Dermatologic Clinics (Antifungal Therapy, Volume 21, Number 3, July 2003)

Dermatol Clin 21 (2003) xi

Preface

Antifungal therapy

Aditya K. Gupta, MD, PhD, FRCP(C) Guest Editor

The prevalence of fungal infections has been increasing over the past few decades, suggesting a growing demand for antifungal therapy to treat such diseases. Fungal infections can be superficial, cutaneous, or systemic, and may be caused by dermatophytes, nondermatophyte molds, or yeasts. Both topical and systemic antifungal agents are being successfully used to treat these infections; however, development of newer antifungal agents is currently underway. This issue of the Dermatologic Clinics discusses the management of fungal infections with emphasis on treatment—in particular, the treatment of various tinea infections, seborrheic dermatitis, pityriasis versicolor, and onychomycosis. The US Food and Drug Administration has not yet approved terbinafine, itraconazole, or fluconazole for the treatment of tinea capitis in children; however, published literature demonstrates that these antifungals are effective and safe when used for fungal infections and that physicians frequently use these agents to treat pediatric patients. Studies have reported a variety of choices for the treatment of tinea pedis. Although oral treatments have generally demonstrated a greater ability to reach deeper layers of skin, topical agents have a lower potential for adverse events. Dermatophytosis complex infections may require treatment for both the fungal and bacterial components of an infection. The incidence of onychomycosis is increased in men, the elderly, diabetics, HIV-positive individuals,

and other subgroups who may be immunocompromised. Treatment of onychomycosis begins with the proper diagnosis of the causative organism. Terbinafine, itraconazole (pulse and continuous), and fluconazole have been effective oral antifungal agents. For some conditions, such as superficial white onychomycosis, a topical agent may be sufficient, while other types of onychomycosis (eg, dermatophytoma) may require combined therapy (eg, surgical or topical and systemic). Nail lacquers may be effective in mild to moderate cases of onychomycosis. As biotechnology and mycology advances, new antifungal agents are also being developed to combat fungal infections. Developments include modified versions of standard antifungal agents and the discovery of entirely new classes of agents for antifungal treatment.

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Aditya K. Gupta, MD, PhD, FRCP(C) Division of Dermatology Department of Medicine Sunnybrook and Women’s College Health Science Center (Sunnybrook Site) University of Toronto 2075 Bayview Avenue Toronto, Ontario M4N 3M5, Canada Mediprobe Laboratories Inc. 490 Wonderland Road South, Suite 6 London, Ontario N6K 1L6, Canada E-mail address: [email protected]

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Tinea corporis, tinea cruris, tinea nigra, and piedra Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Maria Chaudhry, HBScb, Boni Elewski, MDc a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Department of Dermatology, University of Alabama, 700 Eighteenth Street South, Suite 414, Birmingham, AL 35233-0009, USA

Tinea infections are among the most common dermatologic conditions throughout the world. Skin ringworm infections, such as tinea corporis and tinea cruris, are primarily caused by the dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum canis. Tinea nigra is an infection of the palms or soles, which may be associated with travel to endemic regions (eg, Southeast United States and Central America). Black or white nodules found along the shaft of the hair may be infections with Piedraia hortae, or Trichosporon species, better known as ‘‘black piedra’’ or ‘‘white piedra.’’ To avoid a misdiagnosis, identification of dermatophyte infections requires both a fungal culture on Sabouraud’s agar media, and a mycologic examination, consisting of a 10% to 15% KOH preparation, from skin scrapings. Topical antifungals may be sufficient for treatment of tinea corporis and cruris and tinea nigra, and the shaving of hair infected by piedra may also be beneficial. Systemic therapy, however, may be required when the infected areas are large, macerated with a secondary infection, or in immunocompromised individuals. Preventative measures of tinea infections include practicing good personal hygiene; keeping the skin dry and cool at all times; and avoiding sharing towels, clothing, or hair accessories with infected individuals.

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

Tinea corporis and cruris Definition Tinea corporis and tinea cruris are superficial dermatophyte infections, commonly known as ‘‘ringworm.’’ Tinea corporis includes all superficial dermatophyte infections of the glabrous skin, excluding the scalp, beard, face, hands, feet, and groin. Tinea cruris includes infections of the genitalia, pubic area, perineal skin, and perianal skin. Etiology and epidemiology Tinea corporis and tinea cruris may be caused by any of the dermatophytes making up the genera Trichophyton, Microsporum, and Epidermophyton [1]. Both conditions are common throughout the world, with men being affected by tinea cruris more frequently than women. The causative organism can invade both the stratum corneum and the terminal hair of the affected areas [2]. Once infected, scales may be transmitted through direct contact between individuals, or indirectly through contact with objects that carry the infected scales [3]. This transfer of infection is thought to occur through arthroconidia that are shed by the infected host in skin scales [4]. Autoinfection by other dermatophytes elsewhere in the body, especially the foot to the groin, may also be a method of contracting a tinea infection [5]. Children are frequently infected with M canis, another causative organism of tinea corporis, especially those exposed to infected animals, such as

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00031-7

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cats, dogs, horses, or cattle. Infection may also be transmitted by transfer of spores from the skin or hair of a child to another host [6]. The most common predisposing factor for most dermatophyte infections in adults is excessive perspiration. In addition, occlusive clothing may provide an environment where the dermatophyte organisms can thrive. Individuals involved in contact sports, such as wrestling, football, or rugby, may also be at risk of acquiring a tinea infection [7].

disease, and pemphigus vegetans may be mistaken for tinea cruris. Cutaneous candidiasis, which often affects women, may be distinguished from tinea cruris of males. Satellite lesions and white pustules of Candida may affect the scrotum, whereas dermatophytes do not. Erythrasma produces a coral fluorescence under Wood’s light, which is not seen in tinea cruris [12].

Clinical manifestation

Because of the broad range of differential diagnosis of dermatophyte infections, it is important to perform a mycologic examination, consisting of a 10% to 15% KOH preparation, from skin scrapings, and a fungal culture on Sabouraud’s agar media. When tinea corporis or tinea cruris infection is suspected, examination of the infected scales from the leading edge of the lesion may reveal septate hyphae coursing through the squamas [8]. Cultures incubated at room temperature should grow the causative organism within 2 weeks.

Tinea corporis and tinea cruris infections may present as an annular erythematous plaque with a raised leading edge and scaling. Clearance occurs in the center of the lesion; however, resolution is often incomplete, because nodules may be left scattered throughout the infected area [2]. The clearance in the center of the lesion may be the manifestation of an immune response of the host to the infecting organism [2]. Pruritus is a common symptom, and pain may be present if the involved area is macerated or secondarily infected [8]. The lesion of tinea cruris extends from the groin down the thighs and backward on the perineum or about the anus; the scrotum and labia majora are generally excluded [9]. Tinea corporis can also present in a non-ringworm fashion, where it may manifest as an erythematous papule or a series of vesicles [4]. When a zoophilic dermatophyte, such as Trichophyton verrucosum, is the responsible organism, an intense inflammatory reaction can result in large pustular lesions or a kerion [8]. In addition, occasionally frank bullae may appear as an expression of the inflammation, causing tinea corporis bullosa [10]. When viable hyphae invade and track down the hair shaft and into the dermis, perhaps because of trauma caused by shaving, inflammatory papules and pustules may develop. In addition, erythema and perifolliculitis may also be part of the clinical picture of Majocchi’s granuloma [9]. Differential diagnosis Other diseases closely resembling tinea corporis are impetigo, nummular dermatitis, and secondary and tertiary syphilis [11]. A tinea corporis eruption that is more papulosquamous in presentation may be mistaken for psoriasis, lichen planus, seborrheic dermatitis, pityriasis rosea, or pityriasis rubra pilaris [8]. The crural region may be infected by other dermatoses that present comparable clinical features as tinea cruris. Psoriasis, seborrheic dermatitis, candidiasis, erythrasma, lichen simplex chronicus, Darier’s

Diagnosis and laboratory findings

Treatment As in many cases of cutaneous fungal infections, topical therapy is sufficient, but systemic treatment is necessary when large areas of the body are involved, the incidence is chronic or recurrent, or when the infection is in immunocompromised patients [13]. Tinea corporis and tinea cruris respond satisfactorily to topical therapies, such as the azoles (sulconazole, oxiconazole, miconazole, clotrimazole, econazole, and ketoconazole); the allylamines (naftifine and terbinafine); benzylamine derivatives (butenafine); and hydroxypyridones (ciclopirox olamine). However, repeated application to large areas of the skin may not always be feasible or convenient for the patient. Thus, oral treatments may be preferred by the patient (Table 1) [14 – 19]. The use of oral ketoconazole has been limited by its rare association with hepatotoxicity [20]. Griseofulvin has a rapid disappearance from the stratum corneum after administration because it is not very keratophilic with poor binding with keratin. Patients may be at a higher risk of relapse [21]. The dosage of terbinafine is 250 mg/d given for 2 to 4 weeks. The triazoles, fluconazole and itraconazole, are also safe and effective treatments for tinea corporis and tinea cruris [18,20]. Fluconazole has shown high clinical and mycologic cure rates with once weekly therapy [22]. Itraconazole is effective when given a regimen of 200 mg daily for 7 days [23]. Topical corticosteroid application is a mistreatment and may lead to

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Table 1 Systemic antifungal treatments for tinea corporis and tinea cruris Tinea infection

Griseofulvin

Terbinafine

Itraconazole

Fluconazole

Ketoconazole

Tinea corporis and cruris

250 mg twice daily until cure is reached [14,15]

250 mg/d for 2 to 4 weeks [16]

200 mg/d for 1 wk [17]

150 – 300mg/wk for 2 to 4 wk [18]

200 mg/d for 4 to 8 weeks [19]

suppression of physical signs [2] and to the development of tinea incognito. Prevention and control Tinea corporis and cruris are dermatophyte infections particularly common in areas of excessive heat and moisture. A dry, cool environment may play a role in reducing infection [9]. In addition, avoiding contact with farm animals and other individuals infected with tinea corporis and cruris may help in preventing infection. In individuals with onychomycosis, it has been observed that there is a higher prevalence of tinea cruris; this may be the result of autoinfection acquired when the individual brushes fungal organisms onto the underwear following contact with the infected feet and toenails. In such an instance it may be prudent to cover the infected toenails by first putting on socks, followed by the undergarment.

Tinea nigra Definition Tinea nigra is an asymptomatic mycotic skin infection affecting the stratum corneum [8]. It occurs mainly on the palms, but may also involve the soles. Tinea nigra infection has also been reported on the neck and trunk. Etiology and epidemiology The organism responsible for tinea nigra, Hortaea werneckii (formally known as Phaeoannellomyces werneckii, Exophiala werneckii, and Cladosporium werneckii), is a dematiaceous fungus commonly found in nature. It has been isolated from superficial dermal lesions in humans, such as inflammatory scalp lesions; macerated interdigital lesions; and environmental sources (such as salted dried fish, soil samples, and house dust) [24,25]. Infection with H werneckii is thought to occur by inoculation through trauma [26]. Incubation times may range from a few weeks to 20 years, and is thought to produce clinical disease when a change in the balance between the fungus and

the host occurs, causing the fungus to proliferate more rapidly [27]. The fungus adheres to the skin in a hydrophobic manner and can survive for prolonged periods in the environmental conditions prevailing on the skin because it is able to endure high salinity and low pH [28]. Tinea nigra typically occurs in children and young adults with female predominance [25]. It is commonly observed in patients living in warm countries or in those who have lived in or visited the tropics or subtropics and brought the infection back to North America [27]. Infection with tinea nigra has been reported from South Africa, Brazil, Panama, Cuba, and Puerto Rico and many cases have been reported from the coastal areas of southeastern United States [29]. Clinical manifestation Hortaea werneckii presents as a brownish black, velvety macular lesion that is neither elevated nor scaly, and occasionally pruritic. The lesion may darken, especially at the borders, while it gradually spreads at an uneven rate, producing an irregular outline [2,8]. Differential diagnosis Because of the similarity in color and growth of the lesion, tinea nigra is most frequently misdiagnosed with pigmented junctional nevus or malignant melanoma [30]. An accurate diagnosis of tinea nigra is important to prevent the diagnostic and excisional surgery [31] and concomitant scarring associated with treatment of nevomelanocytic lesions. Tinea nigra can also be mistaken for a lentigo, pityriasis (tinea) versicolor, drug eruption, chromhidrosis, contact dermatitis, syphilis, pinta, or staining from a variety of chemical or dyes [8,31]. Diagnosis and laboratory findings Culture of tinea nigra grows readily at room temperature, but sometimes slowly on primary isolation averaging 2 to 4 weeks before identification is possible [31]. Microscopic examination of scrapings of the stratum corneum reveals numerous dark-col-

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ored branching septate hyphae and round to oval spores with some budding. The colonies are initially moist, shiny, black, and yeast-like [30]. Treatment Tinea nigra responds to treatments with keratolytics (Whitfield’s ointment) and simple abrasion; however, topical imidazoles, such as 2% miconazole cream and 2% ketoconazole cream, are more popular [32]. Topical thiabendazole and ciclopirox olamine may also be effective [33,34]. Topical tolnaftate and oral griseofulvin are usually ineffective, and topical undecylenic acid gives variable results [35].

nodules along the hair shaft characterize black piedra, with the fungal activity limited to the cuticle and with no penetration of the hair shaft. Black piedra is more frequent and less sporadic than white piedra. White piedra is characterized by white-to-tan nodules along the shafts of hair in the scalp, beard, eyebrows, eyelashes, and groin, genital and perigenital area [37]. Numerous discrete, soft nodules that are barely visible to the naked eye are attached to the hair shaft, and produce a gritty sensation when palpated [44]. The nodules may be detached easily, and the affected hairs may be split or broken [36]. T asahii and T inkin can behave as opportunistic pathogens, particularly in immunosuppressed patients, where they can cause serious and life-threatening symptoms [45].

Piedra Differential diagnosis Definition Piedra, meaning stone in Spanish, is limited to the hair shaft without involvement of the adjacent skin [36]. Two varieties of piedra may be seen: black piedra and white piedra. Etiology and epidemiology The causative organism of black piedra, P hortae, and Trichosporon ovoides, T inkin and T asahii, of white piedra have a worldwide distribution. Black piedra occurs frequently in humid, wet tropical areas and is common in certain tropical areas of central South America and Southeast Asia, whereas white piedra occurs in semitropical and temperate countries [37]. P hortae has been found on the hairs of animals, including primates, and stagnant water, soil, and vegetables [38]. It has been suggested that for some native populations, black piedra may have cosmetic importance [39]. The natural habitats of Trichosporon species are soil, lake water, and plants, and such fungi are occasionally seen as normal flora of the human skin and mouth [40]. White piedra has been found on animal hairs, including monkeys, horses, and lower mammals [41]. Infection with piedra does not seem related to personal hygiene or exposure to an infected person, nor does white piedra of the pubic hair seem to spread by sexual contact [42]. Clinical manifestation Black piedra is a condition that presents as a stone-hard black nodule on the scalp, beard, moustache, and pubic hair shaft [43]. Brown-black hard

Clinically, many hair disorders can be confused with piedra [36]. White and black piedra should be distinguished from each other and nits, hair casts, developmental defects of the hair shaft, and trichomycosis axillaris [8]. Infections can co-exist with dermatophyte or Candida infections, and erythrasma [9]. White piedra should be differentiated from pediculosis [46]. Diagnosis and laboratory findings Infection with P hortae (black piedra) reveals tightly packed, darkly pigmented hyphae, asci, and ascospores attached to the hair shaft, whereas infection with Trichosporon species (white piedra) shows loosely arranged hyphae, blastoconidia, and arthroconidia attached to the hair shaft [37]. Fungal cultures are performed on Sabouraud’s dextrose agar. Some Trichosporon species involved in white piedra (eg, T ovoides) are inhibited by cycloheximide, which is found in dermatophyte test medium, Mycosel, and Mycobiotic [37]. Treatment Shaving or clipping the infected hair is the treatment of choice for both types of piedra; however, this method may not be esthetically pleasing to all patents, especially women. Antifungal therapy may be initiated in conjunction with shaving [8]. Black piedra may be treated with oral terbinafine [43]. Effective therapies against white piedra include imidazoles, ciclopirox olamine, 2% selenium sulfide, 6% precipitated sulfur in petrolatum, chlorhexidine solution, and zinc pyrithione [37]. In the older literature other

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reported treatments are Castellani’s paint, amphotericin B lotion, and 2% to 10% glutaraldehyde [37]. Prevention and control Black piedra rarely occurs after treatment; however; white piedra is prone to sporadic recurrence and familial spread may also occur [37]. The cause of spreading is not known. There is suggestion of person-to-person transmission and transmission through animal contacts; however, both are rare [45]. Travel abroad is not the source of infection of piedra [8]. If untreated, black piedra may last for several years. It is suggested that individuals with either black or white piedra avoid spreading the infection by not sharing combs, hairbrushes, and other hair accessories [43].

References ¨ dega˚rd A. [1] Faergemann J, Mo¨rk NJ, Haglund A, O A multicentre (double-blind) comparative study to assess the safety and efficacy of fluconazole and griseofulvin in the treatment of tinea corporis and tinea cruris. Br J Dermatol 1997;136:575 – 7. [2] Hay RJ, Moore M. Mycology. In: Champion RH, Burton JL, Burns DA, Breathnach SM, editors. Textbook of dermatology. 6th edition. United Kingdom: Blackwell Science; 1998. p. 1277 – 376. [3] Drake LA, Dinehart SM, Farmer ER, Goltz RW, Graham GF, Hordinsky MK, 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 Dermatol 1996;34:282 – 6. [4] Kohl TD, Lisney M. Tinea gladiatorum. Sports Med 2000;29:439 – 47. [5] Sadri MF, Farnaghi F, Danesh-Pazhooh M, Shokoohi A. The frequency of tinea pedis in patients with tinea cruris in Tehran, Iran. Mycoses 1998;43:41 – 4. [6] Ginter G. Microsporum canis infections in children: results of a new oral antifungal therapy. Mycoses 1996;39:265 – 9. [7] Beller M, Gessner BD. An outbreak of tinea corporis gladiatorum on a high school wrestling team. J Am Acad Dermatol 1994;31:197 – 201. [8] Martin AG, Kobayashi GS. Superficial fungal infection: dermatophytosis, tinea nigra, piedra. In: Feedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, editors. Fitzpatrick’s dermatology in general medicine. 5th edition. USA: McGraw-Hill; 1999. p. 2337 – 57. [9] Elgart ML, Warren NG. Superficial and deep mycoses. In: Moschella SL, Hurley HJ, editors. Dermatology. 3rd edition. Philadelphia: WB Saunders; 1992. p. 869 – 941. [10] Terragni L, Marelli MA, Oriani A, Cecca E. Tinea corporis bullosa. Mycoses 1993;36:135 – 7.

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[24] Mok WY. Nature and identification of Exophiala werneckii. J Clin Microbiol 1982;16:976 – 8. [25] Tseng SS, Whittier S, Miller SR, Miller SR, Zalar GL. Bilateral tinea nigra plantaris and tinea nigra plantaris mimicking melanoma. Cutis 1999;64:265 – 8. [26] Shannon PL, Ramos-Caro FA, Cosgrove BF, Flowers FP. Treatment of tinea nigra with terbinafine. Cutis 1999;64:199 – 201. [27] Blank H. Tinea nigra: a twenty-year incubation period. J Am Acad Dermatol 1979;1:49 – 51. [28] Go¨ttlich E, de Hoog GS, Yoshida S, et al. Cell-surface hydrophobicity and lipolysis as essential factors in human tinea nigra. Mycoses 1995;38:489 – 94. [29] Conant NF, Smith DT, Baker RD, Callaway JL. Tinea nigra palmaris. Manual of clinical mycology. 3rd edition. Philadelphia: WB Saunders; 1971. p. 494 – 502. [30] Palmer SR, Bass JW, Mandjana Rmandojana R, Wittler RR. Tinea nigra palmaris and plantaris: a black fungus producing black spots on the palms and soles. Pediatr Infect Dis J 1989;8:48 – 50. [31] Merwin CF. Tinea nigra palmaris: review of literature and case report. Pediatrics 1965;36:537 – 41. [32] Gupta G, Burdern AD, Shankland GS, Fallowfield ME, Richardson MD. Tinea nigra secondary to Exophiala werneckii responding to itraconazole. Br J Dermatol 1997;137:483 – 4. [33] Carr JF, Lewis CW. Tinea nigra palmaris: treatment with thiabendazole topically. Arch Dermatol 1975; 111:904 – 5. [34] Sayegh-Carren˜o R, Abramovits-Ackerman W, Gio´n GP. Therapy of tinea nigra plantaris. Pharmacol Ther 1989;28:47 – 8.

[35] Burke WA. Tinea nigra: treatment with topical ketoconazole. Cutis 1993;52:209 – 11. [36] Smith JD, Murtishaw WA, McBride ME. White piedra (Trichosporosis). Arch Dermatol 1973;107:439 – 42. [37] Drake LA, Dinehart SM, Farmer ER, Goltz RW, Graham GF, Hordinsky MK. Guidelines of care for superficial mycotic infections of the skin: piedra. J Am Acad Dermatol 1996;34:122 – 4. [38] Figueras MJ, Guarro J, Zaro L. New findings in black piedra infection. Br J Dermatol 1996;135:157. [39] Coimbra Jr. CEA, Santos RV. Black piedra among the Zoro´ Indians from Amazoˆnia (Brazil). Mycopathologia 1989;107:57 – 60. [40] Kwon-Chung KJ, Bennett JE. Piedra. In: Cann C, Colaiezzi T, Hunsberger S, editors. Medical mycology. Philadelphia: Lea & Febiger; 1992. p. 183 – 98. [41] de Almeida Jr. HL, Rivitti EA, Jaeger RG. White piedra: ultrastructure and a new microecological aspect. Mycoses 1990;33:491 – 7. [42] Gold I, Sommer B, Urson S, Schewach-Millet M. White piedra. Int J Dermatol 1984;23:621 – 3. [43] Gip L. Black piedra: the first case treated with terbinafine (Lamisil). Br J Dermatol 1994;130(suppl 43): 26 – 8. [44] Benson PM, Odom RB. White piedra. Arch Dermatol 1983;119:602 – 4. [45] Walzam M, Leeming JG. White piedra and Trichosporon beigelii: the incidence in patients attending a clinic in genitourinary medicine. Genitourin Med 1989;16: 331 – 4. [46] Mostafa WZ, Al Jabre SH. White piedra in Saudi Arabia. Int J Dermatol 1992;31:501 – 2.

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Seborrheic dermatitis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Robyn Bluhm, HBSc (Hons), BA, MAb,c, Elizabeth A. Cooper, BSc, BEScb, Richard C. Summerbell, PhDd, Roma Batra, PhD, MSc, MPhilb a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c University of Western Ontario, London, Ontario, Canada d Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands

Seborrheic dermatitis presents as red, flaking, greasy-looking patches of skin that are located most commonly on the scalp, nasolabial folds, eyebrows, ears, and chest. In some patients, flexural areas may also be involved. Moreover, the extent of flaking and erythema may vary. Although seborrheic dermatitis in adults may be clinically similar to infantile seborrheic dermatitis (including cradle cap), the former is not common in children. Rather, it tends to make its first appearance around the time of puberty, with the increase in skin lipids that occurs at this time. It is particularly common in adolescents and young adults, and is relatively rare in the middle aged. In patients over the age of 50 years, however, seborrheic dermatitis again becomes quite common [1,2]. It is more common in men than in women. Overall, its prevalence in immunocompetent adults is estimated to be between 1% and 3% [3]. The incidence of seborrheic dermatitis is unusually high among patients with AIDS, ranging from 30% to 83% [3 – 5]. In patients with chronic seborrheic dermatitis, the lesions often worsen in the winter; however, the effect of increased sunlight on seborrheic dermatitis is unclear. Although there is some evidence that exposure to sunlight can improve the clinical appearance of seborrheic dermatitis [6], it has also been reported that some patients

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

may develop seborrheic dermatitis subsequent to psoralen plus type A ultraviolet light therapy [7]. The relationship between seborrheic dermatitis and dandruff is also controversial. Some investigators regard a diagnosis of ‘‘seborrheic dermatitis of the scalp’’ as a way of describing severe dandruff, whereas others believe that the term ‘‘dandruff’’ should be used for any flaking of the scalp, regardless of etiology [8 – 12]. The recent resurgence of interest in the role of Malassezia yeasts in the development of seborrheic dermatitis has provided additional evidence that, in most cases, dandruff is a mild form of seborrheic dermatitis. Some authors believe that dandruff is a noninflammatory form of seborrheic dermatitis [13,14]. Seborrheic dermatitis is often seen in conjunction with other skin diseases, including rosacea, blepharitis or ocular irritation, and acne vulgaris [15 – 19]. It is also common in patients with other skin diseases associated with Malassezia species, such as pityriasis versicolor and Malassezia folliculitis [20,21].

Malassezia yeasts Seven of the nine known Malassezia yeast species are normal commensals of adult human skin. These species are Malassezia furfur, M sympodialis, M dermatis, M restricta, M slooffiae, M obtusa, and M globosa [22 – 24]. M pachydermatis is not considered to be a normal human commensal because it is

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primarily zoophilic. The new species M equi has been detected in horses [25]. The species that have been commonly associated with seborrheic dermatitis are M globosa and M restricta [3,26]. Other investigators, however, have also found M furfur, M sympodialis, M obtusa, and M slooffiae [26]. These commensals require an exogenous source of lipids to grow, and tend to appear on the skin at around the time of puberty. Moreover, their distribution on the skin (most commonly on the face, scalp, and trunk) occurs on lipid-rich areas of the body. Further evidence that these yeasts require lipids comes from the fact they have the ability to produce lipases [27,28]. The lipases are involved in the release of arachidonic acid, which is involved in the inflammation of skin [29].

Seborrheic dermatitis and Malassezia yeasts: causal relationship? Early researchers believed that Malassezia yeasts played a causative role in seborrheic dermatitis; however, a causal mechanism was not found [30,31]. In view of this, and because Malassezia yeasts occur on healthy skin of people both with and without seborrheic dermatitis lesions, the suggestion that Malassezia yeasts were responsible for this disease lost popularity. Instead, investigators viewed seborrheic dermatitis as primarily being a disorder caused by hyperproliferation. The efficacy of the antifungal agent ketoconazole in the treatment of seborrheic dermatitis has revived interest in the potential role of Malassezia yeasts in this disease [32,33]. Some researchers believe that Malassezia yeasts are present in unusually high numbers on the scalp of patients with dandruff or seborrheic dermatitis [34,35]. There are others who have shown that there are no significant differences in the number of Malassezia counts on lesional skin of seborrheic dermatitis patients compared with nonlesional skin in healthy subjects [36,37]. Some investigators have found that in seborrheic dermatitis, the density of Malassezia species is lower in lesional skin compared with nonlesional skin [23]. A number of factors may explain the variability of results found when measuring the fungal load. Firstly, Malassezia are not only restricted to the skin surface but are also present within the layers of the stratum corneum [38]. Ideally, the full thickness of skin squama should be examined to give a true picture of Malassezia counts [29,39]. Secondly, the variety of sampling techniques used by various authors further complicates the problem and makes comparison between studies very

difficult. Thirdly, it has also been suggested by Gupta et al [23] that the use of synthetic detergents and shampoos might reflect artifactual patient factors that might be associated with reduced colony counts. Despite this complexity, and the controversy that has ensued from it, there is increasing acceptance of the proposition that Malassezia yeasts play some role in the development of seborrheic dermatitis. Further evidence for this is that ketoconazole, an antifungal agent, significantly decreases the number of Malassezia yeasts in seborrheic dermatitis patients, and thereby improves the clinical appearance of the disease. Immune response in seborrheic dermatitis Because there are no clear differences in yeast carriage levels between seborrheic dermatitis patients and healthy controls, it has been suggested that a predisposition to this disease involves some sort of immune or inflammatory reaction. T-cell function may be depressed in patients with seborrheic dermatitis and there may be an increase in the number of natural killer cells, or in the levels of IgA and IgG antibodies found in serum [40]. Two studies have shown, however, that patients with seborrheic dermatitis do not seem to have elevated IgG antibody titers against the yeasts [40,41]. The authors of these studies suggest that seborrheic dermatitis is caused by an abnormal reaction of the skin to the yeasts themselves or to some toxin that they produce. There is evidence that there is a strong inflammatory reaction involved in seborrheic dermatitis, including an increase in NK1+ and CD16+ cells, activation of complement, and an increased production of inflammatory interleukins in lesional skin, compared with levels found in nonlesional skin in these patients and in the skin of healthy controls [42]. Seborrheic dermatitis is also associated with immune deficiency, most notably in HIV-positive and AIDS patients. In this population, seborrheic dermatitis has been reported to occur much more commonly than it does in the general population [43]. Reported figures range from 34% to 83% [44,45]. Seborrheic dermatitis in HIV-positive and AIDS patients is relatively severe and lesions of the extremities are common [45 – 48]. As the immune deficiency in these patients becomes progressively worse, so do the lesions of seborrheic dermatitis [47,49]. These differences in the clinical presentation of seborrheic dermatitis in HIV-positive and AIDS patients have led to the suggestion that the ‘‘seborrheic-like’’ dermatitis associated with AIDS should be regarded as a distinct clinical condition that is secondary to the immune deficiency [48].

Table 1 Clinical use of nonspecific topical agents to treat seborrheic dermatitis Reference Study design Body site treated

Outcome

Comments

Shampoos by technician in study facility twice weekly for 4 wk: [A] Selenium sulfide 2.5% shampoo (N = 95) [B] See ketoconazole (Table 2) [C] Placebo shampoo twice weekly (N = 49)

Reduction in mean total adherent dandruff score: [A] 66.7% reduction [B] 73% reduction [C] 44.5% reduction

Assessment occurred at day 29 from baseline. Score was calculated from visual examination of adherent scale in six scalp areas. The presence of scale was rated from 0 (none) to 9 – 10 (severe, heavy). Selenium sulfide was significantly more effective than placebo, but there was no significant difference in the efficacy of selenium sulfide and ketoconazole.

Treatment for 3 wk; if scalp not free of lesions, an extra 3 wk was given [A] 15% propylene glycol/35% ethanol/50% water (N = 18) [B] 50% propylene glycol/50% water (N = 19)

Scalp condition cleared: [A] 16/18 (89%) [B] 6/19 (32%)

Assessment 5 d after last treatment. Significantly better clearing with propylene glycol, measured by quadrant area severity score (percent of quadrant area score x severity score). Also noted a significant reduction in P. orbiculare numbers with propylene glycol vs vehicle

Treatment for 4 wk (cross-over design in nine centers) or 6 wk (parallel design in two centers) [A] 8% lithium succinate ointment with 0.05% zinc sulfate (N = 82) [B] Vehicle (N = 78)

Mean improvement in global score, from baseline (parallel arms, and first arms of cross-over only): [A] +23 mmVAS [B] +8 mmVAS

Mean improvement from baseline was scored using a visual analog scale. The scale summed the following parameters, each given a score between 0 and 3: redness, scaling, greasiness, itching, overall clinical impression, percent of area involved. There was a significant difference between lithium succinate ointment and vehicle

Hydrocortisone Stratigos et al [84]

Once daily for 4 wk:

RDB Face and chest

[A] 1% hydrocortisone cream (N = 34) [B] See ketoconazole (Table 2)

 50% improvement in global evaluation: [A] 34/36 (94.4%) [B] 29/36 (80.5%)

Assessment occurred 1 month after baseline. Response to treatment was measured as a percent of improvement in global evaluation score

Faergemann [71]

Treatment nightly for 3 wk; If not cured, another 3 wk given: [A] 1% hydrocortisone cream (N = 24) [B] and [C] See miconazole (Table 2)

Subjects cured of lesions: [A] 17/24 (70.8%)

Evaluation occurred at 5 d posttreatment (3 or 6 wk of treatment). There was no significant difference among the cure rates in the three treatment groups.

Propylene glycol Faergemann [94] RDB Scalp

Lithium succinate Gould et al [64] RDB Any affected sites treated

RDB Scalp

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Abbreviations: RDB, randomized, double-blind trials; VAS, visual analog scale.

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Regimen (N evaluable)

Selenium sulfide Danby et al [13] RDB Scalp

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Table 2 Clinical use of topical antifungal agents to treat seborrheic dermatitis Reference Study design Body site treated

Outcome

Comments

Shampoos by technician in study facility twice weekly for 4 wk: [A] Ketoconazole 2% shampoo (N = 94) [B] Vehicle (N = 49) [C] See selenium sulfide (Table 1)

Reduction in mean total adherent dandruff score: [A] 73% reduction [B] 44.5% reduction [C] 66.7% reduction

Stratigos et al [84] RDB Face and chest

Once daily for 4 wk: [A] Ketoconazole 2% cream (N = 36) [B] See hydrocortisone (Table 1)

 50% improvement in global evaluation: [A] 29/36 (80.5%) [B] 34/36 (94.4%)

Assessment occurred at day 29 from baseline. Score was calculated from visual examination of adherent scale in six scalp areas, as rated on a scale of 0 (none) to 9 – 10 (severe, heavy). Ketoconazole was significantly more effective than placebo. Assessment occurred 1 month after baseline. Response to treatment was measured as a percent of improvement in global evaluation score.

Skinner et al [82] RDB Scalp, face, chest

Twice daily for 1 mo: [A] 2% ketoconazole cream (N = 20) [B] Vehicle (N = 17)

> 75% improvement in global evaluation: [A] 18/20 (90%) [B] 3/17 (17.6%)

Global evaluations of ‘‘total clearing’’ or ‘‘good’’ (> 75% improvement) at the end of 1 month of treatment. No significant difference in treatments.

Carr et al [75] RDB Scalp

Daily for 4 wk, then crossed over at week 8 to opposite treatment, for 4 wk: [A] 2% ketoconazole cream (N = 10) [B] Vehicle (N = 9)

Improvement in clinical grade of scalp scaling: [A] 14/19 subjects (74%) [B] Not reported

Pie´rard et al [79] RDB Face and chest

Twice daily for 4 wk: [A] Ketoconazole 2% emulsion (N = 23) [B] Vehicle (N = 16)

Squire and Goode [83] Randomized, Investigator-blind Scalp

Three times a week for 4 wk: Mean dandruff score (maximum score = 64): [A] 2% ketoconazole shampoo (N = 54) [A] 12.1 (mean = 38.5 at baseline) [B] 1.5% ciclopirox olamine/3% salicylic [B] 15.8 (mean = 37.1 at baseline) acid shampoo (N = 102)

Scalp clinical grade 0 (none) – 3 (severe) during the treatment period. Change in clinical score with ketoconazole use was significant ( P < .01), whereas there was no significant change in scores during placebo use.  75% improvement in global evaluation score: Results are given in an intention to treat analysis [A] 18/25 (72%) of global evaluation score. [B] 8/25 (.32%) Double-blind set-up, but test products had distinct odors that investigators believed subjects using the product would be able to determine which treatment they had received. There was a significant improvement from baseline, but no significant difference between comparators.

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Regimen

Ketoconazole Danby et al [13] RDB Scalp

Pie´rard-Franchimont et al [80] Open randomized Scalp

Global clinical evaluation of ‘‘healed’’ or ‘‘markedly improved’’: [A] 20/32 (62.5%) [B] 30/33 (90.9%) Pierard-Franchimont and Pierard [81] Once daily for 3 wk: Reduction in overall clinical symptom severity: RDB [A] 2% ketoconazole and 0.05% desonide Week: [A]-[B] Face in anhydrous gel (N = 9) 1: 49% – 23% [B] Unmedicated anhydrous gel (N = 9) 2: 84% – 29% 3: 92% – 42%

Global clinical evaluation of ‘‘healed’’ or ‘‘markedly improved’’ at treatment end. There was a significant difference between the two groups ( P < .001). The fast response to treatment and the limited additional improvement between weeks 2 and 3 of the treatment suggest that this combination product may be efficacious with once daily applications for 2 wk.

Treatment nightly for 3 wk; If not cured, another 3 wk given: [A] 2% miconazole cream (N = 22) [B] 2% miconazole/1% hydrocortisone cream (N = 23) [C] See hydrocortisone (Table 1)

Subjects cured of lesions: [A] 15/22 (68.1%) [B] 19/21 (90.5%)

Evaluation was at 5 d after cessation of treatment (3 or 6 wk of treatment). There was no significant difference among the cure rates seen in the three treatment groups.

Two applications three times a week for 6 wk: [A] Bifonazole 1% shampoo, (N = 22) [B] Vehicle (N = 22)

Moderate to marked improvement in physician overall impression of treatment: [A] 16/22 (72.7%) [B] 7/32 (31.8%)

Zienicke et al [74] RDB Face

Once daily use for 4 wk: [A] Bifonazole 1% shampoo (N = 37) [B] Vehicle

Overall clinical rating of ‘‘healing’’ or ‘‘improvement’’: [A] 34/37 (91.9%) [B] 32/43 (74.4%)

Patients were evaluated as improved. Patients in this study were diagnosed with either seborrheic dermatitis or seborrhea of the scalp, because the authors considered the two conditions to represent parts of a spectrum of the same disease. Overall clinical rating of therapy after 6 wk. There were no significant differences in overall clinical rating between the two groups.

Metronidazole Parsad et al [85] RDB Face and chest

Twice daily for 8 wk: [A] Metronidazole 1% gel (N = 21) [B] Placebo (N = 17)

Global evaluation of marked to complete improvement: [A] 14/21 (66.7%) [B] 2/17 (11.8%)

Bifonazole Segal et al [72] RDB Scalp

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Miconazole Faergemann [71] RDB Scalp

Twice weekly for 4 wk: [A] Ketoconazole 1% shampoo (N = 32) [B] Ketoconazole 2% shampoo (N = 33)

Global evaluation of marked to complete improvement defined to be >50% improvement at week 8. (cotinued on next page)

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Reference Study design Body site treated Ciclopirox Dupuy et al. [86] RDB Face

Squire and Goode [83] Randomized, Investigator-blind Scalp

Regimen

Outcome

Comments

Twice daily application until total clinical remission, or a maximum of 28 d; Followed by a once daily maintenance phase for 28 d: [A] Ciclopirox olamine 1% (N = 57) [B] Vehicle (N = 72) Three times a week for 4 wk: [A] 1.5% ciclopirox olamine/3% salicylic acid shampoo (N = 102) [B] 2% ketoconazole shampoo (N = 54)

Complete disappearance of erythema and scaling of test lesions: [A] 25/57 (43.8%) [B] 11/72 (15.3%)

Evaluation occurred at end of treatment period and reflected the number of patients who responded to treatment (response defined as complete disappearance of erythema and scaling of test lesions).

Mean dandruff score (maximum score = 64): [A] 12.1 (mean = 38.5 at baseline) [B] 15.8 (mean = 37.1 at baseline)

Double-blind set-up, but test products had distinct odors that investigators believed subjects using the product would be able to determine which treatment they had received. There was a significant improvement from baseline, but no significant difference between comparators.

Abbreviation: RDB, randomized, double blind trials.

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Table 2 (continued )

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In addition to the clinical differences seen in the seborrheic dermatitis presentations of HIV-positive and HIV-negative patients, there are also histologic and molecular differences. The common histologic appearance of seborrheic dermatitis varies somewhat over time, with more recent lesions showing a characteristic ‘‘spongiform’’ appearance that distinguishes them from psoriasis [50]. Over time, the lesions become less spongiotic and develop follicular plugs of orthokeratotic and parakeratotic cells, and uneven rete ridges [50]. Civatte [51] described seborrheic dermatitis as a cyclical disease (at least at the histologic level), with periodic ‘‘squirting’’ of granulocytes from the dermal papilla subsequent to a period of edema. There tends also to be increased epidermal proliferation and focal parakeratosis [52]. In HIV-positive and AIDS patients, by contrast, biopsies demonstrate widespread parakeratosis, keratocytic necrosis, leukoexocytosis, and a superficial perivascular infiltrate of plasma cells [46]. Hyperkeratosis also develops in long-standing lesions [53]. At a molecular level, biopsies taken from lesional skin of AIDS patients show expression of heat-shock proteins (HSP65 and HSP72), which does not occur in HIV-negative patients with seborrheic dermatitis or psoriasis [54]. These changes are thought to be caused by altered interactions between T cells and keratinocytes in AIDS patients [54]. Other diseases associated with seborrheic dermatitis In addition to its association with immunosuppression, seborrheic dermatitis is common in patients with Parkinson’s disease. In most of these patients, there has been a long-standing and severe elevation in sebum levels [55]. It has been suggested that the pooling effect of sebum on the face of patients with Parkinson’s disease, whose facies often demonstrate decreased mobility, has a permissive effect on the growth of Malassezia yeasts, although this is speculative [56]. Seborrheic dermatitis is also common in patients with mood disorders; however, it is unclear if there is a neurologic cause for this association, or whether lifestyle and hygiene factors are more important [6,57].

Treatment Traditional treatment for seborrheic dermatitis involved the use of keratolytic agents or corticosteroids. Since the discovery that ketoconazole is an effective treatment for this disorder, a great deal of research has been performed to determine the efficacy of antifungal agents in the treatment of seborrheic dermatitis.

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Nonspecific agents commonly used to treat seborrheic dermatitis include preparations containing selenium sulfide or sulfur (Table 1). Sulfur has a keratolytic action because of its ability to form hydrogen sulfide on interaction with keratinocytes [58]. Coal tar, whether as whole coal tar or crude coal tar extract, has also been shown to be effective against seborrheic dermatitis [59,60]. Lithium succinate is also effective [61 – 65]. Although some have suggested that this compound has in vitro activity against Malassezia spp., others have claimed that it is not an antifungal agent, but has an anti-inflammatory effect [63,65]. Topical corticosteroids are also commonly used to treat seborrheic dermatitis (see Table 1). These agents have an anti-inflammatory effect. Although in the past high-potency steroids were used for this indication; the adverse effects associated with prolonged use of potent corticosteroids lessened their popularity [66,67]. Currently, low-potency corticosteroids are preferred [68]. A variety of antifungal medications have been tested as potential treatments for seborrheic dermatitis (Table 2). Zinc pyrithione has both a nonspecific keratolytic and an antifungal activity. It is available in a 2% shampoo, a 1% shampoo, and a cream formulation [66,69,70]. Several of the topical azole agents are also used in the treatment of seborrheic dermatitis. Both bifonazole and miconazole have been shown to be effective; however, ketoconazole remains the most commonly prescribed azole medication [71 – 74]. Unlike topical steroids, ketoconazole does not carry a risk of skin atrophy or telangiectasia with prolonged use. Ketoconazole is available as a 2% cream, a 2% shampoo, an oil-in-water emulsion, and a foaming gel [33,75 – 84]. All of these preparations have been shown to be effective. More recently, fluconazole and metronidazole have shown potential as treatments for this indication [85,86]. In addition to the azoles, which have a fungistatic action, topical terbinafine has been demonstrated to be an effective treatment for seborrheic dermatitis of the scalp. A 1% solution, used once a day for 4 weeks, both improved the lesions of seborrheic dermatitis and reduced the number of Malassezia organisms colonizing the treated areas [87]. Another topical agent that has been recently investigated is ciclopirox. As the olamine salt, ciclopirox is available as a 1% shampoo and a 1% cream [88,89]. A ciclopirox gel, containing the free acid of ciclopirox instead of the salt, is also available. In addition a new class of medications, topical tacrolimus ointment and pimecrolimus cream, are being recommended for treating seborrheic dermatitis and other skin disorders [90]. Topical tacrolimus and pimecrolimus not only lack side effects associated

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Table 3 Clinical use of oral antifungal agents to treat seborrheic dermatitis

Ketoconazole Ford et al [32] RDB crossover Scalp

Itraconazole Caputo and Barbareschi [92] Open, nonrandomized Treatment sites not specified

Terbinafine Scaparro et al [93] Randomized, investigator-blind At least two body sites (scalp, face, trunk, axilla)

Regimen

Outcome

Comments

First treatment for 4 wk, then crossed-over to opposite treatment at end of week 4: [A] Ketoconazole, 200 mg/d [B] Placebo (oral, identical to ketoconazole)

Considerable improvement in scalp scaling: [A] 12/17 (70%) [B] 2/17 (12%)

Significant improvement in scalp scaling for ketoconazole versus placebo ( P < .01). Of five subjects failing to respond to ketoconazole, three subsequently improved when given a higher dose of ketoconazole

Itraconazole, 200 mg/d for 7 consecutive days (N = 160)

Overall improvement rating: Excellent: 55/160 (34.4%) Good: 64/160 (40%) Moderate: 30/160 (18.7%) Insignificant: 11/160 (6.9%)

Assessment occurred at follow-up, 30 d after treatment.

4-week treatment regimens: [A] Oral terbinafine, 250 mg/d for 4 wk (N = 30) [B] Placebo ointment applied twice daily for 4 wk (N = 30)

Mean global clinical score at week 12: [A] 1.2 (baseline 7.7) [B] 6.3 (baseline 7.4)

Terbinafine was significantly more effective than placebo in the treatment of seborrheic dermatitis ( P < .0001). Improvement was assessed on the basis of a global clinical score, which was the sum of the scores for erythema, scaling, and itching (each on a 0 – 3 scale).

Abbreviation: RDB, randomized, double-blind study.

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Reference Study design Body site treated

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with corticosteroids but also have been shown to have potent antifungal activity against M furfur and Pityrosporum ovale in vitro [91]. If the seborrheic dermatitis is particularly widespread or is refractory to topical treatment, an oral treatment may be preferred (Table 3). Oral ketoconazole, 200 mg daily for 4 weeks, has been shown to be effective against seborrheic dermatitis of the scalp and body [32]. Despite its efficacy, however, oral ketoconazole has the potential for adverse effects, particularly with prolonged use. Alternative treatments have been investigated. Itraconazole, 200 mg/ d for 7 days, may be effective in the treatment of seborrheic dermatitis [92]. Oral terbinafine, which is ineffective in the treatment of pityriasis versicolor, may be effective against seborrheic dermatitis when taken 250 mg/d for 4 weeks [93].

Summary Seborrheic dermatitis is present in 1% to 3% of immunocompetent adults, and is more prevalent in men than in women. Seborrheic dermatitis may be seen in conjunction with other skin diseases, such as rosacea, blepharitis or ocular rosacea, and acne vulgaris. Malassezia yeasts have been associated with seborrheic dermatitis. Abnormal or inflammatory immune system reactions to these yeasts may be related to development of seborrheic dermatitis. Treatment modalities for seborrheic dermatitis include keratolytic agents, corticosteroids, and more recently, antifungal agents. Antifungal agents do not carry a risk of skin atrophy or telangiectasia with prolonged use, and it is more prudent to consider antifungals than corticosteroid preparations. The wide range of antifungal formulations available (creams, shampoos, or oral) provides safe, effective, and flexible treatment options for seborrheic dermatitis.

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Pityriasis versicolor Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Roma Batra, PhD, MSc, MPhilb, Robyn Bluhm, HBSc, MA, BAb, Jan Faergemann, MD, PhDc a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Department of Dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden

Pityriasis versicolor (tinea versicolor) is a common superficial fungal infection of the skin. The prevalence of the disorder varies with the seasons; cases of pityriasis versicolor are more common in the warmer months and in tropical climates. In Scandinavia, approximately 1% of the population has been reported to be affected by pityriasis versicolor [1 – 3], whereas rates as high as 50% have been reported in some tropical countries [4,5]. The lesions are also more extensive in tropical climates compared with temperate climates [6]. Although studies have reported that pityriasis versicolor is more common in one sex or the other [1,7 – 9], the overall consensus is that persons of either sex are equally likely to develop this infection.

Taxonomy The causative organisms of pityriasis versicolor are the lipophilic yeasts of the Malassezia species. This genus was originally known as Pityrosporum, and was thought to consist of two species, P ovale and P orbiculare [10], although many investigators believed that these two forms actually represented variants of a single species [11,12]. The name Malassezia was also used for these yeasts, with many authors reserving the designation M furfur for the mycelial form of the yeast seen in skin scales from patients with

pityriasis versicolor. The other species of Malassezia that was recognized at this time was M pachydermatis. In 1990, a third species, M sympodialis, was isolated by Simmons and Gue´ho [13]. The taxonomy of the genus Malassezia was further revised in 1996 by Gue´ho et al [14]. Their taxonomy retained M pachydermatis, M sympodialis, and M furfur, and distinguished between these species on the basis of their morphologic, physiologic, and genetic characteristics. Four new species, M restricta, M globosa, M slooffiae, and M obtusa, were characterized, bringing the total number of species up to seven. With the exception of M pachydermatis, which does not require an exogenous lipid source and tends to be isolated from animals, all of the Malassezia species are isolated from human skin. They are present with varying frequency, however, both overall and with regard to particular body sites. Recent work has suggested that the species most commonly found on patients with pityriasis versicolor are M globosa (50% to 60%) [15,16] or M sympodialis (3% to 59%) [17 – 21]. Other species, such as M furfur and M slooffiae, may be found in range of 1% to 10% [16,17,20,21]. It seems that the epidemiology of Malassezia yeasts may vary with geographic region.

Clinical presentation

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

Because of the lipid requirement of the Malassezia yeasts, both the yeast and the mycelial form tend to be found most often on lipid-rich areas of the body, including the face, scalp, and trunk. Pityriasis versi-

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00039-1

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color is primarily located on the chest, back, and upper arms, although facial involvement may also occur in some patients. Clinically, the lesions present as flaky round or oval maculae, although in larger lesions the flaking may be apparent only at the outer border of the macule. These lesions may be hypopigmented (these lesions are particularly noticeable in dark-skinned patients) or hyperpigmented; a single patient may have both types of lesions. The color of hyperpigmented lesions varies from pink or tan to dark brown or black. Some patients may experience mild pruritus, although for most patients, pityriasis versicolor is asymptomatic and is chiefly a cosmetic concern. Although Malassezia yeasts are found on almost all adult human beings, in those individuals who develop pityriasis versicolor, the organisms transform from the saprophytic, round-celled, or yeast phase to a mycelial phase. It is not clear what causes this transformation, although endogenous host factors are known to play a role. There is likely a genetic component to susceptibility, but it seems that the cause may be multifactorial [22]. Other factors that may contribute to the development of pityriasis versicolor include malnutrition [23], use of oral contraceptives [24], and hyperhidrosis [7,25]. The risk of development of pityriasis versicolor is higher in immunocompromised patients than in a healthy population [26 – 28]. Pityriasis versicolor is uncommon before puberty, possibly because of the changes in skin sebum levels that occur at this time, although some cases have been reported in children [29 – 31], particularly in tropical countries [32]. When children do develop pityriasis versicolor, facial involvement is more common than it is in adults [31,33]. The incidence of pityriasis versicolor also decreases in later life; it is less common for older adults to develop pityriasis versicolor [34]. Again, this decease may be related to alterations in sebum production, which also tends to decrease with age. Malassezia yeasts are found on healthy skin of most adults, but biopsies taken from patients with pityriasis versicolor show that these yeasts can also invade the cells of the stratum corneum. It has been suggested, however, that only the hyphal form of the yeast is able to invade cells [35]. Skin samples taken from lesional skin show that Malassezia may be present in all layers of the stratum corneum, although it is least often found in the lower part of the horny layer. In cases where the organism has penetrated keratinocytes, the normal horizontal direction of the skin cells may be disrupted in the superficial and middle layers of the stratum corneum [36]. The skin cells also seem to swell and may even split, expelling the cell matrix and organelles. Loss of keratin struc-

ture in these cells results in a ‘‘clear zone’’ around the invading yeast cells [36,37]. Alternatively, it has been reported that the keratin within cells invaded by Malassezia yeasts may be replaced by an amorphous, lipid-dense material [38]. The keratolytic activity of the yeasts may be caused by either mechanical or chemical breakdown of the keratin [37]. There are also histologic differences between hyperpigmented and hypopigmented lesions in pityriasis versicolor. Hyperpigmented lesions seem to contain more spores and hyphae than either normal or hypopigmented skin [39]. Merkel cells may have an increased activity, because they contain compound melanosomes and secretory granules. It has been suggested that the presence of the fungus may cause Merkel cells to differentiate from epidermal cells [40]. Also, melanin production may be inhibited by azelaic acid or lipoxygenase [41,42]. The appearance of melanocytes in hyperpigmented lesions of pityriasis versicolor is also altered; they may be larger, are more likely to be singly distributed, and are hypertrophic [37]. The hyperpigmentation of these lesions, however, may not be simply a result of increased melanin activity. In fact, hyperpigmentation has been reported in a patient with both pityriasis versicolor and vitiligo [43]. Instead, it has been hypothesized that the lighter hyperpigmented maculae are the result of a mild inflammatory reaction to the yeasts in the skin. A perivascular inflammation and lymphocyte infiltration has been reported in both hypopigmented and hyperpigmented skin [44], although the infiltrate is more pronounced in hyperpigmented skin [45]. In hypopigmented lesions, there may be a decrease in melanosomes in the stratum spinosum [37] and the horny layer may be slightly hyperkeratotic. The mechanism underlying hypopigmentation is unclear. At one point, it was believed that the fungus blocked ultraviolet light [46]. Hypopigmentation has also been seen, however, in skin that has not been exposed to the sun. Indole pigments formed by M furfur have recently been found to be potent ultraviolet filters [47], but these pigments do not seem to be produced by any of the other Malassezia species.

Diagnosis It is relatively easy, in most cases, to diagnose pityriasis versicolor, although the varied presentation of the lesions may be confusing to the inexperienced clinician. The differential diagnosis includes vitiligo (in patients with hypopigmented lesions); chloasma; tinea corporis; pityriasis alba; pityriasis rosea; pityriasis rotunda [48]; secondary syphilis; and pinta. In

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addition, seborrheic dermatitis and confluent and reticulated papillomatosis of Gougerot-Carteaud syndrome may also resemble pityriasis versicolor; these two latter diseases may also be caused by Malassezia species [49 – 51]. The distinguishing feature of pityriasis versicolor, however, is the transformation from the yeast to a mycelial form, resulting in a characteristic ‘‘spaghetti and meatballs’’ appearance of the yeast under the microscope. Skin scrapings for diagnosis should be taken from the border of a lesion, because this flaking region contains the highest numbers of fungi [23], and transferred to a glass slide. A solution of 10% to 15% potassium hydroxide (KOH) added to the sample helps to dissolve the keratin and debris; this process is accelerated when the slide is gently heated, although even if left at room temperature, the sample should be ready to view in 15 to 20 minutes. The hyphae and spores of the yeast can be viewed easily under the light microscope. A skin biopsy is generally not required in the diagnosis of pityriasis versicolor. A culture is useful to determine which of the six lipophilic Malassezia species the causative organism is in a particular case, but because this information does not currently affect treatment options, culturing the yeast is not necessary for diagnosis. If a culture is performed, it should be borne in mind that standard media do not promote the growth of Malassezia yeasts because these yeasts require an exogenous lipid source. Olive oil may be added to the culture medium; more frequently, Leeming-Notman agar [12] or modified Dixon agar are used to culture Malassezia [15]. Wood’s light is also a useful diagnostic tool for some cases of pityriasis versicolor. This light is a filtered ultraviolet light with a peak of 365 nm. Under this light, the lesions, and often surrounding areas of skin with subclinical levels of infection [52,53], fluoresce a bright yellow or gold color. Wood’s light examination is positive in only one third of cases [54], most likely those in which the causative organism is M furfur.

Treatment There are a number of options available for the treatment of pityriasis versicolor, and both topical and oral medications have been shown to be effective. Because of the importance of endogenous host factors in the development of pityriasis versicolor, relapse is common. There has been an interest in the development of prophylactic treatment. In addition to the risk of relapse, patients should also be cautioned that, even though pityriasis versicolor can be treated ef-

415

fectively within 2 weeks or less of therapy, it may be some time before the skin returns to its normal appearance. The pigmentary changes seen in this disorder may take some time to resolve, particularly in the case of hypopigmented lesions. In the case of hyperpigmented lesions the color changes in the skin are thought to be caused by a combination of inflammation, as suggested by the observation of perivascular inflammation in lesional skin from pityriasis versicolor patients [37] and increased melanocyte activity. In fact, melanocytes have been shown to be stimulated by inflammation [55]. Topical therapies A variety of topical treatments are available for pityriasis versicolor (Table 1). Earlier treatment options involved the use of nonspecific agents that did not have direct activity against Malassezia, but physically or chemically remove infected stratum corneum. These treatments include selenium sulfide [56 – 58], propylene glycol [59], sulfur with salicylic acid [60,61], and benzoyl peroxide [44]. More common now are antifungal medications that have a fungistatic (eg, the azoles) or fungicidal (eg, terbinafine) activity against Malassezia yeasts. Topical azole medications, such as bifonazole, clotrimazole, and miconazole, have been shown to be effective in the treatment of pityriasis versicolor. The treatment regimen may vary; bifonazole has been shown to be effective in as little as a single application [62,63], although it is also used as a 3-day treatment [63]. A study with miconazole showed that the drug was effective in a 2% cream formulation applied twice daily for 3 weeks [64]. More recent azole compounds, such as ketoconazole and fluconazole, have largely replaced these older compounds. Ketoconazole is available as a 2% cream [65], a 2% shampoo [66], and as a foaming gel [67]. Again, treatment durations may vary, although both the shampoo [66] and foaming gel [67] may be effective with only a single use. Fluconazole, unlike the other topical agents used to treat pityriasis versicolor, is a triazole. In one study [68], fluconazole shampoo 2% has been shown to be more effective than placebo with 5 days of treatment. In addition to the azoles, other topical antifungal agents are commonly used to treat pityriasis versicolor. Terbinafine, which is an allylamine and has a fungicidal activity, is available as a 1% solution, a cream [69], a gel [70], and a spray [71]. All of these have been shown to be effective in the treatment of pityriasis versicolor. The treatment regimen most commonly used is 7 days of twice-daily treatment [72].

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Table 1 Randomized, controlled trials of topical treatments for pityriasis versicolor Methodology

Selenium sulfide Hersle [57]

Open

Chu [56]

Open, randomized

Sanchez and Torres [58]

Double-blind, randomized

Katsambas et al [102]

Single-blind, randomized

Regimen (N evaluable) [A] 2.5% selenium disulfide suspension applied once (N=30) [B] Same as [A], but with prophylactic treatment one evening every third mo for 1 y (N=29) [A] 2.5% selenium sulfide shampoo once daily for 6 d, then weekly for 6 wk (N=18) [B] See bifonazole section [A] Selenium sulfide 2.5% lotion (N=48) [B] Selenium sulfide 2.5% lotion with added colorants (N=38) [C] Vehicle with added colorants (N=46) [A] Selenium sulfide shampoo 2.5% nightly on d 1, 2, and 3; placebo on d 4 to 6 (N=65) [B] See econazole section

Clinical responsea

Mycological curea

Comments

[A] 30/30 (100%) [B] 29/29 (100%)

[A] 30/30 (100%) [B] 29/29 (100%)

Relapse rates in the two groups up to 24 mo follow-up were 53% in group [A] and 14% in group [B]

[A] 18/18 (100%)

[A] 18/18 (100%)

Selenium sulfide is equally effective to bifonazole shampoo

Not evaluated

[A] 39/48 (81.3%) [B] 27/38 (71.1%) [C] 7/46 (15.2%)

[A] 58/65 (89.2%)

[A] 58/65 (89.2%)

Evaluations occurred at day 44 and were reported as number of patients achieving both clinical and mycologic cure

Evaluations occurred at 2 wk posttreatment

Propylene glycol Faergemann, Fredriksson [59]

Open

Propylene glycol 50% in water twice daily for 2 wk

20/20 (100%)

Not evaluated

Benzoyl peroxide Prestia [44]

Open

[A] 5% benzoyl peroxide once daily for 4 wk (N=7) [B] 10% benzoyl peroxide once daily for 4 wk (N=2)

[A] 7/7 (100%) [B] 2/2 (100%)

Evaluated by Woods’ Evaluations occurred at 2 wk light (see comments) posttreatment. One patient (treatment group not reported) was positive under Woods’ light examination at follow-up

Sulfur-salicylic acid Bamford [59]

Randomized, controlled

[A] 2% sulfur-2% salicylic acid shampoo nightly for 1 wk (N=22) [B] Placebo (N=17)

[A] 21/22 (95.5%) [B] 6/17 (35.3%)

[A] 20/22 (90.9%) [B] 1/17 (58.9%)

Evaluations occurred at 3 wk posttreatment

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

Reference

Whitfield ointment Clayton et al [103]

Randomized, double-blind [A] Whitfield ointment twice daily for 4 wk (N=17) [B] See clotrimazole section

Open

del Palacio Hernanz et al [62]

Open, randomized

Mora and Greer [104]

Double-blind, randomized

Soyinka [105]

Open

Herna´ndez-Pe´rez [106]

Double-blind, randomized

Segal et al [107]

Double-blind, randomized

Amichai [108]

Open

Aste et al [69]

Single-blind, randomized

[A] 1% bifonazole lotion: single application (N=30) [B] 1% bifonazole lotion daily for 14 d (N=31) [A] Bifonazole 1% solution, once daily for 1 d (N=30) [B] Bifonazole 1% solution once daily on d 1 and d 3 (N=30) [C] Bifonazole 1% solution once daily on d 1, 3, and 6 (N=30) [A] Bifonazole 1% cream nightly for 2 wk (N=14) [B] vehicle (N=15) 1% bifonazole once daily for 28 d or until cure (N=20) [A] Bifonazole 1% cream once daily for 2 wk (N=32) [B] Bifonazole 1% cream once daily for 1 wk, followed by placebo once daily for 1 wk (N=29) [A] Bifonazole 1% shampoo once daily for 2 d, followed by vehicle for 5 d (N=9) [B] Bifonazole 1% shampoo once daily for 7 d (N=8) [C] Vehicle once daily for 7 d (N=9) Bifonazole 1% shampoo once daily for 3 wk (N=22) [A] Bifonazole 1% cream twice daily for 2 to 4 wk (N=20) [B] see terbinafine section

Results were reported for [A] 20/47 sites of [A] 20/47 sites of infection (42.6%) both clinical and mycologic infection (42.6%) [B] 28/50 sites (60%) [B] 28/50 sites (60%) cure, but not for each parameter separately [A] 22/30 (73.3%) [A] 18/30 (60%) Evaluations occurred at 3 wk [B] 21/30 (70%) [B] 19/30 (63.3%) posttreatment [C] 27/30 (90%) [C] 25/30 (83.3%)

[A] 10/14 (71.4%) [B] 8/15 (83.3%)

[A] 11/14 (78.6%) [B] 11/15 (73.3%)

Evaluations occurred at 2 wk posttreatment

20/20 (100%)

20/20 (100%)

[A] 30/32 (93.8%) [B] 28/28 (100%)

[A] 31/31 (100%) [B] 27/28 (100%)

Evaluations occurred 3 and 14 d posttreatment Evaluation occurred 2 wk posttreatment; not all patients were assessed for all parameters.

[A] 4/9 (44.4%) [B] 6/8 (75%) [C] 0/9 (0%)

[A] 4/9 (44.4%) [B] 6/8 (75%) [C] 0/9 (0%)

Evaluations occurred at end of treatment period (1 wk after baseline); results were reported in terms of both clinical and mycologic cure

22/22 (100%)

Not reported

[A] 20/20 (100%)

[A] 19/20 (95%)

Study subjects were children, aged 9 to 14 y Follow-up occurred at 2 wk post-treatment (ie, 4 to 6 wk from baseline) 417

(continued on next page)

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

Bifonazole Hay et al [63]

80% of patients cured overall; no statistically significant difference between treatment groups

418

Table 1 (continued) Regimen (N evaluable)

Mycological curea

Comments

2% fenticonazole lotion applied once daily for maximum of 21 d (N=23)

17/23 (74%)

17/23 (74%)

Results were reported for both clinical and mycologic cure, but not for each parameter separately

1% butenafine hydrochloride cream applied daily for 2 wk (N=87). 1% butenafine hydrochloride cream applied daily for 2 wk (N=86).

44/87(51%)

48/87(55%)

30/86 (35%)

43/86(50%)

Evaluation occurred at 6 wk posttreatment Evaluation occurred at 6 wk posttreatment

Clotrimazole 1% once daily for one wk (N=22) [A] Clotrimazole 1% solution twice daily for 28 d (N=16) [B] See tioconazole section

19/22 (86.4%)

22/22 (100%)

15/16 (94%)

16/16 (100%)

Double-blind, randomized

[A] Sulconazole nitrate 1% cream twice daily for 3 wk (N=80) [B] See miconazole section

[A] 71/80 (88.8%)

[A] 74/80 (92.5%)

Evaluations occurred at treatment end (3 wk); no significant difference between treatments

Miconazole Tanenbaum et al [64]

Double-blind, randomized

[A] 2% miconazole nitrate cream, twice daily for 3 wk (N=85) [B] See sulconazole section

[A] 74/85 (87%)

[A] 70/85 (82.4%)

Fredriksson [77]

Single-blind, randomized

[A] Miconazole 2% cream twice daily for up to 28 d (N=4) [B] See tioconazole section

[A] 4/4 (100%)

[A] 4/4 (100%)

Evaluations occurred at treatment end (3 wk); no significant difference between treatments Evaluations occurred at 6 wk posttreatment; reported as complete (clinical and mycologic) cure

Methodology

Fenticonazole Aste et al [73]

Single-blind, randomized

Butenafine Package insert [74 ]

Randomized

Package insert [74]

Randomized

Clotrimazole Gip [109]

Open

Alchorne et al [75]

Open

Sulconazole Tanenbaum et al [64]

Evaluations occurred at 3 mo posttreatment Follow-up occurred at week 8 (2 wk posttreatment)

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

Clinical responsea

Reference

Double-blind, randomized

[A] Econazole nitrate 1% cream daily for up to 21 d (N=67) [B] Vehicle (N=59)

[A] 51/67 (76.1%) [B] 33/59 (55.9%)

[A] 14/67 (20.9%) [B] 22/59 (37.3%)

Katsambas et al [102]

Single-blind, randomized

[A] Econazole 1% shampoo nightly for 6 consecutive nights (N=65) [B] See selenium sulfide section

[A] 60/65 (92.3%)

[A] 60/65 (92.3%)

Ketoconazole Savin et al [65]

Double-blind, randomized

[A] Ketoconazole 2% cream once daily [A] 34/51 (66.7%) for 11 to 22 d (mean: 14 d (N=51) [B] 11/50 (22%) [B] Placebo (N=50)

[A] 43/51 (84.3%) [B] 11/50 (22%)

el Euch et al [67]

Open

Ketoconazole 2% foaming gel for 30 d (N=48)

20/48 (41.6%)

42/48 (87.5%)

Terbinafine Savin and Horwitz [65]

Double-blind, randomized

[A] Terbinafine 1% solution twice daily for 7 d (N=85) [B] Vehicle (N=43)

[A] 69/85 (81.1%) [B] 13/43 (30.2%)

[A] 69/85 (81.1%) [B] 13/43 (30.2%)

Faergemann et al [70]

Double-blind, randomized

[A] Terbinafine gel once daily for 7 d (N=28) [B] Vehicle (N=29)

[A] 21/28 (75%) [B] 4/29 (14%)

[A] 21/28 (75%) [B] 4/29 (14%)

Aste et al [69]

Single-blind, randomized

[A] 20/20 (100%)

[A] 20/20 (100%)

[A] 36/76 (47.4%) [B] 10/34 (29.4%)

[A] 36/76 (47.4%) [B] 10/34 (29.4%)

Vermeer and Staats [111]

[A] Terbinafine cream 1% for 2 to 4 wk (N=20) [B] See bifonazole section Double-blind, randzomized [A] Terbinafine 1% solution twice daily for 1 wk (N=76) [B] Vehicle (N=26)

Evaluations are given for 3 wk after baseline, when only the most refractory cases were seen; clinical cure rates given are for patients with ‘‘excellent’’ response Evaluations occurred at d 44 and were reported as number of patients achieving both clinical and mycologic cure

Follow-up occurred at between 2 and 10 wk posttreatment; at 2 wk of treatment, the code was broken for nonresponders and those on vehicle were switched to active treatment Follow-up occurred at treatment end

Patients were evaluated on the basis of effective treatment (ie, clinical and mycologic cure); evaluations occurred at wk 8 Follow-up occurred at wk 8; evaluations are given in terms of effective treatment (ie, clinical and mycologic cure) Follow-up occurred at 2 wk posttreatment (ie, 4 to 6 wk from baseline) Cure rates are given for combined clinical and mycologic cure; data are reported from an intentionto-treat analysis

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Econazole Vicik et al [110]

420

Table 1 (continued) Methodology

Tioconazole Del Palacio Hernanaz et al [76 ] Open

Alchorne et al [75]

Open

Haroon et al [78]

Open

Fredriksson [77]

Single-blind, randomized

a

Regimen (N evaluable)

Clinical responsea

Mycological curea

Comments

Tioconazole 1% spray twice daily for 30 d (N=7)

7/7 (100%)

7/7 (100%)

[A] Tioconazole 1% lotion twice daily for 28 d (N=16) [B] See clotrimazole section Tioconazole 1% dermal cream twice daily for 3 wk (N=65)

16/16 (100%)

16/16 (100%)

Patients were evaluated on basis of combined clinical and mycologic cure Follow-up occurred at wk 8 (2 wk posttreatment)

53/65 (81.5%)

53/65 (81.5%)

[A] Tioconazole 1% cream twice daily for up to 28 d (N=6) [B] See miconazole section

[A] 6/6 (100%)

[A] 6/6 (100%)

Results are given for assessment at 4 weeks posttreatment unless otherwise stated.

Evaluations occurred at wk 6 (3 wk posttreatment); patients were evaluated on the basis of complete (clinical and mycologic) cure Evaluations occurred at 6 wk posttreatment; reported as complete (clinical and mycologic) cure

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

Reference

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

421

Table 2 Randomized, controlled trials of ketoconazole in the treatment of pityriasis versicolor Regimen (N evaluable)

Reference

Methodology

Savin [112]

Double-blind, [A] 4 wk 200 mg daily [A] 33/34 (97%) randomized ketoconazole (N=34) [B] 3/32 (9%) [B] Placebo (N=32)

Urcuyo and Zaias [84]

Double-blind, [A] 2 wk 200 mg daily [A] 9/10 (90%) randomized ketoconazole (N=10) [B] 2/10 (20%) [B] Placebo (N=10)

Fernandez-Nava et al [90]

Open, randomized

[A] Single dose 400 mg ketoconazole (N=60) [B] 10 d 200 mg daily ketoconazole (N=60) Hay et al [63] Double-blind, [A] 5 d 200 mg randomized ketoconazole plus placebo to 25 d (N=12) [B] 15 d 200 mg ketoconazole plus placebo to 25 d (N=12) [C] 25 d 200 mg ketoconazole (N=12) Faergemann Open [A] 200 mg and Djarv [95] ketoconazole daily for 3 wk [B] 200 mg ketoconazole daily for 5 wk Zaias [113] Double-blind [A] 200 mg ketoconazole daily for 5 d then placebo for 5 d (N=59) [B] 200 mg ketoconazole daily for 10 d [C] placebo daily for 10 d Shemer et al [99] Open, [A] 400 mg ketoconaozle 7 d apart (N=36) [B] and [C] See fluconazole chart Farshcian Double-blind [A] 200 mg et al [88] ketoconazole in a single dose repeated weekly for 2 wk (N=50) [B] see fluconazole table

Clinical cure

Not evaluated

[A] 10/12 (83%) [B] 9/12 (75%) [C] 8/12 (67%)

Mycological cure

Comments

[A] 33/34 (97%) Complete cure at 8 wk; [B] 3/32 (9%) there was a significant difference (P< .05) between the two groups [A] 9/10 (90%) Figures are given for [B] 2/10 (20%) both clinical and mycologic cure; there was a significant difference (P< .05) between the two groups [A] 25/60 (42%) Mycological cure only, [B] 31/60 (52%) at 1 mo

[A] 10/12 (83%) Clinical and mycologic [B] 9/12 (75%) cure at 28 d [C] 8/12 (67%)

[A] 26/32 (81%) [A] 26/32 (81%) Clinical and [B] 32/32 (100%) [B]32/32 (100%) mycologic cure 2 wk after treatment end

84% 90% 17%

Clinical and mycologic cure at 30 d; there was no significant difference between ketoconazole groups, but both were significantly different than placebo

Not reported

30/36 (83%)

Mycologic cure rate 4 wk after start of treatment

[A] 41/50 (82%)

[B] 44/50 (88%)

No significant differences in efficacy between ketoconazole and fluconazole

Adapted from Gupta AK, Bluhm R, Summerbell RC. Pityriasis versicolor. J Acad Dermatol Venereol 2000;16:19 – 33.

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Table 3 Randomized controlled trials of itraconazole in the treatment of pityriasis versicolor Reference

Regimen Methodology (N evaluable)

Faergemann [114]

Double-blind

Swinyer a

Double-blind

Savin and Bolognia a

Double-blind

Brody a

Double-blind

Shmunes a

Double-blind

Hickman [116]

Double-blind

Cuce et al [117]

Open

del PalacioHernandez et al [118]

Open

Estrada [119]

Open

[A] 2 wk 100 mg itraconazole daily (N=15) [B] Placebo (N=14) [A] 7 d 200 mg itraconazole daily (N=8) [B] Placebo (N=8) [A] 7 d 200 mg itraconazole daily (N=13) [B] Placebo (N=14) [A] 7 d 200 mg itraconazole daily (N=16) [B] Placebo (N=16) [A] 7 d 200 mg itraconazole daily (N=15) [B] Placebo (N=15) [A] 7 d 200 mg daily itraconazole (N=18) [B] Placebo (N=18)

[A] 200 mg itraconazole daily for 5 d (N=15) [B] 200 mg itraconazole daily for 7 d (N=21) [A] 200 mg once daily for 5 d (N=15) [B] 100 mg once daily for 10 d (N=15)

Clinical cure

Mycological cure

[A] 10/15 (67%) [B] 1/14 (7%)

[A] 11/15 (73%) [B] 0/14 (0%)

[A] 4/8 (50%) [B] 0/8 (0%)

[A] 7/8 (88%) [B] 0/8 (0%)

Evaluated in terms of mycologic cure and clinical response at wk 5

[A] 69% [B] 7%

Evaluated in terms of mycologic cure and clinical response at wk 5

Comments

[A] 10/16 (63%) [B] 2/16 (13%)

[A] 16/16 (100%) Evaluated in terms [B] 4/16 (29%) of mycologic cure and clinical response at wk 5

[A] 13/15 (87%) [B] 0/15 (0%)

[A] 13/15 (87%) [B] 0/15 (0%)

Evaluated in terms of mycologic cure and clinical response at wk 5

[A] 12/18 (67%) [B] 5/18 (28%)

[A] 16/18 (89%) [B] 1/18 (6%)

[A] 19/21 (90%) [B] 19/21 (90%)

[A] 19/21 (90%) [B] 19/21 (90%)

Clinical cure defined as ‘‘no visual evidence of disease,’’ evaluated at wk 5; significant difference in cure rates between itraconazole and placebo (P< .01) Clinical and mycologic cure; evaluated at 4 wk after end of treatment

[A] 14/15 (93%) [B] 13/15 (87%)

[A] 14/15 (93%) [B] 13/15 (87%)

Not reported [A] 200 mg itraconazole daily for 5 d (N=22) [B] 100 mg itraconazole daily for 10 d (N=20)

[A] 15/20 (75%) [B] 21/22 (95%)

Evaluation of cure defined as mycologic cure plus healing or only mild residual lesions at 3 wk posttreatment Patients were evaluated at end of treatment; cure was given as mycologic cure only

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Table 3 (continued) Reference

Regimen Methodology (N evaluable)

Fioroni et al [120]

Open

Galimberti et al [121]

Open

Massone et al [122]

Open

Montero-Gei et al [100]

Open

Morales-Doria [123]

Open

Panconesi and Difonzo [124]

Open

Shemer et al [99]

Open

Simoni and Cilli [125] Open

[A] 200 mg itraconazole daily in a single dose (N=13) [B] 200 mg itraconazole daily in a divided dose (N=15) [A] 200 mg itraconazole once daily for 5 d (N=13) [B] 200 mg itraconazole once daily for 10 d (N=15) [A] 100 mg itraconazole daily for 10 d (N=10) [B] 200 mg itraconazole daily for 5 d (N=10) [A] 200 mg itraconazole daily for 1 wk [B] and [C] See fluconazole table [A] 100 mg twice daily for 5 d (N=24) [B] 100 mg daily for 5 d (N=23) [A] 200 mg itraconazole daily in a single dose for 5 d (N=15) [B] 200 mg itraconazole daily in a divided dose for 5 d (N=15) [A] 200 mg itraconazole daily for 1 wk (N=35) [B] 100 mg itraconazole daily for 2 wk (N=34) [C] See fluconazole table [A] 200 mg itraconazole daily in a single dose for 5 d (N=15) [B] 200 mg

Clinical cure

Mycological cure

[A] 13/13 (100% [B] 15/15 (100%)

[A] 13/13 (100% [B] 15/15 (100%)

Clinical and mycologic cure 4 wk after end of treatment

[A] 77% [B] 87%

Clinical and mycologic cure at 28 d posttreatment

Comments

[A] 10/10 (100%) [A] 10/10 (100%) Clinical and [B] 8/10 (80%) [B] 8/10 (80%) mycologic cure 4 wk after beginning treatment [A] 22/30 (73%)

[A] 24/30 (80%)

Assessment at 30 d posttreatment

Not reported

[A] 23/24 (96%) [B] 20/20 (100%)

Mycologic cure at 28 d after start of treatment

[A] 15/15 (100%) [A] 15/15 (100%) [B] 15/15 (100%) [B] 15/15 (100%)

Not reported

[A] 30/35 (85%)

Mycologic cure rate 4 wk after baseline

[A] 15/15 (100%) [A] 15/15 (100%) Clinical and [B] 15/15 (100%) [B] 15/15 (100%) mycologic cure; evaluated 4 wk after end of treatment (continued on next page)

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Table 3 (continued) Reference

Regimen Methodology (N evaluable)

del Palacio Hernanz et al [118]

Open

Ko¨se et al [126]

Open

Clinical cure

itraconazole daily in a divided dose for 5 d (N=15) [A] 200 mg [A] 4/20 (20%) itraconazole daily for 5 d (N=20) [B] See selenium sulfide in Table 1 [A] 400 mg single [A] 18/24 (75%) dose of [B] 21/26 (81%) itraconazole (N=24) [B] 200 mg of itraconazole daily for 7 d (N=26)

Mycological cure

Comments

[A] 4/20 (20%)

Clinical and mycologic cure 3 wk posttreatment

[A] 20/24 (83%) [B]23/26 (88%)

Evaluation occurred at 6 wk after baseline

a See Ref. [128]. Adapted from Gupta AK, Bluhm R, Summerbell RC. Pityriasis versicolor. J Eur Acad Dermatol Venereol 2000;16:19 – 33.

Fenticonazole, which is an imidazole and has antimycotic activity, has been found to be effective in the treatment of pityriasis versicolor [73]. Fenticonazole 2% lotion has been found to be effective and its efficacy is comparable with that of bifonazole. Butenafine, a benzylamine derivative and a synthetic antifungal agent, is also used for treating pityriasis versicolor [74]. It is available as a 1% cream. Tioconazole, a 1-substituted imidazole, has also been found effective in the treatment of pityriasis versicolor [75 – 78]. It is available as a 1% lotion, cream, or spray. The treatment regimen used is 3 to 4 weeks applied twice daily. Ciclopirox olamine is a hydroxypyridone with a broad-spectrum antifungal activity [79]. The 1% cream formulation has been shown to be more effective than either vehicle or clotrimazole cream [79]. A ciclopirox gel 0.77% formulation is also available. Oral therapies Oral therapy may be preferred in the case of patients with particularly severe or widespread involvement of the skin. Patients may also prefer oral therapy because it is more convenient and less time consuming than topical treatment. This preference, in turn, may lead to increased patient compliance. In addition, the shorter duration of many oral regimens may also contribute to increased patient compliance. Griseofulvin, which was the first commonly used oral

antifungal agent, is not effective against infection with Malassezia species [80]. Terbinafine, although effective when used as topical therapy, does not provide an effective oral treatment for pityriasis versicolor [81]. Interestingly, it has recently been reported that oral terbinafine is an effective treatment for seborrheic dermatitis, which is also thought to be caused by Malassezia yeasts [82,83]. Ketoconazole was the first available oral therapy for pityriasis versicolor (Table 2). Early studies used a treatment regimen of 4 weeks, 200 mg/d; however, shorter treatment durations were soon found to be effective in many cases. Studies have shown that 2-week [84], 10-day [85], or 5-day [86] therapy is effective. Shorter treatment regimens have also been developed, including 400 mg given once a day for 3 days or administered 12 hours apart for three doses [87]. Another common regimen is 400 mg of ketoconazole given once a week for 2 weeks [88,89]. It has also been reported that a single 400-mg dose of ketoconazole may be effective [90], although relapse rates with this treatment could be higher than with other treatment regimens [91]. Reports of the danger of hepatotoxicity with ketoconazole led to the search for other azoles for this indication. Itraconazole is a triazole that is effective and safe when used to treat pityriasis versicolor [99,100, 114 – 126] (Table 3). Absorption of this drug is enhanced when the medication is taken with food [92].

A.K. Gupta et al / Dermatol Clin 21 (2003) 413–429

Itraconazole is effective with a dosage of 200 mg/d taken for either 5 or 7 days; the minimum cumulative dose for itraconazole is 1000 mg [93]. Both ketoconazole and itraconazole have shown promise as prophylactic treatments for pityriasis versicolor. Because of the importance of endogenous host factors in the development of this disease, many patients experience recurrent outbreaks. Ketoconazole has been shown to prevent relapse in patients when administered as a single 400-mg dose [94] or in a regimen of 200 mg/d for 3 consecutive days, once a month [95]. More recently, itraconazole given once monthly in a single 400-mg dose (four capsules of 100 mg each) has been shown to have a significant prophylactic effect [96]. In this study the duration was 6 months; it is not known what the result would be if itraconazole was administered on a long-term basis beyond 6 months Fluconazole also shows promise as a treatment for pityriasis versicolor (Table 4). Several open studies have been performed, using various treatment regi-

425

mens. One dose-finding study [97] obtained a cure rate (clinical and mycologic cure) of 87% at 28-day follow-up when 300 mg of fluconazole was given once weekly for 2 weeks (N = 603). Similarly, a second study [98], which assessed clinical and mycologic cure at week 4 after 50 patients were treated with 300-mg fluconazole once weekly for 2 weeks, reported a cure rate of 98%. There are also active-comparator studies evaluating the efficacy of treatments with two different drugs to treat pityriasis versicolor. Because of the differences in dosage regimens, these have been open studies. In one study [99], the compared regimens were itraconazole, 200 mg/d for 1 week; itraconazole, 100 mg/d for 2 weeks; and ketoconazole, 400 mg/d for 1 day, repeated 1 week later. There were no significant differences between the three treatments. In a second study [100] itraconazole, 400 mg/d in two divided doses for 15 days, was compared with fluconazole, 600 mg/d in two divided doses for 15 days. Again, there were no significant differences

Table 4 Oral fluconazole in the treatment of pityriasis versicolor Reference

Methodology

Farshchian et al [88]

Double-blind

Amer et al [97]

Open, randomized

Faergemann [127]

Open

Montero-Gei et al [100]

Open

Shahid et al [98]

Open

Regimen (N evaluable)

Clinical cure

Mycologic cure

Comments

[A] 300 mg fluconazole in a single dose, once weekly for 2 wk [B] see ketoconazole table [A] Single 150-mg dose fluconazole weekly for 4 wk (N=207) [B] Single 300-mg dose fluconazole weekly for 4 wk (N=190) [C] Single 300-mg dose repeated at 2 wk (N=206) Single dose fluconazole 400 mg (N=23)

39/50 (78%)

41/50 (82%)

No significant difference between groups

Not reported

[A] 161/207 (78%) [B] 178/190 (93%) [C] 179/206 (87%)

Mycologic cure assessed 28 d after last day of treatment

17/23 (74%)

Not reported

[A] Single 450 mg fluconazole (N=30) [B] Two 300-mg doses of fluconazole given 1 wk apart (N=30) 300 mg fluconazole once weekly for 2 wk (N=50)

[A] 18/30 (60%) [B] 23/30 (77%)

[A] 18/30 (60%) [B] 23/30 (77%)

Clinical cure 3 wk posttreatment Assessment at 30 d posttreatment

49/50 (98%)

49/50 (98%)

Adapted from Gupta AK, Bluhm R, Summerbell RC. Pityriasis verisolor. J Eur Acad Dermatol Venereol 2000;16:19 – 33.

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between the two groups. Itraconazole has also been compared with topical therapy with selenium sulfide [101]. Itraconazole was given 200 mg/d for 5 days and selenium sulfide was applied once daily for 7 days. Both groups responded to therapy, but many patients reported a preference for oral treatment. This preference may translate into increased patient compliance with oral treatment.

[17] [18]

[19]

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Treatments of tinea pedis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Melody Chow, HBScb, C. Ralph Daniel, MDc, Raza Aly, PhDd a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Department of Dermatology, University of Mississippi Medical Center, 971 Lakeland Drive, Suite 659, Jackson, MS 39216-4609, USA d Room AC 34, Box 0517, Department of Dermatology, University of California Medical Center, San Francisco, CA 94143-0517, USA

Tinea pedis, also known as ‘‘athlete’s foot,’’ is a superficial skin infection of the feet caused predominantly by dermatophytes. It is one of the most common superficial fungal infections [1].

Etiology and epidemiology Tinea pedis affects at least 10% of the world population at any given time [2]. It is suspected that these infections did not become common until the late nineteenth and early twentieth century, when occlusive shoes became more popular [3]. Tinea pedis is more common among men than women, and is generally uncommon in children [4]. The lateral toes are most often affected, particularly in the web space between the fourth and fifth toes. Individuals with a generalized immune deficiency, such as AIDS or HIV, tend to be predisposed to the development of tinea pedis. Patients with a history of atopic dermatitis have an increased incidence of tinea pedis [3]. Infections occur more often in tropical and semitropical climates, especially during the summer months [2].

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

Trichophyton rubrum is the most common causal organism of tinea pedis; however, Trichophyton mentagrophytes and Epidermophyton floccosum are also frequent causes of infection [3]. Nondermatophyte molds, including Scytalidium hyalinum or S dimidiatum, and Scopulariopsis brevicaulis are also known to cause tinea pedis; in some instances nondermatophytes may produce symptoms similar to tinea pedis caused by T rubrum [5]. The fungal infection usually begins on the foot. In some instances, the individual may exhibit the ‘‘two foot one hand’’ pattern, the cause of which is not known [6,7]. When tinea manuum is present it is prudent to observe for tinea pedis; however, most individuals with tinea pedis do not have tinea manuum. The fungal organisms that cause tinea pedis may also be responsible for tinea manuum, with T rubrum being the most frequent etiologic agent.

Clinical manifestation There are three general clinical presentations of tinea pedis: (1) interdigital, (2) moccasin, and (3) vesicobullous. Interdigital disease is the most common form of tinea pedis, and can be a chronic condition. Often there is fissuring, scaling, and maceration of the interdigital or subdigital areas, particularly the 4 – 5 toe web, with the potential to spread to the sole of the foot. A whitish buildup of scales, with underlying weepy red erosions, forms on the skin [3,8].

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00032-9

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Hyperhidrosis, pruritus, and a foul odor may be present. Infections are most often caused by T rubrum and T mentagrophytes [4,9]. ‘‘Dermatophytosis simplex’’ is the term used to describe the most uncomplicated form of interdigital tinea pedis. If infection progresses to a more severe form, however, the patient may become relatively disabled [10]. Secondary bacterial infection is more likely to occur when there has been a breakdown of the skin. An overgrowth of bacteria can manifest as a lesion that is inflamed and macerated; this symptomatic form of interdigital tinea pedis has been termed ‘‘dermatophytosis complex’’ [11]. Moccasin-type tinea pedis is characterized by fine silvery scales, with underlying pink to red skin. It is predominantly caused by T rubrum [8]. The term ‘‘moccasin’’ developed because the most commonly affected areas are the soles, heels, and sides of the feet [9]. A dry, hyperkeratotic presentation is the mild, relatively asymptomatic form of moccasin foot; however, this form is unattractive, and usually chronic. Moderate to severe presentations of moccasin tinea pedis may manifest with cracked and inflamed skin, erythema, and odor, and in some instances progress to onychomycosis [12]. The nail can become a reservoir for dermatophytes [8]. Vesicobullous tinea pedis is the least common form [8]. T mentagrophytes is the most common causal organism [8]. Vesicobullous tinea pedis may present with acute and highly inflammatory vesicular or bullous lesions [11]. Initially, there is inflammation at the in-step of the foot; however, inflammation may spread over the entire sole [4]. The mildest form of vesicobullous tinea pedis starts with the development of small, isolated vesicles filled with clear fluid. Although the vesicles may rupture independently, and the disease resolves spontaneously, recurrence is common [8]. If infection is allowed to progress the vesicles may coalesce into large, acute, pruritic, spreading, ulcerative, and often erosive bullae [4,8]. Tinea manuum may present as a chronic, dry, scaly, hyperkeratotic fungal infection. It is most commonly caused by T rubrum [6], and found primarily on the palm of the hand, with minimal erythema and occasional extreme dryness [6].

Differential diagnosis It can be difficult to diagnose tinea pedis when it is severe. Misdiagnosis may result when the overgrowth of secondary bacteria is so extensive that the dermatophytes are forced deeper into the stratum corneum, masking the presence of fungal organisms

[3]. Bacterial infection caused by staphylococci, streptococci, or gram-negative organisms may result in inflammation and odor. Not only can these organisms cause foot infections in the absence of tinea pedis, but may also be present with the fungal infection [9]. The presence of interdigital scaling should invoke the consideration of candidiasis; erythrasma; and soft corns, also known as ‘‘callosities’’ [2]. Erythrasma and candidiasis are generally asymptomatic with minor fissuring, and may be present in the toe cleft [9]. Tinea pedis is relatively uncommon among children; the diagnosis of peridigital dermatitis or atopic dermatitis should also be considered in this age group [2]. The differential diagnosis also includes psoriasis, dyshydrotic eczema, contact dermatitis, pityriasis rubra pilaris, and Reiter’s syndrome [9]. Infections of the hand should not result in the immediate diagnosis of tinea manuum. Dermatophyte infections can be difficult to differentiate from allergic contact dermatitis, pompholyx, psoriasis, atopic dermatitis, and lamellar dyshidrosis [10]. Valuable clues may also be obtained from examination of the fingernails and toenails. The possibility of the ‘‘two foot one hand’’ disease should be kept in mind [7].

Diagnosis and laboratory findings To confirm the diagnosis of tinea infection, it is necessary to obtain a skin sample from the affected area, preferably from the active borders of the lesion or the roof of a vesicle [8]. The scrapings should be mounted in 10% to 20% aqueous potassium hydroxide (KOH preparation) to identify the presence of fungus [3,8]. A negative result, however, does not necessarily disqualify the possibility of dermatophyte infection. A culture of the sample helps identify the causative fungal organism.

Prevention and control Recurrence of tinea pedis is not uncommon. When a fungal infection is present at any anatomic site, the feet and hands should be examined for possible onychomycosis, tinea pedis, and tinea manuum. The nails in particular may act as a reservoir of infection. It is important to control flare-ups and prevent spread of infection, especially in diabetics and immunocompromised persons. Infected individuals should wear nonocclusive footwear, like sandals; if this is not possible, shoes should be alternated every 2 to 3 days to air them out [3].

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Antifungal powders may be placed in shoes daily. Natural fiber socks and shoes should be worn and changed often. Communal baths, showers, and swimming pool floors should be avoided, because these areas spread infection especially easily. The hosing of these floors may help to reduce the incidence of infection [9]. After showering it is especially important that the feet are dried thoroughly, particularly between the toes.

Treatment Treatments for tinea pedis are varied, and include both topical and oral medications. Topical agents are generally effective and relatively inexpensive. In some instances, topical antifungal agents may not penetrate far enough into the keratinous tissue adequately to eliminate dermatophyte fungal organisms. This may result in relapses and chronic tinea pedis. Systemic agents may result in improved efficacy; however, adverse events can be more severe compared with topical therapies, with increased potential for drug interactions. The following list displays various antifungal agents used to treat tinea pedis in adults (approved in the United States), and includes their formulations and treatment regimens. Note that the information presented is for guidance only. For up-to-date information concerning approval status and dosage regimens, please review relevant product monographs and package inserts. Azole Imidazole [13] Clotrimazole (Topical: cream 1%, lotion 1%, solution 1%) Twice daily (morning and evening) for 4 weeks Econazole (Topical: cream 1%) Once daily for 1 month Ketoconazole (Oral: tablets) 200 to 400 mg daily for 1 to 2 months (Topical: cream 2%) Once to twice daily for 6 weeks Miconazole (Topical: aerosol 1% and 2%, aerosol powder 2%, cream 1% and 2%, lotion 1% and 2%, powder 2%, solution 1%, tincture 2%) Twice daily (morning and evening) for 1 month Oxiconazole (Topical: cream 1%, lotion 1%) Once or twice daily for 1 month Sulconazole (Topical: cream 1%, solution 1%) Twice daily for 4 weeks

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Triazole Fluconazole [13] (Oral: tablets, suspension) 50 mg once weekly for 2 to 6 weeks Itraconazole [14] (Oral: capsules) 100 mg once daily with a meal for 30 days Benzylamine [13] Butenafine (Topical: cream 1%) Twice daily for 7 days Once daily for 14 days Allylamine [13] Naftifine (Topical: cream 1%, gel 1%) Cream once daily for 4 to 6 weeks Gel twice daily (morning and evening) for 4 to 6 weeks Terbinafine (Topical: cream 1%, solution 1%) Twice daily (morning and evening) for at least 1 to 2 weeks Hydroxypyridone [13] Ciclopirox (Topical: gel 0.77%, solution 8%, cream 0.77%, lotion 0.77%) 0.77% twice daily (morning and evening) for 4 weeks Other [13] Griseofulvin (Oral: capsules, suspension, tablets) 660 or 750 mg daily for 4 to 8 weeks Tolnaftate (Topical: aerosol 1%, aerosol powder 1%, cream 1%, powder 1%, solution 1%) Twice daily (morning and evening) for 4 to 6 week A search was performed on PubMed (1966 to June 2002) on the various treatments of tinea pedis. Studies included were English, human, and clinical trials; non-English, nonhuman trials were excluded. Tables 1 to 4 summarize the studies reviewed.

Azole Imidazoles Bifonazole Bifonazole is an imidazole derivative that, unlike other imidazoles, possesses a structure that does not contain a halogen. It has a broad spectrum of antifungal activity, with the capability of being retained in skin for 36 to 48 hours, and persists twice as long as clotrimazole or miconazole [15]. It has been suggested that because of the lipophilic properties of bifonazole, which aids in the retention time in the skin [16], a once-daily treatment regimen may be effective in treating fungal infections. One doubleblind randomized trial, one single-blind randomized

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Table 1 Efficacy of various oral single-treatment regimens for tinea pedis Treatment

Authors

Tanuma et al (1998) [28]

Open, randomized, One hundred fourteen comparative infections (58 weekly treatment regimen; 56 daily treatment regimen)

Open-labeled

Itraconazole Bonifaz and Saul Open-design, (2002) [30] prospective, noncomparative Schuller et al (1998) [31]

No. patients

Double-blind, randomized

Six adults, hyperkeratotic tinea pedis Forty-four adults

One hundred thirty-four adults (64,400 mg/1 wk; 69,100 mg/4 wk)

Regimen

Efficacy results

Adverse events related to treatment

Fluconazole, 150 mg/wk until clinical cure; maximum 6 wk; Fluconazole, 50 mg/d until clinical cure; maximum 6 wk Follow-up, 1 mo after end of treatment Fluconazole, 100 mg once daily for 8 wk Follow-up, 1 wk posttreatment Itraconazole, 400 mg/d for 7 d Follow-up, 30 and 60 d after treatment Either itraconazole, 400 mg/d for 1 wk followed by placebo for 3 weeks or itraconazole, 100 mg/d for 4 wk, with assessment for up to 6 wk

Positive clinical response (cure or marked improvement = weekly: 90% (26/29); daily: 100% (24/24) Mycologic cure = weekly: 76% (22/29); daily: 91% (20/22) No significant differences in efficacy

Weekly: two patients abnormality in hepatic function, headache, eruption (one discontinued because of eruption) Daily: three patients: hyperlipidemia, nausea, and headache (none discontinued)

100% mycologic cure No complete cure (all showed good clinical improvement; none showed excellent improvement) Clinical and mycologic cure = 27% (end of treatment); 93.1% (30-d follow-up); 84.4% (60-d follow-up)

No adverse events observed. No abnormal laboratory findings.

Mycologic cure = 400 mg/1 wk: 29% (end of treatment); 62% (wk 6 of follow-up); 63% (end of follow-up); 100 mg/4 wk: 46% (end of treatment); 76% (wk 6 of follow-up); 75% (end of follow-up) Clinical response = 400 mg/1 wk: 79% (end of treatment, wk 6 of follow-up); 81% (end of follow-up); 100 mg/4 wk: 70% (end of treatment); 79% (wk 6 of follow-up); 75% (end of follow-up)

400 mg/1 wk: 13 adverse events reported, including headache, conjunctivitis, vomiting, and nausea; during treatment, 18 patients displayed laboratory abnormalities. 100 mg/4 wk: nine adverse events reported, including allergic reaction, vertigo, dizziness, headache, and periorbital edema; during treatment, 15 patients displayed laboratory abnormalities

Three adverse events were reported, including moderate headache and moderate dyspepsia

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Triazoles Fluconazole Nozickova et al (1998) [47]

Study type

Double-blind, randomized, placebo-controlled

Seventy-two adults (36 itraconazole; 36 placebo)

Itraconazole, 200 mg twice daily for 1 wk Follow-up for a total of 9 wk

Decroix (1995) [29]

Open

Twenty adults

Itraconazole, 200 mg twice daily for 1 wk Follow-up for a total of 5 wk

Smith et al (2001) [49]

Open-labeled, randomized, prospective, multicenter

Seventeen HIV-positive adults

Terbinafine, 250 mg once daily for either 2 or 4 wk, with assessment for total 8 wk

Selcßuki et al (1993) [50]

Open, multicentre

Thirty-three patients

White et al (1991) [51]

Double-blind, Twenty-eight placebo-controlled, individuals >16 y parallel group with diagnosed tinea pedis or manuum (14 terbinafine; 14 placebo) Double-blind, Forty-one adults randomized, (23 terbinafine; placebo-controlled 18 placebo)

Terbinafine, 250 mg once daily for 4 wk, with 2-wk follow-up Terbinafine, 250 mg once daily for 2 wk, with assessments for a total of 8 wk

Savin and Zaias (1990) [52]

Terbinafine, 125mg twice daily for 6 wk, with 2-wk follow-up

Mycologic cure = 56% (follow-up end point) Clinical response = 75% (follow-up end point) Overall success = 53% (follow-up end point) Reduction in symptom severity scores = 88% Mycologic cure = 5% (wk 1); 45% (wk 3); 85% (wk 5) Clinical response = 10% (1 wk); 95% (wk 3 and 5) Complete cure = 85% of all patients

Seven reports of adverse events, including headache, abdominal pain, and pruritus, all of mild or moderate severity

No adverse events reported

Mycologic cure = 47% (of all patients); 65% (follow-up) Clinical cure = 82% (of all patients) Effective treatment = 35% (of all patients); 47% (follow-up) Complete cure = 1% (of all patients); 1% (follow-up) Mycologically negative = 93.3% (end of therapy)

Headache (mild severity) and bilirubinemia (mild severity)

No significant alterations in biochemical and hematologic tests

Mycologic cure = 23% (2 wk); 64% (4 wk); 71% (6 wk); 86% (8 wk) Effective therapy = 8% (2 wk); 43 (4 and 6 wk); 71 (8 wk)

Two adverse events probably or possibly related to treatment, including desquamation of skin and mild diarrhoea

Overall efficacy = 59% (6 wk); 65% (8 wk)

No adverse events related to treatment

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Allylamines Terbinafine

Svejgaard et al (1998) [48]

435

436

Table 2 Efficacy of various topical single-treatment regimes for tinea pedis Treatment Imidazoles Bifonazole

Study type

No. Patients

Regimen

Efficacy results

Tanuma et al (2000) [53]

Open

Ninety-six cases (48 nonocclusive, over-lapping application; 48 occlusive application)

Bifonazole 1% cream and 10% urea ointment applied once daily within 10 min of bathing (group 1) or cream and ointment applied followed by occlusive dressing (group 2) for 12 wk with observations at 2, 4, 8, and 12 wk

Mycologic eradication rate = group 1: 93.8% (wk 12); group 2: 95.8% (wk 12) Pathogen elimination = group 1: 26.8% (wk 1); 48.7% (wk 4); 85% (wk 8); 90% (wk 12); group 2: 53.7% (wk 2); 82.1% (wk 4); 90% (wk 8); 96.9% (wk 12)

Tanuma and Nishiyama (1997) [15]

Open

Thirty patients (15 bifonazole alone; 15 bifonazole and urea)

Bifonazole 1% solution (group 1) or bifonazole 1% solution and 10% urea ointment (group 2) once daily in the evening for 3 mo

Final rate of ‘‘marked improvement’’ + ‘‘moderate improvement’’= group1: 60.4%; Group2: 83.3% Improvement rate = group1: 9.5% (wk2); 25% (wk4); 55% (wk8); 57.6% (wk12); group2: 33.3% (wk2); 60% (wk4); 75.0% (wk8); 81.3% (wk12) Final overall efficacy rate = group1: 93.8%; group2: 93.8% Clinical improvement (‘‘moderate improvement’’ + ‘‘marked improvement’’) rate = group1: 46.2%; group2: 83.3% Fungal eradication rate = group1: 0% (2 wk); 6.7% (4 wk); 13.3% (8 wk); 40% (12 wk); group2: 13.3% (2 wk); 26.7% (4 wk); 60% (8 wk); 80% (12 wk) Overall efficacy rate = group1: 46.7% (12 wk); group2: 86.7% (12 wk)

Adverse events related to treatment Group 1: no adverse events observed Group 2: 3 adverse events including itching and newly generated small blisters

No adverse reactions reported by patients

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Authors

Double-blind, randomized, placebo-comparison

Fifty-four adults (23 bifonazole; 31 vehicle)

Galimberti et al (1984) [54]

Open, multicentre

Three hundred twentynine patients

Barkes et al (1979) [17]

Open

Forty-two patients

Clotrimazole 1% cream applied twice daily (in the morning and at bedtime) with evaluations at d 7 and d 30

Smith et al (1977) [18]

Double-blind, randomized, controlled

Sixty-six male patients, 30 with interdigital tinea pedis; 36 with hyperkeratotic tinea pedis (33 clotrimazole; 33 vehicle)

Clotrimazole 1% solution applied twice daily for 4 wk (interdigital) or 6 wk (hyperkeratotic), with examinations at 2-wk intervals

One hundred fifty patients (133 clotrimazole solution; 17 clotrimazole cream)

Clotrimazole 1% solution twice daily for 4 to 6 wk or clotrimazole 1% cream twice daily for 4 to 6 wk

Spiekermann and Double blind, Young (1976) [55] randomized, multicenter

Mycologic response = 50% (2 wk); 87% (last visit) Negative culture results = 91% (last visit) Overall response rate = 91% Very good (clinical cure, negative mycology) overall outcome = 84% (2-wk follow-up) Good (clinical improvement, negative mycology) overall outcome = 9.5% (2-wk follow-up) Clinical improvement = 81% (7 d); 87% (30 d) Patients assessment of efficacy as good to excellent = 72% (7 d); 90% (30 d) Final mycologic conversion to negative = interdigital: 73%; hyperkeratotic: 61%; all patients: 67% Final response of excellent (clinical and laboratory cure) = interdigital: 60%; hyperkeratotic: 56%; all patients: 58% Microscopy conversion = solution: 67% (end of treatment); cream: 65% (end of treatment) Culture conversion = solution: 78% (end of treatment); cream: 86% (end of treatment) Clinical improvement = solution: 80% (end of treatment); cream: 76% (end of treatment)

Three patients reported adverse events including mild to moderate burning sensation No side effects observed; excellent tolerance

Five adverse events were reported including itching and burning; however, these events disappeared after 2 to 3d No adverse events reported

Adverse events included irritation, stinging, or burning

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Clotrimazole

Bifonazole 1% solution applied once in the evening for 4 wk, with weekly evaluations and a 2-wk follow-up posttreatment Bifonazole 1% gel once daily, after showering, for 3 wk, with follow-up evaluations 3 d and 2 wk after end of treatment

Smith and Tschen (1987) [16]

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438

Table 2 (continued ) Treatment

Authors

No. Patients

Regimen

Fenticonazole Albanese et al (1992) [56]

Double blind, placebo-controlled, prophylactic

Ketoconazole Lester (1995) [21]

Open-labeled, multicenter

Twenty-seven patients at Fenticonazole 2% powder 2 mo (13 fenticonazole; once daily for 4 mo 14 placebo) 24 patients at 4 mo (12 fenticonazole; 12 placebo) Two hundred thirty-two adults Ketoconazole 2% cream once daily for up to 8 wk, with a 4 wk follow-up

Greer (1987) [20]

Double-blind, Sixty subjects (30 once daily randomized, active use; 30 twice daily use) comparator-controlled

Greer and Jolly (1987) [19]

Double-blind, Sixty-two subjects (evaluated randomized, active during treatment) 60 subjects comparator-controlled (evaluated during follow-up [ie, wk 8])

Ketoconazole 2% cream once daily with placebo cream or twice daily for 4 wk, with a 4 wk follow-up Ketoconazole 2% cream once daily with placebo cream or twice daily for 1 mo, with 4-wk follow-up

Open, randomized, active comparatorcontrolled

Lanoconazole 1% cream (group 1) or 1% lanoconazole cream/10%

Lanoconazole Tanuma et al (2001) [57]

Forty-three patients (20 lanoconazole only; 23 lanoconazole and urea)

Efficacy results

Adverse events related to treatment

Relapse rates = 0% (2 mo); 17% (4 mo)

No adverse events recorded with excellent tolerance

Reduction of mean total symptom scores = 9.5 (baseline); 2.5 (wk4); 1.4 (wk8); 1 (follow-up) – significant differences between all visits Reduction of average infected surface area = 59.1cm2 (baseline); 24.5cm2 (wk4); 21.8cm2 (wk8); 7.6cm2 (follow-up) Marked or excellent improvement to treatment = 63% of patients (4wk); 82% as evaluated by physicians (8wk); 81% as evaluated by patients (8wk) Moderate improvement to treatment = 24% of patients (4wk) Response to treatment = 95% of patients Negative cultures = once daily: 77% (8wk); twice daily: 86% (8wk) Efficacy = once daily: 87% (8wk); twice daily: 87% (8wk) Cure rate = once daily: 63% (4wk); 77% (8wk); twice daily: 60% (4wk); 73% (8wk) Response to treatment = 87% of all patients Clinical improvement rate (% of ‘moderate improvement’) = group 1: 70%; group 2: 95.7%

Three patients reported adverse events, including severe irritation (erythema and pruritus), itchy, blistering eruption, and a mild, stinging sensation

No adverse events reported

Local adverse events reported including itching and burning

No adverse events reported

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Study type

urea ointment (group 2); once daily for 12 wk

Miconazole

Double-blind, randomized

Forty-five men (20 miconazole; 25 placebo)

Brugmans et al (1970) [59]

Double-blind, controlled

Fifty men

Neticonazole Tsuboi et al (1996) [60]

Randomized controlled, multicenter

Ninety-six patients (44 nonocclusive application; 52 occlusive application)

Oxiconazole

Double-blind, randomized, vehicle-controlled, parallel-group, multicentre

Four hundred four patients (136 monotherapy; 134 combo therapy; 134 vehicle)

Elewski et al (1996) [24]

No adverse events reported

No adverse events observed

Non-occlusive: 1 report of pruritus Occlusive: 1 report of contact dermatitis

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Gentles et al (1975) [58]

Fungal eradication rate = Group 1: 5% (4wk), 70% (12 wk); group 2: 43.5% (4 wk), 95.7% (12 wk) Final usefulness rating = group1: 40.7%; group 2: 95.7%; usefulness rates were significantly higher in group 2 (P < .05) than group 1 Mycologic clearance after 4 wk Miconazole 2% cream treatment = 60% (12/20 patients) each evening, and Mycologically clear patients at miconazole 2% powder 4 wk still free of infection at applied each morning and 8 wk (4 wk posttreatment) = after bathing for 4 wk; 58.3% (7/12) negative mycology at 4 wk resulted in continued Clinical clearance = 80% (4 wk) use of powder for additional Absence of symptoms = 70% Beneficial treatment rate = 80% 4 wk Complete cure = 96% Miconazole nitrate 1% (end of treatment) lotion in the morning and Improvement was maintained evening for 6 d in 1 wk, throughout 6-wk follow-up, followed by miconazole with miconazole treatment nitrate 1% powder in the significantly better than vehicle morning and miconazole ( P < .001), than baseline control lotion in the evening for ( P < .001) and very similar to 6 d/wk for 3 wk (ie, total cure at end of treatment (P= .92) of 4 wk treatment), with Mycologically positive results = 6-wk follow-up about 30% (end of treatment) Negative KOH preparation rates = Neticonazole 1% cream nonocclusive: 52% (4 wk); once daily for 4 wk with occlusive: 75% (4 wk) simple application Marked or moderate improvement (nonocclusive) or with in clinical signs = nonocclusive: overnight occlusive 59% (4 wk); occlusive: 81% dressing (4 wk) Mycologic cure = monotherapy: Oxiconazole cream 1% 61.8% (d 28); 65.3% (d 42). applied twice daily for Combo: 61.9% (d 28); 81.5% 4 wk (monotherapy) or (d 42) Overall cure = oxiconazole and monotherapy: 27.4% (d 28); fluticazone propionate

Thirty one adverse events reported, including burning and pruritus 439

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Table 2 (continued ) Treatment

Benzylamine Butenafine

Study type

No. Patients

Akers et al (1989) [27]

Double-blind, randomized, parallel, multicenter

Two hundred twenty-nine patients

Reyes et al (1998) [61]

Double-blind, randomized, placebo-controlled, multicenter

One hundred five patients (53 butenafine; 52 vehicle)

Regimen

Efficacy results

0.05% cream twice daily for 1 wk followed by 3 wk of oxiconazole alone (combo) or vehicle twice daily for 4 wk, with assessments on d 2, 3, 7, 14, 28 (end of treatment), and 24 (posttreatment) Sulconazole nitrate 1% cream twice daily for 4 wk, and if necessary 2 additional wk, with follow-up 2 wk after end of treatment

38.8% (d 42). Combo: 23.8% (d 28); 37.5% (d 42)

Butenafine hydrochloride cream 1% or vehicle applied once daily for 4 wk, with evaluation at 1, 2, and 4 wk and follow-up at 8 wk

Adverse events related to treatment

Mycologic results (negative KOH and culture = 70% (end of treatment) Favorable clinical results = 67% (end of treatment) Clinical and mycologic cure = 59% (end of treatment) Mycologic relapse 2 wk after end of treatment = 18% Clinical relapse 2 wk after end of treatment = 10% Cures maintained 2 wk after end of treatment = 77%

Twelve adverse events reported, including itching, tingling, and burning at treated sites

Mycologic cure = 91% (4 wk); 83% (8 wk) Effective treatment rate = 58% (4 wk); 68% (8 wk) Investigator global assessment of clinical response as good to cleared = 88.7% (4 wk); 84.9% (8 wk) Patient assessment as somewhat to greatly improved since pretreatment = 98.1% (4 wk); 93.4% (8 wk)

One possibly related report of moccasintype tinea pedis on the plantar surface

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Sulconazole

Authors

Terbinafine

Double-blind, randomized, placebo-controlled, parallel-group

Two hundred seventy-one adults (132 butenafine; 139 vehicle)

Butenafine 1% cream or vehicle twice daily application for 7 d Follow-up 42 d

Mycologic/clinical cure = 30 (23%) of 132 Mycologic cure = 98 (74%) of 132

Tschen et al (1997) [62]

Double-blind, randomized, vehicle-controlled, parallel, multicentre

Eighty patients (40 butenafine; 40 vehicle)

Butenafine 1% cream once daily for 4 wk, with evaluations at 1, 2, and 4 wk, and 4 wk after cessation of treatment

Mycologic cure = 40% (1 wk); 88% (4 wk); 88% (8 wk) Median total signs and symptoms score reduction = 11 to 2 (baseline to wk4); 11 to 1 (baseline to wk8) Effective clinical response = 68% (4 wk); 78% (8 wk) Effective treatment = 55% (4 wk); 70% (8 wk) Overall cure = 23% (wk8) ‘‘Somewhat or greatly improved’’ global assessment of clinical response = 97.5% (4 wk); 95% (wk 8)

Naftifine Gel Study Group (1991) [63]

Double-blind, randomized, parallel-group

Study A: 88 patients (42 naftifine; 46 placebo) Study B: 228 patients (117 naftifine; 111 placebo)

Naftifine gel 1% or placebo gel twice daily for 4 wk Follow-up at week 6.

Mycologic cure = study A: 56% naftifine; 16% placebo (P < .001); study B: 73% naftifine; 17% placebo (P < .001)

Korting et al (2001) [64]

Double-blind, placebo-controlled, prospective, parallel-group

Seventy adults (35 terbinafine; 35 vehicle)

Terbinafine 1% cream once daily for 7 d with 7 wk follow-up

Mycologic cure = 91.4% (end of study) Signs and symptoms score = statistically significant

Butenafine: one report of mild burning or stinging Vehicle: reports of burning or tingling, and elevated AST/ALT Adverse event included mild burning sensation

Study A: adverse events included burning, stinging or itching; no withdrawals Study B: adverse events included burning, erythema, irritation, rash, stinging, pain, pruritic vesicles, foul odor, pruritus; two placebos withdrew from study Four recorded adverse events, but none related to the drug

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Allylamine Naftifine

Savin et al (1997) [33]

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442

Table 2 (continued ) Treatment

Authors

Study type

No. Patients

Regimen

Double-blind, randomized, vehicle-controlled, multicenter

One hundred fifty-three individuals > 12 y (104 terbinafine; 49 vehicle)

Terbinafine 1% in a vehicle solution twice daily for 7 d with 7-wk follow-up

Tanuma, et al (2000) [66]

Open

Thirty five patients

Terbinafine 1% cream once daily for 12 wk

Evans et al (1994) [67]

Double-blind, randomized, parallel-group, multicentre

Sixty five adults (18 1-d treatment; 18 3-d treatment; 17 5-d treatment; 12 7-d treatment)

Terbinafine 1% cream applied once daily for 1 d or 3 d or 5 d or 7 d, with assessments at 8, 14, 28, (trial endpoint), and 84 (relapse investigation) d

difference between Terb and vehicle by visit 4 (d 42) Effective treatment = 74.3% (end of treatment) Patient assessment = 75.8% very good or good treatment Investigator assessment = 72.7% very good or good treatment Mycologic testing = 96% negative cultures (1wk) Clinical and mycologic recurrence = 7% Tolerability rate = 97% good or very good tolerability by patients and investigators Improvement rate of symptoms = 17.3% (2wk); 46.5% (4 wk); 69.6% (8 wk); 95.5% (12 wk) Overall fungal eradiation rate = 30.4% (2wk); 30.8% (4wk); 87.0% (8 wk); 95.5% (12 wk) Final overall efficacy evaluation = 88.6% very effective or effective treatment Mycologic cure = 1-d: .78% (d 28); 94% (d 84). 3-d: 83% (d 28); 67% (d 84). 5-d: 82% (d 28); 88% (d 84). 7-d: 83% (d 28); 92% (d 84) Effective treatment = 1-d: 61% (d 28); 61% (d 84). 3-d: 78% (d 28); 67% (d 84). 5-d: 71% (d 28); 88%

Adverse events related to treatment

f15% experienced at least one adverse event, most being mild or not related to the drug

No adverse drug reaction occurred

One adverse event reported, uncertain of its relation to the drug, of pruritus on the back

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Lebwohl et al (2001) [65]

Efficacy results

Double-blind, randomized, placebo-controlled

One hundred ninety-three (97 terbinafine; 96 vehicle)

Terbinafine 1% cream twice daily for 2 wk, with assessments after 1, 2, 4, 6, and 8 wk

Berman et al (1992) [35]

Double-blind, randomized, placebo-controlled, multicentre

One hundred fity-nine adults (80 terbinafine; 79 placebo)

Terbinafine 1% cream twice daily for 1 wk, with evaluations at 2, 4, and 6 wk

Savin (1990) [69]

Double-blind, randomized, placebo-controlled

Twenty-seven adults (13 terbinafine; 14 placebo)

Terbinafine 1% cream twice daily for 4 wk, with 2-wk follow-up

Smith et al (1990) [70]

Double-blind, randomized, placebo-controlled

Twenty adults (10 terbinafine; 10 placebo)

Terbinafine 1% cream twice daily for 4 wk, with 2-wk follow-up

Four cases of local adverse events possible or probably related to treatment, with no discontinuation

No adverse events reported

No adverse events reported

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Savin et al (1994) [68]

(d 84). 7-d: 67% (d 28); 90% (d 84) Mycologic response = 69% (final visit) Clinical response = 69% reduction of composite score (end point) Reduction of moderate to severe disease from 94% to 29% Mycologic response = 51% (1 wk); 88% (6wk) Signs and symptoms = 47% reduction (1wk); 79% reduction (6wk) Overall = severity score decreased from 2.3 (baseline) to 1.6 (1wk) to 0.9 (6wk) Global assessment = 72% cleared or marked improvement (6wk); 78% excellent or good treatment of lesions (6wk) Mycologic efficacy = 44% (1wk); 100% (4wk and 6wk) Clinical efficacy = erythema, desquamation, pruritus, incrustation, vesiculation, and pustules were significantly reduced compared with baseline scores Overall efficacy = Terb was significantly superior than placebo Mycologic efficacy = f40% (3wk); 90% (4wk); 88% (at follow-up) Clinical efficacy = statistical difference was achieved in 3 and 4 wk compared with placebo Overall efficacy = 60% (4 wk); 78% (at follow-up)

No adverse events reported

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Table 2 (continued ) Treatment

Authors

Regimen

Efficacy results

Double-blind, parallel-group, multicenter

One hundred seventy-eight patients enrolled (87 ciclopirox; 67 vehicle)

Ciclopirox olamine 1% lotion twice daily for 28 d, with evaluations on d 15 and 29, and a 2-week posttreatment follow-up (d 43)

Adverse events included two reports of pruritus and one report of burning

Kligman et al (1985) [39]

Double-blind, parallel group, multicentre

One hundred sixty-eight patients (85 ciclopirox olamine; 83 vehicle)

Ciclopirox olamine 1% cream applied twice daily for 4 wk, with weekly evaluations, and follow-up 1 and 2 wk after completion of treatment

Mycologic cure = 86.6% (d 29); 75.6% (d 43) Clinical cure = 23.9% (d 29); 58.2 (d 43) Combined cure (mycologic + clinical) = 23.9% (d 29); 56.1% (d 43) Rate of change of cultures from positive to negative = 48.8% (visit1); 77.6% (visit2); 88.2% (visit3); 89.4% (visit4); 88.5% (visit5); 80.3% (visit6) Mycologic response was significantly better with ciclopirox from visit2 through to the end of study period Total clinical response (cure + improvement) = 82% (visit1); 91% (visit2); 93% (visit3); 93% (visit4); 91% (visit5); 87% (visit6)

Weller et al (1998) [72]

Double-blind, randomized

Thirty five adults (19 acidified nitrite; 16 control)

Mycologic cure = 95% (2 wk); 94.7% (4 wk); 81.3% (6 wk) Combined (clinical + mycologic) cure = 31.6% (6 wk)

Adverse events included superficial staining at treatment site and epididymitis

Gomez et al (1986) [73]

Double-blind, placebo-controlled, parallel

Fourty adults (20 tolcicate; 20 placebo)

Salicylic acid 3% cream and potassium nitrite 3% cream or salicylic acid 3% cream and aqueous cream applied twice daily for 4 wk, with evaluations weekly and a 2-wk follow-up Tolciclate 1% solution applied twice daily until clinical and mycologic cure was obtained or up

Tolcicate

Final global assessment of excellent (clinical cure + negative KOH and culture results) = 45%

No adverse effects observed

One adverse event reported

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No. Patients

Hydroxypyridone Ciclopirox Aly et al (1989) [71]

Other Salicylic acid

Adverse events related to treatment

Study type

to 6 wk treatment with weekly assessments, and a 2-wk follow-up

Smith et al (1974) [43]

Double-blind, prophylactic

One hundred twenty inmates (71 tolnaftate; 49 vehicle)

Tolnaftate 1% powder twice daily for 8 wk, followed by follow-up examinations for 4 successive wk

Undecylenic acid

Chretien et al (1980) [46]

Double-blind, randomized, placebo-controlled

With dermatophyte culture: 43 undecylenic acid; 42 placebo

Undecylenic 2% acid/zinc undecylenate 20% powder versus placebo powder 4 wk treatment Follow-up at wk 6

Smith et al (1977) [74]

Randomized

One hundred two individuals (27 group1; 30 group2; 21 group3; 22 group4)

Aly et al (1994) [75]

Open, placebocontrolled, induced infection study

Sixteen adults, with a total of 58 lesions (each subject acted as one’s own control; 28 grise; 30 placebo)

Zinc undecylenate 20% and undecylenic acid 2% powder (group 1) or overthe-counter undecylenic acid powder (group 2) or talc vehicle (group 3) applied feet and insides of socks for 6 wk or no treatment (group 4) during study period 0.15 mL of 1% griseofulvin twice daily for 14 d

Griseofulvin

Mycologically negative lesion = 89% (2 wk)

No adverse events reported

No adverse reactions noted in any patients

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Tolnaftate

Negative KOH preparation rate = 60% (end of treatment); 50% (follow-up) Negative fungal culture rate = 100% (end of treatment); 50% (follow-up) Number of ‘‘normal’’ (normal clinical examination and negative laboratory results) subjects at end of treatment = 23/28 (82.1%) Tolnaftate was superior (P< .01) to vehicle and no treatment Negative fungal culture = undecylenic: 20/23 (87%); vehicle: 5/22 (23%); P < .001 Negative KOH = undecylenic: 77%; vehicle: 48% (P= .004) Significant reduction of itching, burning and sweating versus placebo (P < .001; P= .026, P= .031, respectively) Clinical and mycologic clearance = group1: 59.3% (6 wk); group2: 46.7% (6 wk); group3: 4.3% (6 wk); group4: 9.1% (6 wk)

No adverse events reported

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Treatment

Authors

Study type

No. Patients

Regimen

Efficacy results

Aly et al (1994) [75]

Double-blind, randomized

One hundred adults at start (50 griseofulvin; 50 placebo); 98 adults at 4 wk (48 griseofulvin; 50 placebo); 94 adults at 6 wk (47 griseofulvin; 47 placebo)

0.15 mL of 1% griseofulvin one daily for 28 d, with a 2-wk posttreatment visit

Mycologically negative results = 79.2% (4 wk); 80.9% (6 wk) Global evaluations of moderate to clear results = 62.5% (4 wk); 78.7% (6 wk)

Adverse events related to treatment Most common adverse events included mild burning or sting and severe local irritation, all of which were transitory and only at the time of application

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Table 2 (continued )

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447

trial, and three open trials demonstrate the efficacy of bifonazole (see Table 2).

trial have shown the efficacy of miconazole in tinea pedis (see Tables 2 and 4).

Clotrimazole Clotrimazole is a chlorinated tritylimidazole, with a wide range of activity against dermatophytes and Candida albicans. It can be fungicidal against dermatophytes and yeasts at a very low concentration [17]. Although clotrimazole has been an effective treatment of tinea pedis [17], it has also been particularly useful in treating tinea cruris, because of its high efficacy against dermatophytes found in the crural folds [18]. Thirteen double-blind trials, 12 randomized trials, 1 parallel trial, 1 randomized trial, and 1 open trial have demonstrated the efficacy of clotrimazole for tinea pedis (see Tables 2 to 4).

Oxiconazole Oxiconazole nitrate is an imidazole antifungal, available as a lotion and cream, which has been found effective in the treatment of tinea pedis, tinea corporis, and tinea cruris. Oxiconazole cream is usually administered once or twice daily [24]. Elewski et al [24] demonstrated that oxiconazole has an anti-inflammatory effect; moreover, this imidazole does not have the potential risk factors associated with steroid use, like skin atrophy. Two double-blind, randomized trials demonstrated the efficacy of oxiconazole in tinea pedis (see Tables 2 and 4).

Ketoconazole Ketoconazole was one of the first broad-spectrum oral imidazoles to be introduced, in 1981, with the distinguishing features of dioxolane and piperazine ring constituent [19]. The use of oral ketoconazole was encouraging; however, the possibility of the development of hepatotoxicity has reduced the oral use of this imidazole [20], especially in instances where treatment for a long duration is required. Topical 2% ketoconazole cream has demonstrated a broad-spectrum of antifungal activity, particularly against Trichophyton, Microsporum, and Epidermophyton species [19,21]. Because of its preferential binding to keratinocytes, it has been suggested that ketoconazole treatment could result in more effective and longer-lasting levels of drug in the stratum corneum, where a once-daily application regimen allows for good cure rates and higher patient compliance [19]. Four double-blind trials and one openlabeled trial have been performed to show the efficacy of ketoconazole in tinea pedis (see Tables 2 to 4).

Miconazole Miconazole nitrate, an imidazole, has a broad spectrum of antifungal and antibacterial activity [22]. Because moisture is one of the key factors for the cause of tinea pedis, spray powders may be effective in preventing further development of the dermatophytosis. Miconazole nitrate 1% has demonstrated a long-lasting drying effect, persisting as long as 6 to 8 hours after the initial spray, indicating hygroscopic properties, where the powder was capable of capturing the excess moisture found in the stratum corneum [23]. Four double-blind trials, two of which were randomized trials, and one single-blind

Sulconazole Sulconazole is an imidazole derivative, with a broad-spectrum in vitro activity against dermatophytes and yeasts, and some gram-positive bacteria, including Staphylococcus aureus, S epidermidis, and Streptococcus faecalis [25]. Sulconazole nitrate 1% cream has displayed similar efficacy to miconazole nitrate 2% cream [26]. A clinical study involving more than 1000 patients demonstrated that sulconazole nitrate 1% cream resulted in no systemic adverse reactions, with mainly transient and mild irritation [26]. A double-blind, randomized trial by Akers et al [27] also supports this observation (see Table 2). Triazoles Fluconazole Fluconazole is an orally administered triazole antifungal agent with potent antifungal activity against cutaneous filamentous fungi, like Microsporum and Trichophyton species [28]. The main mechanism of action is the inhibition of ergosterol synthesis in fungal cell membranes. Fluconazole is highly selective for fungal cells; its affinity for animal and human cytochrome P-450 is very low in comparison with fungal P-450. Fluconazole persists in the skin following completion of therapy and may remain effective for about a month after the last treatment applied [28]. One open-labeled and one open randomized trial demonstrated the efficacy of fluconazole as a treatment of tinea pedis. Fluconazole is not approved by the Food and Drug Administration (FDA) for the treatment of tinea pedis (see Table 1). Itraconazole Itraconazole is an oral antifungal agent, with a broad spectrum of activity against a variety of fungi.

448

Table 3 Efficacy of various comparative oral treatment regimens for tinea pedis Comparative treatment

Terbinafine versus Itraconazole

Study type

Savin (1990) [76]

Savin (1989) [77]

Tausch et al (1998) [78]

No. patients

Regimen 1

Regimen 2

Regimen 1

Twenty eight adults Double-blind, randomized 2-wk (16 terbinafine; 12 griseofulvin) follow-up and 6 – 15 mo telephone questionnaire

Terbinafine, 125mg twice daily for 6 wk

Griseofulvin, 250mg twice daily for 6 wk

Double-blind, randomized, parallel-group 2-wk follow-up, and 6 – 15 month relapse survey

Twenty eight adults (16 terbinafine; 12 griseofulvin)

Terbinafine, 125mg twice daily for 6 wk

Griseofulvin, 250mg twice daily for 6 wk

Effective treatment = 75% (6wk); 88%(8wk) Sustained clearing after 6 – 15mo = 94% two minor reports of adverse events, including frequent stools, and itching and urticaria Mycologic clearing = 94% (6wk); 100% (8wk) Effectively cleared = 88% (8wk) Adverse events included itching of hands and urticaria (moderate severity), and frequent stools (mild severity)

Double-blind, randomized, multicentre, phase III; assessment up to total of 6 wk

Three hundred four Terbinafine, patients (151 terbinafine; 250mg once 153 itraconazole) daily for 14 d

Itraconazole, 200mg twice daily for 7 d followed by placebo for 7 d

Regimen 2

Effective treatment = 27% (6wk); 45% (8wk) Sustained clearing after 6 – 15mo = 30% four reports of adverse events, including amenorrhea, polymenorrhea, diarrhea, and indigestion Mycologic clearing = 27% (wk); 55% (8wk) Effectively cleared = 45% (8wk) Adverse events included amenorrhoea (severe severity), polymenorrhoea (moderate severity), and diarrhoea and indigestion (mild severity) Mycologic cure = 79% Mycologic cure = 80% (6 wk) (6 wk) Healed or markedly Healed or markedly improved clinical improved clinical response = 91% (6wk) response = 93% (6wk) Very good or good Very good or good tolerability = 97% (2wk) tolerability = 97% (2wk) Twenty eight patients Twenty one patients reported adverse events reported adverse events during treatment, including during treatment, including headache, abdominal pain, headache, abdominal pain, nausea, vomiting, and nausea, vomiting, and hypertrigliceridemia hypertrigliceridemia

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Terbinafine versus Griseofulvin

Efficacy results / adverse events Authors

Hay et al (1995) [79]

Double-blind, randomized, parallel-group, double-dummy; assessments up to total 16 wk

Terbinafine, 250mg daily for 2 wk

Itraconazole, 100mg once daily for 4 wk

Mycologic cure = 40% (4 wk); 75% (8wk); 78% (16 wk) Effective treatment = 69% (8wk); 71% (16wk) Fifty-two adverse events reported, including gastrointestinal disorders and headaches

De Keyser et al Double-blind, (1994) [80] randomized, parallel-group, multicentre; follow-up at wk 8

One hundred seventeen adults (51 terbinafine; 66 itraconazole)

Terbinafine, 250mg once daily for 2 wk

Itraconazole, 100mg once daily for 2 wk

Kim and Yoon (1993) [81]

Forty-four adults (22 terbinafine; 22 itraconazole)

Terbinafine, 250mg once daily for 2 wk followed by placebo for 2 wk

Itraconazole, 100mg once daily for 4 wk

Very good or good tolerability = over 95% Negative mycology = 27.5% (2wk-end of treatment); 86.3% (8wk) Absent or minimal symptoms = 94.1% (8wk) Twenty-three adverse events reported in 18 patients, including gastrointestinal complaints Mycologic cure = 22.7% (wk2); 63.6% (wk4) Two adverse events reported in one patient, including nausea and abdominal distension, which were of mild severity

Single-blind, randomized

Mycologic cure = 33% (4 wk); 73% (8wk); 69% (16 wk) Effective treatment = 67% (8wk); 55% (16wk) Forty-six adverse events reported, including gastrointestinal disorders, headaches, stomach pain, and vomiting Very good or good tolerability = over 95% Negative mycology = 28.8% (2wk-end of treatment); 54.5% (8wk) Absent or minimal symptoms = 72.7% (8wk) Ten adverse events reported in 10 patients, including gastrointestinal complaints Mycologic cure = 18.1% (wk2); 68.1% (wk4) Two adverse events reported, including nausea, abdominal distention, and indigestion, which were of mild severity

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One hundred twentynine adults (65 terbinafine; 64 itraconazole)

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450

Comparative treatment

Efficacy results / adverse events Authors

Study type

No. patients

Regimen 1

Regimen 2

Regimen 1

Regimen 2

Voravutinon (1993) [82]

Double-blind, randomized; follow-up up to 8 wk

Fourty-nine patients (23 terbinafine; 26 itraconazole)

Terbinafine, 250mg once daily for 2 wk

Itraconazole, 100mg once daily for 4 wk

Won et al (1993) [83]

Single-blind, randomized

Sixty adults (30 terbinafine; 30 itraconazole)

Terbinafine, 250mg Itraconazole, once daily for 2 wk 100mg once followed by placebo daily for 4 wk for 2 wk

Mycologic cure = 48% (4wk); 82.6% (8wk) Two adverse events possibly related to treatment included nausea and malaise, which were mild and transient Mean clinical severity reduction = 1.23 F 0.85 to 0.27 F 0.34 (4 wk) Two adverse events reported in six patients, including symptomless transient elevation of liver enzymes and mild gastric discomfort

Mycologic cure = 27% (4wk); 80.8% (8wk) Three adverse events possibly related to treatment included nausea and headache, which were mild and transient Mean clinical severity reduction = 1.46 F 0.85 to 0.36 F 0.39 (4 wk) Mild gastric discomfort reported in eight patients

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Table 3 (continued )

Terbinafine versus Clotrimazole

Barnetson et al (1998) [84]

Double-blind, randomized, parallel-group, double-dummy; assessment up to wk 12

One hundred thirty seven patients > 16y (63 terbinafine; 74 clotrimazole cream)

Terbinafine, 250mg for 1 wk

Double-blind, randomized for total 12 wk

Twenty-nine patients (14 griseofulvin; 15 ketoconazole)

Griseofulvin, 200mg once daily 4 wk, and up to 8 wk

Griseofulvin versus Clotrimazole

Double-blind, randomized for a total 6 mo

Seventy-three plantar or intertriginous tinea pedis plantar: 16 griseofulvin; 16 clotrimazole inter: 14 griseofulvin; 15 clotrimazole

Griseofulvin, 125mg four times daily and placebo cream twice daily for 3 mo

Zaias et al (1978) [12]

Mycologic cure = 72% (wk4); No statistical significance between treatments (wk12)

Clinical signs and symptoms = rapid improvement, but no statistical difference between the treatments (wks1, 4, 12) Ketoconazole, Mycologic cure = 200mg once 21% (wk2); 29% (wk4); daily for 4 wk, 57% (wk8) and up to 8 wk Adverse events not given Clotrimazole, Complete clinical 1% cream twice clearing and negative daily and placebo mycology = Plantar: tablet four times 93.8% (3mo); daily for 3 mo 68.6% (6mo). Inter: 78.6% (3mo); 42.9% (6mo) Adverse events not given

Mycologic cure = 71% (wk4); No serious adverse events related to treatments (also in terb group)

Mycologic cure = 20% (wk2); 33% (wk4); 53% (wk8) Adverse events not given Complete clinical clearing and negative mycology = plantar: 31.3% (3mo); 18.8% (6mo). Inter: 46.7% (3mo); 20.0% (6mo) Adverse events not given

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Griseofulvin Roberts et al versus (1987) [42] Ketoconazole

Clotrimazole, 1% cream twice daily for 4 wk

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452

Table 4 Efficacy of various comparative topical treatment regimens for tinea pedis Comparative treatment

Efficacy results / adverse events Authors

No. patients

Regimen 1

Itraconazole Patel et al versus (1999) [85] Clotrimazole

Double-blind, randomized, parallel-group, multicentre, prospective Assessment up to 12 wk

Two hundred eleven adults (105 terbinafine; 106 clotrimazole)

Schopf et al (1999) [86]

Randomized, multicentre; Evaluations up to 8 wk

Four hundred twenty nine patients > 12 y (217 terbinafine; 212 clotrimazole)

Elewski et al (1995) [87] (Follow-up of Bergstresser et al 1993 [88])

Double-blind, randomized, multicentre, comparative Assessment 12 to 15 mo

Ninety-three of the mycologically cured patients

Mycologic cure = 55.8% (wk1) Efficacy of treatment = 75% – 80% rated very good or good by both subjects and investigators Relapse rate = 19% Fourteen adverse events considered related to treatment, including burning, hypersensitivity, stinging and exacerbation of pruritus, headache, cellulitis, and insomnia Efficacy of treatment = 91% Terbinafine 1% Clotrimazole 1% Efficacy of treatment = 92% Combined mycologic and Combined mycologic and solution twice daily solution twice clinical = 82% clinical = 83% for 1 wk, followed daily of 4 wk Fifteen adverse events by 3 wk of vehicle Seventeen adverse events recorded in 13 patients possi- recorded in 11 patients possibly, probably or bly, probably or definitely drug related, most being mild definitely drug related, or moderate severity, including most being mild or moderate severity, including burning, burning, scaling, erythema, scaling, erythema, new new lesions, itching, and lesions, and itching maceration No further antifungal No further antifungal Follow-up to Follow-up to treatment for at least a treatment for at least a terbinafine 1% clotrimazole year = 1-wk treatment: 1% cream twice year = 1-wk treatment: cream twice 23%; 4-wk treatment: 31% 42%; 4-wk treatment: 47% daily for 1 wk daily for 1 wk or Adverse events not given Adverse events not given or 4 wk 4 wk Terbinafine 1% cream twice daily for 1 wk, followed by 3 wk of placebo

Regimen 2 Clotrimazole 1% cream applied twice daily for 4wk

Regimen 1 Mycologic cure = 84.6% (wk1) Efficacy of treatment = 75% – 80% rated very good or good by both subjects and investigators Relapse rate = 15% Fourteen adverse events considered related to treatment, including burning, hypersensitivity, stinging, and exacerbation of pruritus

Regimen 2

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Study type

Clotrimazole 1% cream twice daily for 1 wk or 4 wk

Evans et al (1993; Double-blind, also reported in parallel group, 1994) [89,90] multicentre Two week follow-up

Two hundred eleven patients > 12y (107 terbinafine; 104 clotrimazole)

Terbinafine 1% cream once daily for 1 wk, followed by 3 wk of placebo

Clotrimazole 1% cream twice daily for 4 wk

Terbinafine versus Ajoene

Ledezma et al (2000) [91]

Forty seven soldiers (14 ajoene 0.6%; 15 ajoene 1%; 18 terbinafine)

Terbinafine 1% twice daily for 1 wk

Ajoene 0.6% or ajoene 1% twice daily for one wk

Double-blind, randomized, multicentre, comparative Assessments up to 12 wk

Double-blind, randomized, comparative Follow-up at 30 and 60 d after treatment

Mycologic response = 81% (1-wk treatment-end point); 85% (4-wk treatment-end point) Relapse/reinfection = 9.3% (1-wk treatment-wk12); 11.4% (4-wk treatment-wk12) Signs and symptoms = 83% (completely absent or mild after 1-wk treatment); 91% (completely absent or mild after 4-wk treatment) Adverse events not given Mycologic cure = over 70% (2 wk); 94% (4 wk-end of treatment); 97% (6wk) Effective treatment = 90% (4 wk and 6 wk) Four adverse events including painful stinging and cracks, increased itching, irritation of eyes and erythema or swelling of skin Mycologic cure = 88% (30 d); 94% (60 d) Differences observed between treatment groups were not statistically significant No adverse events observed

Mycologic response = 30% (1-wk treatment-end point); 68% (4-wk treatment-end point) Relapse/reinfection = 47% (1-wk treatment-wk12); 30% (4wk treatment-wk12) Signs and symptoms = 56% (completely absent or mild after 1-wk treatment); 78% (completely absent or mild after 4-wk treatment) Adverse events not given Mycologic cure = over 54% (2 wk); 73% (4 wk-end of treatment); 84% (6wk) Effective treatment = 59% (4 wk and 6 wk) Three adverse events probably or certainly related to treatment included erythema, soreness, and a red rash

Mycologic cure = 0.6% ajoene: 60% (30 d); 72% (60 d). 1% ajoene: 100% (30 d); 100% (60 d) Differences observed between treatment groups were not statistically significant Five patients reported slight burning sensation

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One hundred ninety- Terbinafine 1% three adults cream twice daily for 1 wk or 4 wk

Bergstresser et al (1993) [88]

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454

Table 4 (continued ) Comparative treatment Clotrimazole versus Naftifine

Efficacy results / adverse events Study type

Smith et al (1992) [92]

One hundred Double-blind, randomized, seventy-six adults multicentre (87 naftifine; Evaluated weeks 1, 89 clotrimazole2, and 4 with betamethasone dipropionate) follow-ups at wk 6 and 8

No. patients

Regimen 1

Regimen 2

Regimen 1

Regimen 2

Clotrimazole 1% with betamethasone dipropionate 0.05% cream combination twice daily for 4 wk

Naftifine 1% cream applied twice daily for 4 wk

Cure rates (negative microscopy and culture = 24% (wk 1); 36% (wk 2); 50% (wk 4); 45% (wk 8) Negative fungal cultures = 39% (wk 1); 54% (wk 2; 70% (wk 4); 55% (wk 6); 55% (wk 8) Relapse rates = 36% (wk 6); 29% (wk 8) Five patients reported adverse events, including fissuring, erythema, burning, edema, pruritus Mycologic cure rate = 0% (wk 2); 18% (wk 4); 38% (wk 6) Global improvement rate = 23% (wk 2); 57% (wk 4); 71% (wk 6) Adverse events included tingling Treatment success rate (mycologic cure and no/mild signs and symptoms) = 32% (wk 2); 51% (wk 4); 58% (wk 6) Significant differences between clotrimazole and naftifine treatment in resolution of signs and symptoms

Cure rates (negative microscopy and culture = 33% (wk 1); 43% (wk 2); 68% (wk 4); 73% (wk 8) Negative fungal cultures = 60% (wk 1); 79% (wk 2; 97% (wk 4); 92% (wk 6); 92% (wk 8) Relapse rates = 7% (wk 6); 9% (wk 8) Two patients reported adverse events, including erythema, eczematous eruptions, and burning Mycologic cure rate = 0% (wk 2); 26% (wk 4); 39% (wk 6) Global improvement rate = 39% (wk 2); 74% (wk 4); 93% (wk 6) Adverse events included erythema and itching Treatment success rate (mycologic cure and no/mild signs and symptoms) = once daily: 33% (wk 2); 60% (wk 4); 66% (wk 6). Twice daily: 27% (wk 2); 67% (wk 4); 81% (wk 6) No significant differences between once daily and twice daily application in resolution of signs and symptoms

Naftifine Double-blind, Podiatric Study randomized, Group (1990) [93] parallel Examinations at wk 2, 4 and 6

Fifty seven patients > 12y (30 naftifine; 27 clotrimazole)

Clotrimazole cream 1% twice daily for 4 to 6 wk

Naftifine cream 1% twice daily for 4 to 6 wk

Smith et al (1990) [94]

Two hundred ten patients > 14y (89 naftifine once daily; 50 naftifine twice daily; 71 clotrimazole)

Clotrimazole 1% cream twice daily for 4 wk

Naftifine 1% cream once or twice daily for 4 wk

Double-blind, randomized, multicentre Examinations at weeks 2 and 4, with follow-up at 6 wk

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Authors

Three patients reported adverse events, including vesicular flare Double-blind, randomized Investigations at 14, 28, and 56 d

One hundred eight patients (54 clotrimazole; 54 ketoconazole)

Clotrimazole 1% cream once daily for 28 d

Ketoconazole 2% cream twice daily for 28 d

Cure or improvement response rates = 62% (28 d; 66% (56 d) Overall cure (mycologic response and negative signs and symptoms) = 2% (d 14); 38% (d 24); 48% (d 56) Relapse or reinfection at or before d 56 = 38% Mycologic response = 53.1% (d 14); 76% (d 28); 83.7% (d 56) Clinical cure = 2% (d 14); 26% (d 28); 56% (d 56) Adverse events including burning

Clotrimazole versus Ciclopirox

Double-blind, randomized, parallel, multicentre Evaluations weekly with follow-up at wk 5 and 7

Eighty seven patients (43 ciclopirox olamine; 44 clotrimazole)

Clotrimazole 1% cream twice daily for 4 wk

Ciclopirox olamine 1% cream twice daily for 4 wk

KOH conversion to negative = 29% (wk 1); 55% (wk 2); 59% (wk 3); 80% (wk 4); 81% (wk 5); 73% (wk 7) Culture conversion to negative: 55% (wk 1); 70% (wk 2); 77% (wk 3); 84% (wk 4); 84% (wk 5); 78% (wk 7) Clinical cure = 0% (wk 1); 2% (wk 2); 18% (wk 3); 41% (wk 4); 43% (wk 5); 46% (wk 7)

Kligman et al (1985) [39]

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Clotrimazole Suschka et al versus (2002) [95] Ketoconazole

Four patients reported adverse events, including blistering, scaling, and contact dermatitis Cure or improvement response rates = 64% (28 d; 60% (56 d) Overall cure (mycologic response and negative signs and symptoms) = 4% (d 14); 40% (d 24); 46% (d 56) Relapse or reinfection at or before d 56 = 30% Mycologic response = 52.1% (d 14); 79.2% (d 28); 76.9% (d 56) Clinical cure = 6% (d 14); 42 (d 28); 64% (d 56) Adverse events including burning, redness, scaling and unspecified pain in both big toes KOH conversion to negative = 33% (wk 1); 58% (wk 2); 79% (wk 3); 84% (wk 4); 85% (wk 5); 79% (wk 7) Culture conversion to negative: 56% (wk 1); 79% (wk 2); 88% (wk 3); 91% (wk 4); 91% (wk 5); 88% (wk 7) Clinical cure = 2% (wk 1); 26% (wk 2); 49% (wk 3); 60% (wk 4); 76% (wk 5); 70% (wk 7)

456

Table 4 (continued ) Comparative treatment

Miconazole versus Tolnaftate

Study type

No. patients

Regimen 1

Fuerst et al (1980) [45]

Double-blind, randomized, parallel group Follow-up at wk 6

One hundred three men (38 undecylenic; 32 tolnaftate; 33 placebo)

Undecylenic acid ointment twice daily for 4 wk

Tschen et al (1979) [44]

Double-blind, randomized, controlled Evaluations weekly for 4 wk

Ninety subjects (30 undecylenic; 30 tolnaftate; 30 placebo)

Undecylenic acid ointment twice daily for 4 wk

Shellow (1982) [22]

Double-blind, randomized Evaluations at d 14 and 28, with follow-up at d 56 Double-blind Assessments on d 14 and 28 with follow-up 4 and 6 wk after therapy

Forty-six adults (22 miconazole; 24 tolnaftate)

Miconazole nitrate 2% aerosol twice daily for 4 wk

Thirty patients with 60 test sites (20 miconazole; 20 placebo; 20 tolnaftate)

Miconazole nitrate 2% cream twice daily for 28 d

Ongley (1978) [96]

Regimen 2

Regimen 1

Total clinical response (cure + improvement) = 71% (wk 1); 82% (wk 2); 91% (wk 3); 91% (wk 4); 86% (wk 5); 84% (wk 7) No adverse events observed Tolnaftate Negative KOH = 65.6% 1% cream Negative culture = 68.7% No significant difference between drugs, or drugs and placebo, but undecylenic acid was significantly cheaper Tolnaftate cream Evaluations of good to twice daily for excellent (clinically 4 wk improved, with negative mycologic result to clinically and mycologically cured) results = 90% (4 wk) No adverse events noted Tolnaftate 1% Overall clinical partial to aerosol twice excellent response = 95.4% daily for 4 wk Negative KOH by d 28 = 95.4% Adverse events included transient stinging Tolnaftate 1% Clinical improvement = cream twice 95% (d 14) daily for 28 d Free of infection = 95% (d 28); 95% (6 wk follow-up) No adverse events reported

Regimen 2 Total clinical response (cure + improvement) = 93% (wk 1); 98% (wk 2); 98% (wk 3); 98% (wk 4); 94% (wk 5); 91% (wk 7) No adverse events observed Negative KOH = 59.2% Negative culture = 66.6% No adverse events reported

Evaluations of good to excellent (clinically improved, with negative mycologic result to clinically and mycologically cured) results = 70% (4 wk) No adverse events noted Overall clinical partial to excellent response = 83.3% Negative KOH by d 28 = 58.3% Adverse events included transient stinging Clinical improvement = 100% (d 14) Free of infection = 75% (d 28); 65% (6 wk follow-up) No adverse events reported

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Undecylenic acid versus Tolnaftate

Efficacy results / adverse events Authors

Miconazole versus Bifonazole

Roberts et al (1985) [97]

Terbinafine versus Naftifine versus Oxiconazole

Author

Study type

Ablon et al (1996) [98]

Double-blind, randomized Examinations at week2, 6, and 10

Thirty-one patients (16 miconazole; 15 bifonazole)

No. Patients Ninety men

Miconazole 2% cream twice daily for 3 wk

Bifonazole 1% Clinical improvement = cream once daily weeping: 67% (3 wk); for 3 wk 67% (6 wk). Itching: 88% (3 wks); 80% (6 wk). Burning: 91% (3 wk); 91% (6 wk). Peeling: 47% (3 wk); 50% (6 wk). Maceration: 62% (3 wk); 60% (6 wk). Fissures: 33% (3 wk); 65% (6 wk) Mycologic cure rates = microscopy: 69% (3 wk); 67% (6 wk). Culture: 73% (3 wk); 64% (6 wk) No adverse events experienced

Clinical improvement = weeping: 67% (3 wk); 67% (6 wk). Itching: 80% (3 wk); 77% (6 wk). Burning: 71% (3 wk); 100% (6 wk). Peeling: 53% (3 wk); 69% (6 wk). Maceration: 73% (3 wk); 77% (6 wk). Fissures: 43% (3 wk); 50% (6 wk) Mycologic cure rates = microscopy: 73% (3 wk); 71% (6 wk). Culture: 73% (3 wk); 71% (6 wk) No adverse events experienced

Efficacy results / adverse events Regimen 1

Regimen 2

Regimen 3

Regimen 1

Regimen 2

Regimen 3

Terbinafine cream once daily for 2 wk

Naftifine gel once daily for 2 wk

Oxiconazole lotion once daily for 2 wk

Clinical cure rate = 42.4% (wk 2); 84.8% (wk 6); 83.8% (wk10) Mycologic cure rate = 33.3% (wk 2); 84.8% (wk 6); 80.6% (wk 10) No adverse events reported

Clinical cure rate = 27.6% (wk 2); 69% (wk 6); 75% (wk10) Mycologic cure rate = 34.5% (wk 2); 69% (wk 6); 75% (wk 10) No adverse events reported

Clinical cure rate = 17.9% (wk 2); 32.1% (wk 6); 30.8% (wk10) Mycologic cure rate = 21.4% (wk 2); 32.1% (wk 6); 26.9% (wk 10) No adverse events reported

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Comparative treatment

Single-blind, randomized Assessment at wk 2, 3 and 6

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It has a high affinity for keratinized tissues, and is found in the stratum corneum for up to 4 weeks following the discontinuation of treatment [29]. Itraconazole is secreted mainly through the sebaceous glands, and to a lesser extent the sweat glands. The palms of hands and soles of feet do not have any sebaceous excretion, and only limited sweat excretion [30]. Because of the persistence of itraconazole in the keratinized layers of the soles and palms, shorter treatment periods are a viable option. It has been suggested that itraconazole, 400 mg/d administered for 7 days, may be effective, with benefits including increased patient compliance and decreased incidence of adverse events [31,32]. Six double-blind randomized trials, two single-blind randomized trials, and two open trials demonstrated that itraconazole is effective in the treatment of tinea pedis. Itraconazole is not FDA approved for this indication (see Tables 1, 3 and 4). Benzylamine Butenafine Butenafine hydrochloride is a benzylamine derivative, with a similar structure and action to the allylamines. The main mechanism of action is the prevention of ergosterol synthesis by inhibition of squalene epoxidase. Butenafine can have fungicidal activity [33]. The agent remains in the skin for at least several days after the final dose, which is beneficial in avoiding relapse or recurrence [33]. Three doubleblind, randomized trials demonstrated the efficacy of butenafine in tinea pedis (see Table 1).

administered orally, terbinafine has been detected in tissues 2 to 4 weeks after the treatment period has been completed [36,37]. This makes terbinafine ideal for short-term treatments, and may increase patient compliance. Often tinea pedis may be recurrent; a short treatment period with rapid clinical efficacy may provide a more appealing therapy compared with longer treatment regimens. Nine doubleblind trials, eight of which were randomized, two single-blind randomized trials, one open trial, and one open-labeled trial demonstrated the efficacy of oral terbinafine (see Tables 1 and 3). Nine double-blind trials, eight of which were randomized, and one open trial showed that topical terbinafine is effective in tinea pedis (see Tables 2 and 4). Hydroxypyridone Ciclopirox Ciclopirox olamine is a broad-spectrum nonimidazole (hydroxypyridone), with both fungistatic and fungicidal activity [38]. It has been shown to be effective in treating tinea pedis [39]. Three doubleblind trials, one randomized trial, and two parallel group trials have shown that ciclopirox is effective in tinea pedis (see Tables 2 and 4). Other

Naftifine Naftifine is an allylamine derivative, which inhibits squalene epoxidase. It has potent fungistatic and fungicidal activity against dermatophytes; however, its in vitro activity against Candida spp and other yeasts is poor [34]. Despite a couple of reports of allergic contact dermatitis, few local adverse events and no systemic adverse effects have been reported [34]. Five double-blind, randomized trials demonstrate the efficacy of naftifine for the treatment of tinea pedis (see Tables 2 and 4).

Griseofulvin Griseofulvin is one of the more traditional oral treatments for fungal infections, having first been used in the 1960s [12,40,41]. Newer antifungals, however, have demonstrated greater efficacy than griseofulvin. Roberts et al [42] suggested that griseofulvin may be ‘‘washed out’’ of the skin by excessive perspiration, and adheres poorly to keratin; this may explain poor efficacy results. Griseofulvin is effective only against dermatophyte infections, which limits treatment use. Persistent interdigital infections, especially those involving hyperhidrosis and T mentagrophytes, have resulted in treatment failures with griseofulvin [42]. One double-blind randomized trial and one open trial reported the efficacy of topical griseofulvin (see Table 2), and four double-blind randomized trials reported efficacy of oral griseofulvin in the treatment of tinea pedis (see Table 3).

Terbinafine Terbinafine is an allylamine with fungicidal activity against dermatophytes, molds, and certain dimorphic fungi [35]. It is available both as a topical and oral formulation. Terbinafine given orally is not FDA approved for the treatment of tinea pedis. When

Tolnaftate Tolnaftate was discovered in Japan in 1962 [43]; it was introduced to North America in 1964 [44]. Tolnaftate has been a common over-the-counter topical medication for tinea pedis. It is active in vitro against dermatophytes, including T rubrum and

Allylamines

A.K. Gupta et al / Dermatol Clin 21 (2003) 431–462

T mentagrophytes; however, it is not effective against Candida spp. and bacteria [45]. Five double-blind trials, three of which were randomized, have demonstrated the effectiveness of tolnaftate in tinea pedis (see Tables 2 and 4). Undecylenic acids and salts Undecylenic acids and salts were first studied in the 1940s, during World War II, where they were used as both a treatment and prophylaxis [46]. They are fatty acid derivatives, with antifungal activity and moderate antibacterial activity [45]. Undecylenic acid has been an inexpensive over-the-counter treatment for tinea pedis. Three double-blind randomized trials and one prospective randomized trial have evaluated the effectiveness of undecylenic acid and salt in tinea pedis (see Tables 2 and 4).

[6]

[7]

[8] [9]

[10]

Summary

[11]

The severity of tinea pedis infection determines the course of treatment required. Mild infections may be resolved using a topical agent. More severe presentations (eg, dermatophytosis complex) may require treatment that eliminates the bacterial and fungal infection. Some topical monotherapies may exhibit both antifungal and antibacterial activity. In other instances, it may be necessary to combine an antifungal agent with an antibacterial agent. If inflammation is present, an agent with known anti-inflammatory action may need to be used. The chronic presentation of tinea pedis (dry type) sometimes does not respond well to topical therapy. In such instances, systemic antifungal therapy is required to ensure that adequate concentrations of the therapeutic agent are present at the site of infection.

[12]

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The diagnosis of onychomycosis James M. Mahoney, DPMa,*, John Bennet, DPMa, Benjy Olsen, DPMb a

Foot and Ankle Institute, College of Podiatric Medicine, Des Moines University, 3200 Grand Avenue, Des Moines, IA 50312, USA b College of Podiatric Medicine, Des Moines University, 3200 Grand Avenue, Des Moines, IA 50312, USA

Onychomycosis is not an uncommon diagnosis; with an increasing number of individuals being treated for these fungal infections clinicians must be aware of the clinical presentation, the causative organisms, and the different treatment modalities available. An important aspect of the management of onychomycosis is proper diagnosis.

Epidemiology In a study of 1038 patients visiting a dermatologist in Ohio, with complaints other than onychomycosis, it was found that 24.3% had dystrophic nails [1]. Assuming that this is representative of the general public, the author concluded that the prevalence of dermatophyte onychomycosis in the United States was 8.7% [1]. In another study, 15,000 patients were evaluated in four different clinics in Ontario, Canada [2]. Approximately 17% of the patients had abnormalappearing nails, and 8% had mycologic evidence of onychomycosis [2]. It was found that 90.5% of the onychomycosis was caused by dermatophyte infection, whereas 7.8% was caused by nondermatophyte molds and 1.7% by Candida species. The projected overall prevalence of onychomycosis in Canada was 6.5% [2].

Anatomy The nail itself is commonly referred to as the ‘‘nail plate,’’ which is composed of compacted, keratinized * Corresponding author. E-mail address: [email protected] (J.M. Mahoney).

epithelial cells. The nail plate is surrounded by other important contributory structures referred to as the ‘‘nail matrix,’’ ‘‘nail bed,’’ ‘‘proximal nail fold,’’ and ‘‘hyponychium.’’ The nail matrix comprises the proximal one quarter to one third of the nail bed [3]. The dorsal and intermediate nail plate, which consist of hard keratins, are produced by cells in the nail matrix [3,4]. The ventral portion of the nail plate, consisting of soft keratins, is produced by the nail bed, to which it is tightly attached [4]. The nail bed is formed by several layers of epithelial cells and is located between the nail matrix proximally and the hyponychium distally [3,4]. The proximal nail fold is the extension of skin that covers the proximal nail plate. The eponychium, the most anterior epidermal extension of the posterior nail fold, has been referred to as the ‘‘cuticle’’; it functions to prevent entry of bacteria and fungi under the posterior nail fold [3]. The hyponychium begins at the free edge of the nail plate and ends at the distal groove. It is a reservoir for keratinous material and acts as a barrier to bacterial and fungal entry into the proximal portions of the nail bed [3].

Clinical classification The appearance of onychomycosis is divided into different clinical presentations: distal lateral subungual onychomycosis, proximal subungual onychomycosis, superficial white onychomycosis, endonyx onychomycosis, and total dystrophic onychomycosis. Distal lateral subungual onychomycosis, the most common fungal infection, is predominantly caused by Trichophyton rubrum. Nondermatophyte molds, such as Scopulariopsis spp, Hendersonula toruloidea, and

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Scytalidium spp, and Candida spp may also cause distal lateral subungual onychomycosis [5,6]. Infection begins at the hyponychium and continues proximally, infecting the stratum corneum of the nail bed with subsequent involvement of the nail plate. This may result in discoloration, thickening of the nail, subungual hyperkeratosis, and onycholysis. Proximal subungual onychomycosis is the least common form of onychomycosis and is usually caused by T rubrum. Infection begins in the stratum corneum of the proximal nail fold, travels to the matrix, and progresses to invade the undersurface of the nail plate [6]. The fungus appears as a white spot under the lunula that progresses distally. Superficial white onychomycosis is an uncommon infection of the superficial nail plate that is generally confined to the toenails [6]. It is commonly caused by Trichophyton mentagrophytes, although nondermatophyte molds (eg, Acremonium, Fusarium, and Aspergillus spp) and Candida spp may be responsible for this infection [5,6]. The causative organisms produce white patches on the surface of the nail plate that later coalesce and may gradually cover the entire nail [6]. Endonyx onychomycosis is clinically characterized by a diffuse milky white discoloration of the affected nail. Nail plate surface and nail thickness appear normal, and hyperkeratosis and onycholysis are absent. This clinical presentation is predominantly caused by Trichophyton soudanense [7]. Total dystrophic onychomycosis is the most advanced form of onychomycosis and appears as a thickened nail bed with only nail debris. It may be the end result of any of the previously mentioned forms of onychomycosis. Alternatively, primary total dystrophic onychomycosis has been described in disease states, such as chronic mucocutaneous candidiasis [8]. In total dystrophic onychomycosis the nail crumbles and disappears resulting in a thickened and abnormal nail bed, which usually retains fragments of nail plate [8].

melanoma, and subungual squamous cell carcinoma [10,11]. Psoriasis can be indistinguishable from onychomycosis because both can result in nail changes that include subungual hyperkeratosis, onycholysis, leukonychia, splinter hemorrhages, and dystrophy [6]. Psoriasis is most widely recognized by pitting of the nail plate; however, alopecia areata and chronic paronychia may also cause pitting [10]. In psoriatic nails, the salmon patch may be present; this is not a feature of onychomycosis [12]. The salmon patch is a yellow or salmon-pink area, irregular in size and shape, and visible through the nail plate [12]. It is possible for onychomycosis and psoriasis to coexist in the same nail [13]. Similarly, chronic dermatitis, as in eczema, may present with thickening, pitting, and transverse ridging of the nail plate [4]. Dermatophyte infections may involve the nails in Darier’s disease; lichen planus; and ichthyotic states, such as keratosis, ichthyosis, and deafness syndrome [6]. Lichen planus of the nail may manifest with longitudinal striations, thinning of the nail plate, subungual hyperkeratosis, onycholysis, and dorsal pterygium [4,10,12]. Yellow nail syndrome may also be mistaken for a fungal infection; however, the light green – yellow discoloration of the nail, the hardness of the nail plate, and its increased longitudinal curvature are typical characteristics of this nail disorder [6]. Trauma is a frequent cause of the abnormal appearance of nails. Any injury to the nail can cause immediate or future dramatic changes in the presentation of the nail plate. Traumatic subungual hematomas may mimic onychomycosis and subungual malignant melanoma. Various dermatologic diseases share similar characteristics with those seen in onychomycosis patients. It is important that these disorders be ruled out before treatment using diagnostic techniques, such as light microscopic (KOH) examination and culture, or histopathologic examination of the nail.

Differential diagnosis

Diagnosing onychomycosis

Many cutaneous disorders have nail manifestations that appear similar to onychomycosis. Approximately 50% of cases thought to be onychomycosis are in fact other types of nail disorders [9]. Other causes of abnormal-appearing nails include psoriasis, chronic onycholysis, lichen planus, alopecia areata, chronic paronychia, hemorrhage or trauma, onychogryphosis, aging, median canalicular dystrophy, pincer nail, yellow nail syndrome, subungual malignant

The number of suspected organisms that may cause onychomycosis is on the rise. Although dermatophytes are still considered to be the primary pathogens, nondermatophyte molds and yeasts should not be ruled out. The clinical presentation of onychomycosis may provide clues to the infecting organism; however, it should be kept in mind that when diagnosing onychomycosis the clinical appearance caused by one fungal species may be indistinguishable from

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that caused by another [4]. Previously described are other dermatologic disorders that mimic the signs and symptoms of onychomycosis. It is important to identify the causative organism before selecting a treatment, especially because some therapies are more effective against certain organisms than others. The common diagnostic procedures used for the identification of pathogenic organisms include microscopic examination of KOH mounts and culture. The traditional KOH preparation can be enhanced with the addition of fluorescent dye Calcofluor white; specimens on these mounts must be viewed with a fluorescent microscope [14]. Counter stains, such as Chlorazol black E or Parker’s blue-black ink, may also enhance visualization [15]. Adding a drop of Chlorazol black E, which is chitin-specific, facilitates the identification of fungi because it stains the carbohydrate-rich wall of the hyphae a blue-black color [1,15]. Although microscopic examination of KOH mounts may permit differentiation between yeast cells, dermatophyte hyphae, and nondermatophyte molds, this technique cannot identify the specific species [5]. Examination of fungal cultures should enable identification of the pathogenic genus and species causing onychomycosis. Some clinicians have expressed difficulty in obtaining positive mycology from nails that have the clinical appearance of onychomycosis [16]. Fungi may not be viable if recovered solely from the distal end of the nail plate and nail bed; adequate samples need to be taken more proximally from the nail unit (including the nail plate and bed), at the junction between the diseased and normal-appearing nail [16 – 18]. Scher and Ackerman [16] examined patients who were likely to have onychomycosis on clinical grounds, but conventional mycologic (KOH and culture) results were negative. It was demonstrated that the organisms were situated deep in the nail bed (eg, in the cornified cells) and the nail plate; this may explain the difficulty of obtaining positive scrapings or cultures from the nail when samples are taken only from the surface of the nail plate [16]. Because organisms other than dermatophytes can cause onychomycosis, it is necessary to culture the sample in two different media. Both media should contain Sabouraud’s glucose agar and antibiotics, such as chloramphenicol and gentamicin; however, one media should also have cycloheximide added to it. Antibiotics, such as chloramphenicol and gentamicin, are added to the media to inhibit bacterial growth; furthermore, the addition of cycloheximide helps inhibit the growth of some yeasts and nondermatophyte molds. Dermatophyte test media (DTM) is another option for culturing dermatophyte fungi. It was first intro-

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duced in 1969 to provide medics in Vietnam a tool to differentiate between dermatophyte and ringworm infections in soldiers [19]. DTM contains nutrients to promote dermatophyte growth; antibiotics (ie, cycloheximide, gentamicin, and chlortetracycline) that suppress most fungal and bacterial contaminants; and the pH indicator phenol red [19,20]. The growth of dermatophytes results in the release of alkaline metabolites into the medium. Within 10 to 14 days, the pH increases resulting in a color change from yellow to red [19]. It is important to note that the color change occurs simultaneously with the appearance of colony growth [20]. Dermatophyte test media is a simple and rapid method of diagnosing dermatophytosis. Limitations of DTM include false-negative results caused by insufficient incubation temperature; the nature and size of the inoculums, which may affect results; and the inability to identify the causative organism [20]. Studies have also demonstrated that the concentration of antifungal antibiotic used in DTM may not inhibit the growth of some nondermatophyte molds and bacteria; such growth can activate the pH indicator system resulting in a color change in the medium similar to that of dermatophytes. Hence, there is a risk of false-positive results. It should be noted that the color change for a nondermatophyte infection is usually delayed and occurs after the colony of the saprobic fungus is well established [20]. Scherer and Kinmon [19] compared DTM with mycology laboratory analysis (fluorescent KOH and culture) for suspected onychomycosis in 100 geriatric patients. A positive DTM culture occurred in 36% of the patients. The DTM culture result had a 52.8% correlation with positive fluorescent KOH preparation and a 50% correlation with positive microscopic fungal culture for dermatophytes [19]. In comparison with DTM, positive fluorescent KOH preparation had a 90.9% correlation with positive microscopic fungal culture for dermatophytes. Negative fluorescent KOH preparation had a 100% correlation with negative microscopic fungal culture for dermatophytes [19]. Given the limitations of DTM, a new medium was recently introduced for the isolation and identification of dermatophytes. Dermatophyte identification medium is a simple, rapid, and specific method of presumptively identifying dermatophytes [21]. For the diagnosis of onychomycosis, it is questionable whether DTM or dermatophyte identification medium cultures should be used routinely because they prevent the outgrowth of potential pathogens, such as yeasts and nondermatophyte molds. Histopathologic examination of nail specimens may be necessary when potassium hydroxide prepa-

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rations and cultures are repeatedly negative in patients with suspected onychomycosis [22]. Reasons why a false-negative microscopic fungal examination may result include the following: infected nail section may not contain fungal hyphae, poor technique used to obtain sample, time constraints or poor techniques used in the mycology laboratory, or the specimen was obtained mainly from distal nail clippings [3]. Borkowski et al [23] compared three methods for the diagnosis of onychomycosis: (1) surgical pathology diagnostic testing, (2) KOH analysis, and (3) culture. When surgical pathology diagnostic testing was applied to nail samples, 36 of 50 cases were positive for fungal elements (hyphae or yeast forms) [23]. Sixteen cases of the KOH preparations and 12 cases of culture were positive for fungal elements (hyphae or yeast forms) [23]. Statistical analysis demonstrated a difference in the sensitivity of the three tests, with surgical pathology diagnostic testing significantly more sensitive than KOH (P = 0.001) and culture (P = 0.001) [23]. There was no significant difference between KOH and culture sensitivity (P = 0.1) [23]. Histologic examination techniques used to obtain nail plate and bed specimens, such as punch and scalpel, have been used infrequently because of the potential risk of permanent nail dystrophy [22]. Typically, the distal most portion of the nail plate is clipped and submitted for histopathologic evaluation using the periodic acid – Schiff stain. The results can be obtained relatively quickly and the record is permanent [24]. Periodic acid – Schiff stain demonstrates the presence of certain polysaccharides, specifically glycogen and mucoproteins, which are present in the walls of the fungal hyphae. A positive periodic acid – Schiff stain is observed when the fungal hyphae appear bright red [3]. According to Lawry et al [25], periodic acid – Schiff testing is 85% sensitive in diagnosing onychomycosis, and 94% sensitive when combined with Sabouraud’s culture. Suarez et al [22] also recommend the combination of periodic acid – Schiff staining and Sabouraud’s culture as the best method for increasing the odds of detecting fungal infection in the nail unit. Other less frequently used techniques used to diagnose onychomycosis include immunohistochemistry and dual-flow cytometry [3,26,27]. These are research methods and can be performed in only a few laboratories. Immunohistochemistry exposes the nail sample to antibodies that are specific to certain fungi; if the fungi corresponding to the antibodies applied are present they are labeled and rendered visible by direct immunofluorescence, immunoperoxidase, or

avidin-biotin complex methods [26]. This technique is useful when identifying mixed infections, and allowing for quantification of the fungal load in the nail plate [26]. Flow cytometry differentiates fungi on the basis of molecular differences. It provides information on both the quantity of fungal pathogen in a nail sample and the family to which it belongs [26].

Antifungal treatment Before treating onychomycosis, diseases that can present with a similar clinical appearance must be ruled out. In addition, the effective management of onychomycosis may depend, in part, on the causal organism identified [28 – 31]. For instance, griseofulvin is only useful against dermatophyte onychomycosis, whereas fluconazole, itraconazole, and terbinafine are broad-spectrum agents with varying degrees of effectiveness against dermatophytes, nondermatophyte molds, and yeasts. It is also important to take into consideration patient preference and other factors relating to the patient. These include, but are not limited to, the overall health status of the patient, medications the patient is on, and previous response to treatment of onychomycosis by other antifungal agents. Treatment of onychomycosis may consist of mechanical, surgical, and chemical procedures to debride or avulse the nail plate, and topical and oral antifungal agents.

Summary The prevalence of onychomycosis is increasing and the primary pathogens may be dermatophytes, nondermatophyte molds, or Candida spp. It may not be satisfactory to treat onychomycosis on the basis of clinical diagnosis alone. Laboratory diagnosis is an important component of the proper management of this fungal infection. Laboratory diagnostic methods for detecting onychomycosis include light microscopy and culture, or histopathology. Management of onychomycosis includes palliation achieved through mechanical debridement of the nail and topical or oral antifungal therapy.

References [1] Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997; 133:1172 – 3.

J.M. Mahoney et al / Dermatol Clin 21 (2003) 463–467 [2] Gupta AK, Jain HC, Lynde CW, MacDonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol 2000;43(2 pt 1):244 – 8. [3] Lemont H. Pathologic and diagnostic considerations in onychomycosis. J Am Podiatr Med Assoc 1997;87: 498 – 506. [4] Baran R, Hay R, Eckart H, Tosti A. Onychomycosis: the current approach to diagnosis and therapy. United Kingdom: Martin Dunitz; 1999. [5] Clayton YM. Clinical and mycological diagnostic aspects of onychomycoses and dermatomycoses. Clin Exp Dermatol 1992;17(suppl 1):37 – 40. [6] Hay RJ, Baran R, Haneke E. Fungal (onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, de Berker DAR, Haneke E, Tosti A, editors. Baran and Dawber’s diseases of the nails and their management. 3rd edition. Oxford: Blackwell Science; 2001. p. 129 – 71. [7] Tosti A, Baran R, Piraccini BM, Fanti PA. Endonyx’’ onychomycosis: a new modality of nail invasion by dermatophytes. Acta Derm Venereol 1999;79:52 – 3. [8] Hay RJ, Baran R, Haneke E. Fungal (onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, editors. Baran and Dawber’s diseases of the nails and their management. 2nd edition. Oxford: Blackwell Science; 1994. p. 97 – 134. [9] Zaias N, Glick B, Rebell G. Diagnosing and treating onychomycosis. J Fam Pract 1996;42:513 – 8. [10] Lynde C. Nail disorders that mimic onychomycosis: what to consider. Cutis 2001;68(2 suppl):8 – 12. [11] Jaffe R. Onychomycosis: recognition, diagnosis, and management. Arch Fam Med 1998;7:587 – 92. [12] Baran R, Tosti A. Nails. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Fitzpatrick’s dermatology in general medicine. 5th edition. New York: McGraw-Hill Companies; 1999. p. 752 – 68. [13] Gupta AK, Lynde CW, Jain HC, Sibbald RG, Elewski BE, Daniel III CR, et al. A higher prevalence of onychomycosis in psoriatics compared with non-psoriatics: a multicentre study. Br J Dermatol 1997;136:786 – 9. [14] Scherer WP, McCreary JP, Hayes WW. The diagnosis of onychomycosis in a geriatric population: a study of 450 cases in South Florida. J Am Podiatr Med Assoc 2001;91:456 – 64. [15] Elewski BE. Diagnostic techniques for confirming onychomycosis. J Am Acad Dermatol 1996;35(3 pt 2): S6 – 9. [16] Scher RK, Ackerman AB. Subtle clues to diagnosis from biopsies of nails: the value of nail biopsy for

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demonstrating fungi not demonstrable by microbiologic techniques. Am J Dermatopathol 1980;2:55 – 7. English MP. Nails and fungi. Br J Dermatol 1976; 94:697 – 701. Gentles JC. Laboratory investigations of dermatophyte infections of nails. Sabouraudia 1971;9:149 – 52. Scherer WP, Kinmon K. Dermatophyte test medium culture versus mycology laboratory analysis for suspected onychomycosis: a study of 100 cases in a geriatric population. J Am Podiatr Med Assoc 2000;90: 450 – 9. Guillot J, Latie L, Deville M, Halos L, Chermette R. Evaluation of the dermatophyte test medium RapidVet-D. Vet Dermatol 2001;12:123 – 7. Salkin IR, Padyhe AA, Kemna ME. A new medium for the presumptive identification of dermatophytes. J Clin Microbiol 1997;35:2660 – 2. Suarez SM, Silvers DN, Scher RK, Pearlstein HH, Auerbach R. Histologic evaluation of nail clippings for diagnosing onychomycosis. Arch Dermatol 1991; 127:1517 – 9. Borkowski P, Williams M, Holewinski J, Bakotic B. Onychomycosis: an analysis of 50 cases and a comparison of diagnostic techniques. J Am Podiatr Med Assoc 2001;91:351 – 5. Machler BC, Kirsner RS, Elgart GW. Routine histologic examination for the diagnosis of onychomycosis: an evaluation of sensitivity and specificity. Cutis 1998; 61:217 – 9. Lawry MA, Haneke E, Strobeck K, Martin S, Zimmer B, Romano PS. Methods for diagnosing onychomycosis: a comparative study and review of the literature. Arch Dermatol 2000;136:1112 – 6. Pierard GE, Arrese JE, De Doncker P, Pierard-Franchimont C. Present and potential diagnostic techniques in onychomycosis. J Am Acad Dermatol 1996; 34(2 pt 1): 273 – 7. Arrese JE, Pierard-Franchimont C, Greimers R, Pierard GE. Fungi in onychomycosis: a study by immunohistochemistry and dual flow cytometry. J Eur Acad Dermatol 1995;4:123 – 30. Gupta AK, Shear NH. The new oral antifungal agents for onychomycosis of the toenails. J Eur Acad Dermatol Venereol 1999;13:1 – 13. Odom RB. New therapies for onychomycosis. J Am Acad Dermatol 1996;35(3 pt 2):S26 – 30. Gupta AK, Sauder DN, Shear N. Antifungal agents: an overview. Part I. J Am Acad Dermatol 1994;30: 677 – 98. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994;30: 911 – 33.

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The use of oral antifungal agents to treat onychomycosis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Jennifer E. Ryder, HBScb a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada

Onychomycosis has been treated for years with oral antifungal agents. With the introduction of griseofulvin in the late 1950s cure rates for tinea capitis improved, and initially there was enthusiasm over this agent to treat onychomycosis. The introduction of the azoles, ketoconazole and later itraconazole and fluconazole, and the allylamine, terbinafine, resulted in the availability of broad-spectrum antimycotic agents that were associated with higher cure rates. Furthermore, itraconazole, fluconazole, and terbinafine have a high benefit:risk ratio when used for this indication. This article reviews the oral antifungal agents used to treat onychomycosis (Table 1).

Griseofulvin Griseofulvin is an oral antifungal agent derived from a species of Penicillium. It was the first significant oral agent available to manage dermatomycoses [1]. Griseofulvin is indicated in the United States for the treatment of tinea infections of the skin, hair, and nails [2]. Griseofulvin is currently used for the management of tinea capitis; its use for the treatment of other dermatomycoses has been superseded by the availability of more effective antifungal agents. Mechanism of action Griseofulvin has a narrow spectrum of action with activity against dermatophytes [3,4]. It inhibits the formation of intracellular microtubules [5], disrupts the mitotic spindle, and prevents cell division of the * Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

fungus. Fig. 1 shows the site of griseofulvin action with respect to the other antifungal agents. Pharmacokinetics Griseofulvin is poorly absorbed after oral administration because of its poor solubility in water. The bioavailability of this agent is improved by the presence of bile acids in the duodenum; it is recommended that griseofulvin be taken with a fatty meal [3]. In addition, using a formulation where the drug is administered in a micronized form can increase its bioavailability [3,6]. After repeated administration, the bioavailability of griseofulvin is decreased [3]. The peak serum concentration occurs approximately 4 hours after drug administration [3]. Eighty-four percent of griseofulvin is bound to plasma proteins, primarily albumin [3]. This drug has a low affinity for keratin, and drug levels decline with plasma levels [5]. Prolonged administration of griseofulvin is required because the drug is fungistatic and it persists in the nail for a very short time, approximately 2 weeks after discontinuation of treatment [3,7]. Griseofulvin is predominantly metabolized to 6-demethyl-griseofulvin by hepatic microsomal enzymes and excreted into the urine as unchanged drug [3]. Its terminal elimination half-life is 9 to 22 hours [3]. Efficacy Although griseofulvin is indicated for the treatment of tinea infections of the skin, hair, and nails, it is used less frequently for the treatment of onychomycosis because of the introduction of broad-spectrum oral antifungal agents that are more effective. Griseofulvin has a narrow spectrum with effective-

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Table 1 Oral agents used to treat onychomycosis Griseofulvin

Itraconazole

Fluconazole

Terbinafine

Approved for the treatment of onychomycosis in the United States Dosing schedule: fingernails

Continuous regimen

Not indicated

Continuous regimen

Daily dose of 500 to 1000 mg until infection is cleared

Spectrum of activity

Dermatophytes

150 – 300 mg/wk, until the affected nail plate has grown out, typically 6 – 9 months 150 – 300 mg/wk, until the affected nail plate has grown out, typically 12 – 18 mo Dermatophytes, some nondermatophyte molds, Candida species

250 mg/d for 6 wk

Dosing schedule: toenails

Continuous regimen: fingernail and toenail Pulse regimen: fingernail (see Note) Pulse regimen: 400 mg/d for 1 wk each mo for 2 pulses Continuous regimen: 200 mg/d for 6 wk Continuous regimen: 200 mg/d for 12 wk

Daily dose of 500 to 1000 mg until infection is cleared

Dermatophytes, some nondermatophyte molds, Candida species

250 mg/d for 12 wk

Dermatophytes, some nondermatophyte molds, Candida species

In the United States, itraconazole pulse therapy is not indicated for the treatment of toenail onychomycosis.

ness extending to dermatophytes only [8,9]. The efficacy of griseofulvin in the management of dermatophyte toenail onychomycosis is low and is associated with high relapse rates. Drug interactions Griseofulvin is contraindicated in individuals with porphyria, hepatocellular failure, and those with a history of hypersensitivity to the antifungal agent [2]. Patients on warfarin-type anticoagulant therapy may

need a dosage adjustment of the anticoagulant. Those individuals using barbiturates, which depress griseofulvin activity, may need the dosage of griseofulvin increased [2]. Griseofulvin should not be administered during pregnancy because of the risk for developing conjoint twins [2]. Adverse events Common adverse events, when reported, are generally caused by hypersensitivity (eg, skin rashes and

Fig. 1. Site of action of antifungal agents. (From Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994;30:914; with permission.)

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urticaria) [2]. Occasionally patients report cases of oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, mental confusion, and impairment of performance of routine activities [2]. The occurrence of severe reactions (eg, proteinuria and leukopenia) is rare and generally associated with high doses, long therapy duration, or both [2].

Ketoconazole Ketoconazole became available in the United States in 1981. It was the first imidazole that could be used to treat systemic mycotic infections [1]. Ketoconazole has a broad spectrum of action that includes dermatophytes and yeasts [3]. Mechanism of action Ketoconazole is primarily fungistatic. As with other azoles, ketoconazole impairs the synthesis of ergosterol by inhibiting the cytochrome P-450 (CYP) enzyme lanosterol 14-demethylase. This inhibition results in accumulation of C14 methylated sterols with depletion of membrane ergosterol. It also inhibits triglyceride and phospholipid biosynthesis; inhibits cell-wall chitin synthesis; and affects membrane permeability, fluidity, and synthesis [8]. The oxidative and peroxidative enzyme systems may also be inhibited, leading to an accumulation of toxic reactive peroxides within the cell [8]. At higher concentrations, ketoconazole also blocks the human CYPdependent demethylation of ergosterol [3]. Fig. 1 shows the site of ketoconazole action with respect to the other antifungal agents. Pharmacokinetics Ketoconazole is well absorbed in individuals with normal gastric acidity. In situations of achlorhydria the bioavailability may be reduced [8,10]. Following oral administration of a single 200-mg dose (taken with a meal), mean peak plasma levels of approximately 3.5 mg/mL are reached within 1 to 2 hours, and subsequent plasma elimination is biphasic [10]. Approximately 99% of ketoconazole is bound to plasma proteins, mainly albumin [10]. Ketoconazole is converted into several inactive metabolites following gastrointestinal absorption [10]. The major route of excretion is through the bile into the intestinal tract. Approximately 13% of the drug is excreted in the urine [10].

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Efficacy Ketoconazole is not recommended for the treatment of onychomycosis because of the potential for hepatotoxicity, and because of the availability of other alternative antifungal agents. Drug interactions Box 1 lists contraindicated drugs and drug interactions that may occur while taking ketoconazole. Box 1 is for guidance only. For complete and up-todate details please consult a current product monograph that is valid for your jurisdiction. Adverse events Adverse events commonly reported by patients administered ketoconazole include nausea or vomiting (approximately 3%); abdominal pain (1.2%); and pruritus (1.5%) [10]. Ketoconazole has also been associated with hepatotoxicity, with an incidence of about 1:10,000 exposed patients [10]. Liver function tests should be measured before and during treatment with ketoconazole. Hepatic injury has usually, but not

Box 1. Drug interactions with ketoconazole [10] Contraindicated with:  Terfenadine, astemizole, cisapride, oral triazolam  Patients hypersensitive to ketoconazole Increase plasma concentration of ketoconazole  Rifampin Drug plasma concentration increased by ketoconazole  Terfenadine, astemizole, cisapride, cyclosporine, tacrolimus, methylprednisolone, midazolam, oral triazolam  Rare cases of elevated plasma concentrations of digoxin Drug plasma concentration decreased by ketoconazole  Increases clearance of cyclosporine by 15% Other  Potent inhibitor of the CYP3A4 enzyme system

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always, been reversible on discontinuation of treatment. Most reported cases of hepatic toxicity have been in patients treated for onychomycosis [10]. Factors that may predispose certain patients to develop symptomatic hepatitis include age of the patient (ie, > 40 years old); the female gender; duration of therapy; or patients previously treated with griseofulvin for onychomycosis [11].

binding and extensive tubular reabsorption, explaining the long half-life [17]. Given the relatively long half-life of the triazole, the dosage regimens used to treat superficial fungal infections are based on once weekly dosing. Following administration of radiolabeled fluconazole, greater than 90% is excreted in the urine, with 11% caused by metabolites, and an additional 2% is excreted in the feces [12]. Efficacy

Fluconazole Fluconazole is a water-soluble biz-triazole that exhibits fungistatic activity in vitro. This triazole is not approved in the United States for the treatment of onychomycosis; however, it has this indication in some other countries. Mechanism of action The triazoles and imidazoles have a similar mechanism of action. Fluconazole inhibits fungal lanosterol 14-a-demethylase. Unlike ketoconazole, fluconazole is much more selective toward the fungal lanosterol 14-a-demethylase, inhibiting this enzyme to a much greater extent than the corresponding mammalian enzyme. Fig. 1 shows the site of fluconazole action with respect to the other antifungal agents. Pharmacokinetics The oral bioavailability of fluconazole is greater than 90% [12]. Fluconazole does not seem to be affected by gastric pH and there is no evidence of first-pass metabolism because the entire drug reaches systemic circulation [12]. Following oral administration, the peak plasma concentration in fasted healthy individuals is between 1 and 2 hours of dosing, with a terminal plasma elimination half-life ranging between 20 and 50 hours [12]. Following oral doses of 50 to 400 mg given once daily, steady-state concentrations are reached within 5 to 10 days [12]. Fluconazole has low lipophilicity and low level of plasma protein binding, approximately 11% [12,13]. Fluconazole has been detected in healthy and affected fingernails and toenails 2 weeks after the start of therapy, when the dosage regimen has been 150, 300, or 450 mg once weekly [14,15]. Measurable fluconazole concentrations in affected fingernails and toenails have been detected 6 months after cessation of treatment (regimen: 150, 300, and 450 mg administered once weekly) [14,16]. Fluconazole is primarily cleared by the renal system; this is attributed to low plasma protein

Fluconazole has proved effective and safe in the treatment of fingernail and toenail onychomycosis [18,19]. In a multicenter, double-blind, randomized, dose-finding study Scher et al [19] compared the efficacy and safety of three different doses of fluconazole (150, 300, or 450 mg) administered once weekly for a maximum of 12 months in the treatment of toenail onychomycosis. At the 6-month follow-up, mycologic cure rates for 150-, 300-, or 450-mg doses were 53%, 59%, and 61%, respectively. The corresponding rates for clinical success were 77%, 79%, and 86%, respectively. There was no significant difference between the fluconazole doses for all efficacy measures [19]. Ling et al [20] evaluated the safety and efficacy of once-weekly fluconazole, 450 mg administered for 4, 6, or 9 months, in the treatment of toenail onychomycosis. Mycologic cure rates at the 6-month follow-up were 34%, 49%, and 61% for the 4-, 6-, or 9-month treatment durations, respectively. The corresponding rates for clinical success were 50%, 54%, and 70%, respectively. The 9-month treatment duration was more effective, both clinically and mycologically, than either 4 or 6 months of therapy [20]. Drug interactions Box 2 lists contraindicated drugs and drug interactions that may occur while taking fluconazole. Box 2 is for guidance only. For complete and up-to-date details please consult a current product monograph that is valid for your jurisdiction. Adverse events The most common adverse events, reported in a study of 4048 patients receiving fluconazole for 7 or more days included headaches (1.9%); skin rash (1.8%); nausea (3.7%); abdominal pain (1.7%); vomiting (1.7%); and diarrhea (1.5%) [12]. Other adverse events that may occur include insomnia, palpitations, sweating, respiratory disorders, and fever [21]. Because fluconazole is not approved in the United States

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Box 2. Drug interactions with fluconazole [12,58 – 63] Contraindicated with:  Cisapride, terfenadine (at fluconazole doses of 400 mg/d or greater) Decrease plasma concentration of fluconazole  Cimetidine, rifampin Increase plasma concentration of fluconazole  Hydrochlorothiazide Drug plasma concentration increased by fluconazole  Cyclosporine, astemizole, tolbutamide, glipizide, glyburide, pheytoin, rifabutin, tacrolimus, theophylline, zidovudine, terfenadine Other  Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants  Unpredictable effect on oral contraceptives  Concomitant use of fluconazole and drugs metabolized by the CYP system may result in elevated serum levels of drugs prolonging the QTc interval for the treatment of onychomycosis, there are no guidelines regarding obtaining laboratory tests when the triazole is used for this indication. It may be prudent to perform baseline liver function tests in a manner similar to that recommended for itraconazole and terbinafine.

Itraconazole Itraconazole, a triazole derivative, was approved in the United States in October 1995 as a continuous therapy for fingernail and toenail onychomycosis [1]. It was later approved in the United States as a pulse therapy for fingernail onychomycosis [1]. Mechanism of action Similar to the other azoles, itraconazole is primarily fungistatic. The triazole disrupts the synthesis of ergosterol. This action reduces membrane-bound en-

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zyme activity and interrupts chitin synthesis, making the cell membrane more permeable [22]. Fig. 1 shows the site of itraconazole action with respect to the other antifungal agents. Pharmacokinetics Itraconazole is highly lipophilic, insoluble in water, and a weak base that is ionized at a low pH [23 – 25]. The oral bioavailability of this azole is maximal when taken with a full meal [26]. Under fasted conditions and in those individuals with relative or absolute achlorhydria, the absorption of itraconazole is increased when administered with a cola beverage [26,27]. It is recommended that the capsule formulation be taken in the fed state. This contrasts with the oral solution formulation, where the bioavailability is maximal when ingested in the fasting state. Approximately 95% of a given dose of itraconazole is bound to plasma proteins, primarily albumin. Despite the high plasma protein binding, itraconazole is extensively distributed to the tissues [22,28]. It has a high affinity for keratinized tissues; this results in tissue levels that are several times higher than peak plasma levels [29]. The azole adheres to the lipophilic cytoplasm of keratinocytes in the nail plate allowing for the progressive buildup and persistence in the nail [30]. Itraconazole (100 mg/d) has been detected in the distal fingernail material after 1 week of therapy [22,31]. The triazole reached a mean maximum of 149 ng/g after 2 months of therapy in the distal portion of the toenail when administered at a dose of 100 mg/d, and 990 ng/g at a dose of 200 mg/d [29]. The mean itraconazole concentrations persisted, for up to 6 months after discontinuation of therapy, more or less unchanged [29]. When administered as a pulse therapy, itraconazole is present in the distal end of fingernails and toenails within 7 to 14 days of therapy [32]. Itraconazole is incorporated into the nail through the nail matrix and nail bed [29,33]. Havu et al [34] compared the pharmacokinetics of continuous (200 mg/d) and intermittent (200 mg twice daily for 1 week per month followed by a 3-week drug-free period) itraconazole dosing schedules for 3 months in the treatment of onychomycosis. With the intermittent schedule, the mean itraconazole and hydroxyitraconazole plasma concentrations increased with consistent magnitude at the end of each 1-week treatment phase and returned to baseline, in most patients, by the end of the 3-week drug-free period. With the continuous schedule, itraconazole and hydroxyitraconazole reached plasma steady-state levels within 4 to 5 weeks of the start of therapy. The

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maximum mean concentration in toenail tips for the intermittent therapy was 305 ng/g at week 24 and 698 ng/g at week 36 for the continuous therapy. Intermittent therapy resulted in higher maximum itraconazole plasma concentrations but lower total systemic exposure compared with the continuous regimen [34]. No significant difference was found in the clinical response or mycologic cure rates for both treatment regimens; although there was a trend for efficacy in favor of the intermittent schedule [35]. Itraconazole is predominantly metabolized by the CYP3A4 isoenzyme system, resulting in the formation of several metabolites, the major metabolite being hydroxyitraconazole [26]. The clearance of itraconazole decreases at higher doses and with duration of therapy, suggesting the clearance may be saturable [36]. Three percent to 18% of the itraconazole dose is fecal excretion and less than 0.03% is excreted through the renal system. Approximately 40% of the dose is excreted as inactive metabolites in the urine [26]. Efficacy Onychomycosis may be treated with itraconazole using either a pulse or continuous regimen; both have proved to be efficacious and safe. In a double-blind, randomized, multicenter, placebo-controlled Canadian study, Gupta et al [37] evaluated the safety and efficacy of pulse itraconazole (200 mg twice daily for 1 week a month for 3 months) in treating toenail onychomycosis. In the itraconazole and placebo groups, mycologic success occurred in 61.5% (N = 78) and 28.4% (N = 74), respectively. The corresponding clinical success rates were 65.4% and 1.4%, respectively [37]. In a multicenter, double-blind study patients were randomly allocated to receive either continuous (200 mg/d) or pulse therapy (400 mg/d for the first week only of each month) with itraconazole for 3 months, with a follow-up 9 months after the start of therapy [35]. After the follow-up period, clinical response rates were 69% and 81% in the continuous and pulse group, respectively. The corresponding mycologic cure rates were 66% and 69%, respectively. Drug interactions Box 3 lists contraindicated drugs and drug interactions that may occur while taking itraconazole. Box 3 is for guidance only. For complete and upto-date details please consult a current product monograph that is valid for your jurisdiction.

Box 3. Drug interactions with itraconazole [1,26,64 – 68] Contraindicated with:  Quinidine; dofetilide; pimozide; oral midazolam; triazolam; cisapride; HMG coenzyme A reductase inhibitors, such as lovastatin and simvastatin, astemizole, terfenadine  Patients with evidence of ventricular dysfunction (eg, congestive heart failure or a history of heart failure)  Patients hypersensitive to itraconazole and its excipients Decrease plasma concentration of itraconazole  Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, isoniazid, antacids, H2-receptor antagonists, proton pump inhibitors, nevirapine Increase plasma concentration of itraconazole  Erythromycin, clarithromycin, indinavir, ritonavir Drug plasma concentration increased by itraconazole  Quinidine, dofetilide, digoxin, carbamazepine, rifabutin, busulfan, docetaxel, vinca alkaloids, alprazolam, diazepam, midazolam, triazolam, dihydropyridines, verapamil, cisapride, lovastatin, simvastatin, atorvastatin, cerivastatin, cyclosporine, tacrolimus, sirolimus, oral hypogycemics, indinavir, ritonavir, saquinavir, alfentanil, buspirone, methylprednisolone, trimetrexate, warfarin, astemizole, terfenadine Other  Inhibitor of drugs metabolized by CYP3A4  Oral contraceptives may be ineffective

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Adverse events In a United States clinical trial, 112 patients with toenail onychomycosis were treated with 200 mg/d for 12 weeks. The adverse events commonly reported were headache (10%); rhinitis (9%); upper respiratory tract infection (8%); sinusitis or injury (7%); diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, or rash (4%); cystitis, urinary tract infection, liver function abnormality, myalgia, or nausea (3%); and appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, or abnormal dreaming (2%) [26]. Rare cases of congestive heart failure and pulmonary edema have been reported [26]. In a Food and Drug Administration review of spontaneous postmarketing reports received between September 1992 and April 2001, itraconazole was suspected to have contributed to or may have been the cause of congestive heart failure in 58 of 94 cases [38,39]. In 26 of these 58 cases, itraconazole was administered for the treatment of onychomycosis [38,39]. Itraconazole should not be administered in patients with evidence of ventricular dysfunction, such as congestive heart failure or a history of congestive heart failure [26]. Only rare cases of symptomatic hepatic injury have been reported, which may result in liver failure, transplantation, and death [26,38,39]. Monitoring of hepatic enzyme test values is recommended in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications [26]. It is also advisable to monitor liver function in patients receiving continuous itraconazole for more than 1 month or at any time a patient develops symptoms suggestive of liver dysfunction (eg, anorexia, nausea, and so forth) [40]. Adverse events associated with the use of itraconazole were usually mild, transient, and reversible on discontinuation of therapy.

Terbinafine Terbinafine, an allylamine, is indicated for the treatment of onychomycosis of the fingernail and toenail caused by dermatophytes [41]. Oral terbinafine was first approved for use in the United Kingdom in February 1991, and later in Canada (May 1993) and the United States (May 1996) [1]. Mechanism of action Terbinafine acts at an earlier stage compared with the azoles by specifically inhibiting fungal ergosterol

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biosynthesis at the point of squalene epoxidation [42]. Squalene epoxidase, a microsomal enzyme, consists of a terminal oxidase that does not belong to the CYP superfamily [43]. As a result of squalene epoxidase inhibition, the treated fungal cells rapidly accumulate squalene and become deficient in the end product of the pathway, ergosterol [42]. It is hypothesized that the fungicidal activity of terbinafine primarily may be caused by the accumulation of high levels of intracellular squalene [42]. Intracellular squalene accumulation may exert a toxic effect on the fungal cell because lipophilic squalene seems to be deposited in lipid droplets in the cytoplasm and cell wall [42,44]. Squalene vesicles may act as a lipid sponge, weakening cellular membranes by extracting their essential lipid components [42,43]. In particular, disintegration of the vacuolar membrane releases lytic enzymes that are potentially lethal to the fungal cell [42]. The fungistatic action may be the result of ergosterol deficiency, which interferes with membrane function cell growth leading to growth arrest. Fig. 1 shows the site of terbinafine action with respect to the other antifungal agents. Pharmacokinetics Terbinafine is well absorbed (greater than 70%) and the bioavailability is approximately 40% as a result of first-pass metabolism [41]. Greater than 99% of terbinafine is nonspecifically bound to plasma proteins [41]. Peak plasma concentrations between 0.8 and 1.5 mg/mL appear within about 2 hours after administration of a single dose [30]. The allylamine is extensively distributed (eg, sebum, stratum corneum, hair) and extremely lipophilic. Terbinafine (250 mg/d) has been detected in the fingernail and toenails after 1 week of treatment [45,46]. In a double-blind randomized study, 20 patients with toenail onychomycosis were treated with terbinafine, 250 mg/d, for 6 or 12 weeks [45]. Terbinafine concentrations ranged between 0.23 and 0.52 mg/g up to week 36 for those treated for 6 weeks and between 0.06 and 1.01 mg/g up to week 48 for those treated for 12 weeks [45]. In a double-blind, randomized parallel group study, a dose response was observed, with less time required to reach negative mycologic status for the 250- and 500-mg groups compared with the 125-mg group [47]. Terbinafine is extensively metabolized before excretion [41]. Its main metabolite is demethylterbinafine; however, unlike itraconazole, no metabolites identified have had antifungal activity similar to terbinafine [41,48]. Approximately 70% of the administered dose is eliminated in the urine [41].

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Efficacy Terbinafine is an effective and safe treatment of fingernail and toenail onychomycosis. In a doubleblind, randomized, prospective study, patients were treated with terbinafine (250 mg/d) for 12 (T12) or 16 weeks (T16), or with itraconazole pulse (400 mg/d for 1 week in every 4 weeks) for 12 (I3) or 16 weeks (I4) [49]. At week 72, in the T12 group, 81 (75.7%) of 107 patients treated were mycologically cured, 59 (54%) of 110 were clinically cured and 49 (46%) of 107 were completely cured [49]. The corresponding values for the T16 group were 80 (81%) of 99, 59 (60%) of 98, and 54 (55%) of 98, respectively [49]. All comparisons showed significantly higher rates of cure in the continuous terbinafine groups compared with the itraconazole groups [49]. The Icelandic and Finnish participants of this study were followed-up for 4 and 5 years, respectively [50,51]. The results of these studies suggest terbinafine should be administered continuously for 4 months; however, the indicated regimen for terbinafine in the treatment of toenail onychomycosis is 3 months [50]. In addition, terbinafine provided superior long-term mycologic and clinical efficacy, with lower relapse rates compared with intermittent itraconazole [51]. Cribier et al [52] and Crawford et al [53] reported similar results. In a long-term study by De Cuyper et al [54], the excellent results achieved with terbinafine at week 48 were maintained up to and beyond 2 years. In addition, failure and relapse rates were much higher in individuals treated with itraconazole compared with terbinafine. These long-term benefits of terbinafine may be related to its primary fungicidal action. These results were similar to those found in a metaanalysis conducted by Haugh et al [55]. Drug interactions Box 4 lists drug interactions that may occur while taking terbinafine. There are no drugs that are contraindicated with terbinafine. Box 4 is for guidance only. For complete and up-to-date details please consult a current product monograph that is valid for your jurisdiction. Adverse events Hall et al [56] conducted four open, prospective, uncontrolled, postmarketing surveillance studies in four countries to broaden the safety database of oral terbinafine. Terbinafine (250 mg/d) was administered for a median duration of 12 weeks (mean 13.2 weeks). The mean age of the 25,884 patients who entered the

Box 4. Drug interactions with terbinafine [1,41,69 – 72] Contraindicated with:  Patients hypersensitive to terbinafine or to any other ingredients of the formulation Decrease plasma concentration of terbinafine  Terbinafine clearance is increased 100% by rifampin Increase plasma concentration of terbinafine  Terbinafine clearance is decreased 33% by cimetidine  Terbinafine clearance is decreased 16% by terfenadine Drug plasma concentration increased by terbinafine  Decreases caffeine clearance by 19%  Decreases theophylline clearance by 14% Drug plasma concentration decreased by terbinafine  Increases clearance of cyclosporine by 15% Other  May affect metabolism of CYP2D6 substrates  May increase or decrease prothrombin times in patients concomitantly taking terbinafine and warfarin

study was 47.8 years, of which 22.7% were greater than 60 years of age, 38.6% had concomitant diseases, and 42.8% were taking other medications. The predominant indication for terbinafine treatment was onychomycosis (72.2%). The incidence of adverse events was 10.5%, with most involving the gastrointestinal system (4.9%) or related to the skin (2.3%). Gastrointestinal disorders most commonly reported were nausea (1.3%); diarrhea (0.8%); abdominal pain (0.8%); and dyspepsia (0.6%). Those adverse events related to the skin commonly reported included rash (0.9%); pruritus (0.3%); urticaria (0.3%); and eczema (0.2%). A small proportion of patients (0.4%) had a known history of hepatobiliary disease. Fifty-five patients reported hepatobiliary events; 45 of these patients had asymptomatic elevations in hepatic enzymes (38 were considered, by investigators, to

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be related to terbinafine). Ten of 55 patients who reported hepatobiliary events experienced symptoms (eg, diarrhea and cholestatic hepatic dysfunction); investigators considered these were potentially related to terbinafine in six patients [56]. Terbinafine is not recommended for patients with chronic or active liver disease. Patients should be assessed for pre-existing liver disease, and before administration of terbinafine, serum transaminase (alanine transaminase and aspartate transaminase) tests should be performed [41]. Only rare cases of symptomatic hepatic injury have been reported, which may result in liver failure, transplantation, and death [41]. Terbinafine may also cause headaches, taste disturbances, and white blood cell disturbances [56,57]. Adverse events associated with the use of terbinafine were usually mild, transient, and reversible on discontinuation of therapy.

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Welbanks L, Bisson R, et al, editors. Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Toronto: Webcom Limited; 2002. p. 1581 – 3. Lamisil (terbinafine hydrochloride tablets) prescribing information. Novartis Pharmaceuticals Corporation; 2001. Available at: http://www.lamisil.com/pi.jsp? checked-y. Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992;126(suppl 39):2 – 7. Jain S, Sehgal VN. Terbinafine, a unique oral antifungal: current perceptions. Int J Dermatol 2000;39: 412 – 23. Ryder NS. The mechanism of action of terbinafine. Clin Exp Dermatol 1989;14:98 – 100. Schatz F, Brautigam M, Dobrowolski E, Effendy I, Haberl H, Mensing H, et al. Nail incorporation kinetics of terbinafine in onychomycosis patients. Clin Exp Dermatol 1995;20:377 – 83. Faergemann J, Zehender H, Millerioux L. Levels of terbinafine in plasma, stratum corneum, dermisepidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol 1994; 19:121 – 6. Finlay AY, Thomas R, Dykes PJ, Smith SG, Jones TC. Descriptive correlations between various doses of oral terbinafine and concentrations in nail. J Dermatol Treat 1994;5:193 – 7. Finlay AY. Pharmacokinetics of terbinafine in the nail. Br J Dermatol 1992;126(suppl 39):28 – 32. Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. The LION Study Group. BMJ 1999;318:1031 – 5. Heikkila H, Stubb S. Long-term results in patients with onychomycosis treated with terbinafine or itraconazole. Br J Dermatol 2002;146:250 – 3. Sigurgeirsson B, Olafsson JH, Steinsson JB, Paul C, Billstein S, Evans EG. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 2002;138:353 – 7. Cribier BJ, Paul C. Long-term efficacy of antifungals in toenail onychomycosis: a critical review. Br J Dermatol 2001;145:446 – 52. Crawford F, Young P, Godfrey C, Bell-Syer SE, Hart R, Brunt E, et al. Oral treatments for toenail onychomycosis: a systematic review. Arch Dermatol 2002; 138:811 – 6. De Cuyper C, Hindryckx PH. Long-term outcomes in the treatment of toenail onychomycosis. Br J Dermatol 1999;141(suppl 56):15 – 20. Haugh M, Helou S, Boissel JP, Cribier BJ. Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials. Br J Dermatol 2002;147: 118 – 21. Hall M, Monka C, Krupp P, O’Sullivan D. Safety of

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oral terbinafine: results of a postmarketing surveillance study in 25,884 patients. Arch Dermatol 1997;133: 1213 – 9. Pollak R, Billstein SA. Safety of oral terbinafine for toenail onychomycosis. J Am Podiatr Med Assoc 1997;87:565 – 70. Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, et al. Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996;24:422 – 8. Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, Harrison NJ, et al. Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther 1991;49:420 – 5. Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, Matas AJ. Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients: a doubleblind, randomized pharmacokinetic and safety study. Transplant Proc 1991;23(1 pt 2):1041 – 2. Jordan MK, Polis MA, Kelly G, Narang PK, Masur H, Piscitelli SC. Effects of fluconazole and clarithromycin on rifabutin and 25-O- desacetylrifabutin pharmacokinetics. Antimicrob Agents Chemother 2000;44: 2170 – 2. Nicolau DP, Crowe HM, Nightingale CH, Quintiliani R. Rifampin-fluconazole interaction in critically ill patients. Ann Pharmacother 1995;29:994 – 6. Gericke KR. Possible interaction between warfarin and fluconazole. Pharmacotherapy 1993;13:508 – 9.

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[64] Buggia I, Zecca M, Alessandrino EP, Locatelli F, Rosti G, Bosi A, et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res 1996; 16:2083 – 8. [65] Ducharme MP, Slaughter RL, Warbasse LH, Chandrasekar PH, Van de Velde V, Mannens G, et al. Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin. Clin Pharmacol Ther 1995;58:617 – 24. [66] MacKenzie-Wood AR, Whitfeld MJ, Ray JE. Itraconazole and HIV protease inhibitors: an important interaction. Med J Aust 1999;170:46 – 7. [67] Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998;64:58 – 65. [68] Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995;333:664 – 5. [69] Gupta AK, Ross GS. Interaction between terbinafine and warfarin. Dermatology 1998;196:266 – 7. [70] Kaplan DL. Terbinafine and potential drug interactions. J Am Acad Dermatol 2000;43(5 pt 1):882 – 4. [71] Warwick JA, Corrall RJ. Serious interaction between warfarin and oral terbinafine. BMJ 1998;316:440. [72] Abdel-Rahman SM, Gotschall R, Kauffman RE, Leeder S, Kearns GL. Investigation of terbinafine as a CYP2D6. Clin Pharmacol Ther 1999;65:465 – 72.

Dermatol Clin 21 (2003) 481 – 489

The use of topical therapies to treat onychomycosis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Jennifer E. Ryder, HBScb, Robert Baran, MDc a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Nail Diseases Center, 42 Rue des Serbes 06400, Cannes, France

Onychomycosis is a fungal infection of the nail unit, which has become increasingly prevalent. Factors that may be attributed to the rise in the prevalence of onychomycosis include an increase in the use of immunosuppressive therapies; aging of the population; tight-fitting footwear; and the use of communal areas (eg, public baths, gymnasiums, health spas, hotel rooms, and so forth). Onychomycosis has been reported to be more prevalent in men than women, among the elderly, diabetics, and other immunocompromised individuals [1 – 3]. Therapeutic options for the treatment of onychomycosis include no therapy, palliative care, mechanical or chemical debridement, topical and systemic antifungal agents, or a combination of two or more of these modalities. Factors that influence the choice of therapy include the presentation and severity of the disease, the current medications the patient is taking, previous therapies for onychomycosis and their response, physician and patient preference, and the cost of therapy. The clinical presentations of onychomycosis include distal-lateral subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis, and total dystrophic onychomycosis. White superficial onychomycosis should respond best to topical therapy because of the superficial nature of this infection. In

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

many instances, it may be possible to mechanically remove the diseased portion of nail using a curette or a similar device; in fact, the day-to-day activities of some patients may produce enough trauma to the nail to dislodge or remove the diseased portion of the superficial nail from the normal-appearing nail. To determine the extent of the literature relating to the use of topical agents for the management of onychomycosis, a Medline search was conducted from the years 1966 to June 2002. The key words that were used included ‘‘topical’’ and ‘‘onychomycosis.’’ Studies were excluded [4 – 12] for reasons including retrospective nature; preliminary data; nonEnglish language format; unable to extract relevant data; only special populations (eg, transplant patients, diabetic patients, and so forth) enrolled; clinical presentations other than distal lateral subungual onychomycosis evaluated; and trials where only fingernail onychomycosis was considered for treatment. This article is confined to the treatment of distal and lateral subungual onychomycosis.

Efficacy parameters Twenty-six studies were included in the evaluation of topical therapies [13 – 38]. Most studies did not define the efficacy parameters used to determine whether a treatment was successful. When efficacy parameters were defined, they were often variable. For instance, mycologic cure was defined as ‘‘negative culture and KOH’’ [13,15,19,24,27,34], ‘‘negative culture’’ only [31], or ‘‘negative culture and a negative or missing microscopy result’’ [22]. Clinical

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00025-1

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response was defined as less than or equal to 10% nail involvement and negative mycology [13], cure or markedly improved [22], percent of involvement [28,29], or 100% remission or 90% to 99% improvement [34]. Complete cure was defined as clear nail and negative mycology [13,15,19,27,34], clinical cure and negative culture [31,32], clinical cure and negative microscopy [38], neither clinical nor microscopic evidence of reinfection [35], or complete clinical recovery and negative microscopy [23].

Ciclopirox and amorolfine nail lacquers The active component in the nail lacquer polymer film is maintained on the nail surface, from which it evenly diffuses through the nail plate keratin thereby reaching the nail bed [39]. After the evaporation of the solvent, the concentration of the active ingredient, ciclopirox or amorolfine, increases to 34.8% and 25%, respectively [39,40]; this enhances transungual diffusion [39]. Ciclopirox nail lacquer Ciclopirox solution 8% is the only approved nail lacquer in the United States for the treatment of onychomycosis. This hydroxypyridone derivative has been marketed worldwide for approximately 25 years and is approved in more than 40 countries worldwide [41]. In December 1999, the nail lacquer was approved in the United States for the treatment of mild to moderate onychomycosis of the fingernails and toenails without lunula involvement, caused by Trichophyton rubrum [13,41]. Mode of action Ciclopirox has a diverse mode of action that targets different metabolic processes in the microbial cell [42]. The main mode of action is its high affinity for trivalent cations, such as Fe3 + and Al3 + [43]. The inhibition of these essential cofactors affects mitochondrial electron transport processes in the course of energy production, thereby impairing microbial metabolism [42]. Ciclopirox also strongly reduces the activity of catalase and peroxidase, which are responsible for the intracellular degradation of toxic peroxides. In addition, nutrient uptake into the internal pool of growing cells may be adversely affected; this can result in intracellular depletion of essential amino acids and nucleotides, which reduces the synthesis of proteins or nucleic acids [42].

Activity of ciclopirox Ciclopirox is a broad-spectrum antifungal agent that exhibits fungicidal activity in vitro against dermatophytes, Candida species, and some nondermatophyte molds. In addition, ciclopirox exhibits antibacterial activity against a number of gram-positive and gram-negative aerobic and anaerobic bacteria [42]. Ciclopirox exhibits anti-inflammatory activity by preventing the formation of 5-lipoxygenase inflammatory mediators, such as 5-hydroxyeicosatetraenoic acid and leukotriene B4; cyclooxygenase inflammatory mediator release (prostaglandin E2); and the cyclooxygenase-mediated synthesis of prostaglandins [42]. Pharmacokinetics In five patients with dermatophyte onychomycosis, a once daily application of ciclopirox nail lacquer for 6 months resulted in serum levels of the drug ranging between 12 and 80 ng/mL and a mean absorption of less than 5% of the applied dose; 1 month after the end of therapy serum and urine levels were below the level of detection [13]. Ciclopirox may be detectable in the nail for up to 2 weeks after discontinuing the application of the nail lacquer [42]. In two vehicle-controlled trials, patients applied ciclopirox topical solution 8% to all toenails and affected fingernails. Twenty-four of 66 randomly chosen patients had detectable serum ciclopirox concentrations in the range of 10 to 24.6 ng/mL at some point during treatment [13]. In an in vitro investigation, radiolabeled ciclopirox applied once to avulsed onychomycotic toenails demonstrated penetration up to a depth of approximately 0.4 mm [13]. In addition, the more diseased the nail (eg, rougher and more fissured nail surfaces) the greater the degree of penetration [44]. Efficacy Table 1 is a summary of the randomized controlled trials (RCTs) where ciclopirox nail lacquer 8% was used to treat onychomycosis caused by dermatophytes, nondermatophytes, and yeasts. In this literature search, two RCTs [13], one open study [36], and two case reports [20] were found. In the two randomized, double-blind, vehiclecontrolled studies, 30 (29%) of 105 and 41 (36%) of 115 patients who applied ciclopirox for 48 weeks were mycologically cured [13]. In an open multicenter study, 60 patients with onychomycosis caused by nondermatophyte molds (Scopulariopsis brevicaulis, Aspergillus niger, Aspergillus fumigatus, and Hendersonula toruloidea) were treated with ciclopirox at least once weekly for up to 6 months

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483

Table 1 Summary of RCTs where ciclopirox nail lacquer 8% solution has been used to treat onychomycosis Study location Study type United States

United States

a b c

Nail matrix involvement Treatment

Double-blind, No randomized, vehicle-controlled, parallel-group, multicenter [13,46] Double-blind, No randomized, vehicle-controlled, parallel-group, multicenter [13,46]

Complete MCa (%) CRb (%) curec (%) Species identified

Ciclopirox applied once daily for 48 weeks Vehicle applied once daily for 48 weeks Ciclopirox applied once daily for 48 weeks Vehicle applied once daily for 48 weeks

30/105 (29)

7/107 (6.5)

6/110 (5.5)

12/106 (11)

1/108 (0.9)

1/109 (0.9)

41/115 (36)

14/116 (12)

10/118 (8.5)

10/114 (9)

1/115 (0.9)

0/117 (0)

T rubrum, T mentagrophytes

T rubrum, T mentagrophytes

MC (mycologic cure): negative KOH and negative culture. CR (clinical response): V10% nail involvement and negative mycology (culture and KOH). Complete cure: clear nail and negative mycology (culture and KOH).

[36]. The mycologic cure rates reported were 85% (KOH preparation) and 90% (culture); however, the combined mycology result was not stated [36]. In a case report, a 75-year-old man applied ciclopirox nail lacquer 8% daily to the toenails for 6 months; this led to the progressive disappearance of symptoms associated with moderate to severe onychomycosis [20]. Tosti et al [7] treated patients with toenail onychomycosis caused by nondermatophyte molds. The clinical presentations included proximal subungual onychomycosis, white superficial onychomycosis, and distal subungual onychomycosis. Twenty-one patients had distal subungual onychomycosis caused by S brevicaulis, Fusarium species, and Acremonium species. The authors concluded that topical therapy was effective in the treatment of onychomycosis caused by some nondermatophyte molds [7]. Combination therapy with ciclopirox nail lacquer A multinational, multicenter, randomized, and evaluator-blinded study is currently evaluating the combination of ciclopirox nail lacquer with terbinafine for the treatment of toenail onychomycosis with involvement of 60% or greater nail plate or matrix disease [45]. Patients receive one of three treatments: (1) terbinafine, 250 mg/d for 12 weeks with 48-week once daily application of ciclopirox nail lacquer; (2) terbinafine, 250 mg/d for 12 weeks; and (3) terbinafine, 250 mg/d for 8 weeks using an intermittent regimen with ciclopirox nail lacquer once daily for 48 weeks [45].

Safety The most common adverse events are the appearance of a rash (eg, periungual erythema and erythema of the proximal nail fold), with some patients reporting a burning or tingling sensation at the application site [13]. Nail disorders were infrequently reported for both the ciclopirox and vehicle group, and consisted of shape change, irritation, ingrown toenail, and discoloration [13]. The adverse reactions were generally mild and often resolved with continued application of ciclopirox nail lacquer [46]. Amorolfine nail lacquer Amorolfine is a topical antifungal agent of the morpholine class. It has a broad-spectrum of activity against yeasts, dermatophytes, and molds responsible for superficial fungal infections. Amorolfine is available in many countries for the treatment of onychomycosis, but is not approved in the United States for this indication. Mode of action Amorolfine acts at two points in the ergosterol biosynthetic pathway, inhibiting D14-reductase and D7-8-isomerase enzymes [47]. Inhibition of these enzymes leads to a lack of cell growth and cell death, and the accumulation of sterol molecules and ignosterol, a sterol containing a D14-double bond [48]. The accumulation of ignosterol and other sterol molecules no longer fulfills the steric requirements of the fungal membrane [48]. Also, ignosterol accu-

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mulation in Candida albicans indicates inhibition of D14-reductase [48,49]. Amorolfine activity Amorolfine demonstrates fungicidal activity toward dermatophytes, dimorphic fungi, C albicans, Cryptococcus neoformans, and dematiaceous fungi; activity is both time and concentration dependent [47,49]. This morpholine derivative has also demonstrated fungistatic activity toward a number of fungal species [47,49]. Pharmacokinetics An in-vitro penetration study examined the penetration of amorolfine (1%, 2%, and 5%) through porcine hoof horn material [50]. The highest accumulation of the drug was seen with the 5% amorolfine lacquer [50]. The penetration profile of the 5% amorolfine lacquer was examined over a 7-day period, where the concentration of amorolfine 5% in the nails increased linearly with a slight curve-shaped line, indicating saturation kinetics [50]. The kinetics of amorolfine in human nails follows an exponential law and the concentration of amorolfine in the upper layer of the nail plate is approximately 100 times higher than in the lowest layer [51]. The total amount of amorolfine in the nail depends on the thickness and consistency of the nail plate [51].

There are data in the literature on two galenic forms of amorolfine, one containing methylene chloride and the other ethanol. Franz [52] examined these two formulations to determine their affect on 5% amorolfine absorption. The rate of amorolfine absorption through a human thumbnail, following a single application, peaked between 5 and 25 hours and declined slowly thereafter in both the methylene chloride and ethanol lacquer. Rates of permeation through the nail ranged between 20 and 100 ng/ cm2/h [52]. In addition, Franz [52] found that amorolfine absorption was somewhat greater from the methylene chloride lacquer than the ethanol lacquer; however, Mensing et al [53] found no statistically significant difference between the two lacquer formulations. Efficacy Table 2 is a summary of the RCTs where amorolfine nail lacquer 5% has been used to treat onychomycosis caused by dermatophytes, nondermatophytes, and yeasts. In this literature search three RCTs [26,31,32] were found. In a comparison study, Lauharanta [26] found 5% nail lacquer was significantly more effective than 2% nail lacquer when applied once weekly for up to 6 months for the treatment of mild to moderate onychomycosis. Two open, randomized studies com-

Table 2 Summary of RCTs where amorolfine nail lacquer 5% solution has been used to treat onychomycosis Study type Open, randomized, parallel, comparative [31]

Open, randomized, multicenter, comparative [32]

Double-blind, randomized, parallel-design, multicenter [26] a b c d

Matrix involvement No

No

No

Treatment

Follow-up

MCd (%)

CRd (%)

Complete cure+ (%)

Amorolfine 5% once weekly for 6 mo Amorolfine 5% twice weekly for 6 mo Amorolfine 5% once weekly for 6 mo or more Amorolfine 5% twice weekly for 6 mo or more Amorolfine 5% once weekly for up to 6 mo

3 mo after treatment end

114/160 (71.2)a

120/160 (75)b

73/160 (45.6)c

125/166 (75.3)a

128/166 (77.1)b

86/166 (51.8)c

3 mo after treatment end

3 mo after treatment end

MC (mycologic cure): negative culture. CR (clinical response): cure or V10% of nail still affected. Complete cure: clinical cure and negative mycologic culture. Efficacy parameter not defined unless otherwise stated.

89/126 (70.6)

58/126 (46)c

108/142 (76.1)

77/142 (54.2)c

31/51 (60)

(38)

Species identified T rubrum, T mentagrophytes, yeasts, others

T rubrum, T mentagrophytes, yeasts, others

T rubrum, T mentagrophytes, yeasts, others

A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489

pared the efficacy and safety of once-weekly versus twice-weekly application of amorolfine [31,32]. Both studies found that cure rates were slightly higher in the twice-weekly groups; however, there was no statistically significant difference between the dosage regimens [31,32].

485

irritation [31,32]. There have been no reports of nonlocal adverse events experienced by the patient.

Other topical therapies Efficacy

Combination therapy with amorolfine nail lacquer In an open, multicenter study 147 patients were randomized to receive amorolfine 5% applied once weekly for 15 months in combination with terbinafine (250 mg/d) administered for 6 weeks (AT6) or 12 weeks (AT12), or terbinafine, 250 mg/d for 12 weeks (T12) [15]. At the end of the 18-month study, greater than 70% of the AT6 patients, approximately 90% of the AT12 patients, and greater than 60% of the T12 patients were mycologically cured (both negative microscopy and culture). The corresponding values for global cure (combined clinical-mycologic response) were 44% (N = 50), 72.3% (N = 47), and 37.5% (N = 48), respectively. The authors concluded that the combination of amorolfine and terbinafine might be an effective treatment for severe onychomycosis with nail matrix involvement [15]. In a similar study, Lecha et al [27] compared the efficacy of combined topical amorolfine and itraconazole with itraconazole alone in the treatment of severe toenail onychomycosis, defined as greater than or equal to 80% involvement of the surface or the matrix region of at least one toenail. Patients were treated with amorolfine 5% nail lacquer once weekly for 6 months in combination with itraconazole (200 mg/d) for 6 weeks (AI-6) or 12 weeks (AI-12), or itraconazole, 200 mg/d for 12 weeks (I-12) [27]. At week 24, statistically more patients in the combined treatment group ( 90%) were mycologically cured (negative microscopy and culture) compared with those treated with itraconazole (< 69%) alone (P < .001). Clinical cure (reduction of  95% in the original diseased nail surface area) was observed at week 24 in 88.1%, 100%, and 90.3% in the AI-6, AI-12, and I-12 groups, respectively. The corresponding values for global cure (combined mycologic-clinical outcome) were 83.7%, 93.9%, and 68.8%, respectively [27]. Safety Amorolfine nail lacquer seems to be a safe treatment of onychomycosis. Adverse events reported by patients included burning, itching, redness, and local pain; these symptoms were tolerable and confined to the application site [31,32]. Few complained of local

Several topical antifungal agents have been used to treat onychomycosis including tioconazole [35,38], miconazole [16,22,33,35], fungoid tincture [28,29], bifonazole urea [17,24], tea tree oil [18,34], topical ketoconazole [25], ciclopirox olamine cream [30,37], and vitamin E [21]. Most of these studies evaluated the effectiveness of topical agents in the treatment of onychomycosis caused by dermatophytes. Table 3 is a summary of the RCTs where topical agents other than ciclopirox and amorolfine nail lacquers have been used to treat onychomycosis caused by dermatophytes, nondermatophytes, and yeasts. In this literature search, five RCTs [18,22,29,34,35], nine open studies [16,17,24,25,28,30,33,37,38], and one case report [21] were found. In the RCTs, few studies mentioned the causative organism. Tea tree oil 5% combined with 2% butenafine was significantly more effective than tea tree oil alone (P < .0001) [34]. Miconazole cream was significantly less effective compared with oral itraconazole [22]. In an open study, Hay et al [38] evaluated the effectiveness of tioconazole 28% nail solution in the treatment of 27 patients with onychomycosis. Six patients, five of whom had fingernail infections, were clinically and mycologically free from infection 2 to 7 months after treatment [38]. Eleven patients showed marked improvement [38]. In an open, multicenter trial, 57% of the onychomycosis patients treated with a combination of 1% ciclopirox solution and cream for a mean duration of 12.7 F 5.6 weeks were free from signs of infection [30]. In an open study, ciclopirox olamine 1% cream was applied two to three times daily for 3 to 24 months in 42 patients with onychomycosis [37]. Fourteen percent of the patients were cured and 36% improved with treatment [37]. Avulsion of the onychomycotic nail before the application of topical agents may be beneficial. The topical treatment of onychomycosis with 1% bifonazole and 40% urea paste produced mycologic cure (negative direct microscopy and culture) rate of 62.5% at week 12 [24]. A similar study, evaluating the effectiveness of 1% bifonazole and 40% urea paste, demonstrated that at month 4, 45 (90%) of 50 patients were culture negative [17].

486

Table 3 Summary of RCTs where topical agents have been used to treat onychomycosis Study type Open, randomized, comparative [35]

NS

NS

NS

Treatment

Follow-up

28% tioconazole applied twice daily for at least 3 mo 2% miconazole tincture applied twice daily for at least 3 mo Miconazole cream twice daily for 6 mo, oral placebo for 6 mo Fungoid tincture applied twice daily for 12 mo

1 month after treatment end

Double-blind, randomized, multicenter [18]

NS

NS

2% butenafine hydrochloride and 5% tea tree oil in cream applied three times daily for 8 wk Placebo containing tea tree oil applied three times daily for 8 wk 100% tea tree oil applied twice daily for 6 mo 1% clotrimazole solution applied twice daily for 6 mo

Abbreviations: MC, mycologic cure; CR, clinical response; NS, not stated. a negative culture and a negative or missing microscopy result. b cured or markedly improved. c percentage of involvement. d Complete cure; neither clinical nor microscopic evidence of reinfection. e clinical cure and negative mycology. f Efficacy parameter not defined unless otherwise stated.

CRf (%)

Complete curef (%)

Species identified

17/19 (89)d

Not given

14/17 (82)d

6 mo after treatment end

143/238 (60)a

79/238 (32)b

Not given

2 mo after treatment end

negative culture: 5/10 (50); negative KOH: 5/10 (50) negative culture: 1/10 (10); negative KOH: 1/10 (10)

3/10 (30)c

Not given

Vehicle for 12 mo

Double-blind, randomized, placebo-controlled [34]

MCf

1/10 (10)c

32/40 (80)e

36 wk after treatment end

T rubrum, T mentagrophytes, T tonsurans

0/20 (0)e

Negative culture: 7/64 (11) Negative culture: 4/53 (8)

T rubrum, T mentagrophytes, other

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Double-blind, randomized, multicenter, parallel-group, comparative [22] Double-blind, randomized, vehicle-controlled study [29]

Matrix involvement

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487

After surgical avulsion of the nail plate, ketoconazole cream 2% was applied to the nail bed until the nail grew back to its normal length in 13 patients (aged 16 to 63 years old). Overall success was achieved in 95.7% of patients [25]. Rollman [33] evaluated the effectiveness of chemomechanical partial nail avulsion, followed by topical miconazole 2% solution applied twice daily for 8 weeks in the treatment of distal subungual onychomycosis. Clinical and mycologic examinations were based on the number of affected nails. Sixty percent of the nails were clinically cured, 63% had negative microscopy, and 58% had negative culture [33].

Summary

Combination therapy

References

A parallel-group double-blind, randomized study, compared the efficacy of topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin in the treatment of onychomycosis caused by dermatophytes [19]. Initially all patients were treated with urea 40% and bifonazole 1% ointment until the infected nail became completely detached. Bifonazole 1% cream was applied to the nail bed every 24 hours and patients were randomized to receive either griseofulvin (500 mg) or placebo for 4 weeks. Four months after therapy, mycologic cure (negative culture and KOH) was achieved in 45 patients (93%) in the combination group and 31 patients (66%) in the placebo group. Complete cure was achieved in 21 patients (43.7%) in the combination group and 10 (20%) in the placebo group [19]. In an open, comparative, randomized study, Arenas et al [14] evaluated the treatment of onychomycosis with itraconazole or griseofulvin alone or in combination with isoconazole 1% or urea 40%. When the systemic agent was combined with isoconazole 1%, 73% of patients treated with itraconazole were 90% to 100% cured compared with 46% of griseofulvin patients (P = .05) [14]. The combination of the systemic agent and urea 40% resulted in 90% to 100% cure rate in 78.5% of itraconazole patients and 42.8% of griseofulvin patients; the results were not significantly different (P = .10) [14]. Hay et al [23] evaluated the effectiveness of combined oral griseofulvin (500 mg administered twice daily) with 28% tioconazole (applied twice daily) compared with griseofulvin only in the treatment of toenail onychomycosis. In the combined treatment group, 69% achieved complete clinical and mycologic remission within 1 year, compared with 41% of those nails treated only with griseofulvin [23].

[1] Gupta AK, Taborda P, Taborda V, Gilmour J, Rachlis A, Salit I, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol 2000;39:746 – 53. [2] Gupta AK. Onychomycosis in the elderly. Drugs Aging 2000;16:397 – 407. [3] Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol 1998;139: 665 – 71. [4] Botter AA. Topical treatment of nail and skin infections with miconazole, a new broad-spectrum antimycotic. Mykosen 1971;14:187 – 91. [5] Downs AM, Lear JT, Archer CB. Scytalidium hyalinum onychomycosis successfully treated with 5% amorolfine nail lacquer. Br J Dermatol 1999;140:555. [6] Seebacher C, Nietsch KH, Ulbricht HM. A multicenter, open-label study of the efficacy and safety of ciclopirox nail lacquer solution 8% for the treatment of onychomycosis in patients with diabetes. Cutis 2001; 68(suppl 2):17 – 22. [7] Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000;42(2 pt 1):217 – 24. [8] Yu B, Zhou G, Wang B, Ben Y, Yan H, Shao Y, et al. A clinical and laboratory study of ciclopirox olamine (8% Batrafen) in the treatment of onychomycosis. Chin Med Sci J 1991;6:166 – 8. [9] Goodfield MJ, Evans EG. Treatment of superficial white onychomycosis with topical terbinafine cream. Br J Dermatol 1999;141:604 – 5. [10] Meyerson MS, Scher RK, Hochman LG, Cohen JL, Pappert AS, Holwell JE. Open-label study of the safety and efficacy of naftifine hydrochloride 1 percent gel in patients with distal subungual onychomycosis of the fingers. Cutis 1993;51:205 – 7. [11] Mahgoub ES. Clinical trial with clotrimazole cream (Bay b 5097) in dermatophytosis and onychomycosis. Mycopathologia 1975;56:149 – 52.

The management of onychomycosis using topical agents has improved with the introduction of ciclopirox and amorolfine nail lacquers; other topical agents may be less effective. The combination of a nail lacquer with an oral antifungal agent may further improve efficacy rates in certain clinical presentations (eg, among those individuals with severe onychomycosis). Topical agents have a favorable adverse events profile. Further studies are required on the treatment of onychomycosis with nail lacquers.

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[12] Lauharanta J, Zaug G, Polak A, Reinel D. Combination of amorolfine with griseofulvin: in vitro activity and clinical results in onychomycosis. JAMA 1993; 9(suppl. 4):23 – 7. [13] Penlac nail lacquer (ciclopirox) topical solution, 8% prescribing information. Dermik laboratories, Inc; 2000. Available at: http://www.dermik.com/prod/penlac/ pi.html. [14] Arenas R, Fernandez G, Dominguez L. Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol 1991;30:586 – 9. [15] Baran R, Feuilhade M, Combernale P, Datry A, Goettmann S, Pietrini P, et al. A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region. Br J Dermatol 2000;142:1177 – 83. [16] Bentley-Phillips B. The treatment of onychomycosis with miconazole tincture. S Afr Med J 1982;62:57 – 8. [17] Bonifaz A, Guzman A, Garcia C, Sosa J, Saul A. Efficacy and safety of bifonazole urea in the two-phase treatment of onychomycosis. Int J Dermatol 1995;34: 500 – 3. [18] Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole. J Fam Pract 1994;38:601 – 5. [19] Friedman-Birnbaum R, Cohen A, Shemer A, Bitterman O, Bergman R, Stettendorf S. Treatment of onychomycosis: a randomized, double-blind comparison study with topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin. Int J Dermatol 1997;36:67 – 9. [20] Galitz J. Successful treatment of onychomycosis with ciclopirox nail lacquer: a case report. Cutis 2001; 68(suppl 2):23 – 4. [21] Goldsmith S. Vitamin E and onychomycosis. J Am Acad Dermatol 1983;8:910 – 1. [22] Haneke E, Tajerbashi M, De Doncker P, Heremans A. Itraconazole in the treatment of onychomycosis: a double-blind comparison with miconazole. Dermatology 1998;196:323 – 9. [23] Hay RJ, Clayton YM, Moore MK. A comparison of tioconazole 28% nail solution versus base as an adjunct to oral griseofulvin in patients with onychomycosis. Clin Exp Dermatol 1987;12:175 – 7. [24] Hay RJ, Roberts DT, Doherty VR, Richardson MD, Midgley G. The topical treatment of onychomycosis using a new combined urea/imidazole preparation. Clin Exp Dermatol 1988;13:164 – 7. [25] Hettinger DF, Valinsky MS. Treatment of onychomycosis with nail avulsion and topical ketoconazole. J Am Podiatr Med Assoc 1991;81:28 – 32. [26] Lauharanta J. Comparative efficacy and safety of amorolfine nail lacquer 2% versus 5% once weekly. Clin Exp Dermatol 1992;17(suppl 1):41 – 3. [27] Lecha M. Amorolfine and itraconazole combina-

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tion for severe toenail onychomycosis; results of an open randomized trial in Spain. Br J Dermatol 2001; 145(suppl 60):21 – 6. Meyerson MS, Scher RK, Hochman LG, Cohen JL, Pappert AS, Holwell JE. Open-label study of the safety and efficacy of fungoid tincture in patients with distal subungual onychomycosis of the toes. Cutis 1992;49: 359 – 62. Montana JB, Scher RK. A double-blind, vehicle-controlled study of the safety and efficacy of fungoid tincture in patients with distal subungual onychomycosis of the toes. Cutis 1994;53:313 – 6. Qadripur SA, Horn G, Hohler T. [On the local efficacy of ciclopirox olamine in onychomycoses]. Arzneimittelforschung 1981;31:1369 – 72. Reinel D, Clarke C. Comparative efficacy and safety of amorolfine nail lacquer 5% in onychomycosis, onceweekly versus twice-weekly. Clin Exp Dermatol 1992; 17(suppl 1):44 – 9. Reinel D. Topical treatment of onychomycosis with amorolfine 5% nail lacquer: comparative efficacy and tolerability of once and twice weekly use. Dermatology 1992;184(suppl 1):21 – 4. Rollman O. Treatment of onychomycosis by partial nail avulsion and topical miconazole. Dermatologica 1982;165:54 – 61. Syed TA, Qureshi ZA, Ali SM, Ahmad S, Ahmad SA. Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream. Trop Med Int Health 1999;4:284 – 7. Tulli A, Ruffilli MP, De Simone C. The treatment of onychomycosis with a new form of tioconazole. Chemioterapia 1988;7:160 – 3. Ulbricht H, Worz K. [Therapy with ciclopirox lacquer of onychomycoses caused by molds]. Mycoses 1994; 37(suppl 1):97 – 100. Wu YC, Chuan MT, Lu YC. Efficacy of ciclopirox olamine 1% cream in onychomycosis and tinea pedis. Mycoses 1991;34:93 – 5. Hay RJ, Mackie RM, Clayton YM. Tioconazole nail solution: an open study of its efficacy in onychomycosis. Clin Exp Dermatol 1985;10:111 – 5. Marty J-PL. Amorolfine nail lacquer: a novel formulation. J Eur Acad Dermatol Venereol 1995;4(suppl. 1): S17 – 21. Gupta AK, Baran R. Ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Dermatol 2000; 43(suppl 4):S96 – 102. Gupta AK. Ciclopirox nail lacquer: a brush with onychomycosis. Cutis 2001;68(suppl 2):13 – 6. Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol 2000; 43(suppl 4):S57 – 69. Gupta AK. Ciclopirox nail lacquer topical solution 8%. Skin Therapy Lett 2000;6:1 – 5. Bohn M, Kraemer K. The dermatopharmacologic profile of ciclopirox 8% nail lacquer. J Am Podiatr Med Assoc 2000;90:491 – 4.

A.K. Gupta et al / Dermatol Clin 21 (2003) 481–489 [45] Gupta A. Exploring regimens to improve efficacy in the treatment of onychomycosis [abstract]. Ann Dermatol Venereol 2002;129:S664. [46] Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol 2000;43(suppl 4): S70 – 80. [47] Haria M, Bryson HM. Amorolfine: a review of its pharmacological properties and therapeutic potential in the treatment of onychomycosis and other superficial fungal infections. Drugs 1995;49:103 – 20. [48] Polak-Wyss A. Mechanism of action of antifungals and combination therapy. J Eur Acad Dermatol Venereol 1995;4(suppl 1):S11 – 6. [49] Polak AM. Preclinical data and mode of action of amorolfine. Clin Exp Dermatol 1992;17(suppl 1):8 – 12.

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[50] Pittrof F, Gerhards J, Erni W, Klecak G. Loceryl nail lacquer: realization of a new galenical approach to onychomycosis therapy. Clin Exp Dermatol 1992; 17(suppl 1):26 – 8. [51] Polak A. Kinetics of amorolfine in human nails. Mycoses 1993;36:101 – 3. [52] Franz TJ. Absorption of amorolfine through human nail. Dermatology 1992;184(suppl. 1):18 – 20. [53] Mensing H, Polak-Wyss A, Splanemann V. Determination of the subungual antifungal activity of amorolfine after 1 month’s treatment in patients with onychomycosis: comparison of two nail lacquer formulations. Clin Exp Dermatol 1992;17(suppl 1):29 – 32.

Dermatol Clin 21 (2003) 491 – 497

Treatment of nondermatophyte mold and Candida onychomycosis Antonella Tosti, MD*, Bianca Maria Piraccini, PhD, MD, Sandra Lorenzi, MD, Matilde Iorizzo, MD Department of Dermatology, University of Bologna, Via Massarenti 1, 40138 Bologna, Italy

Mold onychomycosis can often be clinically suspected because of the presence of periungual inflammation. Treatment with systemic antifungals is very effective in onychomycosis caused by Aspergillus sp. Scopulariopsis brevicaulis and Fusarium sp. infection are difficult to eradicate and treatment with systemic antifungals should always be associated with topical treatment with nail lacquers. Candida onychomycosis is always a sign of immunodepression. Systemic treatment with itraconazole or fluconazole is usually effective, but relapses are very common.

Mold onychomycosis Onychomycosis caused by molds is becoming increasingly common worldwide (Table 1) [1 – 5]. Nondermatophytic molds account for up to 15% of nail infections in Bologna. Molds that are responsible for onychomycosis include S brevicaulis, Acremonium sp, Aspergillus sp, Fusarium sp, Scytalidium sp, Onychocola canadensis, and Alternaria sp [6]. Different modalities of nail invasion by molds are reported in Table 2. Treatment of mold infection depends on the type of onychomycosis and the responsible mold. Distal subungual onychomycosis Distal subungual onychomycosis from molds is clinically similar to distal subungual onychomycosis

* Corresponding author. E-mail address: [email protected] (A. Tosti).

caused by dermatophytes (Fig. 1) except for the possible presence of painful periungual inflammation. This is common in distal subungual onychomycosis caused by S brevicaulis or Fusarium sp (Figs. 2 and 3). Involvement of the sole is absent except for S brevicaulis infection, which may occasionally produce tinea pedis (Fig. 4). Nail and periungual pigmentation can occur in infection caused by Scytalidium sp. Proximal subungual onychomycosis Proximal subungual onychomycosis caused by molds can be suspected from clinical examination because it is frequently associated with periungual inflammation and purulent discharge (Figs. 5 – 8). White superficial onychomycosis White superficial onychomycosis caused by molds differs from white superficial onychomycosis caused by dermatophytes in that nail plate involvement is deeper and more extensive (Figs. 9 and 10). This can be verified easily when scraping the

Table 1 Prevalence of mold onychomycosis in various countries Country

Year and reference

Prevalence (%)

Istanbul (Turkey) Hong Kong (China) Athens (Greece) Milan (Italy) Helsinki (Finland)

1999 1997 1998 2000 1995

2.1 3 6.5 9 12.5

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[1] [2] [3] [4] [5]

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Table 2 Modalities of nail invasion by nondermatophytic molds

Scopulariopsis brevicaulis Acremonium sp Aspergillus sp Fusarium sp Onychocola canadensis Scytalidium sp Alternaria sp

Distal subungual onychomycosis

Proximal subungual onychomycosis

+ + + + + + +

+

superficial nail plate to obtain specimens for mycology [7].

Treatment Distal and proximal subungual onychomycosis Distal and proximal subungual onychomycosis caused by Aspergillus sp can be treated with systemic

Fig. 1. Distal subungual onychomycosis (DSO) caused by Acremonium sp. The clinical picture is identical to that of DSO caused by dermatophytes.

White superficial onychomycosis

+ +

+ + +

+

+

terbinafine, 250 mg/d for 2 to 3 months, or itraconazole, 400 mg/d for 1 week a month for 2 to 3 months. In the authors’ experience Aspergillus sp onychomycosis responds very well to systemic treatment with both drugs. Mycologic cure is usually associated with clinical cure and relapses are extremely rare (Figs. 11 and 12). Distal and proximal subungual onychomycosis caused by Acremonium sp, S brevicaulis, Fusarium sp, O canadensis, and Scytalidium sp are very difficult to cure [8 – 10].

Fig. 2. DSO caused by Scopulariopsis brevicaulis. Note proximal spreading with periungual inflammation.

A. Tosti et al / Dermatol Clin 21 (2003) 491–497

Fig. 3. DSO caused by Fusarium solani. The proximal nail fold shows erythema and nail swelling.

Scopulariopsis brevicaulis infection In the authors’ experience systemic antifungals (itraconazole and terbinafine) fail to produce mycologic cure in half of the patients (Figs. 13 and 14). The combination of topical antifungals in nail lacquer with systemic treatment increases the percentage of cure. About one fourth of patients remain mycologically positive, however, even after prolonged admin-

Fig. 4. Tinea pedis caused by S brevicaulis.

493

Fig. 5. Proximal subungual onychomycosis (PSO) caused by molds: S brevicaulis. The presence of periungual inflammation suggests the diagnosis.

istration of combined systemic and local therapy. Periodical nail avulsion can be helpful but requires frequent care and is not always accepted by patients. Fusarium sp infection Fusarium sp onychomycosis is very difficult to treat. Systemic antifungals alone are not effective in most cases and the combination of systemic and topical treatments produces mycologic cure in only one third of patients (Figs. 15 and 16). Most cases of onychomycosis caused by Fusarium sp do not improve even after long-term treatment. Nail avulsion is also of little help. Scytalidium sp infection Scytalidium sp infections do not respond to systemic treatment. Patients with this infection are very difficult to manage and nail avulsion and topical treatment are usually ineffective. Recently, a case of complete cure of Scytalidium hyalinum fingernail onychomycosis using amorolfine nail lacquer has been reported [11].

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Fig. 6. PSO caused by molds: F oxysporum. The presence of periungual inflammation suggests the diagnosis.

Onychocola canadensis infection Onychocola canadensis is usually resistant to treatment and most of the cases reported in the literature were not cured by any treatment [12].

Candida onychomycosis

Fig. 7. PSO caused by molds: Aspergillus flavus. The presence of periungual inflammation suggests the diagnosis.

evidence indicates that chronic paronychia is an environmental condition caused or worsened by irritants or allergens. Management of chronic paronychia is similar to that of chronic hand dermatitis and includes protective measures (gloves or barrier creams); topical steroids; and systemic steroids in severe cases. This has been confirmed by a recent double-blind study that showed that topical steroids

Candida onychomycosis is a rare condition that exclusively affects immunocompromised individuals. These include patients with chronic mucocutaneous candidiasis, patients with HIV infection, and patients treated with immunosuppressive drugs. Chronic paronychia Although Candida is frequently isolated from the proximal nail fold of patients with chronic paronychia, the presence of the yeast in this condition should be considered a secondary phenomenon (Fig. 17). Systemic antifungals are of no value in the treatment of chronic paronychia, because Candida eradication does not produce cure of the disorder. Accumulating

Fig. 8. PSO caused by molds: Aspergillus terreus. The presence of periungual inflammation suggests the diagnosis.

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495

Fig. 9. White superficial onychomycosis (WSO) caused by molds: Aspergillus candidus.

Fig. 12. Clinical and mycologic cure after treatment with systemic antifungals.

Fig. 10. WSO caused by molds: A terreus. The nail plate is diffusely involved.

Fig. 13. DSO caused by S brevicaulis.

Fig. 11. PSO caused by A terreus.

Fig. 14. This patient (shown in Fig. 13) was treated with systemic terbinafine and systemic itraconazole (pulse therapy) without benefit.

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Fig. 15. DSO caused by F solani.

Fig. 16. This patient (shown in Fig. 15) was mycologically cured combining systemic itraconazole (pulse therapy) with topical amorolfine nail lacquer.

Fig. 17. Chronic paronychia: erythema and swelling of the proximal nail fold with absence of the cuticle. Colonization by Candida is a secondary phenomenon.

Fig. 18. Nail thickening and periungual swelling caused by Candida onychomycosis in a patient with chronic mucocutaneous candidiasis.

Fig. 19. Diffuse leukonychia of several nails caused by Candida onychomycosis in a patient undergoing chronic corticosteroid treatment.

Fig. 20. Candida onychomycosis in a patient with chronic mucocutaneous candidiasis.

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References

Fig. 21. Clinical and mycologic cure of patient in Fig. 20 after treatment with systemic fluconazole.

are more effective than systemic antifungals in treating the condition [13]. Candida onychomycosis Nail invasion by Candida produces primary total onychomycosis associated with periungual swelling. In severe cases the nails are thickened and yellowbrown in color (Fig. 18), whereas in mild cases the nail is not hyperkeratotic and shows a diffuse leukonychia (Fig. 19). Treatment of Candida onychomycosis is complicated by the fact that underlying immunodeficiency causes repetitive relapses of the nail infection. Results of treatment depend more on the immunologic status of the patients than on the used antifungals. Itraconazole and fluconazole are equally effective in treating Candida onychomycosis (Figs. 20 and 21). Itraconazole can be used both as continuous treatment at the dosage of 200 mg/d or as pulse therapy at the dosage of 400 mg/d for 1 week a month [14,15]. Fluconazole can be used at the dosage of 50 mg/d or as pulse therapy at the dosage of 300 mg/wk. Duration of treatment is 6 weeks for fingernails and 3 months for toenails. In patients with chronic mucocutaneous candidiasis relapses are the rule and some patients may fail to respond to normal dosages and require higher or even double dosages of antifungals. The necessity to prolong and re-administer systemic antifungals for years may be responsible for fungal resistance. Both ciclopirox olamine and amorolfine nail lacquers are effective against Candida and can be used in association with systemic antifungals.

[1] Kiraz M, Yegenoglu Y, Erturan Z, et al. The epidemiology of onychomycoses in Istanbul. Turkey. Mycoses 1999;42:323 – 9. [2] Kam KM, Au WF, Wong PY, et al. Onychomycosis in Hong Kong. Int J Dermatol 1997;36:757 – 61. [3] Rigopoulos D, Katsiboulas V, Koumantaki E, et al. Epidemiology of onychomycosis in southern Greece. Int J Dermatol 1998;37:925 – 8. [4] Gianni C, Cerri A, Crosti C. Non-dermatophytic onychomycosis. An underestimated entity? A study of 51 cases. Mycoses 2000;43:29 – 33. [5] Heikkila H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol 1995;133:699 – 703. [6] Baran R, Hay R, Haneke E, et al. Onychomycosis: the current approach to diagnosis and therapy. London: Martin Dunitz; 1999. [7] Piraccini BM, Lorenzi S, Tosti A. Deep white superficial onychomycosis due to moulds. J Eur Acad Dermatol Venereol 2002;16:532 – 3. [8] Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by non-dermatophytic moulds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000;42(2 pt 1):217 – 24. [9] Gupta AK, Gregurek-Novak T, Konnikov N, et al. Itraconazole and terbinafine treatment of some nondermatophyte molds causing onychomycosis of the toes and a review of the literature. J Cutan Med Surg 2001; 5:206 – 10. [10] De Doncker PR, Scher RK, Baran R, et al. Itraconazole therapy is effective for pedal onychomycosis caused by some nondermatophyte molds and in mixed infection with dermatophytes and molds: a multicenter study with 36 patients. J Am Acad Dermatol 1997; 36(2 pt 1):173 – 7. [11] Downs L, Downs A. Scytalidium hyalinum onychomycosis successfully treated with 5% amorolfine nail lacquer. Br J Dermatol 1999;140:555. [12] Gupta AK, Horgan-Bell CB, Summerbell RC. Onychomycosis associated with Onychocola canadensis: ten case reports and a review of the literature. J Am Acad Dermatol 1998;39:410 – 7. [13] Tosti A, Piraccini BM, Ghetti E, et al. Topical steroids versus systemic antifungals in the treatment of chronic paronychia: an open, randomized double blind and double dummy study. J Am Acad Dermatol 2002; 147:73 – 6. [14] Tosti A, Piraccini BM, Vincenzi C, et al. Itraconazole in the treatment of two young brothers with chronic mucocutaneous candidiasis. Pediatr Dermatol 1997;14: 146 – 8. [15] Tosti A, Piraccini BM, Lorenzi S, et al. Candida onychomycosis in HIV infection. Eur J Dermatol 1998; 8:173 – 4.

Dermatol Clin 21 (2003) 499 – 505

How to improve cure rates for the management of onychomycosis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Jennifer E. Ryder, HBScb a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada

The availability of the new oral antifungal agents terbinafine, itraconazole, and fluconazole and the lacquers ciclopirox and amorolfine has provided additional options for the management of onychomycosis. Epidemiology studies have shown that the prevalence of onychomycosis ranges from 6.5% to 12.8% [1,2]. Factors associated with the development of onychomycosis include a history of tinea pedis [3]; family history of onychomycosis [4]; increasing age (elderly patients greater than 60 years old more frequently affected) [5]; male gender [5,6]; previous trauma to the nail [2,6]; peripheral arterial disease [7]; and smoking [7]. Certain special populations (ie, approximately one third of diabetic subjects and one fifth of HIV-positive individuals) are expected to have onychomycosis [8,9]. This article reviews strategies that may improve cure rates and reduce failure following treatment of onychomycosis. Also discussed are ways in which recurrence of onychomycosis can be reduced once cure is reached.

Strategies to improve efficacy Correct diagnosis of onychomycosis Clinical and laboratory diagnosis of onychomycosis are important in the management of this infection. It should be noted that not all abnormal-appearing nails * Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

have onychomycosis; in fact, only approximately 50% of nails that seem to be abnormal may have documented onychomycosis [6]. In certain instances, abnormal-appearing nails may be caused by psoriasis, eczema, trauma, lichen planus, or another disorder. In addition, onychomycosis may coexist with another nail disease, such as psoriasis [10]. Light microscopy and culture examination determines the presence of fungal filaments and the identity of the causative organism. Some nondermatophyte organisms, for instance Scytalidium species, produce infections that may clinically mimic the symptoms and signs seen in dermatophyte infections [11]. Stringent criteria are required to ensure proper diagnosis of nondermatophyte infections. Such criteria should include microscopic examination, culture, and as an alternative, histologic examination of nail material. Direct microscopic examination involves treating nail material with potassium or sodium hydroxide to demonstrate whether fungal filaments or hyphae or pseudohyphae, consistent with the organism isolated in culture, are present. The use of fluorescent microscopy using stains, such as Calcofluor, may aid in the detection of fungal filaments [12]. To confirm that a nondermatophyte mold is the sole etiologic agent, a repeated culture of the suspected causal organism in the absence of any growth of a dermatophyte on two or more separate occasions in time is required [13]. Recent literature suggests that a strong statistical correlation, with the likelihood that a nondermatophyte is the etiologic organism, occurs when 11 or more out of every 15 inocula planted are culturepositive in combination with a positive light microscopic examination [13].

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00026-3

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The type of medium used to culture nail samples can affect the results and limit the identification of the causative organisms. For instance, culture media that contains cycloheximide may prevent or retard nondermatophyte growth. It is imperative that nail samples are cultured on cycloheximide-free media and cycloheximide-supplemented media. Histopathologic examination of nail material may be an alternative to microscopy and culture; this technique also provides a permanent record and permits re-evaluation of the specimen [14]. It may not be possible, however, to identify the nature of the organism when this method is used. Choose the most appropriate antifungal agent The effective management of onychomycosis may, in part, be dependent on the causative organism [15,16]. The newer oral and topical antifungal agents are effective therapies in treating dermatophytes and some nondermatophytes [17 – 28]. These agents, however, are not equally effective and this may partially explain some therapeutic failures [29]. Correct identification of the causative organism may aid in the selection of an optimum treatment [30]. In general, compared with the data that are available for the management of dermatophytes with the antifungal agents, there is relatively less information regarding the use of these antimycotics for the treatment of Candida species and nondermatophyte molds. Certain organisms, such as Scytalidium dimidiatum and Onychocola canadensis, may be poorly responsive or unresponsive to any of the currently available oral antifungal agents, griseofulvin, terbinafine, itraconazole, and fluconazole [31 – 33]. Griseofulvin is not effective against Candida species or nondermatophyte molds. Studies have shown that terbinafine is effective in treating dermatophyte and nondermatophyte infections; however, the response is more variable in the latter [34]. For instance, C parapsilosis responds better to terbinafine treatment than C albicans, possibly because the allylamine is fungicidal toward C parapsilosis and fungistatic toward C albicans [24,35]. Onychomycosis caused by Candida species and some nondermatophyte molds may respond to itraconazole [20,36, 37]. Fluconazole may also be effective in treating nondermatophyte mold and Candida nail infections; however, there is relatively little literature to support this indication for the triazole [38 – 40]. Ciclopirox and amorolfine nail lacquers are broad spectrum and may be effective in the management of onychomycosis caused by Candida species and some nondermatophyte molds [41].

Bioavailability of the oral antifungal agent may contribute to efficacy The bioavailability of the antifungal agent may, in some instances, be enhanced when given with a meal or beverage. The absorption of griseofulvin from the gastrointestinal tract varies among individuals; this is mainly caused by the insolubility of the drug in the aqueous media of the upper gastrointestinal tract [42]. The absorption of griseofulvin can be improved if taken after a meal with a high fat content [42]. Similarly, the oral bioavailability of itraconazole is maximal when taken with a full meal [43]. In patients with relative or absolute achlorhydria or those taking gastric acid suppressors (eg, H2 receptor antagonists) the absorption of itraconazole is increased when administered with an acidic drink, such as a cola beverage [43]. Terbinafine and fluconazole are not influenced markedly by concomitant food intake. Drug interactions may lead to unfavorable results Drug interactions may affect the concentration of the oral antifungal agent in the systemic circulation and at the site of interest (ie, the nail unit [for more details see the article by Katz and Gupta elsewhere in this issue]). The clearance of terbinafine is increased 100% by rifampin (CYP450 enzyme inducer); decreased 33% by cimetidine (CYP450 enzyme inhibitor); but unaffected by cyclosporine [44]. In vitro studies have shown that terbinafine inhibits CYP2D6mediated metabolism; this may affect compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, b-blockers, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors type B [44]. Itraconazole and hydroxyitraconazole (the major metabolite) are both inhibitors of CYP3A4. The plasma concentration of some drugs that are metabolized by CYP3A4 may be increased when these agents are administered with itraconazole; as a result, the therapeutic effects or side effects of these drugs may be increased or prolonged [43]. There are several drugs that are contraindicated with itraconazole because their drug plasma concentration is increased by the triazole. The contraindicated drugs include astemizole; terfenadine; cisapride; certain cholesterol-lowering agents that are inhibitors of hydroxymethyglutaryl coenzyme A reductase (eg, simvastatin, lovastatin); some benzodiazepines (oral midazolam and triazolam); pimozide; quinidine; and dofetilide [43,45]. Inducers of CYP3A4 (eg, nevirapine) may decrease the plasma concentrations of itraconazole resulting in its ineffectiveness [43]. In turn, inhibitors of CYP3A4 (eg, erythromycin

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and clarithromycin) may increase the plasma concentrations of itraconazole; in these cases, patients should be monitored closely for any pharmacologic effects of the azole [43]. The coadministration of terfenadine with fluconazole at multiple doses of 400 mg or higher is contraindicated [46]. The triazole is also contraindicated with cisapride [46]. Fluconazole levels are increased when administered with hydrochlorothiazide, but decreased with rifampin [46]. A significant increase in prothrombin time response occurs when warfarin and fluconazole are coadministered [46]. When fluconazole is administered, the drug levels of the following may increase: cisapride, phenytoin, cyclosporine, theophylline, zidovudine, tolbutamide, glipizide, and glyburide [46]. Reports have been published suggesting that the concomitant administration of fluconazole with rifabutin or tacrolimus may lead to elevated levels of the azole [46]. Griseofulvin may interact with anticoagulants; patients on warfarin-type anticoagulant therapy may require a dosage adjustment during and after treatment. The concomitant administration of griseofulvin and oral contraceptives may reduce the effectiveness of the latter [42]. Poor patient compliance Patient compliance with the drug regimen should be monitored carefully because the lack of compliance may result in inadequate drug levels and subsequent failure to eradicate the fungus. Boosted antifungal therapy with an oral or topical agent Failure to respond to therapy may, in part, be caused by resting fungal cells that are refractory to the action of the current oral and topical antifungals [47]. Pierard et al [47] examined nail fragments that were deposited on Sabouraud’s agar plates and found that aerial hyphae frequently grew out of the nail plate itself before invading the culture media. The authors proposed that if such effects could be induced and combined with an antifungal agent this may result in a fungitoxic effect against the fungal cells within the nail [47]. Thirteen patients were instructed to apply amorolfine 5% nail lacquer onto the affected nail, once weekly [47]. Every second day a piece of agar plate was applied to the affected nail for 24 hours for 1 week; thereafter, amorolfine was applied once weekly for 3 consecutive weeks. Five of 13 patients were mycologically cured after 1 month of treatment and a further

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six after a second 1-month treatment [47]. The results suggest that boosted antifungal topical therapy may be an alternative approach in difficult-to-treat onychomycosis. Similar results were observed when Sabouraud’s agar was used with itraconazole pulse therapy. Pierard et al [48] also proposed that boosted oral antifungal therapy might increase treatment effectiveness, and decrease adverse effects, cost of therapy, and duration. A risk involved in these therapeutic approaches is the potential to stimulate the growth of fungal organisms unresponsive to the antimycotic agent. The nail surface should be cleaned before applying the agar plate to minimize or eliminate opportunistic microorganisms. It should be noted that the techniques of boosted antifungal topical therapy and boosted oral antifungal therapy have yet to achieve widespread acceptance because of concerns of uncontrolled growth of dermatophytes or nondermatophyte molds, with subsequent systemic spread. Booster or supplemental oral therapy In the treatment of toenail onychomycosis, terbinafine, 250 mg, is generally administered daily for 12 weeks. The standard regimen for itraconazole is three-pulse therapy (200 mg twice daily for 1 week with 3 weeks between each pulse). Pharmacokinetic data suggest that there is a window of opportunity for booster therapy, in which additional drug could be prescribed after the start of treatment [49]. During this window, which may be between month 6 and 9 from the start of therapy, it may be possible to administer terbinafine for an extra 4 weeks or an extra pulse of itraconazole to enhance cure rates of onychomycosis [50]. Beyond 9 months from the start of therapy, drug concentrations within the nail may fall to such an extent that a short burst of extra therapy is not sufficient to affect a cure [49]. Supplemental oral therapy should be considered in the following situations: poor outgrowth of nail (eg, there is less than 50% reduction in the initial nail plate area that was diseased at baseline [51]); a thickened nail plate (ie, greater than 2 mm); lateral onychomycosis [52]; severe onychomycosis (eg, proximal involvement or 75% of the nail plate or bed is diseased); dermatophytoma [53]; a patient with immunosuppression; a patient with a history of relapse; and when the culture is still positive 6 months from the start of antifungal therapy. Supplemental mechanical therapy In some instances it may be prudent to consider combining mechanical debridement and partial avul-

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sion of the nail with oral or topical antifungal therapy. For example, in cases where there is lateral nail plate involvement or a longitudinal spike (dermatophytoma) is present, there may be a benefit to combining partial nail avulsion with antifungal therapy [52 – 55]. Similarly, nail debridement or avulsion has been used as supplemental therapy when the nail plate is substantially thick [50,56,57]. Sequential therapy of antifungal agents terbinafine and itraconazole Terbinafine and itraconazole both prevent the formation of ergosterol, an essential component of the fungal cell membrane. Terbinafine specifically inhibits fungal ergosterol biosynthesis at the point of squalene epoxidation; this causes the treated fungal cells to accumulate the intermediate squalene and become deficient in the end product of the pathway, ergosterol [58]. Itraconazole inhibits the cytochrome P-450 enzyme, lanosterol 14-a demethylase, with resultant inhibition in the conversion of lanosterol to ergosterol [45]. Depletion of ergosterol causes damage to the fungal cell membrane altering its function and permeability. It is thought that the use of terbinafine and itraconazole in sequential therapy may be an effective regimen because the synthesis of ergosterol is prevented at two distinct steps in the pathway [59]. A prospective, single-blind, randomized, comparative, parallel-group study evaluated 75 patients with toenail onychomycosis [59]. The patients received two pulses of itraconazole (200 mg twice daily for 1 week) followed by one pulse of terbinafine (250 mg twice daily for 1 week). Seventy-two percent of patients were mycologically cured at week 72 from the start of therapy, with a relapse rate of 13.3% [59]. A similar study on fingernail onychomycosis had 20 patients receiving one pulse of itraconazole (200 mg twice daily for 1 week) followed by a pulse of terbinafine (250 mg twice daily for 1 week) [60]. Six months from the start of therapy, 19 of 20 patients were mycologically cured [60]. Sequential therapy with itraconazole and terbinafine may reduce the duration of active drug therapy and provide a cost-effective alternative to the standard approved regimens used to treat onychomycosis [61]. In addition the duration of time a patient has to discontinue a contraindicated drug is reduced [59,60]. The combination of therapeutic agents may result in increased efficacy, a broader spectrum of action, improved patient tolerability, and reduced patient exposure to each individual drug. These benefits can be the result of drug synergy [62,63]. Few studies

have been conducted using the combination of two oral antifungal agents. Currently a prospective, multicenter, evaluator-blinded, randomized, parallel group study is evaluating the combination of terbinafine and itraconazole in the treatment of toenail onychomycosis. The regimen involves itraconazole, 200 mg/d, administered for 4 weeks; at week 2, terbinafine, 250 mg/d, is commenced for the duration of 4 weeks. To date, this regimen has been safe and effective [64]. There are preliminary data suggesting the role of combining therapy using terbinafine and fluconazole to treat onychomycosis [65]. The combination of topical and oral antifungals can provide dual drug penetration when treating onychomycosis. Topical agents may directly penetrate the nail plate, including the lateral margins; oral agents accumulate in the nail bed [62]. The treatment of severe onychomycosis may be improved with the combination of oral and topical agents [63,66 – 68]. Successful treatment of onychomycosis has been demonstrated with the combination of amorolfine and terbinafine [66,67]. Baran et al [66,67] compared the effectiveness of the following treatment groups: 15 months of once-weekly topical amorolfine lacquer in combination with 6 weeks (AT6) or 12 weeks (AT12) of oral terbinafine (250 mg/d); or oral terbinafine alone for 12 weeks (T12). At month 18, 44% (N = 50), 72.3% (N = 47), and 37.5% (N = 48) in the AT6, AT12, and T12 groups, respectively, were mycologically and clinically cured [66]. In an open, randomized clinical study, Lecha [63] compared the combination of topical amorolfine with oral itraconazole therapy with itraconazole monotherapy. Patients with severe toenail onychomycosis were treated with amorolfine 5% nail lacquer once weekly for 24 weeks and itraconazole, 200 mg, once daily for 6 or 12 weeks, or only itraconazole, 200 mg once daily, for 12 weeks. At week 24, greater than 90% of patients in the combination group were mycologically cured; however, less than 69% of those treated with itraconazole monotherapy reached mycologic cure (P < .001) [63]. There may be synergy in vitro when ciclopirox is used in combination with terbinafine and itraconazole. Furthermore, there are clinical data suggesting that ciclopirox may also be effective when combined with itraconazole [68,69] or terbinafine [68].

Strategies to reduce relapse and reinfection Onychomycosis may seem to be treated successfully; however, relapse or reinfection may occur following antifungal therapy. Relapse of onychomy-

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cosis is the ‘‘re-appearance of the same episode of disease, whatever time has elapsed’’; reinfection is the ‘‘re-appearance of a new episode of the same disease caused by a new infection’’ [70]. To minimize the recurrence of onychomycosis patients should be educated about proper nail care: nails should be kept cut short and clean; socks worn should be made of absorbent material (eg, cotton); feet should be dried completely following a bath or shower; and when appropriate, antifungal foot powders should be applied to shoes [5,71]. Lifestyle modifications may also be necessary, such as wearing proper footwear when walking in communal areas (eg, public baths, gymnasiums, health spas, and so forth); wearing comfortable shoes of correct size and fit; and discarding old or worn shoes that may have a high density of fungal spores. Other measures that may reduce the recurrence of onychomycosis include treating family members and close friends with tinea pedis or onychomycosis and prophylactic treatment with a topical antifungal agent [5]. The management of onychomycosis using antifungal agents still remains to be the approved regimen within the package inserts. Other regimens, such as those discussed in this article, may be worthy of consideration when there is a poor response or failure.

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Management of onychomycosis in children Antonella Tosti, MD*, Bianca Maria Piraccini, PhD, MD, Matilde Iorizzo, MD Department of Dermatology, University of Bologna, Via Massarenti 1, 40138 Bologna, Italy

Although onychomycosis is not common in children, the prevalence of this condition in the pediatric population is increasing [1,2]. Children with onychomycosis should be examined for the presence of tinea capitis (fingernail infection with anthropophilic dermatophytes) and tinea pedis. Because susceptibility to onychomycosis is probably inherited, parents of affected children should also be evaluated for onychomycosis or tinea pedis (Figs. 1 and 2). Most children with onychomycosis have distal subungual onychomycosis and require systemic treatment. For this reason the diagnosis of onychomycosis should always be mycologically confirmed. Differential diagnosis of onychomycosis in children includes nail psoriasis (Fig. 3); congenital malalignment of the big toenail (Fig. 4); subungual exostosis; subungual warts (Fig. 5); subungual hematoma (Fig. 6); paronychia caused by finger sucking; and parakeratosis pustolosa (Fig. 7). Although griseofulvin is still considered the treatment of choice in dermatophyte infections of children, this possibly may not apply to onychomycosis, because the duration of treatment (9 to 12 months) and high frequency of treatment failure make it unrecommendable. Drugs for the treatment of fungal infection in children would ideally be available in a liquid and tasteful formulation, but most antifungals (eg, terbinafine, itraconazole, and fluconazole) are available as tablets or capsules that are difficult to swallow and cannot be divided easily into fractions to obtain the perfect proweight dosage. Although itraconazole is also available in an oral solution, this

* Corresponding author. E-mail address: [email protected] (A. Tosti).

is not approved for onychomycosis and contains cyclodextrin, which may cause diarrhea in children. Similarly, fluconazole exists in the form of oral suspension, which is administered easily to children, but again is not approved. Strategies that can be used for administering systemic antifungals in children include chopping the terbinafine tablet into small pieces and putting them into the chocolate cream of a chocolate-filled biscuit, or opening the itraconazole capsule and mixing the content with fatty food, such as peanut butter, jelly, or bread. Terbinafine, itraconazole, and fluconazole are usually well tolerated, safe, and side effects are rare and minor [3 – 6]. Laboratory monitoring of the liver function, however, is always advisable. Dosages for treatment of childhood onychomycosis with systemic antifungals are as follows: Terbinafine Less than 20 kg: 62.5 mg/d (0.25 tablet) 20 to 40 kg: 125 mg/d (0.50 tablet) 40 kg: 250 mg/d (1 tablet) Duration of treatment is the same as for adults (ie, 6 weeks for fingernails and 3 months for toenails) Itraconazole 5 mg/kg/d as pulse treatment (1 week a month) Duration is two pulses for fingernails and three pulses for toenails Fluconazole 3 to 6 mg/kg once a week Duration is 12 to 16 weeks for fingernails and 18 to 26 weeks for toenails Topical antifungals can possibly better penetrate the thin nail plate of children and are used as firstchoice treatment by several authors. Their efficacy,

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Fig. 1. Distal subungual onychomycosis (DSO) caused by Trichophyton rubrum in a 10-year-old child.

Fig. 4. Congenital malalignment of the big toenail producing distal onycholysis.

Fig. 2. DSO caused by T rubrum in the child’s mother. Fig. 5. Onycholysis and subungual hyperkeratosis caused by a viral wart.

Fig. 3. Toenail psoriasis in a child: the presence of onycholysis with erythematous border suggests the diagnosis of psoriasis.

Fig. 6. Subungual hematoma.

A. Tosti et al / Dermatol Clin 21 (2003) 507–509

509

References

Fig. 7. Parakeratosis pustolosa producing distal hyperkeratosis and onycholysis.

however, is usually scarce. Chemical nail avulsion facilitates nail penetration and explains the success of bifonazole-urea ointment in up to 70% of cases [7]. Experience with topical antifungals in nail lacquer is limited [8].

[1] Philpot CM, ShuttleWorth D. Dermatophyte onychomycosis in children. Clin Exp Dermatol 1989;14:203 – 5. [2] Chang P, Logemann H. Onychomycosis in children. Int J Dermatol 1994;33:550 – 1. [3] Gupta AK, Chang P, Del Rosso JQ, et al. Onychomycosis in children: prevalence and management. Pediatr Dermatol 1998;15:464 – 71. [4] Gupta AK, Sibbald RJ, Lynde CW, et al. Onychomycosis in children: prevalence and treatment strategies. J Am Acad Dermatol 1997;36(3 pt 1):395 – 402. [5] Huang PH, Paller AS. Itraconazole pulse therapy for dermatophyte onychomycosis in children. Arch Pediatr Adolesc Med 2000;154:614 – 8. [6] Gupta AK, Del Rosso JQ. Management of onychomycosis in children. Postgrad Med 1999;31 – 7. [7] Bonifaz A, Ibarra G. Onychomycosis in children: treatment with bifonazole-urea. Pediatr Dermatol 2000;17: 310 – 4. [8] Pena-Penabad C, Garcia-Silva J, Almagro M, et al. Superficial white onychomycosis in a 3-year-old human immunodeficiency virus-infected child. J Eur Acad Dermatol Venereol 2001;15:51 – 3.

Dermatol Clin 21 (2003) 511 – 520

The efficacy and safety of terbinafine in children Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth A. Cooper, HBSc, BEScb, Charles W. Lynde, MD, FRCP(C)c a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Division of Dermatology, Department of Medicine, University Health Network (Toronto Western site) and the University of Toronto, 3 Ovida Boulevard, Toronto, Ontario L3P 7N8, Canada

Terbinafine is an allylamine antifungal agent, which has been used effectively to treat both superficial and systemic mycoses in the adult population. Terbinafine use in pediatric superficial fungal infection, particularly tinea capitis, has also been effective, and is summarized in this article. Tinea capitis is the most common fungal infection among the pediatric population, occurring mainly in prepubescent children. The incidence of tinea capitis has been increasing over the last several years. Lobato et al [1] found that the rate of prescriptions have increased by 209.7% for black children, by 140.4% for white children, and by 84.2% for all children. Since its availability in 1991, terbinafine has been approved for the management of tinea capitis in many countries including Australia, New Zealand, China, Japan, most South American countries, India, Sri Lanka, many African counties, and several European nations. Terbinafine has also been used successfully in pediatric cases of onychomycosis, and other superficial fungal infections.

Terbinafine Terbinafine is a lipophilic allylamine compound that is well absorbed ( > 70%) and binds strongly and nonspecifically to plasma proteins (99%) [2,3]. Ab-

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

sorption is not altered when terbinafine is taken with food [3,4]. Terbinafine penetrates keratinized tissues, and enters the stratum corneum and sebum by direct diffusion through the dermis and living epidermis [5,6]. Terbinafine accumulates in skin rapidly, to higher concentrations than in the plasma; plasma concentrations are poor indicators of concentrations in target organs [5]. The elimination half-life of terbinafine is about 17 to 36 hours [2,3]. Radiolabeled terbinafine exhibits a triphasic plasma concentrationtime profile of elimination with a component that has an even longer half-life [7]. The excretion of terbinafine in the urine and feces is 80% and 20%, respectively [8,9]. Terbinafine reduces the conversion of squalene to squalene epoxide by inhibiting the enzyme squalene epoxidase. Ultimately, the reduction in squalene epoxide leads to a decrease in ergosterol, which is an essential component of fungal cell membranes [10]. The excess of squalene may also damage cellular membranes, causing the release of lytic enzymes from vacuoles. These actions may be responsible for the fungicidal in vitro action of terbinafine [10]. Terbinafine is highly selective for fungal squalene epoxidase, which may be caused by differences in amino acid sequences compared with mammalian squalene epoxidases [11]. The concentration ratio for the inhibition of mammalian cholesterol synthesis versus fungal ergosterol synthesis is 4000:1 [7], and it is unlikely that terbinafine affects the synthesis of cholesterol in animals and humans [12]. The minimum inhibitory concentration of terbinafine is extremely low in vitro against both dermato-

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phyte species (0.001 to < 0.06 mg/mL) and a spectrum of nondermatophytes [13]. Organisms include Aspergillus species, Scopulariopsis brevicaulis, Sporothrix schenckii, Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Cryptococcus neoformans, Fonsecaea, Phialophora, Madurella, Acremonium, certain Candida species, and dimorphic fungi. Terbinafine is metabolized extensively by a wide range of cytochrome P-450 (CYP) enzymes, including CYP1A2, CYP3A4, and CYP2C9 [14]. Terbinafine inhibits CYP2D6 [14,15]. Drugs metabolized by CYP2D6 may be affected by terbinafine usage, including monoamine oxidase inhibitors, b-blockers, selective serotonin reuptake inhibitors, and tricyclic antidepressants [8]. Cyclosporine clearance is increased [3,16]. Other possible interactions include rifampin (100% increase in terbinafine clearance) and cimetidine (33% decrease in terbinafine clearance) [3]. No effects on antipyrine or digoxin metabolism were noted [3]. There are no drugs that are contraindicated with terbinafine.

Tinea capitis In the 1940s and early 1950s Microsporum audouinii was the most common organism responsible for tinea capitis in North America; however, since the late 1980s to 1990s, in North America, there has been a shift in causative agents, with Trichophyton tonsurans largely replacing M audouinii. Gupta and Summerbell [17] noted that in 1985, T tonsurans was responsible for 9% of confirmed cases of tinea capitis in Ontario, Canada, whereas in 1996 it was responsible for 76% of cases. Wilmington and Frieden [18] indicated that between 1974 and 1978, T tonsurans caused 41.7% of the cases of tinea capitis in the San Francisco Bay area, and increased to 87.5% between 1986 and 1993. Terbinafine use in tinea capitis has been discussed in many studies and case reports, for both Trichophyton and Microsporum infections [12,19 – 52]. The use of terbinafine to treat tinea capitis is summarized in Tables 1 and 2. Terbinafine is generally found to be effective in Trichophyton-caused tinea capitis over shorter dosage periods than for Microsporum tinea capitis. Studies are underway to determine more optimal treatment schedules using terbinafine for Microsporum tinea capitis. The standard dosing regimen (62.5 mg/d for body weight 10 to 20 kg; 125 mg/d for body weight 20 to 40 kg; 250 mg/d for body weight more than 40 kg) may be insufficient in some infections, and it has been suggested that dosing

be considered on a milligram per kilogram per day basis instead. Tinea capitis caused by Trichophyton species Table 1 summarizes studies involving treatment of Trichophyton species with terbinafine [12,21,29, 35,36,46]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d for body weight 10 to 20 kg, 125 mg/d for body weight 20 to 40 kg, 250 mg/d for body weight greater than 40 kg. High rates of efficacy have been observed when the standard regimen is used to treat tinea capitis for a duration of 2 to 4 weeks, with cure rates of 65% to 100% when evaluated 12 weeks from the start of therapy. Improvement in the disease state continues in patients followed-up for a few weeks after active terbinafine therapy is stopped. Friedlander et al [29] noted that better rates of complete cure were obtained in patients using doses amounting to more than 4.5 mg/kg/d, regardless of treatment duration. Tinea capitis caused by Microsporum species Table 1 summarizes studies involving treatment of Microsporum species with terbinafine [23,27,35, 47,48,50]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d (for body weight of 10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (more than 40 kg). The duration of treatment generally ranges from 2 to 8 weeks. When the standard terbinafine dosing regimen is used and active therapy administered for 6 to 8 weeks the efficacy of therapy when evaluated at follow-up (complete cure or effective cure) has ranged from 71.4% to 77.6% [23,47]. Romero et al [53] obtained clinical cure in 22 (84%) of 26 patients with Microsporum tinea capitis after 6 to 8 weeks of standard-dose terbinafine treatment [53]. When complete cure was considered in relation to dosages on a per kilogram basis, all patients who received greater than 7 mg/kg/d were clinically cured. Of the four failures, the mean dose was only 5.4 mg/kg/d. The authors suggested that effective treatment of Microsporum tinea capitis required 7.5 mg/kg/d for 6 weeks. Other papers have also noted that higher doses of terbinafine were

Table 1 Cure rates produced by standard terbinafine dosing of children with Trichophyton or Microsporum tinea capitis

Microsporum species treated with terbinafine Authors Hamm et al [35] No. of patients 7 Duration of active 1 therapy (wk) Assessment week from 12 start of therapy Complete cure 0% 0/7 Effective cure 14% 1/7 Mycologic cure

Friedlander et al [29] 50 1

Haroon et al [12] 51 2

Hamm et al [35] 14 2

Friedlander et al [29] 55 2

de Freitas et al [24] 20 4

Haroon et al [12] 57 4

Friedlander et al [29] 54 4

12

12

12

12

12

12

12

42% 21/50 56% 28/50

60.8% 31/51 80.4% 41/51

64% 9/14 86% 12/14

49% 27/55 69% 38/55

95% 19/20

66.7% 38/57 85.9% 49/57

56% 30/54 65% 35/54

Haroon et al [36] 10 6 8

80% 8/10 90% 9/10

100% 20/20 Schwinn et al [50] 12 1–2

Pierini et al [48] 11 4

Schwinn et al [50] 6 5 – 6 (1 – 2, then 4)

Dragos and Lunder [27] 22 6

Peharda et al [47] 15 8

12

NR

12

NR

14

12

0% 0/7 8.3% 1/12

8

100% 11/11

100% 11/11

Hamm et al [35] 5 2

0% 0/5 0% 0/5

Nejjam et al [46] 11 6

Crespi [23] 140 8 8 77.6% 83/107

66.7% 4/6 32% 7/22

A.K. Gupta et al / Dermatol Clin 21 (2003) 511–520

Trichophyton species treated with terbinafine Authors Haroon Hamm et al [12] et al [35] No. of patients 53 9 Duration of active 1 1 therapy (wk) Assessment week 12 12 from start of therapy Complete cure 49.1% 44% 26/53 4/9 Effective cure 73.6% 56% 39/53 5/9 Mycologic cure

71.4% 10/14 78.6% 11/14

Std dose regimen used = Terbinafine capsule/tablet by weight: 62.5 mg/d (10 – 19 kg), 125 mg/d (20 – 40 kg), 250 mg/d (> 40 kg). Complete cure = mycology (KOH and culture) negative and no clinical signs. Effective cure = mycology (KOH and culture) negative and minimal to no clinical signs. Mycologic cure = mycology (KOH and culture) negative. 513

514

Table 2 Comparative studies of terbinafine and griseofulvin for the treatment of tinea capitis Terbinafine versus griseofulvin

Reference

Mean Study No. of pts age (y) description

Terba Duration (wk)

Grisb Duration (wk)

Organisms

Terbinafine Follow-up Cure Rate (weeks) Outcome Observed

Griseofulvin Cure Rate Observed

Statistics: Significance

Terb:56 Gris: 49

8.9

Randomized, double-blind

4 (capsules)

8 (capsules)

Trichophyton sp.

12

EC

93% 79.6% P = .0840 52/56 39/49 CI:89.4 – 96.3 CI: 73.8 – 85.3

Terb:25 Gris: 25

6.8

Randomized, double-blind

4 (tablets)

8 (tablets)

T tonsurans, M canis

12

CC

Memisoglu et al 1999 Turkey [44] Gupta et al 2001 Canada/South Africa [33] Fuller et al 2001 UK [30]

Terb:32 Gris:35 Terb:50 Gris:50

6.8

Double- blind 4 (capsules)

8 (capsules)

EC

5.75

Randomized, single-blind

Trichophyton sp. and 12 Microsporum sp Trichophyton sp. 12

76% 19/25 CI:67.5 – 84.5 78% 25/32 94% 47/50

44% P < .05 11/25 CI:34.1 – 53.9 74% NR 26/35 92% Not significantd 46/50

5.8

Randomized, 4 (tablets) open, parallelgroup, ITT

10 mg/kg/d, 8 (suspension)

Randomized, double-blind, ITT

6:35 pts 8:33 10:33 12:32

20 mg/kg/d, Microsporum sp. 12 (suspension)

63%(41/65) 65%(42/65) 9%(1/11) 18%(2/11) 62.1%(18/29) 60%(18/30) 48.1%(13/27) 43.5%(10/23)

47%(27/58) 53%(31/58) 50%(5/10) 70%(7/10) 84% 21/25

Terba Duration

Itrac Duration

2

2

Lipozencic et al Multicenter [43]

Terb:77 Gris:70

Terb:133 Gris:30

7.7

2 – 3 (capsules) 20 mg/kg/d, 6 (capsules)

Trichophyton sp. Microsporum sp.

8 12 8 12 16

CC

EC EC

CC

P = .07 NR P = .06 NR P = 0.121 (Armitage trend test)

Terbinafine versus itraconazole

Reference

No. of pts

Jahangir et al 1998 Pakistan [39]

Terb:27 Itra: 28

Gupta et al 2001 Canada/South Africa [33]

Terb:50 Itra:50

7.85

5.4

Randomized, double-blind

Randomized, single-blind

2–3

5 mg/kg/d, 2–3

Organisms

Terbinafine Follow-up Cure Rate (wk) Outcome Observed

Itraconazole Cure Rate Observed

Trichophyton sp.

12

CC

12

EC

12

CC

64.3% 18/28 85.7% 24/28 CI:79.1 – 92.3 82% 41/50s

Trichophyton sp.

59.3% 16/27 77.8% 21/27 CI:69.8 – 85.8 94% 47/50

Significance Not significant P > .05 Not significant P > .05 Not significantd

A.K. Gupta et al / Dermatol Clin 21 (2003) 511–520

Alvi et al 1993 Pakistan [19] (also Haroon et al [37]) Ca´ceres-Rı´os et al 2000 Peru [22]

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required to produce adequate cure rates in Microsporum tinea capitis [43,54].

515

the terbinafine group; however, logistic regression did not determine any significant difference in effective therapy rates for the two treatments.

Tinea capitis: terbinafine versus griseofulvin Terbinafine treatment for 4 weeks produced similar cure rates of Trichophyton tinea capitis compared with 8 weeks of griseofulvin capsules or suspension in the comparative studies (see Table 2) [19,22,30, 33,44]. These studies used the standard dosing regimen of terbinafine: 62.5 mg/d (10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (> 40 kg). The dosage of griseofulvin was 10 mg/kg/d; 20 mg/kg/d; or a regimen of 125 mg/d (10 to 20 kg), 250 mg/d (20 to 40 kg), and 500 mg/d (> 40 kg). Lipozencic et al [43] performed a randomized, double-blind study on the effectiveness of terbinafine for 6 to 12 weeks using the standard dosage regimen, compared against griseofulvin suspension 20 mg/kg/d given for 12 weeks on the treatment of Microsporum tinea capitis (see Table 2). At the 16-week follow-up assessment the complete cure (negative mycology and no clinical signs) was terbinafine (6 weeks), 62.1% (N = 29 patients); terbinafine (8 weeks), 84% (N = 30 patients); and griseofulvin, 84% (N = 25 patients) ( P = not significant). Tinea capitis: terbinafine versus itraconazole Terbinafine for 2 to 3 weeks produced cure rates, which were similar to 2 to 3 weeks use of itraconazole for Trichophyton tinea capitis (see Table 2) [33,39]. Tinea capitis: terbinafine versus fluconazole In a comparative study where patients had Trichophyton tinea capitis, terbinafine for 2 to 3 weeks produced rates of effective therapy similar to 2 to 3 weeks of fluconazole (94% and 84%, respectively; intention to treat analysis) [33]. The fluconazole group had more severe cases of tinea capitis than

Onychomycosis Although onychomycosis is relatively uncommon in children, it has been observed to be increasing in prevalence [55]. There is no approved treatment for onychomycosis in children in North America; however, the recommended dosage regimen for terbinafine is 62.5 mg/d (for body weight of < 20 kg); 125 mg/d (20 to 40 kg); and 250 mg/d (> 40 kg). The duration of treatment should be daily for 6 weeks for fingernail onychomycosis and for 12 weeks for toenail onychomycosis [56]. Ungpakorn et al [57] reported a case of a 2-yearold boy treated with terbinafine, 62.5 mg/d for 6 weeks [57]. The cultures became negative at the end of the fourth week, with no clinical or mycologic evidence of onychomycosis when evaluated 36 weeks after therapy. The side effect of acute urticaria, which appeared after 4 weeks of treatment, subsided after antihistamines were administered. Terbinafine was not discontinued and there were no other side effects or instances of urticaria reported. Goulden and Goodfield [58] reported onychomycosis in three children, ages 5, 8, and 13 years old treated with terbinafine, 250 mg/d. All three had previously failed to respond to griseofulvin. One patient needed 6 months of treatment, whereas the other two required 3 months of therapy to achieve clinical and mycologic cure. No side effects were seen in any of the patients during the course of treatment or following the end of therapy. Gupta et al [55,59] treated five patients, ages 4 to 9 years, with terbinafine for toenail onychomycosis. Terbinafine, 62.5 to 125 mg/d, was administered for 4 to 12 weeks. Four (80%) of five patients were clinically and mycologically cured.

Notes to Table 2: Abbreviations: NR, not reported; CC, complete cure (mycology negative and no clinical signs); EC, effective cure (mycology negative and minimal to no clinical signs); MC, mycologic cure (KOH negative and culture negative). a Terbinafine capsule/tablet dosage by weight: 62.5 mg/d (10 – 20 kg); 125 mg/d (20 – 40 kg); 250 mg/d (> 40 kg), unless otherwise specified. b Griseofulvin capsule/tablet dosage: 125 mg/d (10 – 20 kg); 250 mg/d (20 – 40 kg); 500 mg/d (> 40 kg), unless otherwise specified. c Itraconazole capsules: 50 mg/d (< 20kg); 100 mg/d (20 – 40 kg); 200 mg/d (> 40kg), unless otherwise specified. d Analysis performed as part of a larger study comparing terbinafine treatment with itraconazole, fluconazole, and griseofulvin.

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Other pediatric fungal infections Two patients treated with a combination of oral terbinafine and oral itraconazole were cleared of Scopulariopsis brevicaulis skin infection. One patient was treated for 2 months and remained completely cleared after 6 months [60]. The second patient was treated for over 11 months before a complete cure was noted, but relapsed 10 months after stopping treatment [61]. A 7 year old with phaeohyphomycosis caused by Exophiala spinifera was administered terbinafine, 500 mg/d for 2 months [62]. He exhibited moderate improvement compared with previously unsuccessful responses with amphotericin B, ketoconazole, and flucytosine. A 2 year old with facial infection caused by Pythium insidiosum responded to terbinafine, 60 mg twice daily, and itraconazole, 125 mg twice daily given for over 12 months. No adverse effects were associated with treatment, and no recurrence was observed after a year and a half [63]. Terbinafine has shown some efficacy in the treatment of cutaneous leishmaniasis [64]. The treatment group studied included some pediatric patients, and no adverse effects were noted.

Safety of oral terbinafine use in children In summarizing the data from the papers reviewed here, 989 children in 20 studies were given terbinafine and monitored for adverse effects [12,21,22,24, 25,27,29,30,34 – 36,39,41 – 43,46,52,57,58,65]. Tinea capitis was the infection in 99.5% of the cases, with most adjusting dosage of terbinafine by weight. Only eight studies reported regular monitoring of liver enzymes and blood; these included over 500 children [12,27,35,36,41,42,46,52]. In total, 106 (10.7%) of 989 children experienced adverse events; however, only eight patients (0.8%) discontinued terbinafine treatment [29,30,43,52]. Table 3 displays the list of specific adverse events that were reported in 93 of 106 children experiencing adverse events, and six of eight children who discontinued terbinafine. These adverse events involved the gastrointestinal system (2.8% patients); cutaneous system (1.2%); and nervous system (0.9%). Abnormalities in hepatic enzymes and hematologic parameters were observed in 1.8% and 1.3% of children, respectively. The adverse events noted in children are within the spectrum noted for adults treated with terbinafine [62,66]. Most events were mild and transient. Terbinafine seems safe for use in children.

Some rare cases of hepatic failure have been noted in treatment of onychomycosis in adults. Most of these were in patients with serious underlying systemic conditions, and had uncertain causal relation to terbinafine use [3].

Discussion Terbinafine has demonstrated a good record of efficacy and safety in treatment of pediatric superficial fungal infections. Terbinafine has been most effective in treating Trichophyton tinea capitis, when using standard dosage regimen. One-week treatments have displayed effective cure rate of 50%, whereas 2- to 4-week durations have provided effective cure rates from 80% to 100%. Treatment duration of 6 weeks or more may be required with Microsporum tinea capitis. Terbinafine is equally as effective as griseofulvin and itraconazole in comparative trials with Trichophyton tinea capitis. The duration of therapy with terbinafine is substantially shorter compared with griseofulvin, and may be associated with fewer adverse effects and higher compliance. Increasing the dosage above what has been used in some studies (eg, 125 mg/d for children 10 to 15 kg body weight, 187.5 mg/d for 16 to 25 kg, and 250 mg/d for > 25 kg) has enabled higher efficacy to be achieved in treatment of Microsporum tinea capitis; in fact, efficacy in a subset of patients treated with this higher dosing over 2 to 4 weeks (complete cure 77.3%) was similar to that obtained using the standard dosage regimen administered over 8 weeks (see Table 1) [48]. The optimal terbinafine dosage for both Microsporum and Trichophyton infection may need to be given on a milligram per kilogram per day basis rather than milligram per day basis. One study of Microsporum infection indicated that patients who received terbinafine doses greater than 7 mg/kg/d were clinically cured, whereas failures averaged a dose of 5.4 mg/kg/d [53]. Data from studies where terbinafine has been used to treat tinea capitis caused by Trichophyton [29] and Microsporum [43] suggest there is a linear relationship between the terbinafine dose and observed cure rates, independent of duration of treatment [67]. The clearance of terbinafine is about 40% higher in children compared with adults [67]. A dose that is approximately the double of the median dose results in a systemic exposure that is comparable with the standard adult dose of 250 mg/d. Modeling conducted by Friedlander et al [29,43,67] suggests that cure rates may approach 80% if a dose of 9 mg/kg/d were to be used, twice the actual median

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517

Table 3 Summary of adverse events noted in children administered oral terbinafine for the treatment of superficial fungal infections

System affected

Total number of events reported (%)

Gastrointestinal events

28 (2.8)

Cutaneous events

Nervous system events

Hepatic enzyme abnormalities

12 (1.2)

9 (0.9)

18 (1.8)

Hematologic parameter abnormalities

13 (1.3)

Other laboratory parameter abnormalities Other

10 (1)

Total

93 / 989 (9.4)

3 (0.3)

Adverse event Unspecified gastrointestinal effects Stomach upset Abdominal pain Anorexia Taste loss Nausea Vomiting Diarrhea Obstipation Weight loss Unspecified skin effects Urticaria Pruritis Rash Headaches Somnolence Hyperesthesia Vertigo Unspecified elevation of liver enzymes Abnormal bilirubin Abnormal alkaline phosphatase Eosinophilia Granulocytopenia Leukopenia Elevation of triglycerides Body ache Fever

dose (approximately 4.5 mg/kg/d) used in the studies. Future investigation into the efficacy and safety of higher doses of terbinafine may provide further guidance regarding the optimal treatment regimen for Trichophyton and Microsporum tinea capitis. In the United States, the use of terbinafine for tinea capitis has increased in response to the gradual increase in daily dosage of griseofulvin [68]. Griseofulvin may also have a higher frequency of adverse effects compared with terbinafine. Griseofulvin is available in an oral suspension, however, whereas terbinafine is only available in a tablet form. Oral suspensions or solutions may be required for young children who are unable to swallow capsules or tablets. To help, the pharmacist may break the terbinafine tablet in smaller pieces when the child may be too young to swallow the tablet [69].

Number of children experiencing AE (%)

Number of children discontinuing due to AE (%)

9 (0.9) 3 2 4 1 4 1 1 2 1 4 5 2 1 4 2 1 2 8

(0.3) (0.2) (0.4) (0.1) (0.4) (0.1) (0.1) (0.2) (0.1) (0.4) (0.5) (0.2) (0.1) (0.4) (0.2) (0.1) (0.2) (0.8)

1 (0.1)

1 (0.1) 2 (0.2)

1 (0.1)

2 (0.2) 8 (0.8) 11 (1.1) 1 (0.1) 1 (0.1) 10 (1.0) 1 (0.1) 2 (0.2) 93/ 989 (9.4)

1 (0.1)

6 / 989 (0.6)

From a pharmacoeconomic viewpoint, a 4-week treatment course of terbinafine for a 30-kg child with Trichophyton tinea capitis in the United States costs US $116.9 (one half of a 250-mg tablet given for 4 weeks; [ie, a total of 14 terbinafine 250-mg tablets each costing average wholesale price US $8.35 per 250 mg tablet] [70]). In contrast, a 6-week course of griseofulvin suspension, 125 mg/5 mL administered at 20 mg/kg/d, costs US $261.3 (average wholesale price of griseofulvin suspension is US $31.11 for a 120 mL bottle [70]) for the same child. There is a substantial cost savings to consider terbinafine in such a clinical situation. There are no guidelines for laboratory monitoring before initiating and during therapy with terbinafine for tinea capitis. It is the author’s practice (AKG) to get blood work based on the medical history and

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examination of the infected child. Baseline blood work and intratherapy monitoring are not performed on a regular basis. Studies where tinea capitis in children has been treated with terbinafine suggest that it is generally a safe agent. Children with systemic mycoses have more adverse effects, depending on underlying illness and types of concomitant medications given. The United States package insert advises pretreatment serum transaminases (alanine transaminase and aspartate transaminase) before starting on terbinafine for the treatment of onychomycosis in adults [9]. It remains to be seen what guidelines physicians will adopt as this agent becomes more widely used for the treatment of tinea capitis in children. Treatment efficacy may be reduced by reinfection from asymptomatic carriers of the infecting organism. Investigations had difficulty establishing the rate of asymptomatic carriage of tinea capitis organisms among family members and schoolmates of infected children, and the treatment course to be used, if any, for asymptomatic carriers [71 – 76]. It has been suggested that the entire family should use a sporicidal shampoo, such as ketoconazole shampoo, when treating Trichophyton tinea capitis to reduce the carrier stage [75].

Summary In summary, terbinafine is a broad-spectrum allylamine, which has been used to treat superficial fungal infections including onychomycosis, and some systemic mycoses in adults. With a fungicidal activity, low minimum inhibitory concentration value, and high selectivity for fungal squalene epoxidase, terbinafine has demonstrated good efficacy in superficial fungal infections. Its lipophilic nature provides excellent, widespread absorption into hair, skin, and nails where it can eradicate fungal infection. Terbinafine has been shown to be effective and safe in several studies of the treatment of tinea capitis and onychomycosis in children. When treating Trichophyton tinea capitis the length of therapy may be 2 or 4 weeks. Microsporum tinea capitis may require somewhat higher or longer doses of terbinafine for adequate efficacy. These regimens still tend to be shorter than treatment with griseofulvin, and terbinafine may provide a higher compliance and a more cost-effective means of managing tinea capitis. It is possible that even higher cure rates and a shorter duration of therapy may be achieved following further optimization of treatment regimens that use a higher daily dosage of terbinafine than is currently recommended. The evidence is strongly in

favor of using terbinafine to treat superficial fungal infections in children.

References [1] Lobato MN, Vugia DJ, Frieden IJ. Tinea capitis in California children: a population-based study of a growing epidemic. Pediatrics 1997;99:551 – 4. [2] Jensen JC. Clinical pharmacokinetics of terbinafine (Lamisil). Clin Exp Dermatol 1989;14:110 – 3. [3] Novartis Pharmaceuticals. Terbinafine (Lamisil) package insert. May 2001. NJ: Novartis Pharmaceuticals; 2001. [4] Leyden J. Pharmacokinetics and pharmacology of terbinafine and itraconazole. J Am Acad Dermatol 1998; 38:S42 – 7. [5] Faergemann J. Pharmacokinetics of terbinafine. Rev Contemp Pharmacother 1997;8:289 – 97. [6] Faergemann J, Zehender H, Jones T, Maibach I. Terbinafine levels in serum, stratum corneum, dermisepidermis (without stratum corneum), hair, sebum and eccrine sweat. Acta Derm Venereol 1990;71: 322 – 6. [7] Birnbaum JE. Pharmacology of the allylamines. J Am Acad Dermatol 1990;23(4 pt 2):782 – 5. [8] Canadian Pharmacists Association. Lamisil package insert. In: Repchinsky C, editor. Compendium of pharmaceuticals and specialties. 36th edition. Toronto: Webcom Limited; 2001. p. 803 – 5. [9] Terbinafine. Systemic. In: USP DI editorial group. Volume I-drug information for the health care professional. 21st edition. Tauton: MICROMEDEX Thomson Healthcare; 2001. p. 2786 – 8. [10] Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992;39:2 – 7. [11] Ryder NS, Favre B. Antifungal activity and mechanism of action of terbinafine. Contemp Pharmacother 1997; 8:275 – 87. [12] Haroon TS, Hussain I, Aman S, Jahangir MJ, Kazmi AH, Sami AR, et al. A randomized double-blind comparative study of terbinafine for 1,2 and 4 weeks in tinea capitis. Br J Dermatol 1996;135:86 – 8. [13] Clayton YM. In vitro activity of terbinafine. Clin Exp Dermatol 1989;14:101 – 3. [14] Vickers AEM, Sinclair JR, Zollinger M, Heitz F, Glanzel U, Johanson L, et al. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos 1999;27:1029 – 38. [15] Abdel-Rahman SM, Marcucci K, Boge T, Gotschall RR, Kearns GL, Leeder JS. Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine. Drug Metab Dispos 1999;27: 770 – 5. [16] Long CC, Hill SA, Thomas RC, Johnston A, Smith SG, Kendall F, et al. Effect of terbinafine on the pharmaco-

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[61] Bruynzeel I, Starink TM. Granulomatous skin infection caused by Scopulariopsis brevicaulis. J Am Acad Dermatol 1998;39:365 – 7. [62] Villars VV, Jones TC. Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 1992;126(suppl 39):61 – 9. [63] Shenep JL, English BK, Kaufman L, Pearson TA, Thompson JW, Kaufman RA, et al. Successful medical therapy for deeply invasive facial infection due to Pythium insidiosum in a child. Clin Infect Dis 1998; 27:1388 – 93. [64] Bahamdan KA, Tallab TM, Johargi H, Mazen Nourad M, Ibrahim K, Hameed El Sherbini A, et al. Terbinafine in the treatment of cutaneous leishmaniasis: a pilot study [abstract]. Int J Dermatol 1997;36:59 – 60. [65] Wilmer A, Wollina U. Oral terbinafine in the treatment of griseofulvin-resistant tinea capitis et faciei et corporis in a 10-month-old girl. Acta Derm Venereol 1998; 78:314. [66] Hall M, Monka C, Krupp P, O’Sullivan D. Safety of oral terbinafine. Results of a postmarketing surveillance study in 25,884 patients. Arch Dermatol 1997; 133:1213 – 9. [67] Friedlander SF, Skerlev M, Lipozencic J, Bretz F, Emady-Azar S, Wraith LA, et al. Relationship between terbinafine dose and complete cure rate in tinea capitis: analysis of phase II randomized trials. J Eur Acad Derm Venereol 2001;15(suppl 2):221. [68] Committee on Infectious Diseases. Tinea capitis. In: Peter G, editor. Red book: report of the Committee on Infectious Diseases. 24th edition. Chicago: American Academy of Pediatrics; 1997. p. 523 – 5. [69] Burkhart CG. Coffee grinders assist pediatric dosing. Cutis 2000;65:276. [70] Cardindale V, editor. Drug topics red book pharmacy’s fundamental reference. Montvale, NJ: Medical Economics Company; 2001. p. 32, 40, 45, 64. [71] Babel DE, Rogers AL, Beneke ES. Dermtophytosis of the scalp: incidence, immune response, and epidemiology. Mycopathologia 1990;109:69 – 73. [72] Frieden IJ. Tinea capitis: asymptomatic carriage of infection. Pediatr Infect Dis J 1999;18:186 – 90. [73] Greer DL. Treatment of symptom-free carriers in management of tinea capitis. Lancet 1996;348:350. [74] Neil G, Hanslo D, Buccimazza S, Kibel M. Control of the carrier state of scalp dermatophytes. Pediatr Infect Dis J 1990;9:57 – 8. [75] Pomeranz AJ, Sabnis SS, McGrath GJ, Esterly NB. Asymptomatic dermatophyte carriers in the households of children with tinea capitis. Arch Pediatr Adolesc Med 1999;153:483 – 6. [76] Williams JV, Honig PJ, McGinley KJ, Leyden JJ. Semiquantitative study of tinea capitis and the asymptomatic carrier state in inner-city school children. Pediatrics 1995;96(2 pt 1):265 – 7.

Dermatol Clin 21 (2003) 521 – 535

Efficacy and safety of itraconazole use in children Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth A. Cooper, HBSc, BEScb, Gabriele Ginter, MDc a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Department of Dermatology, University of Graz, Universitats-Klinik fur Dermatologie, Auenbruggerplatz 8, Graz A-8036, Austria

Since its’ discovery in 1980, itraconazole capsules have been approved in the United States for the treatment of adults with fungal infections including onychomycosis of fingernails and toenails, blastomycosis, histoplasmosis, and aspergillosis in patients who are intolerant of, or refractory to, amphotericin B. Itraconazole is also available in an oral solution, which is approved for treatment of oropharyngeal and esophageal candidiasis in immunocompromised adults. Itraconazole has frequently been used in pediatric cases of superficial and systemic fungal infection, although it has not been approved for pediatric use by the Food and Drug Administration. Itraconazole is generally safe and effective against most fungal organisms causing superficial and systemic infection in children. Dosages of 5 mg/kg/d have given a wide range of successful antifungal treatment, with few serious side effects being noted despite a wide range of underlying physiologic states. In the treatment of superficial fungal infections, pulse therapy may lessen the duration of treatment required, and can reduce the risk of adverse events occurring. Development of the itraconazole oral solution has made it easier to treat younger children who have trouble swallowing capsules. More safety data are required, however, in the use of the solution formulation to treat superficial fungal infections in children.

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

The oral solution has also improved the availability of the drug in patients with reduced stomach acidity, who are typically in a high-risk group for systemic fungal infection. Itraconazole seems to be effective and safe for the treatment of superficial fungal infections in children. The spectrum of adverse events noted is comparable with adults, and adverse effects are relatively infrequent.

Itraconazole Itraconazole is a triazole antifungal agent that inhibits the fungal cytochrome P-450 enzyme 14-ademethylase from removing the 14-a methyl group from lanosterol, an ergosterol precursor that is an essential component of the fungal cell membrane. Itraconazole has a wider spectrum of activity than griseofulvin, including dermatophyte fungal organisms (Trichophyton, Microsporum, and Epidermophyton); Candida species; Aspergillus species; and several other organisms that cause systemic mycoses. Absorption of capsules is best in the highly acidic environment of the stomach after a full meal. Itraconazole capsules should be given at least 2 hours after administration of medications that reduce stomach acidity, such as aluminum hydroxide, H2-blockers, or proton pump inhibitors. Alternatively, itraconazole can be administered immediately after a ‘‘classic’’ cola beverage to ensure a high-acid environment required for adequate itraconazole absorption [1,2].

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00030-5

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Itraconazole is highly bound to plasma proteins (99.8%) and is lipophilic, with a high affinity for keratin, such that the drug accumulates in the tissues to levels 2 to 20 times higher than serum concentrations at the site of the fungal infection. Penetration into the cerebrospinal fluid is poor [3]. Metabolism is primarily through the liver, by the cytochrome P-450 3A4 enzyme system. Itraconazole has a low affinity for mammalian P-450 enzymes versus fungal cytochrome P-450 enzymes, and has less potential for drug interaction than some other antifungals, such as ketoconazole. Monitoring liver function is recommended, however, for durations of continuous therapy exceeding 4 weeks time. The metabolite of itraconazole, hydroxyitraconazole, is also active against fungal organisms, with comparable activity with the parent compound [4]. The half-life of itraconazole is relatively long, approximately 1 to 1.5 days following doses of 200 to 400 mg/d for 14 days [5,6]. Because of its lipophilicity and long elimination half-life, itraconazole levels in the stratum corneum exceed the plasma levels, and may persist in skin and toenails for 4 weeks and 9 to 12 months, respectively, following discontinuation of a standard course of therapy [7,8]. In contrast, griseofulvin has poor affinity for keratin and is thought to diffuse out from the skin and nails within days following discontinuation of therapy [9,10]. Itraconazole is metabolized using the cytochrome P-450 3A4 enzymes, and is contraindicated with many drugs that also interact with cytochrome P-450 3A4 enzymes, including quinidine; pimozide; dofetilide; the antihistamines terfenadine and astemizole; cisapride; the longer-acting benzodiazepines triazolam and oral midazolam; and the 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors, such as lovastatin and simvastatin [11,12]. In many countries terfenadine, astemizole, and cisapride are no longer available. Table 1 presents drugs that may interact with itraconazole [11,12]. This list is not allinclusive. The therapeutic efficacy of oral contraceptives may be reduced with the use of itraconazole, although the mechanism producing this interaction is unclear [13 – 15]. Itraconazole capsules should not be used for onychomycosis in patients with evidence of past or current ventricular dysfunction, such as congestive heart failure [12]. Itraconazole oral solution Itraconazole oral solution (10 mg/mL itraconazole in 400 mg/mL hydroxypropyl-b-cyclodextrin solution) is available for use in immunocompromised

adult patients with oral or esophageal candidiasis. The oral solution has a broad spectrum of activity, and includes many strains of Candida that are fluconazole-resistant. Its bioavailability is 30% greater than itraconazole capsules because of the cyclodextrin vehicle, and in contrast to itraconazole capsules maximal absorption is obtained when taken on an empty stomach [16]. This formulation has been used to overcome the problem of treating children who have reduced absorption of itraconazole capsules because of frequent nausea or vomiting, or reduced stomach acidity. It has also been used for children who have difficulty in swallowing itraconazole capsules. The solution has a pleasant taste and is generally well accepted by children. Initial studies using itraconazole oral solution for the treatment of tinea capitis and onychomycosis in children used a dosage of 3 mg/kg/d that was found to be both effective and safe. Subsequently it was decided to suggest the dosage of 3 to 5 mg/kg/d for the oral formulation (Aditya Gupta with Piet de Doncker, personal communication, October 2000). The hydroxypropyl-b-cyclodextrin – itraconazole complex has been shown to dissociate immediately during digestion, and does not interfere with itraconazole metabolism or action. The hydroxypropyl-b-cyclodextrin is absorbed minimally (< 0.5%) from the gastrointestinal tract after oral administration [17]. It is nondegradable, and may complex other elements, possibly producing diarrhea and other gastrointestinal effects. If administered intravenously, 80% to 90% of the hydroxypropyl-b-cyclodextrin is excreted through the kidney, such that dosage may need alteration if the patient is experiencing renal failure. Metabolism in the liver following the oral or intravenous route is minimal, and unlikely to affect hepatic or renal function. Hydroxypropyl-b-cyclodextrin has been associated with an increase in exocrine pancreas neoplasia in rats. Studies indicated this was related to cholecystokinin, and was suspected to be a rat-specific mechanism, because no other species tested (dogs or mice) had a similar reaction to oral dosing [17]. It would be beneficial to have more safety data in the use of itraconazole oral solution to treat superficial mycosis in children. Dosage regimens of itraconazole When using itraconazole capsules to treat superficial fungal infections in children, suggested dosages by body weight are presented in Table 2 [9,18 – 21]. When the patient weight exceeds 50 kg, then the adult dose, between 200 and 400 mg/d, should be administered. There are isolated reports where itra-

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523

Table 1 Drug interactions with itraconazole capsules

Category of drug

Drug name

Antiarrhythmics

Digoxin Quinidinea Dofetilidea Carbamazepine Phenobarbital Phenytoin Astemizolea Terfenadinea Clarithromycin Erythromycin Rifabutin Isoniazid Rifampin Busulfan Docetaxel Vinca alkaloids Pimozidea Alprazolam Diazepam Oral midazolama Triazolama Dihydropyridines Verapamil Cisapridea

Anticonvulsants

Antihistamines Macrolide antibiotics Antimycobacterials

Antineoplastics

Antipsychotics Benzodiazepines

Calcium channel blockers Gastointestinal motility agents Gastric acid suppressors and neutralizers HMG coenzyme A-reductase inhibitors

Immunosuppressants

Oral hypoglycemics Protease inhibitors

Nonnucleoside reverse transcriptase inhibitors Miscellaneous

Antacids H2-receptor antagonists Proton pump inhibitors Atorvastatin Cerivastatin Lovastatina Simvastatina Cyclosporine Tacrolimus Sirolimus Oral hypoglycemics Indinavir Ritonavir Saquinavir Nevirapine Alfentanil Buspirone Methylprednisolone Trimetrexate Warfarin

Abbreviation: Y, yes. a Contraindicated with intraconazole. Data from references [11] and [12].

Increased plasma drug concentration

Increased plasma concentration of itraconazole

Y Y Y Y

Decreased plasma concentration of itraconazole

Y Y Y

Y Y Y Y Y

Y Y Y

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Y Y Y

Y Y Y Y Y

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Table 2 Dose regimens for itraconazole treatment Tinea capitis < 10 kg 10 – 20 kg 21 – 30 kg 31 – 40 kg

40 – 49 kg

> 49 kg

Continuous therapy (capsules) 50 mg/d (5 mg/kg/d) 1 capsule on alternate days 1 capsule per day 1 capsule per day or 1 capsule per day alternated with 2 capsules per day 1 capsule per day alternated with 2 capsules per day, or 2 capsules per day 2 capsules per day

Pulse therapya (capsules) 50 mg/d (5 mg/kg/d) 1 capsule on alternate days 1 capsule per day 1 capsule per day or 1 capsule per day alternated with 2 capsules per day 1 capsule per day alternated with 2 capsules per day, or 2 capsules per day 2 capsules twice a day

1 – 3 pulses

Pulse therapya (oral solution) 3 to 5 mg/kg/d of 100 mg/10 mL solution

1 – 3 pulses

Pulse therapya (capsules) 5 mg/kg/d 400 mg/d

1 pulse

1 wk 4 wk

1 pulse

1 wk 2 wk

Pulse therapya (capsules) 5 mg/kg/d 200 mg/d

Pulse therapya (capsules) 5 mg/kg/d 200 mg twice daily

2 pulses

6 wk 6 wk

3 pulses

12 wk 12 wk

Pulse therapya (capsules) 5 mg/kg/d 200 mg twice daily

2 – 4 wk

Tinea pedis and manus (5 mg/kg/d) < 50 kg  50 kg

Continuous therapy (capsules) 5 mg/kg/d 100 mg/d

Tinea corporis and cruris (5 mg/kg/d) < 50 kg  50 kg

Continuous therapy (capsules) 5 mg/kg/d 100 mg/d

Fingernail onychomycosis (5 mg/kg/d) < 50 kg  50 kg

Continuous therapy (capsules) 5 mg/kg/d 200 mg/d

Toenail onychomycosis (5 mg/kg/d) < 50 kg  50 kg

Continuous therapy (capsules) 5 mg/kg/d 200 mg/d

a 1 week on active treatment, then 3 weeks off treatment = 1 pulse. Data from references [9], [18] and [21].

conazole, 600 mg/d, has been used with low to no incidence of adverse effects [22]. It is recommended, however, that the daily dosage of itraconazole should not exceed 400 mg/d in the treatment of superficial fungal infections. A pulse-dosing schedule has been used to treat tinea capitis and onychomycosis in children. In pulse dosing, the patient takes itraconazole daily for 1 week, then has 3 weeks off without medication. Itraconazole levels remain high because of the accumulation of drug in keratin, and frequency of dosing is reduced compared with continuous therapy. This may be more convenient for some patients and parents or caregivers. Additional pulses are recommended if myco-

logic or clinical cure has not been achieved; if cure is achieved, pulse dosing can be stopped. Frequency and duration of drug administration can be tailored to severity of infection and clinical response to treatment. Studies in children have shown the pulse regimen to be associated with few adverse effects [23,24]. The pulse regimen may also reduce the cost of treatment. The pharmacokinetics of itraconazole by children may not be identical to that of adults. Gastric acid secretion is lower than adult levels until age 3 years, and may reduce the absorption of itraconazole in young children. Neonates have slower gastric emptying, which may increase their absorption of itracona-

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zole. Greater phase I metabolic clearance in children versus adults, and less phase II metabolic reactions, such as glucuronidation, may alter the pharmacokinetic profile of itraconazole in children versus adults [25]. These pharmacokinetic alterations may be even more pronounced in children with severe underlying medical conditions, such as cystic fibrosis, severe burns, or cancer. Chemotherapy may lessen the absorption of itraconazole if vomiting is frequent, or if mucositis is present [26]. In these clinical situations, it may be advisable to monitor itraconazole levels to ensure therapeutic levels are reached.

Tinea capitis Itraconazole is effective in the treatment of tinea capitis caused by both ectothrix and endothrix species. When itraconazole is used to treat tinea capitis caused by Trichophyton tonsurans and T violaceum (endothrix) using continuous therapy the duration of therapy is generally 2 to 4 weeks. When the causative organism is Microsporum canis (ectothrix) the duration of therapy is generally 4 to 6 weeks. The recommended dosage regimen is 5 mg/kg/d for both the capsules and the oral solution. There are two regimens that can be used: continuous and pulse. It needs to be emphasized that for both the continuous and pulse regimens the recommended dosage of itraconazole remains at 5 mg/kg/d. Continuous treatment with itraconazole capsules has been used in 12 studies found in the literature ( > 10 patients in the study) (Table 3). Continuous treatment from 4 to 8 weeks produced good cure rates in most of these studies. The follow-up period of these rates varied considerably between studies. Dosage regimens provided adequate cure rates in these studies, regardless of species causing tinea capitis. One study used only a 2-week treatment period for Trichophyton infection and found an effective cure rate of 85.7% [27]. A second study also found good cure rates for Trichophyton infection with 2 or 3 weeks of itraconazole therapy [28]. Few patients experienced adverse events during the continuous-treatment regimen. Continuous treatment also was found to be effective against Microsporum species. Continuous treatment with the itraconazole oral solution showed excellent efficacy against M canis, with somewhat longer treatment durations than are required for Trichophyton infection (Table 4). Pulse dosing provided good rates of complete cure (mycologically negative and no clinical signs or symptoms, excluding hair loss) against Trichophyton spp. using both itraconazole capsules and the itraco-

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nazole oral solution (see Table 4). The pulse regimen is active therapy (5 mg/kg/d, capsules) for 1 week and a period off treatment for 3 weeks. The patient is seen in follow-up at week 4 from the start of therapy, and an additional pulse of therapy is administered if the patient has clinical evidence of tinea capitis remaining. Additional pulses are generally required for moderate (two to three pulses) to severe tinea capitis (three pulses). There are data to suggest that some patients may require more than three pulses of itraconazole. Pulse dosing seems promising as a treatment for tinea capitis that minimizes a child’s exposure to drug. Large-scale clinical studies need to be done to confirm these findings. There are very few comparative studies between itraconazole and other antifungal agents in tinea capitis. The study by Lopez-Gomez et al [29] was a double-blind, randomized trial comparing griseofulvin (500 mg/d for 6 weeks; N = 17 patients) with itraconazole (100 mg/d for 6 weeks; N = 18 patients) with most patients having M canis tinea capitis. For both groups, the mycologic cure and effective therapy rates (mycologic cure with only minimal clinical symptoms and signs) were similar. In another study, Jahangir et al [27] compared the efficacy of itraconazole (< 20 kg, 125 mg/d; 20 to 40 kg, 100 mg/d; > 40 kg, 200 mg/d; N = 28) with terbinafine (< 20 kg, 62.5 mg/d; 20 to 40 kg, 125 mg/d; > 40 kg, 250 mg/d; N = 27), with the treatment duration being 4 weeks. In most cases the causative organism was T violaceum. The mycologic cure rate and rate of effective therapy (mycologic cure with only minimal symptoms and signs) was higher in the group treated with itraconazole, although there was no significant difference in efficacy between the two groups. A large-scale comparative trial by Gupta et al [28] compared griseofulvin (20 mg/kg/d  6 weeks), terbinafine (< 20 kg, 62.5 mg/d; 20 to 40 kg, 125 mg/d; > 40 kg, 250 mg/d; for 2 or 3 weeks), itraconazole (5 mg/kg/d  2 or 3 weeks), and fluconazole (6 mg/kg/d  2 or 3 weeks) in the treatment of Trichophyton species tinea capitis. No significant difference was found in rates of effective treatment (intention-to-treat rates) between the four groups at week 12. Rates of effective treatment were as follows: griseofulvin (week 12 evaluable, 100%; intention-to-treat rates, 92%); terbinafine (week 12 evaluable, 97.9%; intention-to-treat rates, 94%); itraconazole (week 12 evaluable, 93.5%; intention-totreat rates, 86%); and fluconazole (week 12 evaluable, 89.1%; intention-to-treat rates, 84%). It was noted that severity was a predictor of treatment success regardless of which treatment was received, with more

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Table 3 Continuous itraconazole capsules for the treatment of tinea capitisa

Dose regimen

Follow-up

Number of patients

Cure rate

Clinical

Laboratory

Continuous, capsules Legendre and Esola-Macre [88]

100 mg/d duration 20 – 73 d, 5 wk

F/U: 4 wk after stopping treatment Organisms: T tonsurans, M canis F/U: 14 wk Organisms: T tonsurans = 1, T mentagrophytes = 1, M canis = 16 Organisms: T tonsurans = 10 F/U: 8 wk after stopping therapy Organisms: M canis = 47, T tonsurans = 5, others = 19 F/U: 4 wk

N = 42 evaluable, Age: < 10 y

CC: 38/42 = 90.5% [95% CI: 86 – 95]

N = 1, tired legs

N = 1, transient increase in serum transaminase levels

N = 18, Age range: 2 – 11 years and one adult, 60 y N = 10 Age: 6 – 11 years N = 71

ET: 15/17 = 88.2% [95% CI: 80.4 – 96]

None

Not mentioned

CC: 9/10 = 90% [95% CI: 80.5 – 99.5] MC: 100 mg: 47/53 = 88.7% [95% CI: 84.5 – 92.9] MC: 50 mg group: 9/15 = 60% [95% CI: 47.4 – 72.6] CC: 20/20 = 100%

None

None

N = 1, papular eruption, uncertain relation to drug

Not mentioned

None

CC: 120/120 = 100%

None

One patients showed slight increase in plasma transaminase; returned to normal within 2 wk of stopping itraconazole Not mentioned

Lo´pez-Go´mez et al [29]

100 mg/d x 6 wk

Greer [83]

100 mg/day x 8 wk

Degreef [81]

50 to 100 mg/d x 6 wk

Retanda et al [92]

100 mg/d x 30 d

Elewski [31]

3 – 5 mg/kg/d x 30 d

F/U: 8 wk Organisms: T tonsurans = 119, M canis = 1

N = 20, Age range: 6 to 10 y

N = 120 Age range:2 – 5 to adult

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Adverse effects Reference

100 mg/d x 4 wk

F/U: 8 wk Organisms: T tonsurans = 54

N = 25 evaluable, 29 lost to follow-up (total = 54 subjects) Age range: 1 – 5 to 11 y

ET: 10/25 = 40% [95% CI: 30.2 – 49.8]

Jahangir et al [27]

< 20 kg, 50 mg/d; 20 – 40 kg, 100 mg/d; > 40 kg, 200 mg/d x 2 wk

N = 28 Age range: majority < 12 y

ET: 24/28 = 85.7% [95% CI: 79.1 – 92.3]

Mo¨hrenschlager et al [89]

< 20 kg, 50 mg/d; > 40 kg, 100 mg/d x 4 wk 3 mg/kg/d x 4 wk 3 mg/kg/d x 8 wk

F/U: 12 wk Organisms: T violaceum = 23, T tonsurans = 2, T mentagrophytes = 2, T verrucosum = 1 Organisms: M canis 26, T violaceum 16. Study 1 Organism: T violaceum 10 Study 2 Organisms: M canis = 22, M audouinii = 2, Trichophyton sp. = 11

N = 42, Age range: 12 to 140 mo N = 10 Average age: 7.5 y (range 1 – 12) N = 35 Average age: 8.3 y (range 5 – 12)

MC: 34/42 = 80.1% [95% CI: 74.9 – 87]

Gupta et al [20]

5 mg/kg/d x 6 wk

5 mg/kg/d x 4 wk

Study 3 Organisms: M canis = 11, T soudanense = 1, T violaceum = 1, Trichophyton spp. = 3

N = 16 Average age: 6.5 y (range 4 – 11)

T violaceum: 6/7 (85.7%)

M canis MC: 15/22 (68.2%) M audouinii MC: 2/2 (100%) Trichophyton sp. 11/11(100%) Total 28/35 (80%) M canis MC: 8/10 (80%) Trichophyton sp. 3/4 (75%) Total 11/14 (78.5%)

headache - 1, vomiting - 2, diarrhea - 1, epistaxis - 1, vomiting - 1, seizure -1 (not related) Two patients: urticaria

Not mentioned

N = 2, transient, reversible indigestion None

None

None

N = 1, cutaneous eruption in patient who dropped- out

None

Monitoring in six patients, no abnormalities Monitoring in 35 patients, no abnormalities

Monitoring in 16 patients; reversible asymptomatic elevation of ALP between x 1 and x 2 upper limit of normal in two patients. ALP was 149 U/L

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Abdel-Rahman et al [79]

(continued on next page)

527

528

Table 3 (continued ) Reference

Dose regimen

Gupta et al [28]

5 mg/kg/d x2 wk or x3 wk

Gupta and Ginter [87]

5 mg/kg/d 2 – 12 wk

Follow-up

FU: 12 wk Organisms: T tonsurans = 35 T violaceum = 15 FU: 12 wk after therapy cessation M canis = 94

Number of patients

N = 50 Age: 5.2

N = 94 Age: 6 y

Cure rate

MC: 43/46 = 93.5% ITT: 43/50 (86%) CC: 41/46 = 89.1% ITT: 41/50 (82%) CC: 94/94 = 100% (Most required 4 – 8 wk of therapy)

Clinical

None

N = 1, moderate diarrhea, patient discontinued at wk 4, cured at FU N = 1, mild stomachache, resolved, did not discontinue

Laboratory in one patient and 146 U/L in the other (normal: < 92 U/L) Not performed; no patients showed symptoms requiring laboratory monitoring Not performed; not clinically indicated in patients

ALP, alkaline phosphatase, CC, complete cure; ET, effective therapy - mycologic cure and minimal symptoms and signs (excluding hair loss which takes several months to return to normal); F/U, follow-up from start of therapy unless otherwise indicated; MC, mycologic cure. a Only those studies  10 patients.

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Adverse effects

Table 4 Continuous itraconazole oral solution, pulse itraconazole capsules, and pulse itraconazole oral solution for the treatment of tinea capitis (  10 patients in study) Adverse effects Reference

Dose regimen

Continuous, oral solution Ginter [50] 5 mg/kg/d x 3 to 11 wk Ginter [38] 5 mg/kg/d x 6.1 wk (average) 5 mg/kg/d x2 – 12 wk

Pulse regimen, capsules Gupta et al [85] 5 mg/kg/d x 1 wk, one to three pulses

Gupta et al [23]

5 mg/kg/d, one to five pulses

Pulse regimen, oral solution Gupta et al [84] 3 mg/kg/d 1 wk, one to three pulses

Number of patients

Cure rate

Clinical

Laboratory

Organisms: M canis

N = 12 Age range: 4 to 13 y N = 31 Average age: 5.7 y

CC: 12/12 = 100%

N = 2, minor gastrointestinal disturbance N = 2, minor gastrointestinal reaction, N = 2, skin rash N = 1, mild diarrhea resolving without cessation of therapy

None

Organisms: M canis

CC: 31/31 = 100%

Not mentioned

FU: 12 wk after therapy cessation M canis = 13

N = 13 Age: 2.8 y

CC 13/13 = 100%

F/U: 12 wk Organisms: T tonsurans = 6, T violaceum = 2, T soudanense = 1, M gypseum = 1 F/U: 12 wk Organisms: T tonsurans = 41, T violaceum = 7, T soudanense = 1, T rubrum = 1

N = 10 Ages range: 4 to 11 y

CC: 10/10 = 100%

None

Not mentioned

N = 37 evaluable, (total = 50 subjects) Ages range: 18 y to adult

CC: 30/37 = 81.1% in up to three pulses [95% CI: 74.7 – 87.5], 35/37 = 94.6% in up to five pulses [95% C I: 90.9 – 98.3]

None

Not mentioned

N = 19 evaluable, 7 lost to follow-up (total = 27 subjects) Age range: 3 to 11 y

CC: 18/19 = 94.7% [95% CI: 89.6 – 99.8]

N = 4 gastrointestinal side-effects

Monitoring performed in six children with no reported adverse-effects

F/U: 12 wk Organisms: T tonsurans = 24, T violaceum = 2, M canis = 1

Not performed; not clinically indicated in patients

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Gupta and Ginter [87]

Follow-up

CC, complete cure; ET, effective therapy — mycologic cure and minimal symptoms and signs (excluding hair loss which takes several months to return to normal), F/U, follow-up from start of therapy unless otherwise indicated, MC, mycologic cure. 529

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severe cases having lower cure rates. None of the patients using terbinafine, itraconazole, or fluconazole reported any adverse events. In most of the studies itraconazole has been used as monotherapy in the treatment of tinea capitis. One study used topical antifungal therapy in addition to oral itraconazole [30]. Itraconazole may also be used in conjunction with ketoconazole or selenium sulfide shampoo [31]. Topical therapies alone are not expected to be effective; however, one study did find 2% ketoconazole shampoo alone effective in Trichophyton tinea capitis [32]. In the opinion of the authors, efficacy is best demonstrated where the oral agent is used as monotherapy for tinea capitis. Shampoos, however, play an important role in reducing the carrier state both in the immediate family contacts and also at school or other areas where the patient may be in close contact with humans for prolonged periods of time. The carrier state may be an important consideration for tinea capitis caused by T tonsurans [33 – 35]. It may also have some degree of importance in M canis tinea capitis [36].

Onychomycosis The data suggest that itraconazole is effective and safe in the treatment of onychomycosis in children, with the preferred regimen being pulse therapy, as in adults. The dosage regimen is 5 mg/kg/d for 1 week on and 3 weeks off between successive pulses. Generally, two and three pulses, respectively, are required for finger and toe onychomycosis. There are a number of studies that have looked at the treatment of onychomycosis with itraconazole in children. Most are case studies or case series. Huang and Paller [37] retrospectively reviewed 17 cases where children with onychomycosis (age 3 to 14 years) were treated with itraconazole pulse therapy (5 mg/kg/d for 1 week, followed by 3 weeks off therapy). This pulse regimen was performed for three to five cycles. Clinically 94% of the subjects were cured, with no adverse events noted. At follow-up, up to 4.25 years later, no recurrence of the onychomycosis was recorded. Ginter [38] conducted an open study of children between the ages of 10 and 17 years. They were given itraconazole, 200 mg/d for 12 weeks. Within 2 to 4 months, clinical and mycologic cure was observed in 10 of the 12 subjects, with one being lost to follow-up. There were no abnormal laboratory findings, nor any clinical adverse events during the duration of the study. The author noted that cure was achieved faster in these children than in previous

experience with adults. On follow-up no relapses were noted, although the author did not mention the time of this follow-up. In another open study, Danilla and Hegyi [39] treated children aged 8 to 13 years with itraconazole pulse therapy with the mean dosage being 150 mg/d administered for 1 week, followed by 3 weeks of no treatment, for three cycles. It was found that 83.3% of the 12 children were clinically and mycologically cured, and another 6.7% showed clinical improvement. There were also no adverse effects and no abnormal laboratory parameters were observed. At follow-up, 6 months from the start of therapy, only one relapse was recorded. Gupta et al [40,41] have treated a number of children with itraconazole pulse therapy, with oral solution (3 mg/kg/d) and capsules (200 mg twice a day). The efficacy of these treatments was excellent, with a clinical response seen in all those treated and mycologic cure in five of six patients. There were no abnormal laboratory findings reported, and only one relapse noted. Large-scale open studies have enrolled children and adults. Two studies were conducted, with 59 and 24 subjects enrolled, respectively [42,43]. It is not certain how many of the subjects were children. In both of these trials, pulse therapy was used, and the results indicate significant effectiveness of itraconazole manifested as clinical or mycologic cures in most subjects. There were no abnormal laboratory values found during the study, and the only adverse effects noted out of a total of 83 subjects were five cases of gastrointestinal complaints. Itraconazole has been shown to be an effective and safe therapy for the treatment of pediatric onychomycosis. Pulse therapy in particular, with the reduced exposure to itraconazole, offers the benefit of a high cure rate coupled with generally mild, transient adverse events.

Other tinea infections A number of open-label studies have been conducted using itraconazole for tinea pedis, tinea manuum, tinea versicolor, tinea corporis, and tinea cruris [10,38,44 – 58]. Many reports combined the outcomes of the individual types of infection, and combined the outcomes of children with those of adults in their analyses [10,38,49 – 51,55,58]. A few reports have focused exclusively on children, some as young as 6 months, using itraconazole therapy ranging from a few days to months depending on the site of the infection [38,45,50,52,53]. The results of treatment

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with itraconazole have been excellent. Mycologic and clinical cures generally reached over 80%, with 100% cure rate being commonly exhibited. Relapses were rare, and in many of the studies clinical improvement continued during the weeks following cessation of therapy. In several comparative trials, itraconazole was shown to be significantly more effective than griseofulvin in curing tinea infections. In the studies where itraconazole has been used in children, the most common adverse events were gastrointestinal complaints and development of a rash. In studies that looked at both adults and children, headaches, abdominal pain, and elevations in liver enzymes were seen as adverse events in a small percentage of patients. Most patients experiencing adverse events found their symptoms normalized on discontinuation of therapy. When itraconazole is considered for the treatment of other superficial mycoses the dosage regimen is that outlined in Table 2. As in adults, the pulse regimen is preferred over the continuous regimen. Itraconazole has also been used successfully in pediatric cases of chronic mucocutaneous candidiasis [59 – 65], sporotrichosis [66 – 73], and leishmaniasis [74 – 78].

Safety of itraconazole use in children In children, itraconazole has demonstrated an excellent safety profile with frequency of adverse effects being reported between 1.9% and 3.5% [9]. The most common adverse events (> 1% incidence) consist of gastrointestinal (nausea, vomiting, or abdominal pain); rash; dizziness; sleepiness; headache; and abnormalities in liver function tests [18,19]. These events are usually mild and transient. Most children have been able to continue with the course of itraconazole treatment [19]. The itraconazole oral solution is associated with similar adverse events, particularly those involving the gastrointestinal tract. Many cases of superficial fungal infection treated with itraconazole have been documented in the literature. Most are case reports. Many reports have also included adults, and the findings do not differentiate between the two populations. In summarizing the available clinical reports on the safety of itraconazole, the authors found 62 papers that included children in their reported use of itraconazole in the treatment of superficial mycoses [2,10,20,23,24,27 – 29,31,37 – 48, 50 – 65,67 – 93]. Over 1650 patients were presented in these papers, of which more than 750 (45%) were children under 18 years of age. Of the 62 papers assessed, 48 papers (77%, approximately 650 children)

531

reported on adverse events experienced: 24 (50%) papers reported no adverse events; 24 (50%) papers found adverse events that were generally mild, transient, and self-limiting as treatment progressed; and 30 (65%) papers reported no significant changes in either blood or biochemical testing results. Specific adverse events were dominated by gastrointestinal disorders. Itraconazole treatment was discontinued in 6 (0.9%) of 650 children because of nausea and vomiting (two patients); epistaxis (one patient); gastrointestinal cramps (one patient); moderate diarrhea (one patient); and bacterial infection (one patient). In most of the trials and case reports where itraconazole has been used to treat patients with superficial fungal infections, laboratory testing has not been performed on a regular basis. Laboratory data, where available, suggest that elevation of liver function tests is an uncommon occurrence. Similarly, there does not seem to be any consistent change in the other laboratory parameters reported. A retrospective analysis of itraconazole capsules in onychomycosis (continuous and pulse therapy; adults) suggested a low potential for hepatic damage exists [94]. In comparison with data available for adverse effects and laboratory abnormalities experienced during adult use of itraconazole therapy, a somewhat lower incidence of events may indicate that the triazole is used more safely in children than in adults. The results are perhaps not surprising given that children are less likely to be on multiple drugs, or have reduced their hepatic reserve as a result of alcoholic disease or other potential hepatotoxins. A careful assessment of medications used should be made, because some children may be concomitantly using medications that can interact with itraconazole, particularly the allergy medications terfenadine and astemizole, and the benzodiazepines. It should be noted that in many countries terfenadine and astemizole are no longer available. The use of pulse therapy regimens (capsules or oral solution) minimizes the duration of treatment, and reduces the potential for experiencing adverse effects without compromising the effectiveness of treatment.

Discussion Although griseofulvin is the only drug approved by the US Food and Drug Administration for the treatment of tinea capitis, its usefulness may be restricted. Griseofulvin has a limited spectrum of activity, which does not include Candida species. Absorption and bioavailability of griseofulvin varies with dietary fat intake and dissolution rate of the drug

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preparation. Griseofulvin is then eliminated quickly from the body once administration is discontinued; dosing regimens must be maintained for long periods (tinea capitis, 6 to 8 weeks continuous dosing; onychomycosis, 6 to 18 months continuous dosing); and the dosage of griseofulvin required to achieve cure in tinea capitis has been increasing gradually over the years in some countries, such as the United States [95]. The long-term dosing, combined with the experience of unpleasant although typically mild side effects, may be difficult to maintain in pediatric patients and may reduce patient compliance, leading to decreased efficacy with griseofulvin. Dosing required with itraconazole may be less than that of griseofulvin, because of the favorable pharmacokinetic profile of itraconazole, and itraconazole efficacy may be similar to that of griseofulvin for both endothrix species (eg, T tonsurans and T violaceum) and ectothrix species (eg, M canis). The shorter durations of therapy that may be possible with itraconazole may then be associated with fewer adverse effects. In the treatment of tinea capitis it remains to be seen whether the continuous or the pulse format will become the preferred regimen. In North America, the authors are of the opinion that compliance will be better with the continuous regimen because it is often difficult for patients to return for regular visits. This may be different in Europe and other countries of the world where it is possible for parents or caregivers to bring the child back to the clinic on a regular basis. The question remains whether the capsules or the oral solution will become the preferred formulation for the treatment of tinea capitis using itraconazole. In the authors’ experience the oral solution has a pleasant taste, is readily accepted by young children, and has been associated with high compliance. Both itraconazole and griseofulvin have a liquid formulation that is available in some countries, and may be an advantage in treating very young children who cannot swallow capsules. The authors have found that the oral itraconazole solution administered at 5 mg/kg/d has been associated with only a few adverse effects, the most common being a looser consistency of bowel movements, but not frank diarrhea, in some children. A question has been raised about the possible carcinogenic potential of the cyclodextrin in the oral solution formulation. Initial animal studies indicated this was likely a species-specific occurrence, because it was only found in rats. There are no data to suggest that cyclodextrin has caused similar effects in mice or dogs [17]. Furthermore, there have been no adverse effect reports to suggest the possibility of this

complication in humans. The relative cost of the oral solution compared with the capsules will also be a factor that determines which formulation gets to be used preferentially.

Summary Current dosing regimens for itraconazole are effective, safe, and versatile for use in superficial fungal infections in children, particularly tinea capitis. Good efficacy rates have been noted in both Trichophyton and Microsporum tinea capitis infections. Itraconazole has a high affinity for keratin, and accumulates to high levels at the site of superficial fungal infections. A pulse regimen may be chosen over continuous dosing, because the accumulation persists after dosing of itraconazole has been stopped. An oral solution of itraconazole is available, and may be more convenient for children who cannot swallow capsules. The oral solution also produces good rates of efficacy, but may be associated with a somewhat higher potential for gastrointestinal adverse events than the capsules. The range of adverse events noted with itraconazole capsules or oral solution use in children is similar to the range in adults. Events are generally mild and transient. Attention must be taken to note any medications that the child is using, because itraconazole is associated with a range of potential drug interactions. This safety of use, in combination with itraconazole’s wide antifungal spectrum and pharmacokinetic properties, which allow for shorter dosing regimens, may make itraconazole a suitable alternative to griseofulvin for pediatric superficial fungal infections.

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Dermatol Clin 21 (2003) 537 – 542

The use of fluconazole to treat superficial fungal infections in children Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth A. Cooper, HBSc, BEScb, Fernando Montero-Gei, MDc a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Department of Dermatology, San Juan de Dios Hospital, University of Costa Rica Medical School, San Jose, P.O. Box 2157-1000, Costa Rica

Cutaneous mycoses make up 7% to 15% of cases seen in pediatric clinic [1]. The most common mycoses are dermatophyte infections (tinea capitis, tinea corporis, tinea pedis, tinea cruris, and tinea unguium); Pityrosporum infections (pityriasis versicolor, Pityrosporum folliculitis); and candidiasis [1]. Tinea capitis is the most common of all these superficial fungal infections [1]. The goal of therapy for tinea capitis is to produce complete cure (a normal-appearing scalp with negative microscopy and fungal culture). Topical therapy is generally preferred to systemic therapy for pediatric infections, especially if it provides an efficacy similar to oral therapy, because topical therapies are generally without the adverse effects associated with oral therapy. Tinea capitis, however, requires systemic therapy, as does tinea unguium [1,2]. Immunocompromised children may require systemic therapy to achieve adequate efficacy when treating superficial fungal infections. Griseofulvin is the gold standard for tinea capitis treatment. It has a good safety profile in pediatric use, and is well tolerated by most children. Recommended dosages are generally 15 to 25 mg/kg/d. The duration of treatment is approximately 6 to 8 weeks for tinea capitis and 6 to 18 months for tinea unguium [1,2]. Absorption of griseofulvin is highly variable and

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

depends on the fat content of concomitant ingested food [1,2]. Concentrations of griseofulvin in tissue decline rapidly after dosing is stopped [1,2]. Side effects, such as gastrointestinal distress and headache, are seen in 20% of patients using griseofulvin, although liver toxicity and other serious adverse events (photodermatitis, peripheral neuropathy, and toxic epidermal necrolysis) are rare [1]. Because of these issues with griseofulvin treatment, newer antifungal agents have been evaluated for efficacy and safety in the treatment of tinea capitis and other pediatric superficial fungal infections. Although the predominant use of fluconazole is in candidiasis infections, this antimycotic has shown some success in tinea capitis treatment, with a good safety profile.

Fluconazole Fluconazole is a triazole antifungal agent that inhibits fungal cytochrome P-450 sterol C-14a demethylation [1,3,4]. This mechanism prevents the formation of ergosterol, which is required for the fungal cell membrane. Like other azoles, fluconazole demonstrates fungistatic activity in vitro. Fluconazole is active against a relatively broad spectrum of organisms, including dermatophyte fungi, Cryptococcus spp, and some Candida spp including C albicans; however, Aspergillus spp is resistant to fluconazole [5].

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00033-0

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Unlike some other new oral antifungals, such itraconazole, fluconazole absorption is not affected by gastric pH levels and does not need to be taken with a meal. Over 90% of fluconazole is absorbed [2,4]. Fluconazole is hydrophilic, with a volume of distribution approximating total body water, and penetrates into all body fluids and tissues (cerebrospinal fluid, meninges, liver, spleen, mucosa, and saliva) [3,4]. Plasma protein binding is 11% to 12%. The terminal plasma elimination half-life is approximately 30 hours. Eighty percent of the dose is eliminated unchanged by the renal system [2]. Fluconazole persists in the skin for a period after active treatment has been completed [1,6]. Levels of fluconazole in the scalp hair can be significantly higher than plasma levels, and may persist for as long as 6 months after cessation of treatment [6]. The levels reached have been shown to be in range of the minimum inhibitory concentrations for the organisms which have been frequently associated with tinea capitis. In the United States, fluconazole is indicated for oropharyngeal or esophageal candidiasis, vaginal candidiasis, and cryptococcal meningitis [7]. Dosages recommended for children with oropharyngeal or esophageal candidiasis are 6 mg/kg on the first day, followed by 3 mg/kg once daily for at least 2 weeks. The recommended dosing for children with acute cryptococcal meningitis is 12 mg/kg on the first day, followed by 6 mg/kg once daily for 10 to 12 weeks after cerebrospinal fluid becomes culture negative. Pharmacokinetic studies performed in children from 9 months old to 15 years old have established a dose proportionality between children and adults (adults:children 100 mg: 3 mg/kg; 200 mg: 6 mg/kg; 400 mg: 12 mg/kg) [7]. Adverse events were experienced by 16% of over 4000 adult patients involved in clinical trials of 7 days or more, and 1.5% discontinued fluconazole because of these events [7]. Adverse events associated with fluconazole use included headaches, skin rash, abdominal pain, diarrhea, nausea, and vomiting [1 – 3,7,8]. Rare serious adverse events noted during clinical trials included exfoliative skin disorders (Stevens-Johnson syndrome and toxic epidermal necrolysis) and hepatic necrosis [3,4,7]. These serious adverse events primarily occurred in patients who had serious underlying health disorders, so the relation of these adverse events to fluconazole use was uncertain. Phase II-III clinical trials found adverse events in 13% of 577 children (age 1 day to 17 years) treated with fluconazole doses up to 15 mg/kg/d for up to 1616 days [3,7]. The most commonly reported adverse events included vomiting (5.4%); abdominal

pain (2.8%); nausea (2.3%); and diarrhea (2.1%). Treatment was discontinued in 2.8% of pediatric subjects because of adverse events, and 1% of pediatric subjects because of laboratory test abnormalities. Fluconazole is more selective of the fungal cytochrome P-450 enzymes than is the antifungal agent ketoconazole, thereby reducing the potential for adverse drug interactions with fluconazole versus ketoconazole [4]. Fluconazole is contraindicated with terfenadine (where fluconazole dosing is  400 mg per day) and with cisapride. Rifampicin increases the clearance of fluconazole. Fluconazole increases the plasma concentration of cyclosporin; warfarin; phenytoin; nortriptyline; tacrolimus; drugs that prolong the QTc interval; and sulfonylurea drugs, such as tolbutamide, glibenclamide-glyburide, and glipizide. Fluconazole may decrease the plasma concentrations of theophylline, and levels of the latter should be monitored when administered concurrently with fluconazole.

Fluconazole in tinea capitis The efficacy of fluconazole in the treatment of tinea capitis has been documented in six studies (Table 1). Four of these were open trials. One paper described five cases where children were treated for tinea capitis on an individual basis with fluconazole [9]. One other paper reported results of a randomized, single-blinded study of fluconazole compared with terbinafine, itraconazole, and griseofulvin [10]. Once-weekly fluconazole dosing regimens were used successfully in two studies [11,12]. Complete cure was produced in Trichophyton spp infections following 8 mg/kg once weekly for 8 to 12 weeks [11]. Most patients received only 8 weeks of treatment. M canis infection treated with 8 mg/kg fluconazole weekly demonstrated a complete cure rate of 94.1% at a follow-up 8 weeks after completion of

Table 1 Suggested dosing regimens for superficial fungal infections using fluconazole Indication

Dose

Tinea corporis, cruris 150 mg once weekly Tinea pedis, manuum 150 mg once weekly Tinea capitis 8 mg/kg once weekly 6 mg/kg/d continuous Onychomycosis Fingernails 150 mg once weekly Toenails 150 mg once weekly Data from references [30] and [31].

Duration 2 – 6 wk 4 – 6 wk 8 – 12 wk 3 – 6 wk 4 – 6 mo 9 – 12 mo

A.K. Gupta et al / Dermatol Clin 21 (2003) 537–542

fluconazole treatment. Treatment was given for Microsporum from 8 to 16 weeks; however, most (12/17) required only 8 weeks to exhibit complete cure [11]. Similar success was found in Microsporum infection treated with 6 or 8 mg/kg once weekly by Montero-Gei [12]. After 4 to 8 weeks of treatment, 100% of patients showed a complete cure, with no relapse noted after a follow-up time that averaged 16 weeks. Only 2 of 20 patients required 8 weeks of treatment. Mercurio et al [9] treated five children who had T tonsurans tinea capitis with fluconazole. Two were treated with fluconazole suspension, 5 mg/kg/d. Both children had negative cultures after 4 weeks of daily fluconazole therapy. Treatment for both was continued for a further 2 weeks while awaiting culture results. A 16 year old was treated with fluconazole after failure to achieve cure with oral griseofulvin, tropical terbinafine, ketoconazole shampoo, and oral ketoconazole, and oral itraconazole. Fluconazole tablets, 200 mg daily, were prescribed and complete cure was achieved after 6 weeks. A 10-year-old boy with a history of seizures, mental retardation, renal failure, and cerebral palsy was treated with fluconazole, 50 mg/d, following an increase of hepatic enzymes, which prompted the discontinuation of itraconazole. Duration of therapy was not provided, but it was noted that at a 3-month follow-up the child showed complete cure. The fifth child was a 3-year-old girl with developmental delay, AIDS encephalopathy, cardiomyopathy, and gastritis. Fluconazole, 45 mg/kg/d, was given intravenously for 4 months, when she showed complete cure. A follow-up at month 6 showed no evidence of relapse. Hepatic and renal function remained within normal limits during the therapy. Solomon et al [13] showed an increase in complete cure rate with increasing dose levels of fluconazole against Trichophyton tonsurans. Doses of 1.5 mg/kg/d for 20 days produced a complete cure rate of 25% after 4 months, whereas doses of 6 mg/ kg/d for 20 days produced a complete cure rate of 89%. Similar rates of complete cure were found by Gupta et al [14] following treatment of Trichophyton spp tinea capitis with fluconazole, 6 mg/kg/d for 2 to 3 weeks. In a comparative trial of fluconazole, itraconazole, terbinafine, and griseofulvin, 6 mg/kg/d of fluconazole for 2 or 3 weeks provided a complete cure rate of 82% (intention-to-treat analysis) at week 12 followup for cases of Trichophyton tinea capitis [10]. Three weeks of therapy were required in 30 of 50 patients. Despite having more severe cases enrolled into the fluconazole group than in the other three groups ( P = 0.003), the fluconazole cure rate at week 12

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was not significantly different from the other three treatment groups. Baseline severity in general, however, was a significant predictor of cure ( P < 0.001) across all groups, with severe cases having lower cure rates than mild or moderate cases. No adverse events were reported with the fluconazole regimen. Kerion tinea capitis has been shown responsive to fluconazole treatment. Treatment of a 3-year-old girl was reported by Hiruma et al [15]. A red, swelling node associated with alopecia and abscesses was noted in the left temporal area, and Microsporum gypseum infection was confirmed by microscopy and culture. Fluconazole, 50 mg once weekly, was given. The node was visibly reduced after 1 week of treatment. Fluconazole was given until week 8, at which point scaling was not observed. Gatti et al [16] treated a 24 year old for kerion with fluconazole, 50 mg/d for 20 days. At 20 days there were no clinical signs of kerion, and microscopy was negative. The patient remained clear of infection after 2 months of follow-up. Gupta et al [10] treated two patients with kerion tinea capitis, using 6 mg/kg/d for 2 or 3 weeks, and both were cured.

Fluconazole in other superficial fungal infections Fluconazole has demonstrated efficacy in the treatment of other superficial fungal infections, such as tinea corporis or cruris; tinea pedis; and tinea versicolor (pityriasis versicolor) [17 – 26]. These infections are relatively uncommon in children; however, these reports suggest that children with such infections could be treated effectively with fluconazole. Fluconazole has been used effectively in small studies to treat onychomycosis in adults, and may also be a potential treatment for children [27 – 29].

Safety of fluconazole in children In the clinical reports on tinea capitis (Table 2), fluconazole seemed safe for use in children. Most adverse events encountered were mild to moderate, and resolved without stopping fluconazole treatment. No patients in the daily fluconazole dosing studies reported experiencing any adverse events, and no patients discontinued treatment because of adverse events [13,14]. No abnormal laboratory values were found in the study by Solomon et al [13]. When using fluconazole once weekly, Gupta et al [11] reported adverse events in 3 (4.9%) of 61 patients. Gastrointestinal upset was the event in all three patients; upset was mild, and did not require discon-

540

Table 2 Summary of reports where fluconazole has been used to treat tinea capitis Study Mean age (y) description

T tonsurans: 44 T violaceum: 6

50

5.9 F 0.3

6 mg/kg/d

Gupta et al 2000 [11]

T violaceum: 33 T tonsurans: 11 M canis: 17

61

5 F 0.3

8 mg/kg once weekly

Gupta et al 1999 [14]

T tonsurans: 38 T violaceum: 4

48 6.2 (42 evaluable)

Infection

Gupta et al 2001 [10]

Mercurio et al 1998 [9] T tonsurans: 5

5

Montero-Gei 1998 [12] M canis: 13 M gypseum: 5 T tonsurans: 2

20

Solomon et al 1997 [13]

T tonsurans (all patients)

41 2 – 15 (27 evaluable)

Gatti et al 1991 [16]

Kerion T mentagrophytes

1

6 mg/kg daily

Varying dose

24

Duration 2 wk (1 additional wk given if therapy not effective at wk 4)

Follow-up

Cure rates

CC: 41/50 (82%) EC: 42/50 (84%) - T tonsurans: 36/44 (81.8%) - T violaceum: 6/6 (100%) (ITT analysis) 8 wk (Trichophyton 8 wk after tx T violaceum: 100% CC spp; extra 4 wk if ended (wk16, CC:24(72.7%) 8wk tx clinically necessary) wk20, or wk24) CC:9 (27.3%) 12wk tx 8 wk (Microsporum spp; T tonsurans: 100% CC extra 4 wk, or extra CC:11 (100%) 8wk tx M canis: 94.1% CC 8 wk, if clinically CC:12(70.6%) 8wk tx necessary) CC:1(5.9%) 12wk tx CC:3(17.6%) 16wk tx 2wk (extra 1 wk if 12 wk CC: 19(45.2%) 2wk tx clinically necessary) CC: 18(42.9%) 3wk tx 37/42 (88.1% overall) Varying treatment All patients cured following regimens and durations fluconazole tx 4wk: 11 16 wk (after tx ended) EC: 100% (all regimens; 6wk: 7 (average) no relapse at follow-up) 8 wk: 2

6 mg/kg once weekly: 4 pts 8 mg/kg once weekly: 16 pts 1.5 mg/kg/d: 8 20 d 3 mg/kg/d: 10 6 mg/kg/d: 9 50 mg/d 20 days

12 wk

6 wk 4 mo 2 mo

CC: 2/8 (25%) 4mo CC: 6/10 (60%) 4mo CC: 8/9 (89%) 4mo Microscopy negative, clinical care

Abbreviations: CC, complete cure (mycologically negative, and complete clearance of clinical signs and symptoms of tinea capitis); EC, effective cure (mycologic cure with clinical cure or few residual symptoms [score less than or equal to 2]); ITT, intention-to-treat; tx, treatment.

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No. of patients

Authors

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tinuation of therapy. Only 1 of 17 patients monitored had an asymptomatic elevation of liver enzymes at week 8 from the start of therapy. Values returned to normal when therapy was finished. No other patients had symptoms or signs that warranted laboratory monitoring. In the other once-weekly study, no patients reported any adverse events [12]. No patients dropped out because of adverse events in either study. There was no mention of adverse events in the case reports [9]. It can be noted, however, that a child with cerebral palsy and renal failure maintained stable renal and hepatic function during the fluconazole, 50 mg/d, regimen.

superficial fungal infections. The predominant use in pediatric superficial fungal infection has been for tinea capitis, and successful treatment has been shown with both daily and weekly fluconazole regimens. The data regarding fluconazole use in superficial fungal infections in children are somewhat limited; however, it seems that there is good potential for the safe use of fluconazole to treat tinea capitis in children. Further studies need to be conducted, particularly in cases of tinea capitis (both T tonsurans and M canis), to determine the optimal treatment regimens using fluconazole.

Discussion

References

Fluconazole, although not approved for use in pediatric superficial fungal infection, has been approved for the treatment of oropharyngeal candidiasis, esophageal candidiasis, and cryptococcal meningitis in children. Currently, only griseofulvin has been approved for use in the treatment of tinea capitis. None of the newer oral antifungals (fluconazole, itraconazole, or terbinafine) has been approved for pediatric use in superficial fungal infection. A liquid formulation of fluconazole is an asset in pediatric dosing, because some children may have difficulty swallowing capsules. Oral formulations of griseofulvin and itraconazole have been used successfully in tinea capitis treatment. Fluconazole oral suspension is produced by reconstituting fluconazole powder in water. The oral suspension is stable for 14 days at 15C to 30C [3,24]. Once-weekly fluconazole dosing may be used instead of continuous therapy. The former regimen minimizes the dose of fluconazole given to the child, reducing potential adverse events related to fluconazole use without reduction in efficacy. Some children who have difficulty returning to the clinic, or who have a poor parental support system, however, may find it difficult to remember to take the once-a-week dose. Fluconazole has generally been safe in both adults and children with few drug interactions that are significant in most children. The physician should, however, be cognizant of potential drug interactions with this triazole (see the article by Katz and Gupta elsewhere in this issue).

[1] Rudy SJ. Superficial fungal infections in children and adolescents. Nurse Pract Forum 1999;10:56 – 66. [2] Gupta AK, Summerbell RC. Tinea capitis. Med Mycol 2000;38:255 – 87. [3] Canadian Pharmacists Association. Diflucan-Pfizerfluconazole-antifungal agent. In: Repchinsky C, editor. Compendium of pharmaceuticals and specialties (CPS) 2002. 37th edition. Toronto: Webcom Limited; 2002. p. 502 – 5. [4] Goa KL, Barradell LB. Fluconazole: an update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs 1995; 50:658 – 90. [5] Meis JFGM, Verweij PE. Current management of fungal infections. Drugs 2001;61(suppl 1):13 – 25. [6] Yeates R, Laufen H, Zimmerman T, Scharpf F. Accumulation of fluconazole in scalp hair. J Clin Pharmacol 1998;38:138 – 43. [7] Lori Murray, editor. Physicians’ Desk Reference. 57th edition. Montvale NJ: Thomson PDR; 2003. [8] Suarez S, Friedlander SF. Antifungal therapy in children: an update. Pediatr Ann 1998;27:177 – 84. [9] Mercurio MG, Silverman RA, Elewski BE. Tinea capitis: fluconazole in Trichophyton tonsurans infection. Pediatr Dermatol 1998;15:229 – 32. [10] Gupta AK, Adam P, Dlova N, Lynde CW, Hofstader S, Morar N, et al. Therapeutic options for the treatment of tinea capitis caused by Trichophyton species: griseofulvin versus the new oral antifungal agents, terbinafine, itraconazole and fluconazole. Pediatr Dermatol 2001;18:433 – 8. [11] Gupta AK, Dlova N, Taborda P, Morar N, Taborda V, Lynde CW, et al. Once weekly fluconazole is effective in children in the treatment of tinea capitis: a prospective, multicenter study. Br J Dermatol 2000; 142:965 – 8. [12] Montero-Gei F. Fluconazole in the treatment of tinea capitis. Int J Dermatol 1998;37:870 – 3. [13] Solomon BA, Collins R, Sharma R, Silverberg N, Jain AR, Sedgh J, et al. Fluconazole for the treatment of

Summary Fluconazole has excellent absorption and good persistence in tissues that suggests it may be useful in

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[14]

[15]

[16] [17]

[18]

[19]

[20]

[21]

[22]

A.K. Gupta et al / Dermatol Clin 21 (2003) 537–542 tinea capitis in children. J Am Acad Dermatol 1997; 37:274 – 5. Gupta AK, Adam P, Hofstader SLR, Lynde CW, Taborda P, Taborda V, et al. Intermittent short duration therapy with fluconazole is effective for tinea capitis. Br J Dermatol 1999;141:304 – 6. Hiruma M, et al. Clinical cases of mycotic granuloma (Celsus’ kerion in children): two cases successfully treated by intermittent therapy with fluconazole and itraconazole. Hifubyo Rinsyo 1995;17:849 – 52. Gatti S, Marinaro C, Bianchi L, Nini G. Treatment of kerion with fluconazole. [letter] Lancet 1991;338:1156. Bhogal CS, Singal A, Baruah MC. Comparative efficacy of ketoconazole and fluconazole in the treatment of pityriasis versicolor: a one year follow-up study. J Dermatol 2001;28:535 – 9. Del Aguila R, Montero-Gei F, Robles M, Perera-Ramirez A, Male O. Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea pedis. Clin Exp Dermatol 1992;17:402 – 6. Faergemann J, Mork NJ, Haglund A, Odegard T. A multicenter (double-blind) comparative study to assess the safety and efficacy of fluconazole and griseofulvin in the treatment of tinea corporis and tinea cruris. Br J Dermatol 1997;136:575 – 7. Faergemann J. Treatment of pityriasis with a single dose of fluconazole. Acta Derm Venereol 1992;72: 74 – 5. Kohl TD, Martin DC, Nemeth R, Hill T, Evens D. Fluconazole for the prevention and treatment of tinea gladiatorum. Pediatr Infect Dis J 2000;19:717 – 22. Kohl TD, Martin DC, Berger MS. Comparison of topical and oral treatments for tinea gladiatorum. Clin J Sport Med 1999;9:161 – 6.

[23] Lesher Jr JL. Oral therapy of common superficial fungal infections of the skin. J Am Acad Dermatol 1999;40:S31 – 4. [24] Montero-Gei F, Perera A. Therapy with fluconazole for tinea corporis, tinea cruris, and tinea pedis. Clin Infect Dis 1992;14(suppl 1):S77 – 81. [25] Suchil P, Montero-Gei F, Robles M, Perera-Ramirez A, Welsh O, Male O. Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea corporis/cruris and cutaneous candidiasis. Clin Exp Dermatol 1992; 17:397 – 401. [26] Tanuma H, Doi M, Yaguchi A, Ohta Y, Nishiyama S, Sekiguchi K, et al. Efficacy of oral fluconazole in tinea pedis of the hyperkeratotic type: stratum corneum levels. Mycoses 1998;41:153 – 62. [27] Assaf RR, Elewski BE. Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot study. J Am Acad Dermatol 1996;35(2 pt 1):216 – 9. [28] Maeng DJ, Hiruma M, Takimoto R, Kawai M, Ogawa H. [Pediatric onychomycosis treated with oral antifungal drugs]. Nippon Ishinkin Gakkai Zasshi 1999; 40:27 – 30. [29] Smith SW, Sealy DP, Schneider E, Lackland D. An evaluation of the safety and efficacy of fluconazole in the treatment of onychomycosis. South Med J 1995; 88:1217 – 20. [30] Gupta AK, Del Rosso JQ. An evaluation of intermittent therapies used to treat onychomycosis and other dermatomycoses with the oral antifungal agents. Int J Dermatol 2000;39:401 – 11. [31] Gupta AK, Hofstader SLR, Adam P, Summerbell RC. Tinea capitis: an overview with emphasis on management. Pediatr Dermatol 1999;16:171 – 89.

Dermatol Clin 21 (2003) 543 – 563

Oral antifungal drug interactions: a mechanistic approach to understanding their cause H. Irving Katz, MDa,*, Aditya K. Gupta, MD, PhD, FRCP(C)b,c a Department of Dermatology, University of Minnesota, 420 Delaware Street S.E., MMC 98, Minneapolis, MN 55455, USA Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada c Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada

b

Oral antifungal medications, such as griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine, are important components in the dermatologists’ armamentarium to treat certain types of cutaneous superficial fungal infections. This is especially true for dermatophyte fungal infections involving the nail unit (onychomycosis); hair shaft (tinea capitis); and in those having widespread involvement (tinea corporis) or in chronic forms, such as diffuses plantar involvement (moccasin tinea pedis). Worldwide, in the past decade, over 100 million persons have received treatment with the three newer oral antifungal agents (ie, fluconazole, itraconazole, and terbinafine) [1]. When oral antifungal drugs are used according to their manufacturer’s recommendation the expectations are that they are generally effective and safe [2 – 9]. Medical professionals may be lulled into a false sense of security, however, unless they consider other medications that their patients are currently on or will be taking during their course of oral antifungal therapy [10,11]. Furthermore, concurrent usage of herbal medications or other agents known to affect hepatic (eg, alcohol) or renal function may also result in drug interactions. Oral antifungal drugs exhibit differences in their innate properties to interact with concurrent drugs [12 – 15]. Overt consequences of oral antifungal drug interactions also vary in their clinical significance. Many oral antifungal drug interactions are theoretical; others are of minor clinical significance but a few may lead to severe iatrogenic adverse

experiences that may include death. This article alerts and demystifies some of the clinically significant oral antifungal drug interactions by exploring their underlying pharmacologic basis. The initial discussion is centered on a mechanistic approach on how oral antifungal drugs interact; this goes beyond rote memorization of an alphabetized list of drugs [16]. The bottom line is that whatever the choice of oral antifungal, an understanding of salient pharmacologic information may help to predict and avoid many serious drug interactions [11,15,17].

Drug interaction definition and pharmacologic mechanisms A drug interaction is an altered pharmacologic response or potency of the drug when it is given with another agent (ie, drug, food, or herbal product). The resultant response may be synergistic, antagonist, or noxious. Mechanistically, many known drug interactions can be classified as being either pharmacokinetic or pharmacodynamic. At times, however, the mechanism for an interaction is either unknown or must be inferred indirectly because similar members of a family or class of drugs have had a particular type of interaction.

Pharmacodynamic drug interaction * Corresponding author. 260 King Hill Road, Golden Valley, MN 55416. E-mail address: [email protected] (H.I. Katz).

Pharmacodynamic drug interactions involve how the drug works in a person (competition for similar

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00037-8

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receptors or a physiologic system) that may have either synergistic or additive or antagonist effects. Pharmacodynamic interactions also include additive adverse experiences that may impair common vital organs, such as the hepatic, renal, cardiac, hematopoietic, or central nervous systems. Next are descriptions and examples of interactions that may represent a pharmacodynamic oral antifungal drug interaction. Negative inotropic cardiac activity Postmarketing reports suggest that itraconazole may rarely precipitate or exacerbate congestive heart failure in certain patients (ie, those with cardiac disease). Animal and human studies have demonstrated that itraconazole might rarely cause clinically significant negative inotropic cardiac effects, which may be transient in nature [4,18]. Based on this, the Food and Drug Administration advises that itraconazole should not be administered in patients with evidence of ventricular dysfunction, such as congestive heart failure or a history of congestive heart failure [4]. Careful consideration and appropriate monitoring should be exercised if itraconazole is administered with other agents that have negative inotropic effects, such as certain calcium channel blockers (eg, verapamil or nifedipine). In such an instance left ventricular cardiac function may be impaired because of the potential additive pharmacodynamic interactions. Hepatotoxicity Mild elevation of hepatic enzymes (ie, 1.5 to 2 times normal) are an infrequent laboratory finding that may occur to a variable degree (approximately 3% to 4%) with the oral antifungals [2 – 6]. Clinically significant rare serious acute hepatocellular, cholestatic, or mixed forms of idiopathic hepatotoxicity, have also been reported with these agents [4]. If a person has preexisting hepatic dysfunction an oral antifungal is not recommended; if used, additional precautions and extra monitoring of liver function tests are prudent. Similarly, when the oral antifungal agents are administered with drugs that are extensively processed by the liver or have an increased potential for liver dysfunction, frequent hepatic monitoring and appropriate counseling may be prudent [19].

Pharmacokinetic drug interactions Pharmacokinetic drug interactions involve how a person handles a drug (ie, absorption, distribution,

biotransformation, and elimination processes) and determines the ultimate bioavailability or blood level of a medication. Most of the relevant drug interactions with oral antifungal agents are pharmacokinetic involving either impaired gastrointestinal absorption, altered P-glycoprotein (Pgp) membrane carrier transport [20], or aberrant substrate biotransformation [12 – 14]. Next are descriptions and examples of pharmacokinetic oral antifungal drug interactions. Gastrointestinal absorption Either the type of meal or the gastric pH temporally affects the bioavailability of griseofulvin, itraconazole capsules, and ketoconazole tablets. For example, the griseofulvin tablet should be given with a fatty meal to maximize its oral absorption [3]. Itraconazole capsules and ketoconazole tablet should be given with meals preferentially in relatively acidic gastric pH milieu for optimal gastrointestinal absorption [4,5]. If the gastric milieu is altered with concomitant coincident use of drugs that increase gastric pH, such as divalent cationic antacids, H2 blockers, proton pump inhibitors, and drugs that contain alkaline buffers, then decreased bioavailability of itraconazole capsules or ketoconazole tablets occurs. The effect of potential gastric alkalinizers on the oral bioavailability of these two oral antifungal agents can be mitigated to some extent by staggering 2 to 4 hours between an alkalinizer and the oral antifungal. In addition, giving either itraconazole capsules or ketoconazole tablets with certain cola beverages (ie, Coca Cola) provides enough acidity to facilitate gastrointestinal absorption of these oral antifungals [21]. Alternatively, in the case of itraconazole, an oral solution formulation is available that is administered best in the fasting state and may be substituted for the capsule formation in certain situations [4,22]. In contrast, the gastrointestinal absorption of fluconazole and terbinafine is not influenced by the gastric milieu per se and can be given irrespective of meals or food. Pgp membrane carrier transporter P-glycoprotein is an energy-dependent membrane transporter that can affect a substrate’s drug bioavailability [23,24]. Pgp is expressed in the apical surface of enterocytes in the small intestine and secretory cells in the renal tubules [25 – 28]. Pgp inhibition may result in increased gastrointestinal absorption or decreased renal excretion with resultant increased bioavailability of individual substrates that are dependent on Pgp. An example of this type of inter-

H.I. Katz, A.K. Gupta / Dermatol Clin 21 (2003) 543–563 Table 1 Examples of P-glycoprotein substrates, inducers, and inhibitors

P-glycoprotein substrates (Examples of major therapeutic classes include certain CYP3A4 substrates, such as antineoplastics and antivirals) Cyclosporine Digoxin Etoposide Itraconazole Loperamide Lovastatin Morphine Nelfinavir Ritonavir Saquinavir Verapamil Vincristine

P-glycoprotein inducers Carbamazepine (possibly) Phenobarbital (possibly) Rifampin St. John’s wort

P-glycoprotein inhibitors (Examples of major therapeutic classes include certain CYP3A4 substrates, such as antifungals, antivirals, and macrolide antibiotics) Amiodarone Chloroquine Clarithromycin Cyclosporine Dipyridamole Erythromycin Itraconazole Ketoconazole Nelfinavir Nifedipine Phenothiazine Primaquine Quinidine Reserpine Ritonavir Tamoxifen Verapamil

Data from references [20], [27], [49], and [50].

action is digoxin toxicity reported in some patients using concurrent itraconazole or ketoconazole [4,5,29]. Mechanistically, digoxin is known to be secreted by a Pgp-dependent distal renal tubule. Itraconazole and ketoconazole are known to inhibit Pgp and prevent the renal excretion of digoxin. Patients who take either itraconazole or ketoconazole and digoxin should be monitored for possible digoxin toxicity. Examples of Pgp substrates, inducers, and inhibitors are listed in Table 1.

Biotransformation Biotransformation is a conversion process following gastrointestinal absorption that changes a lipophilic parent drug substrate into more water-soluble metabolites to facilitate elimination from the host by the hepatobiliary or renal systems [30 – 32]. Relative-

545

ly simple hydrolysis, acetylation, or glucuronidation may be involved. Complex metabolic intermolecular changes involving varied enzymes may cause predicable types of chemical transformation. Such metabolism can begin in the gut wall, but most such metabolism usually occurs in the liver. Interference with metabolism is a frequent mechanism involved in oral antifungal drug interactions that may cause significant adverse experiences or therapeutic ineffectiveness [12 – 14]. The cytochrome P-450 (CYP) mixed-function-oxidase enzymes are vital catalysts for an orderly metabolic breakdown involved in the biotransformation of many xenobiotic drugs. Examples of CYP substrates, inducers, and inhibitors are summarized in Tables 2 through 4. A CYP substrate may require one or more separate CYP (ie, CYP2C9, CYP2D6, and CYP3A4) for optimal metabolic breakdown to occur. Normal CYP activity exerts rate limiting effects on blood levels of a substrate especially if only a single CYP is involved. Generally, the nonmetabolized parent drug has the most therapeutic activity and the greatest potential for an adverse experience. Usually the resultant metabolites have less therapeutic activity and less potential for adverse experience. CYP inhibition results in less CYP enzy-

Table 2 Examples of CYP2C substrates, inducers, and inhibitors CYP2C substrates (Examples of major therapeutic classes include angiotensin II blockers, nonsteroidal anti-inflammatory agents, and oral hypoglycemics) Amitriptyline Celecoxib Desogestrel Diclofenac Fluoxetine Fluvastatin Glyburide Ibuprofen Mefenamic acid Naproxen Nateglinide Phenytoin Piroxicam Tamoxifen Tolbutamide Warfarin (s-warfarin) Zafirlukast

CYP2C inducers Rifampin

CYP2C inhibitors (Examples are a mixed diverse class of drugs, such as certain azole antifungals and sulfonamides) Amiodarone Fluconazole Fluconazole Fluvoxamine Gemfibrozil Imatinib mesylate Isoniazid Lovastatin Miconazole Nateglinide Phenylbutazone Sulfaphenazole Trimethoprim Zafirlukast

Data from references [14], [51], and [52].

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Table 3 Examples of CYP2D6 substrates and inhibitors CYP2D6 substrates (Examples of major therapeutic classes include antiarrhythmics, antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, and tricyclic antidepressants)

CYP2D6 inhibitors (Examples of major therapeutic classes include antiarrhythmics, antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, and tricyclic antidepressants)

Amitriptyline (in part) Carvedilol Clomipramine Codeine Desipramine Dexfenfluramine Dextromethorphan Donepezil (partial) Fenfluramine Flecainide Fluoxetine Fluvoxamine (in part) Galanthamine Imipramine (in part) Metoprolol Mexiletine Nortriptyline (in part) Paroxetine Perphenazine Propafenone Risperidone Thioridazine Timolol Tolterodine Tramadol Venlafaxine

Amitriptyline Cimetidine Clomipramine Fluoxetine Haloperidol Imatinib mesylate Paroxetine Propafenone Quinidine Ritonavir Terbinafine

Data from references [31,53 – 55].

matic activity, decreased rates of biotransformation leading to increased substrate blood levels, and possible toxicity for those drugs that undergo extensive first-pass metabolism or have narrow therapeutic windows is summarized in Table 5 [33]. The onset of a CYP inhibition can occur within hours or a few days. In contrast, CYP induction involving the synthesis of newly formed CYP, may not reach levels to cause an effect for days or weeks. CYP induction increases the rate of biotransformation leading to subtherapeutic substrate blood levels and hence potential therapeutic failure. The duration of altered CYP effects depends on the half-life of the substrates, inhibitor, or inducer. Next are descriptions and examples of CYP-mediated oral antifungal drug interactions.

CYP inhibition Azole antifungals include ketoconazole and its chemical-related entities in the triazole group itraconazole and fluconazole. The azole class of antifungals can cause CYP inhibition [34]. Ketoconazole and itraconazole are known to cause clinically significant CYP3A4 inhibition at ordinary therapeutic doses [4,5,12 – 14]. Fluconazole may also inhibit CYP3A4, but at doses greater than 200 mg/d [14]. CYP3A4 is the most plentiful human hepatic cytochrome and is involved in the metabolism of about 50% of all drugs (CYP3A4 substrates) [35]. Examples of CYP 3A4 substrates, inducers, and inhibitors from Table 4 with relatively narrow therapeutic windows include certain antiarrhythmics (ie, dofetilide, quinidine); benzodiazepines (ie, midazolam, triazolam); dihydropyridine calcium channel blockers (ie, nifedipine, felodipine); and HMG coenzyme A reductase inhibitors (ie, lovastatin, simvastatin). Ketoconazole or itraconazole in the presence of a CYP3A4 substrate with a relative narrow therapeutic window, such as simvastatin, can result in significant impaired simvastatin biotransformation, leading to elevated blood levels and potential rhabdomyolysis. The concurrent use of itraconazole, ketoconazole, or possibly fluconazole (> 200 mg/d) with simvastatin should be avoided [2,4,5,14]. Fluconazole is a CYP2C9 inhibitor [2]. Examples of CYP2C substrates from Table 2 include angiotensin II inhibitors (ie, irbesartan, losartan); nonsteroidal antiinflammatory drugs (ie, diclofenac, ibuprofen); oral hypoglycemics (ie, glipizide, tolbutamide); and oral anticoagulants (ie, warfarin). Patients who are given warfarin and fluconazole require careful monitoring of their international normalized ratio and adjustment of warfarin dosing to prevent excessive anticoagulant activity and bleeding. Terbinafine is a known potent CYP2D6 inhibitor [36,37]. Examples of CYP2D6 substrates from Table 3 include certain beta-blockers (ie, carvedilol, timolol); selective serotonin reuptake inhibitors (ie, fluoxetine, paroxetine); and tricyclic antidepressants (ie, clomipramine, nortriptyline). Even with this robust list of potential drugs, however, there has been a paucity of validated CYP2D6 terbinafine interactions in the literature [13,38 – 41]. A confirmed case of nortriptyline-terbinafine interaction, however, resulting in overt toxicity has been reported [38]. Nevertheless, such limited documentation of a terbinafine CYP2D6 inhibition does not preclude the possibility for this type of reaction; however, the published data suggest that clinically significant reactions are uncommon [6,13,42 – 46].

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Table 4 Examples of CYP3A substrates, inducers, and inhibitors CYP3A substrates (Examples of major therapeutic classes include anesthetics, antianxiety agents, antiarrhythmics, antineoplastics, calcium channel blockers, corticosteroids, ergot derivatives, HMG coenzyme A reductase inhibitors, macrolide antibiotics, oral contraceptives, protease inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants) Alfentanil Alprazolam Amiodarone Amitriptyline Amlodipine Atorvastatin Bexarotene Buprenorphine Busulfan Carbamazepine Cisapride Citalopram Clindamycin Clomipramine (partial) Cyclosporine Dapsone Delavirdine Dexamethasone Diazepam Diltiazem Disopyramide Docetaxel Donepezil Doxorubicin Dronabinol Ergotamine Erythromycin Estrogens, oral contraceptives Ethosuximide Etoposide Felodipine Fentanyl Ifosfamide Imatinib mesylate Imipramine (partial) Indinavir Isradipine Ketoconazole Lansoprazole Levobupivacaine Lidocaine (partial) Lopinavir Losartan Lovastatin Methylergonovine

CYP3A inducers (Examples of major therapeutic classes include anticonvulsants, antimycobacterial, and antivirals) Carbamazepine Dexamethasone Efavirenz Ethosuximide Griseofulvin Lansoprazole Modafinil Nevirapine Phenobarbital Phenytoin Primidone Rifabutin Rifampin St. John’s wort Troglitazone

CYP3A inhibitors (Examples of major therapeutic classes include anesthetics, antiarrhythmics, azole antifungals, beta-blockers, calcium channel blockers, macrolide antibiotics, protease inhibitors, and selective serotonin reuptake inhibitors) Agenerase Amiodarone Cannabinoids Cimetidine Clarithromycin Delavirdine Erythromycin Fluconazolea Fluvoxamine Grapefruit juice Imatinib mesylate Indinavir Itraconazole Ketoconazole Metronidazole Miconazole Nefazodone Nelfinavir Norfloxacin Ritonavir Saquinavir Sertraline Troleandomycin Zafirlukast

(continued on next page)

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Table 4 (continued ) CYP3A substrates (Examples of major therapeutic classes include anesthetics, antianxiety agents, antiarrhythmics, antineoplastics, calcium channel blockers, corticosteroids, ergot derivatives, HMG coenzyme A reductase inhibitors, macrolide antibiotics, oral contraceptives, protease inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants) Miconazole Midazolam Modafinil Navelbine Nefazodone Nelfinavir Nicardipine Nifedipine Nimodipine Nisoldipine Ondansetron Oral contraceptives Paclitaxel Pimozide Pioglitazone Prednisone Quinidine Quinine Rifampin Ritonavir R-warfarin Saquinavir Sertraline Sildenafil Simvastatin Sirolimus Tacrolimus Tamoxifen Temazepam Testosterone Triazolam Verapamil Vinblastine Vincristine Warfarin Zileuton Ziprasidone (partial) a

Fluconazole doses > 200 mg/d [14] Data from references [30], [31], and [56].

CYP3A inducers (Examples of major therapeutic classes include anticonvulsants, antimycobacterial, and antivirals)

CYP3A inhibitors (Examples of major therapeutic classes include anesthetics, antiarrhythmics, azole antifungals, beta-blockers, calcium channel blockers, macrolide antibiotics, protease inhibitors, and selective serotonin reuptake inhibitors)

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Table 5 Examples of drugs with narrow therapeutic windows Drug class

Members of drug class

Antiarrhythmics Anticoagulants Anticonvulsants Antipsychotics Benzodiazepines Antineoplastics Ergot derivatives HMG coenzyme A reductase inhibitors Immunosuppressants Monoamine oxidase inhibitors Oral hypoglycemics Tricyclic antidepressants Opioids Others

Amiodaronec, digoxind, flecainideb, propafenoneb, quinidinec Heparin, warfarina,c Carbamazepinec, ethosuximidec, phenytoina Perphenazineb, pimozidec, risperidoneb, thioridazineb Alprazolamc, midazolamc, triazolamc Busulfanc, doxorubicinc, etoposidec,d, vinblastinec,d, vincristinec Ergotaminec, methylergonovinec Atorvastatinc, fluvastatina, lovastatinc, simvastatinc Cyclosporinec,d, tacrolimusc, rapamycin c Phenelzineb, tranylcypromineb Chlorpropamidea, glimepiridea, glipizidea, glyburidea, tolbutamidea Amitriptylineb,c, imipramineb,c, nortriptylineb Alfentanilc, morphined Oral contraceptivesc, potassium supplements

a

CYP2C9 substrate. CYP2D6 substrate. c CYP3A4 substrate. d P-glycoprotein substrate. Data from Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet 2001;40:833 – 68. b

CYP induction Ketoconazole, itraconazole, and to a partial extent fluconazole are CYP3A4 substrates; hence, their bioavailability can be influenced by concurrent CYP3A4 inducers [4,5,12 – 14]. Examples of CYP3A4 inducers from Table 4 include certain anticonvulsants (ie, carbamazepine, phenobarbital, and phenytoin); antimycobacterial drugs (ie, rifampin, rifabutin); nevirapine; and St. Johns wort. Ketoconazole, itraconazole, and fluconazole in the presence of a potent CYP3A4 inducer, such as rifampin, can significantly affect the bioavailability of these agents leading to potential therapeutic oral antifungal failure. In addition, the bioavailability of terbinafine is reduced if given concurrently with rifampin [6].

Inference guidance In some instances, because of a drug interaction between an object drug and a particular antifungal agent, it has been inferred that other antifungal agents in the same class may exhibit the same interaction.

An example is the caution that is advised concerning the use of itraconazole and oral sulfonylurea hypoglycemic agents, such as glyburide or tolbutamide. The presumed reason for this caution is that severe hypoglycemia has been reported in some persons receiving other azole-class oral antifungals (ie, fluconazole) when given with oral hypoglycemics [2,47]. From a pharmacologic view, however, such a reaction with itraconazole and certain oral hypoglycemics is difficult to explain. Glyburide and tolbutamide are both CYP2C9 substrates. Fluconazole is a CYP2C9 inhibitor that certainly could decrease metabolism and increase blood levels of the aforementioned oral hypoglycemics leading to clinically significant hypoglycemia. Itraconazole, however, is thought not to be a CYP2C9 inhibitor. If such a reaction occurs with itraconazole it must be rare [48]. Tables 6 through 10 present selected oral antifungal drug interactions. By definition they are incomplete. Examples of important pharmacodynamic, pharmacokinetic, and drug information for each oral antifungal are listed in a tabular summarized format. The format consists of interacting drugs; consequences of the interaction; known mecha-

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Table 6 Examples of fluconazole pharmacodynamicsa, pharmacokineticsb, and drug interactionsc Potential consequences of Specific interacting drug the drug interaction Amphotericin B [57]

Celecoxib [58]

Postulated decreased amphotericin B (polyene antimicrobial) efficacy Increased celecoxib (CYP2C9 substrate) levels with increased risk for adverse experiences

Pharmacologic mechanism

Interdiction

Pharmacodynamic antagonism by fluconazole

Monitor antifungal activity

Fluconazole is a CYP2C9 inhibitor

Initiate celecoxib dosing at lowest level, monitor carefully, and adjust dose as needed Carefully monitor antifungal efficacy and adjust fluconazole dose if needed Coadministration contraindicated

Cimetidine [2]

Decreased fluconazole oral bioavailability

Unknown

Cisapride [2,14]

Increased cisapride levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death with higher fluconazole dosing Increased citalopram (CYP3A4 substrate) levels that can cause prolongation of CNS effects Increased cyclosporine (CYP3A4 substrate) levels that may heighten risk for hypertension or renal toxicity Increased dofelitide (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Citalopram [2,14,59]

Cyclosporine [14,60]

Dofetilide [14,61]

Felodipine [2,14]

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d) Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d) Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Increased levels of felodipine (CYP3A4 substrate) can cause edema Increased levels of glipizide (CYP2C9 substrate) can cause hypoglycemia

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d) Fluconazole is a CYP2C9 inhibitor

Glyburide [2]

Increased levels of glyburide (CYP2C9 substrate) can cause hypoglycemia

Fluconazole is a CYP2C9 inhibitor

Hydrochlorothiazide [2]

Increased fluconazole levels

Lovastatin [2,5,14]

Increased lovastatin (CYP3A4 substrate) levels can heighten risk for myopathy or rhabdomyolysis

Hydrochlorothiazide interferes with renal elimination of fluconazole Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Midazolam [4,5,14,62]

Increased midazolam (CYP3A4 substrate) levels that can cause prolongation of CNS effects (prolonged somnolence)

Glipizide [2]

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Carefully monitor and adjust citalopram dose if needed Carefully monitor and adjust cyclosporine dose if needed

Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitor itraconazole Carefully monitor and adjust felodipine dose if needed Carefully monitor for hypoglycemia (blood glucose) and adjust oral hypoglycemic dose if needed Carefully monitor for hypoglycemia (blood glucose) and adjust oral hypoglycemic dose if needed Carefully monitor and adjust fluconazole dose if needed Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitor itraconazole Coadministration not recommended at high fluconazole doses because combination contraindicated (continued on next page)

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Table 6 (continued ) Potential consequences of Specific interacting drug the drug interaction

Oral hypoglycemics [2]

Phenytoin [2]

Pimozide [14,63]

Prednisone [2,14,64]

Quinidine [4,14]

Rifabutin [2,14,65]

Rifampin [2]

Sildenafil [14,66]

Simvastatin [5,14,67]

Sirolimus [14,68]

Increased levels of oral sulfonylurea hypoglycemics (CYP2C9 substrates) can cause hypoglycemia Increased phenytoin (CYP2C9 substrate) levels with increased risk for adverse experiences Increased pimozide (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death

Case report of addisonian crisis when fluconazole was withdrawn in a liver transplant patient who was receiving prednisone (CYP3A4 substrate) maintenance immunosuppression Postulated increased quinidine (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death Increased rifabutin (CYP3A4 substrate) levels with increased risk for adverse experiences (uveitis) and theoretically decreased fluconazole (partial CYP3A4 substrate) levels with heightened risk for reduced antifungal activity Decreased fluconazole (partial CYP3A4 substrate) levels with heightened risk for reduced antifungal activity

Pharmacologic mechanism

Fluconazole is a CYP2C9 inhibitor

Fluconazole is a CYP2C9 inhibitor Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)and rifabutin causes CYP3A4 induction

Rifampin causes CYP3A4 induction

Increased sildenafil (CYP3A4 and CYP2C9 substrate) levels can heighten risk for adverse experiences Increased simvastatin (CYP3A4 substrate) levels can heighten risk for myopathy or rhabdomyolysis

Fluconazole is a CYP2C9 inhibitor at therapeutic doses and CYP3A4 inhibitor at higher doses (> 200 mg/d) Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Increased sirolimus (CYP3A4 substrate) levels with heightened risk for adverse experiences

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Interdiction with imidazole CYP3A4 inhibitor itraconazole Carefully monitor for hypoglycemia (blood glucose) and adjust oral hypoglycemic dose if needed Carefully monitor and adjust phenytoin dose if needed Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitors itraconazole and ketoconazole Careful monitoring may be needed for patients who are maintenance prednisone immunosuppression following the withdrawal of fluconazole or other CYP3A4 inhibitors Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitor itraconazole Carefully monitor for adverse experiences (uveitis), antifungal efficacy, and adjust dosing if needed

Consider using higher fluconazole dose or carefully monitor antifungal efficacy and adjust fluconazole dose if needed Use a lower sildenafil dose and carefully monitor

Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitor itraconazole Carefully monitor and adjust sirolimus dose if needed (continued on next page)

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Table 6 (continued) Potential consequences of Specific interacting drug the drug interaction Tacrolimus [2,14,69]

Theophylline [2,70]

Triazolam [5,14,71]

Warfarin [2,14,72]

Zidovudine [2,73,74]

Increased tacrolimus (CYP3A4 substrate) levels with heightened risk for adverse experiences (nephrotoxicity, hypertension) Increased theophylline (CYP1A2 substrate) levels with increased risk for adverse experiences Increased triazolam (CYP3A4 substrate) levels that can cause prolongation of CNS effects (prolonged somnolence)

Increased warfarin levels (CYP2C9 and CYP3A4 substrate) with enhanced anticoagulation effects and heightened risk for bleeding Increased zidovudine (glucuronosyltransferase substrate) levels

Pharmacologic mechanism

Interdiction

Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Carefully monitor and adjust tacrolimus dose if needed

Unknown because fluconazole Carefully monitor and adjust is not a CYP1A inhibitor theophylline dose if needed Fluconazole is a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Fluconazole is a CYP2C9 inhibitor at low doses and a CYP3A4 inhibitor at higher doses (> 200 mg/d)

Fluconazole is a glucuronosyltransferase inhibitor

Coadministration not recommended at high fluconazole doses because combination contraindicated with imidazole CYP3A4 inhibitors itraconazole and ketoconazole Carefully monitor international normalized ratio and adjust warfarin dose if needed

Monitor and adjust zidovudine dose if needed

Abbreviation: CNS, central nervous system. a Examples of pharmacodynamics Synthetic azole (triazole) class of oral antifungal that blocks the biosynthesis of fungal membranes by inhibiting selectively an essential fungal enzyme P-450 alpha demethylase Rarely can cause serious idiosyncratic hepatotoxicity b Examples of pharmacokinetics Gastrointestinal absorption: no prohibitions Biotransformation: CYP3A4 substrate (only about 11%), CYP2C9 inhibitor, CYP3A4 inhibitor at high does (> 200 mg/d) c Examples interacting drug classes Monitor CYP2C9 for decreased biotransformation and elevated substrate levels (see Table 2) Avoidance or contraindications for CYP3A4 substrates with narrow therapeutic windows with the potential serious adverse experiences, such as certain benzodiazepines, HMG coenzyme A reductase inhibitors, and those metabolically impaired substrates that can cause QT interval prolongation with fluconazole doses usually above 200 mg/d [14] Monitor CYP3A4 substrates for decreased biotransformation and elevated substrate levels with fluconazole doses usually above 200 mg/d (see Table 4) [14]

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Table 7 Examples of griseofulvin pharmacodynamicsa, pharmacokineticsb, and drug interactionsc Potential consequences of the drug interaction

Pharmacologic mechanism

Interdiction

Aspirin [75]

Decreased aspirin oral bioavailability

Presumed decreased aspirin absorption

Oral contraceptives [3]

Decreased oral contraceptive levels and increased risk for oral contraceptive failure Decreased griseofulvin levels

Griseofulvin is a CYP3A4 inducer

Monitor aspirin therapeutic efficacy and alter dosing as needed Monitor oral contraceptive or use an additional form of nonhormonal contraception Monitor griseofulvin therapeutic efficacy and alter dosing as needed Caution and measures to avoid or limit UV light exposures (proper clothing and UV light blockers) Caution and measures to theophylline clinical response and blood levels if needed Carefully monitor international normalized ratio and adjust warfarin dose if needed

Specific interacting drug

Phenobarbital [3]

Phenobarbital is a CYP inducer

Porfimer [3,76]

Postulated increased risk for adverse experiences after UV light exposure

Griseofulvin and porfimer are photosensitizers

Theophylline [77]

Decreased theophylline levels

Unknown

Warfarin [3]

Decreased anticoagulant activity

Griseofulvin is a CYP3A4 inducer

a

Examples of pharmacodynamics Griseofulvin is an oral antifungal fungistatic antibiotic derived from Penicillium species with a limited antidermatophyte spectrum Rare serious idiosyncratic hepatotoxicity Photosensitivity Rare hematotoxicity b Examples of pharmacokinetics Gastrointestinal absorption: optimal absorption occurs with a fatty meal Biotransformation: CYP3A4 inducer c Examples of interacting drug classes Monitor CYP3A4 substrates for accelerated biotransformation and decreased substrate levels (see Table 4) Barbiturates reduces griseofulvin bioavailability Alcohol and alcohol-containing medications may cause disulfiram-like adverse experiences Photosensitizers may increase risk for UV light adverse experiences

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Table 8 Examples of itraconazole pharmacodynamicsa, pharmacokineticsb, and drug interactionsc Potential consequences of Specific interacting drug the drug interaction Alfentanil [4]

Alprazolam [4,78]

Amphotericin B [4,57]

Agenerase [4,79] Antacids [4]

Atorvastatin [4,80,81]

Bexarotene [4,82]

Buspirone [4,13]

Busulfan [4,83]

Carbamazepine [4,84]

Cilostazol [4,85]

Cimetidine [4]

Cisapride [4]

Pharmacologic mechanism Interdiction

Increased alfentanil (CYP3A4 substrate) levels that can cause prolongation of CNS effects Increased alprazolam (CYP3A4 substrate) levels that can cause prolongation of CNS effects (prolonged somnolence)

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust alfentanil dose if needed

Itraconazole is a CYP3A4 inhibitor

Postulated decreased amphotericin B (polyene antimicrobial) efficacy Increased itraconazole (CYP3A4 substrate) levels Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Increased atorvastatin (CYP3A4 substrate) levels can heighten risk for myopathy or rhabdomyolysis

Pharmacodynamic antagonism by itraconazole Agenerase is a CYP3A4 inhibitor Cationic antacids cause gastric alkalinity

Coadministration contraindicated. Use other non – CYP-dependent benzodiazepine agents, such as lorazepam, oxazepam, or temazepam Monitor antifungal activity

Increased bexarotene levels increase the risk for adverse experiences Increased buspirone (CYP3A4 substrate) levels that can cause prolongation of CNS effects Increased busulfan (CYP3A4 substrate) levels that can cause increased adverse experiences Postulated decreased itraconazole (CYP3A4 substrate) levels and increased carbamazepine (CYP3A4 substrate) levels that heighten the risk for adverse experiences [13] Postulated increased cilostazol (CYP3A4 substrate) levels with theoretical heightened risk for adverse experiences Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Increased cisapride (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death

Itraconazole is a potent CYP3A4 inhibitor

Avoid if possible by prescribing a non-CYP3A4 HMG coenzyme A reductase inhibitor (ie, pravastatin or fluvastatin) or carefully monitor and adjust atorvastatin dose if needed Carefully monitor and adjust bexarotene dose if needed

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust buspirone dose if needed

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust busulfan dose if needed

CYP3A4 induction by carbamazepine and CYP3A4 inhibition by itraconazole

Coadministration not recommended

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust cilostazol dose if needed

Cimetidine is an H2 blocker that causes gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust itraconazole dose if needed Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

(continued on next page)

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Table 8 (continued) Potential consequences of Specific interacting drug the drug interaction Citalopram [4,59]

Clarithromycin [4] Cyclosporine [4,60]

Diazepam [4]

Didanosine [4]

Digoxin [4,29,86]

Docetaxel [4]

Dofetilide [4]

Erythromycin [4] Famotidine [4,87]

Felodipine [4,88]

Grapefruit juice [89]

Haloperidol [90]

Indinavir [4,91]

Increased citalopram (CYP3A4 substrate) levels that can cause prolongation of CNS effects Increased itraconazole (CYP3A4 substrate) levels Increased cyclosporine (CYP3A4 substrate) levels that may heighten risk for hypertension or renal toxicity Increased diazepam (partial CYP3A4 substrate) levels that can cause prolongation of CNS effects Decreased ketoconazole tablet (optimal absorption in acid gastric pH) levels bioavailability with heightened risk for reduced antifungal activity Increased digoxin (P-glycoprotein substrate) levels with heightened risk for digoxin toxicity Increased docetaxel (CYP3A4 substrate) levels with heightened risk for adverse experiences Increased dofelitide (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death Increased itraconazole (CYP3A4 substrate) levels Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for subtherapeutic antifungal activity Increased felodipine (CYP3A4 substrate) levels with heightened risk for edema formation Report of decreased oral itraconazole capsules bioavailability with heightened risk for subtherapeutic antifungal activity Increased haloperidol (CYP3A4 substrate) levels with heightened risk for neurologic adverse experiences Increased itraconazole (CYP3A4 substrate) and indinavir (CYP3A4 substrate) levels with heighten risk for adverse experience [92,93]

Pharmacologic mechanism Interdiction Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust citalopram dose if needed

Clarithromycin is a CYP3A4 inhibitor Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust itraconazole dose if needed Carefully monitor and adjust cyclosporine dose if needed

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust diazepam dose if needed

Antacid buffers in didanosine cause gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Pgp inhibition reducing renal excretion of digoxin by itraconazole Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust digoxin dose if needed Carefully monitor and adjust docetaxel dose if needed

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated

Erythromycin is a CYP3A4 inhibitor Famotidine is an H2 blocker that causes gastric alkalinity

Carefully monitor and adjust itraconazole dose if needed Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust felodipine dose if needed

Unknown

Avoid simultaneous administration. Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola.

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust haloperidol dose if needed

Itraconazole and indinavir are both CYP3A4 inhibitors

Carefully monitor and adjust indinavir or itraconazole dosage if needed (continued on next page)

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Table 8 (continued) Potential consequences of Specific interacting drug the drug interaction

Pharmacologic mechanism Interdiction

Isoniazid [4]

Decreased itraconazole (CYP3A4 substrate) levels and itraconazole therapeutic failure may occur Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Increased lovastatin (CYP3A4 substrate) levels can heighten risk for myopathy or rhabdomyolysis

Unknown

Coadministration not recommended

Lansoprazole is a proton pump inhibitor that causes gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Itraconazole is a CYP3A4 inhibitor

Increased methylprednisolone (CYP3A4 substrate) levels with increased corticosteroid effects Increased midazolam (CYP3A4 substrate) levels that can cause prolongation of CNS effects (prolonged somnolence) Postulated decreased itraconazole (CYP3A4 substrate) levels with heightened risk for reduced antifungal activity [97] Increased felodipine (CYP3A4 substrate) levels with heightened risk for edema formation Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Postulated increased levels of oral sulfonylurea (CYP2C9 substrates) hypoglycemics

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated. If HMG coenzyme A reductase inhibitor is needed consider fluvastatin or pravastatin. Carefully monitor and adjust methylprednisolone dose if needed Coadministration contraindicated. Use non – CYP3A4dependent agent.

Lansoprazole [94]

Lovastatin [4]

Methylprednisolone [4,95] Midazolam [4,62]

Nevirapine [4,96]

Nifedipine [4]

Omeprazole [4]

Oral hypoglycemics [4]

Phenobarbital [13,98]

Phenytoin [4]

Pimozide [4,63]

Postulated decreased itraconazole (CYP3A4 substrate) levels with heightened risk for subtherapeutic antifungal activity [13] Decreased itraconazole (CYP3A4 substrate) levels with heightened risk for subtherapeutic antifungal activity [13] Increased pimozide (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death

Itraconazole is a CYP3A4 inhibitor

Nevirapine is a CYP3A4 inducer

Coadministration not recommended

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust felodipine dose if needed

Omeprazole is a proton pump inhibitor that causes gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Mechanism for itraconazole not known but other azole class drugs (ie, miconazole and fluconazole) interact with oral hypoglycemics causing severe hypoglycemia Phenobarbital is a CYP3A4 inducer

Carefully monitor for hypoglycemia (blood glucose) and adjust oral hypoglycemic dose if needed

Coadministration not recommended

Phenytoin is a CYP3A4 inductor

Coadministration not recommended

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated

(continued on next page)

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Table 8 (continued) Potential consequences of Specific interacting drug the drug interaction Quinidine [4]

Ranitidine [4]

Rifabutin [4,13]

Rifampin [4]

Ritonavir [4,99,100]

Saquinavir [4,101]

Sildenafil [66]

Simvastatin [4,67]

Sirolimus [4,68]

Sodium bicarbonate [4]

Sucralfate [4,103]

Tacrolimus [4,69]

Triazolam [4,71]

Increased quinidine (CYP3A4 substrate) levels with heightened risk for QT interval prolongation, torsades de pointes, ventricular tachycardia, or death Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Decreased itraconazole (CYP3A4 substrate) levels with increased risk for reduced antifungal activity and increased rifabutin (CYP3A4 substrate) levels Decreased itraconazole (CYP3A4 substrate) levels with increased risk for reduced antifungal activity [13] Increased itraconazole (CYP3A4 substrate) and ritonavir (CYP3A4 substrate) levels with increased risk for adverse experience [92,93] Increased saquinavir (CYP3A4 substrate) levels with increased risk for adverse experiences Postulated increased sildenafil (CYP3A4 substrate) levels and heightened risk for adverse experiences (hypotension, priapism) [102] Increased simvastatin (CYP3A4 substrate) levels can heighten risk for myopathy or rhabdomyolysis Increased sirolimus (CYP3A4 substrate) levels with heightened risk for adverse experiences Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Decreased oral itraconazole capsule (optimal absorption in acid gastric pH) bioavailability with heightened risk for reduced antifungal activity Increased tacrolimus (CYP3A4 substrate) levels with heightened risk for adverse experiences Increased triazolam (CYP3A4 substrate) levels that can cause prolongation of CNS effects (prolonged somnolence)

Pharmacologic mechanism Interdiction Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated

Ranitidine is an H2 blocker that causes gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

CYP3A4 induction by rifabutin and CYP3A4 inhibition by itraconazole

Coadministration not recommended

Rifampin is a CYP3A4 inducer

Coadministration not recommended

Itraconazole and ritonavir are both CYP3A4 inhibitors Itraconazole is a CYP3A4 inhibitor

Caution advised. Carefully monitor and adjust ritonavir or itraconazole dosage if needed Carefully monitor and adjust saquinavir dose if needed

Itraconazole is a CYP3A4 inhibitor

Avoid or carefully monitor and adjust sildenafil dose if needed

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated. If HMG coenzyme A reductase inhibitor is needed consider fluvastatin or pravastatin. Carefully monitor and adjust sirolimus dose if needed

Itraconazole is a CYP3A4 inhibitor Sodium bicarbonate is a chemical neutralizer that causes gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Cationic buffer cause gastric alkalinity

Stagger 2 – 4 h between dosing with agents and give itraconazole with Coca Cola

Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust tacrolimus dose if needed

Itraconazole is a CYP3A4 inhibitor

Coadministration contraindicated. Use non – CYP3A4-dependent agent. (continued on next page)

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Table 8 (continued) Potential consequences of Specific interacting drug the drug interaction Trimetrexate [4] Verapamil [4]

Vinblastine [4,104]

Vincristine [4,104]

Warfarin [4,72]

Postulated increased trimetrexate (CYP3A4 substrate) levels Increased verapamil (CYP3A4 substrate) levels with increased risk of fluid retention and congestive heart failure Increased vinblastine levels with heightened risk for adverse experiences Increased vincristine (CYP3A4 substrate) levels with risk of tinnitus Increased warfarin (CYP2C9 and CYP3A4 substrate) levels with increased anticoagulation effects and heightened risk for bleeding

Pharmacologic mechanism Interdiction Presumed itraconazole is a CYP3A4 inhibitor Itraconazole is a CYP3A4 inhibitor and additive negative inotropic cardiac effects Itraconazole is a CYP3A4 inhibitor

Carefully monitor and adjust trimetrexate dose if needed Carefully monitor and adjust verapamil dose if needed or consider using another noninteracting agent. Carefully monitor and adjust vinblastine dose if needed

Itraconazole is a CYP3A4 Carefully monitor and adjust inhibitor vincristine dose if needed Itraconazole is a CYP3A4 Carefully monitor international inhibitor normalized ratio and adjust warfarin dose if needed

CNS, central nervous system. a Examples of pharmacodynamics Synthetic azole (triazole) class of oral antifungal that blocks the biosynthesis of fungal membranes by inhibiting selectively an essential fungal enzyme P-450 alpha demethylase Rarely can cause serious idiosyncratic hepatotoxicity and negative inotropic cardiac effects b Examples of pharmacokinetics Gastrointestinal absorption: acidic gastric pH needed for optimal absorption of capsule formulation Gastrointestinal absorption and renal elimination: P-glycoprotein inhibitor Biotransformation: CYP3A4 substrate and CYP3A4 inhibitor c Examples drug classes Contraindication for CYP3A4 substrates with narrow therapeutic windows with the potential serious adverse experiences, such as certain benzodiazepines, HMG coenzyme A reductase inhibitors, and those metabolically impaired substrates that can cause QT interval prolongation Avoidance of agents that can reduce antifungal therapeutic activity by simultaneous ingestion of gastric alkalinizes or concurrent administration of certain CYP3A4 inducers (see Table 4), such as antimicrobials and anticonvulsants Monitor CYP3A4 substrates for decreased biotransformation and elevated substrate levels (see Table 4)

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Table 9 Examples of ketoconazole pharmacodynamicsa, pharmacokineticsb, and drug interactionsc Potential consequences of Specific interacting drug the drug interaction Alcohol [5]

Oral hypoglycemics [5]

Phenytoin [5]

Temporary disulfiram-like reaction (ie, flushing, headache) lasting an hour or so Postulated increased levels of oral sulfonylurea (CYP2C9 substrates) hypoglycemics

Decreased ketoconazole (CYP3A4 substrate) levels with heightened risk for subtherapeutic antifungal activity and altered phenytoin (CYP2C9 substrate) levels with increased risk for adverse experiences [13]

Pharmacologic mechanism

Interdiction

Unknown, although ketoconazole may inhibits alcohol oxidase in vitro [105] Mechanism for ketoconazole not known but other azole class drugs (ie, miconazole and fluconazole) interact with oral hypoglycemics causing severe hypoglycemia Phenytoin CYP3A4 is an inducer and ketoconazole is a potent CYP3A4 inhibitor

Avoid alcohol ingestion

Carefully monitor for hypoglycemia (blood glucose) and adjust oral hypoglycemic dose if needed

Caution advised because coadministration not recommended with another imidazole CYP3A4 inhibitor itraconazole. If used carefully monitor and adjust ketoconazole or phenytoin dosage as needed

(Note many of the ketoconazole interactions are similar to or identical to those listed for itraconazole; refer to itraconazole for potential individual interacting object drugs. See Table 8.) a Examples of pharmacodynamics Synthetic azole class of oral antifungal that blocks the biosynthesis of fungal membranes by inhibiting selectively an essential fungal enzyme P-450 alpha demethylase (see Table 8) Rarely can cause serious idiosyncratic hepatotoxicity (see Table 8) b Examples of pharmacokinetics Gastrointestinal absorption: acidic gastric pH needed for optimal absorption of tablet formulation (see Table 8) Gastrointestinal absorption and renal elimination: P-glycoprotein inhibitor (see Table 8) Biotransformation: CYP3A4 substrate and inhibitor (see Table 8) c Examples interacting drug classes Contraindication for CYP3A4 substrates with narrow therapeutic windows with the potential serious adverse experiences, such as certain benzodiazepines, HMG coenzyme A reductase inhibitors, and those metabolically impaired substrates that can cause QT interval prolongation (see Table 8) Avoidance of agents that can reduce antifungal therapeutic activity by simultaneous ingestion of gastric alkalinizers or concurrent administration of certain CYP3A4 inducers (see Table 4), such as antimicrobials and anticonvulsants (see Table 8) Monitor CYP3A4 substrates for decreased biotransformation and elevated levels (Tables 4 and 8)

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Table 10 Examples of terbinafine pharmacodynamicsa, pharmacokineticsb, and drug interactionsc Specific interacting drug

Potential consequences of the drug interaction

Cimetidine [6]

Pharmacologic mechanism Interdiction

Increased terbinafine (substrate for multiple CYPs) levels (‘ 30%) Cyclosporine [6,106,107] Decreased cyclosporine (CYP3A4 substrate and P-glycoprotein inhibitor) levels ( f 15%)

Cimetidine is a CYP inhibitor Unknown

Nortriptyline [6,38,111]

Terbinafine is a CYP2D6 inhibitor

Rifampin [6]

Terfenadine [6]

Theophylline [6,108]

Warfarin [6,109 – 112]

Postmarketing study revealed no evidence of an interaction; however, case report of confirmed increased nortriptyline (CYP2D6 substrate) levels and toxicity Fifty percent decreased terbinafine (substrate for multiple CYPs) levels with increased risk for reduced antifungal activity Small decreased terbinafine (substrate for multiple CYPs) levels with risk for reduced antifungal activity Decreased theophylline (CYP1A2 substrate) elimination ( f15%) Premarketing and postmarketing studies revealed no evidence of an interaction; however, there are separate case reports of altered warfarin (CYP2C9 and CYP3A4 substrate) levels in two patents

Monitor terbinafine safety profile Monitor cyclosporine trough levels in organ transplant patients or immunomodulatory overt clinical effects in other nonorgan transplant patients Be cognizant for clinical adverse experiences or abnormal laboratory values

Rifampin is a broad CYP inducer

Monitor antifungal therapeutic activity and adjust terbinafine dose as needed

Unknown

Monitor antifungal therapeutic activity

Unknown

Monitor clinical adverse experiences and elevated theophylline levels Good clinical practice is to monitor international normalized ratio; adjust warfarin dose if needed

Unknown

a

Examples of pharmacodynamics Synthetic allylamine class of oral antifungal that blocks the biosynthesis of fungal membranes by inhibiting an essential enzyme squalene epoxidase Rare serious idiosyncratic hepatotoxicity b Examples of pharmacokinetics Gastrointestinal absorption: no prohibitions Biotransformation: substrate for multiple cytochromes enzymes (ie, CYP1A2, CYP2C8, CYP2C9, CYP2E1, CYP3A), CYP2D6 inhibitor c Examples of interacting drug classes Monitor certain CYP2D6 substrates with narrow therapeutic windows, such as tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors type B (see Table 3)

nism (where known) for the interaction; and interdiction comments.

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Dermatol Clin 21 (2003) 565 – 576

New antifungal agents Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth Tomas, HBSc, MScb a

Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada

Fungal infections, both invasive and superficial, have become increasingly more frequent over the last few decades. An increase in the number of immunocompromised patients associated with AIDS and organ transplantation, and increased use of invasive instruments, such as urinary catheters, has increased the number of patients who are at high risk of invasive fungal infection [1]. In the past, Candida albicans has most frequently been the cause of such infections; however non-albicans Candida spp. have become more prevalent as agents of infection, as have species that were not previously associated with invasive infection [2 – 4]. Use of current antifungal drugs can be limited by toxicity, low efficacy rates, and drug resistance [1]. Of the various classes of antifungal drugs in use, lipid-based formulations of the polyene macrolide amphotericin B (AmB) are being pursued as a method of improving efficacy in invasive fungal infections, and new azoles have been developed for use in both systemic and superficial fungal infections. A newer class of agents, the echinocandins, is also showing high potential in the treatment of many fungal infections. The new agents and delivery systems within the various classes of antifungals are at various stages of development, and will help contribute to an increase in the number of agents available for many types of fungal infections. A primary factor in the decision to use an antifungal drug in vivo is a minimum inhibitory concentration (MIC) of the drug in vitro, which suggests the

* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).

target fungal species is susceptible to that drug. The National Committee for Clinical Laboratory Standards (NCCLS) Subcommittee on Antifungal Susceptibility Tests has provided guidelines to increase the reproducibility of MIC testing of filamentous fungi (document M38-P) [5]. Standardized testing methods in document M27-A apply only to Candida spp. and Cryptococcus neoformans [5]. Difficulties may be had in determining MIC of non-Candida spp. because of variability in type of medium, incubation temperature and time, end point definition, buffer concentration, and inoculum size [5 – 7]. Determination of MIC values remains an important method of identifying organisms that are likely to exhibit resistance to particular antifungal treatments, despite the potential difficulties in assessing MICs. It should be noted that MIC values in vitro might not necessarily correlate with the in vivo efficacy noted [5,8]. Clinical testing in vivo must be done to confirm any finding in vitro, both in determining that the drug has reliable antifungal activity in vivo relative to low MIC values found in vitro, and detecting reduced in vivo efficacy of antifungals suggested by increasing MIC values in vitro.

Lipid formulations of polyenes The polyenes were first developed in the early 1950s and these include nystatin and AmB [9]. Polyenes are fungicidal and act by increasing the permeability of the cell membrane by targeting ergosterol in the membrane [1]. Although AmB has been the most widely used antifungal for systemic infections, its clinical use has been limited because of its high level of toxicity, and toxicity has been related

0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00024-X

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to significantly increased costs of therapy [1,10]. Furthermore, nystatin has not been developed to treat systemic fungal infections because of its significant nephrotoxicity [1]. To improve the therapeutic index for polyene macrolides, different lipid formulations of these drugs have been generated including AmB lipid complex, AmB colloidal dispersion, liposomal AmB, and liposomal nystatin. Liposomal nystatin is currently in phase III clinical trials, whereas the lipid formulations of AmB are licensed for use in the treatment of invasive fungal infections in patients refractory or intolerant to standard AmB. These new formulations have been shown to have a broad spectrum of activity against pathogenic fungi including Candida spp., C neoformans, and Aspergillus spp. with less toxicity in vivo compared with the parent compound [11 – 15]. One disadvantage associated with the lipid formulations is their increased cost, potentially limiting the usefulness of these new agents [14 – 16]. Despite their broad spectrum of activity in vitro, AmB and nystatin have limited use for cutaneous infections because they are not active for dermatophyte infections, although they can be useful for superficial Candida infections [1,17]. In vitro testing of liposomal AmB and AmB lipid complex shows that these drugs may be effective in treating Candida spp., which grow as biofilms [18]. Biofilms are a significant source of device-related microbial infection, and tend to have reduced susceptibility to standard antifungal treatment. In vivo randomized comparative testing of liposomal AmB (1 or 3 mg/kg/d) versus conventional AmB in the treatment of 134 adults and 204 children with pyrexia of unknown origin showed that 3 mg/kg/d of liposomal AmB had a significantly higher success rate than conventional AmB ( P = .03; success defined to be a resolution of fever [ < 38
C] for a minimum of 3 consecutive days and no development of new fungal infection until study end at neutrophil recovery to 0.5  109/L) [19]. This success included a twofold to sixfold decrease in drug-related adverse events ( P V .01) with liposomal AmB relative to conventional AmB. A lower incidence of severe drug-related side effects with liposomal AmB relative to conventional AmB was also noted (1% and 12% of patients, respectively; P < .01). Furthermore, no nephrotoxicity was noted in the patients using 1 mg/kg/d liposomal AmB compared with a 3% incidence of nephrotoxicity in patients using 3 mg/kg/d liposomal AmB, and 23% incidence of nephrotoxicity in patients using conventional AmB ( P < .01; assessments did not include patients using nephrotoxic drugs). A randomized, double-blind, multicenter clinical trial used liposomal AmB to treat moderate to severe

disseminated histoplasmosis in 81 AIDS patients [20]. This trial found that liposomal AmB in comparison with conventional AmB had increased rates of success (88% versus 64% with conventional AmB); fewer infusion-related side effects (25% versus 63%, respectively; P = .002); and reduced nephrotoxicity (9% versus 37% of patients, respectively; P = .003) Liposomal AmB was found to be effective therapy for aspergillosis in a phase I-II clinical trial, and was well tolerated up in the tested doses ranging from 7.5 to 15 mg/kg body weight/d [21]. Review of the clinical use of liposomal AmB suggests that this new formulation is effective and significantly safer for use in patients with a variety of underlying medical conditions and infecting organisms, including C neoformans [22 – 28]. Further testing needs to be directed toward establishing optimal dosing, total dose, and adequate start and stop points for therapy [25,28].

Azoles Since 1944, azoles have become an important component in the management of invasive fungal infections including those caused by dermatophytes [29]. The family of azole antifungal agents can be classified according to the number of nitrogens in the azole ring. The imidazoles, including ketoconazole, miconazole, and clotrimazole, contain two nitrogens, whereas triazoles, such as itraconazole and fluconazole, contain three [29]. Azoles are fungistatic in vitro and inhibit the cytochrome P-450 – dependent enzyme lanosterol demethylase (14-a-sterol demethylase). This enzyme is critical for the synthesis of ergosterol, an essential component of fungal plasma membranes [29]. Although 14-a-sterol demethylase is also involved in mammalian cholesterol synthesis, azoles are therapeutic because they have a much higher affinity for the fungal CYP450 enzyme than the human CYP450 enzyme [29]. Voriconazole, ravuconazole, and posaconazole are the three main new triazole drugs to be introduced in this family of antifungals. Voriconazole (UK-109, 496) Voriconazole is available in oral and intravenous (IV) formulations [30]. This drug was clinically approved by the Food and Drug Administration in May 2002 for the treatment of invasive aspergillosis and for the treatment of infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. in patients intolerant of, or refractory to, other therapy [31].

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Voriconazole is a synthetic derivative of fluconazole differing from fluconazole by the substitution of a triazole group with a fluoropyrimidine moiety and by the addition of a methyl group to the propyl backbone [30]. These structural differences translate into improved activity over fluconazole with the additional methyl group increasing the affinity of the drug for the target enzyme (14-a-sterol demethylase) [30]. In addition, the pyrimidine and fluorine groups have been shown to increase potency and in vivo efficacy, respectively [30]. Pharmacokinetics Voriconazole exhibits nonlinear pharmacokinetics, potentially because of saturation of its metabolism [30]. Maximum plasma concentrations occur within 1 or 2 hours following dosing (similar for IV and oral route of administration) [31]. The oral bioavailability is approximately 96% [31]. Voriconazole has extensive distribution in humans, with a steady-state volume of approximately 4.6 L/kg [31]. Serum levels have been noted to range from 2 to 6 mg/mL with varying doses of voriconazole [8]. Voriconazole exhibits moderate binding to plasma proteins, estimated at 58% [31]. Voriconazole is metabolized by the hepatic cytochrome P-450 enzymes, especially CYP2C19, CYP2C9, and CYP3A4 [31]. In vitro susceptibility testing Many studies have tested the antifungal activity of voriconazole in vitro, according to NCCLS methods [8]. Voriconazole has demonstrated a broad-spectrum in vitro activity against numerous isolates of Candida spp. [6,32 – 42], Cryptococcus [43 – 45], Scedosporium spp. [46], Trichosporon spp. [47], Aspergillus spp. including AmB-resistant clinical isolates [48 – 53], Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum [54]. Voriconazole was also found to have good in vitro activity against dermatophytes including isolates of Epidermophyton floccosum, Microsporum spp., and Trichophyton spp. [7,53,55]. One study found that voriconazole had one of the lowest geometric mean MIC values (MIC50 = 0.06 and MIC90 = 0.25) of a panel of antifungal drugs including itraconazole, ketoconazole, miconazole, clotrimazole, terbinafine, AmB, and fluconazole for 508 strains of dermatophytes belonging to 24 species [55]. The MIC values, however, were not significantly different compared with the MIC values obtained for clotrimazole, terbinafine, itraconazole, or miconazole. These MIC values for voriconazole were comparable with previously reported data [53]. Another study, using the NCCLS broth macrodilution method, showed that voriconazole was more

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active than ketoconazole, griseofulvin, and fluconazole in vitro for 19 different species (100 strains) of dermatophytes, although it was less active than itraconazole and terbinafine (MIC50 = 0.5 mg/mL and MIC90 = 1 mg/mL) [7]. The differences in activity and MIC values may reflect differences in methodology and lack of standard protocols to test filamentous fungi and dermatophytes [7,55]. Reproducibility of MIC values has improved with the published recommendations made by the NCCLS standards (document M27-A). NCCLS methodology is particularly limited in azole MIC determination, however, by the interpretation of trailing growth of fungi in the presence of azoles. This subjective evaluation of end point determination may give a wide range of MIC values, leading to overestimation of resistance of organisms to azoles [56]. Further standardization, such as using a 24-hour incubation time rather than 48 hours suggested by NCCLS, and using spectrophotometers to determine optical densities associated with growth, may add to the reproducibility of MIC values where azoles are being tested [56,57]. In vivo studies In addition to the efficacy demonstrated in vitro, voriconazole has been shown to be effective in various animal models including those with systemic candidiasis, pulmonary and intracranial cryptococcus, disseminated aspergillosis, and invasive pulmonary aspergillosis [29,58 – 60]. In a lethal, immunosuppressed guinea pig model of invasive aspergillosis, voriconazole was found to be more effective than AmB and itraconazole in the clearance of Aspergillus from tissues [61]. The oral administration of voriconazole was twice daily as a 10 mg/mL suspension at 5 or 10 mg/kg/d. Itraconazole was given at the same dose. AmB was administered intraperitoneally at a dose of 1.25 mg/kg/d. Treatment with voriconazole enhanced survival and significantly reduced colony counts in the tissue compared with those of animals not receiving antifungal therapy. In vitro fungicidal activity was seen with voriconazole against all four species of Aspergillus tested [61]. Several studies in humans have demonstrated the potential for voriconazole to treat invasive fungal infections. Sixty-nine children, aged 9 months to 15 years, with various fungal infections (42 aspergillosis, 8 scedosporiosis, 4 invasive candidiasis, and 4 other invasive fungal infections) who were refractory to or intolerant to conventional antifungal therapy were treated with voriconazole within the compassionate release program [62]. Subjects received voriconazole at a loading dose of 6 mg/kg every 12 hours

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IV for 1 day followed by 4 mg/kg every 12 hours IV thereafter. Oral loading doses, depending on tolerability, were 400 mg twice a day for two doses for patients weighing 40 kg or more and 200 mg twice a day for two doses for patients weighing less than 40 kg. Oral maintenance doses were 200 or 100 mg twice a day for patients weighing greater than or equal to 40 or less than 40 kg, respectively. Underlying conditions included hematologic malignancies (27 patients) and chronic granulomatous disease (13 patients). At the end of therapy (median duration 93 days) 45% (26) of patients had a complete or partial response; 7% (4) had a stable response; 43% (25) failed therapy; and 7% (4) were discontinued because of intolerance. Efficacy was determined by global assessment of clinical, radiologic, and microbiologic response. Twenty-three patients experienced voriconazole-related adverse events, the most common being elevation in hepatic transaminases or bilirubin (N = 8); skin rash (N = 8); abnormal vision (N = 3); and photosensitivity reaction (N = 3) [62]. Three children discontinued voriconazole therapy (one with photosensitivity reaction plus cheilitis, two with elevated hepatic transaminases). An open, noncomparative, multicenter study looked at voriconazole use in 116 immunocompromised patients with invasive aspergillosis [63]. Subjects were given two IV loading doses of 6 mg/kg at 12-hour intervals, followed by 3 mg/kg intravenously at 12-hour intervals, eventually changing to oral therapy (200 mg twice daily for 4 to 24 weeks). Initial IV therapy was given from 1 to 40 days (mean, 11.5 days). Oral voriconazole was given from 2 to 219 days (mean, 77 days). Response was graded clinically and by radiographic analysis. Voriconazole was the primary therapy in 60 (52%) of the patients. Good responses were seen in 48% of the patients; complete response (resolution of all clinical signs and symptoms and complete or nearly complete radiographic resolution) was observed in 14% of patients; and partial response (at least 50% improvement in radiologic findings, and major improvement or resolution of the signs and symptoms) was seen in 34%. A stable response (some improvement with less than 50% radiologic improvement) was seen in 21% of patients and 31% failed to respond to therapy. In a recent randomized clinical trial of primary therapies for definite or probable cases of invasive aspergillosis, voriconazole produced a higher rate of response and an increased survival rate at 12 weeks than AmB [64]. Voriconazole (IV, two doses of 6 mg/kg body weight on day 1, then 4 mg/kg twice daily for at least 7 days, followed by 200 mg voriconazole orally twice daily) was used in 144 subjects,

compared with IVAmB (1 to 1.5 mg/kg/d) in 133 subjects. Allogeneic hematopoietic-cell transplantation, acute leukemia, and other hematologic diseases were the underlying diseases in most patients being treated. Response at week 12 (complete response or partial response) was noted in 52.8% of patients using voriconazole (20.8% complete response, 31.9% partial response) versus 31.6% of patients using AmB (16.5% complete response, 15% partial response). The survival rate at 12 weeks for voriconazole was 70.8% versus 57.9% in AmB. Additionally, voriconazole produced significantly fewer severe drug-related adverse events than AmB, although transient visual disturbances occurred in 44.8% of patients using voriconazole. In an international, open-label, randomized, multicenter trial, voriconazole was compared with liposomal AmB in 837 patients with neutropenia and persistent fever for empirical antifungal therapy [65]. Voriconazole (N = 415) was given intravenously at a loading dose of 6 mg/kg of body weight every 12 hours for two doses followed by a maintenance dose of 3 mg/kg every 12 hours (or 200 mg orally every 12 hours after at least 3 days of IV therapy). Liposomal AmB (N = 422) was given at 3 mg/kg intravenously per day. Therapy was given for up to 3 days after neutrophil recovery, or up to a maximum of 12 weeks. The overall success rates, as judged by composite outcome score, were 26% and 30.6% with voriconazole and AmB, respectively (successful composite outcome score if patient did not have a breakthrough fungal infection, survived for 7 days beyond the end of therapy, did not discontinue therapy prematurely, had resolution of fever during the period of neutropenia, and was successfully treated for any baseline fungal infection). Patients receiving voriconazole had fewer cases of breakthrough fungal infections, severe infusion-related reactions, and nephrotoxicity compared with liposomal AmB – treated patients [65]. Infusion-related adverse events experienced with voriconazole (  1% incidence) included abnormal vision (infusion-related altered perception of light, 21.9%); flushing (3.4%); chills (13.7%); and nausea (9.4%). Visual hallucinations (in most cases, distinct from infusion-related altered perception of light) occurred in more patients in the voriconazole group than the liposomal AmB group (4.3% versus 0.5%, respectively). Overall, adverse events, such as mild visual disturbances, have been reported to occur in approximately 30% of patients receiving voriconazole in clinical trials [31]. These visual side effects include altered or enhanced visual perception, blurred vision, color vision change, or photophobia by an unknown mechanism of action [31]. Other reported adverse

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events included rashes (most mild to moderate severity) and elevated liver function enzymes [31,66]. Ravuconazole (BMS-207147, ER-30346) Structurally, ravuconazole is similar to fluconazole with a thiazole in the place of a second triazole. Ravuconazole is available only in an oral formulation and it is currently in phase II clinical trials. Single- and multiple-dose studies indicate that ravuconazole has a long terminal half-life of approximately 100 hours, longer than other azoles [60,67 – 70]. It has been well tolerated in single doses of 800 mg/d, and 400 mg/d for up to 14 days, with headache being the most reported adverse event [67]. In vitro susceptibility testing Ravuconazole has been shown to have a broad spectrum of activity against pathogenic fungi including Aspergillus spp., C neoformans, Candida spp. [29,36,39,41,49,69,71 – 74], and Trichosporon spp. [47]. Ravuconazole seems to have a broader anticandidal spectrum than itraconazole and fluconazole in vitro and it is potentially fungicidal against C neoformans [72]. One study found that the activity of ravuconazole against Candida spp. was comparable with that of posaconazole and voriconazole and greater than that of fluconazole and itraconazole, with the exception of C glabrata, where ravuconazole was less active than voriconazole [41]. Ravuconazole has also been shown in vitro to have activity against dermatophytes including Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum gypseum, Microsporum canis, and Epidermophyton floccossum [72,73]. The 25 dermatophyte strains tested by Fung-Tomc et al [72] were found to be highly susceptible to ravuconazole (MICs V 0.13 mg/mL). Another study showed the activity of ravuconazole against dermatophytes to be two to eight times greater than those of itraconazole and over 32 times higher than that of fluconazole [73]. In comparison with AmB, ravuconazole activity was comparable against M canis and 8 to 16 times greater against T mentagrophytes, T rubrum, and M gypseum [73]. In vivo studies Ravuconazole has been shown to be effective in several animal models. Safety and dose-dependent efficacy were demonstrated in the treatment of experimental invasive and pulmonary aspergillosis, candidiasis, cryptococcosis, and histoplasmosis [73, 75 – 79]. In rat models of oral candidiasis, ravuconazole was shown to have efficacies greater than or comparable with itraconazole and fluconazole [76].

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The efficacy of ravuconazole was also evaluated in comparison with fluconazole in a severe combined immunodeficient mouse model of orogastric candidosis that simulates the disease occurring in AIDS patients [80]. Mice were treated with ravuconazole at a dose of 1, 5, or 25 mg/kg/d for 12 days or with fluconazole at 5 or 25 mg/kg/d. Ravuconazole was more efficacious than fluconazole and it demonstrated a dose-dependent improvement in the clearance of colony-forming units in the esophagus, stomach, small intestine, and cecum. Ravuconazole showed the potential to be beneficial therapeutically for mucosal candidosis in immunocompromised patients. In human subjects, ravuconazole has been shown to be active in the treatment of oropharyngeal and esophageal candidiasis in immunocompromised patients [81,82]. In a randomized, double-blind study, the efficacy and safety of ravuconazole (400 mg once daily) was compared with fluconazole (200 mg once daily) for the treatment of esophageal candidiasis in immunocompromised patients [81]. Seventy-one subjects were treated for 21 days and response was assessed 7 to 11 days after the last day of therapy. Thirty-one (86%) of 36 patients in the ravuconazole group and 14 (78%) of 18 in the fluconazole group were cured at the first follow-up visit. C albicans was the most commonly isolated pathogen (49 of 59 isolates). Adverse events associated with ravuconazole treatment included abdominal pain (8%); diarrhea (6%); pruritus (6%); and rash (6%). In vivo data may also support the use of ravuconazole for the treatment of dermatophyte infections. A phase I-II randomized, double-blind, double-dummy placebo-controlled, dose ranging study of the pharmacokinetics, efficacy, and safety of ravuconazole was conducted for the treatment of toenail onychomycosis [83]. Subjects received ravuconazole orally at doses of 200 mg once daily, 100 mg once weekly, 400 mg once weekly, or placebo for 12 weeks. After 48 weeks, effective treatment rates (mycologic cure and clinical cure or improvement) were 200 mg/d (22 [56%] of 39); 100 mg/wk (4 [10%] of 39); 400 mg/wk (3 [8%] of 37); and placebo (3 [15%] of 20), suggesting that ravuconazole, 200 mg daily for 12 weeks, may be an effective and safe therapy for onychomycosis. It was observed that steady-state serum levels of ravuconazole of 3000 ng/mL correlated with a successful clinical and mycologic response. Posaconazole (SCH 56,592) Posaconazole is currently in phase III trials. It is an analogue of itraconazole with a 1,3-dioxolone backbone [1].

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Pharmacokinetics Pharmacokinetic studies conducted in neutropenic oncology patients demonstrated that posaconazole was well absorbed at oral concentrations of 200 mg every day, 400 mg every day, and 200 mg four times a day. The half-life has been estimated to be 22 hours and maximum concentrations were attained 3 hours after dosing [84]. In vitro susceptibility testing In vitro studies demonstrate that posaconazole has a broad spectrum of activity against Aspergillus spp. [49,85]; Candida spp., including strains resistant to fluconazole [29,41,86,87]; C neoformans [36,41,88]; Trichosporon spp. [47]; Zygomycetes [89]; and dermatophytes [90,91]. One study demonstrated that posaconazole had in vitro activity comparable with itraconazole and terbinafine against dermatophyte species and it was more effective against yeast and nondermatophyte fungi [91]. In vivo studies In vivo studies have also shown posaconazole to be effective in murine models of invasive aspergillosis [92], histoplasmosis [93], coccidioidomycosis, disseminated fusariosis [60], P boydii infections [94], and in an experimental neutropenic murine model of zygomycosis infected with three Mucor spp. [95]. The efficacy of posaconazole has also been demonstrated in animal models of superficial fungal infections. In a hamster model of vaginal candidiasis, posaconazole at a single oral dose of 2.5 or 10 mg was more effective than fluconazole. Topical administration of posaconazole at 0.25 or 0.5% was also more effective than oral fluconazole, oral itraconazole, and topical miconazole in a guinea pig model of T mentagrophytes infection. Oral administration of posaconazole was also more effective than oral fluconazole and itraconazole in terms of reducing fungal burden, but it was comparable with these agents at reducing lesion severity [29]. The efficacy of posaconazole was compared with fluconazole for the treatment of oropharyngeal candidiasis in a multicenter trial [67]. Both drugs were administered at a single dose of 200 mg followed by 100 mg/d and they had similar clinical and mycologic responses and safety profiles.

Azole cross-resistance Resistance to drug action can occur by various mechanisms including modification of the drug itself, modification in quantity or quality of the drug target,

or reduced access to the target. The resistance may result from a combination of these mechanisms [96]. Modifications of the azoles have not yet been documented as a factor in resistance [96]. Some species of Candida have differing binding affinities of azoles to the target enzyme 14-a-demethylase, which may account for some differences in azole activity between species [96]. Some evidence also suggests that efflux of fluconazole may also contribute to development of fluconazole resistance in some Candida species, and this efflux may be achieved by increased expression of the multidrug resistance transporter proteins (especially MDR1) [40,96]. Pfaller et al [40] did not find this to be a significant mechanism of azole cross-resistance at the time of the study. Overexpression of 14-a-demethylase has been noted in an azole-resistant strain of C glabrata, and was suspected to be the mechanism of cross-resistance exhibited with itraconazole and fluconazole in this strain. The mechanism seemed to be specific to C glabrata, and operated in conjunction with efflux mechanisms; overexpression of 14-a-demethylase likely has a limited role in the cross-resistance of Candida spp. to azoles [96]. Altered membrane sterol composition (methylated sterols, such as methylfecosterol replacing ergosterol) was a factor in resistance found in an azole-resistant and polyeneresistant C albicans mutant [96]. Subsequent research found no correlation between sterol composition and azole susceptibility in other strains of C albicans, and sterol pattern is not suspected to be a significant component of azole resistance [96]. These mechanisms may not be azole-specific, and may be a cause of cross-resistance noted between established and new azole antifungal agents. Reduced susceptibility of fluconazole-resistant isolates of Candida spp. to voriconazole and itraconazole may be an indication that azole cross-resistance is developing [97]. This resistance was specific to isolates of C tropicalis, but not C albicans, C glabrata, and C krusei, suggesting that cross-resistance can be species-specific [8,97]. Results of in vitro susceptibility testing of 50 isolates of C neoformans showed potential cross-resistance of itraconazole with fluconazole [44]. Cross-resistance to itraconazole, miconazole, and voriconazole was also noted in 13 isolates of S apiospermum [98]. Posaconazole did not show cross-resistance with these other four azoles, and may have a mechanism of action or mechanism of resistance that differs from the other azoles tested [98]. Heterogeneity in susceptibility to the azoles has been reported [98,99]. Elevated MICs with in vitro itraconazole use on Aspergillus fumigatus were gen-

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erally not associated with elevations in voriconazole or ravuconazole MICs, and the lowest MICs for voriconazole and ravuconazole were noted in highly itraconazole-resistant isolates [99]. The similarity of MIC values for voriconazole and ravuconazole may indicate that these two azoles have similar modes of action and mechanisms of resistance. Posaconazole did not show elevations of MIC in conjunction with increased MIC values of the azoles itraconazole, miconazole, and voriconazole [98]. This heterogeneity in susceptibility suggests that there are differences in activity of azoles, and different mechanisms of resistance to the azoles that may explain the lack of cross-resistance between some azoles despite apparent structural similarities. The mechanisms of azole action and resistance themselves are not well understood, and further studies into azole susceptibility patterns are required.

Echinocandins and pneumocandins The fungal cell wall provides a unique target for antifungals because they are composed of b-(1,3)-D glucan, mannan, and chitin. These fungal components have no mammalian counterpart, allowing for selective toxicity [1]. The new antifungal echinocandins and pneumocandins are inhibitors of the fungal cell wall b-(1,3)-D-glucan synthase enzyme complex. Caspofungin (MK-0991), the first of the echinocandins to receive Food and Drug Administration approval, was approved in January 2001 for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies. Anidulafungin (LY303366) is in phase III trials for esophageal candidiasis and phase II studies for invasive candidiasis. Micafungin (FK463) is in phase II trials. Pharmacokinetics Caspofungin is excreted primarily by hepatic metabolism and has an elimination half-life of 9 to 12 hours. Following a single dose of 70 mg, the plasma protein binding was found to be approximately 96% [100]. In vitro susceptibility testing In vitro testing has shown the echinocandins to exhibit fungicidal activity against Candida spp. including C albicans, C tropicalis, and C glabrata [101 – 104]. In vitro activity has also been demonstrated against Aspergillus spp. [100,101,105]. Caspofungin has limited activity against C neoformans because it contains little or no b-(1,3)-D-glucan syn-

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thase [106]. In vitro testing of caspofungin and micafungin shows that these drugs may be effective in treating Candida spp. biofilms associated with device-related microbial infections and resistance to standard anticandidal agents [18]. Although a broad spectrum of activity has been demonstrated in vitro for glucan synthesis inhibitors, methods for susceptibility testing have not been standardized and the correlation between the results of susceptibility tests and the clinical outcome is unclear [100]. In vivo studies The efficacy of caspofungin has been demonstrated in various animal models of infections with Candida, Aspergillus, and Histoplasma, including mouse models of disseminated aspergillosis [107], candidiasis [108,109], cryptococcosis [110], and in immunocompromised murine models of Pneumocystis carinii [111]. Studies have shown caspofungin to be effective in patients with oropharyngeal and esophageal candidiasis [112,113]. A multicenter, double-blind, randomized phase II trial was performed to evaluate the efficacy, safety, and tolerability of caspofungin in comparison with AmB in 128 adults with endoscopically verified Candida esophagitis [113]. Patients received 50 and 70 mg/d of caspofungin by IV infusion for 14 days. Seventy-four percent and 89% of patients in the 50- and 70-mg groups, respectively, achieved clinical success as verified by endoscopy. Clinical success was achieved in 63% of patients receiving 0.5 mg/kg/d of AmB. Therapy was discontinued in 24%, 4%, and 7% in patients receiving AmB, 50 and 70 mg of caspofungin, respectively. Patients in the caspofungin groups had significantly fewer drug-related adverse events. The most frequently reported adverse events associated with caspofungin were fever, phlebitis, headache, and rash.

Summary Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates, and drug resistance. New formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungals have demonstrated therapeutic potential. These new agents may provide additional options for the treatment of superficial fungal infections and they may help to overcome the limitations of current treatments. Liposomal formulations of AmB have a broad spectrum of activity against invasive fungi, such as

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Candida spp., C neoformans, and Aspergillus spp., but not dermatophyte fungi. The liposomal AmB is associated with significantly less toxicity and good rates of efficacy, which compare or exceed that of standard AmB. These factors may provide enough of an advantage to patients to overcome the increased costs of these formulations. Three new azole drugs have been developed, and may be of use in both systemic and superficial fungal infections. Voriconazole, ravuconazole, and posaconazole are triazoles, with broad-spectrum activity. Voriconazole has a high bioavailability, and has been used with success in immunocompromised patients with invasive fungal infections. Ravuconazole has shown efficacy in candidiasis in immunocompromised patients, and onychomycosis in healthy patients. Preliminary in vivo studies with posaconazole indicated potential use in a variety of invasive fungal infections including oropharyngeal candidiasis. Echinocandins and pneumocandins are a new class of antifungals, which act as fungal cell wall b-(1,3)-D-glucan synthase enzyme complex inhibitors. Caspofungin (MK-0991) is the first of the echinocandins to receive Food and Drug Administration approval for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies, and has been effective in patients with oropharyngeal and esophageal candidiasis. Standardization of MIC value determination has improved the ability of scientists to detect drug resistance in fungal species. Cross-resistance of fungal species to antifungal drugs must be considered as a potential problem to future antifungal treatment, and so determination of susceptibility of fungal species to antifungal agents is an important component of information in development of new antifungal agents. Heterogeneity in susceptibility of species to azole antifungals has been noted. This heterogeneity suggests that there are differences in activity of azoles, and different mechanisms of resistance to the azoles, which may explain the present lack of cross-resistance between some azoles despite apparent structural similarities. The mechanisms of azole action and resistance themselves are not well understood, and further studies into azole susceptibility patterns are required.

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Antifungal drugs used for systemic mycoses Roderick J. Hay, DM, FRCP, FRCPath Medicine and Health Sciences, Queens University, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK

Fungal infections are conventionally grouped into superficial, subcutaneous, and systemic infections according to the main site of clinical involvement. Although there is some overlap between these groups (certain organisms, such as Candida sp, cause superficial infections limited to the mucosal surfaces or deep infections affecting internal organs), generally this division is useful clinically. The systemic mycoses, once rare diseases, are now well recognized as important causes of morbidity and mortality in both otherwise healthy individuals and compromised patients. This change, from rare to part of everyday practice, has come about for a number of reasons, such as the recognition of the wide range of clinical presentations of the endemic mycoses; the discovery of new agents of disease, such as Penicillium marneffei; the increased use of medical and surgical interventions that affect host resistance to infecting organisms; and, latterly, the spread of AIDS.

Classification of systemic mycoses The main infections known as ‘‘systemic mycoses’’ are as follows: Endemic respiratory mycoses Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis Blastomycosis Infections caused by P marneffei Opportunistic mycoses Systemic candidiasis

E-mail address: [email protected]

Aspergillosis Zygomycosis Cryptococcosis Others (eg, infections caused by Fusarium, Bipolaris, and so forth) The endemic mycoses are respiratory infections, which are normally self limiting, and most of those exposed to infection remain well but become sensitized to the causative fungus (eg, develop a positive delayed-type skin test). These infections have welldefined endemic areas and often the causative organisms are present in the environment, such as the soil. The ecologic niche occupied by the organisms that causes endemic mycoses are varied and range from semi-desert areas of the Americas with coccidioidomycosis to the humid tropics of Southeast Asia (P marneffei). Infections can be acquired by those visiting such areas and long-term residents. In acute phases of these infections respiratory symptoms and fever and clinical signs suggestive of immune complex – mediated responses, such as erythema nodosum, erythema multiforme, and arthritis, may occur. In chronic infections the disease may be confined to the lungs or disseminate from the primary site of infection. Skin lesions of different morphologies from papules to ulcers or cellulitis may result from dissemination. It is important to remember that these are systemic diseases and that skin lesions are often accompanied by deep foci of infection elsewhere; investigation for evidence of internal disease, through CT scans, blood cultures, or serology, is an important part of management. Management generally involves the use of antifungals to cure these infections [1]. Not all patients require therapy, however, and in particular in the self-limiting phases treatment is not necessarily given. This is often the case in the acute pulmonary

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phase of infection with such diseases as histoplasmosis, where in many individuals recovery occurs with supportive management, rest, and analgesics; specific antifungals are used for the more severely ill. Chronic pulmonary or disseminated forms of the endemic mycoses are potentially fatal without treatment. The opportunistic infections follow a different clinical pattern. These infections have a worldwide distribution and are mainly seen in the immunosuppressed including those with underlying diseases, such as AIDS, or the recipients of solid organ or stem cell transplants. Additionally, other medical or surgical interventions may predispose to opportunistic fungal infection (eg, the insertion of intravenous or intracavitary cannulae or stents). Because they often present with nonspecific signs and symptoms, such as fever, and the laboratory diagnostic tests currently available may have a low level of predictability, opportunistic mycoses are often difficult to recognize early; but they carry a high mortality. Skin lesions are always associated with systemic spread and often herald the presence of widespread disease. Although previously patients with some infections, such as candidemia, where recovery could follow removal of an intravenous line were not given specific antifungal therapy, nowadays it is the usual practice to treat all patients with opportunistic systemic mycoses using antifungals [2].

Management of systemic mycoses Treatment strategies The antifungal drugs currently used for the treatment of systemic fungal diseases belong to two large families: the polyenes and the azoles. In addition, there are a number of other medications. Most of the more recently developed antifungal drugs have broad-spectrum antifungal activity in vitro and inhibit the wide variety of different fungi that cause systemic fungal disease. Many are available as either oral or intravenous therapies. In vitro some behave as cidal compounds (ie, the concentration at which they inhibit growth, the minimum inhibitory concentration, is the same or very close to the concentration at which they destroy the fungi, the minimum cidal concentration). It remains unclear with antifungals as with antibacterials how this translates into clinical practice, particularly because many of the systemic mycoses are infections that occur in the severely immunosuppressed patient and in widely differing environments in the human body. Drug pharmacokinetics, regional bioavailability, host and drug re-

sistance, and varying local tissue drug levels all contribute to determining the outcome of treatment. For this reason treatment failures may occur in patients receiving cidal drugs. Other factors that contribute to the selection of treatment of patients with systemic fungal disease are mortality rates and the difficulty of proving the diagnosis by laboratory methods. The mortality rates of certain infections, particular opportunistic mycoses, are very high without treatment. Invasive zygomycosis (mucormycosis) and aspergillosis occurring in the immunosuppressed patient are almost uniformly fatal in untreated patients. In the patient with continuing severe neutropenia the mortality rate from invasive aspergillosis exceeds 70%, even with therapy [3]. Disseminated endemic mycoses, such as histoplasmosis, are also fatal. Delay in instituting treatment presents a severe risk to patients. In the case of the endemic mycoses the clinical features and laboratory diagnostic tests are usually sufficiently specific and sensitive for the clinician to initiate treatment with confidence in the diagnosis. This is not necessarily the case with opportunistic infections, where the clinical signs are often nonspecific and the results of laboratory tests equivocal. A number of features are responsible. These include a low positive return from blood cultures possibly caused by the comparative infrequency of fungemic episodes, cross-reactivity in antibody tests with nonpathogenic fungi, and fluctuating antibody production in the presence of immunosuppression. This is a particular problem in patients at most risk of a fatal outcome of infection, such as those with severe neutropenia. The recognized difficulty of proving a diagnosis in the face of a potentially life-threatening disease led to the development of a number of different strategies for the management of systemic fungal infections. The main strategies for the management of systemic mycoses Prophylaxis. Antifungals are given before any infection is present to prevent the development of serious disease [4]. This strategy entails identifying those likely to develop progressive infections and using the appropriate drug to forestall the development of illness. Usually, but not always, orally absorbed antifungals are used as prophylaxis. There is a dearth of clinical trials adequate to establish the precise benefits of such an approach. Empiric therapy. In this approach treatment with a broad-spectrum antifungal is started at the earliest sign of a potential infection, usually fever, and before

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the diagnosis is clearly established. Typically empiric antifungal treatment is given to the febrile neutropenic patient if there is no response 48 to 96 hours after the institution of empiric antibacterial therapy. It follows that many (possibly as many as four of five of those receiving empiric antifungal therapy) may not have a fungal infection. Empiric therapy is used for those at risk from mycoses, such as invasive aspergillosis, where there is severe mortality. There is still disagreement on the selection of patients suitable for this approach and some suggest that heavy dependence on empiric therapy is unnecessary. It is a common clinical practice, however, particularly in the immunosuppressed patient with fever. Curative therapy. This is the familiar form of treatment where antifungal therapy is given to patients to treat a recognized and diagnosed infection. Most fungal infections seen in dermatology fall into this category. Given the problems with disease recognition in the systemic opportunistic infections described previously, however, curative therapy is not always used in these infections, empiric treatment or prophylaxis taking its place. Curative antifungal therapy is the usual approach to the management of endemic mycoses. Suppressive therapy. Classically, this has been used for the management of patients with AIDS where there is evidence that stopping antifungal therapy will be followed by relapse of the fungal infection. The approach has been adopted in cryptococcosis, histoplasmosis, and other endemic mycoses. Long-term antifungal suppressive therapy is usually commenced after primary antifungal treatment given for 2 to 3 weeks and is a way of ensuring that relapse does not occur. Common suppressive treatment regimens depend on oral azoles, such as fluconazole and itraconazole. There is now evidence, however, that in many patients receiving highly active antiretroviral therapies (HAART) this form of suppressive treatment may no longer be necessary because it has proved possible to stop suppressive medication in some cases without subsequent relapse [5]. Wider application of this strategy does require more evidence of its efficacy combined with effective methods of screening for relapse of infection. Some of the antigen detection methods used in mycology may prove useful in this respect. As yet molecular tools, such as polymerase chain reaction, have not been assimilated into routine diagnostic use. There are also other strategies used in the systemic mycoses that are different to those used with superficial disease. An example is protective isolation [6].

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Some invasive fungi spread in the environment, usually as airborne spores, both at home and in hospital. The periods during which patients are most at risk from infection because of low levels of immunity are likely to occur in hospital (eg, immediately after stem cell grafting). With this in mind, it is a common practice to isolate patients from environmental exposure in specifically designed rooms with high-efficiency air filtration. The antifungal agents used for systemic mycoses The approach to the selection of antifungals for use in the systemic mycoses is somewhat different to that adopted for superficial infections. The polyene antifungals, for instance, are still widely used in systemic infections. Because systemic pathogens may vary considerably in their in vitro sensitivities to antifungals, their distribution, and their pharmacokinetics, there is often a choice of drug to be made depending on the organism implicated, underlying predisposition, current immunosuppressive therapy, and location of the infection. Polyenes and their use in systemic mycoses In distinction to the synthetic azoles, the polyenes are derived from Streptomyces sp and, although a large number of different polyene derivatives are known, there are few in clinical use. The main polyenes are amphotericin B, nystatin, and natamycin. Amphotericin B was the earliest of these agents to be developed for human use and is given intravenously. Polyenes function by binding to the cell membrane of fungal cells and causing leakage after disrupting this cell barrier. Although they show the highest affinity to ergosterol-based lipid layers, they also bind to cholesterol-based membranes and can cause toxicity as a result to human cells, such as erythrocytes and the cells of the proximal renal tubule. The development of all these drugs has been hampered by this potential severe toxicity [7] and difficulty in developing new polyene compounds by modifying their molecular structure. More recent experimental additions to the polyene group were partricin and mepartricin, but neither has been developed further. In addition, attempts to modify the molecular structure of amphotericin B to produce new active agents, such as the methyl esters of amphotericin B, have not been successful because the resulting products were associated with new toxicities, such as cerebral lipodystrophy. Amphotericin B, which is derived from Streptomyces nodosus, is the only polyene widely used as a parenterally

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administered drug; it is also available as an oral tablet or pastille in some countries. Nystatin and natamycin are purely topical agents, given as either creams; pastilles; suspensions; or, in the case of nystatin, as a vaginal tablet. Amphotericin B is metabolized in the liver and poorly penetrates body cavities, cerebrospinal fluid, and urine. The polyenes have a broad in vitro spectrum of activity against a wide range of fungi including the major systemic pathogenic fungi, such as Aspergillus and Candida spp [8]. Amphotericin B is widely used for the treatment of deep mycoses despite side effects. Combinations of amphotericin B with a lipid (eg, in a liposome) have been developed as a means of reducing the nephrotoxicity of the intravenous parent drug. Three commercial lipid-associated amphotericins are available [9]: (1) AmBisome (a true liposome); (2) amphotericin B lipid complex (Abelcet, a ribbon-like lipid binding amphotericin B); and (3) amphotericin B colloidal dispersion (Amphocil, a suspension of lipid disks) [10]. It does not seem that these combinations have different modes of action but in the case of AmBisome there is evidence that the active drug (ie, amphotericin B) is directly transferred from the lipid droplet to the fungal cell membrane. These formulations are comparatively expensive, but it has been argued that the lower risk of renal damage and the costs of consequent management and prolonged hospital stay may make these compounds comparatively cost effective [11]. At present there have been no comparative studies between these drugs, although they have been compared with the conventional formulation of amphotericin B, and it is not possible to provide an objective assessment of the relative merits of these drugs. All seem to produce a lower rate of renal impairment than the conventional amphotericin B formulation and the incidence of acute reactions, such as chills and fever, varies between different studies. The use of amphotericin B combined with Intralipid has been recommended by some authors, although there are few clinical studies on which to base a judgment and there is insufficient work on the potential side effects. Indications for polyenes The polyene antifungal, amphotericin B, is widely used as a systemic agent for the treatment of systemic mycoses, such as aspergillosis and candidosis. The newer lipid-associated amphotericins are used for similar indications including the empiric treatment of the febrile neutropenic patient. Amphotericin B is normally given in a dose of 1 mg/kg/d in 5% dextrose solution [12]. The drug is

formulated with deoxycholate and may be destabilized in solution by the addition of other medications to the infusion. It is used in the treatment of many of the systemic mycoses and, although its place has often been assumed by other drugs for specific indications, it is still used particularly where patients are seriously ill and where a rapid response is required. For this reason it is often named ‘‘the gold standard of antifungal therapy.’’ Despite this accolade it is as well to remember that even with amphotericin B treatment the mortality of invasive aspergillosis in the severely neutropenic patients remains higher than 70%. Average treatment times are highly variable and it is given until there is clinical recovery and usually for a minimum period of 2 weeks, but this may be extended. Treatment is usually given by slow infusion over a 4-hour period, and even so there are often immediate reactions, such as fever or hypotension. Although one potential advantage of the lipidassociated amphotericins is that the dose can be raised without significant toxicity, most clinical trials have concentrated on a predetermined dose, usually 3 mg/kg/d, rather than higher doses [9]. At this level there is evidence of comparable efficacy versus amphotericin B itself but with reduced serious toxicity. The lipid-associated amphotericin B – based compounds are not without renal toxicity, although this is less frequent and generally occurs at higher doses (eg, above 5 mg/kg/d). Nonetheless, renal function should be closely monitored. In addition to the lipid-associated amphotericins there is also a new lipid nystatin preparation (Nyotran) in development [13]. Nystatin has not been used as a parenteral drug on its own and the specific role of the new formulation is yet to be determined. Amphotericin B or the lipid-associated amphotericins are used for the empiric therapy of febrile neutropenic patients [12]. Here the drug is used to cover febrile episodes and is given at does of up to 1 mg/kg/d, or in the case of Ambisome, Abelcet, or Amphocil at 3 mg/kg/d. There is evidence of clinical equivalence in efficacy for both Abelcet [14] and Ambisome [9] versus conventional amphotericin B. The duration of therapy depends on defervescence of the fever or the definitive diagnosis of an infection, which modifies the course of treatment. These drugs are also used for the primary treatment of systemic mycoses; again the dose of amphotericin B is 1 mg/kg/d and for lipid-associated drugs is 3 mg/kg/d [11]. Systemic candidiasis, aspergillosis, cryptococcosis, and endemic mycoses are all treated in the same way. Responses of coccidioidomycosis particularly in widely disseminated or meningeal

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forms of the infection remain unpredictable [1]. It is important to note the following:  In AIDS patients amphotericin B is usually used

for primary treatment of cryptococcosis with or without flucytosine for a duration of up to 3 weeks, usually 2 weeks. It is given in AIDS patients with histoplasmosis and P marneffei infections for similar periods [15]. In each case long-term suppressive treatment is then given with oral azoles. Usually this approach is adopted in the case of severe disease. This approach may be altered in the light of new information becoming available on the impact of HAART on the need for long-term antifungal suppressive therapy.  There is less evidence of efficacy for endemic mycoses for lipid-associated amphotericins in any patient group and guidelines on the appropriate doses are not available. There is evidence, however, of efficacy in histoplasmosis.  Combination therapy with other drugs has been used from time to time. These have included flucytosine (see later); rifampicin; and azoles. There is objective evidence to support the value of an amphotericin B and flucytosine combination in cryptococcal meningitis. The combination has also been used in invasive candidiasis [2]. There have been no controlled assessments or comparative studies of lipid-associated polyenes and flucytosine. The combination of an azole and a polyene generally has been avoided because there are in vitro data that suggest that there may be antagonism between the two families of drugs. There is still lack of objectively assessed clinical experience with the use of azole-polyene combinations.

Side effects and drug interactions The side effects of intravenous amphotericin B are well described and may seriously limit its usage [3,7]. They can be divided into immediate and longterm effects. The main immediate effect is fever and chills in addition to local irritation resulting in thrombophlebitis. These immediate effects may be very severe, however, and patients can develop hypotensive episodes during the earliest stages of treatment. The drug is often given under cover of steroids or antihistamines. In the longer term amphotericin B is associated with other forms of cell damage including potassium loss, anemia, and renal failure. Renal impairment may result from renal tubular damage or from reduced renal plasma flow.

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Those patients receiving over 3 g of amphotericin B, however, often show some form of renal impairment. In addition, concerns about renal impairment or renal function developing rapidly during treatment are common reasons for changing or stopping therapy. Other potentially nephrotoxic drugs are best avoided, where possible, although there are little data to support an interaction. As described previously, the new lipid-associated amphotericin B formulations are less toxic compared with the same dose of the conventional amphotericin formulation. At higher doses renal impairment may occur; however, is not clear if this follows a similar mechanism. Chills and fever are less frequent but can occur. Azole antifungals The largest family of antifungals in common use is the azole family, a group that can be subdivided further into two distinct subdivisions: the imidazoles and the triazoles. The chemical structure of both is based on an azole ring with different side chains that affect the solubility, antifungal activity, and probably drug resistance properties of each compound. These are all synthetic compounds. The earliest azole to be used in systemic disease was miconazole, which was given intravenously. Although efficacy was limited miconazole seemed to be particularly effective in infections because of a mold that is an increasingly recognized problem: Scedosporium apiospermum (Pseudallescheria boydii). Intravenous miconazole was dissolved in Cremophor and was associated with side effects, such as rashes and urticaria and bronchospasm thought to be caused by mast cell degranulation. It is now seldom used. Its development, however, paved the way for the emergence of ketoconazole as an oral treatment, followed by the triazoles, itraconazole and fluconazole. Voriconazole, ravuconazole, and posaconazole are newer triazole agents shortly to become available in some countries. Many azoles have been developed for topical use, although some, particularly the triazoles, are effective in the treatment of deep mycoses. Ketoconazole (oral), itraconazole (oral and intravenous), fluconazole (oral and intravenous), and miconazole (intravenous) all have systemically active formulations. The azoles are metabolized in the liver and affect fungal cell-membrane synthesis through inhibition of cytochrome P-450 – dependant 14-a demethylation, which is responsible for a key stage in the synthesis of ergosterol in the cell membrane. Some azoles show affinity for certain human cytochrome P-450 isoen-

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zymes, a property that may lead to drug interactions or competition with human metabolic processes. This is an important consideration when using azoles in the treatment of systemic mycoses where patients are often already receiving other drugs with which azoles may interact. There is, however, considerable variation among the different drugs in this respect. Ketoconazole may inhibit adrenal biosynthesis of androgens at high concentrations, which limits its use at higher dosage (over 600 mg daily) in systemic mycoses. The triazoles show less interaction with this human metabolic pathway. Apart from fluconazole and voriconazole most azoles penetrate cerebrospinal fluid and urine in low concentrations. The azoles have a broad spectrum of activity against many fungal pathogens, although fluconazole, miconazole, and ketoconazole are not effective for Aspergillus infections. By contrast, itraconazole, voriconazole, and posaconazole are active in vitro against a wider variety of mold fungi including aspergilli and some dimorphic and dematiaceous (pigmented) fungi. Fluconazole is less active against mold fungi and there are instances of both primary (Candida krusei, Candida glabrata) and secondary (Candida albicans) antimicrobial resistance to this compound. Ketoconazole Ketoconazole is an imidazole antifungal available as topical therapy or as an oral tablet (200 mg). Ketoconazole is used topically for the treatment of superficial mycoses and to a more limited extent as an oral preparation; it is active in the treatment of oropharyngeal candidosis in doses of 200 to 400 mg daily. In AIDS patients or those receiving chemotherapy for the treatment of malignancy ketoconazole is usually given in double dosage because absorption is often impaired in these patients, mainly because of lack of gastric acidity. In addition, it is used for some systemic or deep mycoses, such as mycetoma caused by Madurella mycetomatis, sporotrichosis, subcutaneous zygomycosis, histoplasmosis, paracoccidioidomycosis, and blastomycosis. For these latter indications its use has largely been superseded by itraconazole. Drug resistance of yeast species to ketoconazole can occur (see later). Itraconazole Itraconazole is an orally active triazole, although there is a more recently introduced intravenous formulation of the drug. Its mode of action, as with all azoles, is through the inhibition of the formation of ergosterol in the fungal cell membrane. Itraconazole is active against a wide range of organisms including dermatophytes; molds, such as aspergilli; dimorphic

fungi, such as Histoplasma and P marneffei [8]; and yeasts, including C albicans. Itraconazole comes in three main formulations: (1) a capsule containing pelleted itraconazole, (2) an oral solution containing itraconazole in cyclodextrin, and (3) an intravenous formulation also containing cyclodextrin. The oral solution is designed for the treatment of oropharyngeal and esophageal candidosis in severely immunocompromised patients To achieve adequate serum levels, itraconazole has to be used at higher dosage in AIDS patients (eg, 200 mg/d) but the oral solution formulation can be given at 100 to 200 mg daily in such patients. Itraconazole is useful in some subcutaneous mycoses, such as sporotrichosis, chromoblastomycosis, and subcutaneous zygomycosis. Its use in systemic infections is less well documented but it has some well-recognized uses [16]. Itraconazole is used as oral prophylaxis in Candida infections or to reduce the risk of systemic infection in compromised patients [17]. It performs as well as fluconazole in this respect and in some studies was more effective in preventing systemic infections. Itraconazole intravenous solution is effective in mold infections [18,19]. In the limited studies performed to date its main value seems to be in aspergillosis, although in vitro it is active against a wider range of mold fungi including pigmented organisms that cause systemic phaeohyphomycosis. Itraconazole is used as primary or secondary treatment in histoplasmosis, paracoccidioidomycosis, blastomycosis, coccidioidomycosis [20], and infections caused by P marneffei [16]. The doses used to induce remission are usually no higher than those used in long-term treatment. In HIV-positive patients it is usually given to the less severely ill patients, amphotericin B being reserved for the acutely sick. Long-term (suppressive) therapy in histoplasmosis [15] and Penicillium infections after initial treatment is used in many countries and in patients not receiving HAART to prevent recurrence of infection. There are a few instances in patients receiving HAART where it has proved possible to stop suppressive itraconazole. Drug resistance to itraconazole is not common but some fungi develop multiple resistance to azoles (see later). Fluconazole Fluconazole is an orally active triazole antifungal [21]. As with other triazoles the main site of action is through the inhibition of the 14-a demethylase enzyme. There are both oral capsule and liquid formulations of fluconazole and an intravenous form for deep infections.

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The drug is active against a range of fungi including yeasts, such as C albicans and Cryptococcus neoformans, and some mold fungi including dermatophytes. It is less active in other mold infections, such as aspergillosis and zygomycosis. It is used as primary therapy for oropharyngeal candidosis in doses of 100 to 200 mg daily. Fluconazole is very active against Candida spp apart from C krusei, C glabrata, and C dubliniensis. It chief uses against systemic mycoses include oral prophylaxis against systemic infection in compromised patients, such as those with AIDS, neutropenia, or patients who have received head and neck irradiation for cancer. It is effective in the prevention of oral candidosis in those patients [4,22]. There is less evidence that it is effective as prophylaxis against systemic infections, particularly those caused by mold fungi. Unfortunately, most of the published studies have been too small to show significant differences with alternative agents. It has been used increasingly for the treatment of systemic infection caused by Candida in both immunocompromised and surgical patients. There is an added advantage in using fluconazole in that it can eradicate yeasts from the urinary tract [23]. Doses used have ranged from 200 to 800 mg daily, although most clinicians use 400 mg daily intravenously or orally. There continues to be a debate as to whether it is as effective as amphotericin B, although published studies indicate that this is the case [24]; many physicians continue to favor the use of amphotericin B for systemic candidiasis in the immunocompromised patient. One potential problem with the use of fluconazole is the fact that many non-albicans Candida spp [25], notably C glabrata and C krusei, are not sensitive to the drug in vitro and there are treatment failures. This has meant that, if on preliminary identification a germ tube negative Candida yeast is found to be the cause of infection, treatment is usually initiated with amphotericin B rather than fluconazole, at least until the culture identification is complete. Fluconazole can be used as primary therapy for cryptococcosis including meningitis [26], although amphotericin B and flucytosine are usually used as the first line of treatment or as preliminary therapy in patients with cryptococcosis and AIDS. Fluconazole is then given as long-term suppressive therapy at 200 to 400 mg daily. There is some evidence that in some patients receiving HAART it is possible to discontinue fluconazole [27]. Alternatively, fluconazole on its own can be used in patients with nonmeningeal cryptococcosis, particularly cutaneous cryptococcosis. Fluconazole can be given in dimorphic infections, such as histoplasmosis, blastomycosis, and paracoc-

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cidioidomycosis. There are insufficient data to allow a comparison with itraconazole in these diseases and generally the latter is given in preference. There have been comparative studies with itraconazole in coccidioidomycosis [20] and responses to both are similar and they are effective in many cases, although there is a recognized tendency for this infection to relapse after therapy. Fluconazole is best avoided as primary treatment for mold fungi or an empiric therapy because the responses of common mold pathogens, such as aspergilli, are less certain. Drug resistance and azoles There is a risk of the development of resistance in C albicans infections in immunocompromised subjects if some azole drugs are continued in the presence of persisting infection [25]. Resistance to fluconazole and ketoconazole is mainly seen in oropharyngeal Candida infections in AIDS patients but resistant strains have been found in other forms of infection. There are three or four different mechanisms for drug resistance including increased drug efflux from the fungal cell (possibly reduced uptake); changes in the drug binding at the active site; and the existence of supplementary paths of cell membrane sterol biosynthesis. Cross-resistance to ketoconazole and to a lesser extent itraconazole may also occur in patients resistant to another azole, such as fluconazole. There is some evidence that the frequency of the isolation of resistant strains can be affected by other factors, such as the wider use of HAART therapy; reduced levels of colonization with resistant strains have been recorded [28]. Equally, the wider use of fluconazole has coincided with the isolation of more non-albicans Candida spp in patients with systemic Candida infections, particularly candidemia [29]. Whether this is a direct consequence of selection pressure on colonizing Candida spp by fluconazole is not known. Drug resistance to amphotericin B is rare although, one Candida sp, C lusitaniae, may be resistant to this drug and cause breakthrough infections [30]. New triazoles Clinical trial experience of voriconazole is limited because the drug is comparatively new and most information is based on anecdotal evidence of efficacy [31,32]. Voriconazole is given with a loading dose of 400 mg twice daily and then 200 mg twice daily. The infections treated so far range from aspergillosis to histoplasmosis but it is too early to comment on its place in the antifungal treatment options. It is available as an oral tablet or as an intravenous compound.

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The main adverse effects reported have been intensification of vision, particularly color vision. This is transient and mainly noticed at the outset of treatment. It is not apparently accompanied by any damage to the retina. Voriconazole has a very wide spectrum of activity against pathogenic systemic fungi, such as Candida spp, cryptococci, aspergilli, and certain other mold fungi [33]. It has been shown to be more active in inducing remission in invasive aspergillosis than amphotericin B in one comparative study in neutropenic patients. Posaconazole [34] is an orally active triazole that is clinically active against a wide range of fungi. It seems to work against aspergillosis, cryptococcosis, and histoplasmosis among others. There are few published studies of the drug at the time of writing. Similarly, ravuconazole [31] has a broad spectrum of activity but clinical experience is limited.

Side effects and drug interactions Oral azoles are associated with a low frequency of adverse reactions, such as nausea, dyspepsia, gastrointestinal discomfort, or headache. The frequency of severe adverse events is low. These are, however, important to note. Ketoconazole causes hepatitis [35] in a small proportion of cases, estimated to be approximately 1:7,000. The risk factors for this are not well understood, although patients with a previous history of liver disease may be at risk. Ketoconazole may also cause gynecomastia in males and menstrual irregularities in women when used in doses over 400 mg daily, problems associated with interferences with androgen metabolism. With itraconazole and fluconazole the incidence of symptomatic hepatitis is much lower; in the case of itraconazole, for instance, less than 1:100,000 cases. With fluconazole it is more difficult to estimate the frequency of adverse reactions because the cohort of patients treated with this drug has been different and includes many with severe systemic disease; attributing hepatic dysfunction in such cases to a single cause is correspondingly difficult. Exceptionally rare adverse events include angioedema (itraconazole); thrombocytopenia (fluconazole); and toxic epidermal necrolysis (fluconazole). There is an important list of drug interactions with the azoles that should be remembered. As a general principle itraconazole is more likely to be associated with drug interactions but those that may cause serious consequences (eg, terfenadine, astemizole, and digoxin) are seen with all azoles. In addition, statins (eg, somatostatin) seem to interact with itraconazole to cause rhabdomyolysis.

Practical applications The following should be borne in mind when selecting azoles for use in the systemic mycoses:  Fungi vary in their sensitivity to azoles. Some-

times even within a single genus there is considerable variation. If using these drugs empirically it is important to select compounds with the broadest spectrum possible (eg, itraconazole or voriconazole).  Azoles may interact with drugs commonly used in patients with systemic mycoses. Cyclosporin, tacrolimus, and rifampicin are all examples. There is some variation in this activity between different azoles with some (eg, itraconazole) seeming to affect the metabolism of these compounds more than others. It is important, where possible, to monitor levels of any competing drugs and adjust their dosage accordingly.  Resistance to azole antifungals is mainly but not exclusively seen with Candida spp where the drug is given in the face of clinical failure, particularly in a patient who is immunocompromised. In some, but not all cases, there is cross-resistance to other azoles, which means that it is possible to try treatment with an alternative azole. Other antifungal agents Other antifungal agents used in systemic mycoses include the allylamines, terbinafine, and flucytosine. Terbinafine has not been used much for systemic mycoses, although it is effective in sporotrichosis and chromoblastomycosis. Flucytosine is generally used as a combination therapy with amphotericin B. Allylamine antifungals The allylamine drugs comprise a smaller group of two compounds: naftifine and terbinafine. There is also a related compound, the benzylamine butenafine, which is available in some countries. These drugs inhibit squalene epoxidase, which is active in the early part of the pathway for the biosynthesis of ergosterol in the fungal cell membrane. They are fungicidal compounds. The antifungal activity seems to depend on two events: the accumulation of squalene, which disrupts intracellular membranes, and the depletion of ergosterol in the membrane. Cidal activity resides mainly with the former property. Terbinafine is best known for its efficacy in dermatophytosis but it is also very active against some mold fungi, such as aspergilli; dimorphic

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pathogens (eg, Sporothrix schenckii); and pigmented fungi [36]. It is somewhat less active against yeasts, such as Candida spp, and is only fungistatic against C albicans. Terbinafine is lipophilic and well absorbed (70%) after oral administration. After oral administration it has a large peripheral volume of distribution and is bound in tissue rich in lipid or keratin. This may affect its use in systemic diseases and key pieces of information, such as the most appropriate doses to be used in deep infections, are not available. Terbinafine is potent against all dermatophytes and it also has activity against a range of mold fungi including aspergilli; dimorphic agents, such as Histoplasma; and Sporothrix. It is less effective against yeasts, such as C albicans, although it can be used topically to treat superficial candidosis. Terbinafine is also used in some deep infections, notably sporotrichosis and chromoblastomycosis, in doses of 250 mg daily. There is limited evidence of efficacy in chronic necrotizing pulmonary aspergillosis and data from experimental animal infections suggesting efficacy in Pneumocystis infections. Terbinafine is associated with a low level of adverse effects after topical use (occasional reports of irritation). After oral treatment a variety of minor problems may occur, such as nausea and dyspepsia. More serious events are occasionally seen, such as alteration of taste or even loss of taste. It is expected to return to normal after 4 weeks. Rare instance of

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hepatic dysfunction presenting with jaundice have been reported. Other very rare drug side effects, such as thrombocytopenia or granulocytopenia, have also been reported. Flucytosine Flucytosine (5-fluorocytosine) functions through the inhibition of fungal thymidylate synthetase. It is active against yeast fungi and is chiefly used with amphotericin B as a combination therapy because of its high level of synergistic activity with this polyene drug. It has been used in chromoblastomycosis in this combination. It is more generally given as treatment in systemic mycoses, such as cryptococcosis. The drug is excreted in urine and dosage should be reduced in patients with renal impairment. Resistance is also seen among Candida and Cryptococcus spp. Flucytosine is given in a dose of 30 to 40 mg/kg four times daily orally or intravenously [2]. The dose should be reduced in patients with renal impairment because the drug is excreted by the kidneys. It is also important to monitor plasma levels of the drug 1 to 2 hours postdose. The optimal levels are between 40 and 60 mg/L and bone marrow toxicity leading to neutropenia and thrombocytopenia can occur if levels rise above 100 mg/L, although this may rarely occur at lower levels. Other side effects include hepatic damage, diarrhea, and anemia. The doses are not altered when it is used as combination therapy. There are insufficient clinical data to provide useful com-

Table 1 Summary of treatment regimens Polyenes Amphotericin B

Lozenges Intravenous

Lipid-associated amphotericin B (eg, AmBisome [liposomal AMB]) Oral azole antifungals Ketoconazole Itraconazole

1 – 2 qid 1 mg/kg/d 3 mg/kg/d

Oral Oral Oral or intravenous

Fluconazole

Oral Oral or intravenous

Terbinafine Flucytosine

Oral Oral or intravenous

200 – 400 mg daily 100 – 200 mg daily oropharyngeal Candidosis 200 – 600 mg daily for systemic mycoses, such as aspergillosis, histoplasmosis, and P marneffei infection 100 – 200 mg daily for oral candidiasis 200 – 600 mg daily for systemic candidosis, cryptococcosis (primary or maintenance) 250 – 500 mg daily Daily. In patients with normal renal function 120 mg/kg daily in four divided doses. Check serum levels in patients with renal impairment (normal 40 – 60 g/L).

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ments on combination therapy with azole antifungals, such as fluconazole, even though the combination is likely to be effective.

[7]

Echinocandins Drugs with efficacy against the cell wall of fungi have been developed, but of the many compounds in preclinical assessment only one is currently available for clinical use. This is caspofungin, an echinocandin that blocks glucan synthase [37,38]. It is available as an intravenous drug for use in the treatment of aspergillosis or candidosis particularly caused by resistant Candida spp. The efficacy in Candida esophagitis is comparable with amphotericin B but with considerably less toxicity. The drug has few reported side effects to date.

[8]

[9]

[10] [11]

[12]

Summary Table 1 summarizes the antifungal agents commonly used for the treatment of systemic mycoses. The treatment of these conditions remains a challenge. This is particularly the case with infections in neutropenic patients where mortality rates remain high despite the development of new drugs and the evaluation of drug combinations. Much attention has been focused on the development of new antifungal drugs that can provide a solution to this problem without concurrent toxicity and without the risk of drug resistance.

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