Pityriasis versicolor

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1 REVIEW ARTICLE JEADV (2002) 16, Pityriasis versicolor Blackwell Science Ltd AK Gupta, * R Bluhm, R Summerbell Division of Dermatology, Department of Medicine, Sunnybrook and Women s College Health Science Center (Sunnybrook site) and the University of Toronto, Toronto, Ontario, Canada, Mediprobe Laboratories Inc., Toronto, Ontario, Canada, University of Western Ontario, London, Ontario, Canada, CBS Fungal Biodiversity Centre, Utrecht, the Netherlands. *Corresponding author, Suite 6, 490 Wonderland Road South, London, Ontario, Canada, N6K 1L6, tel. (519) ; fax (519) ; agupta@execulink.com ABSTRACT Pityriasis versicolor is a common superficial fungal infection of the skin. It is caused by Malassezia spp., which are normal human saprophytes. Under certain conditions, both exogenous and endogenous, the fungus can convert from a yeast to a pathogenic mycelial form. This alteration results in mild inflammation of the skin, and in characteristic clinical and histological changes. The taxonomy of Malassezia spp. has recently been modified to include six obligatorily lipophilic species, all of which can be found on human skin, plus one non-obligatorily lipophilic species, which only rarely colonizes human hosts. Learning objectives At the conclusion of this learning activity, participants should be aware of the role of Malassezia in the development of pityriasis versicolor, the clinical and histological changes arising from this dermatosis, and the diagnosis and treatment of this disorder. Key words: fungus, Malassezia, pityriasis, review, tinea, versicolor Received: 3 October 2001, accepted 5 November 2001 Introduction Pityriasis versicolor (tinea versicolor) is a superficial fungal infection of the skin, appearing most commonly on the upper trunk, as well as on the upper arms, neck and face. As suggested by its name, pityriasis versicolor may manifest in different colours, ranging from pink or tan to dark brown or even black. The lesions have a characteristic flaking appearance, although in larger lesions this can be evident only at the border of the macule, and can be hypopigmented or hyperpigmented. Generally, the lesions take the form of round or oval macules or papules, although in advanced cases the lesions may become confluent. Whereas some patients experience mild pruritus, pityriasis versicolor is generally asymptomatic, and most patients complain primarily about the cosmetic appearance of the disease. History and taxonomy It is now recognized that the causative organisms of pityriasis versicolor are Malassezia spp. These have been placed in the order Malasseziales, class Ustilaginomycetes, phylum Basidiomycota. 1 The presence of yeast cells in skin scrapings taken from individuals with pityriasis versicolor may have been described as early as 1835 by Eichstedt. 2 In 1853, Robin isolated a fungus in the scale from pityriasis versicolor lesions, which was termed Microsporum furfur. 2 In 1874, the round and oval budding cells of the organism were described by Malassez. Bizzozero later described both spherical and oval budding cells similar to the spores of Malassez. 2 These organisms were named Saccharomyces sphaericus and S. ovalis, respectively. Sabouraud 3 emphasized the variable morphology of the yeast cells, and suggested the name Pityrosporum malassezi. The organism was first cultured in 1913 by Castellani and Chalmers and termed Pityrosporum ovale. 4 A second form of the yeast, P. orbiculare was named by Gordon in 1951, 5 following the isolation of both spherical and oval yeasts from lesional and non-lesional skin. This was the first indication that the organism causing pityriasis versicolor was part of the normal flora of human skin. For a long time, it was uncertain whether P. orbiculare and P. ovale were different organisms, or simply different forms of the same organism. P. ovale and P. orbiculare differed in prevalence in different geographical locations, for example, P. orbiculare was reported from Sweden and P. ovale from Britain and the 2002 European Academy of Dermatology and Venereology 19

2 20 Gupta et al. United States. 6 Borelli, 7 working in a tropical climate, found that the two forms of Pityrosporum were often found in the same patient, with P. orbiculare being cultured mainly from the chest, neck, face and upper limbs, and P. ovale from the trunk below the waist, the upper buttocks and the thighs. He also noted that P. ovale was more prevalent in a slightly older population, and other studies indicate that this is also the case in small children. 8,9 This evidence, combined with the lipophilic character of the yeast, suggest that of the two forms, P. orbiculare is more commonly associated with pityriasis versicolor, as the lesions are more frequent on the trunk and upper arms. Furthermore, pityriasis versicolor has a low prevalence in the older population. Borelli, however, suggested the existence of two pityriasis versicolors, one caused by M. furfur and the other by M. ovalis. 10 Mounting evidence from microscopic, 2,6 mycological 11,12 and immunological studies suggested that M. furfur and M. ovalis were morphological variants of the same yeast, perhaps representing different phases in a complex life cycle. In addition to these human commensals, the genus Malassezia contains a non-obligatory lipophilic yeast, M. pachydermatis. This species was first discovered in and is known to colonize animals, but is rarely found on human skin. In 1990, a new lipophilic yeast, M. sympodialis, was reported by Simmons and Guého. 18 This yeast is distinguished from other Malassezia spp. by its unipolar, sympodial budding. Currently, it is accepted that there are seven species in the genus Malassezia, six of which are obligatorily lipophilic and often found on human skin, and one non-obligatorily lipophilic form, M. pachydermatis, which rarely infects the human host. Guého et al. 19,20 described the seven species, distinguishing between them using primarily physiological tests. In light of the new classification, the results from older works should be evaluated carefully because it is often unclear which one or several Malassezia spp. the experiments relate to. The different Malassezia spp. may also be distinguished using molecular techniques, such as G + C reassociation values, rrna comparison and karyotyping. Recently, rapid molecular identification techniques based on polymerase chain reaction and restriction digests have been described. 21,22 Based on studies conducted within the last 5 years, it appears that the organism most frequently associated with pityriasis versicolor may not be M. furfur ; possible candidates include M. globosa 23,24 and M. sympodialis. 25 Mayser and collaborators 26,27 however, have pointed out that indole compounds apparently responsible for a fluorescence often seen in pityriasis versicolor lesions illuminated with a Wood s lamp are formed in vitro only by M. furfur, suggesting that this species is aetiological in at least some lesions. Ultrastructural analysis While Wood s light examination and light microscopy indicate the presence of Malassezia spp. on the skin, they cannot demonstrate the viability of the fungus. Scanning or transmission electron microscopy may indicate changes in the ultrastructure of the organism well before either clinical or light microscopic improvement is seen. 28 Samples taken from pityriasis versicolor lesions show that the Malassezia yeast may be present in all layers of the stratum corneum, although it is least prevalent in the lower part of the horny layer. 29,30 In approximately one-third of patients the organism may have a perifollicular distribution. 29 The organisms may be located both intracellularly and between the keratinocytes, 31 although it has been suggested that only the hyphal and not the spore form of the yeast actually invades cells. Intercellular invasion by the organism may result in the disruption of the normal, horizontal direction of skin cells in the superficial and middle layers of the stratum corneum. 32 Invasion of host cells results in a clear zone around the pathogen, which is due to a loss of keratin structure in the cell. 32,33 The cells of the horny layer appear to swell and split, 32 resulting in a loss of the cell matrix and organelles; these changes might be due to a loss of keratin. The keratolytic activity of the yeast may be due to mechanical or to chemical breakdown of the keratin. 33 Borgers et al. 34 report that the keratinous content of cells invaded by Malassezia spp. may be largely replaced by an amorphous, lipiddense material; furthermore, lipid-like droplets may also be present between the keratinocytes. Dense granules resembling glycogen have been visualized in the stratum spinosum; 35 however, other investigators 36 have failed to replicate these findings. In hypopigmented lesions, the horny layer may be slightly hyperkeratotic. There does not seem to be a difference between hypopigmented and uninvolved skin with respect to the number and distribution of melanocytes, 36 although there is a decease in melanosomes in the stratum spinosum. 33 While many patients first become aware that they have pityriasis versicolor when they develop hypopigmented areas upon exposure to the sun, it is unlikely that hypopigmentation is, as had been originally hypothesized, due to the blocking of ultraviolet light by the fungus 37 or to the products of the lipidification of the cells. 34 Hypopigmentation has been observed at anatomical sites that have not been exposed to the sun; furthermore, hypopigmentation has been seen in infants who have not been exposed to the sun. 36 Indole pigments formed by M. furfur have recently been found to be potent ultraviolet filters. 38 In hyperpigmented lesions, the stratum corneum may be thicker than in either normal or hypopigmented skin, 33 and both spores and hyphae are more numerous than in other samples. 39 Merkel cells in hyperpigmented skin contain compound melanosomes and secretory granules, suggesting an increase in the activity of these cells. It has been postulated that the fungus may cause Merkel cells to differentiate from epidermal cells. 40 In addition to these histological changes, the melanocytes in hyperpigmented lesions show characteristic alterations. They may appear larger, are more likely singly distributed, and hypertrophic. 33 The hyperpigmentation in lesions of pityriasis

3 Pityriasis versicolor 21 versicolor may not necessarily be the result of an increase in melanin activity, as hyperpigmentation has been reported in a patient with both pityriasis versicolor and vitiligo. 41 While the darkest lesions could be the result of changes in melanosome formation, it is possible that red and fawn-coloured macules are due to a mild inflammatory reaction. This hypothesis is consistent with the perivascular inflammation and lymphocyte infiltration reported in both hypo- and hyperpigmented skin. 33 The inflammatory cell infiltrate is more pronounced in hyperpigmented skin, 39 and while the inflammation itself may be responsible for some change in skin colour, melanocytes have themselves been shown to be stimulated by inflammation. 42 Thus, in the darkest lesions of pityriasis versicolor, it is probable that discoloration is a result of both inflammation and increased melanin production. Three distinct forms of the organism have been identified using electron microscopic techniques: 32 conidia, budding yeasts and mycelia. The cell walls of conidia are smooth on the outer surface. The inner surface protrudes slightly, pushing the cytoplasmic membrane into the cytoplasm. Malassezia may exhibit a thinner cell wall when grown in culture than it develops in vivo. 28,43,44 The mycelium is segmented by septa and fibrils occur in the septum. Internally, the organism contains large vacuoles, most of which appear empty, has few mitochondria, and an endoplasmic reticulum that can be clearly distinguished. Pityriasis versicolor may result from conversion of the organism to the mycelial phase. After approximately 2 weeks of antifungal therapy, the fungal cells begin to appear wrinkled, with some fragmenting of the organism. 45 In fact, intracellular disorganization or mummification has been observed as early as 6 days after starting treatment with itraconazole 44 or 3 days after treatment with topical ciclopirox olamine. 28 In the latter study, the cytoplasm of the fungal cells showed large areas of lysis, 28 especially in cells that lie between, rather than inside, keratinocytes. Gross changes to the cell surface are not visible by direct microscopy until well after these intracellular changes have begun. 28 Immune response to Malassezia in pityriasis versicolor Malassezia spp. form part of the normal human skin flora, and antibodies to P. orbiculare have been reported both in patients with pityriasis versicolor and normal controls. 46,47 Antibodies are found less frequently in children and in the elderly. 48 The superficial location of the Malassezia organism in the skin, that is, within the stratum corneum, suggests that the immune response is likely to be minimal. However, it has been suggested that patients receiving oral corticosteroids or immunocompromised individuals may exhibit superficial fungal infections that are more prevalent or severe, indicating that there may be an immune component to the development of pityriasis versicolor. Sometimes an inflammatory response with perivascular inflammation may be present in association with pityriasis versicolor. This inflammation has been thought to contribute to the coloration of the paler hyperpigmented lesions. The perivascular infiltrate contains lymphocytes, plasma cells and histiocytes, 36,49 which are involved in the immune reaction. Malassezia furfur can also activate complement by both the classical and alternative pathways, 13 contributing to the inflammation often seen in pityriasis versicolor patients. Antibodies against Malassezia are found in both pityriasis versicolor patients and normal subjects. 46 In some experiments, antibody titres have been shown to be elevated in patients, although other investigators have found no difference between patients and controls. 53 It appears that a significant humoral immune response occurs only with infection by the fungus, rather than in mere colonization. Even under these circumstances, cellular immunity is thought to play a more important part than humoral immunity. 54 In those individuals in whom pityriasis versicolor is present on a relatively chronic basis, a defect in cell-mediated immunity may exist. Otherwise well individuals with pityriasis versicolor produce fewer lymphokines compared with normal controls. 55 In addition, a large number of Langerhans cells are found in the epidermis in pityriasis versicolor lesions 56 and an increase in T cells has been reported in both the dermis and epidermis of lesional skin. 57 The majority of these T cells are thought to be helper/inducer cells, although some suppressor/cytotoxic cells are also present. Patients also exhibit a diminished lymphocyte transformation response to the fungus. 13 In addition to the role of the immune system in the development of pityriasis versicolor, other endogenous factors have been suggested. With the exception of M. pachydermatis, the Malassezia spp. are all obligatorily lipophilic species, requiring medium- or long-chain (C 12 C 24 ) fatty acids in the culture medium. 2,58,59 The relationship between the amount and kind of free fatty acids on the skin and the tendency to develop pityriasis versicolor has been investigated with inconclusive results. 60 It is not known whether the microbial flora influence, or are influenced by, skin lipids, or both. In vitro, the addition of glucose or asparagine to the culture medium promotes growth of the yeast. 59 Cholesterol and cholesterol esters added to culture also stimulate the induction of hyphae. 61 Epidemiology Pityriasis versicolor is most commonly a disease of teenagers and young adults. Because of the lipid requirements of Malassezia, the yeasts are rarely found on the skin of young children and older individuals, but are usually present during the years when sebum production is highest. Despite the fact that most adults have the yeast on their skin, conversion from the yeast to the mycelial form of the organism is required for

4 22 Gupta et al. pityriasis versicolor to develop. This transformation is related to both exogenous and endogenous factors. Endogenous factors mediating the development of pityriasis versicolor include malnutrition, 62 use of oral contraceptives, 63 use of systemic corticosteroids or immunosuppressants, and hyperhidrosis. 64,65 Pityriasis versicolor is more common in the tropics than in temperate climates; furthermore, it is more common in the summer than in the winter months. Most frequently, lesions are generally restricted to anatomical sites that are covered by clothing, suggesting the role of increased heat and moisture in the pathogenesis of the lesions. Athletes may be particularly prone to pityriasis versicolor, but whether this is due to excessive sweating is unclear. 66,67 While hygiene is not an important factor in the development of the disease, application of creams or lotions to the skin may exacerbate the tendency to develop lesions in those prone to the disease Despite the link between pityriasis versicolor and malnutrition, socioeconomic status is not a predictor of the likelihood that a patient will develop pityriasis versicolor. 71 The development of pityriasis versicolor may be related to an altered immune response to the organism In patients with immune deficiency disorders such as human immunodeficiency virus or acquired immune deficiency syndrome 74,75 and visceral leishmaniasis, 76 pityriasis versicolor may be more prevalent, and may manifest in unusual forms or locations, 73,77 or with greater severity than in an immunocompetent individual. 74 However, it has also been suggested that pityriasis versicolor is no more prevalent in human immunodeficiency virus patients, 78 even though other fungal infections might be. Pityriasis versicolor lesions restricted to the irradiated field have been reported in association with radiation therapy. 79 Pityriasis versicolor has also been reported in patients undergoing lithium therapy for mood disorders. 80 Endogenous factors also contribute to the development of pityriasis versicolor. While some studies have found that pityriasis versicolor is more common in men than in women, 64,81,82 other studies have reported the opposite. 8,83 The weight of the evidence suggests that gender probably plays no significant part in the propensity to develop pityriasis versicolor. The lack of conjugal cases combined with the common appearance of pityriasis versicolor in more than one member of a family suggest a genetic component to susceptibility. Based on the distribution of the disease in first, second and third degree relatives, it seems this susceptibility is due to multifactorial inheritance. 84 Among children, pityriasis versicolor is generally rare, although cases are more common in tropical climates. 85 Paediatric cases of pityriasis versicolor have been reported more frequently from Europe 86,87 compared with North America. 88 In children, facial involvement may be more common than in adults. 86,89 Pityriasis versicolor has been rarely reported in infants under 2 years of age and in most of these cases the infant was premature and placed in intensive care following birth (but see Congly 90 for an exception to this general rule). One case of an outbreak on the chest of a 2-week-old infant was reported, 91 and the authors suggest that the hot, humid environment of the incubator may have been a contributing factor. Premature neonates are more often found to have the yeast on their skin, regardless of whether they develop lesions. This may be because these infants are handled more frequently by health care personnel than are babies born at term. 92 Climatic or genetic conditions may also affect the age at which colonization with Malassezia first occurs. 93 It is unusual for older adults to suffer from pityriasis versicolor. 94 This is thought to be due to the reduction in sebum production that occurs with increasing age. However, the hospitalized elderly may be at a higher risk for developing pityriasis versicolor; 95 this could be explained by the fact that they are relatively more immunocompromised, they may get more hot and sweaty, especially if their clothes are not changed frequently, and the frequency of bathing may be reduced in some cases. While pityriasis versicolor is the only dermatological disorder conclusively shown to be caused by Malassezia, 96 the occurrence of other diseases may be associated with an alteration in the colonization density of the organism. Pityrosporum folliculitis is characterized by inflammation of the hair follicles, resulting in an acne-like eruption. 97,98 Seborrhoeic dermatitis has also been associated with an overgrowth of Malassezia yeasts, 99 although other studies 100 have found no difference in Malassezia counts in lesional and normal skin of seborrhoeic dermatitis patients. Instead, these authors suggest that seborrhoeic dermatitis is due to an abnormal reaction to the Malassezia on the skin, rather than to overgrowth. 100 That there is a link between the fungus and the development of seborrhoeic dermatitis seems clear, because treatment with antifungal medications such as ketoconazole results in both amelioration of the lesions and a decrease in the number of Malassezia organisms present on the skin. 101,102 Seborrhoeic dermatitis may be present concomitantly with pityriasis versicolor. 83 A possible association has been suggested between Malassezia yeasts and transient acantholytic dermatosis, 103 and confluent and reticulated papillomatosis of Gougerot-Carteaud Systemic infections with Malassezia have also been reported These are generally nosocomial, and occur in neonates and, less frequently, in adults receiving total parenteral nutrition supplemented with lipids. The recent reclassification of the genus Malassezia provides the opportunity for a more detailed examination of the relationship between the various species and the infections with which they are associated. The prevalence of pityriasis versicolor in Scandinavia is approximately 1% of the population. 83,110,111 In tropical countries, cases of pityriasis versicolor are more prevalent, reaching as high as 50% in some areas. 112,113 Even within these countries, susceptibility can vary, 114 and among those prone to infection, relapse is almost inevitable. A South African study 115 suggests that patients with chronic pityriasis versicolor may undergo

5 Pityriasis versicolor 23 spontaneous remission; however, others report that it is unusual for this to occur. 46 The sites of predilection for pityriasis versicolor are the trunk and upper arms; however, it has been reported to be present at numerous other sites. Pityriasis versicolor can also occur on the scalp, with or without accompanying dandruff. 116,117 In adults who show facial involvement, these lesions are often secondary to pityriasis versicolor of the trunk and upper arms. 118,119 Lesions can also occur on the penis, 77, most commonly with involvement of the trunk as well, although occasionally as the only area of outbreak. Lesions have been reported in other unusual locations, without any involvement of the trunk: neck and groin, 73 the nipple and periareolar area (in a male patient), 123 the groin and axillae, the groin and perineum, 124 the webbing of the left hand and the antecubital fossae and forearms. 125 While these are rare occurrences, they indicate that a diagnosis of pityriasis versicolor should not be ruled out simply because the clinical presentation of the cutaneous eruption does not reflect the anatomical distribution that would normally be expected of pityriasis versicolor. Diagnosis Generally, it is relatively easy to diagnose pityriasis versicolor. However, the varied presentation of the lesions may confuse the inexperienced clinician. The differential diagnosis includes vitiligo (especially in the case of dark-skinned patients with hypopigmented lesions), chloasma, tinea corporis, seborrhoeic dermatitis, pityriasis rosea, pityriasis alba, erythrasma, confluent and reticulated papillomatosis of Gougerot and Carteaud, pityriasis rotunda, 126 secondary syphilis and pinta. Wood s light examination may help in the diagnosis of pityriasis versicolor. Under Wood s light (filtered ultraviolet light with a peak of 365 nm), the lesions of pityriasis versicolor fluoresce a bright yellow or gold colour. Often, this fluorescence includes the areas immediately surrounding clinically visible lesions, indicating that the infection is spreading. 53,127 Wood s light may also be useful for differential diagnosis, as the colour of fluorescence is characteristic of the mycelial form of Malassezia. However, Wood s light provides a positive response in only one-third of cases, 128 most likely those involving Malassezia furfur. 26,27 Mycological examination can be used to confirm the diagnosis of pityriasis versicolor. Specimens for light microscopic examination should be taken from the scaling edges of the lesion, as these areas are most likely to contain a larger number of microorganisms. 62 Either tape or the edge of a scalpel can be used to scrape gently a small amount of skin from the lesion. (See Payne 129 for an outline of the procedure.) Prior to performing light microscopic examination, the addition of 10 15% potassium hydroxide to the sample helps dissolve the keratin and debris, facilitating examination for fungal elements. Gentle heating of the glass slide speeds dissolution of keratin, although if left at room temperature, the sample should be ready to view under the microscope in min. Light microscopic examination reveals that the yeast has a characteristic spaghetti and meatballs appearance, as both hyphae and spores are present. Albert s solution 130 toluidine blue, 0.15 g, malachite green 0.2 g, glacial acetic acid 1 ml, 95% ethanol 2 ml and distilled water 110 ml 2 can be used instead of potassium hydroxide. 131 A skin biopsy is generally not necessary in the diagnosis of pityriasis versicolor. As the causative agent requires a lipid-rich medium for growth, culture in standard media will not allow the yeast to grow. In addition, as Malassezia yeasts are found on % of the normal population, 69,132 growth of the organism in culture does not necessarily indicate pityriasis versicolor. The development of pityriasis versicolor is associated with a shift in the organism from its yeast to its pathological mycelial form. While experimental infection of humans with Malassezia has produced pityriasis versicolor lesions in both patients and normal volunteers, 6,8,64,133 in those not prone to this disease it is difficult to induce infection. Generally, the inoculation site must be occluded, and olive oil added to the area. Even under these conditions the experimental lesions tend to clear spontaneously. 6,8,133 Clearly, endogenous host factors are an important part of the process of conversion from yeast to mycelial fungus. Treatment Pityriasis versicolor responds well to a variety of topical or oral antifungal agents. Because the conversion of Malassezia yeasts to the mycelial form is thought to be due, in part, to endogenous host factors, recurrence is common, and clinicians may consider prophylactic treatment for those who have a propensity for repeated bouts of the disease. Topical treatments Non-specific antifungal agents These agents are, relatively speaking, the older treatments available for pityriasis versicolor and are so-called because the majority do not have activity directly against the fungus. Generally, they act by physically and/or chemically removing infected dead tissue in the stratum corneum and/or affecting cell turnover rates. 134 Selenium sulphide 125, Available as a 2.5% lotion, cream or shampoo. It has been effective in the treatment of pityriasis versicolor. 135,136 Some patients may complain about its unpleasant odour. 136 Propylene glycol A keratolytic agent that is often used as a base in other topical medications. On its own, however, it has been shown to be effective against pityriasis versicolor. 138

6 24 Gupta et al. Whitfield s ointment Contains benzoic acid (which has a fungistatic action) and salicylic acid (which has a keratolytic action) in a ratio of 2 : 1 (usually 12% : 6%). 139 This treatment has been shown to be effective against pityriasis versicolor. 140,141 Sulphur and salicylic acid Several studies have reported the effectiveness of this combination of agents in the treatment of pityriasis versicolor. 142,143 Other non-specific agents used to treat pityriasis versicolor These include povidone-iodine paint, 144 benzoyl peroxide 145 and tretinoin cream. Specific topical antifungal agents Halprogin This is a halogenated phenolic ether that is fungicidal to Malassezia. 139 It is an effective treatment for pityriasis versicolor. 146 Zinc pyrithione The efficacy of zinc pyrithione shampoo 1% versus its vehicle has been shown in two studies. 147,148 The treatment period in both reports was 2 weeks. Tolciclate Like tolnaftate, tolciclate is a member of the thiocarbamate group of antifungal agents. The mechanism of action is to block sterol biosynthesis in fungal cells by inhibiting squalene epoxidase. 149,150 Both cream and lotion formulations, each 1%, are effective against pityriasis versicolor. 151,152 Ciclopirox olamine Is a hydroxypyridone and has a broadspectrum antifungal action. 153 The 1% cream formulation has been shown to be more effective than both vehicle and clotrimazole 1% cream. 153 The effectiveness of ciclopirox olamine has been supported in a number of studies. 154,155 Azoles These have a fungistatic effect, inhibiting the biosynthesis of ergosterol and thus disrupting the formation of fungal cell membranes. Bifonazole. May produce irreversible changes in Malassezia yeasts that can be seen using electron microscopy. 156,157 Multiple treatment options have been reported: bifonazole cream 1%, spray 1%, solution 1%, gel 1%, powder 1% and shampoo 1% In some patients a single application may be effective, 161,162 although a 3-day treatment schedule has been shown to be more effective. 162 Clotrimazole. A broad-spectrum imidazole reported to be effective against pityriasis versicolor in both open 163,164 and controlled, double-blind 165,166 trials. Comparative studies 140,141,167 have shown clotrimazole 1% cream to be as effective as Whitfield s ointment, but more acceptable to patients. Fluconazole. Unlike the other topical azoles used to treat pityriasis versicolor, fluconazole is a triazole. In a 2% shampoo, fluconazole is more effective than placebo with 5 days of treatment. 168 Ketoconazole. The 2% cream formulation has been reported, in a double-blind, randomized study, to be more effective than placebo. 169 Ketoconazole 2% shampoo 170 and foaming gel 171 can be effective with only 1 day of treatment, although longer treatment durations have been reported. Miconazole and econazole. These two synthetic phenythyl imidazole derivatives are closely related. Both have been shown to be effective in the treatment of pityriasis versicolor. Miconazole nitrate 2% cream is effective when applied twice daily for 2 weeks. 172 Econazole nitrate has been reported to be effective as a 1% foaming solution, cream or shampoo when used once daily. Sertaconazole. The 2% cream formulation applied twice daily for 4 weeks has been shown to be effective in the treatment of pityriasis versicolor. 176 Sulconazole. One study 177 suggests that sulconazole 1% cream may be used to treat pityriasis versicolor successfully. Tioconazole. This is a 1-substituted imidazole. Both the 1% lotion and the 1% solution have been shown to be effective in pityriasis versicolor. 178,179 Griseofulvin Oral griseofulvin is not an effective treatment for pityriasis versicolor; however, it has been used topically for this condition. 180 Terbinafine This is a member of the fungicidal class of allylamines. These drugs, like the thiocarbamates, work by inhibiting squalene epoxidation during sterol synthesis, thus disrupting membrane synthesis in fungi. 181 As a 1% solution, terbinafine has been shown to be more effective than vehicle with 7 days of twice-daily treatment. 182,183 Terbinafine cream 184 and gel 185 have also been shown to be effective. While terbinafine can be used for the topical treatment of pityriasis versicolor, it is ineffective when used as systemic treatment for this indication. 186 Oral treatments The advantages of oral medications may include increased patient compliance; oral therapy can be more convenient and less time-consuming for the patient. However, some physicians may prefer to reserve systemic treatment for cases in which the pityriasis versicolor involves a large area of the skin, when the disease is recurrent or patient preference is for oral therapy. Griseofulvin Oral griseofulvin is not effective against Malassezia infection. 180 Ketoconazole This was the first effective oral azole developed against pityriasis versicolor. The drug is effective in 200 mg doses. 187 In early studies, the duration of therapy was 4 weeks,

7 Pityriasis versicolor 25 Table 1 Randomized, controlled trials of ketoconazole in the treatment of pityriasis versicolor Reference* Blinding Therapeutic regimens Assessment Cure rate Savin et al (n = 66) 187 Double-blind (A) 4 weeks 200 mg daily ketoconazole Complete cure at 8 weeks 97% (B) Placebo 0% Urcuyo and Zaias(n = 20) 188 Double-blind (A) 2 weeks 200 mg daily ketoconazole Complete cure at 4 weeks 90% (B) Placebo 20% Fernandez-Nava et al. (n = 120) 191 Open (A) Single dose 400 mg ketoconazole Mycological cure at 1 month 42% (B) 10 days 200 mg daily ketoconazole 51% Hay and Midgley (n = 36) 190 Double-blind (A) 5 days 200 mg ketoconazole plus placebo to Clinical and mycological cure at 28 days 83% 25 days (B) 15 days 200 mg ketoconazole plus placebo 75% (C) 25 days 200 mg ketoconazole 67% Faergemann and Djarv (n = 32) 195 Open (A) 200 mg ketoconazole daily for 3 weeks 2 weeks after treatment end 81% (B) 200 mg ketoconazole daily for 5 weeks 100% Zaias (n = 59) 194 Double-blind (A) 200 mg ketoconazole daily for 5 days then Clinical and mycological cure at 30 days 84% placebo for 5 days (B) 200 mg ketoconazole daily for 10 days 90% (C) Placebo daily for 10 days 17% *When studies included patients with other dermatoses, only the number of pityriasis versicolor patients is reported. Some studies reported cure rates assessed at several time points; the one closest to 4 weeks from start of therapy is reported here. Indicates significant difference (P < 0.05). No significant difference between ketoconazole groups, but both were significantly different than placebo. although later studies suggested that shorter courses of treatment were also effective, 2 weeks, days 189 or even 5 days. 190 A single, 400 mg dose of ketoconazole may also be effective, 191 although relapse rates could be higher than with the other treatment regimens. 192 Another option is three doses of ketoconazole 400 mg administered 12 h apart or at 7-day intervals. 193 A summary of randomized clinical trials using systemic ketoconazole in the treatment of pityriasis versicolor is given in Table ,188,190,191,194,195 Itraconazole Drug absorption of itraconazole is enhanced when the medication is taken with food. Itraconazole is effective at a dosage of 200 mg/d, 190 when taken for either 5 or 7 days. The minimum cumulative dose for itraconazole is 1000 mg, although an improved efficacy is more likely to occur with the regimen of 200 mg/d for 7 days. 196 Table 2 summarizes the randomized clinical trials that have been conducted using itraconazole to treat pityriasis versicolor Fluconazole This has also been investigated for its potential use in the treatment of pityriasis versicolor. To date, there have been several open studies suggesting that fluconazole is an effective treatment option for this indication. These studies are summarized in Table Comparative studies evaluating efficacy in pityriasis versicolor (Table 4) Few comparative studies have been performed to assess the relative efficacies of the three oral therapies. One study 215 has found itraconazole (200 mg daily for 1 week, or 100 mg daily for 2 weeks) and ketoconazole (400 mg/d 7 days apart) to be equally effective. Itraconazole has also been compared with fluconazole. One study 216 found no significant differences between itraconazole 400 mg/d in two divided doses for 15 days and 600 mg fluconazole daily in two divided doses for the same length of time. In another study, 217 complete cure was found to be more common in patients receiving itraconazole (200 mg daily for 7 days) compared with fluconazole in a single 450 mg dose, although there was no significant difference between the drugs when patient improvement was assessed. Itraconazole (200 mg/d for five consecutive days) has also been compared with topical selenium sulphide (once-daily application for 7 days). 218 The oral treatment was found to be more acceptable to patients, although all patients in both groups responded to therapy. Prophylactic treatment While pityriasis versicolor is relatively easy to treat, the importance of endogenous host factors and uncontrollable environmental factors in the development of the disease mean that recurrence may be common, especially in predisposed individuals. Ketoconazole has been shown to prevent relapse in patients when administered as a 400-mg dose, once per month 219 or as 200 mg/d for three consecutive days, once per month. 195 Follow-up for up to 11 months showed a low rate of recurrence in patients receiving prophylactic treatment. Itraconazole 400 mg one dose (four capsules of 100 mg each) given once a month for 6 months has been demonstrated to be significantly more effective than placebo. 220

8 26 Gupta et al. Table 2 Randomized controlled trials of itraconazole in the treatment of pityriasis versicolor Reference* Blinding Therapeutic regimens Assessment Cure rate Hickman (n = 36) 197 Double-blind (A) 7 days 200 mg daily itraconazole Mycological cure at week 5 89% (B) Placebo 6% Wishart (n = 6) 198 Single-blind (A) Up to 2 months 50 mg daily itraconazole (or until cure) (B) Up to 2 months 100 mg daily itraconazole (or until cure) Clinical and mycological cure Faergemann Double-blind (A) 2 weeks 100 mg itraconazole daily Clinical cure at end of treatment 66.7% (n = 33) 199 (B) Placebo 7.2% Swinyer (n = 16) 200 Double-blind (A) 7 days 200 mg itraconazole daily (n = 8) Mycological cure and clinical 75% (B) Placebo (n = 8) response at follow-up 4 weeks 0% post-treatment Savin and Bolognia Double-blind (A) 7 days 200 mg itraconazole daily (n = 13) Mycological cure and clinical 69% (n = 27) 200 (B) Placebo (n = 14) response at follow-up 4 7% weeks post treatment Brody (n = 33) 200 Double-blind (A) 7 days 200 mg itraconazole daily (n = 16) Mycological cure and clinical 100% (B) Placebo (n = 14) response at follow-up 4 2.9% weeks post-treatment Shmunes Double-blind (A) 7 days 200 mg itraconazole daily (n = 15) Mycological cure and clinical 87?% (n = 30) 200 (B) Placebo (n = 15) response at follow-up 4 weeks post treatment 0% Hickman and Whitmore (n = 35) 200 Panconesi et al. Open (A) 200 mg itraconazole daily in a single (n = 30) 201 dose for 5 days (B) 200 mg itraconazole daily in a divided dose for 5 days del Palacio- Hernandez et al. (B) 100 mg once daily for 10 days (n = 15) (n = 30) 202 Galimberti et al. Double-blind (A) 7 days 200 mg itraconazole daily (n = 18) Mycological cure and clinical 89% (B) Placebo (n = 17) response at follow-up 4 weeks 6% post-treatment at end of treatment 100% Open (A) 200 mg once daily for 5 days (n = 15) Mycological cure plus healing 93% or only mild residual lesions 87% at 3 weeks post-treatment (n = 28) 203 (B) 200 mg itraconazole once daily for 10 days (n = 15) 28 days post-treatment 87% Open (A) 200 mg itraconazole once daily for 5 days (n = 13) Clinical and mycological cure at 77% Faergemann Open (A) 50 mg itraconazole daily for up to 4 weeks (n = 14) Clinical and mycological cure at 4 79% (n = 27) 204 (B) 100 mg itraconazole daily for up to 4 weeks (n = 13) weeks after treatment began 100% Estrada (n = 42) 205 Open (A) 200 mg itraconazole daily for 5 days (n = 22) Mycological cure at end of 75% (B) 100 mg itraconazole daily for 10 days (n = 20) treatment 95% Morales-Doria Open (A) 100 mg twice daily for 5 days (n = 24) Mycological cure at 28 days after 95% (n = 47) 206 (B) 100 mg daily for 5 days (n = 23) start of treatment 100% Delescluse et al. Open (A) 50 mg daily for 14 days (n = 17) Clinical and mycological cure or 65% (n = 73) 207 (B) 100 mg daily for 5 days (n = 12) marked improvement (clinical 64% (C) 100 mg daily for 10 days (n = 12) response) 1 week after the end 58% (D) 100 mg daily for 15 days (n = 12) of treatment 85% (E) 200 mg daily for 5 days (n = 20) 100% Fioroni et al. (n = 30) 208 Open (A) 200 mg itraconazole daily in a single dose (n = 15) (B) 200 mg itraconazole daily in a divided dose (n = 15) Clinical and mycological cure; 4 weeks after end of treatment Massone et al. Open (A) 100 mg itraconazole daily for 10 days (n = 10) Clinical and mycological cure; 100% (n = 20) 209 (B) 200 mg itraconazole daily for 5 days (n = 10) 4 weeks after beginning 73% treatment Simoni and Cilli Open (A) 200 mg itraconazole daily in a single dose for 5 days Clinical and mycological cure; 100% (n = 30) 210 (B) 200 mg itraconazole daily in a divided dose for 5 days 4 weeks after end of treatment 100% Cuce et al. Open (A) 200 mg itraconazole daily for 5 days (n = 21) Clinical and mycological cure; 19/21 (n = 42) 211 (B) 200 mg itraconazole daily for 7 days (n = 21) 35 days after start of treatment 19/21 Not given as a function of time: 100% for both groups 100% 13/15 (2 dropouts) 100% *When studies included patients with other dermatoses, only the number of pityriasis versicolor patients is reported. Some studies reported cure rates assessed at several time points; the one closest to 4 weeks is reported here. Indicates significant difference (P < 0.05).

9 Pityriasis versicolor 27 Table 3 Fluconazole in the treatment of pityriasis versicolor Reference Type of study Interventions Assessment Cure rates Amer et al. (n = 603) 212 Open (A) single 150 mg dose fluconazole weekly for 4 weeks (n = 207) (B) single 300 mg dose fluconazole weekly for 4 weeks (n = 190) (C) single 300 mg dose repeated at 2 weeks (n = 206) Faergemann (n = 23) 213 Open Single dose fluconazole 400 mg (n = 23) post-treatment Shahid et al. (n = 50) 214 Open 300 mg fluconazole once weekly for 2 weeks (n = 50) Mycological cure 28 days after last day of treatment 78% 93% 87% Clinical cure 3 weeks 74% Clinical and mycological cure at week 4 98% Table 4 Comparison studies of different drugs in the treatment of pityriasis versicolor Reference Type of study Interventions Assessment Cure rates Köse (n = 64) 215 Open (A) 600 mg fluconazole daily in two divided doses for 15 days (n = 32 35) (B) 400 mg itraconazole daily in two divided doses for 15 days (n = 32 37) Clinical and mycological cure at 12 weeks post-treatment Montero-Gei et al. (n = 90) 216 Open (A) Single 450 mg dose of fluconazole (B) Two 300 mg doses of fluconazole given Mycological cure at day 30 after start of treatment 1 week apart (C) 200 mg itraconazole daily for 1 week 80% Shemer et al. (n = 105) 217 Open (A) 200 mg itraconazole daily for 1 week (n = 35) Mycological cure rate at 4 weeks 85% (B) 100 mg itraconazole daily for 2 weeks (n = 34) after start of treatment 81% (C) 400 mg ketoconazole 7 days apart (n = 36) 83% del Palacio Hernanz et al. Open (A) 200 mg itraconazole daily for 5 days (n = 20) Clinical (no residual lesions) and 20% (n = 40) 218 (B) 2.5% selenium sulphide shampoo once daily for mycological cure 3 weeks after 45% 7 days (n = 20) treatment end 80% clinical; 88% mycological 74% clinical; 80% mycological 70%* 97%* References 1 Fell JW, Boekhout T, Fonseca A et al. Biodiversity and systematics of basidiomycetous yeasts as determined by large-subunit rdna D1/D2 domain sequence analysis. Int J Syst Evol Microbiol 2000; 50: Sloof WC. Pityrosporum sabouraud. In: Lodder J, editor. The Yeasts: a Taxonomic Study. North-Holland Publishing Co., Amsterdam, 1970: Sabouraud R. Maladies du cuir chevelu. II. Les maladies desquamatives. Masson, Paris, Castellani C, Chalmers AJ. Manual of Tropical Medicine, 2nd edn. Wm Wood, New York, Gordon MA. Lipophilic yeastlike organisms associated with tinea versicolor. J Invest Dermatol 1951; 17: Faergemann J, Fredriksson T. Experimental infections in rabbits and humans with Pityrosporum orbuiculare and P. ovale. J Invest Dermatol 1981; 77: Borelli D. Pityriasis versicolor due to Malassezia ovalis. Mycopathologia 1985; 89: Faergemann J. Tinea versicolor and Pityrosporum orbiculare: mycological investigations, experimental infections and epidemiological surveys. Acta Derm Venereol (Suppl)(Stockh) 1979; 86: Faergemann J, Fredriksson T. Age incidence of Pityrosporum orbiculare on human skin. Acta Derm Venereol 1980; 60: Borelli D. Pityriasis versicolor: unicity or duality? Mycopathologia 1990; 111: 3 4 (Letter). 11 Salkin IF, Gordon MA. Polymorphism of Malassezia furfur. Can J Microbiol 1977; 23: Caprilli F, Mercantini R, Nazzaro-Porro M et al. Studies of the genus Pityrosporum in submerged culture. Mycopathol Mycol Appl 1973; 51: Sohnle PG, Collins-Lech C. Analysis of the lymphocyte transformation response to Pityrosporum orbiculare in patients with tinea versicolor. Clin Exp Dermatol 1999; 49: Alexander S. Loss of hair and dandruff. Br J Dermatol 1967; 79: Tanaka M, Imamura S. Immunological studies on Pityrosporum genus and Malassezia furfur. J Invest Dermatol 1979; 73: Faergemann J, Tjernlund U, Scheynius A et al. Antigenic similarities and differences in genus Pityrosporum. J Invest Dermatol 1982; 78:

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