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Fungal infections of the skin and nail: new treatment options Expert Rev. Anti Infect. Ther. Early online, 1–17 (2014)

Matthew L Eldridge1, Cindy J Chambers2, Victoria R Sharon2 and George R Thompson III*1,3 1 Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, USA 2 Department of Dermatology, University of California – Davis, One Shields Ave, Tupper Hall, Rm 3138, Davis, CA 95616, USA 3 Department of Medical Microbiology and Immunology, Coccidioidomycosis Serology Laboratory, University of California – Davis, One Shields Ave, Tupper Hall, Rm 3138, Davis, CA 95616, USA *Author for correspondence: [email protected]

Knowledge of the currently available antifungal agents, along with clinical, microbiologic and histopathologic methods, can help the medical professional optimally manage skin and nail fungal infections. With regards to treatment of fungal disease of the skin or nail, there are a variety of systemic antifungal agents, including several newer agents that have different formulations, tolerability, adverse effect profiles and spectrum of activity. This review will highlight the clinically important fungal infections of the skin and nail and describe the activity and role of antifungal treatment. KEYWORDS: antifungal therapy • cutaneous infection • dermatophyte • fluconazole • isavuconazole • itraconazole • posaconazole • voriconazole

Fungal infections of the skin and nails reflect a large spectrum of disease, from superficial and potentially self-limited infections, such as the common dermatophyte infections, to severe disease with dissemination or local invasion into deeper tissue. Superficial disease is the most commonly encountered fungal dermatologic manifestation, of which there are several important diseases to recognize. Similarly, many of the organisms that cause skin disease can also cause nail infections as well. Subcutaneous mycoses, though much less commonly seen, are notable for developing at sites of traumatic inoculation. In addition, the endemic mycoses and other fungal pathogens can cause infections either as a manifestation of disseminated disease or by direct inoculation. Diagnosis is made based on the clinical, microbiologic, laboratory and histopathologic criteria for each pathogen and disease. With regards to treatment of fungal skin or nail infections, diagnosis of the causative process or specific organism is paramount as it informs the selection of an appropriate antifungal agent. Systemic and topical therapy and the unique role these agents play in the treatment of fungal infections will be covered in this review. Superficial Dermatophytoses

Dermatophyte infections are the most common fungal cause of superficial infection of

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the human body [1,2]. These fungi have developed the unique ability to grow on keratin, a key structural component in skin, hair and nails. Dermatophytes invade the stratum corneum of the epidermis, and very rarely cause invasive disease [3]. Superficial dermatophyte infections are also known as tinea or ringworm due to their classic annular appearance on the skin. Tinea infections are often named according to anatomic location (e.g., tinea pedis for foot involvement) and thrive in moist and warm areas of the body. Dermatophytoses are composed of three genera of moulds: Trichophyton, Epidermophyton and Microsporum, and have a similar clinical presentation. Dermatophyte infection follows exposure to other humans, fomites, animals or soil; however, not every exposed individual will become infected. Predisposing factors, such as immunosuppression, alter the risk of infection and extent of disease. Unusual presentations or failure to respond to treatment should prompt further evaluation for immunologic dysfunction [4]. Prior treatment, usually with topical steroids, can mask the classic appearance of these lesions (i.e., tinea incognito; FIGURE 1). The diagnostic test of choice for tinea infection is a potassium hydroxide (KOH) preparation of a hair shaft or skin scraping (sampled from an active lesional border consisting of erythema and

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Figure 1. Tinea incognito. The classical appearance of tinea corporis is altered by preceding topical corticosteroid use.

scale) to demonstrate characteristic hyphae and spores. Cultures must be obtained in order to identify the fungal species responsible, if needed as KOH results do not distinguish among tinea species. In rare cases, cultures must be sent to a reference laboratory for identification using both phenotypic and genomic analysis. A Wood’s lamp is often of limited utility as most dermatophytes do not fluoresce under UV light, with the exception of the zoonotic Microsporum, which fluoresces blue-green. Tinea capitis

Tinea capitis is a common dermatophyte infection of the scalp, particularly in children, caused by pathogens in the genera Trichophyton and Microsporum. Clinical presentation varies based on the causative organism, typical location of invasion (within or outside the hair shaft) and host immune response, and may

Figure 2. Kerion. Severe pustular eruption with abscess formation following tinea capitis. Photo courtesy of Dr. Marc Silverstein (UC-Davis Department of Dermatology).

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range from mild non-inflammatory alopecia with or without scaling to a severe pustular eruption with abscess formation known as a kerion (FIGURE 2) [5]. Black dot tinea capitis (BDTC), most frequently caused by T. tonsurans, is one of the most common dermatophyte infections in children worldwide, though adults may also be affected, particularly if immunocompromised [4]. AfricanAmericans are particularly predisposed to infection, which is often spread from child to child by fomites or among exposure or re-exposure to asymptomatic or inadequately treated household contacts [6]. Clinically, BDTC is recognized as an erythematous, slowly enlarging scaling patch on the scalp, which may go unnoticed until alopecia ensues. The black dot pattern is caused by the characteristic breakage of hair shafts at the level of the scalp, which can be viewed as comma or corkscrew-appearing hairs under dermoscopic magnification. Cases can be associated with significant inflammation and lymphadenopathy, which may aid in the differentiation of tinea capitis from alopecia areata and other less inflammatory causes of alopecia [7]. Gray patch tinea capitis (GPTC), caused by Microsporum audouinii or M. canis, begins as a scaly erythematous patch on the scalp that spreads centrifugally over several weeks. Inflammation may subside while the lesion persists. Unlike the lower breakage point of BDTC, hair shafts within the lesions of GPTC often break several millimeters above the scalp surface giving lesions a frosted or grey patch-like appearance. Both BDTC and GPTC may progress to kerion formation, an immune response to fungal infection characterized by boggy exudative nodules that may be complicated by bacterial superinfection. Favus, caused by T. schoenleinii, is the most rare and severe form of tinea capitis, now primarily restricted to rural areas of central Asia, the Middle East and Africa [8]. Lesions are characterized by chronic, thick, yellow, crusted plaques (known as scutula) and may be associated with scaring alopecia or permanent hair loss. Griseofulvin is the first choice for treatment of tinea capitis secondary to Microsporum spp., while terbinafine is preferred for tinea capitis known to be due to Trichophyton species, particularly when a shorter duration of therapy is desired [9]. The efficacy of itraconazole and fluconazole is similar to griseofulvin [10,11]. Topical treatment of tinea capitis exhibits low efficacy due to limited hair shaft penetration and should not be performed. Identification of household contacts also plays an important role in management, as they represent sources of reinfection. Some authors have suggested treatment of household contacts with antifungal shampoo (2.5% selenium sulfide shampoo or ketoconazole 2% shampoo) [6]. If inadequately treated, permanent alopecia, kerion or abscess formation and rarely systemic illness may occur [5]. Tinea barbae, similar to tinea capitis, is a dermatophyte infection of the bearded area of the face and neck and occurs predominantly in adolescent and adult males. Treatment concerns are similar to tinea capitis, although shaving or hair Expert Rev. Anti Infect. Ther.

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depilation is recommended in addition to antifungal therapy in cases of tinea barbae.

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Tinea corporis

Dermatophyte infection of the body classically presents as an annular patch with a peripheral rim of erythema and scaling with central clearing. Cases are most commonly caused by T. rubrum, T. mentagrophytes or T. tonsurans, respectively, and can occur after contact with affected individuals or animals. Tinea gladiatorum is a type of tinea corporis, which occurs primarily in athletes, particularly wrestlers, due to direct skin-to-skin contact. While dermatophytes usually cause superficial infection, infrequently they can invade the dermis and subcutaneous tissue. Majocchi’s granuloma (FIGURE 3), typically caused by T. rubrum, presents clinically as a folliculitis with pink to red perifollicular papules, pustules or nodules, and may occur secondary to minor skin trauma (such as shaving) or in the setting of immune compromise [12]. In contrast to the treatment of tinea capitis, topical agents (TABLE 1) such as clotrimazole or econazole are effective for tinea corporis. Topical nystatin is not effective due to its inactivity against dermatophytes. In patients with severe or extensive disease, or in the immunocompromised, a systemic agent such as terbinafine, fluconazole or itraconazole is preferred over griseofulvin [13,14].

Figure 3. Majocchi’s granuloma. Photo courtesy of Dr. Jasdeep Sharma (UC-Davis Department of Dermatology).

secondary dermatitis. Wood’s lamp examination of the feet may be done to differentiate erythrasma, commonly caused by Corynebacterium spp., which fluoresces coral red, from tinea.

Tinea cruris

Table 1. Topical antifungal agents.

Also known as ‘jock itch’, tinea cruris is a dermatophyte infection of the groin or crural fold that is often associated with intense pruritus. It usually starts along the inner thigh and can involve the perineum or spread down the thigh classically sparing the scrotum (unlike candidal intertrigo, see below). Most cases are caused by T. rubrum, however, T. mentagrophytes and Epidermophyton floccosum have also been implicated. Treatment is similar to tinea corporis with topical agents used first-line in addition to the avoidance of tight-fitting clothing when possible.

Azoles: treatment of dermatophytes, Candida spp., and tinea versicolor

Tinea pedis/tinea manuum

Tinea pedis, or athlete’s foot, typically caused by T. mentagrophytes and T. rubrum, is the most common dermatophyte infection worldwide. It can be acute or chronic, and may present clinically with interdigital erythema, maceration and scaling, most prominently between the 4th and 5th webbed spaces or in a ‘moccasin’ distribution with erythema and scaling extending from the bottom to the medial and lateral foot. Either variant may arise in conjunction with associated vesicles and/or bullae (inflammatory or vesicular variant) and/or superficial erosions, which can be prone to secondary bacterial infection. Commonly, patients will present with a moccasin-like distribution of both feet with or without interweb space involvement in addition to involvement of the palmar aspect of one hand (i.e., one-hand-two feet tinea). Tinea pedis is often seen with adjacent toenail involvement (onychomycosis) or tinea infection at distant sites, and more rarely may lead to an idiosyncratic (id) reaction causing a local or generalized informahealthcare.com

Clotrimazole

b.i.d.

Econazole

q.d.

Ketoconazole

q.d. (shampoo or cream)

Luliconazole

q.d.

Miconazole

b.i.d.

Sertaconazole

b.i.d.

Sulconazole

Once or b.i.d.

Allylamines: treatment of dermatophytes and tinea versicolor Naftifine

Once per day (cream), or twice (gel)

Terbinafine

Once or b.i.d.

Benzylamines: treatment of dermatophytes and tinea versicolor Butenafine

Once or b.i.d. depending on site of infection

Polyenes: treatment of Candida infections (not effective against dermatophytes) Nystatin

Two- to three-times daily

Other Ciclopirox

b.i.d.

Tolnaftate

b.i.d.

b.i.d.: Twice daily; q.d.: Once daily.

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Figure 4. Classic appearance of onychomycosis.

Tinea manuum is a dermatophyte infection of the hand and presents similarly to tinea pedis. Tinea pedis and tinea manuum can usually be treated with a topical antifungal cream for 4–6 weeks, although interdigital tinea pedis may only require 1 week of therapy. Treatment with allylamines (terbinafine or naftifine) produces a slightly higher cure rate than treatment with an azole [15]. Chronic or refractory disease likely requires treatment with oral therapy including terbinafine 250 mg daily for 2 weeks, itraconazole 200 mg daily for 1 week or fluconazole 150 mg once weekly for 2–6 weeks. Griseofulvin is also an option, although is less effective and requires 4–8 weeks of therapy [16]. Tinea nigra

Tinea nigra, also known as superficial phaeohyphomycosis, is most frequently caused by Hortaea werneckii (which is not a dermatophyte, yet clinically the disease retains its tinea nomenclature). Tinea nigra has also been described due to Stenella araguata in two patients in Venezuela [17] and a tinea nigra-like lesion in an HIV-positive Brazilian child was found secondary to a new species, Cladophialophora saturnica [18]. These organisms very rarely cause superficial infection. When present, however, they usually manifest as hyperpigmented lesions on palms or soles [19]. Treatment with several weeks of topical antifungal agents with or without topical keratolytics (salicylic acid, urea, glycolic acid or lactic acid) is generally sufficient for disease clearance. Onychomycosis

The term onychomycosis refers to any fungal infection of the nail, and comprises dermatophytes, yeast and non-dermatophyte moulds [20,21]. It is important to determine that a fungus is present in the nail before initiating systemic therapy, as nail dystrophy secondary to trauma, eczema, psoriasis and other inflammatory conditions may clinically mimic onychomycosis (FIGURE 4), which is implicated in only 50–60% of abnormal nail findings [20]. The pathogenesis of onychomycosis of the toenails and fingernails varies. Dermatophytes (particularly T. rubrum, doi: 10.1586/14787210.2014.960849

T. mentagrophytes and E. floccosum) cause the majority of toenail infections while yeasts (Candida albicans) are the most common cause of fingernail infections [20–22]. Nondermatophyte moulds are an uncommon cause of infection in the toenail and very rarely in the fingernails (see below for other fungal infections) [20]. The distal portion of the nail is much more frequently involved than the proximal portion. Proximal disease implies more severe immune compromise, and can be a clinical marker of underlying HIV [23]. Factors that increase the risk of onychomycosis include nail trauma, tight shoes, use of locker rooms, immune compromise, diabetes, increased age, hyperhidrosis and the use of broadspectrum antibiotics [24]. Diagnosis is made via nail clipping, which can be sent for culture as well as hematoxylin and eosin and periodic acid-Schiff stains, which provide rapid identification of the presence of fungal elements, but does not provide identification to the species level. Culture results should be interpreted with caution; however, as nail acquisition is a nonsterile procedure and can often grow multiple organisms that may reflect the presence of contaminants. Adjunctive measures, including dilute vinegar foot soaks, keeping nails trimmed, use of topical antifungal and absorbent powders on the feet and in footwear as well as avoidance of potential opportunities for reexposure, may be helpful in preventing recurrence [5]. Topical antifungals are potential options in the absence of lunula involvement. Ciclopirox, available as an antifungal nail lacquer, has shown mycologic cure rates from 46 to 85% after 48 weeks [25]. Similarly, topical amorolfine exhibited both clinical and mycologic cure in 45–59% of patients after 6 months of therapy [26,27]. Topical efinaconazole was recently approved for the treatment of onychomycosis and after 4 weeks of therapy cure has been observed in 15–18% of patients [28]. Recurrence rates following cessation of topical therapy are high. Due to the long duration required for topical therapy, systemic therapy is often preferred. Terbinafine (250 mg daily) is typically recommended as first-line therapy; a 6-week course preferred for fingernail onychomycosis and a 12-week course for toenail disease [29]. Itraconazole has also shown a higher cure rate than griseofulvin [30], however, drug costs frequently limit the ability to prescribe itraconazole over other options. Fluconazole is not as effective as itraconazole or terbinafine [31]. Newer systemic triazoles such as posaconazole and voriconazole have almost no role in the treatment of onychomycosis or dermatophytes, given the availability of alternative agents, the requirement for therapeutic drug monitoring and the high costs of these medications. Pityriasis versicolor

Pityriasis versicolor, also known as tinea versicolor (though not a dermatophyte), is a cutaneous fungal infection caused by Malassezia spp. that classically leads to coalescing oval patchy flat discoloration (hypo- or hyperpigmentation, or occasionally mild erythema) of the skin (FIGURE 5). Primarily caused by M. globosa, M. sympodialis and M. slooffiae have also been implicated with M. furfur infrequently isolated in carefully Expert Rev. Anti Infect. Ther.

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performed studies [32]. Humidity and increased temperatures promote fungal growth and as such the disease is seen more commonly in warm climates [33]. Clinically, the infection presents as multiple slightly wrinkled or atrophic-looking oval macules coalescing into patches with either hypo- or hyperpigmentation and fine overlying scale, particularly when scraped. The trunk is the classic site of involvement, however, infection also affects the neck and proximal limbs, whereas the face, particularly the forehead, is more likely to be involved in pediatric patients [34]. The diagnosis is made based on the characteristic appearance of the rash and a KOH scraping demonstrating a classic ‘spaghetti and meatball’ pattern of hyphae and spores. Wood’s lamp ultraviolet evaluation may additionally demonstrate a pale yellow to light green florescence of active lesions. Notably, areas of dyspigmentation may persist for weeks to months after resolution despite adequate treatment. Treatment with topical antifungal preparations, most commonly ketoconazole 2% or selenium sulfide 2.5% shampoo, applied from the neck down for 10–15 min before rinsing twothree-times weekly for 2–4 weeks, is generally adequate for disease clearance. Treatment with oral antifungal agents (fluconazole 300 mg once weekly for 2 weeks or itraconazole 200 mg daily for 7 days) have been found to be highly effective and may be preferable in patients with recalcitrant disease. Regardless of treatment strategy, disease recurrence rates are high, particularly in warm and/or moist climates. Patients with frequent disease recurrences may benefit from the ongoing use of topical antifungal shampoos (i.e., ketoconazole 2%) to the body one- to two-times weekly or a once-monthly dosing of an oral antifungal agent for maintenance/preventative therapy [5]. Candida intertrigo

Intertrigo is an inflammatory condition of closely opposed skin surfaces caused by friction, often complicated by cutaneous infection with Candida species. The infectious risk is increased in settings that increase skin friction or moisture as well as impaired immune response. Though typically found in the groin, axilla, inframammary or infra-abdominal folds and webbed spaces of digits, intertrigo can arise nearly anywhere on the body at sites of skin apposition [35,36]. Candidal intertrigo classically presents as beefy red plaques, often with peripheral scaling and characteristic brightly erythematous satellite papules in areas of skin apposition. Less commonly, painful erosions, maceration, crusting and oozing may occur [37]. The diagnosis is often made clinically, though can be confirmed by KOH skin scraping or culture. Treatment with topical nystatin, ciclopirox or azole creams (clotrimazole, miconazole or econazole), used twice daily (b.i.d.) for 2–3 weeks, or until 1 week after clinical disease clearance is generally adequate. Antifungal powder vehicles may be substituted or used in combination with cream preparations in instances of excessive moisture. Patients should also be instructed to avoid tight-fitting clothing and dry the affected areas thoroughly after bathing to reduce moisture retention and reinfection. Rarely, systemic antifungal agents may be necessary for severe or recalcitrant informahealthcare.com

A

B

C

Figure 5. Tinea versicolor. (A) Classic appearance with hyperpigmented macules (may also be hypopigmented) and fine overlying scale. (B) Wood’s lamp examination of tinea versicolor. (C) Microscopic examination of potassium hydroxide (KOH)-treated skin scraping revealing ‘spaghetti and meatballs’ appearance of fungal hyphae and spores.

disease [5]. In these cases, fluconazole 100 mg daily or itraconazole 200 mg b.i.d. are sufficient. Cutaneous candidal infection can also manifest as balanitis in men, which clinically presents as a pruritic or painful erythematous rash of the penis that is associated with diabetes, immune compromise, lack of circumcision and sexual contact with partners with recurrent vulvovaginal candidiasis [38,39]. Candidal mastitis may occur in lactating women and is sometimes associated with pain out of proportion to exam in addition to prior maternal or infant Candida infection [40,41]. Subcutaneous

Eumycetoma (fungal mycetoma) and chromoblastomycosis (CBM) are clinical syndromes caused by melanized or dematiaceous fungi and represent two of the most common subcutaneous fungal infections worldwide [42]. These organisms are found in soil or plant debris in tropical or sub-tropical regions and typically affect individuals in rural settings. Clinically, eumycetoma and chromoblastomycosis infections begin as painless subcutaneous papules most typically on the lower leg at the site of traumatic inoculation progressing into draining sinuses and verrucous plaques, respectively. Of note, many bacteria can also cause what is clinically recognized as mycetoma, however, these are better defined as actinomycetoma and will not be covered in this review. Eumycetoma

The majority of eumycetoma infections are caused by Madurella mycetomatis. Scedosporium (Pseudallescheria) boydii, Falciformispora senegalensis and Trematosphaeria grisea (formerly Madurella grisea), though dozens of organisms have been identified worldwide (TABLE 2) [43,44]. Madura foot clinically occurs following traumatic inoculation of the lower extremity resulting initially in a slow growing, painless nodule [44]. Over months to decades, the lesions can form large plaques with draining sinus tracts and grains (representing colonies of the infecting organism), which are pathognomonic for diagnosis. Black grains imply a fungal cause, while yellow or white grains suggest either a fungal or bacterial etiology [43]. Over time, infection may extend beyond the subcutaneous tissue and infrequently involve adjacent muscle, doi: 10.1586/14787210.2014.960849

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Table 2. Most common agents of eumycetoma and chromoblastomycosis [44]. Disease

Fungal genus and species

Eumycetoma

Black granules Cochliobolus lunatus† Exophiala spp. Falciformispora senegalensis Madurella mycetomatis Medicopsis romeroi Trematosphaeria grisea‡ White granules Acremonium falciforme Acremonium recifei Aspergillus nidulans Fusarium spp. Microsporum audouinii Neotestudina rosatii Scedosporiumboydii§ No color predilection Aspergillus fumigatus (although typically green) Cladosporium spp. Geotrichum candidum Neoscytalidium dimidiatum Rhinocladiella atrovirens

Chromoblastomycosis

Fonsecaea pedrosoi Cladophialophora carrionii Fonsecaea compacta Phialophora verrucosa



Curvularia lunata. Madurella grisea. Scedosporium apiospermum or Pseudallescheria boydii.

‡ §

lymph nodes or bone. Deep tissue biopsy for culture and microscopic evaluation can be helpful for diagnosis. Treatment involves wide margin surgical excision followed by systemic antifungal therapy targeted to the cultured organism (most commonly itraconazole, posaconazole or voriconazole, with

amphotericin B formulations reserved for severe disease) to reduce the risk of underlying bone infection [5]. Chromoblastomycosis

The most common fungi that cause CBM are Fonsecaea pedrosoi and Cladophialophora carrionii, though other agents have been implicated (TABLE 2) [45]. The lower limbs are the most common sites of traumatic inoculation, though any exposed skin can be affected. The lesions begin as papules or pustules and slowly enlarge to become verrucous plaques [46]. Diagnosis is made by culture and histopathology; the pathognomonic feature of CBM on biopsy is the ‘copper penny’ Medlar body (FIGURE 6). Treatment is challenging, and may be best approached by a combination of surgical excision (when possible) followed by prolonged systemic antifungal therapy (itraconazole, posaconazole, voriconazole or flucytosine [5-FC]). Fluconazole is not effective (TABLE 3). Phaeohyphomycosis

Phaeohyphomycosis describes the infections caused by dematiaceous moulds. These organisms reside in soil or organic matter and contain a melanin-like pigment in their cell walls. There are many fungal species that cause phaeohyphomycosis, though infection with these organisms is rare. Organisms include Exophiala, Bipolaris, Alternaria, Exserohilum and Phoma species, among many others. Similar to mycetoma and CBM, most infections are due to direct traumatic inoculation in the skin and can occur in immunocompetent or immunosuppressed individuals [47–49]. The subcutaneous form of this infection is also known as a mycotic cyst. The mainstay of therapy is surgical excision when possible. In cases not amenable to surgical resection, prolonged courses (>12 months) of oral antifungal agents including posaconazole, voriconazole and itraconazole have proven efficacious, however, close clinical follow-up with frequent re-evaluation of tissue cultures, histology or radiographic imaging to ensure disease clearance is required [5]. Invasive mycoses Aspergillosis

Figure 6. Chromoblastomycosis. Infection of the skin and subcutaneous tissue has led to atrophic non-painful skin changes. The pathognomonic finding of chromoblastomycosis is Medlar bodies (arrow) – sclerotic cells that are globe shaped, cigarcolored and thick walled (commonly referred to as copper pennies).

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Aspergillus spp. are saprophytic moulds found worldwide that can cause a variety of clinical disease in humans, including aspergilloma, allergic bronchopulmonary aspergillosis and invasive aspergillosis [50]. The cutaneous manifestations of aspergillosis can be primary or secondary. Primary disease is caused by the entry of Aspergillus conidia through areas of skin breakdown including surgical sites, injuries, burn wounds, solid organ transplants and contaminated adhesive dressings for venous access [51–53]. Secondary cutaneous aspergillosis occurs due to invasive disease, primarily of the lungs. The dermatologic findings of both primary and secondary cutaneous disease can be non-specific and vary from single to multiple firm or necrotic papules to subcutaneous nodules with or without bullae and ulceration. The lesions can be tender or non-tender and usually affect the extremities as a result of hematogenous spread. The majority of cutaneous infections are Expert Rev. Anti Infect. Ther.

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Table 3. Antifungal spectrum of activity against common moulds and yeast. Disease/organism

AMB

FLU

ITR

POS

VOR

ISA

ECH

5-FC

Tinea/dermatophytes

+

+

+

+

+

+

?

-

Pityriasis versicolor

?

+

+

+

+

?

?

-

Onychomycosis

Empiric toenail: same as for dermatophytes. Fingernail: same as Candida Treatment depends on fungus identified

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Candida spp. C. albicans

+

+

+

+

+

+

+

+

C. glabrata

+

±

±

+

+

±?

+

+

C. krusei

+

-

±

+

+

+

+

±

C. tropicalis

+

+

+

+

+

+

+

+

C. parapsilosis

+

+

+

+

+

+

±

+

C. guillermondii

+

+

+

+

+

+

-

+

C. lusitaniae

-

+

+

+

+

+

+

+

A. fumigatus

+

-

+

+

+

+

+

-

A. flavus

±

-

+

+

+

+

+

-

A. terreus

-

-

+

+

+

+

+

-

A. niger

+

-

±

+

+

+

+

-

+

-

±

+

+

+

+

-

+

+

+

+

+

+?

-

+

±

-

-

+

+

±

-

-

±

-

-

+

-

±

-

-

Sporotrichosis

+

-

+

?

?

±

-

-

Blastomycosis

+

+

+

+

+

+

±

-

Histoplasmosis

+

±

+

+

+

+

±

-

Coccidioidomycosis

+

+

+

+

+

+

-

-

Paracoccidioidomycosis

±

+

+

+

+

+

-

-

§

+

±

+

+

+

?

?

±

+

+

+

+

+

?

±

±

±

-

+

+

±

?

-

?

Chromoblastomycosis

±

-

+

?

±

?

-

+



+

-

+

+

+

?

+

-

††

Aspergillus spp.

A. nidulans ††

Cryptococcus spp. ††

Fusarium spp. ††

Mucorales

Endemic mycoses

Penicilliosis



Adiaspiromycosis {

Eumycetoma

#

Phaeohyphomycoses †

Infection requires debridement in almost all circumstances. Very limited data [98]. Limited data, mostly in vitro [136]. { Treatment depends on organism. # Limited data; disease relapse frequent. Role for physical treatment (surgery, cryotherapy, etc.) for early lesions. †† Role for physical treatment (surgery, cryotherapy, etc.) for primary or early lesions. Terbinafine and griseofulvin have a limited role in the treatment of infections other than the dermatophytes and are thus not included. AMB: Amphotericin; ECH: Echinocandins; 5-FC: Flucytosine; FLU: Fluconazole; ISA: Isavuconazole; ITR: Itraconazole; POS: Posaconazole; VOR: Voriconazole; (+) implies antifungal activity against isolates, (-) implies no or limited activity against isolate, (±) implies variable activity against isolates. ‡ §

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be prescribed [56]. If cutaneous disease occurs concurrently with CNS infection, standard treatment for cryptococcal meningitis should be initiated (amphotericin B + 5-FC) (TABLE 3). Isavuconazole, currently in Phase III clinical trials, has shown promising activity against Cryptococcus and may be indicated in the future for disseminated disease [57]. Notably, C. gattii, compared with C. neoformans, affects immunocompetent hosts more frequently and may have reduced susceptibility to fluconazole [58–60]. Fusariosis

Figure 7. The characteristic acute angle branching seen in invasive aspergillosis. Other hyaline moulds may give this same histologic appearance so attempts to obtain cultures for definite identification are essential.

due to Aspergillus fumigatus or A. flavus, with A. terreus and other species noted less commonly. Diagnosis is made by skin biopsy and culture. Histopathology showing narrow, septate, acute-angle branching hyphae is suggestive of Aspergillus spp. (FIGURE 7), however, multiple other hyaline fungi demonstrate this appearance. Primary cutaneous disease may be surgically excised followed by rapid initiation of antifungal therapy. The drug of choice for invasive aspergillosis is voriconazole [54], although amphotericin B formulations, the echinocandins (which may be used as monotherapy) and other azoles (itraconazole, posaconazole and isavuconazole) have also been successfully used. Notably, Aspergillus spp. are not susceptible to fluconazole, and Aspergillus terreus, A. lentulus and other ‘cryptic’ species may be resistant to amphotericin B (TABLE 3). Cryptococcosis

Cryptococcal disease is overwhelmingly caused by Cryptococcus neoformans and C. gattii. Clinically, cryptococcus causes meningitis and pulmonary disease, particularly in immunocompromised patients (notably HIV and solid organ transplant recipients). Cutaneous disease is most often due to dissemination in the setting of immunosuppression. In HIV patients, the lesions characteristically resemble papules with central umbilication, similar to molluscum contagiosum. The cutaneous manifestations of cryptococcal disease, however, can be quite variable, and all suspicious lesions warrant a biopsy for culture and histopathology, the latter demonstrating large spherical yeast cells with a thick capsule. Rarely, skin infection can occur by direct inoculation without evidence of disseminated disease, and often presents on the hands as whitlow or at other sites of exposed skin [55]. Localized cutaneous disease may be surgically excised (if desired) followed by initiation of systemic antifungal therapy. In the absence of dissemination to the CNS or the presence of fungemia, fluconazole (6 mg/kg/day) or another triazole may doi: 10.1586/14787210.2014.960849

Fusarium is a filamentous fungus found worldwide in soil and on plants. Clinically, Fusarium spp. can cause local infection or disseminated disease, particularly in individuals with severe immune compromise [61]. The dermatologic manifestations of Fusarium, however, can be seen in both immune competent and compromised patients. In immunocompetent individuals, fusariosis can be an uncommon cause of onychomycosis, but can also present as a tinea-like rash. Rarely, deeper skin infections occur at sites of trauma [62]. In immunocompromised individuals, Fusarium can be localized as noted above, or disseminated with lymphangitic spread, leading to multiple papules or nodules with erythema and central necrosis. Cellulitis can also be present, usually on the extremities. The lesions are often painful, however, individuals with severe immune compromise may have subtle presentations due to lack of an immune response to the infection. Diagnosis can be made by culture and biopsy of skin lesions. Histopathology will demonstrate narrow, acute-angle branching, septate hyphae. Notably, unlike many other disseminated fungal infections, blood cultures are often positive in the setting of fusariosis [62]. Surgical excision of localized disease may be possible and the systemic antifungals posaconazole or voriconazole (±amphotericin B although susceptibility testing should be obtained) should be used for generalized or systemic disease. Isavuconazole has promising activity against Fusarium and may be indicated in the future for disseminated disease. Notably, fluconazole and itraconazole are not active against Fusarium (TABLE 3). Mucorales

Mucorales, also known as mucormycosis, refers to a class of fungi comprising the Mucorales, including Mucor, Rhizopus, Rhizomucor and Lichtheimia (formerly Absidia) [63]. The organisms are ubiquitous in nature and found on plant matter and in soil. Disease almost always occurs in patients with underlying immune compromise predominantly due to direct inoculation of the spores at sites of skin breakdown, including burn wounds or dressings, catheter insertion sites and traumatic wounds and presents as necrotic lesions, ulcers, nodules or erythematous papules [64,65]. Infection of the sinuses, classically in poorly controlled diabetics is a medical emergency and can result in significant morbidity and mortality if not rapidly addressed [66,67]. Diagnosis can be made by culture, or the organisms can be recognized on Expert Rev. Anti Infect. Ther.

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Fungal infections of the skin & nail

histopathology as broad, aseptate ribbon-like and irregularly branched hyphae. Treatment involves surgical resection, when possible, along with systemic antifungal therapy (liposomal amphotericin B). The role of posaconazole in treatment has not yet been fully defined, although it is frequently used as step-down therapy following intolerance to liposomal amphotericin B or after clinical and radiologic improvements have been observed. In addition, isavuconazole has shown promising activity against Zygomycetes and may be indicated in the future, although similar to posaconazole, it is unlikely to play a role as primary therapy. Fluconazole, itraconazole and voriconazole are not active against the Zygomycetes (TABLE 3). Given significant risk of dissemination with associated mortality, avoidance of high-risk environment and systemic antifungal prophylaxis in high-risk immunocompromised individuals (neutropenia secondary to chemotherapy or hematopoietic stem cell transplant) as well as those on chronic high-dose systemic corticosteroids are important measures in the prevention of opportunistic mycotic infections. Endemic mycoses Sporotrichosis

Sporotrichosis is a subacute to chronic infection found worldwide caused by Sporothrix spp. Although S. schenckii is the most frequently implicated species, others have been found causal as well [68,69]. Most skin infections are due to direct inoculation associated with trauma and exposure to soil or the outdoors, however, zoonotic transmissions have been increasingly described particularly with cats due to a relatively large inoculum of organisms in their cutaneous ulcers [70,71]. Clinically, most cases of sporotrichosis manifest as fixed cutaneous or lymphocutaneous disease, however, uncommon extracutaneous manifestations (most commonly osteoarticular) can occur [72]. Fixed cutaneous lesions typically occur as a single nodule on the skin several weeks after traumatic inoculation, which may evolve over time into firm subcutaneous or ulcerated nodules arising along lymphatic channels and accompanied by lymphadenopathy (known as sporotrichoid spread). Disseminated sporotrichosis can manifest as diffuse skin lesions, along with other sites of involvement, and is most commonly seen in HIV or other immunocompromising conditions. Oral saturated solution of potassium iodide (SSKI) has been used as a low-cost treatment option for sporotrichosis, however, treatment is limited by side effects (iododerma, gastrointestinal upset and thyroid suppression). Current guidelines favor oral itraconazole (200 mg/day continued for 2–4 weeks after resolution of lesions) in lymphocutaneous or fixed cutaneous sporotrichosis [73]. Patients clinically unresponsive to this dose should receive itraconazole 200 mg b.i.d., or terbinafine 500 mg orally b.i.d.. Fluconazole (400–800 mg daily) is uncommonly used in the treatment of sporotrichosis. Notably, voriconazole is not active in vitro against S. schenckii [74] and experience with posaconazole is limited. informahealthcare.com

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Coccidioidomycosis

Coccidioidomycosis refers to the clinical infection associated with two dimorphic fungi: Coccidioides immitis, found in the San Joaquin Valley, and C. posadasii, found in the desert regions of the Southwestern USA, Mexico and other parts of Central and South America [75–77]. The fungus is present in the soil and thrives in warm and dry environments. Infectious arthroconidia are inhaled into the lungs typically leading to asymptomatic pulmonary infection in the majority of individuals, although acute or subacute pneumonia can occur [78]. Less commonly, patients can develop severe or disseminated disease, most frequently in immunocompromised states, large inoculum exposure and certain racial backgrounds (African Americans, Pacific Islanders), which may lead to dissemination to the skin and other organs [78]. Cutaneous manifestations are diverse and can include localized or disseminated papules, nodules, plaques, abscesses or ulcerations. Patients may also present with a variety of diffuse macular or hypersensitivity eruptions (where no viable organisms are present) including erythema nodosum, Sweet’s syndrome, acute generalized exanthematous pustulosis, erythema multiforme and reactive interstitial granulomatous dermatitis [79,80]. Disseminated disease can be suggested by serum coccidioidal antibody complement fixation titers >1:16, but definitive diagnosis is made by culture and lesional biopsy with demonstration of the large characteristic spherule. Treatment involves prolonged systemic antifungal therapy for severe or disseminated disease (fluconazole, itraconazole, posaconazole, voriconazole or an amphotericin B formulation are acceptable) (TABLE 3). Fluconazole 400–800 mg daily is the mainstay of therapy with other triazoles reserved for intolerance or toxicity with fluconazole. Although newer triazoles including posaconazole and voriconazole are quite effective [81], a lack of prospectively conducted trials and the costs of these agents has relegated them to second-line therapy for coccidioidomycosis. Blastomycosis

Blastomyces dermatitidis and B. gilchristii, are dimorphic fungi that thrive in moist soils [82]. The former is broadly distributed throughout the world, however, it is most common in North, Central and South America and is endemic to the Southeast and Midwest regions of the USA, while the latter has only recently been discovered and its distribution is not yet certain. Most cases of blastomycosis occur in people with outdoor exposures, where fungal spores are acquired via inhalation typically leading to pneumonia. Disseminated disease most often affects the skin followed by bones (osteomyelitis), joints and the genitourinary tract (including the prostate), and is more likely in the setting of immune compromise. The dermatologic manifestations of blastomycosis include papules, which can evolve into pustular, verrucous or ulcerative lesions with overlying scale and crust that can mimic the autoimmune ulcerative disease, pyoderma gangrenosum. While the lungs are typically the site of inoculation, cutaneous manifestations are sometimes seen in the absence of active pulmonary disease. Infrequent doi: 10.1586/14787210.2014.960849

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cases of primary cutaneous blastomycosis have been described in the setting of dog bites or accidental laboratory inoculation [83]. Diagnosis can be made by culture or with biopsy and recognition of the thick-walled, broad-based buds characteristic of Blastomyces spp. A urine antigen test is available, though it is not specific and appears to be most useful in the setting of severe or disseminated disease [84,85]. In severe disseminated disease, an amphotericin B formulation is favored for treatment, however, fluconazole, itraconazole, posaconazole and voriconazole may be used in mild-to-moderate disease and continued for several months beyond the time of symptom resolution [86]. Posaconazole and voriconazole exhibit efficacy in the treatment of blastomycosis, but little clinical data exist supporting their use over alternative agents (TABLE 3).

Mucocutaneous involvement in disseminated disease is common and may present as painful ulcerations called ‘moriform stomatitis’ due to its morphology or verrucous plaques, helping to differentiate paracoccidioidomycosis from leishmaniasis [5]. Diagnosis is made by visualization of the organism on biopsy or skin scrapings, in addition to cultures. The organism characteristically appears as a mother yeast cell with multiple narrownecked budding cells resembling a pilot’s or mariner’s wheel. Quantitative immunodiffusion is highly sensitive, specific and readily available making it an excellent serological diagnostic test and tool for ongoing therapeutic monitoring [93]. Treatment for paracoccidioidomycosis involves prolonged systemic antifungal therapy with fluconazole, itraconazole or voriconazole (6–12 months) [94], with amphotericin B formulations used only in those with severe disease (TABLE 3).

Histoplasmosis

Histoplasma spp. are dimorphic fungi found worldwide. The two varieties of histoplasmosis that cause disease in humans are Histoplasma capsulatum var capsulatum and var duboisii (the latter referred to as African histoplasmosis), which is generally rare but associated with skin or joint manifestations [87]. The lungs serve as the portal of entry and most instances of infection are self-limited [88]; however, disseminated disease including skin or oral manifestations can occur, particularly in the setting of immune compromise or exposure to a large inoculum [89]. Clinically, cutaneous histoplasmosis can present as a papular or nodular eruption that is classically non-specific and exceedingly difficult to distinguish on clinical exam alone. Oral lesions (ulcers) are quite common in the setting of disseminated disease. Diagnosis is made by histopathology and culture, and urine antigen can be helpful in the setting of disseminated disease. Rare cases of primary cutaneous histoplasmosis at sites of direct inoculation have also been described. While asymptomatic localized disease may be self-limited and clinically monitored, like blastomycosis, lipid amphotericin B formulations are the treatment of choice for severe disease followed by itraconazole, although successful treatment with voriconazole and posaconazole has also been described but is limited to retrospective series and case reports (TABLE 3) [90]. Paracoccidioidomycosis

Paracoccidioidomycosis is a systemic illness caused by the dimorphic fungus Paracoccidioides brasiliensis, endemic to central and South America, particularly Brazil [91]. The fungus is believed to reside in the soil in very humid tropical to subtropical regions, and as such most frequently affects rural farm workers [92]. The lungs are the primary portal of entry and most patients are asymptomatic, although primary cutaneous paracoccidioidomycosis can occur via direct inoculation of the intraoral or perioral skin via contaminated sticks or leaves [5]. Approximately 90% of paracoccidioidomycosis infections represent the chronic form, with symptoms often developing months to years after the initial infection [91]. However, pulmonary disease and hematogenous or lymphatic dissemination to nearly any site in the body, including the skin, can occur. doi: 10.1586/14787210.2014.960849

Penicilliosis

Talaromyces marneffei (formerly Penicillium marneffei) is a dimorphic fungus endemic to Southeast Asia (associated with the bamboo rat Rhizomys spp.) that primarily affects immunocompromised individuals, including persons with advanced HIV, hematologic malignancies and those receiving immunosuppressive therapy [95,96]. The organism is often inhaled, and in the setting of immune compromise can lead to fungemia and dissemination to many sites, including the skin. Clinically, penicilliosis can present as a generalized papular or acneiform rash on any part of the body, and may be accompanied by pulmonary or systemic symptoms. Diagnosis is made by culture and histopathology. Successful treatment requires a prolonged course of an oral antifungal agent, preferably itraconazole or voriconazole [97]. Amphotericin B formulations are reserved for severe disease. Adiaspiromycosis

Adiaspiromycosis represents human disease caused by the fungal genus Emmonsia. This dimorphic fungus has recently been described as a cause of disseminated disease in individuals with advanced HIV in South Africa [98]. Clinically, patients presented with a clinical picture similar to pulmonary tuberculosis. Cutaneous manifestations of disseminated disease include multiple skin lesions, ranging from papules and plaques to ulcers. Diagnosis is made via biopsy and culture. Treatment with a systemic antifungal agent including amphotericin B, fluconazole, itraconazole, posaconazole or voriconazole is warranted, although little clinical data regarding effective treatment of Emmonsia spp. exist [99]. Systemic antifungal agents Azoles

The triazoles are a fungistatic class of agents that inhibit the 14-a-demethylase enzyme, leading to an interruption of ergosterol synthesis in the fungal cell wall membrane. Agents within this class include fluconazole, itraconazole, posaconazole, voriconazole, isavuconazole and ravuconazole. Fluconazole, voriconazole and ravuconazole are structurally similar to each other, Expert Rev. Anti Infect. Ther.

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while posaconazole is structurally similar to itraconazole [100]. Each azole’s affinity for 14-a-demethylase varies, largely explaining the differing spectra of activity. The azoles inhibit several human CYP-dependent enzymes, which increase the risk of potential drug interactions with varying clinical effects. Drug interactions are often azole-specific and should be closely evaluated prior to drug initiation (detailed drug interactions can be found elsewhere). The triazoles have been associated with QTc prolongation and should be used cautiously with other QTc prolonging agents [101–103]. Fluconazole

Fluconazole is a commonly prescribed azole due to its excellent oral bioavailability, high skin tissue penetration, tolerability, relatively few drug interactions and side-effect profile [104]. It is often very well tolerated, with headache, alopecia and anorexia being the most commonly reported side effects [105]. Unlike other agents in the triazole class, fluconazole dosing needs to be adjusted for creatinine clearance. It is effective against many fungal skin and nail infections, including dermatophytes, pityriasis, most Candida spp. (with the exception of C. krusei and certain isolates of C. glabrata), Cryptococcus, several of the endemic mycoses and others. It is not active against species of Aspergillus, Fusarium or the agents of mucormycosis (TABLE 3). Itraconazole

Itraconazole has excellent skin and nail penetration, with detectable drug levels noted in the stratum corneum of some body areas for weeks after drug cessation [106]. Although an intravenous preparation was previously in use, it is currently available only as a capsule or liquid formulation. Itraconazole capsules are dependent upon an acidic environment for optimal absorption. Due to potentially unpredictable absorption, it is often useful to check drug levels. Concurrent administration of acid-lowering medications causes erratic drug absorption, and patients are recommended to take itraconazole with food or a cola beverage [107]. Like fluconazole, itraconazole is effective against dermatophytes, pityriasis and most Candida spp., however, it does have activity against Aspergillus spp. compared with fluconazole which does not. While generally well tolerated, itraconazole has been associated most commonly with nausea and vomiting, followed by elevated triglycerides, hypokalemia, transaminitis, skin rash, and, rarely, congestive heart failure due to negative inotropic activity [108,109]. Potential drug interactions need to be carefully assessed given the potential for inhibition of CYP3A4-dependent pathways with itraconazole. Posaconazole

Posaconazole is a lipophilic second-generation antifungal triazole with a broader spectrum of activity than itraconazole, despite a similar molecular structure. Posaconazole has activity against many of the Mucorales, as well as improved activity against Aspergillus spp. compared with itraconazole [110] (TABLE 3) and has demonstrated efficacy as prophylaxis and treatment for invasive fungal disease [111–114]. There are currently two informahealthcare.com

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formulations available: an oral suspension and a newly developed oral tablet. The absorption of the oral suspension can be challenging, but is maximized when given with fatty food, nutritional supplements or acidic beverages [115,116]. Acidlowering medications, such as H2 blockers or proton pump inhibitors, may decrease posaconazole serum levels [117]. Drug level monitoring can help ensure adequate drug delivery as peak serum concentrations show considerable variability between patients even when absorption parameters are optimized. In contrast to the oral suspension, the delayed-release oral tablet has the benefit of improved bioavailability, with adequate serum drug levels attained even when fasting, as well as predictable dose responses that allow for once-daily dosing [118,119]. Both formulations are generally very well tolerated, with gastrointestinal and hepatic side effects being the most commonly reported [114]. Posaconazole is an inhibitor of CYP3A4, although is not itself metabolized via the P450 system. Drug– drug interactions similar to those of other CYP3A4 inhibitors may occur. Voriconazole

Voriconazole is a second-generation triazole available in oral and intravenous formulations with a similar chemical structure to fluconazole. Voriconazole has a broad spectrum of activity against many moulds, with the exception of the Mucorales, and is the drug of choice for invasive aspergillosis [120,121] (TABLE 3). Non-linear metabolism is noted in adults, and the unpredictability of enzymatic activity during administration has sparked an interest in routine therapeutic drug monitoring [100]. Higher serum levels of voriconazole (>5.5 mg/l) have been associated with increased risk of CNS side effects, including visual hallucinations and encephalopathy. Other common side effects include photosensitivity, solar lentigines, increased risk of cutaneous malignancy over prolonged treatment periods, skin rash and elevated liver enzymes [122]. Voriconazole is a moderate inhibitor of CYP3A4, and a weak inhibitor of CYP2C19 and CYP2C9. These latter two isoenzymes exhibit genetic polymorphism causing wide variations in voriconazole pharmacokinetics in certain patient populations, and also the potential for a number of drug–drug interactions. Isavuconazole

Isavuconazole is a newer, triazole antifungal in development (undergoing Phase III trials as of this writing) available in both oral and intravenous formulations [123,124]. It is a broadspectrum agent, with activity against most Candida spp. (including fluconazole-resistant strains), Aspergillus spp. (including itraconazole-resistant strains) and dermatophytes [125]. In addition, it has promising activity against Fusarium, Cryptococcus and the Mucorales (TABLE 3) [123]. Pharmacologic studies indicate moderate deviation from linear kinetics, but much less than that observed with voriconazole, and fewer apparent drug interactions than itraconazole or voriconazole [124]. doi: 10.1586/14787210.2014.960849

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Amphotericin

Amphotericin B is a polyene antifungal (along with nystatin, available only as topical formulation) that binds directly to ergosterol within the fungal cell wall membrane, and disrupts cell wall permeability. The intravenous formulations concentrate adequately in skin and nail tissue and have a broad antifungal spectrum (with specific resistances noted to Aspergillus terreus and Candida lusitaniae, among others) (TABLE 3). Broadspectrum fungicidal properties, effectiveness in the setting of severe disease and years of clinical experience account for the drug’s continued use, despite significant toxicities and notable infusion-related reactions, including fever, chills, rigors, myalgias, bronchospasm, nausea and vomiting, tachycardia, tachypnea and hypertension [126]. While more costly, amphotericin lipid formulations have a much improved side-effect profile, most notably, a lower incidence of nephrotoxicity [127]. Terbinafine

Terbinafine is a synthetic allylamine developed by chemical modification of naftifine (a topical antifungal agent) [128]. Terbinafine inhibits fungal sterol biosynthesis by reversibly inhibiting squalene epoxidase. The subsequent ergosterol depletion from the fungal cell membrane is fungistatic, although the intracellular accumulation of squalene exerts a fungicidal effect in some species [129]. Available in oral and topical formulations, systemic therapy with terbinafine is widely distributed to poorly perfused body tissues including the nail, stratum corneum, hair and dermis-epidermis, making it an ideal drug for cutaneous fungal infections. In fact in a meta-analysis of oral agents used for the treatment of onychomycosis, terbinafine exhibited the highest cure rate (78 ± 6%) [31]. Its role in the treatment of systemic mycoses has largely been supplanted by newer agents, however, it still has a role in the treatment of sporotrichosis for patients failing itraconazole therapy [73]. Terbinafine is a potent CYP2D6 inhibitor and thus interacts with the metabolism of other drugs that are substrates for this enzyme including paroxetine, venlafaxine, codeine, metoprolol and others suggesting pharmacovigilance with all coadministration. Terbinafine is generally well tolerated, although abnormal liver enzymes, gastrointestinal complaints, skin rash and dysgeusia are seen in

Fungal infections of the skin and nail: new treatment options.

Knowledge of the currently available antifungal agents, along with clinical, microbiologic and histopathologic methods, can help the medical professio...
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