Candidiasis

Candidiasis is most commonly caused by Candida albicans, which is ubiquitous on healthy skin as well as in the oropharyngeal cavity, gastrointestinal tract, genitourinary tract, and vagina. C. albicans and other Candida species can cause minor localized infections, including oral thrush, vaginal yeast infections, and cutaneous intertriginous infections. Invasive candidiasis is an infection of the blood (candidemia) and/or organs and is more common in immunocompromised individuals (e.g., neonates, patients with diabetes, or individuals with HIV). Mucocutaneous candidiasis can be treated with either topical antifungal agents (e.g., clotrimazole) or systemic therapy. Invasive infections require systemic antifungal therapy (e.g., with fluconazole or caspofungin), and in some cases, surgical management (e.g., removal of indwelling medical devices, debridement of focal invasive infections).

Pathogen

• Most common: Candida albicans (C. albicans)
  • A type of dimorphic fungus that can form:
    • Oval, budding yeast and hyphae and long pseudohyphae at 20^oC
    • Germ tubes at 37^oC
  • Ubiquitous on healthy skin as well as in the oropharyngeal cavity, gastrointestinal tract, genitourinary tract, and vagina
• Other candida species: e.g., C. krusei, C. glabrata, C. tropicalis, C. parapsilosis ^[1]

Risk factors

• Immunosuppression is the main risk factor for infection.
  • HIV
  • Diabetes mellitus
  • Neutropenia
  • Certain patient groups (e.g., ICU, transplant patients, surgical patients, and neonates)
• Imbalance in local flora
  • Medications: e.g., antibiotics, steroids, cytostatic agents, immunosuppressive therapy
  • ↑ Estrogen levels during pregnancy
• Compromised skin
  • Excessive moisture (e.g., diaper rash)
  • Local lesions (e.g., older patients with dentures, patients with burns)
• Hematologic malignancies (e.g., acute myeloid leukemia, multiple myeloma)
• Smoking cigarettes
• Congenital disorders, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED): an inherited autoimmune disease caused by a mutation in the AIRE gene that manifests with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.
• Presence of central venous catheter (CVC) ^[2]

C. albicans appears almost universally in low numbers on healthy adults but can cause disease in certain high-risk patients, especially those who are immunocompromised.

References:^{[3][4][5][6][7][8]}

• Local infection: imbalance in local flora (e.g., triggered by antibiotic use) → local overgrowth of C. albicans → local mucocutaneous infection (e.g., oropharyngeal infection, vaginitis)
• Systemic (invasive) infection: local mucocutaneous infection → breach of skin/mucosal barrier or translocation (IV catheterization, ascending infection in pyelonephritis, or resorption via GIT) → direct invasion of bloodstream (candidemia) → spread to visceral tissues → disseminated organ infection (e.g., pyelonephritis, endocarditis)

References:^{[3][9][10][11]}

Subtypes and variants ^[13]

Mucosal infections

Mucosal infections typically manifest with white plaques.

• Oral thrush (pseudomembranous candidiasis)
  • White plaque in the oral cavity that can be scraped off, revealing red, inflamed, and/or bleeding areas
  • Cottony feeling in the mouth, loss of taste, and sometimes pain while eating
  • Fissuring at the corners of the mouth
• Atrophic oropharyngeal candidiasis ^[14]
  • Most common in older adults, typically manifesting under upper dentures
  • Characteristic: erythema without plaques
  • Usually manifests with pain while eating and while wearing dentures
• Esophageal candidiasis
  • Retrosternal odynophagia
  • Often manifests concurrently with oral thrush
• Vulvovaginitis
• Balanitis

Cutaneous infections

Cutaneous infections typically manifest with erythematous patches (often with satellite lesions).

• Mammary candidiasis ^[15][16][17]
  • Risk factors (in the infant or mother) include mucocutaneous candidiasis or recent antibiotic use
  • Erythematous, shiny, or flaky areolas and nipples
  • Painful breastfeeding: deep, stabbing, and/or burning pain in nipples (may radiate to the breast)
• Intertriginous skin infection: occurs in, e.g., axillae, groin, gluteal folds, beneath the breasts, or abdominal folds
• Diaper dermatitis: common in infants
  • Peak incidence: 3–4 months of age
  • Develops as a result of prolonged wetness and diaper occlusion

• Onychomycosis
• Chronic mucocutaneous candidiasis
• Erosio interdigitalis blastomycetica: a candidal infection in the web spaces of the digits
  • Risk factors include wet working environment (e.g., dishwashing, bartending) and hyperhidrosis.
  • Lesions often appear moist, white, and macerated.

Esophageal candidiasis is an AIDS-defining condition in patients with HIV, but oral thrush is not.

Diagnostics ^[13]

Mucocutaneous candidiasis is a clinical diagnosis that does not require confirmatory testing.

• KOH test (potassium hydroxide test) ^[13][18]
  • Uses: to confirm diagnosis of vulvovaginal candidiasis, oral thrush, skin infections (e.g., candidal intertrigo), or onychomycosis ^{[14][19][20][21]}
  • Technique: performed on a wet mount preparation of scrapings or smears
  • Findings: budding yeasts, hyphae, and pseudohyphae
• Tissue or fluid culture
  • To confirm diagnosis and test for antifungal susceptibilities
  • To rule out a bacterial pathogen (e.g., Staphylococcus aureus) in suspected mammary candidiasis ^[22][23]
• EGD: with mucosal brushing and/or biopsy ^[24]
  • Indication: lack of response to empiric treatment for suspected candidal esophagitis ^[24]
  • Findings
    • Direct visualization: white mucosal plaque-like lesions
    • Pathology: fungal spores, pseudohyphae, multiple abscesses, and neutrophil-predominant inflammatory reaction ^[24]
• Blood tests: e.g., HIV testing, HbA1c, to screen for underlying conditions

Treatment of mucocutaneous candidiasis

Prescribe topical or systemic therapy on an individualized basis (e.g., patient preference, disease severity). The following information applies to adults and children. ^[12]

• Vulvovaginal candidiasis ^[2][25]
  • Topical treatment: topical azole for 3–14 days (e.g., clotrimazole; or miconazole)
  • Systemic treatment: a single dose of oral fluconazole (for nonpregnant adults)
  • See “Vaginal yeast infection” for dosing.
• Oropharyngeal candidiasis ^[2]
  • Topical nystatin OR clotrimazole OR miconazole for 7–14 days ^[2][12]
  • Systemic treatment (recommended for moderate to severe disease, persistent symptoms after topical treatment, immunocompromised individuals)
    • First-line: oral fluconazole for 7–14 days ^[2][12]
    • Second-line: other azoles (e.g., itraconazole, voriconazole) or echinocandins (e.g., caspofungin) ^[2]
• Esophageal candidiasis ^[2]
  • First line: oral or IV fluconazole for 14–21 days ^[12]
  • Second-line: echinocandins (e.g., caspofungin or micafungin), amphotericin B, or voriconazole
• Mammary candidiasis
  • Provide treatment for the breastfeeding parent and the infant.
    • Lactating individual: topical miconazole , topical clotrimazole ; if unsuccessful, consider oral fluconazole (off-label) ^[16]
    • Breastfeeding child: topical nystatin
  • Encourage continued breastfeeding. ^[17][26]
• Intertrigo with candidal superinfection
  • Topical: nystatin OR an azole, e.g., clotrimazole ^[12][19]
  • Systemic treatment: oral fluconazole (off-label) ^[27]
• Onychomycosis due to Candida ^[20][28]
  • Topical treatment: e.g., ciclopirox solution
  • Systemic treatment: e.g., fluconazolex
  • Additional measures, e.g., nail trimming or removal

Fluconazole is first-line therapy for oropharyngeal and esophageal candida. Alternative agents (i.e., for fluconazole-refractory infection) include echinocandins, amphotericin B, and voriconazole. ^[2]

Clotrimazole, miconazole, and nystatin are the most commonly used topical antifungal agents for mucocutaneous candidiasis.

Subtypes and variants ^[29]

• Candidemia: Symptoms vary depending on the severity of infection.
  • Fever, chills, fatigue
  • Skin rash
  • Abdominal and muscle pain
  • Headache
  • Neurological deficits, vision changes
  • Sepsis (difficult to distinguish from bacterial sepsis)
• Focal invasive infections: can manifest alone or concurrently with candidemia
  • Endophthalmitis, chorioretinitis
  • Pneumonia (pulmonary candidiasis)
  • Meningitis
  • Endocarditis
  • Abscesses, e.g., in muscle tissue

Candidal infiltration of organs can occur either directly from the source of infection (e.g., ventriculoperitoneal shunt in meningitis) or via hematogenous spread (e.g., embolic spread in endocarditis).

Diagnostics ^[2][30]

Initial studies

• Blood cultures: low sensitivity and prolonged time to positivity (∼ 2–3 days) ^[2][30]
• Tissue biopsy or sterile fluid studies: best confirmatory test
  • Specimens obtained from affected sterile sites in deep-seated infection ^[30]
  • All samples should be sent for culture, microscopy, and histopathology (including silver stain).
• β-D-glucan assay
  • Tests for the presence of β-D-glucan carbohydrate, which is a cell wall component in many fungal species
  • Nonspecific for invasive infection: Use as an adjunct to cultures. ^[2]
• Candida PCR of blood sample: unclear role in diagnosis and management
• Cross-sectional imaging: to evaluate for suspected abscess (e.g., intraabdominal or pulmonary) which can then be sampled for diagnostic confirmation

Candida in blood cultures is not considered a contaminant. However, isolation of Candida in respiratory or urine cultures often represents colonization. ^[2]

Follow-up studies

If invasive candidiasis is confirmed, consider the following studies in consultation with a specialist (e.g., ophthalmology, infectious disease).

• Dilated ophthalmological examination ^[2]
  • For all patients with candidemia ^[2]
  • Consider for patients with clinical features of endophthalmitis.
• Echocardiogram: in patients with risk factors for infective endocarditis ^[30]

Treatment of invasive candidiasis

General principles

• Consult an infectious disease specialist for guidance on antifungal therapy.
• Ensure control of infectious source as early as possible, e.g., removal of infected central lines, indwelling bladder catheter, infected prosthetics.
• Provide other localized therapies (e.g., surgical debridement) as indicated.

Candidemia ^[2][30]

• Initiate empiric antifungal therapy for confirmed cases.
  • Preferred: echinocandin, e.g., caspofungin , micafungin , or anidulafungin ^[2]
  • Alternative
    • Fluconazole : for noncritically ill patients without prior azole exposure ^[2]
    • Liposomal amphotericin B : Due to drug toxicity, only use if there is limited availability of other agents or intolerance or resistance to other agents. ^[2]
• Adjust antifungal regimen based on susceptibility data.

Focal invasive infections ^[2]

• Intraabdominal candidiasis: Initiate empiric treatment of candidemia for patients with evidence of infection and/or risks for intraabdominal candidiasis (e.g., necrotizing pancreatitis, anastomotic leak).
• Endocarditis and/or CIED infections
  • Initial antifungal therapy
    • Liposomal amphotericin B with or without flucytosine ^[2]
    • OR echinocandin, e.g., caspofungin , micafungin , or anidulafungin ^[2]
  • Chronic suppression
    • Consider for patients with a prosthetic valve and/or unremoved hardware.
    • Regimen: fluconazole ^[2]
• Candidal suppurative thrombophlebitis: liposomal amphotericin B , fluconazole , or an echinocandin (e.g., caspofungin , or micafungin ) ^[2]
• Osteoarticular infection: fluconazole OR an echinocandin (e.g., caspofungin , micafungin ) ^[2]
• Endophthalmitis: systemic antifungal therapy, e.g., fluconazole
• Candidal CNS infection (e.g, meningitis, brain abscess): liposomal amphotericin B with or without flucytosine ^[2]
• Symptomatic candidal UTI: systemic antifungals (e.g., fluconazole ) ^[2]