Infectious Diseases

Candida

OVERVIEW: What every practitioner needs to know

Are you sure your patient has candidiasis? What should you expect to find?

Key symptoms

  • Mucosal

    • Oral (Figure 1)

      • Burning, altered taste sensation

    • Vulvovaginal/balanitis

      • Pruritus, burning

      • Discharge, dyspareunia

  • Cutaneous

    • Intertriginous (Figure 2)

      • Itch, burning, and/or pain

    • Chronic paronychia (Figure 3)

    • Swelling, pain of nail fold; abnormal growth of nail plate

Figure 1.

Oral candidiasis.

Figure 2.

Beefy red plaques with exudate and satellite papules, note scrotal involvement.

Figure 3.

Paronychia.

Key physical findings

  • Mucosal

    • Oral

      • Gray-white plaques on tongue, buccal mucosae, pharynx, and/or palate with macerated, reddish bases

      • Atrophic type has smooth surface with red, glazed appearance

      • May have associated angular cheilitis: maceration and transverse fissures of the oral commissures

    • Vulvovaginal

      • Erythematous, edematous, macerated labia

      • Erythematous, eroded, edematous cervix

      • Watery to white, thick and curd-like vaginal discharge

    • Balanitis

      • Erythematous, sometimes eroded patches on glans, prepuce, and/or distal shaft

      • May have exudate

  • Cutaneous

    • Intertriginous locations most commonly: groin, intergluteal cleft, under pannus or pendulous breasts, axillae, perineum/perianal

      • Pink to red moist patches with macerated scale at the periphery; superficial satellite pustules present

    • Chronic paronychia

      • Redness, tenderness, edema of proximal and/or lateral nail folds

      • Darkening and dystrophy of nail plate

How did the patient develop candidiasis? What was the primary source from which the infection spread?

  • Candida species, particularly C. albicans, are commonly found on the skin and in the gastrointestinal and genitourinary tracts of humans.

  • Most infections are endogenous. Human-to-human spread does occur.

Which individuals are of greater risk of developing candidiasis?

Risk factors for the development of candida infection include:

  • Mucosal

    • Oral

      • Healthy infants, inhaled corticosteroids, diabetes mellitus, elderly (poorly fitting dentures), poor nutritional status, antibacterial therapy, human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS), malignancy

    • Vulvovaginal/balanitis

      • Pregnancy, diabetes, antibacterial therapy, HIV/AIDS, noncircumcised partner, malignancy

      • Role of tamoxifen and oral contraceptives is controversial

  • Cutaneous

    • Concurrent intertrigo, antibacterial therapy, HIV/AIDS, obesity (skin folds), occlusion, topical steroid use, diabetes, tight clothing

Beware: there are other diseases that can mimic candidiasis:

  • Mucosal

    • Oral

      • Leukoplakia, nutritional deficiency (atrophic variant of candidiasis)

    • Vulvovaginal

      • Contact dermatitis (allergic or irritant)

    • Balanitis

      • Plasma cell balanitis, psoriasis, contact dermatitis (allergic or irritant)

  • Cutaneous

    • Intertriginous: noncandidal intertrigo, tinea cruris, inverse psoriasis, seborrheic dermatitis, erythrasma, contact dermatitis (allergic or irritant)

    • Chronic paronychia: acute paronychia, herpetic whitlow, onychomycosis

What laboratory studies may you order and what should you expect to find?

Results that confirm the diagnosis

Laboratory studies are typically not required for the diagnosis of oral or cutaneous candidiasis. However, fungal stains and culture can be helpful if the diagnosis is in question.

  • Mucosal

    • Oral: 10% potassium hydroxide (KOH) or Gram stain (GS) examination and/or fungal culture of whitish exudate

      • Masses of hyphae, pseudohyphae, and yeast spores

      • Candida spp. growth

    • Vulvovaginal: 10% KOH, GS, and/or culture of discharge

      • Hyphae and pseudohyphae among epithelial cells

      • Candida spp. growth

  • Cutaneous

    • Scraping of periphery of eroded plaque or pustule contents

      • 10% KOH or GS examination and/or fungal culture of whitish exudate

        • Masses of hyphae, pseudohyphae, and yeasts

        • Candida spp. growth

What imaging studies will be helpful in making or excluding the diagnosis of candidiasis?

Imaging studies are not typically required for the diagnosis of mucocutaneous candidiasis. However, radiographic imaging may reveal ulcers, diverticula, or dilation of the esophagus when this organ is involved. The preferred method of evaluation for esophageal candidiasis is upper endoscopy.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has candidiasis, what therapies should you initiate immediately?

  • Dermatology: when diagnosis is in question, and initial treatment is unsuccessful.

  • Gastroenterology: when esophageal candidiasis is suspected

Key principles of therapy

  • Whenever possible, use topical agents, as the risk of serious side effects will be reduced compared to systemic agents. However, there are some circumstances when an oral agent may be preferred.

  • The topical agents are available as creams, lotions, aerosols, shampoos, suppositories, lozenges, troches, ointments, and powders (nystatin). The choice of formulation will be determined by the availability of the chosen drug and location of candidiasis to be treated.

  • Most antifungals marketed to treat tinea are also effective for candidiasis. These include the azoles (clotrimazole, miconazole, econazole, oxiconazole, ketoconazole, sulconazole), ciclopirox olamine, the allylamines (naftifine and terbinafine), butenafine, and nystatin.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

The vast majority of mucocutaneous disease is caused by C. albicans, which is often susceptible to the above mentioned antifungal agents. Other Candida species rarely cause disease; these include C. tropicalis, C. pseudotropicalis, C. krusei, and C. glabrata (typically vulvovaginitis). Other than C. glabrata, the more uncommon causes of mucocutaneous candidiasis are also susceptible to the aforementioned antifungal agents. C. glabrata is typically seen in the setting of refractory vulvovaginitis and is resistant to the azoles.

Nystatin powder should only be used if there is significant moisture in the intertriginous regions involved. The cream and ointment are sufficient and less messy.

A Cochrane review, most recently updated in 2009, suggests that, for oropharyngeal candidiasis in those with HIV, oral fluconazole is superior to nystatin suspension for clinical cure and was no different than oral posaconazole, ketoconazole, itraconazole, or clotrimazole troches. Topical gentian violet, oral ketoconazole, and miconazole tabs were similar and superior to nystatin suspension. When considering mycological cure, both oral fluconazole and itraconazole were superior to clotrimazole troches. Single dose versus multiday dosing of oral fluconazole appeared equivalent for both clinical and mycological cure. Treatment options are summarized in Table I.

Table I.

Treatment Options for Candidiasis
Disease Antifungal Dose/formulation Alternatives Level of evidence
Oral Clotrimazole troches 10mg; 5 times per day Nystatin 4–6mL of 100,000U/mL four times a dayHIV/AIDS:Fluconazole 200mg orally every day for 5 to 10 days OR 150mg orally for 1 dayRefractory disease:Itraconazole 200mg every day for 5 to 10 daysOther:Ketoconazole 200mg orally every day A
Vulvovaginalbalanitis Fluconazole 150mg orally for 1 day Topical:Clotrimazole 100mg suppository per vaginal at bedtime for 7 days (200mg per vaginal for 3 days)Oral:Fluconazole 100–200mg orally every day OR itraconazole 200mg orally every day for 5 to 10 daysCandida glabratasuspected:Topical—boric acid 600mg per vaginal every day for 14 days, amphotericin B lotion, flucytosine A
Cutaneous ClotrimazoleMiconazoleKetoconazoleTerbinafineNystatin 1% cream twice a day2% cream twice a day2% cream twice a day1% cream twice a day100,000U/g cream, ointment, powder Extensive/refractory Disease:Fluconazole 150mg orally every Week for 4Ketoconazole 200mg orally every day for 2 to 6 weeksParonychia:Trial of topical therapy. If fails, weekly fluconazole should be initiated A

Other key therapeutic modalities

  • When treating candidal intertrigo, the use of Domeboro compresses (aluminum acetate powder is dissolved in tap water; a cloth is submerged, wrung so as not to drip, then placed on the involved skin and allowed to evaporate for 15 to 20 minutes, resulting in drying of the area) 3 to 4 times per day, when significant moisture is present, can help reduce maceration. Treatment should continue until the excess moisture is controlled.

  • The use of topical corticosteroids for the first 1 to 3 days of therapy is controversial. They have been used to reduce the inflammation caused by the cutaneous infection with candida and have been associated with more rapid resolution of symptoms. It is important that, if used, they are utilized only briefly during the initial course and that only low potency steroids (hydrocortisone 2.5% cream/ointment, desonide 0.05% cream/ointment) be used in the skin folds to reduce the risk of side effects.

What complications could arise as a consequence of candidiasis?

  • Mucocutaneous candidiasis itself does not typically lead to complications. However, oropharyngeal candidiasis in those with HIV/AIDS or other immunosuppression may be at increased risk for developing esophageal candidiasis.

  • When severe, cutaneous candidiasis can cause erosions in the intertriginous region(s) of involvement.

  • The skin is not commonly the source for candidemia, unless the patient is immunosuppressed and has an indwelling intravenous catheter.

What should you tell the family about the patient's prognosis?

  • Even in those with HIV/AIDS, mucocutaneous candidiasis is considered a very treatable disease, although recurrences are common.

Add what-if scenarios here:

  • Recalcitrant vulvovaginal candidiasis: When treating vulvovaginal disease, if the disease is recalcitrant to oral fluconazole, one must consider the possibility of C. glabrata as the etiologic agent. A culture may be helpful in this case.

  • Oropharyngeal candidiasis: In a patient with HIV/AIDS, it is important to investigate symptoms of esophageal involvement (odynophagia, dysphagia, feeling of food sticking in the esophagus, nausea, vomiting).

How do you contract candidiasis and how frequent is this disease?

C. albicans is a commensal organism on the skin, in the entire gastrointestinal tract, female genital tract, and expectorated sputum of most humans.

Mucocutaneous candidiasis is a common disease; however, the exact epidemiology is not known. In those with AIDS, approximately 90% will develop oropharyngeal candidiasis at some point.

Intertriginous cutaneous candidiasis may be more common in the summer when the temperatures are higher.

Most infections are endogenous; however, human-to-human transmission does occur.

What pathogens are responsible for this disease?

Candida albicans is the most common culprit. Other species may cause disease: C. tropicalis, C. glabrata, C. pseudotropicalis, and C. krusei.

How do these pathogens cause candidiasis?

Because Candida is a common commensal organism, it requires an opportunity to become a pathogen. This occurs when the skin or mucous membrane barrier is disturbed. This can occur with maceration, causing erosions in the intertriginous regions, an increase in the skin pH from occlusion, or a decrease in the normal bacterial flora as a result of antibacterial use. Under these circumstances Candida species may overgrow and cause the mucocutaneous diseases described.

Candida exists in two forms on mucocutaneous surfaces. The yeast form is more readily kept at bay by the innate and adaptive immune system than the organism's hyphal form. In the latter form, nets of mycelia create a biofilm that when combined with host immune cells, debris and matrix comprise the fungal plaques seen in thrush. This biofilm has increased capacity to adhere to the mucosal surface, invade tissue, and defy phagocytosis by hose cells.

In addition to an intact barrier, the innate immune system plays a role in keeping Candida species in check. These include Toll-like receptors, cathelicidins, and dendritic cells. There appear to be two different immune responses to the Candida. One is less robust and does not result in an inflammatory cytokine response and tolerates limited numbers of yeast cells seen in the commensal state. The second leads to inflammatory cytokine production and activation of inflammasomes inhibiting candidal invasion.

The innate immune system is aided by the adaptive immune system, particularly when the organism invades the dermis, submucosae, or blood stream. Lymphocytes play a role in regulating phagocytosis with type 1 T helper (Th1) cytokines stimulating phagocytosis and Th2 inhibiting the process. As HIV advances, the Th2 response becomes more prominent; this may represent one reason why patients with AIDS are more susceptible to mucocutaneous candidiasis.

Th17 lymphocytes appear to be important in the control of candidal infections. They have a primary defensive role in mucosal surfaces and their depletion as HIV advances may contribute to the onset and progression of mucosal candidiasis.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Pienaar, ED, Young, T, Holmes, H.. "Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children". Cochrane Database Syst Rev.. 2010 Nov 10. pp. CD003940.

(Systematic review of randomized-controlled trials on the treatment of oropharyngeal candidiasis in those with HIV.)

James, WD, Berger, TG, Elston, DM.. Andrews' diseases of the skin. Saunders-Elsevier. 2011. pp. 297-301.

(Excellent review of the salient features of mucocutaneous candidiasis.)

Reiger, A, Chen, TM, Cockerell, CJ., Bolognia, JL, Jorizzo, JL, Rapini, RP. "Cutaneous manifestations of HIV infection and HIV-related disorders". Dermatology. Mosby-Elsevier. 2008. pp. 1171.

(Limited review of mucocutaneous candidiasis in the setting of HIV infection.)

Williams, J, Coulson, I., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. "Seborrhiec eczema". Treatment of skin disease comprehensive therapeutic strategies. Saunders-Elsevier. 2010. pp. 694-6.

(This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A: Double-blind studies, B: Clinical trial with greater than or equal 20 subjects, C: Clinical trial with less than 20 subjects, D: Case series of more than 4 subjects, and E: Anecdotal case reports.)

Edwards, JE, Mandell, GL, Bennett, JE, Dolin, R. "Chapter 257, Candida Species". Principles and practice of infectious diseases. 2015. pp. Churchill Livingstone-Elsevier.

(Thorough review of Candida including epidemiology, clinical manifestations, and treatment.)

Cassone, A, Cauda, R.. "Candida and candidiasis in HIV-infected patients: where commensalism, opportunistic behaviour and frank pathogenicity lose their borders". AIDS. vol. 26. 2012. pp. 1457-72.

Guidelines on the Treatment of Skin and Oral HIV-Associated Conditions in Children and Adults. World Health Organization. 2014.

(Well-referenced guide to treatment, particularly relevant for resource-constrained settings.)

ICD-9 Codes

112.0 - Oral candidiasis

112.1 - Vulvovaginal candidiasis

112.2 - Balanitis

112.3 - Cutaneous candidiasis

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