Topical and Systemic Antifungals in Dermatology Practice PDF

Expert Review of Clinical Pharmacology ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20 Topical and systemic antifungals in dermatology practice Murat Du...

Expert Review of Clinical Pharmacology ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20 Topical and systemic antifungals in dermatology practice Murat Durdu, Macit Ilkit, Yalda Tamadon, Ali Tolooe, Haleh Rafati & Seyedmojtaba Seyedmousavi To cite this article: Murat Durdu, Macit Ilkit, Yalda Tamadon, Ali Tolooe, Haleh Rafati & Seyedmojtaba Seyedmousavi (2016): Topical and systemic antifungals in dermatology practice, Expert Review of Clinical Pharmacology, DOI: 10.1080/17512433.2017.1263564 To link to this article: http://dx.doi.org/10.1080/17512433.2017.1263564 Accepted author version posted online: 19 Nov 2016. Submit your article to this journal Article views: 1 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierj20 Download by: [Athabasca University] Date: 22 November 2016, At: 19:39 Publisher: Taylor & Francis Journal: Expert Review of Clinical Pharmacology DOI: 10.1080/17512433.2017.1263564 Review Topical and systemic antifungals in dermatology practice Murat Durdu1, Macit Ilkit2, Yalda Tamadon3, Ali Tolooe3, Haleh Rafati4, and Seyedmojtaba Seyedmousavi 5, 6, #, * 1 Department of Dermatology, Faculty of Medicine, Başkent University Adana Hospital, Adana, Turkey 2 Division of Mycology, Department of Microbiology, Faculty of Medicine, University of Çukurova, Adana, Turkey 3 Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran 4 Department of Biochemistry, Erasmus University Medical Center, the Netherlands 5 Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands 6 Invasive Fungi Research Center, Mazandaran University of Medical Sciences, Sari, Iran *Correspondence: Seyedmojtaba Seyedmousavi # Present address: Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), BG 10 RM 11C106, 10 Center Dr., 9000 Rockville Pike, Bethesda, MD 20892, United States of America. Tel: (301) 402-5139. E-mail: [email protected] 1 ABSTRACT Introduction: Dermatophytosis is generally defined as an infection of the hair, nails, or glabrous skin. These infections are caused by the keratinophilic fungi Trichophyton spp., Microsporum spp., and Epidermophyton, which have been recovered from both symptomatic and asymptomatic individuals. Although dermatophytosis is generally not a life-threatening condition, these types of infections are among the most common infections worldwide, and their incidence has continued to increase consistently in recent years. Area covered: This article provides an overview of the general characteristics of dermatophytes, including their taxonomy and epidemiology, as well as the different clinical forms and laboratory diagnostics of dermatophytosis. We further classify the topical and systemic antifungal compounds currently used to treat dermatophyte infections. Expert Commentary: Antifungal therapy is a central component of patient management for dermatophytosis, and depending on the strategy chosen, topical and/or systemic drugs can be used. However, for effective treatment, it is important to correctly determine the causal agents at the species level, which will enable administration of suitable therapeutics and initiation of appropriate management strategies. KEY WORDS Antifungals, dermatophytosis, Epidermophyton, Microsporum spp. , tinea, Trichophyton spp. 2 1. Introduction Dermatophyte fungi first emerged following World War II, not only in Europe but also all over the world [1,2]. An aging population, close human-to-human or animal-to-human contact, sport and tourism activities, sharing of objects (socks, shoes, slippers, combs, pillows, etc.), communal living, or inhabiting an endemic region are all considered potential risk factors for dermatophytic infection [3,4]. The anthropophilic species Trichophyton rubrum is the most common dermatophytic fungus worldwide, and its eradication has thus far posed an intractable challenge to society [5,6]. Such dermatophyte fungi, particularly anthropophiles (T. rubrum, Trichophyton tonsurans, Trichophyton violaceum, Epidermophyton floccosum, and Microsporum audounii), may also cause epidemics owing to close contact between infected individuals and society. Although several dermatophyte species are endemic to certain countries (e.g., (i) Trichophyton concentricum is endemic in remote and humid tropical areas in the Southwest Pacific, Southeast Asia, Central and Soth America and (ii) Trichophyton megninii is endemic in Portugal, Corsica, and Sardinia) , human infection rates do not vary with respect to education status or ethnicity. Therefore, dermatophytes and dermatophytoses remain an important public health issue, and all strata of society should be educated as to how humans generally encounter these fungi and how to prevent infection. Of note, a variety of oral and topical antifungal agents are available for the treatment of superficial fungal infections caused by dermatophytes [10,11]. However, for effective treatment, it is important to correctly determine the causal agents at the species level, which will enable administration of suitable therapeutics and initiation of appropriate management strategies [5,6]. In this paper, we present a brief overview of our current understanding of the 3 classification of dermatophytosis based on clinical findings and patterns of dermatophytic infections, as well as contemporary methods of their management with conventional and novel antifungal compounds. 2. Taxonomy Dermatophytes are ascomycetes with septate hyphae, and are most closely related to the pathogenic fungus Coccidioides immitis within the order Onygenales, whose members share the morphological feature of septate hyphae [3,4]. Dermatophytes are categorized into three asexual genera (anamorph: Trichophyton, Epidermophyton and Microsporum, and an associated sexual state (teleomorphs), was previously classified in the genus Arthroderma [3,4]. There are at least 40 species of dermatophytes that are capable of infecting humans. Dermatophytes can also be classified into three distinct groups according to their ecological characteristics: (i) anthropophilic (human-specific), (ii) zoophilic (animal-specific), and (iii) geophilic (soil-specific). Notably, all of these groups are able to infect humans, although anthropophilic dermatophytes (e.g., T. rubrum) are associated with long-term chronic, but limited disease and tissue destruction. In contrast, zoophilic species (M. canis) can cause acute and severe disease in humans. The effects of the geophilic species (e.g., M. gypseum) are intermediate between those of acute geophiles and chronic anthropophiles [2,12]. 3. Epidemiology It is generally considered that dermatophytic infections are the most common types of human fungal infections worldwide. Tinea pedis, commonly known as Athlete’s foot, is 4 particularly common in the developed world , whereas tinea capitis is relatively more prevalent in developing countries. It is estimated that dermatophytoses are responsible for at least half a billion dollars in healthcare costs. Furthermore, the dermatophyte flora varies among countries or in among different regions within a country. Thus, the flora of dermatophytes present in a given area can change over time, indicating the importance of close and continuous monitoring within a region. 4. Clinical manifestations Dermatophytes are able to use keratin as a sole nutrient source [16,17]. They invade and grow on the hair, nails, and skin, but do not infect mucosal surfaces. The transmission of dermatophytoses may occur by direct contact with an infected host or by contact with contaminated objects and environments. Clinically, dermatophytic infections are designated as different forms of tinea (also known as “ringworm”) according to the body site involved: the scalp (tinea capitis), beard and moustache area (tinea barbae), face (tinea faciei), hand (tinea manuum), groin and skin folds (tinea cruris), other skin regions (tinea corporis), feet (tinea pedis), and nails (tinea unguium). In addition to these symptomatic infections, the carrier state or asymptomatic carriage of dermatophytes has been well-described in the literature, and these fungi have been widely recovered from a healthy appearing scalp, nails, and skin [19,20]. Dermatophytic infections can also lead to various complications, including immune dermal (id) reactions (see below), bacterial superinfection, Majocchi’s granulomas, tinea incognito, lymphangitis, and cellulitis, and can spread to other sites. Furthermore, 5 dermatophytic infections may induce a T-helper type 2 response that can aggravate atopic dermatitis, chronic rhinitis, and asthma [9,21]. 4.1. Tinea capitis Tinea capitis is one of the most common causes of pediatric dermatophyte infections of the scalp, with a propensity for attacking the hair shafts and follicles. Tinea capitis predominantly affects preadolescent children, accounting for up to 92.5% of all cases of dermatophytosis in children younger than 10 years, but is infrequent in infants aged under 1 year. The disease is rare in adults, although it is occasionally found in elderly patients. Because of its clinically atypical manifestations in adults, other inflammatory disorders are often initially considered in place of dermatophytosis, requiring anti-inflammatory topical corticosteroid therapy. Tinea capitis usually presents in six different clinical forms: (i) gray patch , (ii) moth-eaten, (iii) black-dot, (iv) diffuse scale, (v) pustular, (vi) kerion, and (vii) favus. Currently, the most prevalent causes of tinea capitis, a fungal infection of the scalp, are Trichophyton tonsurans (in North America, northern Europe, and Japan) [24,25] and Microsporum canis (worldwide) [26,27]. 4.2. Tinea corporis Tinea corporis is a dermatophyte infection of the skin of the trunk and extremities, except for the feet, palms, scalp, and groin (Figure 1C). These infections may be transmitted directly from humans (including T. rubrum, T. tonsurans, E. floccosum, T. concentricum, anthropophilic T. interdigitale), animals (M. canis, zoophilic T. interdigitale, T. mentagrophytes, and T. verrucosum), soil (M. gypseum), or via autoinoculation from reservoirs such as tinea pedis, tinea cruris, or tinea capitis. Overall, the anthropophilic 6 species T. rubrum, the zoophilic species M. canis and T. mentagrophytes, and the geophilic species M. gypseum are most frequently reported as the causal agents of tinea corporis. In patients with tinea capitis, infections may spread to the neck and upper trunk, whereas the buttocks and lower trunk are generally affected in patients with tinea cruris. Clinically, the classic presentation is single or multiple annular lesions with scales across the entire erythematous border. The lesions may be serpiginous or annular (ringworm-like), and can also be vesicular or pustular. Zoophilic or geophilic agents may cause follicular micropustules and show vellus hair involvement, which leads to resistance to topical antifungal treatment. Given that potassium hydroxide examination of the scales may be negative, vellus hair samples should also be taken for direct microscopic examination for an accurate differential diagnosis. If tinea corporis is misdiagnosed and mistakenly treated with topical corticosteroids, inflammatory dermal nodules or plaques with follicular orifices oozing with pus may develop. These inflammatory lesions are similar to a kerion of the scalp or beard (tinea incognito). In particular, for patients with tinea pedis or tinea unguium, tinea incognito can be ruled out as a potential diagnosis in cases with resistant eczema-like patches. In addition, in patients with tinea corporis caused by zoophilic organisms, kerion-like inflammatory plaques or nodules may develop. 4.3. Tinea imbricata Tinea imbricata is a chronic superficial mycosis caused by the anthropophilic dermatophyte T. concentricum. Tinea imbricata is characterized by widespread, annular, erythema gyratum repens-like multiple concentric, polycyclic, scaly lesions with minimal inflammation , and is endemic to three geographical areas: southwest Pacific, southeast Asia, and 7 Central and South America. Tinea imbricata in travelers returning from endemic areas is exceptionally rare. Tinea imbricate can be successfully treated with griseofulvin and terbinafine cream. Tinea imbricata-like concentric scaly rings may also develop due to T. interdigitale and T. tonsurans infections. The latter form is very rare and is known as tinea indecisiva. 4.4. Tinea faciei Tinea faciei is a dermatophytic infection limited to the face, except for the moustache and beard areas of the adult male. Accordingly, some authors have also referred to tinea faciei as “tinea corporis located on the face and hand”. Tinea faciei may develop directly from an external source (e.g., due to infections of the T. mentagrophytes species complex via an infected pet mouse), or autoinoculation from reservoirs such as tinea pedis, tinea cruris, or tinea capitis (T. rubrum and T. concentricum). In close-contact sports such as wrestling, T. tonsurans has been reported to cause outbreaks of tinea faciei due to (i) human-to-human contact, (ii) auto-inoculation from an anatomical site, or (iii) from the mat. The clinical features of tinea faciei vary considerably. However, it is generally characterized by annular or circinate erythematous, centrifugally growing, discretely scaly patches or plaques. Simple papular lesions and erythematous patches of a few vesicles or pustules may also be found. The most common complaints of patients are itching, burning, and exacerbation after sun exposure. Dermatophytes can cause red face syndrome (Figure 1B). For this reason, tinea faciei may be confused with other causes of red face syndrome such as lupus erythematosus, psoriasis, rosacea, seborrheic dermatitis, and polymorphic light eruption. 8 4.5. Tinea manuum Tinea manuum is a dermatophyte infection of the hand. Although any species of dermatophyte may infect the skin of the hand, this is nonetheless a rare infection site for these fungi. The most common pathogen causing tinea manuum is T. rubrum. Unlike eczema and psoriasis, tinea manuum shows unilateral involvement in about half of all cases. However, unilateral tinea manuum may be accompanied by bilateral tinea pedis (see below). T. rubrum is usually the causal pathogen of this two-feet/one-hand syndrome, but occasionally T. interdigitale is involved. It is usually spread from lesions of tinea pedis or onychomycosis as a result of scratching. Possible predisposing factors are manual work, hyperhydrosis, existing inflammatory conditions, poor peripheral circulation, palmar keratoderma, and frequent use of alkaline soaps [37,38]. Clinically, dermatophyte infections of the dorsal surface of the hand are similar to tinea corporis. Infection of the palmar skin may exhibit different clinical manifestations such as palmar hyperkeratosis, exfoliating, vesicular and erythematous patches, and follicular scaly papules. Palmar hyperkeratotic plaques is the most common form, and is unilateral in about half of all cases. Involvement of the flexural creases is a characteristic sign. Other clinical variants include crescentic exfoliating scales, circumscribed vesicular patches, and discrete red, papular, and follicular scaly patches. Vesicles may show an annular, segmental, or dyshidrosiform pattern. Furthermore, palmar bullous lesions have also been reported in patients with tinea manuum due to zoophilic T. verrucosum and T. rubrum infection. Tinea manuum can also mimic cellulitis and lymphangitis. If it is untreated, it spreads to the dorsal surface of the hand, and annular erythematous patches or plaques with scales may be seen. 9 4.6. Tinea cruris Tinea cruris, also called as tinea inguinalis, is a superficial fungal infection of the groin and adjacent skin (Figure 1D). Although T. rubrum is a common causal pathogen, anthropophilic T. interdigitale and E. floccosum and rarely zoophilic Microsporum canis have been isolated from patients with tinea cruris. Zoophilic dermatophytes, especially T. mentagrophytes and T. verrucosum, have also been reported in these cases. Possible predisposing factors are having recently visited a tropical climate, wearing tight-fitting clothes, sharing clothing with others, sport activity, diabetes mellitus, and obesity. Men are more frequently affected than women, and tinea cruris usually develops between 18 and 60 years of age. However, children and babies may also be affected. It is usually spread from tinea pedis or onychomycosis. In addition, dermatophytes can infect the skin via contaminated objects and from the floors of bathrooms, showers, saunas, gymnasiums, or hotel bedrooms. In the early stages, lesions begin as erythematous plaques with sharp margins on the inside of the proximal thigh, and then the lesions move from the groin down to the thighs. In men, the left side is more frequently affected since the skin on this side is usually in more intimate contact with the scrotum. When left untreated, the lesions may spread from the thigh to the scrotum, penis, gluteal folds, and mons pubis. Furthermore, tinea cruris may also spread to other folds, especially to the axillae, inframammary folds, and umbilicus. The inframammary folds and axillae may be the primary region of infection. The severity of scaling observed is variable. If scaling is severe, it may mask the erythematous reaction. If inflammation is severe, it can mimic other inflammatory diseases such as eczema, psoriasis, seborrheic dermatitis, invers psoriasis, Hailey-Hailey diseases, and intertrigo. For this reason, tinea cruris is often incorrectly treated with topical 10 corticosteroid therapy, which leads to incognita. Vesicles and bullae are very rare. Cases of tinea cruris due to T. rubrum are often associated with tinea pedis and generally manifest as chronic lesions. Dermal nodules are commonly found in these lesions, and extension of the infection from the groin to the lower back and the abdomen is common. When carefully examined, a few pustules may be determined. Satellite lesions may also be seen, which are sometimes fused with the primary lesion. The most important subjective symptom is mild or severe itching. Scratching may lead to lichenification and autoinoculation of new sites either near or distant from the primary lesions. The inflammatory lesions can cause difficulty in walking because of itching and burning. Secondary bacterial infections may develop in areas affected by tinea cruris, sometimes causing painful lymphadenopathy [18,34]. 4.7. Tinea pedis Tinea pedis is a common fungal infection of the foot and often serves as a reservoir for dermatophyte infections of other anatomical sites [41,42]. Its incidence is higher in hot and humid climates, and is associated with sporting activities and hyperhidrosis. Tinea pedis usually presents in four different clinical forms: (i) interdigital, (ii) inflammatory (vesiculobullous), (iii) chronic hyperkeratotic (moccasin), and (iv) ulcerative tinea pedis. In addition to these clinical forms, verrucous and pustular forms have also been reported [44,45]. Asymptomatic infections (occult tinea pedis) are also common, with a prevalence of 36–88%, particularly among athletes. T. interdigitale causes the majority of the occult cases of tinea pedis [46-48], and damp foot conditions may lead to aggravated symptoms due to co-infections with bacteria. 11 4.8. Tinea unguium Dermatophytic onychomycosis, also known as tinea unguium, refers to a fungal infection of the fingernails and toenails, which is the most common nail disease in adults. It develops due to dermatophytes, yeasts, or molds, or a combination of two (or more) fungi from all three groups. Tinea unguium represents an onychomycosis that is specifically caused by dermatophytes, and is the most common form, with the majority of cases caused by T. rubrum (70%) and anthropophilic T. interdigitale (20%). The toenails tend to be affected more than the fingernails because of their slower growth, reduced blood supply, and frequent confinement in dark, moist environments. Predisposing factors are distorted nails, a history of trauma, genetic predisposition, hyperhidrosis, and psoriasis. Onychomycosis usually presents in seven different clinical forms described below. 4.8.1. Distal lateral subungual onychomycosis (DLSO) Fungal nail infections begin at the lateral or distal undersurface of the nail plate and then spread to the nail plate and bed. The main clinical features are distal and lateral subungual hyperkeratosis, onycholysis, and discoloration. Onycholysis is occasionally the only clinical symptoms. Discoloration is usually white or yellowish, but brown to black longitudinal melanonychia is more common in tinea unguium caused by dermatophytes such as the nongranular pigment-producing species T. rubrum var. nigricans. When untreated, infection can progress proximally, causing linear channels or “spikes”. 4.8.2. Proximal subungual onychomycosis (PSO) In PSO, the pathogens are spread from the proximal nail folds. PSO is quite rare and occurs more frequently in immunosuppressed patients, especially those with HIV/AIDS. 4.8.3. Superficial onychomycosis 12 This form may present as a range of dyschromias, and is mostly caused by T. rubrum, followed by T. interdigitale. According to the pathogen involved, the discoloration may be white, black, or brown [52,53]. 4.8.4. Endonyx onychomycosis In this variant of onychomycosis, the nails show white discoloration. Characteristically, there is no inflammation of the nail bed or subungual hyerkeratosis. This form of onychomycosis is usually caused by T. soudanense. However, other organisms such as T. violaceum have also been isolated in these cases. 4.8.5. Mixed-pattern onychomycosis Combinations of two or more patterns of onychomycosis may be found. The most common combinations are PSO and SO or DLSO and SO. 4.8.6. Total dystrophic onychomycosis In total dystrophic onychomycosis, the dermatophytes cause prominent acanthosis and hyperkeratosis in the nail bed epithelium. Clinically, it is observed as subungual hyperkeratosis. The most characteristic sign of this onychomycosis is yellow streaks medially or laterally that frequently reach the nail matrix (Figure 1F). 4.8.7. Secondary onychomycosis Tinea unguium may develop in a nail affected with another nail condition such as traumatic nail dystrophy or psoriasis. Appearance of the nail varies depending on the type of primary disease. 4.9. Majocchi’s granuloma Long-standing tinea corporis can progressively disseminate into the subcutaneous tissues and cause a perifollicular granulomatous reaction called Majocchi’s granuloma, which is due 13 to a complication of the long-term use of potent topical corticosteroids or chemotherapeutic agents, or systemic immunosuppression [57,58]. Clinically, Majocchi’s granuloma is characterized by inflammatory nodular, papular, or pustular lesions that generally develop on the limbs. The discrete or grouped papules and nodules can typically be found on the more active borders of the erythematous plaques or alone; additionally, in some rare cases, they can be keloidal or verrucous in nature. Unlike kerions, Majocchi’s granuloma lesions do not suppurate until late in their course, unless secondary impetigo occurs. Pustules and crust are observed on the erythematous plaques. Red-purple, or occasionally brown, papular and nodular lesions may resolve spontaneously without cutaneous scarring; however, lesions may result in eventual atrophic and hypertrophic scar formation [57-59]. Features of cellulitis such as indurated plaques without papules, nodules, or pustules have been observed in 5.4% of all cases. Although subjective complaints are usually not reported, pruritus (10.9%) and slight tenderness following the application of pressure (9.5%) have been observed. Vulvar swelling was reported in one case. Majocchi’s granuloma may have a variable clinical presentation such as abscess formation, especially if occurring in an immunodeficient host [61,62]. Inflammatory subcutaneous masses with grains (mycetoma) have also been reported, although very rarely. 4.10. Id reaction An id reaction refers to a distant skin reaction caused by circulating antibodies or activated T lymphocytes directed against microbial antigens [63,64], which may complicate allergies and asthma and contribute to refractory atopic disease. As a rule, diagnosis of an id reaction relies on negative testing for fungal pathogens in direct smears or histopathologic preparations, and secondary reactions should resolve spontaneously after treatment of the 14 primary dermatophyte infection. Patients with an id reaction tend to show a positive skin reaction to Trichophyton or Epidermophyton. The incidences of dermatophyte id reactions (dermatophytid) with tinea capitis, tinea corporis, and tinea pedis have been reported to be 0.2%, 5%, and 17%, respectively [67,68]. The incidence of id reactions is generally similar in adults and children (4.6% and 4.2%, respectively), and varies according to the fungal pathogen species involved. The frequencies of dermatophytid due to members of the T. mentagrophytes complex, T. rubrum, and E. floccosum have been determined to be 34.6%, 5.5%, and 16.7% of cases with dermatophyte infections, respectively. Id reactions have been reported in different forms such as vesicular, morbilliform, and scarlatiniform, and present as a lichenoid rash, urticaria, anaphylaxis, erythema multiforme, erythema nodosum, and erythema annulare centrifugum. Rarely, systemic symptoms such as high fever, anorexia, generalized lymphadenopathy, splenomegaly, and hematologic alterations (leukocytosis and lymphocytosis) may develop. 5. Laboratory diagnosis The information reviewed above clearly demonstrates the wide variety of the clinical manifestations of dermatophyte infections. In addition, misdiagnosis is possible with only a clinical examination, given that these manifestations can mimic those of various other infectious or inflammatory diseases. For this reason, a fungal culture, microscopic examination of skin scrapings, or culture-independent molecular techniques should be conducted to obtain a definitive diagnosis of dermatophytic infections [71,72]. Conditions of sampling, transporting, storage, and handling of specimens are very important for obtaining a correct diagnosis. 15 6. Treatment of dermatophyte infections In general, the most important considerations in the treatment of dermatophyte infections, including asymptomatic dermatophyte infections such as tinea pedis or onychomycosis, are to eliminate any aggravating factors; improve hygiene of the skin, hair, and nails; and avoid prolonged humid environments. Specifically, patients with tinea corporis and tinea capitis should be closely examined for possible infections or as carriers of an animal source such as those found on pets, in order to ensure that the optimal therapeutic measures are taken. Importantly, topical and systemic antifungal therapy remains a central component of patient management for dermatophytosis. 6.1. Systemic antifungals Systemic antifungal agents can be grouped into four classes based on their site of action in pathogenic fungi, and include the polyenes, azoles, echinocandins, and nucleoside analogs. 6.1.1. Polyenes Polyenes constitute the oldest class of systemic antifungal drugs. More than 200 polyene macrolides have antifungal activity, and most are produced by the soil actinomycete Streptomyces. Polyenes bind to ergosterol, the main component of fungal membrane sterols, and form large pores that disrupt cell function [75,76]. This interaction results in the formation of transmembrane pores that disrupt cell permeability, resulting in rapid cellular damage or death. The polyenes currently available for the treatment of systemic fungal infections are amphotericin B and nystatin. 6.1.2. Azoles Azoles are cyclic organic molecules characterized by a core 5-member azole ring, which can be divided into two groups based on the number of nitrogen atoms on the azole ring: the 16 imidazoles and triazoles with two and three nitrogen atoms within the azole ring, respectively. The azoles inhibit the synthesis of ergosterol from lanosterol in the fungal cell membrane by the binding of the free nitrogen atom of the azole ring to the iron atom of the heme group of a fungal enzyme [79,80]. Their target enzyme is the cytochrome P450 (CYP)-dependent 14-α-demethylase (CYP51 or Erg11p), which catalyzes the targeted synthetic reaction. The inhibition depletes ergosterol, and methylated sterols accumulate in the cell membrane and either inhibit the growth or induce the death of fungal cells, depending on the species and antifungal compound involved. Overall, the azoles are the most widely used class of antifungal drugs. One imidazole (ketoconazole) , and five triazole compounds (fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) have been clinically approved and are currently widely used for the prevention and treatment of several life-threatening fungal diseases [82,83]. The triazoles have different affinities for the CYP-dependent 14-a- demethylase, which in turn results in variability of the susceptibilities to fungal infection, side effects, and drug–drug interactions. 6.1.3. Echinocandins The echinocandins are the only class of antifungal agents that directly target the fungal cell wall [85,86]. They are semi-synthetic amphiphilic lipopeptides formed during the fermentation of some fungi such as Zalerion arboricola or Aspergillus nidulans var. echinulatus. The echinocandins inhibit β-1,3-D-glucan synthase, which catalyzes the biosynthesis of glucan, a key component of the fungal cell wall. Of note, mammalian cells do not contain this polysaccharide target (1, 3-β-D-glucan), and therefore direct human cell toxicity is minimal. The echinocandins that are currently approved for clinical use include caspofungin, micafungin, and anidulafungin. 17 6.1.4. Nucleoside analogs Flucytosine (5-fluorocytosine or 5-FC) is the only systemic antifungal agent belonging to the class of nucleoside analogs. It was the first agent used for the treatment of invasive mycoses in 1968. Flucytosine is the fluorinated analog of cytosine and was discovered in 1957 as an analog of the cytostatic chemotherapeutic agent 5-fluorouracil (5-FU), which is used for antitumor therapy. After it penetrates the cell wall, which is controlled by the enzyme cytosine permease, 5-FC is converted to 5-FU by the enzyme cytosine deaminase and then is further converted to 5-fluorouridine. After three phosphorylation steps, it is incorporated into RNA instead of uracil, which results in the blockade of protein synthesis. This pathway leads to reduced DNA synthesis because of a reduction in the available nucleotide pool. 6.2. Recommended systemic antifungals for treating dermatophytosis Systemic antifungal agents currently recommended for the treatment of dermatophytosis are classified in Table 1. 6.2.1. Griseofulvin Griseofulvin is a metabolite of Penicillium griseofulvum and Penicillium janczewski that inhibits cell wall synthesis. It binds to tubulin and disrupts both the alpha and beta subunits by inducing conformational changes via impaired processing of newly synthesized cell wall constituents at the growing tips of hyphae. Griseofulvin mainly concentrates in keratinocytes; therefore, it is only used for noninvasive dermatophyte infections. Overall, all of the dermatophytes (Microsporum spp., Trichophyton spp., and Epidermophyton) are susceptible to griseofulvin. Since the late 1950s, griseofulvin has been the gold standard for the systemic therapy of tinea capitis. However, the advent of 18 newer antifungals that exhibit more favorable pharmacokinetic and toxicity profiles has largely relegated griseofulvin to a second-line agent against dermatophytoses. The main disadvantage of griseofulvin is the long duration of treatment required (6–12 weeks or longer), which may lead to reduced compliance. Another challenge is the high expense of griseofulvin because of the large quantity of drug required for a cure. Moreover, the efficacy of griseofulvin has decreased in recent years owing to the decreased susceptibility of the infective fungi due to changes in epidemiology and genetic mutations , and now requires larger doses and longer treatment durations. 6.2.2. Terbinafine Terbinafine is an allylamine antifungal agent that has largely replaced the use of griseofulvin for the treatment of dermatophytic infections and onychomycosis. Its antifungal activity is mediated via the noncompetitive inhibition of squalene epoxidase (SE), an enzyme that acts on its substrate squalene, an early intermediate in the fungal ergosterol biosynthesis pathway [100,101]. Notably, terbinafine inhibits the enzymatic activity of fungal SE at a very low concentration (noncompetitive inhibition) than that required to inhibit the mammalian counterpart (4000-fold higher concentration needed; competitive inhibition). This drug is well absorbed from the gastrointestinal tract and then rapidly diffuses from the bloodstream into several skin tissue compartments, including the dermis and epidermis. In addition, terbinafine can remain in the stratum corneum and nails for several months after stopping the medication, even after very short-term therapy. Moreover, terbinafine is highly lipophilic, and is highly (>99%) plasma protein-bound in humans, which impairs its distribution to the brain and cerebrospinal fluid, and leads to its high concentration in the hair follicles, skin, nail plate, and adipose tissue. 19  Several studies have reported the excellent activity of terbinafine against dermatophytes in vitro, including infections of T. rubrum, T. mentagrophytes, and E. floccosum, and ringworm infections, including tinea pedis, tinea cruris, tinea corporis, and tinea unguinum. Terbinafine has been widely reported to elicit a strong clinical response against Trichophyton species, with the cure rate reaching >80% [104,105]. Terbinafine has demonstrated a good toxicity profile at the recommended dosage. Most of the reported side effects are generally limited to gastrointestinal upset and, rarely, hepatotoxicity [106,107]. 6.2.3. Fluconazole Fluconazole is a first-generation triazole drug that exhibits antifungal activity against most of the common clinical isolates of Candida and Cryptococcus spp. and the endemic molds Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis. However, fluconazole lacks efficacy against molds such as Aspergillus spp.. It is a water-soluble compound with 10% protein binding, which distributes well throughout the body, leading to better efficacy in vivo. Fluconazole has been recommended for treating tinea capitis. Previous studies have shown that high doses of fluconazole (≥4–8 mg/kg per week) applied for long durations (12–16 weeks) are required regardless of the fungus type. 6.2.4. Itraconazole Itraconazole is another first-generation drug that is structurally similar to ketoconazole. It is a high-molecular-weight, highly hydrophobic, highly protein-bound (>99%), and water- insoluble compound, which exhibits a broader range of antifungal activity than fluconazole. Itraconazole remains the preferred azole for use in human patients to treat non-life- threatening systemic mycoses that do not involve the central nervous system. 20 Itraconazole is effective against both Microsporum and Trichophyton species and offers an alternative to griseofulvin for the treatment of kerion and non-inflammatory tinea capitis. 6.2.5. Other systemic antifungals as effective treatment alternatives To date, no clinical study has been conducted using polyenes, posaconazole, voriconazole, isavuconazole, and/or echinocandins for the treatment of tinea infections. However, several in vitro studies reported the susceptibility profiles of clinical dermatophytes isolated from tinea infections over a wide geographical range to newer antifungals. Overall, for all tested strains, posaconazole, terbinafine, voriconazole, amphotericin B, itraconazole, and caspofungin showed low minimum inhibitory concentrations, whereas flucytosine did not exert notable inhibitory effects [104,105,111-116]. 6.3. Topical antifungals A wide variety of topical agents belonging to different classes of antifungals are available as creams, ointments, gels, lotions, powders, shampoos, and other formulations. Table 2 provides a list of the currently available topical antimycotic substances used in routine clinical practice that are highly effective against dermatophytes. Of note, topical antifungal compounds alone can reduce the transmission of spores. Topical antifungals can be applied to the skin, nails, or mucous membranes, or can be applied vaginally to kill or inactivate fungi. Regardless of the actual mechanism of action of the drug, or the viscosity, hydrophobicity, and acidity of the formulation, the drug's ability to penetrate or permeate deeper skin layers is an important property impacting the therapeutic efficacy of topical antifungals [117-119]. 21  Topical terbinafine and butenafine creams are usually effective for the treatment of tinea glabrosa within 2 weeks. In cases of tinea cruris, topical tolnaftate, terbinafine, and the imidazoles for 2–4 weeks is recommended. In the topical treatment of tinea pedis, imidazoles (e.g., bifonazole, clotrimazole, econazole, miconazole, and sertaconazole), ciclopirox olamine (hydroxypyridone), allylamine (terbinafine), amorolfine (morpholine), and tolnaftate (thiocarbamate) may be used. Topical antifungals are usually applied twice daily for 4 weeks. However, bifonazole and terbinafine may be used once a day. Butenafine may be used once daily for 4 weeks or twice daily for 1 week. In addition, luliconazole (1% cream) showed clinical improvement even when used only once daily for 1 week. In onychomycosis, topical antifungal agents such as 28% tioconazole, 8% ciclopyroxolamine, efinaconazole, 5% tavaborole solution, and amorolfine nail paint should be limited for the treatment of superficial onychomycosis (except in transverse or striate infections) cases involving less than 80% of the distal nail plate or when systemic antifungals are contraindicated. 7. Conclusion Overall, the treatment of dermatophyte infections is based on the clinical picture and mycological identification of the etiologic agent down to species level. Depending on the strategy chosen, topical and/or systemic drugs can be used. The newer antifungal drugs such as terbinafine and novel triazoles such as posaconazole and voriconazole have the main advantage of a shorter treatment duration than required with fluconazole, itraconazole, and griseofulvin, and may remain present in fungicidal concentrations for several weeks after the course of treatment has been completed. These characteristics allow for a short treatment 22 duration and prevention of re-infection, thus popularizing their use in the treatment of dermatophytosis in clinical practice. 8. Expert commentary Dermatophytosis is not a life-threatening infection; however, it is one of the most common dermatophytic infections in the world. Of note, the incidence of dermatophytosis has continued to increase continuously in recent years. Antifungal therapy is a central component of patient management for dermatophytosis. However, for effective treatment, it is important to correctly determine the causal agents at the species level to prescribe suitable therapeutics and initiate appropriate management strategies. 9. Five-year view Several in vitro and in vivo studies suggest that the newer generation of antifungals, including voriconazole, posaconazole, and echinocandins, might be considered as effective alternatives to the currently recommended antifungals for the treatment of dermatophytoses. In addition, efforts are underway to develop newer antifungals for the treatment of dermatophytosis, including: Luliconazole (33525), VT-1161, LAS41003, and ME- 1111. 10. Key issues Dermatophytes are keratinophilic fungi, classified into three genera: Trichophyton, Epidermophyton, and Microsporum. There are at least 40 species of dermatophytes that are capable of infecting humans. Dermatophytic infections are considered the most common types of human fungal infections worldwide. 23  The transmission of dermatophytoses may occur by direct contact with an infected host or by contact with contaminated objects and the environment. Dermatophytic infections are designated as different forms of tinea (also known as “ringworm”) according to the body site involved: the scalp (tinea capitis), beard and moustache area (tinea barbae), face (tinea faciei), hand (tinea manuum), groin and skin folds (tinea cruris), other skin regions (tinea corporis), feet (tinea pedis), and nails (tinea unguium). Treatment of dermatophyte infections relies on the clinical picture and mycological identification of the etiologic agent down to the species level. Topical and systemic antifungal therapy remains a central component of patient management for dermatophytosis. Griseofulvin, terbinafine, fluconazole, and itraconazole are currently recommended systemic antifungal agents for the treatment of dermatophytosis. A wide variety of topical antifungal agents belonging to different classes of antifungals are available for the treatment of dermatophytosis in the form of creams, ointments, gels, lotions, powders, shampoos, and other formulations. Funding This paper was not funded. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. 24 References *-Papers of interest 1. Borman AM, Campbell CK, Fraser M, Johnson EM. 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Evaluation of microdilution and disk diffusion methods for antifungal susceptibility testing of dermatophytes. Med Mycol, 45(7), 595-602 (2007). 115. Ghannoum M, Isham N, Sheehan D. Voriconazole susceptibilities of dermatophyte isolates obtained from a worldwide tinea capitis clinical trial. Journal of clinical microbiology, 44(7), 2579-2580 (2006).* This paper reports the susceptibility profile of terbinafine against dermatophyte isolates obtained from patients with tinea capitis worldwide. 116. Bao YQ, Wan Z, Li RY. In vitro antifungal activity of micafungin and caspofungin against dermatophytes isolated from China. Mycopathologia, 175(1-2), 141-145 (2013). 117. Gupta AK, Cooper EA. Update in antifungal therapy of dermatophytosis. Mycopathologia, 166(5-6), 353-367 (2008). 118. Sugiura K, Sugimoto N, Hosaka S et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrobial agents and chemotherapy, 58(7), 3837-3842 (2014). 119. Trommer H, Neubert RH. Overcoming the stratum corneum: the modulation of skin penetration. A review. Skin pharmacology and physiology, 19(2), 106-121 (2006). 120. van Zuuren EJ, Fedorowicz Z, El-Gohary M. Evidence-based topical treatments for tinea cruris and tinea corporis: a summary of a Cochrane systematic review. The British journal of dermatology, 172(3), 616-641 (2015). 121. Gupta AK. Butenafine: an update of its use in superficial mycoses. Skin therapy letter, 7(7), 1-2, 5 (2002). 122. Khanna D, Bharti S. Luliconazole for the treatment of fungal infections: an evidence- based review. Core evidence, 9, 113-124 (2014). 33 Figure 1. Clinical manifestations of dermatophyte infections. A. Erythematous nodule with suppurative discharge and loss of hair due to kerion Celsi B. Red face syndrome due to tinea faciei C. Multiple annular plaques with scales across the entire erythematous border on the back due to tinea corporis D. Erythematous scaly plaques due to tinea cruris E. Erythematous scaly plaque on the back of the foot in a patient with tinea incognito F. Yellow longitudinal streaks on multiple nails due to total dystrophic onychomycosis 34 Figure 2. Microscopic examinations of dermatophytic infections. A. KOH preparation of a toenail scraping showing several septate hyphae (arrows) (×1,000 magnification) B. Closer view of the septate hyphae (arrow) (× 1,000 magnification) C. Calcofluor stain showing positive fluorescent staining of hyphae (arrows) (× 1,000 magnification) D. May-Grünwald Giemsa stain from tzanck smear of bullous tinea pedis showing hypae (arrows) (× 1,000 magnification) 35  Table 1. Recommended indications of systemic antifungal drugs against dermatophyte infections Year Route of Class of antifungals Name approved by Brand name Dosage formulation Indication Recommended Dose administration the US FDA IV formulation (50-mg vial), Amphotericin B 1957 Fungizone IV, PO - - suspension (100-mg) Amphotericin B-lipid ABLC, Polyens 1995 IV IV formulation (100-mg vial) - - complex Abelcet ABCD, Amphotericin B 1996 Amphocil, IV IV formulation (50-mg vial) - - colloidal dispersion Amphotec Liposomal 1997 AmBisome IV IV formulation (50-mg vial) - - amphotericin B Nystatin 1976 Fungicidin PO Suspension, 100,000 units/ml - - Ketoconazole 1981 Nizoral PO Tablet, 200 mg - - Children: 3-5 mg/kg/day for 4-8 weeks Tinea capitis Suspension, 350- or 1400-mg; Diflucan Adults: 50 mg/day for 4-7 weeks Fluconazole 1990 PO tablet, 50-, 100-, 150-, or 200- or 150 mg/week for 4-8 weeks mg 150-450 mg/week for 3-6 months Onychomycosis for fingernails or 6-12 months for toenails Children: 3-5 mg/kg/day for 4 weeks Tinea capitis Adults: 100-200 mg/day for 4 Azoles weeks Interval therapy: 200 mg/day fr Capsule, 100 mg; Solution, 10 one week, followed by an interval Itraconazole 1992 Sporanox PO, IV mg/ml; injection ampule, of three weeks for 3 to 4 moths. 10mg/ml Continuous therapy: 100 mg Onychomycosis twice daily for 3 months. Note for treatment duration:: shorter treatment is recommended if only 1 fingernail is affected. 36  Tablet 50 and 200 mg; Voriconazole 2002 Vfend PO, IV Suspension, 200 mg/5 ml; - - Injection, 200 mg/vial Suspension 40mg/ml, Tablet delayed release 100mg, Posaconazole 2006 Noxafil PO, IV - - Injection 300mg/16.7 ml (18mg/ml) Capsule 186 mg, Injection Isavuconazole 2015 Cresemba PO, IV - - 372mg Lyophilized powder for Caspofungin 2001 Cancidas IV injection (50- and 70- - - mg/vials) Eraxis (in U.S. Lyophilized powder for Echinocandins and Russia), Anidulafungin 2006 IV injection (50- and 100- - - Ecalta (in mg/vials) Europe) Lyophilized powder for Micafungin 2005 Mycamine IV - - injection (50 and 100 mg/vials) Nucleoside analogs Flucytosine 1971 ANCOBON Oral Capsule, 250- or 500- mg - - Children weighing 35-60 pounds - 125 mg to 187.5 mg daily. Pediatric patients weighing over 60 pounds - 187.5 mg to 375 mg daily. Tinea capitis, Children and infants 2 years of age and younger - dosage has not GRIFULVIN V, tinea corporis, been established. GRIS-PEG, Suspension 125 mg/5ml, tinea pedis, Antimetabolite Griseofulvin 1971 Oral Adults: Daily administration of GRISACTIN, Tablet 250 or 500 mg tinea cruris, 375-750 mg (as a single dose or in ULTRAGRIS tinea barbae, divided doses). and tinea unguium (onychomycosis) Note for treatment duration: Tinea capitis, 4 to 6 weeks; tinea corporis, 2 to 4 weeks; tinea pedis, 4 to 8 weeks; tinea unguium-depending on rate of growth-fingernails, at least 4 months; toenails, at least 6 37  months. Children < 25 kg: 125 mg/day for Tinea capitis 4-6 weeks Adults: 250 mg/day for 4-6 weeks One 250 mg tablet, once daily for Allylamines Terbinafine 1992 Lamisil Oral Tablet 250 mg Fingernail onychomycosis 6 weeks One 250 mg tablet, once daily for Toenail onychomycosis 12 weeks IV, intravenous; US FDA; US Food and Drug Administration; ABLC, AmB-lipid complex; ABCD, AmB colloidal dispersion. 38 Table 2. Topical antifungal drugs currently used in clinical practice Class of antifungals Name Amphotericin B Polyens Nystatin Natamycin Ketoconazole Clotrimazole Miconazole Sertaconazole Tioconazole Bifonazole Fenticonazole Isoconazole Efinaconazole Luliconazole Azoles Bifonazole Butoconazole Croconazole Eberconazole Econazole Flutrimazole Enilconazole Lanoconazole Neticonazole Oxiconazole 39  Tioconazole Terbinafine Allylamines Naftifine Butenafine Morpholine derivatives Amorolphine HCL Piridone derivatives Ciclopirox olamine Thiocarbamate Tolnaftate Oxaborole Tavaborole Thiocarbamate Tolnaftate 40