Tinea versicolor: Epidemiologic, clinical, and therapeutic aspects Dante Borelli, MD,a Paul H. Jacobs, MD,b and Lexie NaIl, PhDb Caracas, Venezuela, and
Stanford, California
Age of the patient, climate, season, and local environmental factors influence the onset and course of tinea versicolor (pityriasis versicolor). A number of effective topical therapies are available. In addition, a single dose of 400 mg oforal ketoconazole eliminates the disease and can be used prophylactically in some cases to prevent recurrence. (J AM ACAD DERMATOL 1991;25:300-5.)
Tinea versicolor is a common superficial fungus infection that most frequently affects the trunk, neck, and/or upper arms. Lesions are slightly scaly, papular, and nummular, or they may be confluent and involve large portions of the body. Color can vary from brown to red; hypopigmented patches may also be present. 1-7
their retrospective study. The age range was from 10 to 65 years; most patients were between 20 and 45 years of age. Tinea versicolor is generally a disease of mature adults, when the sebaceous glands are most active; however, studies performed in the tropics indicate that tinea versicolor in childhood is common. 6
EPIDEMIOLOGIC ASPECTS
ETIOLOGY
Prevalence
Nomenclature
Although tinea versicolor occurs worldwide, it is especially common in hot, humid tropical climates; for example, in Samoa and Liberia, almost half the adult population may be affected. An overall prevalence rate of 30% or more probably occurs in tropical zones. 6, 7 The actual frequency of the disease in temperate climates is not known. 8 In the U.S. National Health Survey (1971 to 1974) 28,000 persons from 1 to 74 years of age, tinea versicolor was found in 0.8%.9, 10 Faergemann and Fredriksson II surveyed 20,962 patients and identified 232 (1.1 %) with tinea versicolor.
There has been much discussion about both the name of the disease and the genus of the causative organism. I Both tinea versicolor and pityriasis versicolor have been used in the literature. Tinea is usually reserved for infections produced by dermatophytes, whereas pityriasis means branlike scaling, which accurately describes the appearance of the lesions. Tinea versicolor, however, is the designation still preferred by most dermatologists. In 1853 Robin l2 identified a fungus, which he termed Microsporonfurfur, in the scale from tinea versicolor. Later it was given the name Malassezia furfur after Malassez, who, in 1874, described round and oval budding cells in the stratum corneum of patients with tinea versicolor. I Castellani and Chalmers 13 first succeeded in culturing the organism and named it Pityrosporum ovale. In the 1950s Gordon l4 isolated spherical and oval yeast strains from both tinea versicolor scales and normal skin. He named the spherical organism Pityrosporum orbiculare. Many investigators have reported that the round and oval forms of the organism are monospecific. 8
Age and sex distribution Faergemann and Fredrikssonll reported that there was a 2: 1 ratio of female to male patients in From Universidad Central de Venezuela, Caracas," and the Department of Dermatology, Stanford University School of Medicine, Stanford. b Reprint requests: Paul Jacobs, MD, Stanford Medical Center, Department of Dermatology, Stanford, CA 94305.
16/1/27435
300
Volume 25 Number 2, Part 1 August 1991
Di$tinctions between the two species P. orbiculare and P. ovale, as well as the difference between the genera Pityrosporum and M alassezia (M furfur and M ovalis) remain an enigma for many mycologists. Borelli et al. 3, 15-18 employ the taxonomic use of the genus. M alassezia for the causal agent of tinea versicolor, whereas Faergemann and Fredriksson 19 and Greer (quoted by Borelli 1?) consider the term M alassezia of historic value and prefer to think of P. orbiculare and P. ovale as the same polymorphic organism. Faergemann and Fredriksson stated that the change between the two forms can be observed, but may depend on geographic location. For example, in Sweden, only P. orbiculare, the round form, is usually seen, whereas in England and in many parts ofthe United States the oval form is more commonly seen. 19 Borelli16 noted that of 175 new patients with tinea versicolor in the centralnorthern part of Venezuela, 23 (13%) had P. ovale, whereas 152 (87%) had P. orbiculare. In another series, 40 patients with P. ovaIe associated with tinea versicolor had a mean age-onset of 31 years and age-at-time-of-studyof 37.5 years, whereas 40 patients with P. orbiculare had a mean age-onset of 20 years and an age-at-time-of-study of 24.5 years. Borelli underscored that the distribution of lesions, as well as age, varied. In patients with P. ovale, tinea versicolor affected mainly the trunk below the waistline, buttocks, and thighs, whereas P. orbiculare had a predilection for the chest, neck, face, and upper limbs. Some workers believe P. ovale and P. orbiculare to be identical, and others consider them to be different; this question has yet to be settled: 19 Faergemann and Fredriksson2o investigated the incidence of lipophilic P. orbiculare and P. ovale on clinically normal skin in children. P. orbiculare was absent in children younger than 5 years old and present in the highest incidence (93%) in 15-year-old children, about the same frequency as in the adult population. In children the colonization starts when sebaceous glands become active. P. ovale could not be cultured, and, according to the researchers,may depend geographic variations in the distribution of these yeasts. During a symposium on oral therapy in dermatomycoses held in Frankfurt in 1985,21 Marcellou posed the question of the phase of the fungus before and after treatment. In his experience the phase that
Tinea versicolor 301 Table I. Conditions associated with an increased frequency of tinea versicolor
Adrenalectomy Cushing's disease Diabetes Pregnancy Malnutrition Severe burns Striae Parenteral steroid therapy Immunosuppression Oral contraceptives Hyperhidrosis Ichthyosis
is responsible for the appearance of the lesions is the hyphal phase, and so he suggested the necessity for estimatingthe proportion ofhyphaI and yeast phases. In healthy skin he was not able to find P. orbiculare, but within lesions a high proportion of the hyphal phase can be seen. Precipitating factors In tinea versicolor P. orbiculare (or, according to Faergemann,8 P. ovale) changes from the round, budding blastospore form to the hyphal form under the influence of endogenous and exogenous predisposing factors (Table I). High temperature and high humidity probably explain the increased frequency oftinea versicolor in tropical regions. In temperate climates, such as Europe, the onset of tinea versicolor is more common during the summer months. 8 According to Borelli, 17 climate has the greatest impact on appearance, spread, and relapse. He has observed patients who had protected themselves for many years, while liv;. ing in Caracas (900 miles above sea level, mean temperatureof21 o C), against relapse ofthe disease by taking prophylactic doses of ketoconazole. The disease in these patients may relapse within a month when they move to Cagua (400 miles above sea level, mean temperature 24 0 C) despite continuation of their prophylactic regimen. Familial aggregation Tinea versicolor is not a contagious disease. There is no higher frequency of this disease in married couples than in the general population, but a hereditary predisposition is suspected. Faergemann and
302
Journal of the American Academy of Dermatology
Borelli et al.
Gut ..... Serum -
/
Basal Cells & Sebum
3-4 weeks
"-Passive Diffusion
60 mg Liver
& Sweat
1 hour
Fig. 1. Ketoconazole reaches the skin through both a slow and a rapid route. The eccrine apparatus allows ketoconazole to rapidly reach the human stratum corneum. Table II. Various topical therapies effective in the treatment of tinea versicolor Selenium sulfide Pyrithione zinc Salicylic acid Propylene glycol HaJoprogin Ciclopirox olamine Several imidazoles
Fredriksson 11 found a positive family history of 18.8% in their prospective series of 48 patients.
CLINICAL ASPECTS The differential diagnosis includes vitiligo, pityriasis alba, and some types of dermatophytosis, psoriasis, andserborrheicdermatitis. Use of the Wood's lamp and microscopy of a KOH preparation usually give the correct diagnosis. 8 Tinea versicolor most frequently occurs on the seborrheic regions of the trunk. In the tropics it often affects the face. In the beginning lesions are often red or light brown; the majority then become depigmented, but hyperpigmented lesions can remain. The primary cOl;l1plaint is cosmetic disfigurement, but moderate itching is reported by about one third of patients. I Diagnosis of tinea versicolor is made on the basis of the combination of the typical clinical picture, a yellow fluorescence with Wood's lamp examination and the evidence in a KOB preparation of round or oval budding cells and hyphae.
Fluorescence is not found when P. orbiculare or P. ovale is grown in vitro, but investigations with the scanning electron microscope and cathodeluminescence clearly demonstrate that the fluorescence resides in the fungal elements, both yeasts and filaments, and not in the host tissues. It can be found in other scaly lesions that are heavily colonized by round or oval Pityrosporum species but that show no filament formation, for example, in the greasy scales of noninflammatory "cradle cap," scalp scaling in some immunosuppressed patients, and in some cases of petaloid seborrheic dermatitis. 6 . None of the immunologic studies that have been conducted has established an explanation for the susceptibility that some patients have for Pityrosporum and their subsequent development of tinea versicolor.
THERAPEUTIC ASPECTS Topical regimens There are a number of effective topical therapies (Table II), but each has certain disadvantages. Some require regular applications, some are cosmetically objectionable, and others have an unpleasant odor. According to Faergemann and Fredriksson,22 all topical therapies are associated with a relatively high recurrence rate (60% to 80%).
Oral ketoconazole Pharmacologic factors. Ketoconazole is a substituted imidazole derivative. 4, 23-27 Early in the investigations ofimidazoles, which began in 1962, it was
Volume 25 N urn ber 2, Part 1 August 1991 discovered that the imidazole or triazole nucleus was essential to antifungal activity.23,24 Clissold and Van Cutsem24 have stated that, as with other imidazole drugs, the main site of action appears to be in the cell membrane. This group of antifungal agents inhibits the biosynthesis of ergosterol, the major membrane lipid of fungi, and interferes with othermembrane lipids. Ergosterol is synthesized de novo by fungi, and this may explain the selective action of imidazole drugs because mammalian cells can utilize, at least temporarily, exogenous cholesterol obtained from the diet. Ketoconazole reaches. the skin through both a slow and a rapid route (Fig. 1). Borelli3 and Artis 28 have stated that the eccrine apparatus is a major route by which ketoconazole rapidly reaches the human stratum corneum. In addition, there may be a toxic effect on the keratinocytes. 29 Toxicity and safety. Adverse reactions to ketoconazole administration are given in Table III. Within the last few years Cauwenbergh23 collated data from more than 4000 patients with cutaneous fungal infections who were treated with ketoconazole. Nausea was the most frequent complaint; this can be reduced by taking the drug with meals. Ketoconazole can cause transient elevation of serum liver enzymes and symptomatic hepatic abnormalities.30 Initially the incidence of the latter was believed to be 1 in 10,000. Subsequent studies by Lewis et a1. 31 indicated 1 in 15,000. Recent estimates on the basis of prescriptions written in 1987 indicate an incidence of 1 in 68,000 (D. T. Mallegol and D. C. Olsen: [Janssen Pharmaceutica], personal communication, June 15, 1988). Selective studies on various treatment schedules. Selective studie~ on the various treatment schedules include the following: 1. In the dose-determining phase, Borelli3 assayed several schedules, including one with a dose of 200 mg and another with the same dose twice a day for 24 days. He successfully treated 42 patients with a single dose of 400 mg of ketoconazole. There were six patients in this group who had not responded or had shown relapse ofthe disease after being treated on other schedules. 2. Treatment schedules with ketoconazole (200 mg dally) for varying times were also reported by Faergemann and Djariv,32 Savin,33 Heel,25 and Haze1. 34
Tinea versicolor 303 Table III. Adverse reactions to ketoconazole
[ Nausea and/or vomiting PTuritus,abdorrrlnalpain Headache, dizziness, somnolence, fever, chills, photophobia, diarrhea, thrombocytopenia At high doses impotence, gynecomastia, oligospermia; ketoconazole does decrease serum testosterone levels but this is not significant at 200 to 400 mg doses. It also decreases ACTH-induced corticosteroid serum levels, but this is not significant clinically. Anaphylaxis after a single dose and a rare case of urticaria have been reported. Idiosyncratic hepatitis Safety in pregnancy has not been established.
Incidence (% )
3 IJh 1% or less
Rare
3. Treatment schedules for short courses of treatment with 200 mg ketoconazole were found to be .effective by Hay and Medgley,35 as well as by Meisel and Wouters.21 Efficacious results were similar with the different dose and treatment duration schedules. 4. Jacobs5 and Rausch and Jacobs2 studied the effect of a single dose of 400 mg ketoconazole in 62 patients (aged 11 to 44 years) with tinea versicolor in central California. After 4 weeks 60 of the patients showed negative findings with Woods light and KOH examination. Patients remained clear of the disease in follow-up examinations for 4 to 15 months (mean 8.3 months). Two patients who were treated successfully were immunosuppressed. Three patients who had been given a single 200 mg dose of ketoconazole each month did not respond as well as patients on the single 400 mg regimen. CONCLUSIONS
Borelli et a1. 3, 15"18 were the first to use ketocona~ zole to treat tinea versicolor and initiated the regimen of a single dose of 400 mg. Hay and Migley 35
304 Borelli et al. and Meisel and Wouters 21 found that a reduction in the duration of treatment did not diminish efficacy. J acobs5 and Rausch and J acobs 2 confirmed the single oral dose 400 mg regimen that cleared 98% of patients. Prophylactic treatment with varying doses was recommended by these investigators to prevent recurrence. We do not support the prophylactic treatment of tinea versicolor because it is not possible to predict when recurrence will occur. Because the mean duration of clearing observed in the Stanford study2 was 8.2 months, it would be preferable to treat with a dose of 400 mg ketoconazole only when and if the disease recurs. It may, however, be useful to administer ketoconazole prophylactically to the immunocompromised patient. 36 REFERENCES 1, Faergemann J. Pityriasis versicolor, tinea nigra, piedra. In: Jacobs PH, Nail L, eds. Antifungal drug therapy: a complete guide for the practitioner. New York: Marcel Dekker, 1990:23-30. 2, Rausch LJ, Jacobs PH. Tinea versicolor treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1. 3. Borelli D. Treatment of pityriasis versicolor with ketoconazole. Rev Infect Dis 1980;2:592-5. 4, Clissold SP. Clinical experience in superficial fungal infections (pityriasis). In: Jones HE, ed. Ketoconazole today. A review of clinical experience. Manchester: ADIS Press, 1987:45-8. 5. Jacobs PH. Evolution in the treatment of pityriasis versicolor. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:119-22. 6. Roberts SOB. Pityriasis versicolor. In: Verbov JL, ed. Superficial fungal infections: new clinical applications in dermatology. Lancaster: MTP Press, 1986:47-72. 7, Robertson LI. Ketoconazole, intraconazole, and pityriasis versicolor. Symposium on discovering antimycotic drugs, Beerse, Belgium, May 22, J?87, 8. Faergemann J. Epidemiology and ecology of pityriasis versicolor in Europe: treatment and prophylaxis. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:89-95. 9. Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADIS Press, 1987. 10. Johnson MLT. Skin conditions and related need for medical care among persons 1-74 years. Series 11, No. 212, DHEW Pub. No. 79-1660. Washington, D.C.: US Department of Health, Education, and Welfare, November 1978. 11. Faergemann J, Fredriksson T. Tinea versicolor with regard to seborrheic dermatitis: an epidemiologic investigation. Arch DermatoI1979;115:966-8. 12, Robin 1853. Quoted by J Faergemann. 13, Castellani A, Chalmers AJ. Manual of tropical medicine. London: Bailliere Tindall, 1913.
Journal of the American Academy of Dermatology 14. Gordon MA. Lipophilic yeastlike organisms associated with tinea versicolor. J Invest DermatoI1951;17:267-72. 15. Borelli D, Rodriquez H, Marcano C. Pitiriasis versicolor. Teratamiento per os con ketoconazole. Rev Fund J M Vargas 1979;2:19-23. 16. Borelli D. Pitiriasis versicolor por Malassezia ovalis. Mycopathologia 1985;89:147-53. 17. Borelli D. Epidemiology, ecology, and treatment of pityriasis versicolor in Latin America (Venezuela). In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985: Ill-7. 18. Borelli D. Malassezia furfur versus Malassezia ovalis. X Congress International Society for Human and Animal Mycology, June 17-July 1,1988, Barcelona, Spain. 19. Faergemann J, Fredriksson T. Experimental infections in rabbits and humans with Pityrosporum orbiculare and P. ovale. J Invest DermatoI1981;77:314-8. 20. Faergemann J, Fredriksson T. Age incidence of Pityrosporum orbiculare in human skin. Acta Derm Venereal (Stockh) 1980;60:531-3. 21. Meisel C, Wouters LHJ. Pityriasis versicolor-oral treatment with ketoconazole focusing on reduction of length of treatment. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:101·6. 22. Faergemann J, Fredriksson T. Tinea versicolor: some new aspects on etiology, pathogenesis, and treatment. Int J Dermatol 1982;21 :8-22. 23. Cauwenbergh G. New areas of research. In: Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADlS Press, 1987:92-9. 24. Clissold SP, Van Cutsem J. Overview of the antimicrobial activity of ketoconazole. In: Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADlS Press, 1987:1-18. 25.. Heel RC. Pityriasis versicolor. In: Levine HB, ed. Ketoconazole in the management of fungal disease. New York: ADlS Press, 1982:89-93. 26. Levin HB. Ketoconazole in the management of fungal disease. New York: ADIS Press, 1982. 27. Borgers M, Van Cutsem J. Ketoconazole induced morphological changes in yeasts and dermatophytes. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:51-60. 28. Artis WM. Final pathway for delivery of oral antifungals to keratinized cornified skin. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:72-7. 29. Wilkinson DI, Jacobs PH. Metabolic effects of ketoconazole on cultured human keratinocytes. Br J Dermatol (In press.) 30. Jacobs PH, NaIl L. Action and safety ofketoconazole: brief literature review. Cutis 1988;42:276-82. 31. Lewis JH, Zimmerman HJ, Benson GD, et al. Hepatic injury associated with ketoconazole: analysis of 33 cases. Gastroenterology 1984;86:503-13. 32. Faergemann J, Djarv L. Tinea versicolor: treatment and prophylaxis with ketoconazole. Cutis 1982;30:542-5, 550. 33. Savin RC. Ketoconazole in pityriasis versicolor-results of
Volume 25 Number 2, Part I August 1991 a placebo-controlled trial. In: MeinhofW, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, Germany, February 1985. Oxford: The Medicine Publishing Foundation, 1985:97-9. 34. Hazen PG. A multicenter clinical trial on the efficacy of ketoconazole in dermatomycoses. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of
Tinea versicolor 305 a symposium, Frankfurt, Germany, February 1985. Oxford: The Medicine Publishing Foundation, 1985:73-7. 35. Hay RJ, Midgeley G. Short course ketoconazoletherapy in pityriasis versicolor. Clin Exp DermatoJ 1984;9:571-3. 36. Cauwenbergh G. Antifungal prophylaxis. In: Jacobs PH, Nall L, eels. Antifungal drug therapy: a complete guide for the practitioner. New York: MarcelDekker, 1990:297-313.
Stanford, California
Age of the patient, climate, season, and local environmental factors influence the onset and course of tinea versicolor (pityriasis versicolor). A number of effective topical therapies are available. In addition, a single dose of 400 mg oforal ketoconazole eliminates the disease and can be used prophylactically in some cases to prevent recurrence. (J AM ACAD DERMATOL 1991;25:300-5.)
Tinea versicolor is a common superficial fungus infection that most frequently affects the trunk, neck, and/or upper arms. Lesions are slightly scaly, papular, and nummular, or they may be confluent and involve large portions of the body. Color can vary from brown to red; hypopigmented patches may also be present. 1-7
their retrospective study. The age range was from 10 to 65 years; most patients were between 20 and 45 years of age. Tinea versicolor is generally a disease of mature adults, when the sebaceous glands are most active; however, studies performed in the tropics indicate that tinea versicolor in childhood is common. 6
EPIDEMIOLOGIC ASPECTS
ETIOLOGY
Prevalence
Nomenclature
Although tinea versicolor occurs worldwide, it is especially common in hot, humid tropical climates; for example, in Samoa and Liberia, almost half the adult population may be affected. An overall prevalence rate of 30% or more probably occurs in tropical zones. 6, 7 The actual frequency of the disease in temperate climates is not known. 8 In the U.S. National Health Survey (1971 to 1974) 28,000 persons from 1 to 74 years of age, tinea versicolor was found in 0.8%.9, 10 Faergemann and Fredriksson II surveyed 20,962 patients and identified 232 (1.1 %) with tinea versicolor.
There has been much discussion about both the name of the disease and the genus of the causative organism. I Both tinea versicolor and pityriasis versicolor have been used in the literature. Tinea is usually reserved for infections produced by dermatophytes, whereas pityriasis means branlike scaling, which accurately describes the appearance of the lesions. Tinea versicolor, however, is the designation still preferred by most dermatologists. In 1853 Robin l2 identified a fungus, which he termed Microsporonfurfur, in the scale from tinea versicolor. Later it was given the name Malassezia furfur after Malassez, who, in 1874, described round and oval budding cells in the stratum corneum of patients with tinea versicolor. I Castellani and Chalmers 13 first succeeded in culturing the organism and named it Pityrosporum ovale. In the 1950s Gordon l4 isolated spherical and oval yeast strains from both tinea versicolor scales and normal skin. He named the spherical organism Pityrosporum orbiculare. Many investigators have reported that the round and oval forms of the organism are monospecific. 8
Age and sex distribution Faergemann and Fredrikssonll reported that there was a 2: 1 ratio of female to male patients in From Universidad Central de Venezuela, Caracas," and the Department of Dermatology, Stanford University School of Medicine, Stanford. b Reprint requests: Paul Jacobs, MD, Stanford Medical Center, Department of Dermatology, Stanford, CA 94305.
16/1/27435
300
Volume 25 Number 2, Part 1 August 1991
Di$tinctions between the two species P. orbiculare and P. ovale, as well as the difference between the genera Pityrosporum and M alassezia (M furfur and M ovalis) remain an enigma for many mycologists. Borelli et al. 3, 15-18 employ the taxonomic use of the genus. M alassezia for the causal agent of tinea versicolor, whereas Faergemann and Fredriksson 19 and Greer (quoted by Borelli 1?) consider the term M alassezia of historic value and prefer to think of P. orbiculare and P. ovale as the same polymorphic organism. Faergemann and Fredriksson stated that the change between the two forms can be observed, but may depend on geographic location. For example, in Sweden, only P. orbiculare, the round form, is usually seen, whereas in England and in many parts ofthe United States the oval form is more commonly seen. 19 Borelli16 noted that of 175 new patients with tinea versicolor in the centralnorthern part of Venezuela, 23 (13%) had P. ovale, whereas 152 (87%) had P. orbiculare. In another series, 40 patients with P. ovaIe associated with tinea versicolor had a mean age-onset of 31 years and age-at-time-of-studyof 37.5 years, whereas 40 patients with P. orbiculare had a mean age-onset of 20 years and an age-at-time-of-study of 24.5 years. Borelli underscored that the distribution of lesions, as well as age, varied. In patients with P. ovale, tinea versicolor affected mainly the trunk below the waistline, buttocks, and thighs, whereas P. orbiculare had a predilection for the chest, neck, face, and upper limbs. Some workers believe P. ovale and P. orbiculare to be identical, and others consider them to be different; this question has yet to be settled: 19 Faergemann and Fredriksson2o investigated the incidence of lipophilic P. orbiculare and P. ovale on clinically normal skin in children. P. orbiculare was absent in children younger than 5 years old and present in the highest incidence (93%) in 15-year-old children, about the same frequency as in the adult population. In children the colonization starts when sebaceous glands become active. P. ovale could not be cultured, and, according to the researchers,may depend geographic variations in the distribution of these yeasts. During a symposium on oral therapy in dermatomycoses held in Frankfurt in 1985,21 Marcellou posed the question of the phase of the fungus before and after treatment. In his experience the phase that
Tinea versicolor 301 Table I. Conditions associated with an increased frequency of tinea versicolor
Adrenalectomy Cushing's disease Diabetes Pregnancy Malnutrition Severe burns Striae Parenteral steroid therapy Immunosuppression Oral contraceptives Hyperhidrosis Ichthyosis
is responsible for the appearance of the lesions is the hyphal phase, and so he suggested the necessity for estimatingthe proportion ofhyphaI and yeast phases. In healthy skin he was not able to find P. orbiculare, but within lesions a high proportion of the hyphal phase can be seen. Precipitating factors In tinea versicolor P. orbiculare (or, according to Faergemann,8 P. ovale) changes from the round, budding blastospore form to the hyphal form under the influence of endogenous and exogenous predisposing factors (Table I). High temperature and high humidity probably explain the increased frequency oftinea versicolor in tropical regions. In temperate climates, such as Europe, the onset of tinea versicolor is more common during the summer months. 8 According to Borelli, 17 climate has the greatest impact on appearance, spread, and relapse. He has observed patients who had protected themselves for many years, while liv;. ing in Caracas (900 miles above sea level, mean temperatureof21 o C), against relapse ofthe disease by taking prophylactic doses of ketoconazole. The disease in these patients may relapse within a month when they move to Cagua (400 miles above sea level, mean temperature 24 0 C) despite continuation of their prophylactic regimen. Familial aggregation Tinea versicolor is not a contagious disease. There is no higher frequency of this disease in married couples than in the general population, but a hereditary predisposition is suspected. Faergemann and
302
Journal of the American Academy of Dermatology
Borelli et al.
Gut ..... Serum -
/
Basal Cells & Sebum
3-4 weeks
"-Passive Diffusion
60 mg Liver
& Sweat
1 hour
Fig. 1. Ketoconazole reaches the skin through both a slow and a rapid route. The eccrine apparatus allows ketoconazole to rapidly reach the human stratum corneum. Table II. Various topical therapies effective in the treatment of tinea versicolor Selenium sulfide Pyrithione zinc Salicylic acid Propylene glycol HaJoprogin Ciclopirox olamine Several imidazoles
Fredriksson 11 found a positive family history of 18.8% in their prospective series of 48 patients.
CLINICAL ASPECTS The differential diagnosis includes vitiligo, pityriasis alba, and some types of dermatophytosis, psoriasis, andserborrheicdermatitis. Use of the Wood's lamp and microscopy of a KOH preparation usually give the correct diagnosis. 8 Tinea versicolor most frequently occurs on the seborrheic regions of the trunk. In the tropics it often affects the face. In the beginning lesions are often red or light brown; the majority then become depigmented, but hyperpigmented lesions can remain. The primary cOl;l1plaint is cosmetic disfigurement, but moderate itching is reported by about one third of patients. I Diagnosis of tinea versicolor is made on the basis of the combination of the typical clinical picture, a yellow fluorescence with Wood's lamp examination and the evidence in a KOB preparation of round or oval budding cells and hyphae.
Fluorescence is not found when P. orbiculare or P. ovale is grown in vitro, but investigations with the scanning electron microscope and cathodeluminescence clearly demonstrate that the fluorescence resides in the fungal elements, both yeasts and filaments, and not in the host tissues. It can be found in other scaly lesions that are heavily colonized by round or oval Pityrosporum species but that show no filament formation, for example, in the greasy scales of noninflammatory "cradle cap," scalp scaling in some immunosuppressed patients, and in some cases of petaloid seborrheic dermatitis. 6 . None of the immunologic studies that have been conducted has established an explanation for the susceptibility that some patients have for Pityrosporum and their subsequent development of tinea versicolor.
THERAPEUTIC ASPECTS Topical regimens There are a number of effective topical therapies (Table II), but each has certain disadvantages. Some require regular applications, some are cosmetically objectionable, and others have an unpleasant odor. According to Faergemann and Fredriksson,22 all topical therapies are associated with a relatively high recurrence rate (60% to 80%).
Oral ketoconazole Pharmacologic factors. Ketoconazole is a substituted imidazole derivative. 4, 23-27 Early in the investigations ofimidazoles, which began in 1962, it was
Volume 25 N urn ber 2, Part 1 August 1991 discovered that the imidazole or triazole nucleus was essential to antifungal activity.23,24 Clissold and Van Cutsem24 have stated that, as with other imidazole drugs, the main site of action appears to be in the cell membrane. This group of antifungal agents inhibits the biosynthesis of ergosterol, the major membrane lipid of fungi, and interferes with othermembrane lipids. Ergosterol is synthesized de novo by fungi, and this may explain the selective action of imidazole drugs because mammalian cells can utilize, at least temporarily, exogenous cholesterol obtained from the diet. Ketoconazole reaches. the skin through both a slow and a rapid route (Fig. 1). Borelli3 and Artis 28 have stated that the eccrine apparatus is a major route by which ketoconazole rapidly reaches the human stratum corneum. In addition, there may be a toxic effect on the keratinocytes. 29 Toxicity and safety. Adverse reactions to ketoconazole administration are given in Table III. Within the last few years Cauwenbergh23 collated data from more than 4000 patients with cutaneous fungal infections who were treated with ketoconazole. Nausea was the most frequent complaint; this can be reduced by taking the drug with meals. Ketoconazole can cause transient elevation of serum liver enzymes and symptomatic hepatic abnormalities.30 Initially the incidence of the latter was believed to be 1 in 10,000. Subsequent studies by Lewis et a1. 31 indicated 1 in 15,000. Recent estimates on the basis of prescriptions written in 1987 indicate an incidence of 1 in 68,000 (D. T. Mallegol and D. C. Olsen: [Janssen Pharmaceutica], personal communication, June 15, 1988). Selective studies on various treatment schedules. Selective studie~ on the various treatment schedules include the following: 1. In the dose-determining phase, Borelli3 assayed several schedules, including one with a dose of 200 mg and another with the same dose twice a day for 24 days. He successfully treated 42 patients with a single dose of 400 mg of ketoconazole. There were six patients in this group who had not responded or had shown relapse ofthe disease after being treated on other schedules. 2. Treatment schedules with ketoconazole (200 mg dally) for varying times were also reported by Faergemann and Djariv,32 Savin,33 Heel,25 and Haze1. 34
Tinea versicolor 303 Table III. Adverse reactions to ketoconazole
[ Nausea and/or vomiting PTuritus,abdorrrlnalpain Headache, dizziness, somnolence, fever, chills, photophobia, diarrhea, thrombocytopenia At high doses impotence, gynecomastia, oligospermia; ketoconazole does decrease serum testosterone levels but this is not significant at 200 to 400 mg doses. It also decreases ACTH-induced corticosteroid serum levels, but this is not significant clinically. Anaphylaxis after a single dose and a rare case of urticaria have been reported. Idiosyncratic hepatitis Safety in pregnancy has not been established.
Incidence (% )
3 IJh 1% or less
Rare
3. Treatment schedules for short courses of treatment with 200 mg ketoconazole were found to be .effective by Hay and Medgley,35 as well as by Meisel and Wouters.21 Efficacious results were similar with the different dose and treatment duration schedules. 4. Jacobs5 and Rausch and Jacobs2 studied the effect of a single dose of 400 mg ketoconazole in 62 patients (aged 11 to 44 years) with tinea versicolor in central California. After 4 weeks 60 of the patients showed negative findings with Woods light and KOH examination. Patients remained clear of the disease in follow-up examinations for 4 to 15 months (mean 8.3 months). Two patients who were treated successfully were immunosuppressed. Three patients who had been given a single 200 mg dose of ketoconazole each month did not respond as well as patients on the single 400 mg regimen. CONCLUSIONS
Borelli et a1. 3, 15"18 were the first to use ketocona~ zole to treat tinea versicolor and initiated the regimen of a single dose of 400 mg. Hay and Migley 35
304 Borelli et al. and Meisel and Wouters 21 found that a reduction in the duration of treatment did not diminish efficacy. J acobs5 and Rausch and J acobs 2 confirmed the single oral dose 400 mg regimen that cleared 98% of patients. Prophylactic treatment with varying doses was recommended by these investigators to prevent recurrence. We do not support the prophylactic treatment of tinea versicolor because it is not possible to predict when recurrence will occur. Because the mean duration of clearing observed in the Stanford study2 was 8.2 months, it would be preferable to treat with a dose of 400 mg ketoconazole only when and if the disease recurs. It may, however, be useful to administer ketoconazole prophylactically to the immunocompromised patient. 36 REFERENCES 1, Faergemann J. Pityriasis versicolor, tinea nigra, piedra. In: Jacobs PH, Nail L, eds. Antifungal drug therapy: a complete guide for the practitioner. New York: Marcel Dekker, 1990:23-30. 2, Rausch LJ, Jacobs PH. Tinea versicolor treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1. 3. Borelli D. Treatment of pityriasis versicolor with ketoconazole. Rev Infect Dis 1980;2:592-5. 4, Clissold SP. Clinical experience in superficial fungal infections (pityriasis). In: Jones HE, ed. Ketoconazole today. A review of clinical experience. Manchester: ADIS Press, 1987:45-8. 5. Jacobs PH. Evolution in the treatment of pityriasis versicolor. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:119-22. 6. Roberts SOB. Pityriasis versicolor. In: Verbov JL, ed. Superficial fungal infections: new clinical applications in dermatology. Lancaster: MTP Press, 1986:47-72. 7, Robertson LI. Ketoconazole, intraconazole, and pityriasis versicolor. Symposium on discovering antimycotic drugs, Beerse, Belgium, May 22, J?87, 8. Faergemann J. Epidemiology and ecology of pityriasis versicolor in Europe: treatment and prophylaxis. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:89-95. 9. Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADIS Press, 1987. 10. Johnson MLT. Skin conditions and related need for medical care among persons 1-74 years. Series 11, No. 212, DHEW Pub. No. 79-1660. Washington, D.C.: US Department of Health, Education, and Welfare, November 1978. 11. Faergemann J, Fredriksson T. Tinea versicolor with regard to seborrheic dermatitis: an epidemiologic investigation. Arch DermatoI1979;115:966-8. 12, Robin 1853. Quoted by J Faergemann. 13, Castellani A, Chalmers AJ. Manual of tropical medicine. London: Bailliere Tindall, 1913.
Journal of the American Academy of Dermatology 14. Gordon MA. Lipophilic yeastlike organisms associated with tinea versicolor. J Invest DermatoI1951;17:267-72. 15. Borelli D, Rodriquez H, Marcano C. Pitiriasis versicolor. Teratamiento per os con ketoconazole. Rev Fund J M Vargas 1979;2:19-23. 16. Borelli D. Pitiriasis versicolor por Malassezia ovalis. Mycopathologia 1985;89:147-53. 17. Borelli D. Epidemiology, ecology, and treatment of pityriasis versicolor in Latin America (Venezuela). In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985: Ill-7. 18. Borelli D. Malassezia furfur versus Malassezia ovalis. X Congress International Society for Human and Animal Mycology, June 17-July 1,1988, Barcelona, Spain. 19. Faergemann J, Fredriksson T. Experimental infections in rabbits and humans with Pityrosporum orbiculare and P. ovale. J Invest DermatoI1981;77:314-8. 20. Faergemann J, Fredriksson T. Age incidence of Pityrosporum orbiculare in human skin. Acta Derm Venereal (Stockh) 1980;60:531-3. 21. Meisel C, Wouters LHJ. Pityriasis versicolor-oral treatment with ketoconazole focusing on reduction of length of treatment. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:101·6. 22. Faergemann J, Fredriksson T. Tinea versicolor: some new aspects on etiology, pathogenesis, and treatment. Int J Dermatol 1982;21 :8-22. 23. Cauwenbergh G. New areas of research. In: Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADlS Press, 1987:92-9. 24. Clissold SP, Van Cutsem J. Overview of the antimicrobial activity of ketoconazole. In: Jones HE, ed. Ketoconazole today: a review of clinical experience. Manchester: ADlS Press, 1987:1-18. 25.. Heel RC. Pityriasis versicolor. In: Levine HB, ed. Ketoconazole in the management of fungal disease. New York: ADlS Press, 1982:89-93. 26. Levin HB. Ketoconazole in the management of fungal disease. New York: ADIS Press, 1982. 27. Borgers M, Van Cutsem J. Ketoconazole induced morphological changes in yeasts and dermatophytes. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:51-60. 28. Artis WM. Final pathway for delivery of oral antifungals to keratinized cornified skin. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, February 1985. Oxford: The Medicine Publishing Foundation, 1985:72-7. 29. Wilkinson DI, Jacobs PH. Metabolic effects of ketoconazole on cultured human keratinocytes. Br J Dermatol (In press.) 30. Jacobs PH, NaIl L. Action and safety ofketoconazole: brief literature review. Cutis 1988;42:276-82. 31. Lewis JH, Zimmerman HJ, Benson GD, et al. Hepatic injury associated with ketoconazole: analysis of 33 cases. Gastroenterology 1984;86:503-13. 32. Faergemann J, Djarv L. Tinea versicolor: treatment and prophylaxis with ketoconazole. Cutis 1982;30:542-5, 550. 33. Savin RC. Ketoconazole in pityriasis versicolor-results of
Volume 25 Number 2, Part I August 1991 a placebo-controlled trial. In: MeinhofW, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of a symposium, Frankfurt, Germany, February 1985. Oxford: The Medicine Publishing Foundation, 1985:97-9. 34. Hazen PG. A multicenter clinical trial on the efficacy of ketoconazole in dermatomycoses. In: Meinhof W, ed. Oral therapy in dermatomycoses: a step forward. Proceedings of
Tinea versicolor 305 a symposium, Frankfurt, Germany, February 1985. Oxford: The Medicine Publishing Foundation, 1985:73-7. 35. Hay RJ, Midgeley G. Short course ketoconazoletherapy in pityriasis versicolor. Clin Exp DermatoJ 1984;9:571-3. 36. Cauwenbergh G. Antifungal prophylaxis. In: Jacobs PH, Nall L, eels. Antifungal drug therapy: a complete guide for the practitioner. New York: MarcelDekker, 1990:297-313.
