THERAPEUTICS FOR THE CLINICIAN The Role of Ketoconazole in Seborrheic Dermatitis Marcel Borgers, PhD; Hugo Degreef, MD Although the prominent broad-spectrum activity SD affects approximately 2% to 5% of the popu- of ketoconazole was reported in the early 1980s, lation worldwide. It is more common in adolescents its effect against Malassezia species was most and young men, but it also is seen in elderly patients, pronounced; thus, it was developed for the treat- patients with neurologic conditions (eg, parkinson- ment of various skin infections in which a link ism, syringomyelia, depression, endocrine disorders), with these fungal species was proposed. Later, a and immunocompromised patients, such as those number of ancillary properties were described for patients with AIDS.1 Dandruff may be a symptom of ketoconazole that comprised its anti-inflammatory, psoriasis or fungal infections, but in most instances, antiseborrheic, and antiproliferative profile. The it may be regarded as a mild form of SD. In some incorporation of ketoconazole in an adapted vehi- cases, the excessive flaking of dead skin, which is cle could further promote its efficacy. Recently, typical of dandruff, may be accompanied by redness a new formulation—an anhydrous gel containing and irritation, thus fulfilling the definition of SD. ketoconazole 2%—was launched in which all of Although SD has been encountered for many the ancillary properties were optimized. years, the etiology of the disorder is poorly under- Cutis. 2007;80:359-363. stood. The disease is regarded as multifactorial, but several hypotheses have been formulated in the past centuries. In the 19th century, seborrhea was eborrheic dermatitis (SD)—or seborrheic supposed to be, as the name indicates, the most eczema, as the disorder is often named in many important eliciting factor. Unna2 coined the term S European countries—is a common superficial seborrheic dermatitis in 1887 because of his hypoth- inflammatory disease that evolves with periods of esis that the disorder was an eczematous condition; flares and remission. The typical distribution and he gave little attention to the microorganisms pres- clinical aspect of SD affect areas of the skin that are ent in the lesions, which he called Flashen Bazillen rich in sebaceous glands, particularly the scalp, face, (bacilles bouteilles). In 1904, Sabouraud3 was the nasolabial folds, eyebrows and postauricular regions, first to give attention to the microorganisms, which chest, and upper back. The lesions are sharply mar- he recognized as yeasts and thus renamed them ginated, erythematous, pruritic papules covered with Pityrosporum. Sabouraud3 initiated the infectious a greasy scale. Their color is pink to salmon-red rather theory that is ongoing to date, though the name of than dark red. the yeast has been changed several times. The Infectious Hypothesis Accepted for publication February 8, 2007. Currently, yeasts of the genus Pityrosporum are classi- Dr. Borgers is from Barrier Therapeutics NV, Geel, Belgium, and the Department of Molecular Cell Biology, Maastricht University, fied as Malassezia in honor of the first description of 4 Netherlands. Dr. Degreef is from the Department of Dermatology, fungi in the scales of dandruff by Malassez in 1874. University Hospital KULeuven, Belgium. In the 1960s and 1970s, Kligman et al5 opposed the Dr. Borgers is cofounder of Barrier Therapeutics, Inc, and fungal origin of SD and proposed a hyperproliferative scientific advisor of Barrier Therapeutics NV. Dr. Degreef is cause because of the presence of an increased cell a consultant for Barrier Therapeutics, Inc. Reprints: Griet Vermeerbergen, Barrier Therapeutics NV, turnover in the epidermis. Cipalstraat 3, B-2440 Geel, Belgium After the genus Pityrosporum was proposed as the (e-mail: [email protected]). causative agent of dandruff and SD by Sabouraud3 VOLUME 80, OCTOBER 2007 359 Therapeutics for the Clinician in 1904, the evolution of its taxonomy and nomen- these yeasts evolved from M sympodialis because of clature became chaotic. In 1977, Pityrosporum ovale specific animal hosts.10 (oval form), Pityrosporum orbiculare (round form), and Malassezia furfur (mycelial form) were consid- Susceptibility of Malassezia Species ered different configurations of the same organism. to Ketoconazole In addition, Malassezia pachydermatis was identi- Ketoconazole was introduced in 1979 as the first fied as a nonlipophilic yeast in animals. In 1990, orally active imidazole compound with activity Cunningham et al6 identified 3 different serovars on against a wide spectrum of yeast, dimorphic fungi, the basis of different surface antigens. The current and polymorphic fungi.12 The drug was recognized for knowledge is derived from the 1995 work of Guillot its prominent anti-Candida, antidermatophyte, and and Guého7 and based on the differences dis- particularly anti-Malassezia properties. The promis- played after ribosomal RNA sequence and nuclear ing clinical results of oral ketoconazole in SD were DNA comparisons. discovered by coincidence.13 Because of the agent’s Six of 7 identified species are lipophilic and possible interference with hepatic functions after oral are encountered in man (Malassezia globosa, intake, the efficacy of topical ketoconazole in SD was Malassezia restricta, M furfur, Malassezia sympodialis, investigated. The preferential location of Malassezia Malassezia slooffiae, Malassezia obtusa), whereas species to the superficial skin layers caused several M pachydermatis is not lipophilic and is found mostly topical ketoconazole formulations to be successfully in animals. Sugita et al8,9 described 2 new species: introduced.14-17 It became clear that ancillary mecha- Malassezia dermatis in 2002, found in patients with nisms unrelated to the drug’s outstanding activity atopic dermatitis, and Malassezia yamatoensis in against Malassezia species play an important role in 2004, found in patients with SD. In 2005, Cabanes the relief of the SD symptoms. et al10 described Malassezia equi (tentative name), a The potency of ketoconazole to inhibit the growth lipophilic yeast mainly present in horses. Malassezia of various new Malassezia species and strains has been nana, as reported by Hirai et al11 in 2004, also is a reported in 2 publications,18,19 which mostly confirm novel lipid-dependent yeast species isolated from the initially reported comparative data with other animals. M nana, M dermatis, and M equi are geneti- azoles.20 Hammer et al18 showed the superiority of cally close to M sympodialis; it is not excluded that ketoconazole over econazole and miconazole nitrate Figure 1. Malassezia sympodialis exposed to solvent (transmission electron microscopy, original magnification 320,100)(A) and 0.1 mg/mL ketoconazole for 24 hours (transmis- sion electron microscopy, original magnification 324,000)(B). Note the induction of mummifi- cation after treatment (ie, the occurrence of cytoplasmic necrosis in the treated culture, even though the surround- ing cell wall apparently remains comparable to the solvent exposed cells). CW indicates cell A B wall; LV, lipid vesicle. 360 CUTIS® Therapeutics for the Clinician (102100 times more potent) on a large number of through production of inflammatory mediators or clinical isolates of M furfur, M sympodialis, M slooffiae, changes in lipase activity.24 Lipases or other toxic M globosa, and M obtusa. A study by Faergemann et al19 substances are known to induce complement activa- comparing ketoconazole with pramiconazole, a tri- tion via alternative pathways, which may result in azole antifungal,21 confirmed the potency of ketocon- an inflammatory response.22 However, an important azole against 7 different Malassezia species (Figure 1). argument against infectious yeast involvement in In the latter study, the obtained minimum inhibi- mediating inflammation is that seborrheic symp- tory concentration values ranged from 0.002 to toms equally can be induced by killed yeasts.25 The 0.1 mg/mL.21 In addition, the Faergemann et al19 study anti-inflammatory effect of ketoconazole has been reported the potent inhibitory effects of ketoconazole proposed in several clinical studies, including stud- on the production of hyphae in M sympodialis from ies involving SD.17,26 The effect of ketoconazole has 0.01 mg/mL onward. To our knowledge, there are no been attributed to the inhibition of 5-lipoxygenase reports in the literature of resistance to Malassezia activity bearing on the production of leukotrienes species with ketoconazole. derived from arachidonic acid.27 However, it cannot Although less pronounced than with miconazole be excluded that the resolution of inflammatory signs nitrate, bacteriostatic effects of ketoconazole against are seen subsequent to barrier restoring effects or anti- Gram-positive bacteria such as Staphylococcus aureus microbial effects.22 have been reported.12 The in vitro data were con- Antiseborrheic Profile—Sebum hypersecretion firmed in vivo after topical application of ketocon- is one of the hallmarks in most cases of SD. It azole to skin lesions induced by S aureus.22 repeatedly has been reported that both oral and In recent years, there has been a resurgence of topical ketoconazole lower the sebum content of interest in Malassezia species, not as an infective seborrheic skin.28,29 Recent investigations30 have agent but as a source of inflammatory or immuno- supported this observation and showed that cul- logic reactions. However, no unambiguous proof has tured human keratinocytes