Cutaneous candidiasis and chronic mucocutaneous candidiasis

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Cutaneous candidiasis and chronic mucocutaneous candidiasis

Caroline Halverstam and Steven R. Cohen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Cutaneous candidiasis

Cutaneous candidiasis is typically caused by Candida albicans, which exists as normal flora of human skin as well as in the gastrointestinal and genitourinary systems. Overgrowth of Candida species is suppressed by normal bacterial flora. Other Candida species occasionally cause mucocutaneous infections, the second most common being Candida tropicalis. Under certain conditions, these Candida species overgrow and become pathogens. Warmth and moisture of the intertriginous skin (axilla, inguinal folds, abdominal creases, inframammary creases), an increased skin pH, and the administration of antibiotics can disrupt the normal bacterial flora, allowing Candida to proliferate. Clinically, candidiasis presents as scaly erythematous patches with satellite papules and pustules. The diagnosis is made either microscopically, with a potassium hydroxide (KOH) preparation revealing spores and pseudohyphae, or by culture.

Management strategy

Topical antifungal agents include, but are not limited to, polyenes, azoles, allylamines, and ciclopirox olamines. Most studies required therapy twice daily for 4 weeks to ensure complete clearance in all patients. Notably, microscopic cure was often present before complete clinical clearance.

Topical corticosteroids are a source of controversy. Although the addition of corticosteroids to local antifungal therapy may reduce local inflammation in acute candidiasis, their use should be limited to 1 or 2 days because of their immunosuppressant properties.

Systemic therapy may be appropriate for cutaneous infections in immunosuppressed patients, in the setting of extensive disease not responding to topical therapy, or in patients non-compliant with topical therapy. Fluconazole 150 mg weekly appears to be as efficacious as fluconazole 50 mg daily or ketoconazole 200 mg daily. As in topical therapy, microscopic cure often precedes complete clinical clearance.

First-line therapies

image Topical antifungal A
image Topical antifungal combined with topical corticosteroids A

Second-line therapies

image Systemic azoles B

Fluconazole versus ketoconazole in the treatment of dermatophytoses and cutaneous candidiasis.

Stengel F, Robles-Soto M, Galimberti R, Suchil P. Int J Dermatol 1994; 33: 726–9.

Patients were treated with either fluconazole 150 mg once weekly plus daily placebo, or ketoconazole 200 mg once daily plus weekly placebo for 2 to 6 weeks. Candida was present in 21 of the evaluable 150 infection sites. Both treatments were clinically effective, with sites of infection responding equally to treatment with fluconazole and ketoconazole. Mycologic cure rates were seen in 68 of 73 fluconazole-treated patients and in 70 of 77 ketoconazole-treated patients. There were no major differences noted in the eradication rates between the various organisms. However, fluconazole offered the advantage of once-weekly oral administration.

A comparison of the efficacy of oral fluconazole, 150 mg/week versus 50 mg/day, in the treatment of tinea corporis, tinea cruris, tinea pedis, and cutaneous candidosis.

Nozickova M, Koudelkova V, Kulikova Z, Malina L, Urbanowski S, Silny W. Int J Dermatol 1998; 37: 703–5.

Patients received either fluconazole 150 mg/week or 50 mg/day until clinically cured or for a maximum of 4 weeks. Of the patients in this study with candidiasis, 10 of 11 patients receiving fluconazole 150 mg weekly had a positive response (microscopic cure with marked clinical improvement) and 12 of 13 taking fluconazole 50 mg daily had a positive response. Thus, weekly treatment was determined to be equivalent to daily dosing.

Clinical trials and double-blind studies of oral antifungals for cutaneous candidiasis are sparse.

Third-line therapies

image Lavender oil E
image Topical mupirocin C

Perianal candidosis: a comparative study with mupirocin and nystatin.

De Wet PM, Rode H, Van Dyk A, Millar AJ. Int J Dermatol 1999; 38: 618–22.

This clinical trial compares the efficacy and clinical outcome of 2% mupirocin in a polyethylene glycol base and nystatin cream for the treatment of diaper candidiasis. Eradication of all Candida organisms was achieved within 2 to 6 days (mean 2.6 days) in 10 patients receiving topical mupirocin therapy (three to four times daily or with each diaper change). The 10 patients who received topical nystatin cream successfully cleared within 5 days (mean, 2.8 days). While both agents eradicated Candida, a major difference was the marked response of the diaper dermatitis to mupirocin, presumably due to its well documented bacteriocidal effects. The authors conclude that mupirocin is an excellent antifungal agent and a superior therapy for diaper dermatitis because of its polymicrobial toxicity.

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of disorders with progressive and recurrent infections of the skin, nails, and mucosal surfaces caused by Candida albicans. The clinical presentation in patients with CMC can range from recurrent or recalcitrant thrush with a mild rash and dystrophic nails to severe generalized crusted plaques. Affected individuals have a defect in T-cell-mediated immunity; specifically, Th17 cells have recently been implicated. CMC typically presents in childhood. Half of those affected are identified as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). APECED is caused by mutations in the AIRE gene, which plays a key role in immunotolerance. It is characterized by hypoparathyroidism, hypothyroidism, and adrenal or gonadal failure. Candida susceptibility in APECED is attributed to autoantibodies directed against IL-17 and IL-22. Malabsorption, gastric cell atrophy, or autoimmune hepatitis occurs in about a third of patients. Alopecia, vitiligo, dental enamel dysplasia, and keratitis are frequent associations.

Other subtypes of CMC include autosomal dominant CMC with or without thyroid disease and autosomal recessive, isolated CMC. Recently, mutations in the STAT1 gene were found to underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses. Thymoma has been also associated with rare cases of IL-17 and IL-22 autoantibody positive CMC.

Management strategy

Once the etiology of the symptoms is confirmed with a positive culture for C. albicans, a work-up should be done to test for immunodeficiency. Patients should also be tested for endocrine dysfunction characteristic of APECED. If clinical suspicion for APECED is high, genetic analysis for the AIRE gene can be performed. An association of CMC with abnormalities in iron metabolism or thymoma has also been reported in adult patients, so iron and radiological studies may be warranted in HIV-negative patients with adult-onset CMC.

Treatment usually begins with an oral azole, most commonly fluconazole or ketoconazole 100–200 mg/day. Intermittent use is often advocated to prevent resistance. However, resistance in CMC patients to these first-line drugs is frequently encountered and alternative options include second-generation azoles such as voriconazole and posaconazole, as well as echinocandins such as caspofungin and micafungin. Amphotericin B can be administered orally with variable response but minimal side effects. Due to toxicity, intravenous amphotericin B should generally be limited to short treatment courses with a transition to alternative therapies. Relapse after withdrawal of these agents is the rule since the inherent immune defect remains. Therapeutic strategies that augment the immune response can be very beneficial, including transfer factor (orally or parenterally) or high-dose cimetidine.

Special investigations

First-line therapies

image Systemic azole antimycotics C

Long-term therapy of chronic mucocutaneous candidiasis with ketoconazole: experience with twenty-one patients.

Horsburgh CR Jr, Kirkpatrick CH. Am J Med 1983; 74: 23–29.

Of the 21 patients in the study, eight had APECED. Patients weighing less than 40 kg were treated with ketoconazole 100 mg/day and patients weighing more than 40 kg were treated with ketoconazole 200 mg/day. All patients responded to treatment. Mucosal lesions improved by a mean of 6.7 days, cutaneous lesions improved by a mean of 22.7 days, and nails responded by a mean of 92.4 days. Adverse effects were infrequent: one patient had drug-induced hepatitis which resolved on discontinuation of the drug and two patients became hypertensive (the relationship of the hypertension to the treatment was unclear). After 12 and 14 months of therapy, two patients remained in remission for at least 7 and 19 months, respectively (they were symptom-free at the time of publication). After an initial response, two patients had relapses while on treatment (one after 6 months, the other after 23 months) and were noted to have resistant isolates.

Voriconazole: a broad spectrum triazole for the treatment of serious and invasive fungal infections.

Maschmeyer G, Haas A. Future Microbiol 2006; 1: 365–5.

This is an excellent review of voriconazole (a second-generation triazole) for treating life-threatening fungal infections. Voriconazole can be given intravenously (6 mg/kg every 12 hours for two doses and then 4 mg/kg every 12 hours for maintenance dosing) or orally (200 mg every 12 hours for individuals over 40 kg and 100 mg every 12 hours for individuals less than 40 kg). It is effective for fluconazole-susceptible and -resistant candidiasis. Voriconazole is well tolerated. Although transient visual disturbances, liver enzyme abnormalities, skin cancers and skin rashes are reported, these rarely lead to discontinuation of treatment.

Successful treatment of chronic mucocutaneous candidiasis caused by azole-resistant Candida albicans with posaconazole.

Firinu D, Massidda O, Lorrai MM, Serusi L, Peralta M, Barca MP, et al. Clin Dev Immunol 2011; 283239.

A 39-year-old female patient with familial CMC who developed candidiasis that was resistant to multiple antifungal drugs was successfully treated with amphoteracin B. She was treated with amphotericin B 50 mg/day intravenously for 2 weeks followed by posaconazole 400 mg twice daily. After 2 months the dose was reduced to 200 mg/day without a relapse in symptoms. When posaconazole was discontinued, a relapse of oral candidiasis occurred after 2 weeks. She was thereafter maintained successfully on cycles of posaconazole 200 mg, three times per day, for a month with a 15-day discontinuation.

Second-line therapies

image Echinocandins E
image Oral amphotericin B E
image Intravenous amphotericin B D

Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis.

Rautemaa R, Richardson M, Pfaller MA, Perheentupa J, Saxen H. Diagn Microbiol Infect Dis 2008; 62: 182–5.

Forty-three isolates of C. albicans were taken from 23 patients with APECED and tested for resistance to various antifungals. Isolates were divided into two groups: fluconazole-susceptible dose-dependent and fluconazole-susceptible groups. All isolates were highly susceptible to amphotericin B and echinocandins. Posaconazole and voriconazole were active against all isolates, but more active in the fluconazole-susceptible group, suggesting a possibility that patients may develop some cross-resistance to these drugs when they take fluconazole.

Third-line therapies

image Transfer factor C
image Cimetidine and zinc sulfate E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Cutaneous candidiasis and chronic mucocutaneous candidiasis

Caroline Halverstam and Steven R. Cohen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Cutaneous candidiasis

Cutaneous candidiasis is typically caused by Candida albicans, which exists as normal flora of human skin as well as in the gastrointestinal and genitourinary systems. Overgrowth of Candida species is suppressed by normal bacterial flora. Other Candida species occasionally cause mucocutaneous infections, the second most common being Candida tropicalis. Under certain conditions, these Candida species overgrow and become pathogens. Warmth and moisture of the intertriginous skin (axilla, inguinal folds, abdominal creases, inframammary creases), an increased skin pH, and the administration of antibiotics can disrupt the normal bacterial flora, allowing Candida to proliferate. Clinically, candidiasis presents as scaly erythematous patches with satellite papules and pustules. The diagnosis is made either microscopically, with a potassium hydroxide (KOH) preparation revealing spores and pseudohyphae, or by culture.

Management strategy

Topical antifungal agents include, but are not limited to, polyenes, azoles, allylamines, and ciclopirox olamines. Most studies required therapy twice daily for 4 weeks to ensure complete clearance in all patients. Notably, microscopic cure was often present before complete clinical clearance.

Topical corticosteroids are a source of controversy. Although the addition of corticosteroids to local antifungal therapy may reduce local inflammation in acute candidiasis, their use should be limited to 1 or 2 days because of their immunosuppressant properties.

Systemic therapy may be appropriate for cutaneous infections in immunosuppressed patients, in the setting of extensive disease not responding to topical therapy, or in patients non-compliant with topical therapy. Fluconazole 150 mg weekly appears to be as efficacious as fluconazole 50 mg daily or ketoconazole 200 mg daily. As in topical therapy, microscopic cure often precedes complete clinical clearance.

First-line therapies

image Topical antifungal A
image Topical antifungal combined with topical corticosteroids A

Second-line therapies

image Systemic azoles B