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FUNGAL SKIN DISORDERS
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DERMATOLOGY
FUNGAL SKIN DISORDERS Stuart J. Rupke, MD
Fungal skin disorders are common in ambulatory care, and the vast majority of office visits for these disorders are to primary care physician^.^^ Furthermore, fungal infections seem to be increasing in prevalence and are highly c~mmunicable.'~ Because of the increase in the population of immunosuppressed individuals, fungal disease may present in unusual or life-threatening forms that may be resistant to treatment.29For these reasons, primary care physicians must be familiar with the differential diagnosis and current treatment of these disorders. DEFINITIONS AND BACKGROUND
Fungi are eukaryotes (organisms with a membrane-bound nucleus) that grow in irregular masses and are devoid of ~hlorophyll.~~ Pathogenic fungi are either unicellular (yeasts) or filamentous (molds that are made of branched structures or h ~ p h a e )Yeast . ~ ~ infections are produced by Candida and Pityrosporum (Malassezia). Fungal skin infections include the common superficial dermatophyte infections such as tinea corporis, cruris, pedis, and the more uncommon deeper skin infections such as sporotrichosis, or cutaneous manifestations of systemic fungal disorders. The systematic study of these organisms began in the nineteenth century. Near the turn of the twentieth century, Raymond Sabouraud, in his landmark work, Les Tiegws, described the microscopic and clinical features of dermatophyte infection^.^^ Robin described systemic candidiasis in 1853, and the genus Candida was established in 1923. In 1846 Eichstedt recognized tinea versicolor as a fungal infection of the skin.28This article From the Department of Family Practice, Saginaw Cooperative Hospitals, Inc., Saginaw; and Department of Family Practice, Michigan State University, College of Human Medicine, East Lansing, Michigan
PRIMARY CARE VOLUME 27 * NUMBER 2 . JUNE 2000
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focuses on superficial dermatophyte and yeast infections of the skin, because these comprise the vast majority of fungal skin diseases seen by the primary care physician. DERMATOPHYTOSIS
The dermatophytes are a group of related fungi that infect and survive on dead keratin, the top layer of the e p i d e r m i ~ .Only ~~,~ rarely, ~ in the immunocompromised host, do they undergo deep invasion or dissemination.22They are divided into three genera based on morphology: Trichophyfon, Microsporum, and Epidermophyton. The Epiderrnophyton genus has only one species, whereas Trichophyton and Microsporum each have several. The dermatophytes can also be divided into three groups based on host preference and natural The geophilic dermatophytes live in the soil, sporadically infect humans, and the result is usually inflammat ~ r y .Zoophilic ~ ~ , ~ ~fungi may reside in pets or rats and may cause suppurative infection in humans, but often are asymptomatic in the Anthrophilic species have adapted to humans, and grow only on human skin, hair, or nails. Many factors are involved in predisposition to dermatophyte infection. Moisture, including occlusive clothing, nonporous shoes, and warm . ~ ~ ~ ~ ~ ~ that ~~~~ humid climates all contribute to d e r m a t o p h y t ~ s i sConditions impair immunity, such as diabetes, HIV infection, and cancer being treated with chemotherapy, increase the risk of i n f e c t i ~ n . ' In ~ , addition, ~~ genetic and racial factors play important roles in the pathogenesis of dermatophyte infection^.^^,' Other factors, such as communal locker rooms, use of oils or excessive hair braiding, or use of oral or inhalational corticosteroids, can contribute to fungal infection^.'^
Diagnosis The most important factor in the diagnosis of superficial fungal infections is the clinical acumen of the physician. The physician must be familiar with the typical and aware of the atypical presentation of fungal disease, and must be aware of other disorders with a similar appearance. In addition, he or she must have a high level of suspicion for fungal disease in the patient with chronic dermatosis who does not respond to corticosteroids.8Tinea incognito refers to a dermatophyte infection with an atypical appearance, because of the previous use of inadequate treatment such as a corticosteroid or other cream.31 The most sensitive test for the diagnosis of superficial fungal infection is the potassium hydroxide (KOH) preparation.s This preparation is quick and easy to It requires a 10% to 20% solution of KOH (an optional method is to mix the KOH with ink to highlight fungal elements), a scalpel blade or cotton swab, a microscope slide and coverslip, a burner
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or cigarette lighter to heat the slide, and a microscope? The outer border of the lesion is scraped with the blade or wiped with the swab, and the debris is placed on a slide. The coverslip is placed over the epithelial debris, one to three drops of the KOH are placed at the edge of the coverslip, and the liquid is drawn under the slip by capillary action. The slide is heated gently (do not boil the contents, which produces artifa~t).~ The slide is examined carefully for the presence of fungal elements, which may be present predominantly in one area of the slide.22Interpretation of the wet mount requires experience. Dermatophytes appear as branching, translucent rod-shaped filaments with septations at irregular intervals.= Culture of suspected skin lesions usually is not necessary because of the high sensitivity of the vast majority of superficial fungal infections to the topical and oral agents.22If the diagnosis is in doubt, culture can be performed on media specific for the suspected infection. For dermatophytosis, Sabouraud's dextrose agar or the commercially available Dermatophyte Test Medium are useful. Dermatophyte Test Medium is faster but slightly less accurate.22Acu-Nickerson medium is available for the identification of Candida species. Malassezia furfur, the pathogen in tinea versicolor, rarely needs to be cultured, and grows in vitro only with the addition of C12- to C14-sized fatty acids to the medium.2sFungal cultures are useful mostly for scalp and nail infections.
CLINICAL TYPES OF DERMATOPHYTE INFECTION Tinea Corporis and Tinea Faciei Tinea of the body and face is sometimes termed collectively tinea corporis, but the American Academy of Dermatology separates the two en ti tie^.^^,'^ All species of dermatophytes belonging to the three genera are capable of producing tinea ~ o r p o r i sThe . ~ ~three most common organisms T ruresponsible, however, are T rubrum, M canis, and T mentagrophyte~.~~ brum actually causes the majority of nonscalp skin infections in the United States and worldwide. Tinea corporis may take several clinical forms. The most common presentation, classic ringworm (tinea circinata) is a lesion that begins as a flat, scaly spot and develops a raised border that advances circumferenOther forms include buIlous tinea corporis, which consists tially (Fig. of vesicles or pustules that may be herpetiform; tinea imbricata, which is characterized by widespread, scaly, polycyclic lesions; and tinea profunda or subcutaneous ab~cess.2~ Tinea incognito may, appear in multiple forms including nodules, kerion, or diffuse scaly lesions.27Zoophilic fungi such as T mentagrophytes, which may be acquired from cattle and rats, may produce uncomfortable, inflammatory lesions with follicular pustules and often with secondary bacterial Differential diagnosis often is difficult. The annular configuration may be confused with granuloma annulare, erythema annulare centri-
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Figure 1. Tinea corporis. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
fugum, or nummular e~zema.2~ Granuloma annulare is a papulonodular eruption below the epidermis that shows little surface skin change.40In erythema annulare centrifugum, there is scaling at the trailing edge of the advancing border instead of over the entire edge, as with tinea corporis. In nummular eczema, there are rounded lesions with crusting or vesiculation throughout the l e ~ i o n . ’ ~ , ~ ~ Tinea faciei, or tinea corporis of the face, often presents in an atypical form that may mimic many dermatologic conditions such as discoid lupus erythematosis, seborrheic dermatitis, rosacea, contact dermatitis, or polymorphous light e ~ u p t i o n . ~ In~one , ~ ,series, ~ ~ 85% of patients also had onychomycosis.2The clinician must have a high degree of suspicion for tinea when examining facial lesions resembling the above conditions (Fig. 2).
Tinea Pedis
Tinea Pedis is generally regarded as a fungal infection of the feet by d e r m a t o p h y t e ~ .In ~ ~severe , ~ ~ cases with macerated interspaces, there may be a positive KOH preparation only one third of the time.I0 Because of this, and because of the frequent involvement of aerobic bacteria in more severe infections, it is an oversimplification to view the disease as simply a fungal infection.16,z6 It is also estimated that one third of patients with tinea pedis have a concomitant nail infection.16,26 Tinea pedis is a common problem, and upward of 70% of the population may have the disease at some time in their life.l0
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Figure 2. Tinea faciei. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
Clinical Types of Tinea Pedis Tinea pedis is grouped into three clinical type^.^^,^^ The chronic, interdigital type is the most common and is characterized by maceration, scaling, and fissuring, particularly in the web space between the fourth Tight, nonporous shoes contribute to this conand fifth toes (Fig. 3).22,10 dition. In mild cases, fungi usually can be recovered from the digital interspaces. In more severe cases, with more maceration and hyperkeratosis, fungi are recovered less than half of the time, and the infection is characterized by overgrowth of aerobic bacteria.22,26
Figure 3. Tinea pedis, interdigital type. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
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A second type of tinea pedis is the dry, scaling, plantar type also known as the moccasin type (See Color Plate 1,Fig. 8)F2p10The sole is usually covered with a fine silvery scale, and the skin is tender and pink.26This type is usually caused by T rubrum, and occasionally T mentugrophytes.26 It often is seen in atopic patients and those with a minor defect in cellmediated immunity.*OThe condition is associated with nail involvement, which may lead to a persistent or recurrent infectionlo Another form, the vesicular or vesiculobullous (wet) type, may mimic acute contact dermatitis. This is the least common form of tinea pedis, and is usually owing to T mentugrophytes.10This often has been a disabling problem for servicemen fighting in warm, moist, humid These servicemen often are prone to relapses.’O Complications of Tinea Pedis There are some important complications of tinea pedis. One is the socalled dermatophytid, or id reaction, which is felt to be caused by an immunologic reaction to the fungus.2zThis is manifested by vesicles, pustules, or even urticaria1 lesions that occur near the site of infection or at a distant site on the body.22,30 It may occur on the feet near the site of the initial infection and resemble dyshidrotic eczema (pompholyx).lo Tinea pedis also may provide a portal of entry for serious bacterial infections in other locations.1oElderly, diabetic, and immunocompromised patients are particularly at risk for this. Patients with prior damage to the lymphatic or venous system in the lower extremity may have recurrent bouts of cellulitis, which are thought to be caused by bacterial entry at the site of tinea pedis, resulting in bacterial invasion of lymphedematous tissue~.~ Tinea Manuum Dermatophyte infection of the hand is referred to as tinea man~um.3O,~ There are two clinical forms of this infection. The first is similar to tinea of the soles with diffuse dryness and hyperkeratosis (Fig. 4). This usually involves only one hand, and may occur as the puzzling one hand two feet presentation when it is associated with tinea pedis.”l5 The second form usually involves the dorsum of the hand, is characterized by scaling and limited inflammation, and often may be mistaken for e ~ z e m a . ~ Tinea Cruris Tinea cruris is a dermatophyte infection of the groin area that often occurs during the summer month^.'^,^ Unlike yeast infections, it does not involve the scrotum or penis.30It is more common in men, in the summer, and in tropical climate^.'^ Often there is a reservoir for the infection elsewhere on the body. Epidemic forms may be caused by E j?occosum, which presents with an active, papulovesicular b0rder.2~The lesions usually are bilateral and scaly, with red-brown centers?
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Figure 4. Tinea manuum. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
YEAST INFECTIONS OF THE SKIN Tinea Versicolor Pityriasis (tinea) versicolor is an infection of the stratum corneum of the skin where sebaceous glands are p r e ~ e n t . ' ~ ,It' ~is. ~caused ~ by the lipophilic yeast, Mulusseziu f u ~ f u r . 'It~ can occur in all age groups, but is most common in postpubertal adults when the sebaceous glands are most active.I7It is worldwide in distribution, but is most common in the tropi c ~ .Pityriasis '~ versicolor can be described as an opportunistic infection, may be seen in association with diabetes mellitus, hepatic, or renal disease, and is much more common in patients infected with the human immunodeficiency virus (HIV) (Fig. 5).36,13
Clinical Forms Pityriasis versicolor can take different clinical forms. The most common presentation is that of multiple white to reddish-brown macules on the chest, back, abdomen, or proximal e x t r e m i t i e ~ .Lightly ~ ~ , ~ ~ scraping these areas with a scalpel blade brings out the characteristic scale, which is described as dust-like or furfuraceous.28This form is primarily a cosmetic problem, because the lesions do not tan along with the surrounding normal skin. Pruritus usually is not prominent, but may be bothersome when the patient is ~weating.'~
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Figure 5. Tinea versicolor. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
A second form, inverse tinea versicolor, refers to disease confined to the flexural areas and can be confused with seborrheic dermatitis, psoriasis, and candidiasis.** Another form of infection with M furfur, pityrosporum folliculitis, is an infection in which the lesion is a 2-mm to 3-mm papule or pustule. This often is associated with diabetes mellitus or prior glucocorticoid exposure, and is more commonly pruritic than the usual form.** Diagnosis and Differential Diagnosis Potassium hydroxide preparation should confirm the diagnosis, and the slide reveals short stubby hyphae and yeast cells.I3Mfurfur is difficult to grow on routine agars, so culture usually is not helpful. Pityriasis rosea, seborrheic dermatitis, vitiligo, and secondary syphilis all need to be considered in the differential diagnosis.28The salmon-colored papules, which have a fine scale when scraped on the trunk or proximal extremities, are characteristic of pityriasis versicolor.
Cutaneous Candidiasis
Candidiasis is a yeast infection caused by members of the genus Candida. The infections are usually caused by C albicans, but occasionally by
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other members of the genus, and generally infect the skin, nails, or mucous membranes.28These infections often are associated with immune deficiency, systemic diseases such as diabetes mellitus, hypothyroidism, and malignancy, or administration of immunosuppressive drugs or corticosteroids.
Clinical Forms
The most common form of Candidiasis is intertrigo. This consists of maceration and peeling between skin folds, and the lesion usually is erythematous with satellite p ~ s t ~ l eCommon s . ~ ~ ~sites ~ ~of occurrence are the gluteal fold, interdigital spaces, and the a~illae.~O Another form is interdigital candidiasis (erosio interdigitalis), which is a chronic infection with macerated tissue in the web spaces of the fingers, especially between the middle and ring fingers.4D Candida miliaria presents as vesiculopustules on the back of bedridden patientsz8Finally, candidal paronychia consists of erythema and swelling of the paronychial area in individuals who often have their hands in water.
TREATMENT OF CUTANEOUS FUNGAL INFECTIONS
Background Effective agents to treat superficial fungal infections have been in existence for less than 50 years. Nystatin was discovered in 1951by Hazen and Brown, and in 1958, griseofulvin became available as the first significant oral agent for superficial fungal infections.2OIn 1969, the imidazoles, clotrimazole and miconazole, were introduced; ketoconazole was developed in 1977, and the triazoles fluconazole and itraconazole became available in the 1980~.~O Since then, the more potent fungicidal allylamines, terbinafine and naftifine, were introduced. Other miscellaneous agents such as ciclopirox olamine and haloprogin also have been introduced in recent years. As noted above, the more commonly used agents are divided into several classes. The polyenes, which include nystatin and amphotericin 8, have limited use in superficial infections, except for treatment of candidosis with nystatin. The azole class includes the imidazoles such as miconazole, ketoconazole, clotrimazole, econazole, sulconazole, and oxiconazole, and the triazoles include itraconazole, fluconazole, and terconazole. The azoles work by inhibiting the synthesis of ergosterol, an essential component of the fungal cell membrane.I9 The allylamines include naftifine and terbinafine, which also inhibit ergosterol synthesis and are fungicidal. Miscellaneous agents include griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, and selenium sulfide.12,z0
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Considerations in Topical Therapy The newer azoles such as oxiconazole and sulconazole remain in the tissues for extended periods, and once daily dosing can be used.I2Despite these factors, no convincing studies have demonstrated superiority of the topical forms of these drugs over the older agents.12The allylamines are fungicidal, and because terbinafine persists in the tissues for up to 7 days after the end of therapy, shorter treatment courses can be used.12,21 Chen and Landfield" analyzed efficacy rates and cost of followup, and concluded that using miconazole initially for dermatophyte infections followed by treatment of resistant infections with a higher priced prescription drug was more economical than initial use of the more expensive prescription drugs for all infections. Other authors believe that some chronic tinea pedis infections may respond better to agents such as topical or oral terbinafine, so initial treatment with a less expensive over-thecounter medication may not be effective or econ~mical.'~
Considerations in Oral Therapy
As mentioned above, oral antifungals may be required to treat hypeikeratotic areas such as nails, palms, and soles, or those patients who have been resistant to topical t h e r a ~ y . ~They ~ , ' ~ may also be needed in patients with chronic infection, granulomatous lesions, or in those who are irnmuno~uppressed.~~ Although the oral agents may be required for eradication of infection in these situations, the risks and benefits of treatment must be examined carefully before embarking on a course of oral therapy. Griseofulvin has been used for over 30 years in the treatment of superficial dermatophyte infection^.^^ It generally has good tolerability, and its efficacy in curing dermatomycoses is in the range of 60%.35Up to 20% of people experience headache, but serious reactions are uncommon, and the drug is generally considered to be Possible serious reactions include lupus-like syndrome, toxic epidermal necrolysis, and leuko~ e n i a . For 3 ~ optimal absorption, griseofulvin should be taken with a fatty meal; however, ultramicrosize griseofulvin was designed to reduce the need to be taken with food.3O The newer classes of agents, the azoles and the allylamines, are effective and generally well tolerated, however most of the efficacy studies have been supported by the pharmaceutical i n d ~ s t r yThe . ~ ~first oral agent available in these classes was ketoconazole. It has broad use in systemic fungal infections, however multiple drug interactions, adrenal and testicular suppression, and severe idiosyncratic hepatotoxicity have been noted.34,21 Because of these factors, use of this drug in cutaneous infections has been limited. This article, therefore, will focus on the other agents; itraconazole, fluconazole, and terbinafine. Itraconazole is a triazole compound, and the triazole ring may be responsible for its increased potency and decreased toxicity.21It is effective
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in candidiasis, dermatophytosis, and pityriasis versicolor. It is well tolerated, and adverse effects have occurred in about 7% of patients treated for 4 weeks or less.34It has a more specific effect on fungal than mammalian cytochrome P-450 systems, and does not induce or inhibit hepatic microsomal systems to the same degree as ketoconazole.21,34 It can, however, potentiate the effects of warfarin, phenytoin, digoxin, astemizole,and cyclosporine.21 Fluconazole, another triazole drug, is also an effective oral agent. It is available in intravenous and oral forms, making it useful in certain hospitalized patients. It is effective in candidiasis, dermatophytosis, and pityriasis v e r s i ~ o l o r . ~ It~achieves J~ high concentrations in the stratum corneum and in sweat, and has been detected in the skin 10 days after discontinuation of therapy, thereby permitting short or pulse-dosed regim e n ~ .It~is~well ,~~ tolerated, and side-effects, which occur in about 16% of patients treated for more than 7 days, primarily involve the gastrointestinal tract.%Severe liver toxicity is rare; it can increase phenytoin concentrations substantially, it may potentiate warfarin and oral hypoglycemics, and it may increase cyclosporine levels substantially.34 Terbinafine, an allylamine, is an effective oral agent, and rapidly penetrates in high concentrations into hair and nails.35It is effective in dermatophytosis but somewhat less so in ~ a n d i d i a s i sIt. ~is~ well tolerated, adverse reactions occur in about 11%of patients, and about half of these are related to the gastrointestinal system (dyspepsia, nausea>.21Serious side-effects are rare, and it does not significantly interact with the hepatic microsomal cytochrome system.21 TREATMENT OF SPECIFIC ENTITIES
Tinea Pedis It generally is recognized that topical therapy is useful in interdigital tinea pedis, but is much less likely to be successful in areas with a thick keratin layer, such as the soles or palms, so systemic therapy is more effective in these areas.I6It is also important to recognize that in this disorder, prophylactic and preventive measures must be used to prevent recurrence. Using less occlusive footwear, avoiding direct contact of the feet with communal shower floors, keeping the surface of the skin dry, and keeping it well hydrated in areas that are prone to cracking are all important measures. Shoe gear can even be treated by enclosing it in an airtight bag with formalin-soaked cotton balls to eradicate fungal spores.’O Interdigital tinea pedis usually is readily treated with topical antifungal agents. Four weeks of clotrimazole 1%cream applied twice daily achieves cure rates of 68% to 71%.3,4One week of terbinafine cream applied twice daily achieved mycologic cure rates of 81% to 88%.4,6 The effectiveness of the shorter course of terbinafine is felt to be caused by its fungicidal action. Econazole, which is effective against dermatophytes, some gram-positive bacteria, and Candida, is also an effective therapy.’*
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When there is significant maceration or erythema, bacterial infection may need to be ruled out with appropriate cultures, and systemic antibiotics may be needed.27 In moccasin-type tinea pedis, several oral agents are effective. One week of itraconazole 200 mg twice daily and 2 weeks of terbinafine 250 mg once daily achieved cure rates of 79% and 80% respecti~ely.~~ Three once-weekly doses of fluconazole 150 mg achieved a 77% cure rate.22Despite the conventional wisdom that moccasin-type tinea pedis requires an oral agent, Evan+ cites a recent study by Savin et al, which showed a 69% cure rate with topical terbinafine used for 2 weeks. The patients who fared best with this last regimen were those who did not have onychomycosis.16 Tinea Corporis
Generally, lesions of tinea corporis that are not widespread respond well to the topical imidazoles, benzylamines, allylamines, and ciclopirox01amine.~~ Lesions usually respond after 2 weeks of twice-daily application, but treatment should be continued for an additional weekJ2 The recurrence rate is high for those with widespread infection, therefore oral therapy must be considered for these conditions. In one study, 1 week of oral terbinafine 250 mg daily resulted in a 100%cure rate in tinea corporis or tinea cruris.18In another study, a 7-day course of oral itraconazole 200 mg daily resulted in a 100% clinical cure rate and a 90% mycologic cure rate.32 Tinea Cruris
In most patients, tinea cruris can be managed with topical antifungals, and haloprogin, tolnaftate, and the imidazoles have been Attention must be given to drying the area, and if significant maceration is present, cool wet Burow’s compresses can be applied over the antifungal cream for 20 to 30 minutes several times daily until the lesions dry.22 Pityriasis Versicolor
The traditional agent has been topical 2.5% selenium sulfide solution applied once daily over the entire affected area, and then washed This is continued for 7 to 14 days or longer, and may be used once or twice monthly after that to prevent re~urrence.’~ The condition has a 60% to 80% recurrence rate, and thus prophylaxis may be needed.I7 All of the topical azoles including ketoconazole, econazole, oxiconazole, and miconazole appear to be equally e f f e ~ t i v eOral . ~ ~ regimens are easier, with much lower rates of recurrence, and may be more desirable. A single 400-mg dose of fluconazole cleared 74% of patients in one open study.I7 Itracon-
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Table 1. SUMMARY OF SUGGESTED TREATMENT SCHEDULES. Condition
Initial Treatment
Dosage
Tinea corporis or cruris
miconazole cream* bid 2-3 wk clortimazole cream* bid 2-3 wk
Tinea pedis interdigital
miconazole cream* bid 4 wk clotrimazole cream* bid 4 wk
Tinea pedis moccasin
itraconazole (PO)
Pityriasis versicolor
Candida intertrigo
~~
Alternatives
Dosage
ketoconazole cream econazole cream terbinafine cream terbinafine (PO) itraconazole (PO) econazole cream ketoconazole cream terbinafine cream fluconazole (PO)
qd 2-3 wks qd 2-3 wks bid 1 wks 250 mg/d; 7 d 200 mg/d; 7 d qd 4 wks qd 6 wks bid 1 wks 150 mg once/ wk; 3 wks bid for 2 wks
200 mg bid for 7 days terbinafine cream terbinafine (PO) 250 mg qd 2 wks ciclopiroxolamine miconazole cream* qd 2 wk cream clotrimazole cream* bid 4 wk selenium sulfide' qd X10 min fluconazole (PO) itraconazole solution 2.5% for 2 wk
nystatin cream or powder) miconazole cream or powder* ~
bid
clotrimazole cream
bid
ketoconazole cream
bid for 2 wks 400 mg once 200 mg qd; 7 days bid
~
*Currently approved by the FDA for these indications.
azole 200 mg daily for 7 days was effective in 94% of patients in a doubleblind, placebo-controlled In contrast, oral terbinafine is not effective with tinea versicolor, but topical terbinafine is effective in 80%to 90% of patients.36 Candidiasis
For candida intertrigo, nystatin in cream or powdered form is effective, as are the azole drugs. The powdered form is especially useful for treating very moist areasz7Adding a topical steroid for a few days may be helpful, but treatment should be concluded with the antifungal agent alone.33Equally important is taking measures to keep the area dry. For candidal balanitis, recommended treatment is clotrimazolecream or a single 150-mg dose of fluconazole.28 Table 1summarizes suggested treatments for several of the conditions discussed in this article. References 1. Allen A, Taplin D: Epidemic trichophyton mentagrophytes infections in servicemen. JAMA 226:864,1973
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2. Alteras I, Sandbank M, David M, et al: 15-Year survey of tinea faciei in the adult. Dermatologica 17765, 1988 3. Barnetson R, Marley J, Bullen M, et a 1 Comparison of one week of oral terbinafine (250mg/day) with four weeks of treatment with clotrimazole 1%cream in interdigital tinea pedis. Br J Derm 139: 675,1998 4. Bergstresser P, Elewski 8, Hanifen J, et al: Topical terbinafine and clotrimazole in interdigital tinea pedis: A multicenter comparison of cure and relapse rates with 1- and 4week treatment regimens. J Am Acad Dermatol28:648, 1993 5. Bergus G, Johnson J: Superficial tinea infections. Am Fam Physician 48:259, 1993 6. Berman B, Ellis C, Leyden J, et al: Efficacy of a 1-week twice-daily regimen of terbinafine 1%cream in the treatment of interdigital tinea Dedis. T Am Acad Dermatol26:956.1992 7. Brodell J, Brodell R Recurrent 1ymphYangitic celhitis syndrome. Contemp Orthopaedics 25:461, 1992 8. Brodell R, Elewski B: Superficial fungal infections: Errors to avoid in diagnosis and treatment. Postgrad Med 101:279, 1997 9. Brodell R, Helms S, Snelson M: Office dermatologic testing: The KOH preparation. Am Fam Physician 43:2061, 1991 10. Brooks K, Bender J: Tinea pedis: Diagnosis and treatment. Clin Podiatr Med Surg 1331, 1996 11. Chen MM, Landefeld S: A cost analysis of topical drug regimens for dermatophyte infections. JAMA 272:1922, 1994 12. Diehl K Topical antifungal agents: An update. Am Fam Physician 54:1687, 1996 13. Drake L, Dinehart S, et a1 Guidelines of care for superficial mycotic infections of the skin: Pityriasis (tinea) versicolor. J Am Acad Dermatol34:287, 1996 14. Drake L, Dinehart S, Farmer E, et al: Guidelines of care for superficial mycotic infections of the skin: Tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis. J Am Acad Dermatol34:282,1996 15. Elewski 8,Zuber T Diagnosis and management of cutaneous mycoses. American Academy of Family Physicians, 1998. 16. Evans E: Tinea pedis: Clinical experience and efficacy of short treatment. Dermatology: 194 (suppl 1):3,1997 17. Faergemann J: Pityriasis versicolor. Sem Dermatology 12976, 1993 18. Farag A, Taha HS: One-week therapy with oral terbinafine in cases of tinea cruris/ corporis. Br J Dermatol131:684,1994 19. Gupta A, Einarson T, Summerbell R, et a 1 An Overview of topical antifungal therapy in dermatomycoses: A North American Perspective. Drugs 55:645,1998 20. Gupta A, Sauder D, Shear N: Antifungal agents: An overview. Part I. J Am Acad Dermatol30: 677,1994 21. Gupta A, Sauder D, Shear N: Antifungal agents: An overview. Part 11. J Am Acad Dermatol30: 911, 1994. 22. Habif T Superficial fungal infections: In Clinical Dermatology, St. Louis, Mosby, 1996 23. Hickman J: A double-blind, randomized, placebo-controlled evaluation of short-term treatment with oral itraconazole in patients with tinea versicolor. J Am Acad Dermatol 34785,1996 24. Kobayashi G, Medoff G: Introduction to the fungi and the mycoses. In Schaechter M, Medoff G, Eisenstein B (eds): Mechanisms of Microbial Disease, ed 2. Williams and Wilkins, Baltimore, 1993 25. Lesher J: Oral therapy of common superficial fungal infections of the skin. J Am Acad Dermatol40: 531,1999 26. Leyden J, Kligman A: Interdigital Athlete's Foot. Arch Dermatol 1141466, 1978 27. Martin A, Kobayashi G: Superficial fungal infection: Dermatophytosis, tinea nigra, piedra. In Freedberg I, Eisen H, Wolff K, et al. (eds):Fitzpatrick's Dermatology in General Medicine. New York, McGraw-Hill, 1998 28. Martin A, Kobayashi G: Yeast infections: Candidiasis, pityriasis (tinea) versicolor. In Fitzpatrick T, et al: Dermatology in General Medicine. New York, McGraw-Hill, 1998 29. Myskowski P, White M, Ahkami R Fungal disease in the immunocompromised host. Dermatol Clin 15:295, 1997
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30. Noble S, Forbes R: Diagnosis and management of common tinea infections. Am Fam Physician 58:163, 1998 31. Nowak M, Brodell R Rapid diagnosis of superficial fungal infections. Postgrad Med 105:179, 1999 32. Parent D, Decrois J, Heenen M: Clinical experience with short schedules of itraconazole in the treatment of tinea corporis and/or tinea cruris. Dermatology 189:378,1994 33. Pariser D: Cutaneous candidiasis: A practical guide for primary care physicians. Postgrad Med 87101,1990 34. Perfect J, Lindsay M, Drew R Adverse drug reactions to systemic antifungals: Prevention and management. Drug Safety 7323,1992 35. Pierard G, Arrese J, Pierard-Franchimont C: Treatment and prophylaxis of tinea infections. Drugs 52:209, 1996 36. Savin R: Diagnosis and treatment of tinea versicolor. J Fam Pract 43:127,1996 37. Singh R, Bharu K, et al: Tinea faciei mimicking lupus erythematosus. Cutis: 53:297,1994 38. Smith E, Fleischer A, Feldman S: Nondermatologists are more likely than dermatologists to prescribe antifungal/corticosteroid products: An analysis of office visits for cutaneous fungal infections, 1990-1994. J Am Acad Dermatol39:43,1998 39. Spraycar M, Randolph E, Pugh M, et a1 PDR Medical Dictionary, Baltimore, Williams and Wilkins. 1995 40. Stewart W, Danto J, Maddin S Dermatology: Diagnosis and Treatment of Cutaneous Disorders, ed 3. St. Louis, Mosby, 1974 41. Swartz J, Lamkins 8: A rapid, simple stain for fungi in skin, nail scrapings, and hairs. Arch Dermatol89:149,1964 42. Tausch I, Decroix J, Gwiezdzinski Z , et al: Short-term itraconazole versus terbinafine in the treatment of tinea pedis or manus. Int J Dermatol37:128,1998 43. Weitzman I, Padhye A: Dermatophytes: Gross and Microscopic. Dermatol Clin 14:9,1996
Address reprint requests to Stuart J. Rupke, MD 1000 Houghton Avenue Saginaw, MI 48602 e-mail rupkes8pilot.msu.edu
DERMATOLOGY
FUNGAL SKIN DISORDERS Stuart J. Rupke, MD
Fungal skin disorders are common in ambulatory care, and the vast majority of office visits for these disorders are to primary care physician^.^^ Furthermore, fungal infections seem to be increasing in prevalence and are highly c~mmunicable.'~ Because of the increase in the population of immunosuppressed individuals, fungal disease may present in unusual or life-threatening forms that may be resistant to treatment.29For these reasons, primary care physicians must be familiar with the differential diagnosis and current treatment of these disorders. DEFINITIONS AND BACKGROUND
Fungi are eukaryotes (organisms with a membrane-bound nucleus) that grow in irregular masses and are devoid of ~hlorophyll.~~ Pathogenic fungi are either unicellular (yeasts) or filamentous (molds that are made of branched structures or h ~ p h a e )Yeast . ~ ~ infections are produced by Candida and Pityrosporum (Malassezia). Fungal skin infections include the common superficial dermatophyte infections such as tinea corporis, cruris, pedis, and the more uncommon deeper skin infections such as sporotrichosis, or cutaneous manifestations of systemic fungal disorders. The systematic study of these organisms began in the nineteenth century. Near the turn of the twentieth century, Raymond Sabouraud, in his landmark work, Les Tiegws, described the microscopic and clinical features of dermatophyte infection^.^^ Robin described systemic candidiasis in 1853, and the genus Candida was established in 1923. In 1846 Eichstedt recognized tinea versicolor as a fungal infection of the skin.28This article From the Department of Family Practice, Saginaw Cooperative Hospitals, Inc., Saginaw; and Department of Family Practice, Michigan State University, College of Human Medicine, East Lansing, Michigan
PRIMARY CARE VOLUME 27 * NUMBER 2 . JUNE 2000
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focuses on superficial dermatophyte and yeast infections of the skin, because these comprise the vast majority of fungal skin diseases seen by the primary care physician. DERMATOPHYTOSIS
The dermatophytes are a group of related fungi that infect and survive on dead keratin, the top layer of the e p i d e r m i ~ .Only ~~,~ rarely, ~ in the immunocompromised host, do they undergo deep invasion or dissemination.22They are divided into three genera based on morphology: Trichophyfon, Microsporum, and Epidermophyton. The Epiderrnophyton genus has only one species, whereas Trichophyton and Microsporum each have several. The dermatophytes can also be divided into three groups based on host preference and natural The geophilic dermatophytes live in the soil, sporadically infect humans, and the result is usually inflammat ~ r y .Zoophilic ~ ~ , ~ ~fungi may reside in pets or rats and may cause suppurative infection in humans, but often are asymptomatic in the Anthrophilic species have adapted to humans, and grow only on human skin, hair, or nails. Many factors are involved in predisposition to dermatophyte infection. Moisture, including occlusive clothing, nonporous shoes, and warm . ~ ~ ~ ~ ~ ~ that ~~~~ humid climates all contribute to d e r m a t o p h y t ~ s i sConditions impair immunity, such as diabetes, HIV infection, and cancer being treated with chemotherapy, increase the risk of i n f e c t i ~ n . ' In ~ , addition, ~~ genetic and racial factors play important roles in the pathogenesis of dermatophyte infection^.^^,' Other factors, such as communal locker rooms, use of oils or excessive hair braiding, or use of oral or inhalational corticosteroids, can contribute to fungal infection^.'^
Diagnosis The most important factor in the diagnosis of superficial fungal infections is the clinical acumen of the physician. The physician must be familiar with the typical and aware of the atypical presentation of fungal disease, and must be aware of other disorders with a similar appearance. In addition, he or she must have a high level of suspicion for fungal disease in the patient with chronic dermatosis who does not respond to corticosteroids.8Tinea incognito refers to a dermatophyte infection with an atypical appearance, because of the previous use of inadequate treatment such as a corticosteroid or other cream.31 The most sensitive test for the diagnosis of superficial fungal infection is the potassium hydroxide (KOH) preparation.s This preparation is quick and easy to It requires a 10% to 20% solution of KOH (an optional method is to mix the KOH with ink to highlight fungal elements), a scalpel blade or cotton swab, a microscope slide and coverslip, a burner
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or cigarette lighter to heat the slide, and a microscope? The outer border of the lesion is scraped with the blade or wiped with the swab, and the debris is placed on a slide. The coverslip is placed over the epithelial debris, one to three drops of the KOH are placed at the edge of the coverslip, and the liquid is drawn under the slip by capillary action. The slide is heated gently (do not boil the contents, which produces artifa~t).~ The slide is examined carefully for the presence of fungal elements, which may be present predominantly in one area of the slide.22Interpretation of the wet mount requires experience. Dermatophytes appear as branching, translucent rod-shaped filaments with septations at irregular intervals.= Culture of suspected skin lesions usually is not necessary because of the high sensitivity of the vast majority of superficial fungal infections to the topical and oral agents.22If the diagnosis is in doubt, culture can be performed on media specific for the suspected infection. For dermatophytosis, Sabouraud's dextrose agar or the commercially available Dermatophyte Test Medium are useful. Dermatophyte Test Medium is faster but slightly less accurate.22Acu-Nickerson medium is available for the identification of Candida species. Malassezia furfur, the pathogen in tinea versicolor, rarely needs to be cultured, and grows in vitro only with the addition of C12- to C14-sized fatty acids to the medium.2sFungal cultures are useful mostly for scalp and nail infections.
CLINICAL TYPES OF DERMATOPHYTE INFECTION Tinea Corporis and Tinea Faciei Tinea of the body and face is sometimes termed collectively tinea corporis, but the American Academy of Dermatology separates the two en ti tie^.^^,'^ All species of dermatophytes belonging to the three genera are capable of producing tinea ~ o r p o r i sThe . ~ ~three most common organisms T ruresponsible, however, are T rubrum, M canis, and T mentagrophyte~.~~ brum actually causes the majority of nonscalp skin infections in the United States and worldwide. Tinea corporis may take several clinical forms. The most common presentation, classic ringworm (tinea circinata) is a lesion that begins as a flat, scaly spot and develops a raised border that advances circumferenOther forms include buIlous tinea corporis, which consists tially (Fig. of vesicles or pustules that may be herpetiform; tinea imbricata, which is characterized by widespread, scaly, polycyclic lesions; and tinea profunda or subcutaneous ab~cess.2~ Tinea incognito may, appear in multiple forms including nodules, kerion, or diffuse scaly lesions.27Zoophilic fungi such as T mentagrophytes, which may be acquired from cattle and rats, may produce uncomfortable, inflammatory lesions with follicular pustules and often with secondary bacterial Differential diagnosis often is difficult. The annular configuration may be confused with granuloma annulare, erythema annulare centri-
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Figure 1. Tinea corporis. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
fugum, or nummular e~zema.2~ Granuloma annulare is a papulonodular eruption below the epidermis that shows little surface skin change.40In erythema annulare centrifugum, there is scaling at the trailing edge of the advancing border instead of over the entire edge, as with tinea corporis. In nummular eczema, there are rounded lesions with crusting or vesiculation throughout the l e ~ i o n . ’ ~ , ~ ~ Tinea faciei, or tinea corporis of the face, often presents in an atypical form that may mimic many dermatologic conditions such as discoid lupus erythematosis, seborrheic dermatitis, rosacea, contact dermatitis, or polymorphous light e ~ u p t i o n . ~ In~one , ~ ,series, ~ ~ 85% of patients also had onychomycosis.2The clinician must have a high degree of suspicion for tinea when examining facial lesions resembling the above conditions (Fig. 2).
Tinea Pedis
Tinea Pedis is generally regarded as a fungal infection of the feet by d e r m a t o p h y t e ~ .In ~ ~severe , ~ ~ cases with macerated interspaces, there may be a positive KOH preparation only one third of the time.I0 Because of this, and because of the frequent involvement of aerobic bacteria in more severe infections, it is an oversimplification to view the disease as simply a fungal infection.16,z6 It is also estimated that one third of patients with tinea pedis have a concomitant nail infection.16,26 Tinea pedis is a common problem, and upward of 70% of the population may have the disease at some time in their life.l0
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Figure 2. Tinea faciei. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
Clinical Types of Tinea Pedis Tinea pedis is grouped into three clinical type^.^^,^^ The chronic, interdigital type is the most common and is characterized by maceration, scaling, and fissuring, particularly in the web space between the fourth Tight, nonporous shoes contribute to this conand fifth toes (Fig. 3).22,10 dition. In mild cases, fungi usually can be recovered from the digital interspaces. In more severe cases, with more maceration and hyperkeratosis, fungi are recovered less than half of the time, and the infection is characterized by overgrowth of aerobic bacteria.22,26
Figure 3. Tinea pedis, interdigital type. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
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A second type of tinea pedis is the dry, scaling, plantar type also known as the moccasin type (See Color Plate 1,Fig. 8)F2p10The sole is usually covered with a fine silvery scale, and the skin is tender and pink.26This type is usually caused by T rubrum, and occasionally T mentugrophytes.26 It often is seen in atopic patients and those with a minor defect in cellmediated immunity.*OThe condition is associated with nail involvement, which may lead to a persistent or recurrent infectionlo Another form, the vesicular or vesiculobullous (wet) type, may mimic acute contact dermatitis. This is the least common form of tinea pedis, and is usually owing to T mentugrophytes.10This often has been a disabling problem for servicemen fighting in warm, moist, humid These servicemen often are prone to relapses.’O Complications of Tinea Pedis There are some important complications of tinea pedis. One is the socalled dermatophytid, or id reaction, which is felt to be caused by an immunologic reaction to the fungus.2zThis is manifested by vesicles, pustules, or even urticaria1 lesions that occur near the site of infection or at a distant site on the body.22,30 It may occur on the feet near the site of the initial infection and resemble dyshidrotic eczema (pompholyx).lo Tinea pedis also may provide a portal of entry for serious bacterial infections in other locations.1oElderly, diabetic, and immunocompromised patients are particularly at risk for this. Patients with prior damage to the lymphatic or venous system in the lower extremity may have recurrent bouts of cellulitis, which are thought to be caused by bacterial entry at the site of tinea pedis, resulting in bacterial invasion of lymphedematous tissue~.~ Tinea Manuum Dermatophyte infection of the hand is referred to as tinea man~um.3O,~ There are two clinical forms of this infection. The first is similar to tinea of the soles with diffuse dryness and hyperkeratosis (Fig. 4). This usually involves only one hand, and may occur as the puzzling one hand two feet presentation when it is associated with tinea pedis.”l5 The second form usually involves the dorsum of the hand, is characterized by scaling and limited inflammation, and often may be mistaken for e ~ z e m a . ~ Tinea Cruris Tinea cruris is a dermatophyte infection of the groin area that often occurs during the summer month^.'^,^ Unlike yeast infections, it does not involve the scrotum or penis.30It is more common in men, in the summer, and in tropical climate^.'^ Often there is a reservoir for the infection elsewhere on the body. Epidemic forms may be caused by E j?occosum, which presents with an active, papulovesicular b0rder.2~The lesions usually are bilateral and scaly, with red-brown centers?
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Figure 4. Tinea manuum. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
YEAST INFECTIONS OF THE SKIN Tinea Versicolor Pityriasis (tinea) versicolor is an infection of the stratum corneum of the skin where sebaceous glands are p r e ~ e n t . ' ~ ,It' ~is. ~caused ~ by the lipophilic yeast, Mulusseziu f u ~ f u r . 'It~ can occur in all age groups, but is most common in postpubertal adults when the sebaceous glands are most active.I7It is worldwide in distribution, but is most common in the tropi c ~ .Pityriasis '~ versicolor can be described as an opportunistic infection, may be seen in association with diabetes mellitus, hepatic, or renal disease, and is much more common in patients infected with the human immunodeficiency virus (HIV) (Fig. 5).36,13
Clinical Forms Pityriasis versicolor can take different clinical forms. The most common presentation is that of multiple white to reddish-brown macules on the chest, back, abdomen, or proximal e x t r e m i t i e ~ .Lightly ~ ~ , ~ ~ scraping these areas with a scalpel blade brings out the characteristic scale, which is described as dust-like or furfuraceous.28This form is primarily a cosmetic problem, because the lesions do not tan along with the surrounding normal skin. Pruritus usually is not prominent, but may be bothersome when the patient is ~weating.'~
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Figure 5. Tinea versicolor. (Courtesy of TJ Zuber, MD, Saginaw, MI.)
A second form, inverse tinea versicolor, refers to disease confined to the flexural areas and can be confused with seborrheic dermatitis, psoriasis, and candidiasis.** Another form of infection with M furfur, pityrosporum folliculitis, is an infection in which the lesion is a 2-mm to 3-mm papule or pustule. This often is associated with diabetes mellitus or prior glucocorticoid exposure, and is more commonly pruritic than the usual form.** Diagnosis and Differential Diagnosis Potassium hydroxide preparation should confirm the diagnosis, and the slide reveals short stubby hyphae and yeast cells.I3Mfurfur is difficult to grow on routine agars, so culture usually is not helpful. Pityriasis rosea, seborrheic dermatitis, vitiligo, and secondary syphilis all need to be considered in the differential diagnosis.28The salmon-colored papules, which have a fine scale when scraped on the trunk or proximal extremities, are characteristic of pityriasis versicolor.
Cutaneous Candidiasis
Candidiasis is a yeast infection caused by members of the genus Candida. The infections are usually caused by C albicans, but occasionally by
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other members of the genus, and generally infect the skin, nails, or mucous membranes.28These infections often are associated with immune deficiency, systemic diseases such as diabetes mellitus, hypothyroidism, and malignancy, or administration of immunosuppressive drugs or corticosteroids.
Clinical Forms
The most common form of Candidiasis is intertrigo. This consists of maceration and peeling between skin folds, and the lesion usually is erythematous with satellite p ~ s t ~ l eCommon s . ~ ~ ~sites ~ ~of occurrence are the gluteal fold, interdigital spaces, and the a~illae.~O Another form is interdigital candidiasis (erosio interdigitalis), which is a chronic infection with macerated tissue in the web spaces of the fingers, especially between the middle and ring fingers.4D Candida miliaria presents as vesiculopustules on the back of bedridden patientsz8Finally, candidal paronychia consists of erythema and swelling of the paronychial area in individuals who often have their hands in water.
TREATMENT OF CUTANEOUS FUNGAL INFECTIONS
Background Effective agents to treat superficial fungal infections have been in existence for less than 50 years. Nystatin was discovered in 1951by Hazen and Brown, and in 1958, griseofulvin became available as the first significant oral agent for superficial fungal infections.2OIn 1969, the imidazoles, clotrimazole and miconazole, were introduced; ketoconazole was developed in 1977, and the triazoles fluconazole and itraconazole became available in the 1980~.~O Since then, the more potent fungicidal allylamines, terbinafine and naftifine, were introduced. Other miscellaneous agents such as ciclopirox olamine and haloprogin also have been introduced in recent years. As noted above, the more commonly used agents are divided into several classes. The polyenes, which include nystatin and amphotericin 8, have limited use in superficial infections, except for treatment of candidosis with nystatin. The azole class includes the imidazoles such as miconazole, ketoconazole, clotrimazole, econazole, sulconazole, and oxiconazole, and the triazoles include itraconazole, fluconazole, and terconazole. The azoles work by inhibiting the synthesis of ergosterol, an essential component of the fungal cell membrane.I9 The allylamines include naftifine and terbinafine, which also inhibit ergosterol synthesis and are fungicidal. Miscellaneous agents include griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, and selenium sulfide.12,z0
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Considerations in Topical Therapy The newer azoles such as oxiconazole and sulconazole remain in the tissues for extended periods, and once daily dosing can be used.I2Despite these factors, no convincing studies have demonstrated superiority of the topical forms of these drugs over the older agents.12The allylamines are fungicidal, and because terbinafine persists in the tissues for up to 7 days after the end of therapy, shorter treatment courses can be used.12,21 Chen and Landfield" analyzed efficacy rates and cost of followup, and concluded that using miconazole initially for dermatophyte infections followed by treatment of resistant infections with a higher priced prescription drug was more economical than initial use of the more expensive prescription drugs for all infections. Other authors believe that some chronic tinea pedis infections may respond better to agents such as topical or oral terbinafine, so initial treatment with a less expensive over-thecounter medication may not be effective or econ~mical.'~
Considerations in Oral Therapy
As mentioned above, oral antifungals may be required to treat hypeikeratotic areas such as nails, palms, and soles, or those patients who have been resistant to topical t h e r a ~ y . ~They ~ , ' ~ may also be needed in patients with chronic infection, granulomatous lesions, or in those who are irnmuno~uppressed.~~ Although the oral agents may be required for eradication of infection in these situations, the risks and benefits of treatment must be examined carefully before embarking on a course of oral therapy. Griseofulvin has been used for over 30 years in the treatment of superficial dermatophyte infection^.^^ It generally has good tolerability, and its efficacy in curing dermatomycoses is in the range of 60%.35Up to 20% of people experience headache, but serious reactions are uncommon, and the drug is generally considered to be Possible serious reactions include lupus-like syndrome, toxic epidermal necrolysis, and leuko~ e n i a . For 3 ~ optimal absorption, griseofulvin should be taken with a fatty meal; however, ultramicrosize griseofulvin was designed to reduce the need to be taken with food.3O The newer classes of agents, the azoles and the allylamines, are effective and generally well tolerated, however most of the efficacy studies have been supported by the pharmaceutical i n d ~ s t r yThe . ~ ~first oral agent available in these classes was ketoconazole. It has broad use in systemic fungal infections, however multiple drug interactions, adrenal and testicular suppression, and severe idiosyncratic hepatotoxicity have been noted.34,21 Because of these factors, use of this drug in cutaneous infections has been limited. This article, therefore, will focus on the other agents; itraconazole, fluconazole, and terbinafine. Itraconazole is a triazole compound, and the triazole ring may be responsible for its increased potency and decreased toxicity.21It is effective
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in candidiasis, dermatophytosis, and pityriasis versicolor. It is well tolerated, and adverse effects have occurred in about 7% of patients treated for 4 weeks or less.34It has a more specific effect on fungal than mammalian cytochrome P-450 systems, and does not induce or inhibit hepatic microsomal systems to the same degree as ketoconazole.21,34 It can, however, potentiate the effects of warfarin, phenytoin, digoxin, astemizole,and cyclosporine.21 Fluconazole, another triazole drug, is also an effective oral agent. It is available in intravenous and oral forms, making it useful in certain hospitalized patients. It is effective in candidiasis, dermatophytosis, and pityriasis v e r s i ~ o l o r . ~ It~achieves J~ high concentrations in the stratum corneum and in sweat, and has been detected in the skin 10 days after discontinuation of therapy, thereby permitting short or pulse-dosed regim e n ~ .It~is~well ,~~ tolerated, and side-effects, which occur in about 16% of patients treated for more than 7 days, primarily involve the gastrointestinal tract.%Severe liver toxicity is rare; it can increase phenytoin concentrations substantially, it may potentiate warfarin and oral hypoglycemics, and it may increase cyclosporine levels substantially.34 Terbinafine, an allylamine, is an effective oral agent, and rapidly penetrates in high concentrations into hair and nails.35It is effective in dermatophytosis but somewhat less so in ~ a n d i d i a s i sIt. ~is~ well tolerated, adverse reactions occur in about 11%of patients, and about half of these are related to the gastrointestinal system (dyspepsia, nausea>.21Serious side-effects are rare, and it does not significantly interact with the hepatic microsomal cytochrome system.21 TREATMENT OF SPECIFIC ENTITIES
Tinea Pedis It generally is recognized that topical therapy is useful in interdigital tinea pedis, but is much less likely to be successful in areas with a thick keratin layer, such as the soles or palms, so systemic therapy is more effective in these areas.I6It is also important to recognize that in this disorder, prophylactic and preventive measures must be used to prevent recurrence. Using less occlusive footwear, avoiding direct contact of the feet with communal shower floors, keeping the surface of the skin dry, and keeping it well hydrated in areas that are prone to cracking are all important measures. Shoe gear can even be treated by enclosing it in an airtight bag with formalin-soaked cotton balls to eradicate fungal spores.’O Interdigital tinea pedis usually is readily treated with topical antifungal agents. Four weeks of clotrimazole 1%cream applied twice daily achieves cure rates of 68% to 71%.3,4One week of terbinafine cream applied twice daily achieved mycologic cure rates of 81% to 88%.4,6 The effectiveness of the shorter course of terbinafine is felt to be caused by its fungicidal action. Econazole, which is effective against dermatophytes, some gram-positive bacteria, and Candida, is also an effective therapy.’*
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When there is significant maceration or erythema, bacterial infection may need to be ruled out with appropriate cultures, and systemic antibiotics may be needed.27 In moccasin-type tinea pedis, several oral agents are effective. One week of itraconazole 200 mg twice daily and 2 weeks of terbinafine 250 mg once daily achieved cure rates of 79% and 80% respecti~ely.~~ Three once-weekly doses of fluconazole 150 mg achieved a 77% cure rate.22Despite the conventional wisdom that moccasin-type tinea pedis requires an oral agent, Evan+ cites a recent study by Savin et al, which showed a 69% cure rate with topical terbinafine used for 2 weeks. The patients who fared best with this last regimen were those who did not have onychomycosis.16 Tinea Corporis
Generally, lesions of tinea corporis that are not widespread respond well to the topical imidazoles, benzylamines, allylamines, and ciclopirox01amine.~~ Lesions usually respond after 2 weeks of twice-daily application, but treatment should be continued for an additional weekJ2 The recurrence rate is high for those with widespread infection, therefore oral therapy must be considered for these conditions. In one study, 1 week of oral terbinafine 250 mg daily resulted in a 100%cure rate in tinea corporis or tinea cruris.18In another study, a 7-day course of oral itraconazole 200 mg daily resulted in a 100% clinical cure rate and a 90% mycologic cure rate.32 Tinea Cruris
In most patients, tinea cruris can be managed with topical antifungals, and haloprogin, tolnaftate, and the imidazoles have been Attention must be given to drying the area, and if significant maceration is present, cool wet Burow’s compresses can be applied over the antifungal cream for 20 to 30 minutes several times daily until the lesions dry.22 Pityriasis Versicolor
The traditional agent has been topical 2.5% selenium sulfide solution applied once daily over the entire affected area, and then washed This is continued for 7 to 14 days or longer, and may be used once or twice monthly after that to prevent re~urrence.’~ The condition has a 60% to 80% recurrence rate, and thus prophylaxis may be needed.I7 All of the topical azoles including ketoconazole, econazole, oxiconazole, and miconazole appear to be equally e f f e ~ t i v eOral . ~ ~ regimens are easier, with much lower rates of recurrence, and may be more desirable. A single 400-mg dose of fluconazole cleared 74% of patients in one open study.I7 Itracon-
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Table 1. SUMMARY OF SUGGESTED TREATMENT SCHEDULES. Condition
Initial Treatment
Dosage
Tinea corporis or cruris
miconazole cream* bid 2-3 wk clortimazole cream* bid 2-3 wk
Tinea pedis interdigital
miconazole cream* bid 4 wk clotrimazole cream* bid 4 wk
Tinea pedis moccasin
itraconazole (PO)
Pityriasis versicolor
Candida intertrigo
~~
Alternatives
Dosage
ketoconazole cream econazole cream terbinafine cream terbinafine (PO) itraconazole (PO) econazole cream ketoconazole cream terbinafine cream fluconazole (PO)
qd 2-3 wks qd 2-3 wks bid 1 wks 250 mg/d; 7 d 200 mg/d; 7 d qd 4 wks qd 6 wks bid 1 wks 150 mg once/ wk; 3 wks bid for 2 wks
200 mg bid for 7 days terbinafine cream terbinafine (PO) 250 mg qd 2 wks ciclopiroxolamine miconazole cream* qd 2 wk cream clotrimazole cream* bid 4 wk selenium sulfide' qd X10 min fluconazole (PO) itraconazole solution 2.5% for 2 wk
nystatin cream or powder) miconazole cream or powder* ~
bid
clotrimazole cream
bid
ketoconazole cream
bid for 2 wks 400 mg once 200 mg qd; 7 days bid
~
*Currently approved by the FDA for these indications.
azole 200 mg daily for 7 days was effective in 94% of patients in a doubleblind, placebo-controlled In contrast, oral terbinafine is not effective with tinea versicolor, but topical terbinafine is effective in 80%to 90% of patients.36 Candidiasis
For candida intertrigo, nystatin in cream or powdered form is effective, as are the azole drugs. The powdered form is especially useful for treating very moist areasz7Adding a topical steroid for a few days may be helpful, but treatment should be concluded with the antifungal agent alone.33Equally important is taking measures to keep the area dry. For candidal balanitis, recommended treatment is clotrimazolecream or a single 150-mg dose of fluconazole.28 Table 1summarizes suggested treatments for several of the conditions discussed in this article. References 1. Allen A, Taplin D: Epidemic trichophyton mentagrophytes infections in servicemen. JAMA 226:864,1973
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