fluconazole-resistant.
C. guilliermondii	White to tan, slightly heaped, shiny, moist, and usually mucoid with smooth edge.	Spherical to ellipsoidal.	May be slow growing (up to 10 days), radiating from centre of masses of budding cells.	Pseudohyphae not produced.	May grow at 42 º C.

Epidemiology

• Refer to Cleveland et al; CID 2012 55:1352.
• The predominant species worldwide (and in Canada) is Candida albicans, by a wide margin, followed by Candida glabrata, Candida tropicalis, and Candida parapsilosis
• Non-albicans species are becoming more common, globally, over the past three decades.
  • Candida dubliniensis associated with HIV esophagitis
  • Candida lusitaniae can develop resistance to amphotericin
  • Candida guilliermondii is multidrug resistant
  • Candida auris still rare but may be emerging. It can be misidentified as other yeasts (most commonly C. haemulonii, but also C. famata, Saccharomyces cerevisiae, and Rhodotorula glutinis).

Clinical Manifestations

Fungemia

• See also candidemia
• Risk factors include colonization, gastrointestinal mucosal disruption, total parenteral nutrition, and immunosuppression

Oropharyngeal Candidiasis

• Risk factors include immunosuppression including diabetes, inhaled corticosteroids, and denture used

Esophageal Candidiasis

• Risk factors include immunosuppression

Vulvovaginal Candidiasis

• Risk factors include colonization from recent antibiotic use, immunosuppression including diabetes, use of oral contraceptives, and pregnancy

Candidal Infection of Skin and Nails

• Risk factors include moisture and occlusion, immersion in water, and peripheral vascular disease
• Candidal skin infections can occur in moist body parts especially where skin occludes, and presents as a pruritic, erythematous rash with a poorly-defined edge that may have vesicles or pustules
• Candidal onychomycosis is most commonly caused by Candida albicans and Candida parapsilosis, followed by Candida glabrata and Candida guilliermondii
• Paronychia can be caused by Candida albicans

Cutaneous Congenital Candidiasis

• Occurs in premature infants
• Presents as a generalized macular erythematous rash
• May become pustular, papular, or vescicular
• May desquamate

Chronic Mucocutaneous Candidiasis

• Occurs in people with T-cell defects, often related to primary immunodeficiency

Urinary Tract Infection

• Occurs in patients with diabetes, with indwelling urinary catheters, urinary obstruction, or recent urological procedures
• True infection most commonly occurs as a result of hematogenous dissemination rather than ascending infection or in patients who are immunocompromised
• Candida species are a common contaminant of urine cultures, especially in women with vulvovaginal candidiasis
• They can also asymptomatically colonize the urinary system, causing asymptomatic candiduria

Pulmonary Infections

• Can occur from hematogenous spread
• Primary, isolated candidal pneumonia is very rare, and is associated with aspiration pneumonia
• Empyema can occur in patients with severe underlying diseases
• Candidal mediastinitis can happen after thoracic surgery, and is associated with high mortality
• Laryngitis or epiglottitis is rare and life-threatening

Endocarditis

• Most common fungal cause of infective endocarditis
• Risk factors include cardiac surgery, prior endocarditis, valvular disease, prosthetic valve, long-term central line, and intravenous drug use
• Clinically presents like bacterial endocarditis, but has a higher risk of embolic events
• Most commonly involves aortic and mitral valves

Pericarditis and Myocarditis

• Risk factors include thoracic surgery or immunosuppression
• Myocarditis is rare, occuring via hematogenous spread in immunocompromised patients
  • Can have heart block and shock
• Pericarditis is also rare, often occurs after thoracic surgery, from hematogenous spread, or from contiguous spread

CNS Infections

• Occurs following neurosurgery or with ventricular shunt infection or with hematogenous spread
• Can cause brain abscess, meningitis, or stroke
• Meningitis can be difficult to diagnose, and requires a large volume of CSF for improved sensitivity

Ocular Candidiasis

• From direct inoculation after ocular surgery or trauma, or with hematogenous spread
• Includes keratitis, chorioretinitis, and endophthalmitis

Bone and Joint Infections

• Rare cause of osteomyelitis and septic arthritis
• Usually from hematogenous spread; other risk factors include surgery, trauma, intraarticular injection, or diabetic foot infection
• Symptoms may only become apparent months after initial hematogenous seeding, especially with vertebral osteomyelitis

Intraabdominal Infection

• Risk factors include abdominal perforation, abdominal surgery, solid organ transplantation, anastomotic leaks, pancreatitis, and peritoneal dialysis

Investigations

• Urine culture if concern for cystitis
• Blood culture
  • Never ignore candidemia!
  • Requires an ophthalmology consult to rule out endophthalmitis (1-3% of cases)
  • Echocardiogram if IVDU or prosthetic valve
• Germ tube test (GTT)
  • If positive, indicates Candida albicans or Candida dubliniensis
  • Identifies fluconazole-sensitive Candidae

Management

• Invasive infections should be treated with an echinocandin until species and susceptibilities are available

Management by Site of Infection

• Superficial infections involving skin or mucosa: can be treated with either topical preparations or low-dose oral fluconazole
• Candidemia: see management of candidemia
• Bone and joint infections
  • Osteomyelitis: likely needs surgical debridement and removal of any implants. Duration of antifungals not well studied, but likely 3 to 12 months
  • Septic arthritis: needs drainage and removal of implants. Duration of antifungals at least 6 weeks.

Fluconazole Susceptibility

Species	Resistance pattern
Candida albicans	Generally fluconazole susceptible
Candida dubliniensis
Candida parapsilosis
Candida tropicalis
Candida glabrata	Often fluconazole resistant, or dose-dependent susceptible
Candida krusei	Inherent fluconazole resistance
Candida lusitaniae	Often amphotericin resistant but fluconazole susceptible

• See also Antifungal spectrum of activity and Pharmacology of Systemic Antifungal Agents, CID 2006

Fluconazole-Susceptible Isolates

• Candidemia: fluconazole 12 mg/kg IV load followed by 6 mg/kg PO/IV daily
  • Can use fluconazole 800 mg daily for isolates that show dose-dependent susceptibility
• Vaginal candidiasis: fluconazole 150 mg PO once, with or without intravaginal clotrimazole
• Oral thrush: fluconazole 100 mg po daily for 7 to 14 days
• Esophageal candidiasis: fluconazole 200 mg PO daily for 14 to 21 days
• Urinary tract infection: fluconazole 200 mg po daily for 7 to 14 days
• Intraabdominal infection: fluconazole 400 mg PO daily

Further Reading

• ESCMID guideline for the diagnosis and management of Candida diseases 2012: non‐neutropenic adult patients. Clin Microbiol Infect. 2012;18(Suppl. 7):19-37. doi: 10.1111/1469-0691.12039
• Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50: doi: 10.1093/cid/civ933