Seborrheic dermatitis: Ketoconazole foam most effective against Malassezia

Houston - Recent research makes clear that the yeast genus Malassezia plays a role in the etiology of seborrheic dermatitis and several other common cutaneous disorders - and that ketoconazole is the most effective treatment for Malassezia overgrowth, an expert says.

"This commensal yeast is capable of inducing a much broader variety of pathologic states than it has been given credit for before," says Theodore Rosen, M.D., chief of the VA Dermatology Service and professor of dermatology at Baylor College of Medicine, Houston.

Etiology

Over the past century, he says, researchers have debated the concept of a Malassezia-based etiology for several common cutaneous disorders, such as seborrheic dermatitis, dandruff and tinea versicolor.

However, he says the development of advanced technologies is helping researchers to settle this debate. In recent years, for example, investigators have documented the ability of Malassezia to stimulate the production of pro-inflammatory cytokines (Watanabe S et al. J Invest Dermatol. 2001 May;116(5):769-773; Donnarumma G et al. Arch Dermatol Res. 2004 Apr;295(11):474-481. Epub 2004 Feb 12), as well as this yeast's high susceptibility to imidazoles (Piérard-Franchimont C, Piérard GE. Dermatology. 2002;204(4):344-347.)

A member of the basidiomycete class of yeasts, the Malassezi a genus is part of the human body's normal commensal cutaneous flora, Dr. Rosen says.

Furthermore, he says Malassezia species live on virtually every body surface, but they occur in greater concentrations in sebum-rich areas. These organisms obtain nutrients by penetrating the stratum corneum, where they degrade sebum to separate fatty acids from triglycerides, leaving behind unsaturated fatty acids on the skin.

Although Malassezia has proven notoriously difficult to culture, M. furfur is usually the easiest to culture - which may explain why it is most frequently isolated for research purposes - while M. restricta and M. obtuse are among the most difficult species to cultivate, Dr. Rosen says.

Predisposing factors

Predisposing factors, such as compromised immunity, oily skin and hot, humid environments, can cause Malassezia to initiate an inflammatory reaction that is characteristic of cutaneous diseases such as seborrheic dermatitis.

From patients with this disorder, researchers have isolated M. furfur, M. globosa, M. restricta and M. obtuse, he says.

Somewhat similarly, researchers have isolated M. restricta and M. globosa from the skin of patients with dandruff, and M. globosa, M. sympodalis, M. restricta, M. yamotoensis, M. furfur and M. japonica from patients with atopic dermatitis, Dr. Rosen says.

In recent years, he says, "The connection between Malassezia and seborrheic dermatitis has become increasingly clear."

For starters, he says that both Malassezia and seborrheic dermatitis occur in areas rich in sebaceous glands. Additionally, he says research suggests that Malassezia may indeed be the cause of seborrheic dermatitis in most cases (Elewski BE et al. J Drugs Dermatol. 2007 Oct;6(10):1001-1008, Ro BI, Dawson TL. J Invest Dermatol Symp Proc. 2005 Dec;10(3):194-197).

Furthermore, the fact that the severity of seborrheic dermatitis decreases when Malassezia counts on the skin decrease provides indirect evidence of the fungal roots of seborrheic dermatitis (Gupta AK. J Am Acad Dermatol . 2004 Nov;51(5):785-798. Review).

Therapy

Modern therapies to combat seborrheic dermatitis frequently combine anti-fungal agents (imidazoles), which have been shown to possess both anti-inflammatory and anti-fungal effects, and corticosteroids, which provide rapid control of flares by targeting inflammation and pruritus, Dr. Rosen says.

Particular benefits of imidazoles include their ability to reduce the number of Malassezia , although the efficacy of antifungal agents can vary depending on the species, he says.

Fortunately, for patients with seborrheic dermatitis, he says, "Malassezia is 10 times more susceptible to ketoconazole than to other imidazoles (Bergbrant IM. Curr Top Med Mycol. 1995;6:95-112. Review)."

The effectiveness of treatment depends largely on the ketoconazole delivery vehicle, Dr. Rosen says.

In this regard, he says that because most topical drugs can't penetrate the skin barrier unassisted, "Researchers have tried various approaches to improving ketoconazole delivery."

These include increasing skin hydration, applying iontophoresis or electroporation, encapsulating the active ingredient within dissolving particles, manipulating the stratum corneum, and chemically enhancing penetration of cell membranes.

Effective vehicle

However, Dr. Rosen says that perhaps the most effective vehicle for delivering ketoconazole through the stratum corneum is VersaFoam HF (Extina, ketoconazole foam 2 percent; Stiefel Laboratories), which has been shown to deliver a greater amount of active ingredient through the skin faster than other topical vehicles that deliver the drug by hydrating intracellular spaces in the stratum corneum (Huang X et al. J Am Acad Dermatol. 2005 Jul;53(1 Suppl 1):S26-S38. Review).

Ketoconazole foam 2 percent (available in the United States) contains 20 mg of ketoconazole USP per gram in a thermolabile, hydroethanolic foam vehicle. It is indicated for topical treatment of seborrheic dermatitis in immunocompetent patients at least 12 years old, but its safety and efficacy for treating fungal infections has yet to be established, Dr. Rosen says.

"Until we have some meaningful data from phase 4 studies," he says, "the optimum dosing regimen for this foam in superficial mycoses, such as tinea pedis, remains unknown."

The VersaFoam HF vehicle enables ketoconazole to penetrate the stratum corneum in small but measurable amounts, he says. Additional advantages of this vehicle include the fact that patients tend to prefer foams when given the option, Dr. Rosen says.

In one study of patients with seborrheic dermatitis, 54 percent said they preferred a foam vehicle. They also rated foam as the most versatile and fastest-absorbing vehicle (Stiefel Laboratories. Data from post-study questionnaire 2006).

Furthermore, he says, "Patients can use VersaFoam HF all over the body - including the face, trunk and scalp."

The vehicle also is free of paraben, preservatives and fragrances, and is non-hydrating and non-drying, he says. DT

Disclosure: Stiefel Laboratories funded the preparation of Dr. Rosen's poster.