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.

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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, Bakent University Adana Hospital,

Adana, Turkey
2
Division of Mycology, Department of Microbiology, Faculty of Medicine, University of

ukurova, 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: Seyedmousavi@nih.gov

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

[7]. 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) [8], 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 [9].

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 Athletes foot, is

4
particularly common in the developed world [9], whereas tinea capitis is relatively more

prevalent in developing countries [13]. It is estimated that dermatophytoses are responsible

for at least half a billion dollars in healthcare costs [14]. Furthermore, the dermatophyte

flora varies among countries or in among different regions within a country [15]. 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 [7].

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 [12]. 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) [18]. 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, Majocchis 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 [22]. The disease is rare in adults, although it is occasionally found in elderly patients

[23]. 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 [18]. 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 [18]. 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 [28].

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 [21].

4.3. Tinea imbricata

Tinea imbricata is a chronic superficial mycosis caused by the anthropophilic dermatophyte

T. concentricum [29]. Tinea imbricata is characterized by widespread, annular, erythema

gyratum repens-like multiple concentric, polycyclic, scaly lesions with minimal inflammation

[30], 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 [31]. Tinea imbricata-like concentric scaly rings may also develop due to T.

interdigitale and T. tonsurans infections [32]. The latter form is very rare and is known as

tinea indecisiva [33].

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 [34]. 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

[35].

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 [34]. It is usually spread from lesions of tinea pedis or

onychomycosis as a result of scratching [36]. 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 [18].

Furthermore, palmar bullous lesions have also been reported in patients with tinea manuum

due to zoophilic T. verrucosum and T. rubrum infection [37]. Tinea manuum can also mimic

cellulitis and lymphangitis [39]. If it is untreated, it spreads to the dorsal surface of the hand,

and annular erythematous patches or plaques with scales may be seen [34].

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 [34]. 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 [40]. 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 [18].

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 [34]. For this reason, tinea cruris is often incorrectly treated with topical

10
corticosteroid therapy, which leads to incognita [21]. 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 [43]. 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 3688%, 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 [49].

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%) [50]. 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 [51]. 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 [52]. 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 [53].

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 [54].

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 [55].

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 [56].

4.8.6. Total dystrophic onychomycosis

In total dystrophic onychomycosis, the dermatophytes cause prominent acanthosis and

hyperkeratosis in the nail bed epithelium [53]. 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) [18].

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 [53].

4.9. Majocchis granuloma

Long-standing tinea corporis can progressively disseminate into the subcutaneous tissues

and cause a perifollicular granulomatous reaction called Majocchis 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, Majocchis 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, Majocchis 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 [60]. Majocchis 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 [63].

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 [65]. 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 [66].

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 [68].

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 [69]. Rarely, systemic

symptoms such as high fever, anorexia, generalized lymphadenopathy, splenomegaly, and

hematologic alterations (leukocytosis and lymphocytosis) may develop [70].

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 [39]. 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 [73].

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

[74]. 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 [77]. 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 [78]. 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--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 [81]. One

imidazole (ketoconazole) [78], 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 drugdrug interactions [84].

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 [87]. The echinocandins inhibit -1,3-D-glucan synthase, which catalyzes the

biosynthesis of glucan, a key component of the fungal cell wall [88]. Of note, mammalian

cells do not contain this polysaccharide target (1, 3--D-glucan), and therefore direct human

cell toxicity is minimal [89]. 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 [90]. 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 [91]. 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 [92]. 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 [93].

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 [94]. Griseofulvin mainly concentrates in

keratinocytes; therefore, it is only used for noninvasive dermatophyte infections [95].

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 [96]. 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 (612 weeks or

longer), which may lead to reduced compliance [97]. 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 [98], 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 [99]. 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) [102].

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 [103]. 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 [103].

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 [100]. 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. [108]. It is a water-soluble compound with 10% protein binding, which

distributes well throughout the body, leading to better efficacy in vivo [109]. Fluconazole

has been recommended for treating tinea capitis. Previous studies have shown that high

doses of fluconazole (48 mg/kg per week) applied for long durations (1216 weeks) are

required regardless of the fungus type [96].

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 [81].

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

[110].

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 [109].

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 [120]. In cases of tinea cruris, topical tolnaftate, terbinafine,

and the imidazoles for 24 weeks is recommended [74]. 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 [116]. Butenafine

may be used once daily for 4 weeks or twice daily for 1 week [121]. In addition, luliconazole

(1% cream) showed clinical improvement even when used only once daily for 1 week [122].

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 [74]. 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
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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-Grnwald Giemsa stain from tzanck smear of bullous tinea pedis showing hypae
(arrows) ( 1,000 magnification)

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 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.

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 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.

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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

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 Tioconazole

Terbinafine

Allylamines Naftifine

Butenafine

Morpholine derivatives Amorolphine HCL

Piridone derivatives Ciclopirox olamine
Thiocarbamate Tolnaftate
Oxaborole Tavaborole
Thiocarbamate Tolnaftate

40