Key notes

 

·       Cutaneous fungal infections are broadly divided into two groups: (1) those that are limited to the stratum corneum, hair, and nails; and (2) those that involve the dermis and subcutaneous tissues

 

·       Superficial fungal infections of the skin are most often due to dermatophytes and Candida spp.

 

·       “Subcutaneous” mycoses are often the result of implantation, while systemic or “deep” mycoses of the skin usually represent hematogenous spread or extension from underlying structures

 

·       In the immunocompromised host, opportunistic fungi, e.g. Aspergillus and Mucor spp., can lead to both cutaneous and systemic infections

 

ORGANIZATION OF CUTANEOUS MYCOSES
Superficial	Involve stratum corneum, hair, or nails
Subcutaneous	Involve dermis or subcutaneous tissue Often due to implantation
Systemic (“deep”)	Involve dermis or subcutaneous tissue
“True” pathogens	Skin involvement usually reflects hematogenous spread or extension from underlying structures
Opportunistic	Primary or secondary skin lesions in immunocompromised hosts

 

Superficial Mycoses

 

Superficial fungal infections are the most common mucocutaneous infections, often caused by an imbalanced overgrowth of mucocutaneous microbiome. Superficial mycoses are due to fungi that only invade fully keratinized tissues, i.e. stratum corneum, hair, and nails. They can be further subdivided into those that induce minimal, if any, inflammatory response, e.g. tinea (pityriasis) versicolor, and those that lead to more substantial cutaneous inflammation, e.g. dermatophytoses. Candida species require a warm humid environment whereas Malassezia species require lipids for growth.

 

SUPERFICIAL MYCOSES OF THE SKIN
	Cutaneous disorder	Pathogen(s)
Minimal, if any, inflammation	Tinea (pityriasis versicolor)	Malassezia furfur, M. globosa
Inflammatory response common	Tinea capitis, barbae, faciei, corporis, cruris, manuum, pedis	Trichophyton, Microsporum, Epidermophyton spp.
	Cutaneous candidiasis	Candida albicans, other Candida spp.

 

 

 

Dermatophytoses

 

Salient features

 

·        Dermatophyte causes infection of keratinized tissues including skin, hair, and nails.

·        Dermatophyte species are contained in 3 genera (Epidermophyton, Microsporum, and Trichophyton), which are further divided according to 3 natural habitats (humans, animals, and soil).

·        Trichophyton is the most common genera isolated.

·        Trichophyton rubrum is the most common cause of dermatophytosis of the skin.

·        Trichophyton tonsurans is the most common cause of tinea capitis.

·        Onychomycosis is the name given to dermatophytosis of the nails.

·        Microscopic examination, culture, Wood light evaluation, and histopathology may all be useful in confirming diagnosis.

·        Several topical and oral antifungals are available for effective treatment of dermatophytosis.

·        Infections involving hair bearing skin and nails typically require oral treatment.

 

Introduction

Dermatophytes are a group of fungi that have the unique ability to invade and multiply within the nonviable keratinized cutaneous structures including stratum corneum, nails, and hair. Arthrospores can survive in human scales for 12 months. Dermatophytosis denotes an infection caused by dermatophytes.

 

Glossary of Terms:

Anthropophilic—preferring humans over other animals as natural habitat

Geophilic—preferring the soil over humans and animals as natural habitat

Zoophilic—preferring animals over humans as natural habitat

Hyphae—long, filamentous fungus cells forming a branching network called mycelium

Arthroconidia—asexual spore produced by segmentation of hyphae

Macroconidia—asexual large multinucleate spores produced by vegetative reproduction

Microconidia—asexual small spores produced by vegetative reproduction

Dematiaceous—melanin in the cell walls of its conidia, hyphae, or both results in a darkly colored fungus

Ectothrix—dermatophyte growth pattern with spores forming a sheath on the outside of the hair shaft

Endothrix—dermatophyte growth pattern with spore formation within the hair shaft

Favus—dermatophyte growth pattern with hyphae and air spaces within the hair shaft

 

TYPES OF DERMATOPHYTES BASED ON MODE OF TRANSMISSION
Category	Mode of transmission	Typical clinical features
Anthropophilic	Human to human by fomites, or by direct skin-to-skin contact	Mild to non-inflammatory, chronic
Zoophilic	Animal to human by fomites, or by direct skin-to-skin contact	Intense inflammation (pustules and vesicles possible), acute
Geophilic	Soil to human	Moderate inflammation

 

 

Morphology:

 

Morphology in lesion, dermatophytes appears as hyphae and arthrospores. In cultures on sabouraud’s agar, they form characteristic colonies consisting of septate hyphae and two types of asexual spores, microconidia and macroconidia. Differentiation into the three genera is based mainly on the nature of macroconidia.

Trichophyton: infects skin, hair & nails,

Microsporum: infects skin & hair but not nails,

Epidermophyton: infects skin & nails but not hair

 

 

PATHOGENESIS OF DERMATOPHYTES

 

Dermatophyte infections involve three main steps:

 

1- Adherence to keratinocytes,

2- Penetration through and between cells,

3- Development of a host response.

 

Dermatophytes produce keratinases (enzymes that break down keratin), which allow adherence and invasion of the fungi into the stratum corneum of skin, hair, and nails, and also to utilize keratin as a source of nutrients for survival. If invasion is successful, clinical disease occurs. As a consequence of keratin degradation, fungal metabolic products diffuse through malphigian layer and the host develops an inflammatory response with subsequent release of pro-inflammatory mediators.

 

Adherence

The first stage of infection involves contact with and adherence of the infectious elements of the fungus (arthroconidia), asexual spores formed by fragmentation of hyphae, to the surface of keratinized tissues. The ability of certain fungi to adhere to a particular host arises from a variety of microbial mechanisms and host factors. Following several hours of successful adherence, the spores begin to germinate and prepare for the next step, invasion.

 

Invasion/Penetration

 

Trauma and maceration facilitate penetration of dermatophytes through the skin. Invasion of germinating fungal elements is further accomplished through secretion of specific proteases, lipases and ceramidases, the digestive products of which also serve as fungal nutrients. Once dermatophytes have invaded (penetration through and between cells) and begun to proliferate in the skin, several mechanisms aid in limiting the infection to dead keratinized tissue. Although the inflammatory responses of ringworm infection involve the Malpighian stratum of the epidermis and the dermis, the fungus itself is found growing only within the stratum corneum of the epidermis, within and around the fully keratinized hair shaft, and in the nail plate and keratinized nail bed. Within these keratinized tissues, the fungus exists only as mycelium and arthroconidia. Fungal mannans in the cell wall of dermatophytes may decrease the rate of keratinocyte proliferation,   thereby reducing the likelihood of the fungus being sloughed off prior to invasion. This mechanism is thought to contribute to the chronicity of infections caused by T. rubrum.

 

Host Response

Defense against the fungi causing ringworm depends on both innate and acquired immune mechanisms. Serum factors such as unsaturated transferrin, inhibiting the growth of dermatophytes by binding to the hyphae. Another important mode of defense is provided by the presence of fatty acids from sebaceous glands, which inhibit dermatophyte growth in vitro. It has been postulated that their presence on the skin in postpubertal children may account for the spontaneous resolution of tinea capitis after this age, and the rarity of new infections in adults. keratinocytes response to invading fungal elements by increasing their proliferation resulting in increased shedding of the fungus as well as secretion of antimicrobial peptides including human β defensin-2 as well as several pro-inflammatory cytokines. These antimicrobial peptides are known to have activity against bacteria, viruses and fungi and to play a key role in protection against skin infections including dermatophytes as well as Candida albicans. The production of cytokines, such as interleukin 1 (IL‐1), by keratinocytes is important in the mobilization of neutrophil defenses. It has been shown that neutrophils, and to a lesser extent monocytes, can kill dermatophyte conidia. It has also been found that dermatophytes are chemotactic and that they can activate the alternative pathway of complement activation.

The degree of host inflammatory reaction depends not only on the host's immune status but also on the natural habitat of the dermatophyte species involved. Interestingly, anthropophilic dermatophytes induce secretion of a limited cytokine profile from keratinocytes in vitro compared to zoophilic species. This difference may reflect the augmented inflammatory response generally observed with zoophilic species.

 

The next level of host defense is cell-mediated immunity resulting in a specific delayed type hypersensitivity response against invading fungi. It is hypothesized that dermatophyte antigen is then processed by epidermal langerhans cells and presented in local lymph nodes to T lymphocytes. The T lymphocytes undergo clonal proliferation and migrate to the infected site to attack the fungus.  Soon, the fungus is cleared, and the lesion spontaneously resolves.

 

Defective cell-mediated immunity may result in chronic or recurrent dermatophytoses.

 

 

Pathophysiology

 

The clinical appearances of the various forms of ringworm infection are the result of the combination of direct damage to the keratinized tissues by the fungus (this applies mainly in hair and nail infections) and of the inflammatory host response. The latter varies widely. At one extreme there is the simple hyperkeratosis seen, for instance, in dry‐type T. rubrum infections; at the other is the pustular, highly inflammatory kerion seen most frequently in zoophilic infections.

 

In classic annular ringworm, the rim of the lesion shows marked inflammatory changes. By contrast, central zone shows less inflammation, possibly following elimination of the fungus in the central zone in stratum corneum. Through the persistence of immunological surveillance, previously infected skin remains free of fungal hyphae compared with uninfected skin, and fungal growth proceeds centrifugally. The epidermal turnover rate is normal within the ring, but more than four times as rapid in the zone where inflammation is maximal.

 

 

Clinical Infection by Structure Involved.

The pathogenesis of epidermomycosis (A) and trichomycosis (B) are different because they involve different structures leading to different clinical manifestations.

(A) Epidermal dermatophyte infection

In epidermomycosis, dermatophytes (green dots and lines) within the stratum corneum not only disrupt the horny layer and thus lead to scaling, but also elicit an inflammatory response (black dots symbolize inflammatory cells), which may then manifest as erythema, papules, and vesicles.  

(B) Hair follicle dermatophyte infections

Hair shaft is involved (green dots) resulting in the destruction and breaking off of the hair. If the dermatophyte infection extends farther down into the hair follicle, it will elicit a deeper inflammatory response (black dots) and this manifest as deeper inflammatory nodules, follicular pustulation, and abscess formation.

 

 

 

 

 

Clinical forms of ringworm infection

 

 

The traditional division of ringworm into different syndromes according to the site of the body infected:

 

·        Tinea corporis

·        Tinea capitis

·        Tinea barbae

·        Tinea faciei

·        Tinea pedis

·        Tinea manuum

·        Tinea cruris

·        Onychomycocis caused by dermatophytes

·        Steroid‐related tinea

·        Dermatophytide reactions

 

 

Tinea corporis

 

Definition

 

Tinea corporis is a dermatophyte infection of the skin of the trunk and limbs, excluding ringworm of specialized sites the hair, nails, palms, soles and groin. The infection is generally restricted to the stratum corneum and most commonly affects exposed skin. Terminal hair in the affected parts may be invaded.

 

Pathophysiology

Tinea corporis can result from human-to-human, animal-to-human (often transmitted by domestic animals) or soil-to-human spread.  In young children infected with Trichophyton rubrum and Epidermophyton floccosum, half of the infections may come from their parents. Spread from existing localized infection (e.g. feet, groins, scalp and nails) is also common. The characteristic annular appearance of ringworm infections results from centrifugally spreads of infection through the horny layer of the epidermis from the point of skin invasion, with elimination of the fungus from the center of the lesion, and the subsequent resolution of the inflammatory host response at that site. This area usually becomes resistant to reinfection. However, many lesions lack any tendency to central clearing. The natural history is variable. Some inflammatory cases of animal infection resolve spontaneously in a few months, while a typical case of T. rubrum tinea corporis may persist for years.

 

Causative organisms

 

Any dermatophyte can potentially cause tinea corporis, but T. rubrum is the most common pathogen worldwide, followed by T. mentagrophytes.

 

 

Clinical features

 

There are multiple clinical presentations of tinea corporis, and they can mimic other dermatologic conditions. As with most dermatophyte infections, the extent of inflammation depends on the causative pathogen and the immune response of the host. Also, because hair follicles serve as reservoirs for infection, areas of the body with more hair follicles may be more resistant to treatment.

 

The site of infection is typically on exposed skin, unless the infection represents an extension from a pre‐existing infection and in such cases, infection may spread from the scalp, down the neck on to the upper trunk, or from the groins on to the buttocks and lower trunk.

 

The typical incubation period is 1 to 3 weeks. Characteristic lesions are circular, usually sharply marginated with a raised edge.  There may be single or multiple plaques. The latter may remain discrete or become confluent. In inflammatory lesions, pustules or vesicles within the active border may dominate and even in mild infections close observation may reveal one or two small pustules. In less inflammatory infections, scaling is a common. The scales are at the leading edge, pointing towards normal skin, whereas in pityriasis rosea they tend to point towards the center of the lesion. Scale may be lessened or absent if topical corticosteroids have been used (tinea “incognito”).  Central resolution, which is a common feature of tinea corporis, is perhaps more frequent in inflammatory lesions. The process is often incomplete, and the central skin may show post inflammatory pigmentation, a change of texture or residual erythematous dermal nodules.

 

Clinical variants

 

Clinical variants of tinea corporis include Majocchi’s granuloma and tinea imbricata.

Majocchi’s granuloma:  usually caused by T. rubrum, is characterized by follicular papulopustules or granulomatous nodules with scale coalescing to form an annular plaque. This variant is commonly seen on the legs in women who have concomitant tinea pedis or onychomycosis and become inoculated after shaving. The combination of trauma and pre-existing fungal disease elsewhere facilitates follicular inoculation of fungus. It represents a deep dermatophyte folliculitis in which the wall of the follicle is disrupted.

Tinea imbricate:  It is a geographically restricted form of tinea corporis (Fiji islands & south East Asia) caused by the anthropophilic dermatophyte T. concentricum.  The infection begins as an erythematous scaling ring; centrifugal spread follows, but within the area of central clearing a second wave of scaling soon arises. The process is repeated to give numerous concentric rings and, as the natural history is normally prolonged, the whole body may become affected. Pruritus is intense and may lead to lichenification.

 

 

Disease course and prognosis

 

Spontaneous resolution can occur but is uncommon.

 

 

Treatment

 

Localized tinea corporis, especially of recent origin, commonly responds to topical therapy applied twice daily, usually for about a month. Topical terbinafine often works in a shorter time period (e.g. 2 weeks). In more widespread infections of recent onset, oral terbinafine or itraconazole will generally be preferred, and may be expected to clear the condition in about 2–3 weeks, depending on the dosage used.

 

 

Treatment ladder

Localized disease, recent onset

·        Topical terbinafine twice daily for 2 weeks

Or

·        Topical azole once or twice daily for 2–4 weeks

Widespread disease

·        Oral terbinafine 250 mg/day 2–3 weeks

Or

·        Itraconazole 100 mg/day 2–4 weeks

 

 

Tinea capitis

 

Definition

 

This is ringworm of the scalp in which there is invasion of the hair shafts by a dermatophyte fungus.

 

Age

 

It is generally a disease of prepubertal children, especially those between the ages of 3 and 7 years, although adult cases are seen, particularly with T. tonsurans infections.

 

Predisposing factors

 

Predisposing factors for tinea capitis include large family size, crowded living conditions, and low socioeconomic class. In addition to transmission from other humans or animals, dermatophyte spread via fomites (hairbrushes, combs, hats, and contaminated grooming instruments).

 

Asymptomatic scalp carriage of dermatophytes constitutes a major source of infection for classmates and siblings. Asymptomatic carriage is most common with the anthropophilic organisms T. tonsurans and T. violaceum. Household contacts may be a significant source of asymptomatic carriers, and co-sleeping and comb sharing seem to be important factors in the spread of disease in this setting.

 

If actual hair infection is to occur, invasion of the stratum corneum of the scalp skin must first develop. Trauma assists inoculation, which is followed, after approximately 3 weeks, by clinical evidence of hair shaft infection.

 

 

Causative organisms

 

The causative pathogens are members of only two genera: Trichophyton and Microsporum. T. tonsurans is currently the most common cause of tinea capitis (accounting for ≥90% of cases), and M. canis is the second most frequent etiology.

 

Pathogenesis

Dermatophytes that invade hair shaft can occur in one of three patterns and is dependent upon the species of dermatophyte involved: ectothrix, endothrix and favus. Dermatophytes establish infection in the perifollicular stratum corneum, entering the hair follicle orifice and then the hair shaft. The funal organism penetrates only those hairs that are growing and therefore affects anagen but not telogen hairs. As the hair grows outwards hyphae are carried to the surface with production of arthroconidia. As a consequence conida have been found in the air in close proximity to hair.

While in favus the infected hair commonly grows to normal lengths, in endothrix infections where arthroconidia are formed the hair shaft, being severely weakened, and breaks at the skin surface. In small‐spored ectothrix infections the shaft tends to fracture a few millimeters above the surface.

 

 

 

 

Ectothrix type

Ectothrix infections occur when both the inside and the outside of the hair shaft are invaded and only the arthroconidia on the surface of the hair shaft may be visualized, although hyphae are also present within the hair shaft. The intrapilary hyphae continue to grow inwards towards the bulb of the hair, until the zone of incomplete keratinization is reached. Growth is then arrested. Further up the shaft, hyphae from the existing mycelium grow outwards from inside the hair and proliferate on its surface. These secondary, extrapilary hyphae grow in a tortuous manner over the surface of the hair shaft, which is growing outwards continuously.  Small arthroconidia (2–3 μm diameters) are formed from these fragmented secondary extrapilary hyphae outside the hair shaft, which rapidly round up to become spherical structures, and are seen as a packed mosaic of spores coating the surface of the hair. This is the small‐spored ectothrix type of hair invasion and is clinically very obvious and occurs as a dry scaling patch of alopecia with little inflammation (that may mimic alopecia areata). This type of ectothrix infection is caused by M. canis, M. audouinii and M. ferrugineum. The cuticle of the hair is destroyed. On Wood's lamp examination, a yellow–green fluorescence may be detected.  

Other species of dermatophytes such as T. verrucosum and T. mentagrophytes show different patterns of hair invasion. Like the Microsporum species, they produce arthroconidia on the surface of the hair and hyphae within it, but these conidia are larger and are arranged in straight chains. This is known as large‐spored ectothrix hair invasion and clinically they present as boggy inflammatory swelling known as a kerion.

 

Endothrix type

In endothrix infections only the inside of the hair shaft is invaded and arthroconidia and hyphae remain within the hair shaft and leave the cortex and cuticle intact. Intrapilary hyphae fragment into arthroconidia up to 8 μm in diameter, which are entirely contained within and completely fill the hair shaft. Hair thus affected is especially fragile, and breaks off close to the scalp surface. Endothrix organisms do not show fluorescence on Woods lamp exam. This pattern of tinea capitis is associated with the appearance of “black dots” which represent broken hairs at the surface of the scalp.  All endothrix-producing agents are anthropophilic (eg, Trichophyton tonsurans, Trichophyton violaceum and Trichophyton sudanense).

 

Favus

Favus is the most severe form of dermatophyte hair infection and is most frequently caused by T. schoenleinii. In favus, longitudinally arranged broad, regularly septate hyphae and air spaces are observed within the hair shaft. Arthroconidia are not usually noted in infected hairs. The affected hair is less damaged than in other types, and may continue to grow to considerable lengths. Blue-white fluorescence by Wood’s light examination is typically seen. Favus presents as thick, yellow crusts composed of hyphae and skin debris (“scutula”). Scarring alopecia may develop in chronic infections.

 

 

 

 

Clinical features

 

Tinea capitis predominates in healthy preadolescent children (6 to 10 years of age); infants are less frequently affected. The incidence in adults is generally low, but it is more commonly seen in the immune compromised, where the presentation may be atypical.

The clinical appearance of tinea capitis is highly variable, depending on the causative organism, type of hair invasion and degree of host inflammatory response. Common features are patchy hair loss with varying degrees of scaling and erythema. A number of clinical patterns exist. 

Clinical variants

 

Non inflammatory

 

Grey patch

Small-spored, ectothrix Microsporum infection typically produces characteristic fine scaling with sharply marginated circular patches of partial alopecia, but showing numerous broken‐off hairs, dull grey from their coating of arthroconidia. Arthroconidia may form a sheath around affected hairs turning them gray. Hair shaft becomes brittle causing them to break off just above the level of the scalp giving the appearance of mowed wheat field on the scalp. Small patches coalesce, forming larger patches. Inflammation may be minimal with anthropophilic fungi (e.g. M. audouinii, M. ferrugineum); however, zoophilic or geophilic species (e.g. M. canis, M. gypseum) typically demonstrate more intense inflammatory response.

 

Endothrix infections (black dots)

 

In T. tonsurans and T. violaceum infections, a relatively non‐inflammatory patches of alopecia with fine scale. Hairs broken off at the level of the scalp surface leave behind grouped black dots (swollen hair shafts visible in the follicular orifice) within patches of alopecia. Normal hairs also remain within patches of broken hairs. The patches are usually multiple. They are commonly angular in outline rather than round and tend to diffuse and poorly circumscribed. While “black dot” tinea capitis tends to be minimally inflammatory, some patients may develop follicular pustules, furuncle-like nodules, or in rare cases kerion—a boggy, inflammatory mass studded with broken hairs and follicular orifices oozing with pus.

 

Diffuse scale

In some cases, alopecia is minimal or absent and infection presents as generalized, diffuse scaling of the scalp, resembling dandruff.

 

Inflammatory

 

Diffuse pustular

In more inflammatory variants, a diffuse, patchy alopecia may coexist with scattered follicular pustules. This may be associated with painful regional lymphadenopathy.

 

Kerion

This is the term given to tinea capitis presenting as a painful inflammatory mass with associated alopecia. It is characterized by boggy, purulent, inflamed nodules and plaques. Hairs do not break off but full out and can be pulled without pain. Follicles may discharge pus. A single plaque is usual, but multiple lesions may occur with involvement of the entire scalp. There is massive purulent secretion from multiple openings, (like the honey from a honey comb).  There may be sinus formation, and on rare occasions mycetoma‐like grains may be found. Thick crusting with matting of adjacent hairs is common. Regional lymphadenopathy is common. This variant represents a delayed host inflammatory response to the causative dermatophyte. Some patients may even become systemically ill with fever and headache.  The lesions heal with scarring alopecia.  Misdiagnosis as bacterial abscess is common; however, secondary bacterial infection may occur. Kerion is commonly seen with zoophilic, large-spore ectothrix species (e.g. T. Mentagrophytes, T. verrucosum); however, this has been superseded in recent years by endothrix infections with either T. tonsurans or T. violaceum, particularly in urban areas.

 

Favus

A chronic, inflammatory tinea capitis typically seen in T. schoenleinii infection, this variant is most commonly encountered in the Middle East and North Africa. Early cases show perifollicular erythema and matting of hair. Later, thick yellow adherent crusted, cup-shaped lesions (‘scutula’) composed of hyphae and keratin debris that are pierced by remaining hair shafts. The lesions produce a fetid odor and shows little tmdency to dear spontaneously. Often results in scarring alopecia. Favus infections fluoresce under Wood’s lamp.

 

Clinical diagnostic aids

Wood’s lamp

Ectothrix Microsporum species demonstrate bright green fluorescence of infected hairs under Wood’s lamp examination. This may aid clinical distinction from nonfluorescent Trichophyton infection (exception: T. schoenleinii can fluoresce dull green).

Clinical pearls

The presence of regional lymphadenopathy in combination with alopecia and/or scale in a child suspected of having tinea capitis is an important diagnostic clue and should encourage appropriate investigation with fungal culture.

 

Histopathology

In tinea capitis, PAS and methenamine silver stains readily reveal hyphae around and within hair shafts. The dermis demonstrates a perifollicular mixed cell infiltrate with lymphocytes, histiocytes, plasma cells, and eosinophils. Follicular disruption leads to an adjacent foreign-body giant cell reaction. Markedly inflammatory lesions such as a kerion demonstrate an acute infiltrate of polymorphonuclear leukocytes within the dermis and follicle. Organisms may not be visualized in kerion since the intense host response destroys many of the fungal organisms. However, fungal antigens may be detectable with immunofluorescent techniques.

 

Differential diagnosis

The differential diagnosis of tinea capitis is extensive, encompassing any condition causing patchy hair loss, scaling or scalp inflammation. Scalp psoriasis, seborrheic dermatitis and atopic dermatitis may be difficult to differentiate from noninflammatory tinea capitis, although these conditions are usually more diffuse, and there may be characteristic signs elsewhere. Alopecia areata is generally non scaly but may occasionally demonstrate erythema. Exclamation-mark hairs must be distinguished from the broken hairs of tinea capitis. Lupus erythematosus, lichen plano pilaris and trichotillomania should also be considered, although they are relatively rare. Inflammatory tinea capitis variants may be misdiagnosed as bacterial folliculitis, folliculitis decalvans or abscesses. Regional lymphadenopathy may be associated with inflammatory variants of tinea capitis. 

 

Disease course and prognosis

 

Without medication there is spontaneous clearing at about the age of

15 years, except with T. tonsurans, which often persists into adult life.

 

 

Treatment

 

Tinea capitis requires oral therapy, because the drug needs to penetrate the hair follicle. Both itraconazole and terbinafine are now licensed for use in children. Terbinafine oral granules are now approved by the FDA for treatment of tinea capitis in children 4 years of age and older. The best length of treatment for T. tonsurans and T. violaceum infections with terbinafine appears to be 1 month. There is some evidence that higher doses of terbinafine may be more effective for Microsporum.

Also important in the management of tinea capitis are preventive measures. Because the disease is contagious, all individuals residing with the infected patient should be examined for signs of tinea capitis and appropriately treated. Chronicity may develop if a child is continually re-exposed from untreated family members. Concomitant therapy with an antifungal shampoo such as 2% ketoconazole two to three times weekly is desirable for the patient because these agents may aid in removing scales and eradicating viable spores, which may help decrease the potential spread of infection and also for household contacts, until the patient is free of disease. Also, combs, brushes and headwear used by the patient should be disinfected or preferably discarded.

Topical treatment alone is not recommended for the management of tinea capitis. Local treatment with a topical antifungal with a fungicidal mechanism of action, such as ciclopiroxolamine or terbinafine cream, may reduce the risk of infecting other people and shortens the duration of systemic treatment. The entire hair of the scalp in all its length should be treated with the antifungal. Treatment should be administered once daily for approximately 1 week.

The treatment of kerion deserves special mention. These markedly inflammatory reactions may result in permanent scarring alopecia, and therefore rapid institution of aggressive therapy is indicated. In addition to antifungal therapy, careful removal of crusts using wet compresses and systemic antibiotics should be considered, especially in the presence of significant crusting, because secondary bacterial infection may concomitantly occur. Skin swab for bacterial culture and sensitivity may be useful in this setting to guide the choice of antimicrobial. Oral glucocorticoids may reduce the incidence of scarring associated with kerions. Although there is no consistent evidence for improved cure rates with use of oral glucocorticoids, they appear to relieve pain and swelling associated with infections. The usual regimen prednisone is 0.5 to 1 mg/kg per day each morning during the first week of antifungal therapy.

 

Treatment ladder

·       Terbinafine: <10 kg, 62.5 mg; 10–20 kg, 125 mg; >20 kg, 250 mg. All given daily for 4 weeks

·       Itraconazole 2–4 mg/kg/day for 4–6 weeks

Itraconazole capsule: simplified dosing:
10-20 kg: 100 mg every other day
21-40 kg: 100 mg daily
>40 kg: 200 mg daily

 

 

Tinea barbae

 

Definition

 

This is ringworm of the beard of the face and neck including moustache area with the invasion of terminal hairs. It is thus a disease of the adult male. Tinea of the chin and upper lip in females and children are considered to be tinea faciei (ringworm of the glabrous skin of the face).

 

 

Predisposing factors

Disease is often acquired from animals. In the past, a common cause of infection was contaminated razors in barbershops. With the increased use of disposable razors and disinfectants, however, the incidence of tinea due to this source has been dramatically reduced.

 

Pathology

 

Infections with T. mentagrophytes and T. verrucosum lead to large‐spored ectothrix invasion with the spores in chains. The other less commonly involved species produces their own characteristic types of hair invasion.

 

 

Causative organisms

 

The causative organisms are typically zoophilic dermatophytes, namely T. mentagrophytes and T. verrucosum.

 

Clinical features

 

Tinea barbae affects the face unilaterally and involves the beard area more often than the moustache. Two forms exist.

Inflammatory Type

The affected men are commonly farm workers. Since zoophilic organisms are the most common culprit and affected areas often have a large number of terminal hair follicles, the clinical presentation tends to be severe, with intense inflammation and multiple follicular pustules. Follicular pustules may coalesce and eventuate in abscess-like collections of pus, sinus tracts, bacterial super infection, kerion-like boggy- crusted plaques and scarring alopecia. Hairs within the affected areas are lusterless, brittle and loose and easily removed with the forceps without causing pain to demonstrate a purulent mass around the root. Patients may have constitutional symptoms such as malaise as well as lymphadenopathy. After 4-6 weeks, these inflammatory lesions settle spontaneously with a degree of immunity, as second bouts are unlikely. 

 

Superficial Type

Caused by anthropophiles such as T. rubrum, this form of tinea barbae is superficial, less inflammatory and resembles tinea corporis or bacterial folliculitis. Consist of dry, circular, reddish, scaly patches. Alopecia may be present in the centre of the lesion in which hair is broken off at the surface but it is reversible. Scattered follicular papules, pustules and small nodules that may be easily mistaken for Staphylococcus aureus folliculitis may develop.

 

 

Differential diagnosis

 

The classic, highly inflammatory lesions are distinguished from boils by their relative lack of pain. Loosened hairs, although present in some bacterial infections, are rarely as obvious as they are in tinea barbae. The presence of Staphylococcus aureus on a swab taken from lesions in this area does not exclude ringworm, as bacterial colonization or frank co‐infection may occur in tinea barbae. Unfortunately, mycological cultures are often negative.

 

 

Treatment

 

Beard infections usually respond satisfactorily to itraconazole or terbinafine, sometimes in combination with topical therapy over a period of 4–6 weeks. Fairly long‐term follow‐up is recommended, and late recurrences undoubtedly occur.

 

 

Tinea faciei

 

Definition

 

Tinea faciei is infection of the glabrous skin of the face with a dermatophyte fungus (the moustache and beard areas of the adult male are excluded).

 

 

Predisposing factors

 

Facial skin may be infected either by direct inoculation of a dermatophyte fungus from an animal (e.g. T. mentagrophytes from an infected pet) or there may be secondary spread from pre‐existing tinea of another body site. The latter pattern is likely to occur with T. rubrum as well as with T. concentricum infections.

 

 

Clinical features

 

Tinea infection of the face is frequently misdiagnosed. Typical annular rings are usually lacking and the lesions are highly photosensitive. Erythema is usual, but scaling is present in less than two‐thirds of cases. A substantial proportion of patients do show annular or circinate lesions, and induration with a raised margin is present in about half. Simple papular lesions, and in some cases completely flat patches of erythema, also occur. A few vesicles or pustules may be found, but these are rarely conspicuous. The application of topical steroids may further modify the appearance.

 

 

Differential diagnosis

 

Because of light sensitivity, the frequent absence of scaling and the somewhat nondescript appearance, this condition may be confused with discoid lupus erythematosus (DLE) and polymorphic light eruption. Moreover, tinea faciei coexisting with DLE has been described. Reluctance to biopsy the face adds to the problem, but if there is possibility of tinea faciei, careful examination and scrapings taken from the skin surface, even if this is not obviously scaly, should enable a diagnosis to be made. If topical steroids have been applied, a cessation of the therapy may be followed a few days later by a great increase in scaling and by appearances much more readily diagnosable.

 

 

Treatment

 

In localized cases, if promptly diagnosed, topical therapy seems to work well, especially with one of the imidazoles. Where delay has occurred before the diagnosis is established, and especially when steroid therapy has modified the condition, terbinafine or itraconazole is generally preferred. Most cases will clear in 3 or 4 weeks, certainly in 6 weeks, but longstanding infections may occasionally need longer periods of treatment.

 

 

Tinea pedis

 

Definition

 

Tinea pedis is a dermatophyte infection of the soles and interdigital web spaces of the feet. Infection of the dorsal aspect of the foot is considered tinea corporis. The term athlete's foot is used to imply any form of toe cleft intertrigo. In this context, the terms tinea pedis or foot ringworm is preferred, which clearly exclude infections caused by bacteria, Candida and non‐dermatophyte moulds. The feet are the most common location for dermatophyte infections.

 

Age

 

The condition is more common in adults than children.

 

Sex

 

Adult males more commonly develop tinea pedis than women.

 

 

Predisposing factors

 

The lack of sebaceous glands and the moist environment created by occlusive shoes are important factors in the development of tinea pedis, which is in most cases initially a lateral web space infection. In fact, tinea pedis is uncommon in populations that do not wear shoes. However, the fungus may be acquired from going barefoot (locker rooms, gyms, public facilities).

 

The spores of dermatophytes survive for months in shoes, carpets, bath mats and showers. The warm moist microenvironment in shoes, coupled with reduced hygiene, hyperhidrosis, increasing age and poor peripheral blood flow are predisposing factors. Using rubber sandals in showers, carefully drying the feet, especially between the toes, and wearing clean shoes and socks are possible preventive measures.

 

Pathology

 

The moist conditions of the toe clefts cause maceration and damage the stratum corneum at the same time that probably favors growth of the fungus. A simultaneous increase in the resident bacteria flora, such as large‐colony coryneforms, may be acting as important co‐pathogens.

 

 

Causative organisms

The dermatophytes that are typically responsible for tinea pedis are T. rubrum, T. interdigitale (previously T. mentagrophytes var. interdigitale), T. mentagrophytes, E. floccosum, and T. tonsurans (in children). Non-dermatophyte pathogens that produce clinical findings identical with tinea pedis include Neoscytalidium dimidiatum and N. hyalinum (moccasin and interdigital types) and, occasionally, Candida spp. (interdigital type). To some extent, fungal species correlates with the clinical forms.

 

Clinical features

 

Tinea pedis may present as any of four forms, or combinations thereof.

Interdigital Type

This common type is predominantly affecting the interdigital and subdigital skin of the feet, and in particular the lateral two toe clefts because they are the tightest of the interdigital spaces and caused by any of the three species. When one spreads the toes, one may find gray-white swollen macerated skin. When the macerated skin is removed, peeling, erosions, fissures, and erythema may be prominent. Under appropriate conditions, the infection will spread to the adjacent sole or instep, but it rarely involves the dorsum. Two aggravating factors are hyperhydrosis and gram negative bacterial coinfection such as pseudomonas and proteus that soon produce the malodor that are characteristic of the dermatophytosis complex (fungal infection followed by bacterial invasion), or “athlete's foot.”

Chronic Hyperkeratotic (Moccasin) Type

In T. rubrum infections, a chronic hyperkeratotic type of tinea pedis is seen.  There is patchy or diffuse hyperkeratosis, erythema, fine silvery white scales and fissures on one or both the soles, heels and the lateral and medial aspects of the feet, in a distribution similar to a moccasin on a foot. The arciform pattern of scales is characteristic. On careful examination, as the scales proceeds along the edge of the foot, erythema at the advancing border may be seen. There may also exist few minute vesicles that heal with collarets of scale less than 2 mm in diameter. The dorsal surfaces of the toes and feet are not often affected, but associated nail infection is very common.

 

Frequently chronic and difficult to cure because of the thickness of stratum corneum on planter surface  and the inability of T. rubrum to elicit an immune response sufficient to eliminate the fungus.

Vesiculobullous Type

Vesiculobullous type of tinea pedis, typically caused by zoophilic strains of T. interdigitale. Sudden eruption of pruritic grouped vesicles, usually on the instep. The vesicles may become pustules and may coalesce forming large bullae that eventually shed their roofs, producing characteristic erosions with scale and erythema at the edge. The roof of such a blister is an ideal specimen for KOH examination. This variety of ringworm frequently goes on to apparent spontaneous cure, but tends to recur in warm weather.

Acute Ulcerative Type

Typically an exacerbation of interdigital tinea pedis, secondarily infected with Gram-negative bacteria produces pustules and purulent ulcers in the web spaces; seen in immunocompromised and diabetic patients.

 

Vesiculobullous and acute ulcerative types commonly produce a vesicular Id reaction, either on the lateral foot or toes, or on the lateral aspects of the fingers.

 

 

Complications and co‐morbidities

 

Each type has different associated morbidities and complications that can affect diagnostic considerations and therapeutic options. These include bacterial superinfection (the “dermatophytosis complex”), dermatophytid reactions, cellulitis (especially in patients who have venous hypertension, harvested saphenous veins, and chronic edema), and even osteomyelitis leading to amputation in diabetics.  Oral antifungal therapy should be considered in diabetics, immunocompromised patients, and those with moccasin-type tinea pedis. Finally, other dermatophyte infections often occur together with tinea pedis – in particular, tinea cruris, onychomycosis, and tinea manuum – and these sites should be examined.

 

 

 

Treatment ladder

 

Mild and moderate interdigital disease

·        Topical imidazole twice daily for 4 weeks

·        Topical terbinafine twice daily for 7 days

·        Tolnaftate powder

Dry type tinea pedis

·        Terbinafine 250 mg/day for 2 weeks

Or

·        Itraconazole 400 mg/day for 1–2 weeks

 

 

Tinea manuum

 

Definition

 

Dermatophyte infections on the dorsal aspect of the hand have a clinical presentation similar to tinea corporis. However, dermatophyte infection of the palm and interdigital spaces has distinct characteristics with infections beginning under rings and is referred to as tinea manuum. The reason for the two different clinical pictures is thought to be related to the lack of sebaceous glands on the palms.

 

Predisposing factors

 

In most cases there is pre‐existing foot infection with or without toenail involvement. A special mention should be made of ringworm beginning under rings and wrist watches, and occupational usage predispose to maceration between the fingers. Poor peripheral circulation and palmar keratoderma are other possible predisposing factors.

 

Causative organisms

The typical causative organisms are the same three anthropophilic species involved in tinea pedis and tinea cruris: T. rubrum, T. mentagrophytes and E. floccosum. Two non-dermatophyte fungi that cause “tinea manuum” are Scytalidium dimidiatum and S. hyalinum.

 

Clinical features

 

Tinea manus is almost always secondary to tinea pedis as infection of the hand is acquired from excoriating and picking infected feet and toenails. 

Most commonly only one hand (singular: tinea manus) is involved, concomitant with infection of both feet (Mosaic-type) and toenails for which the term “two feet–one hand” syndrome has been coined and the two share clinical features such as chronicity and hyperkeratosis. The hand affected is often the dominant one, suggesting that direct inoculation onto the more active hand is likely. Trichophyton rubrum infection may take several different clinical forms.

The most common variant is the hyperkeratotic form, there is diffuse fine, firmly adherent, dry scaling on an erythematous background of the palms and fingers, often accentuated in the flexural creases, that fails to respond to emollients. The hands feel very dry and rough. However, circumscribed vesicular and pustular patches may be present, especially when zoophilic dermatophytes involved. Tinea unguium of the involved hand can serve as a clue to the diagnosis, but infection of all the fingernails is uncommon.

 

Differential diagnosis

Dermatophyte infections of the palm are often quiet and chronic, commonly passing unnoticed or misdiagnosed. One must always check the feet and groin. If the changes are symmetric, psoriasis or dermatitis is more likely, while asymmetric or unilateral changes suggest tinea. When the interdigital spaces or nail folds are involved, candidiasis is strongly indicated.

 

Unilateral scaling should always alert the clinician to the necessity of taking scrapings. Nail changes may help: pitting suggests psoriasis, but subungual hyperkeratosis if present should always be scraped. If the palmar infection spreads to the dorsal surface, more classic annular lesions may be seen, although this happens relatively infrequently. Tinea manuum, like tinea cruris and tinea faciei, is sometimes modified by inappropriate treatment with topical steroids leading to further diagnostic difficulties.

 

 

Treatment of tinea Pedis and Manuum

Mild and moderate interdigital tinea pedis without bacterial involvement is treated topically with allylamine, imidazole, ciclopirox creams. Topical imidazole is applied twice daily for 4 weeks. Terbinafine cream applied twice daily for 1 week is effective in 66% of cases. For dry type tinea pedis oral antifungal is required. The dosing schedule of oral terbinafine is 250 mg daily for 2 weeks. Itraconazole in adults is given 400 mg daily for 1 week, 200 mg daily for 2–4 weeks, or 100 mg daily for 4 weeks with similar efficacies of all regimens, whereas itraconazole in children is administered at 5 mg/kg/day for 2 weeks. Fluconazole 150 mg weekly for 3–4 weeks is also effective. Topical or systemic corticosteroids may be helpful for symptomatic relief during the initial period of antifungal treatment of vesiculobullous tinea pedis. Maceration, denudation, pruritus, and malodor obligate a search for bacterial coinfection by Gram stain and culture, the results of which most often demonstrate the presence of Gram-negative organisms including Pseudomonas and Proteus. Patients suspected of having Gram-negative coinfections should be treated with a topical (potassium permanganate followed by a topical antifungal is preferred) or systemic antibacterial agent based on the culture and sensitivity report. Associated onychomycosis is common; if present, more durable treatment of the onychomycosis is necessary to prevent recurrence of tinea pedis.

 

Chronic ringworm infections of the palm are not easily cleared, and oral therapy is always needed. Itraconazole and terbinafine are both effective in this condition. Most cases clear with 2–4 weeks of treatment.

 

 

Tinea cruris

 

Definition

 

Tinea cruris is a dermatophyte infection of the inguinal region, in particular the inner aspects of the upper thighs and crural folds, with occasional extension onto the abdomen and buttocks.  It is the second-most common type of dermatophytosis worldwide.

 

Epidemiology

 

This disease is more often seen in adult men than in women, since the scrotum provides a warm and moist environment that encourages fungal growth and men are more likely to have tinea pedisand onychomycosis as a source of dermatophytes.

 

 

Predisposing factors

 

Tinea cruris is frequently associated with tinea pedis because clothing that is brought over the feet is contaminated and then comes in contact with skin in the groin region. The old advise> Always put your socks on before your underwear. Thus, one should check the feet of all patients with groin rashes. Finally, all the factors that lead to intertrigo, such as obesity, inadequate personal hygiene, hyperhydrosis, prolonged sitting on plastic or non-absorbent surfaces, tight synthetic clothing, and even diabetis mellitus, may play a role. It is common during the hot summer when the humidity is high.

 

 

Causative organisms

 

T. rubrum is the main cause; T. interdigitale and E. floccosum also account for some cases.

 

TINEA CRURIS: COMMON CAUSATIVE PATHOGENS
Dermatophyte	Clinical features
Trichophyton rubrum	1.   Most common cause of tinea cruris 2.   Infection tends to be chronic 3.   Fungus not viable in scale (e.g. on furniture, rugs, linens) for long periods of time 4.   Frequent extension of infection from the groins to the perianal, buttocks, the lower back, pubic and lower abdomen is common. The penis is occasionally affected.
Epidermophyton floccosum	1.   Commonly associated with “epidemics” of tinea cruris in locker rooms or dormitories 2.   Infection is acute (rarely chronic) 3.   Arthroconidia are viable in scale (e.g. on furniture, rugs, linens) for long periods of time 4.   Infection limited to the genitocrural crease and the medial upper thigh 5.   Causative agent of “eczema marginatum” (well-demarcated borders with multiple small vesicles or, sometimes, vesiculopustules)
T. mentagrophytes, in particular var. mentagrophytes	1.   Infection tends to be more severe and acute, with intense inflammation and pustule formation 2.   May rapidly spread to the trunk and lower extremities, causing a severe inflammatory condition 3.   Often acquired from animal dander

 

 

Clinical features

 

The initial sign of infection is usually an area of erythema and pruritus in the fold between the scrotum and the inner thigh. Characteristic lesions are well demarcated annular erythematous plaques, curved with sharp margins with a scaly raised advancing border that may contain pustules or even vesicles extending from the groin fold down the upper inner aspect of the thighs, just where the scrotum usually touches the leg. Dermal nodules forming beading along the edge are commonly found in older lesions. Pruritus is common, as is pain when plaques are macerated or secondarily infected. The disease can remain unilateral or become bilateral.

 

The duration of infection depends on the causative pathogen. Infections with T. rubrum tend to be chronic, sometimes with leathery and lichenified lesions. In contrast, the zoophilic form of T. mentagrophytes (previously T. mentagrophytes var. mentagrophytes) often causes acute infections with a prominent inflammatory component that may include pustules. The scrotum itself is generally spared in tinea cruris. If the scrotum is involved or there are erosions or satellite pustules, cutaneous candidiasis should be considered.

 

 

Differential diagnosis

 

Candidosis, which is more common in women, does not have a distinct raised margin. White pustules are often found, satellite lesions are numerous and small, and often produces collarette scale as the tiny pustules rupture is characteristic. Pityriasis versicolor may be localized to the groin but is usually non‐inflammatory and asymptomatic, as is erythrasma. Central clearing is rarely found in either of these infections.

 

 

Treatment

 

In cases of recent onset, topical therapy can be expected to be curative within 2–4 weeks. Topical terbinafine and the imidazoles are better tolerated in the flexural areas, and if the diagnosis is in doubt terbinafine and the imidazoles have the advantage of being effective against Candida as well. Where the condition has been present for many months, or has spread to the pubic area, the natal cleft or the buttocks, and where topical steroids have been used, systemic treatment is strongly recommended. Oral terbinafine and itraconazole usually produce a remission in 1–2 weeks. Some patients relapse even after this therapy and a longer course of therapy may work in these recalcitrant cases.

 

Treatment ladder

 

Recent‐onset disease

·        Topical terbinafine or imidazoles twice daily for 2 weeks

Chronic or extensive disease

·        Oral terbinafine 250 mg/day for 1–2 weeks

Or

·        Itraconazole 100 mg/day for 2–4 weeks

 

Infection control

 

The reduction of perspiration and enhancement of evaporation from the crural area are important prophylactic measures. The area should be kept as dry as possible, especially drying thoroughly after bathing, wearing of loose underclothing and trousers, plain talcum powder or antifungal powders are helpful, weight reduction (if obese), laundering contaminated clothing and linens, and treating concomitant tinea pedis. Greater control of tinea pedis might lead to fewer cases of tinea cruris. A person suffering from tinea pedis or cruris should not lend towels to others, even if they have been laundered.

 

 

Onychomycosis

 

Definition

 

Onychomycosis is a fungal infection of the toenails or fingernails that may involve any component of the nail unit, including the matrix, bed, or plate. The infection may be due to a dermatophyte, yeast, or non dermatophyte mould. The term "tinea unguium" is used specifically to describe invasive dermatophytic onychomycosis. The disease course is chronic.

 

 

Epidemiology

 

The disease is twice more frequent among men than women, and it seems to increase with age.

 

Onychomycosis is the most prevalent nail disease and accounts for approximately 50% of all causes of onychodystrophy. It affects up to 14% of the population with an increasing prevalence among older individuals. Onychomycosis is also increasing in incidence among children and adolescents and accounts for up to 20% of dermatophyte infections diagnosed in children. Risk factors for nail infection include nail trauma, immunosuppression such as HIV infection, diabetes mellitus, and peripheral vascular insufficiency. The increasing prevalence of this disease may be secondary to wearing of tight shoes, increasing numbers of individuals on immunosuppressive drugs, and an increased use of communal locker rooms. The dermatophytosis commonly begins as tinea pedis before extending to the nail bed, where eradication is more difficult. This site serves as a reservoir for local recurrence or for infections spreading to other areas. Up to 40% of patients with toenail onychomycosis show concomitant skin infections, most commonly tinea pedis (30%).

 

 

Causative organisms

 

A variety of fungi have been implicated in the causation of OM. Most commonly, the source of infection is the infected surrounding skin and the same organism is detectable from both sites. Dermatophytes account for ~90% of cases of onychomycosis, and the remainder are due to yeasts or non-dermatophyte molds.   Although all dermatophytes can cause tinea unguium, Microsporum spp. does so very rarely. The most common causative pathogens are T. rubrum, T. interdigitale, T. tonsurans (in children), and E. floccosum. Yeasts generally invade already damaged nails (like in chronic paronychia) or nails in immunosuppressed (as in chronic mucocutaneous candidiasis). Candida albicans is the most common yeast responsible followed by C. parapsilosis.  Among NDM, the commonly isolated species are Aspergillus and Scopulariopsis brevicaulis.  Although, there is still much debate as to whether most NDMs actually cause nail infection or they are mere laboratory contaminants or secondary invaders of already damaged nails, the accumulating evidence highly suggests that some NDMs can be true primary invaders. 

Although nail infections may be the only manifestation of fungus disease in a patient, in the great majority of cases they are associated with tinea pedis or tinea manuum. Toenail infections are considerably more common than fingernail infections, and only rarely does fingernail onychomycosis occur without concurrent toenail infection. A single nail may be involved, but more commonly, multiple nails on one or both hands or feet are affected.

Interestingly, about 50% of cases of fingernail-related onychomycosis are caused by Candida spp, whereas non dermatophyte molds are not detected in diseased fingernails. Onychomycosis due to dermatophytes occurs more frequently in toenails than in fingernails. Conversely, candidal onychomycosis more commonly affects the fingernails. In addition, most episodes of Candida onychomycosis begin as paronychial infections ("whitlow"). In other words, infection begins in the structures around the nail rather than in the nail itself. Again, the opposite is generally true of dermatophytic onychomycosis.

 

NON-DERMATOPHYTE MOLDS THAT CAN CAUSE ONYCHOMYCOSIS
Fungus	Key features
Fusarium spp.	Superficial white pattern*
Aspergillus spp.	Superficial white pattern*
Acremonium	Superficial white pattern*
Scopulariopsis brevicaulis	Lateral yellow–brown discoloration KOH of nail reveals lemon-shaped conidia and atypical hyphae
Neoscytalidium hyalinum	Distal and lateral nail invasion†
Neoscytalidium dimidiatum	Distal and lateral nail invasion†

* Deeper invasion of the nail plate can also occur.

† May also be associated with paronychia or tinea pedis.

 

 

Pathogenesis

 

Both mechanical and chemical factors have a role to play in the Invasion of nail apparatus by fungi. The essential steps are surface adhesion followed by invasion into the sublayers. The site and pattern of invasion which leads to production of different clinical types of OM can be seen from [Figure]. Nail involvement occurs by penetration of fungal elements and secretion of enzymes that degrade the skin components. Dermatophytic fungi have been shown to have keratinolytic, proteolytic and lipolytic activities. The hydrolysis of keratin by proteinases not only facilitates invasion into tissues, but also provides nutrition to the fungi. Nails being skin appendages undergo essentially the same pattern of invasion. However, the nail apparatus has some unique features to offer.

 

The knowledge of the immune mechanisms operative in the nail apparatus is still preliminary. Structurally, the nail apparatus is exposed to a harsh environment and is prone to damage and invasion by various organisms. The unique anatomy of the nail is prone to provide easy portals of entry to pathogens, through the proximal nail fold and the distal nail edge. However, these are physically protected by the cuticle and the distal solehorn, respectively [Figure]a. The nail apparatus has certain essential immunological differences as compared to that of skin. The nail unit is isolated from the body's cell-mediated immunity (CMI).  It is a site of relative immune privilege due to a very low level of expression of MHC (Major histocompatibility) Class 1a antigens, local production of potent immunosuppressive agents, dysfunction of antigen presenting cells (APC) and inhibition of Natural Killer (NK) cell activity.  Also, dermatophytes are strongly keratinophilic organisms. This is because of their ability to form perforating organs due to which they quickly digest keratin. On the other hand, there are various protective mechanisms at play as well. Nail unit has been shown to possess a strong innate immunity. There is increased local expression of antimicrobial peptide (human cathelicidin LL-37) in the nail. Cathelicidin LL-37 is not expressed in human skin under normal circumstances, but it gets induced upon exposure to infection or inflammation. However, it is strongly expressed in the nail unit. Being a soluble antimicrobial, it has been shown to have potent activity against Pseudomonas aeruginosa and Candida albicans.  In addition, a differential distribution of immune cells has been observed in different parts of the nail apparatus. There is a high density of CD4+ cells in the proximal nail fold (PNF) and very low density in the proximal nail matrix (PNM). CD8+ T cells are rarely seen in and around PNF, nail bed, and PNM. The density of Langerhans cells is higher in epithelium of the PNF and nail bed as compared to that of the nail matrix.  The Langerhans cells and macrophages in the nail matrix are functionally impaired with respect to their capability of antigen presentation.

In short, due to a lack of effective cell-mediated immunity, the nail apparatus is susceptible to invasion by fungal organisms, if it gets exposed due to various predisposing factors. Hence, OM is usually a chronic infection not associated with inflammation. The nail plate offers an ideal ecological niche for fungal organisms where they can persist for long durations. Any physical compromise of the protective and self-containing structure of the nail apparatus exposes it to an early invasion by fungi which are then very difficult to eradicate.

Physical restrictions to the microbial invasion of nail also get compromised under certain circumstances. Various predisposing factors include vascular diseases, atopy, obesity, diabetes and sports.  Most patients with Candidal OM are involved in occupations that predispose to repeated minor trauma or are engaged in domestic activities which involve wet work.  It is known that most dermatophyte species affect the ventral and middle layers of the nail plate, where the keratin is comparatively soft, and in close proximity to the underlying living cells. On the ventral surface, the junctions between cells are more flexible than the tight junctions in the dorsal part. The ventral surface has a highly irregular topography with parallel grooves and ridges providing excellent channels for hyphae to penetrate the nail plate.  Also, the intercellular junctions in the ventral plate are more flexible than the tight junctions in the dorsal nail plate. The intermediate layer is involved less commonly, while the dorsal nail plate is rarely involved except in case of white superficial onychomycosis.  The dorsal nail plate is the hardest part and has increased calcium content.

Species differences in fungal pathogenecity have also been reported with Trichophyton mentagrophytes being a more active destroyer than Trichophyton rubrum.  This active pathogenecity for the nail could be a result of mechanical or enzymatic processes. 

Figure: Pathogenesis of Onychomycosis (a) Anatomical structure of the normal nail unit. (b) Pattern of fungal invasion in distal lateral subungual onychomycosis. (c) Pattern of fungal invasion in endonyx onychomycosis. (d) Pattern of invasion in superficial white onychomycosis. (e) Pattern of invasion in PSOM. (f) Fungal involvement in a case of TDOM

Clinical features

 

The pattern of invasion, if correlated clinically, can be seen to give rise to different clinical types of OM [Figure]b-f.

Onychomycosis has 5 main subtypes, as follows:

·        Distal lateral subungual onychomycosis (DLSO)

·        Endonyx onychomycosis (EO)

·        White superficial onychomycosis (WSO)

·        Proximal subungual onychomycosis (PSO)

·        Candidal onychomycosis

Patients may have a combination of these subtypes. Total dystrophic onychomycosis, the most advanced form of any subtype. Presentation varies by subtype.

 

 

Distal lateral subungual onychomycosis (DLSOM): [Figure]b.

 

DLSO is the commonest clinical type of onychomycosis. It begins with invasion of the stratum corneum of the hyponychium. The infection then progresses to involve the nail bed and subsequently the ventral nail plate. The infecting organism migrates proximally through the nail plate (against the tide of growth of the nail plate).  Hyperproliferation or altered differentiation of the nail bed in response to the infection results in subungual hyperkeratosis. With further progression of infection, there is yellowing, crumbling and thickening of the distal nail plate as well as distal onycholysis, which provides an ideal environment for further proximal invasion and growth of the dermatophyte. Yellow streaks in the central portion of the nail plate are commonly observed. Eventually, the entire nail bed and plate may become involved (total dystrophic pattern).

Although commonly starting with a single affected nail, other digits later become invaded. Toenails are involved much more commonly than fingernails. First and fifth toenails are infected most frequently. Involvement of the fingernails is usually unilateral. When fingernails are involved, pattern is usually two feet and one hand.  

This type is usually caused by dermatophytes, especially T. rubrum and less commonly T. mentagrophytes, T. tonsurans, and E. floccosum.

 

Endonyx onychomycosis (EOM):[Figure]c.

 

In this variant, there is a primary and exclusive attack on the nail plate with the fungus growing between the nail plate lamellae. This pattern of invasion is specific for T. soudanense (and possibly T. violaceum) and may reflect its high affinity for hard keratins.  Clinically, EOM is seen as a diffuse milky-white discoloration of the affected nail plate, forming irregular wide waves with pits and lamellar splits,  but, in contrast to distal lateral subungual onychomycosis, no evidence of subungual hyperkeratosis or onycholysis is present.

Nail plate surface and nail thickness are normal. A large number of fungal hyphae are visible within the nail plate with absence of fungal elements in the nail bed and hyponychium. 

Superficial white onychomycosis (SWO)[Figure]d.

 

It is less common than DSO (estimated proportion of onychomycosis cases, 10%) and occurs when fungi invade the dorsal part of the nail plate directly. The dorsal surface of the nail plate is eroded in well-circumscribed powdery white patches, often away from the free edge. The nail becomes roughened and crumbles easily. It is distinguishable from other causes of leukonychia by the powdery nature of the white material, which can easily be scraped away, revealing a solid nail underneath. The white patches then coalesce and spread to involve the whole surface of the nail plate. SWO occurs primarily in the toenails. Molds produce a deep variety of white superficial onychomycosis characterized by a larger and deeper nail plate invasion.

 

The most common etiologic agent in SWO is T. interdigitale, although non dermatophyte molds such as Aspergillus, Scopulariopsis, and Fusarium are also known pathogens. Candida species may invade the hyponychial epithelium to eventually affect the entire thickness of the nail plate.

 

In HIV patients, SWO has been documented in fingernails as well, and is generally caused by T. rubrum and superficial infection may coexist with proximal white subungal onychomycosis

Proximal white subungal onychomycosis (PWSO):[Figure]e. 

A relatively uncommon subtype, and occurs when organism first invades stratum corneum of the proximal nail fold and then penetrates to the nail matrix and the undersurface of the newly formed nail plate, and migrate distally. Clinically, PWSOM presents as an area of leukonychia in the proximal nail plate that moves distally with nail growth. Other features are proximal onycholysis, subungual hyperkeratosis and destruction of the proximal nail plate. It may also present as a pattern of proximal to distal longitudinal leukonychia affecting a single digit, an isolated transverse leukonychial band, or multiple transverse bands separated by areas of normal nail.  This pattern has been described in both finger and toenails.

 

In proximal subungual onychomycosis caused by molds, leukonychia is typically associated with marked periungual inflammation.

T. rubrum is the commonest causative agent. Patients with PSO should be screened for HIV, as PSO has been considered a marker for this disease.

 

Candida onychomycosis

 

Nail invasion by Candida is not common because the yeast needs an altered immune response as a predisposing factor to be able to penetrate the nails. Despite the frequent isolation of Candida from the proximal nail fold or the subungual space of patients with chronic paronychia or onycholysis, in these patients Candida is only a secondary colonizer. In chronic mucocutaneous candidiasis, the yeast infects the nail plate and eventually the proximal and lateral nail folds.

In patients with chronic mucocutaneous candidiasis or immunodepression, several or all digits are affected by total onychomycosis associated with periungual inflammation. The digits often take on a bulbous or drumstick appearance.

 

Total dystrophic onychomycosis (TDOM): [Figure]f

This type presents as total destruction of the entire nail apparatus including whole thickness of the plate, the nail bed and matrix. The involved nail becomes crumbles and disappears, leaving behind an abnormal thickened nail bed.  It may be primary e.g. in cases with chronic mucocutaneous candidiasis or secondary to any of the four previous forms.

 

 

Laboratory Studies

 

OM has distinct clinical presentation, however, the key features are shared with other onychopathies like psoriasis and lichen planus. Hence, clinical examination in isolation is seldom sufficient to make a diagnosis of OM. Therefore, laboratory diagnosis of onychomycosis must be confirmed before beginning a treatment regimen. A negative mycological result does not rule out onychomycosis, because direct microscopy may be negative in up to 10% of cases and culture in up to 30% of cases.

 

The diagnosis of NDM OM is based on the presence of at least three of the following six criteria. These include identification of NDM in nail by direct microscopy; isolation of NDM in culture; repeated isolation in culture; inoculums counting; failure to isolate a dermatophyte in culture; and histology. 

 

Algorithm for the laboratory diagnosis of OM

 

 

Sampling techniques

Isolation of the fungal pathogen from nail is reportedly more difficult than for skin and hair. Conventionally, the material is taken from the distal end of the nail, despite the fact that the infection is advancing proximally. The hyphae at the distal end of the nail are less likely to be viable, hence less likely to grow on culture media. Hence, culture results improve if samples are taken from more proximal sites. Proximal sampling may be more uncomfortable for the patients but it should be the norm as far as possible.

Nail clippers should be used to include full thickness of the nail. Subungual debris is a good source with superficial scrapings being helpful only in cases of SWO. Culture sensitivity from samples collected by drilling techniques has been found to be statistically superior to those collected by curettage. Drilling technique can be horizontal or vertical (especially useful for PSOM).  In an Indian study, the use of dental drill for collection of nail samples significantly improved the culture yield for fungus.

Conventional methods of identifying causative organisms

Direct microscopy

A 20% potassium hydroxide (KOH) preparation in dimethyl sulfoxide (DMSO) is a useful screening test to rule out the presence of fungi. Before obtaining a specimen, the nails must be clipped and cleansed with an alcohol swab to remove bacteria and debris. The preparation does not require heating or prolonged incubation if DMSO is a component of the KOH solution.

 

In distal lateral subungual onychomycosis, a specimen should be obtained from the nail bed by curettage. The onycholytic nail plate should be removed and the sample should be obtained at a site most proximal to the cuticle, where the concentration of hyphae is greatest.

 

In proximal subungual onychomycosis, the overlying nail plate must initially be pared with a No. 15 blade. Then, a sample of the ventral nail plate may be taken.

 

A No. 15 blade may also be used to remove a specimen from the nail surface in white superficial onychomycosis.

 

Specimens suspected of candidal onychomycosis should be taken from the affected nail bed closest to the proximal and lateral edges.

 

Nail fragments must be small enough for examination under low power. Large pieces of nail plate may be pulverized prior to microscopy by using a hammer or a nail micronizer. Counterstains, such as chlorazol black E or Parker blue-black ink, may be used to accentuate the hyphae. It is reported that drilling to obtain specimens and taking the sample from a more proximal site yield better results. 

 

Culture

Direct microscopy cannot identify the specific pathogen involved in onychomycosis. A fungal culture must be used to identify the species of organism.  Non dermatophyte molds may be resistant to the conventional therapy used for the more common dermatophytes.  Therefore, 2 types of growth medium should be used, one with cycloheximide (dermatophyte test medium [DTM], Mycosel, or Mycobiotic) to select for dermatophytes and one without cycloheximide (Sabouraud glucose agar, Littman oxgall medium, or inhibitory mold agar) to isolate yeasts and non dermatophyte molds.

Cultures should be obtained from pulverized nail scrapings or clippings while the patient has abstained from antifungal medication for at least 2 weeks.

Cultures are incubated for three to four weeks and examined weekly. Fungal colonies are judged on the basis of growth patterns, color and microscopic formation of macro and microconidia or other typical growth features.  If growth is seen on both types of media, the infective agent is probably a dermatophyte, whereas growth only on the cycloheximide-free medium indicates that the infective agent may be an NDM.  Additional special culture media such as Potato Glucose Agar or Urea Agar may be needed to definitively differentiate between dermatophyte species. 

 

Diagnosis of NDM requires more than one laboratory analysis to show consistency of fungal growth. If NDM infection is present in the first culture, the patient should be re-examined on next visit and three separate samples should be taken from the affected nail.  If NDM is confirmed in all three of the cultures taken, the diagnosis of NDM is considered established and appropriate treatment can be started. 

Histologic Findings

 

Surgical pathology testing for OM using PAS (periodic acid Schiff stain) is the current Gold standard for the diagnosis of OM.  

 

Histologic examination of the nail is a very useful alternative to culture or KOH testing. Nail clippings may be sent to the laboratory for diagnosis in a formalin-filled container, or, as a last resort, an incisional nail biopsy (by punch or scalpel) may be performed to help confirm the diagnosis. Staining in the laboratory should be performed with periodic acid-Schiff stain (PAS) or methenamine silver stain to reveal fungal elements.

 

For histopathological examination, rather large nail clippings are taken, fixated for 4-8 hours in formalin and then softened [using agents like Potassium hydroxide (KOH), 5% trichloroacetic acid, 10% Tween- 40, or chitin softening solution containing mercuric chloride].  Softened tissue sample are fixed in 10% buffered phosphate formalin for 24 h, dehydrated and then embedded. Semi-thin sections (5 microns) are taken using a microtome and stained with periodic acid-Schiff (PAS), the procedure altogether taking about 24-48 hours.  

A comparison of diagnostic methods revealed that a nail biopsy and staining with PAS is the most sensitive technique available to diagnose onychomycosis.  Examining formalin-fixed, PAS-stained specimens has a higher probability (a higher negative predictive value) than KOH examination in determining that a patient is disease free if the test results are negative.

 

PAS is found to be the most sensitive single test for the diagnosis for OM with a sensitivity of 82%, followed by culture (53%) and direct microscopy (48%). Histopathology not only proves the presence of fungus within the nail plate, but also gives a valuable clue to the level of invasion and its arrangement. Staining with Grocott methenamine-silver (GMS) has been shown to be qualitatively superior to PAS as it provides greater contrast between fungus and surroundings thus making identification easier. However, the procedure is more complex. 

Histopathological examination is useful for distinguishing between dermatophytes, yeast and NDM and allows for examination of mycelia threads and spore morphology in detail. However, the time required for the procedure is the disadvantage which needs to be overcome.

Hyphae are seen between the nail laminae parallel to the surface and have a predilection for the ventral nail and stratum corneum of the nail bed. The epidermis may show spongiosis and focal parakeratosis, and there is a minimal dermal inflammatory response. In WSO, the organisms are present superficially on the dorsal nail and display unique “perforating organs” and “eroding fronds.” In candidal onychomycosis there is invasion of pseudohyphae throughout the entire nail plate, adjacent cuticle, granular layer, and stratum spinosum of the nail bed, as well as the hyponychial stratum corneum. As in direct microscopy, histopathologic diagnosis does not identify the species of causative pathogen.

 

 Newer methods

Polymerase chain reaction (PCR

 

Polymerase chain reaction (PCR) assays have been developed to detect fungal DNA from infected nails.  A highly sensitive nested PCR assay using species-specific primer pairs based on the 28S ribosomal RNA gene has been developed. This methodology permits detection of both dermatophytes and nondermatophytes. 

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS)

This technique is based on the detection of biochemical characteristics which are a result of the activity of mycological infections or noninfectious diseases. These are represented by proteolytic degradation products of native nail proteins. The technique analyses the protein patterns of nail samples by using small amounts of peptides derived from tryptic digests of collected samples. The peptide patterns of affected samples are identified by comparison with known peptide spectra from nail disorders stored in an already existing data base.  The technique does not require any living or nonliving fungal material to prove or to rule out OM. It is also able to discriminate between OM and nonfungal nail disorders offering a distinct advantage over the conventional methods of KOH and culture which only prove or rule out presence of fungi.  Observer skill is less important compared to other newer methods, as the results depend on software assisted analysis. The preparation of nail material is simple. The method is also fast, with results available within 24 hours.

Phase contrast hard X-ray microscopy

This technique uses phase contrast microscopes utilizing synchrotron radiation.  Synchrotron radiation can provide a precise image of an extremely small object because of its brightness and high spatial resolution (upto 70 nm).  Hence, it can precisely image the internal structure of dermatology specimens. This helps in observing minute structures without requiring fixatives or stains.  Resolution is also much improved.  The major advantage with this technique of microscopy is that, just like histopathology, it provides direct evidence of fungal invasion of nail plate, showing that the fungi are pathogenic.

 

Dermoscopy

 

Dermoscopy is useful to distinguish distal subungual onychomycosis from traumatic onycholysis. In distal subungual onychomycosis, the proximal border of the onycholytic area is jagged owing to the presence of yellow-white spikes that project into the proximal nail plate. This patterned has been reported as the "aurora borealis" pattern. 

 

 

 

Differential diagnosis

 

The destructive changes of the nail plate and nail bed produced by dermatophytes can be mimicked closely by psoriasis. Fine pitting of the dorsal nail plate is never produced by fungal infections and strongly suggests psoriasis, as does the oil-drop sign away from the free edge.  Paronychia caused either by bacteria or by Candida, usually affects the nail plate proximally and laterally, while the free edge is often spared, at least initially. Conversely, swelling of the nail fold is rare in dermatophyte infections, and purulent discharge is never a feature of uncomplicated tinea unguium.  Ringworm of the nails is rarely symmetrical, and it is common to find the nails of only one hand affected. The skin of the feet and of the palms should always be examined carefully. Nail clippings or scrapings are essential, and direct microscopy should be carried out with great care, as culture often fails with nail plate material. For this reason, it is wise to sample any obvious skin lesions present, as these are usually infected with the same organism and will be more likely to yield a positive culture.

 

Prognosis

 

The goals for antifungal therapy are mycological cure and a normal looking nail. Mycological cure can be evaluated at the end of treatment, while clinical cure requires several more months owing to slow nail growth. 

 

Clinical trials have repeatedly demonstrated higher efficacy for terbinafine compared with other antifungal treatments.

Yellow streaks along the lateral margin of the nail and/or presence of yellow onycholytic areas in the central portion of the nail (dermatophytoma) are associated with a poor response to treatment.

 

Residual nail changes persist in most patients as a result of the frequent association of onychomycosis with traumatic toenail dystrophies.

 

Onychomycosis caused by molds, particularly Fusarium species, are often not responsive to systemic therapy.

 

Recurrence (relapse or reinfection) of onychomycosis is not uncommon, with reported rates ranging from 10-53%. 

Fungal infections of the fingernails have a much more favorable prognosis than toenail infections.

 

Treatment

Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails, the severity of nail involvement, associated tinea pedis, along with efficacy and potential adverse effects of any treatment regimen. While it seems reasonable not to treat minimal nail involvement, concurrent tinea pedis should always be treated, particularly in the setting of diabetes mellitus, to prevent cellulitis. A systemic treatment is always required in proximal subungual onychomycosis and in distal lateral subungual onychomycosis involving the lunula region. White superficial onychomycosis and distal lateral subungual onychomycosis limited to the distal nail can be treated with a topical agent. Because the rate of recurrence remains high, even with newer agents, the decision to treat should be made with a clear understanding of the cost and risks involved, as well as the risk of recurrence. Photodynamic therapy and lasers may represent future treatment options. 

Medications for onychomycosis can be administered topically or orally. A combination of topical and systemic treatment increases the cure rate. Adjunctive surgical measures may also be used.

 

Topical therapy for onychomycosis is as follows:

·        Ciclopirox olamine 8% nail lacquer solution

·        Amorolfine 5% nail lacquer solution

·        Efinaconazole 10% topical solution (the first FDA-approved topical triazole for toenail onychomycosis)

·        Tavaborole 0.5% topical solution, an oxaborole solution (boron-containing compound)

·        Can be used in WSO and DLSO limited to the distal nail

·        Should be limited to cases involving less than half of the distal nail plate or for patients unable to tolerate systemic treatment

·        Topical treatments may be useful to prevent recurrence in patients cured with systemic agents

 

Oral therapy for onychomycosis is as follows:

·        Terbinafine

·        Itraconazole

·        Fluconazole and posaconazole are off-label alternatives

·        Systemic treatment is always required in PSO and in DLSO involving the lunula region

 

Nonpharmacologic approaches include the following:

·        Laser treatment

·        Photodynamic therapy

·        Mechanical, chemical, or surgical nail avulsion

·        Chemical removal with a 40-50% urea compound in patients with very thick nails

·        Removal of the nail plate as an adjunct to oral therapy

 

Laser treatment can be combined with topical antifungals. 

 

 

Topical antifungals

In those patients involving less than half of the distal nail plate, superficial white onychomycosis and/or contraindication for systemic treatment, topical therapy should be considered. Agents commonly used include ciclopirox olamine 8%, amorolfine, and efinaconazole 10% nail solutions.  Topical treatments alone are generally unable to cure onychomycosis because of insufficient nail plate penetration. Ciclopirox and amorolfine solutions have been reported to penetrate through all nail layers but have low efficacy when used as monotherapy.  They may be useful as adjunctive therapy in combination with oral therapy or as prophylaxis to prevent recurrence in patients cured with systemic agents. 

Ciclopirox 8% lacquer applied to the nail and surrounding skin at bedtime daily for 7 days and then removed with rubbing alcohol and repeat the application for 48 weeks achieved mycologic cure in 29%–36% of cases and clear nails (clinical cure) in 7% of mild to moderate cases of onychomycosis caused by dermatophytes. Despite its much lower efficacy compared with oral antifungal agents, use of topical ciclopirox avoids risk of drug interactions. Amorolfine is mainly used as a treatment for onychomycosis in the absence of matrix involvement in the form of 5% nail lacquer applied after abrading the nail once or twice weekly until the regeneration of nail (approximately 6 months in fingernail and 12 months in toenail onychomycosis). It is the first member of a new class of antifungal drugs, the morpholine derivatives, which show activity against yeasts, dermatophytes and molds that cause onychomycosis. Amorolfine may have higher mycologic cure rates (38%–54% after 6 months of treatment) compared to ciclopirox lacquer.

 

New topical antifungals treatments

 

E­finaconazole

 

It is a topical triazole antifungal agent. It inhibits fungal lanosterol 14α-demethylase involved in the biosynthesis of ergosterol, a constituent of fungal cell membranes. E‑ naconazole (Jublia 10% solution) is a topical imidazole active against dermatophytes and yeasts. It received FDA approval in 2014. Having a low affinity for keratin, this drug is able to penetrate the nail plate easily and selectively target pathogenic fungi. Despite having a higher molecular weight than ciclopirox, its low surface tension is thought to allow better penetration. Once within the nail, efinaconazole is observed to have a better efficacy than what is noted for ciclopirox. Studies showed that a single application of efinaconazole to the hyponechium was able to reach the site of infection at the nail bed and underside of the nail plate. Studies showed that the drug was able to penetrate the nail without disrupting the polish, resulting in a similar concentration as seen in control specimens free of polish.

 

Tavaborole

Tavaborole is boron based topical antifungal containing oxaborole molecules approved in 2014. It is available as 0.5% topical solution.

 

The increased affinity for fungal enzymes allows the drug to be selective against the pathogen without interfering with host protein synthesis. It is indicated for the treatment of onychomycosis caused by T. rubrum and T. mentagrophytes; however, it is also effective against an array of less commonly encountered pathogens, such as yeast. The low molecular weight of tavaborole allows for easy nail penetration. Drug levels in the nail remain high even at three months after treatment cessation. Using liquid chromatography and mass spectrometry, ex-vivo cadaveric nail studies showed significantly higher drug penetration of tavaborole compared to ciclopirox. Moreover, studies evaluating the e­ffects of nail polish on drug penetration determined that the presence of nail polish did not hinder the transungual delivery of tavaborole and might even enhance it. Despite the concern of boron-related toxicity, tavaborole appears to have an excellent safety profile, showing no cytochrome enzyme inhibition and negligible plasma levels after topical use.

 

Auriclosene

Auriclosene is a broad-spectrum antibacterial and antifungal agent belonging to a family of compounds known as aganocides. Current clinical studies are focusing mainly on the treatment of impetigo, conjunctivitis, and urinary catheter infections. However, preclinical studies have assessed its utility in the treatment of onychomycosis; an in-vitro evaluation on a cadaveric model utilized nanoemulsion lacquers and gel formulations to assess the growth inhibition of dermatophytes, which showed significant drug penetration and fungal eradication.

 

ME1111

ME1111 is a fungicidal compound e­ffective against dermatophytes, reaching sufficiently high concentrations in the nail to overcome the minimum inhibitory concentration (MIC) of these organisms. The ability of this drug to exert antifungal activity in the presence of keratin has not been assessed. However, the e­ffect of ME1111 showed selective toxicity to the fungal organisms. Phases I and II clinical trials assessing the pharmacokinetics and safety of ME1111 were recently completed, but results have not been published yet.

 

Luliconazole

Luliconazole is an imidazole antifungal with an added ketone dithioacetate component. In spite of its higher molecular weight, a modified molecular structure endows this novel antifungal with lower keratin affinity and, in turn, potentially improved potency. This drug is FDA-approved in a cream formulation for the treatment of fungal infections of the skin. Studies pertaining to onychomycosis used solutions of 5% applied daily for 48 weeks and assessed outcomes at the end of the treatment course; at this concentration, randomized control studies showed similar efficacy for Luliconazole and other approved topical treatments.

 

Systemic Therapy

An oral antifungal is required for onychomycosis involving the matrix area, or when a shorter treatment regimen or higher chance for clearance or cure is desired. Selection of the antifungal agent should be based primarily on the causative organism, the potential adverse effects, and the risk of drug interactions in any particular patient.

The newer generation of oral antifungal agents (itraconazole and terbinafine) has replaced older therapies in the treatment of onychomycosis.  They offer shorter treatment regimens, higher cure rates, and fewer adverse effects. Fluconazole and the new triazole posaconazole   (both not approved by the US Food and Drug Administration [FDA] for treatment of onychomycosis) offer an alternative to itraconazole and terbinafine. The efficacy of the newer antifungal agents lies in their ability to penetrate the nail plate within days of starting therapy. Evidence shows better efficacy with terbinafine than with other oral agents. To decrease the adverse effects and duration of oral therapy, topical treatments and nail avulsion may be combined with oral antifungal management

 

Terbinafine is fungistatic and fungicidal against dermatophytes, Aspergillus, and less so against Scopulariopsis. Terbinafine is not recommended for candida onychomycosis since it demonstrates variable efficacy against Candida species. A course of terbinafine 250 mg daily for 6 weeks is effective for most fingernail infections, while a minimum 12-week course is required for toenail infections. Most adverse effects are gastrointestinal such as diarrhea, nausea, taste disturbance, and elevation of liver enzymes. Evidence suggests that a 3-month continuous regimen of terbinafine is the most effective oral treatment for onychomycosis of the toenails available today. Clinical cure rates are approximately 50%, although the success rate is lower in patients over 65 years.  

Itraconazole is fungistatic against dermatophytes, nondermatophyte molds and yeasts. Safe and effective schedules include pulse dosing with itraconazole 400 mg daily for 1 week per month or a continuous dose of 200 mg daily, both of which require 2 months or 2 pulses of treatment for fingernails and at least 3 months or 3 pulses for toenails. Itraconazole is dosed by weight in children at 5 mg/kg/day. Elevated liver enzymes occur in 0.3%–5% of patients during therapy and return to normal within 12 weeks of discontinuation. Although itraconazole has a broader spectrum of activity than terbinafine, studies have shown a significantly lower rate of cure (about 25% vs. 50%) and higher relapse rate (about 50% vs. 20%) with itraconazole compared with terbinafine.  Fluconazole is fungistatic against dermatophytes, some nondermatophyte molds, and Candida. The usual regimen for fluconazole is 150–300 mg once weekly for 3–12 months.

Some, possibly 15% of patients, fail to respond to these drugs, and there is a strong clinical impression that results are much better in younger patient in that has faster linear nail growth and relative absence of coexisting ischemic or traumatic dystrophy is probably important factors. Poor peripheral circulation seems to have an adverse effect on treatment.

Avulsion of the nail or removal of the infected areas with a drill or burr as adjuncts to antifungals is occasionally valuable. The use of 40% urea cream under occlusive dressing is an alternative approach to treatment, particularly in oral treatment failures. The addition of the imidazole, 1% bifonazole, to the urea paste has produced good responses in some patients with involvement of the entire nail plate. When a single great toenail is infected, these procedures are worthy of serious consideration.  The use of combined treatment with either terbinafine or itraconazole with amorolfine may be more effective than oral therapy alone.

Although “cure” rates of up to 80% (or higher with prolonged therapy) have been reported with newer antifungal drugs (itraconazole, fluconazole and terbinafine), recurrent disease, especially in toenails, is common. Preventive measures include breathable footwear and cotton socks, antifungal or absorbent powders, frequent nail clipping and avoiding re-exposure (e.g. not going barefoot in locker rooms). Old shoes often harbor large numbers of infectious organisms and should be discarded or treated with disinfectants or antifungal powders.

INDICATORS OF MORE SEVERE ONYCHOMYCOSIS WITH A POOR RESPONSE TO TREATMENT
Nail factors	·       Subungual hyperkeratosis >2 mm thick (Measurement of nail plate plus nail bed).   ·       Significant lateral involvement   ·       Dermatophytoma (Streak or patch representing a subungual pocket of densely packed hyphae; removal prior to initiating antifungal therapy can be helpful).   ·       >50% involvement of nail bed   ·       Slow nail growth rate   ·       Total dystrophic onychomycosis   ·       Matrix involvement
Patient factors	·       Immunosuppression   ·       Peripheral arterial disease   ·       Poorly controlled diabetes mellitus

 

Treatment ladder

First line

·        Oral terbinafine 250 mg/day for 6 weeks for fingernails, for 3 months for toenails

Or

·        Itraconazole 400 mg/day for 1 week, monthly for 2–3 months for fingernails, for 3–4 months for toenails

Second line

 

Topical treatment with amorolfine or ciclopirox olamine can be used in mild infections affecting the distal nail plate only or superficial white onychomycosis.

 

Guidelines Summary

 

In 2014, the British Association of Dermatologists published updated evidence-based guidelines for the management of onychomycosis.  Treatment recommendations are given for both adults and children (ages 1-12 y).

 

Adult systemic treatment recommendations are as follows:

 

·        Terbinafine as first line of treatment for dermatophyte onychomycosis and generally preferred over itraconazole; not recommended for patients with active or chronic liver disease (level A)

·        Itraconazole as first line of treatment for dermatophyte onychomycosis (level A)

·        Fluconazole may be a useful alternative in patients unable to tolerate terbinafine or itraconazole (level B)

·        Griseofulvin is no longer a treatment of choice owing to lower efficacy and higher relapse rates compared with terbinafine and itraconazole (level C)

·        Combination treatment recommended if response to topical monotherapy is likely to be poor (level D)

 

Adult topical treatment recommendations are as follows:

·        Amorolfine or tioconazole are useful for superficial and distal onychomycosis (level D)

·        Ciclopirox is useful for superficial and distal onychomycosis and for patients in whom systemic therapy is contraindicated (level D)

 

Adult other treatment recommendations are as follows:

 

·        Surgical avulsion, debridement alone, and photodynamic therapy (PDT) not recommended

 

Children systemic treatment recommendations are as follows:

·        Terbinafine as first line of treatment for dermatophyte onychomycosis and generally preferred over itraconazole (level A)

·        Itraconazole is first line of treatment for dermatophyte onychomycosis (level A)

·        Fluconazole considered as second line if itraconazole and terbinafine contraindicated or not tolerated (level B)

·        Griseofulvin considered as second line if itraconazole and terbinafine contraindicated or not tolerated (level C)

 

Steroid‐modified tinea (tinea incognita)

 

Introduction

 

These are ringworm infections modified by corticosteroids (systemic or topical) prescribed for some pre‐existing pathology or given mistakenly for the treatment of misdiagnosed tinea.

Normally, the clinical diagnosis of tinea depends heavily on the inflammatory changes involved. This inflammatory response may be almost totally suppressed by corticosteroids, systemic or topical. At the same time, it is probable that the resistance to infection mediated by the immune response, especially the cell‐mediated response, is diminished by corticosteroids. In this situation, the patient suffers doubly: the infection is less likely to be diagnosed, and the patient has been rendered more susceptible to that infection.

With patients on systemic steroids (perhaps treated with additional immunosuppressive agents or irradiation), the degree of modification is often minor, but even in these cases it may be sufficient to mislead, especially on the face. With topical steroids, the degree of modification can be profound. The usual sites where this problem occurs are the groins, lower legs, face and hands, but tinea circinata elsewhere may be steroid treated.

 

Clinical features

 

History

 

The history is characteristic. The patient is often satisfied initially with the treatment. Itching is controlled and the inflammatory signs settle. But there is a relapse on stopping treatment, with varying rapidity. Further applications bring renewed relief and the cycles are repeated. In the groins, the patient may develop few persistent nodules, which become insuppressible by the steroid preparation.

 

Presentation

 

Typically, the raised margin is diminished. Scaling is lost and the inflammation is reduced to a few nondescript nodules. Often, a bruise‐like brownish discoloration is seen, especially in the groins. On the face, the picture may be modified by superimposed perioral dermatitis with papules and tiny pustules. Steroid‐modified eyelid infection may closely resemble a sty. With chronic use, atrophy, telangieciectasia and, in the groins and axillae, striae are likely to be observed. In some cases, concentric rings of erythema are seen among the atrophy and telangiectasia. Presumably, these represent waves of fungal growth. The eruption remains localized but, especially in E. floccosum infections, it spreads more widely. Strong fluorinated steroids seem most likely to produce this syndrome, but even 1% hydrocortisone cream can, on occasions, modify tinea to a confusing extent.

 

Differential diagnosis

 

The differential diagnosis of other steroid‐modified infections in the groin, particularly candidosis, must be considered, and these may be indistinguishable without cessation of therapy and mycological investigations.

 

Investigations

 

Scrapings may be difficult to obtain in a patient who is currently applying a steroid cream, but if he or she stops it for a few days an upsurge of inflammation with marked scaling often occurs, making clinical diagnosis easier and facilitating the taking of scrapings. In such samples, fungal mycelium is usually abundant but scrapings taken while steroids are still being applied may show very few fungal elements, unless a fluorescent whitener is used.

 

Treatment

 

Whatever site is affected, it is often best to treat steroid‐modified ringworm with oral therapy, allowing a few applications of topical steroid to continue until the terbinafine or itraconazole has begun to take effect. It is wise to use 1% hydrocortisone cream or at least a weaker steroid than that originally prescribed, and also to warn the patient about a possible rebound in spite of these measures. Follow‐up to ensure steroid cream has been stopped and cure obtained is mandatory.

 

 

Dermatophytide reactions

 

Definition

 

This is a non‐infective inflammatory cutaneous eruption representing an allergic response to a distant focus of dermatophyte infection. A local DTH response to systemically absorbed fungal antigen is observed.

 

Predisposing factors

 

The essential criteria required for the diagnosis of an ide reaction to a dermatophyte infection are the following:

1.   Proven dermatophyte infection, which usually becomes highly inflamed before the appearance of the secondary rash.

2.   A distant eruption, which is demonstrably free of ringworm fungus.

3.   Spontaneous disappearance of the rash when the ringworm infection settles, with or without treatment.

4.   The morphology of the ide eruption should match one of the following well‐recognized types.

 

Clinical features

1.   A widespread eruption of small follicular papules grouped or diffusely scattered. The eruption is symmetrical, usually pronounced on the trunk, but in severe cases extending down limbs, even at times covering the face. Sometimes the follicular papules are topped by horny spines. The common cause of this type of ide reaction is a scalp ringworm kerion, typically caused by T. verrucosum. On occasions, T. tonsurans and M. audouinii may be responsible, when they produce inflamed ringworm. Treatment of the original ringworm lesion may play a part in initiating the process.

2.   A pompholyx‐like ide affecting the web spaces and palmar surfaces of the fingers, the palms and sometimes the dorsal surfaces of the hands. This eruption is characteristically associated with an acutely inflammatory tinea pedis, which may have arisen spontaneously or as a result of inappropriate treatment. The palmar and web space skin may be covered with papules or vesicles. On occasions, bullae or pustules may occur. Clinically, this is indistinguishable from a constitutional eczema of the pompholyx variety, and the diagnosis of a dermatophytide in this clinical situation demands rigorous application of the criteria outlined above.

 

DIAGNOSTIC PROCEDURES OF DERMATOPHYTOSIS

The clinical diagnosis of a dermatophyte infection can be confirmed by microscopic detection of fungal elements, by identification of the species through culture, or by histologic evidence of the presence of hyphae in the stratum corneum. In addition, fluorescence patterns under Wood's light examination may support a clinical suspicion.

 

Microscopic Examination

Although microscopic evaluation of potassium hydroxide (KOH)-treated samples does not allow for speciation or characterization of the susceptibility profile, it is used as a quick and inexpensive bedside tool to provide evidence of dermatophytosis.

Scale from skin should be collected by scraping the involved area with a dull edge outward from the advancing margins. Full thickness nail clippings should involve the dystrophic portion, as proximal from the distal edge as possible without causing injury. Hairs should be plucked (not cut). The specimen is then placed on a glass slide and adds 1–2 drops of a 10%–20% KOH solution and covered with a cover slip and then examined under low power microscope. Slightly warming the slide with a low intensity flame allows better penetration of the KOH solution into keratin.

All the dermatophyte species appear identical in skin and nail samples. Septate and branching hyphae without constriction at the branching point may be visualized under microscopic examination with 10%–20% KOH preparation. The hyphae are very even in diameter along their length and regularly septate. In some specimens the hyphae fragment to form arthroconidia, which disarticulate when mature, and may then round up and increase notably in size. These germinate to produce true hyphae. The chlorazol black E stain can help to highlight fungal elements in KOH preparations. Use of calcofluor, a fluorescent stain specific for the chitin in the fungal cell wall, and examination with a fluorescent microscope can also demonstrate fungi (apple-green fluorescence).

Hair invasion results in three distinct patterns: ectothrix, arthrosporic endothrix and favus endothrix and these are readily distinguishable by the arrangement and the size of the fungal elements. When trying to determine whether infection is endothrix or ectothrix, it is useful to note that the pigment in the hair clearly delineates the edge of the hair shaft, and can be used as a marker to judge whether the fungus is entirely confined within the hair or has formed an ectothrix sheath of arthroconidia on the surface. Low-power microscopy will reveal: (1) Ectothrix—small or large arthroconidia forming a sheath around the hair shaft, (2) Endothrix—arthroconidia within the hair shaft, or (3) Favus endothrix —hyphae and air spaces within the hair shaft.

Because KOH examination may yield false-negative results in up to 15% of cases, patients suspected of having dermatophytosis on clinical impression should be treated. Culture confirmation should be considered whenever systemic treatment is warranted, such as in the case of tinea capitis.

 

Culture

Sabouraud's dextrose agar (SDA) is the most commonly used isolation medium for dermatophytes and it serves as the medium on which most morphologic descriptions are based. Elimination of contaminant molds, yeast and bacteria is achieved by the addition of cycloheximide and chloramphenicol (+/−gentamicin) to the medium making it highly selective for the isolation of dermatophytes. The development of colonies can take 5–7 days in the case of Epidermophyton floccosum and up to 4 weeks for Trichophyton verrucosum. Cultures are incubated at room temperature (20°C–25°C) for at least 4 weeks before being finalized as no growth.

Dermatophyte test medium (DTM) is an alternative isolation medium that contains the pH indicator phenol red. The medium turns red when dermatophyte proteolytic activity increases the pH to 8 or above, and it remains amber with the growth of most saprophytes. Nondermatophyte acidic byproducts turn the medium yellow.

 

Histopathology

 

Skin biopsy is not often employed in the workup of typical dermatophytoses. Localized cutaneous eruptions suspected to represent dermatophytosis with equivocal KOH examination are often treated despite the lack of confirmation. Biopsy may confirm the diagnosis when a systemic agent is being considered for treatment of a recalcitrant or more widespread eruption. Biopsy may be used to aid in the diagnosis of Majocchi's granuloma in which KOH examination of scale on the surface may more often be negative. Biopsy is also sometimes useful in confirming the presence of hyphae involving hair shafts on the scalp in tinea capitis, although culture is necessary to allow speciation of the pathogen. When present, hyphae may be appreciated in the stratum corneum on hematoxylin and eosin staining. However special stains, most commonly periodic acid-Schiff (PAS) and methenamine silver stains, highlight hyphae that may otherwise be subtle in appearance on routine staining. Whereas culture is the most specific test for onychomycosis, PAS examination of nail clippings is the most sensitive and it obviates the need to wait weeks for a result.

 

Wood's Light Fluorescence

Examination of involved hair bearing areas, such as the scalp or beard, with a Wood's lamp (365 nm) may reveal pteridine fluorescence of hair infected with particular fungal pathogens. Hairs that fluoresce should be selected for further examination, including culture. While ectothrix organisms M. canis, M. audouinii and M. ferrugineum will fluoresce yellow-green on Wood's light examination, the endothrix organisms T. tonsurans and T. violaceum will not fluoresce.

 

Dermoscopy

The comma hairs, which are slightly curved, fractured hair shafts, and corkscrew hair shave been described as the dermoscopic marker of tinea capitis. Broken and dystrophic hairs are also seen. However, in tinea corporis, the involvement of vellus hair as seen on dermoscopy is an indicator of systemic therapy.

Polymerase chain reaction and nucleic acid sequence based amplification

These tests not only help in the rapid and early diagnosis of infection but also help in determining drug resistance, and include:

·        Uniplex PCR for direct dermatophyte detection in clinical samples: A PCR for the direct detection of dermatophytes in skin scales is available as in-house PCR-ELISA assay which separately identifies numerous dermatophyte species. In a pilot study, the sensitivity and specificity of the test compared to cultures was 80.1% and 80.6%

·        Multiplex PCR for fungal detection in dermatophytes: Commercially available multiplex PCR tests enable simultaneous amplification of 21 dermatomycotic pathogens with subsequent DNA detection by means of agarose gel electrophoresis.

 

 

Common Laboratory Dermatophyte Identification Methods

Laboratory Test	Method	Function	Findings
Potassium hydroxide preparation	Scales from the advancing border, subungual debris, or affected hair removed and placed on a glass slide. KOH 10% dropped on specimen and covered with a cover slip. The undersurface of the glass slide may be gently heated with a low-lit flame.	KOH solution and gentle heating softens keratin and highlights the dermatophyte.	Long narrow septated and branching hyphae
Culture	Sabouraud medium (4% peptone, 1% glucose, agar, water)	Facilitates growth of dermatophytes	Microscopic morphology of microconidia and macroconidia, along with culture features including surface topography and pigmentation.
	Modified Sabouraud medium (addition of chloramphenicol, cycloheximide, and gentamicin)	Facilitates growth of dermatophytes and inhibits growth of non-Candida albicans, Cryptococcus, Prototheca species, P. werneckii, Scytalidium species, Ochroconis gallopava
Histolopathology special stains: periodic acid-Schiff and Grocott's methenamine silver	Tissue may be obtained by skin or nail biopsy techniques	Stains fungal cell wall to detect fungal elements in tissue sections	Pink (PAS) or black (GMS) fungal elements noted in the stratum corneum

Proper collection of skin, hair, and nails is important. Following these simple guidelines will help the clinician to achieve the most accurate diagnosis.

 

Differential diagnosis

Careful clinical examination is the first and most important step in diagnosing dermatophyte infections. Because many other conditions can mimic dermatophytoses, KOH examination and/or culture are often necessary to confirm the diagnosis.

Colonial morphology, microscopic examination of conidia (the asexual propagules formed de novo by the fungus), allow precise identification of the dermatophyte. The presence or absence of microconidia (usually small and unicellular) and macroconidia (usually larger and multicellular) and the typical features of each (such as shape and cell wall texture) remain fairly consistent among genera. Other distinguishing microscopic features include the identification of arthroconidia (infective fungal elements) and chlamydoconidia. Sometimes, conidia may not be present in culture (“sterile” organism), and the hyphal patterns (spiral, pectinate, antler, racquet, and nodular bodies) may be important in identification of the organism. The color, texture and topography of the colony are features that are unique to a particular species.

 

 

Management

 

Multiple topical and systemic antifungal agents are available to treat dermatophytoses of skin, hair and nails.

Topical antifungals are the first-line treatment for many patients with uncomplicated, localized or mild cutaneous dermatophyte infections. Patients should be counseled on the rule of two, i.e. topical antifungal to be applied 2 cm beyond the margin of lesion twice a day for at least 2 weeks beyond clinical resolution. The major potential adverse reaction is irritant (or, occasionally, allergic) contact dermatitis, usually from the alcohols or other components in the vehicle. Systemic antifungal therapy, although associated with both a higher incidence of side effects including potentially severe adverse reactions and the potential for drug–drug interactions, is typically required for infections involving hair bearing skin such as tinea capitis and tinea barbae, and nails ( tinea unguium) and is also needed for infections involving extensive areas of skin, or associated with excessive inflammatory reactions. The newer oral azoles, such as fluconazole or itraconazole and terbinafine, are now the preferred oral treatments for extensive or severe dermatophytosis rather than griseofulvin. The adjunctive use of topical products containing glycolic acid, lactic acid or urea may help to reduce the amount of hyperkeratosis in infections such as tinea manuum and tinea pedis.

 

 

 

 

ANTIFUNGAL targets. (a) Antifungal targets on the fungal cell. (b) Influence of individual active substances on ergosterol biosynthesis

 

 

Oral antifungal drugs

 

Terbinafine

Terbinafine is a member of the allylamine antifungals that act by the inhibition of squalene epoxidase in the formation of the fungal cell membrane. This enzyme acts at an early stage in membrane biosynthesis, and the accumulation of squalene is thought to destabilize the cell membrane. The two main antifungal compounds are naftifine and terbinafine. Both are active in vitro against dermatophytes in addition to other fungi; terbinafine is also active against Sporothrix schenckii, some Aspergillus species and Histoplasma capsulatum. The drug is fungicidal rather than fungistatic. Although it is not licensed for use in children, it has been widely used off‐label in this group of patients. Terbinafine can be given topically or orally. When given orally, it is rapidly taken up into the stratum corneum and it persists in nails at high concentrations for several months. These may exceed the minimum inhibitory concentration 80 days after the end of therapy. Terbinafine is given orally in a dosage of 250 mg/day. It has produced rapid and long‐lasting remissions in nail disease and persistent tinea pedis, as well as tinea corporis. A smaller tablet form of 125 mg is available for the treatment of children. There are few drug interactions reported for terbinafine, and side effects are uncommon. The spectrum of side effects includes headache, nausea (usually in the first week; apply medication in the evening), and (rarely) usually reversible taste loss. Terbinafine can worsen psoriasis or provoke it de novo (usually within the first 4 weeks of treatment), and drug-induced subacute-cutaneous LE can also occur, especially if risk factors (pre-existing connective tissue diseases) are present. Hepatic reactions, although reported, are exceptionally rare. Drug rashes including erythema multiforme or toxic epidermal necrolysis are also seen on occasion.

 

Itraconazole

This is an orally active azole of the triazole series. It has similar activity to ketoconazole, but without the risk of hepatotoxicity. Its mode of action is through the inhibition of the cytochrome P450‐dependent demethylation stage in the formation of ergosterol on the fungal cell membrane. It is active in vitro against all the main superficial fungal pathogens including Candida albicans, pityriasis versicolor, as well as a wide range of fungi that cause deep infections such asaspergillosis, histoplasmosis and cryptococcosis. Itraconazole rapidly penetrates to the outer stratum corneum and is also found in sebum. It is avidly bound to keratin‐containing tissues, and in nails, for instance, may persist long after cessation of therapy. It has been shown that after 3 months of 200 mg/day itraconazole, levels in the toenail persist for up to 6 months. This feature allows a range of different dose regimens. The initial treatment first described involving 100 mg/day itraconazole have been superseded by higher or intermittent (pulsed) therapy. The currently preferred regimen uses 400 mg/day, given as two daily doses of 200 mg. In tinea corporis, 1 week of therapy is sufficient, and in tinea pedis, 2 weeks. For onychomycosis, a regimen of 400 mg/day for 1 week every month for 3 months is usually given. Occasionally, longer periods of treatment are needed. It is effective in tinea capitis also. There is some evidence that its absorption is impaired in the presence of phenobarbital. It also interacts with coumarin anticoagulants, ciclosporin, rifampicin, digoxin and statins. Side effects are uncommon and mainly consist of nausea and abdominal discomfort. Hepatic reactions are exceptional and liver function should be monitored if it is used for longer than 1 month. It has been associated with heart failure and cardiac arrhythmias in those at risk.

 

Fluconazole

Fluconazole is an orally active triazole antifungal used for the treatment of dermatophyte infections (tinea), pityriasis versicolor and mucocutaneous candidosis and also systemic mycoses. In dermatophytosis it is given in a regimen of 150 mg/week for 2–3 weeks for tinea corporis and tinea cruris, and somewhat longer for dry‐type tinea pedis. It is also reported to be effective given in weekly doses in onychomycosis. There are fewer interactions than with itraconazole but, like the latter, side effects are rare and mainly confined to gastro‐intestinal discomfort. However, drug resistance in Candida species, particularly C. krusei and C. glabrata, has been described. There is also C. albicans resistance in some patients, particularly in those with HIV/AIDS. It should be used with caution in those at risk of cardiac arrhythmias.

 

 

Treatment of dermatophytosis

 

 

Disease	Topical Treatment	Systemic Treatment
Tinea capitis	Only as adjuvant Selenium sulfide 1% or 2.5% Zinc pyrithione 1% or 2% Povidone iodine 2.5% Ketoconazole 2%	Adults: ·       Terbinafine, 250 mg/day × 2–4 weeks ·       Itraconazole 200mg/day × 2–4 weeks ·       Fluconazole, 6 mg/kg/day × 3-6 weeks Children: ·       Terbinafine daily x 2-4 weeks Weight < 20 kg = 62.5 mg/day Weight 20-40 kg = 125 mg/day Weight > 40 kg = 250 mg/day   ·       Itraconazole, 5 mg/kg/day (maximum 200mg) × 2–4 weeks
Tinea barbae	Only as adjuvant Topical antifungals	·       Terbinafine, 250 mg/day × 2–4 weeks ·       Itraconazole, 200 mg/day × 2–4 weeks ·       Fluconazole, 200 mg/day × 4–6 weeks
Tinea corporis/cruris	Allylamines Imidazoles Butenafine Ciclopirox	Adults: ·       Terbinafine, 250 mg/day × 2–4 weeks ·       Itraconazole, 200 mg/day × 1 week ·       Fluconazole, 150–300 mg/week × 4–6 weeks Children: ·       Terbinafine daily × 2 weeks (as for T. capitis) ·       Itraconazole, 5 mg/kg/day (maximum 200mg) × 1 week
Tinea pedis/manuum	Allylamine Imidazoles Ciclopirox	Adults: ·       Terbinafine, 250 mg/day × 2 weeks ·       Itraconazole, 200 mg twice daily × 1 week ·       Fluconazole, 150 mg/week × 4-6 weeks Children: ·       Terbinafine daily × 2 weeks (as for T. capitis)   ·       Itraconazole, 5 mg/kg/day (maximum 200mg) × 2 weeks
Onychomycosis	Ciclopirox Amorolfine	Adults: ·       Terbinafine, 250 mg/day × 6–12 weeks ·       Itraconazole, 200 mg/day × 2–3 months Or pulse 400mg/day x 1 week/month for 2-3 months ·       Fluconazole, 150–300 mg/week × 3–12 months Children: ·       Terbinafine daily × 6–12 weeks Weight < 20 kg = 62.5 mg/day Weight 20-40 kg = 125 mg/day Weight > 40 kg = 250 mg/day   ·       Itraconazole 1 week/month for 2-3 months Weight < 20 kg =5 mg/kg/day Weight 20-40 kg = 100 mg/day Weight 40-50 kg = 200 mg/day Weight >50 kg = 200 mg twice daily ·       Fluconazole, 6 mg/kg/week × 3–6 months

 

 

 

Treatment failures

 

Failure of topical therapy

 

Most failures of topical therapy are caused by inaccurate diagnosis or by inappropriate use of topical therapy (e.g. in hairy areas) or because the treatment is not used. Once or twice daily application for several weeks is usually required for success. Many dermatoses respond, at least temporarily, to any bland application, and imidazole compounds in particular have considerable antibacterial properties.

 

Failure of oral therapy

 

When a patient fails to respond to terbinafine, fluconazole or itraconazole, the following points should be checked:

1.   Is the diagnosis correct? If necessary, repeat scrapings.

2.   Has the patient been taking the tablets regularly?

3.   Is the patient taking any potentially competitive drugs?

4.   In spite of taking them correctly, is the patient failing to absorb the antibiotic? An estimation of itraconazole levels, which is sometimes poorly absorbed, may be helpful.

5.   In some patients with onychomycosis, poor penetration of drugs into defined linear streaks or nail edge areas of nail plate infection may account for treatment failure. Surgical removal of these abnormal nail areas, often after softening with urea ointment, may be useful.

6.   Is there coexisting pathology such as HIV/AIDS or arterial disease?

7.   Is a co‐pathogen or secondary infection present? This should be considered in the feet and in the case of kerions, and perhaps in groin infections too. In nails, the coexistence of non‐dermatophyte fungus should be considered. Scopulariopsis brevicaulis, apart from causing infections of the toenails in its own right, may coexist with Trichophyton rubrum or T. interdigitale and seems, at least on occasions, to cause failure of treatment. Nail removal may be indicated in this instance.

8.   Antifungal resistance. This phenomenon is sufficiently uncommon among dermatophytes to make routine testing unnecessary, but where treatment failure occurs without any other explanation, it is possible to estimate the sensitivity of the causal organism. This should be performed by a specialist laboratory. Apart from true resistance, tolerance, in which the organism apparently becomes clinically resistant to the drug in the tissues but is sensitive in vitro, may also, be important.

9.   Reinfection. As ringworm fungi can frequently be isolated from the environment, when there are cases of ringworm of the scalp, and from clothing after laundering, it is highly likely that patients whose infection has been eradicated may be re infected from these sources. Unfortunately, there is no proven way to avoid this.

Despite running through this checklist, dermatologists may not come up with an adequate explanation for treatment failure. In these situations, the use of one of the alternatives is a logical further step.

 

 

(IADVL) task force against recalcitrant tinea (ITART) consensus on the management of glabrous tinea (INTACT), 2020

 

Definitions

Glabrous tinea: Dermatophytosis involving the skin of any site, except terminal hair-bearing areas of the scalp and face (tinea capitis/tinea barbae), palms (tinea manuum), soles (tinea pedis) and nails (tinea unguium); notwithstanding the true meaning of glabrous as “without hair”. It constitutes tinea corporis, tinea cruris and tinea faciei, and may also include involvement of hair bearing regions without invasion of hair by fungi.

 

Chronic dermatophytosis: Presence of glabrous tinea for a duration of six months or longer, continuous or recurrent, with or without treatment. Duration was earlier considered to be more than one year.

 

Recurrent dermatophytosis: Reoccurrence of the glabrous tinea after 4 weeks of stopping treatment following clinical cure but less than 6 weeks

 

Relapse: Relapse denotes the occurrence of dermatophytosis (lesions), after a longer period of infection-free interval (6–8 weeks) in a patient who has been cured clinically.

 

Resistant dermatophytosis: Failure to eliminate dermatophytosis despite administration of one or more antifungal agents for an adequate dose and duration, based on clinical judgment due to proven mycological resistance to the drugs.

 

Naïve case: A patient with glabrous tinea who has not received any prior treatment.

 

Corticosteroid modified tinea: Glabrous tinea whose morphology is altered due to topical or systemic corticosteroids, but is still recognisable or diagnosable.

Tinea incognito: Glabrous tinea in which the morphology is markedly altered due to the suppression of inflammation by corticosteroids or other immunosuppressants such that it is not easily recognisable as tinea.

 

Over-the-counter (OTC) medications: Medications purchased from a pharmacy without prescription by a qualified healthcare professional

 

Clinical cure: Complete resolution of symptoms and signs with or without post-inflammatory changes at the end of treatment

 

Mycological cure: Complete subsidence of symptoms and signs with negative mycological reports (direct microscopy and/or culture) at the end of the treatment.

 

BSA: The area of outstretched palm from the wrist to the tip of the fingers can be considered roughly 1% of the body surface area. Less than 3% can be counted mild, 3–10% as moderate, and more than 10% as severe, in terms of the extent of involvement.

 

Recalcitrant tinea infection: This is a generic term that may refer to relapse, recurrence, persistence of infection, chronic infection, corticosteroid-modified and resistant cases, with poor or no response to standard treatment.

 

Trichophyton Rubrum Syndrome is defined as

(A) Skin lesions at the following four sites:
(1) Feet, often involving soles;
(2) Hands, often involving palms;
(3) Nails; and
(4) At least one lesion in another location other than (1) (2) or (3), except for the groin.
(B) Positive microscopic analyses of potassium hydroxide preparations of skin scrapings, in all four locations.
(C) Identification of Trichophyton rubrum by cell culture at three of the four locations at least.
For diagnosis of TRS, the criteria (A) and (B) and (C) have to be fulfilled.

 

 

Laboratory diagnosis

 

Role of various laboratory methods in the diagnosis of dermatophytosis

Principle	Method	Comments
Direct microscopic examination	Direct microscopy using potassium hydroxide mount and its modifications	An office procedure with relatively high sensitivity
		Should be done whenever feasible, especially if there is diagnostic difficulty on clinical examination
Histopathology	Histopathology with special stain with periodic acid Schiff (PAS) stain	Indicated in suspected Majocchi granuloma or deep dermatophytosis
Isolation by culture and species identification	Fungal culture on Sabouraud’s dextrose agar	Sensitivity is low, but specificity is high; considered as the gold standard in the diagnosis
		May be performed whenever feasible for confirmation of clinical diagnosis and to understand the epidemiological trends in a region
Identification of species and subspecies by molecular diagnostic methods	Sequencing of the internal transcribed spacer (ITS) region of the ribosomal DNA, Random Amplified Polymorphic DNA (RAPD), Amplified Fragment Length Polymorphism (AFLP), mitochondrial DNA (mt DNA) restriction analysis, Sequencing of protein-encoding genes, polymerase chain reaction (PCR) fingerprinting.	Requires specially equipped laboratory with trained manpower
		Currently utilised for research purposes but may find a place in conventional diagnosis in future
Identification of species and subspecies by proteomic signature	Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry	Requires specially equipped laboratory with trained manpower
		Currently used for research purposes but may find a place in conventional diagnosis in future
Antifungal sensitivity testing (AFST)	Microbroth dilution method	Tedious procedure requiring trained manpower
		Lack of reference data on minimum inhibitory concentration (MIC) of antifungal drugs used against dermatophytes.
		If facilities are available, it should be considered whenever there is a strong suspicion of antifungal resistance
Identification of mutation causing antifungal resistance	Real Time Polymerase chain reaction (RT PCR), Sequencing of DNA	Requires equipped laboratory with trained manpower; currently utilised for research purpose
		Whenever there is strong suspicion of antifungal resistance it may be considered

Diagnosis of dermatophytosis has lately become more challenging, with atypical morphological variants being more commonly seen, of which many are attributable to topical corticosteroid abuse. When clinical diagnosis is difficult, experts recommended direct microscopic examination as an office procedure with potassium hydroxide (KOH) mount, a test with high sensitivity, to confirm dermatophytosis. The specimen should be obtained by scraping the lesion's active margin when present or from its scaly region and transported in a sterile, thick dry black sheet of paper to the laboratory, if the facility is not available in the outpatient clinic. It is advisable to perform a microscopic examination of 10% KOH mount of skin scrapings in every case, for a better treatment outcome and should be observed 15–30 min after preparation, to improvise the sensitivity. Dermatophytes are visualized as hyaline, long, branching, septate hyphae with/without arthrospores. But direct microscopy does not help to identify the species. If feasible, the organism can be isolated by culture in modified Sabouraud's dextrose agar with antibiotics and cycloheximide, to understand the epidemiological trends in a region and for possible therapeutic implications. Macroscopic appearance of culture colony and microscopic morphological features of the microconidia, macroconidia and other vegetative structures can help to identify the various species

Histological diagnosis of dermatophytosis is not done routinely but can be useful in diagnosis of unusual clinical presentations like Majocchi granuloma and deep dermatophytosis. Staining with periodic acid Schiff (PAS) stain can ease identification of hyphae in tissue.

Antifungal susceptibility testing (AFST) studies to know the local drug susceptibility patterns and molecular diagnostic techniques required for the accurate identification of the dermatophyte species may be considered in research institutes or if reference laboratories are available. However, there was no consensus on the utility of real time polymerase chain reaction (RT-PCR) and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) in the current scenario, since these are relatively new and the clinical implications are not known.

 

 

General measures

 

Consensus on points for counseling patients with dermatophytosis

Points for discussion with patients	Expected impact
Current scenario of dermatophytosis in India	Patients will understand the gravity of the situation and follow medical advice accurately
Taking regular bath (at least once a day)	Reduces fungal load due to exfoliation of scales
Wiping the body dry (especially intertriginous area and toe clefts)	Prevents high moisture in those parts, minimizing chances of fungal colonization
Regular washing of clothes in hot water and drying in sunlight inside out	Reduces chances of re-infection from infected clothes
Storing and washing clothes of infected patients separately	Reduces chances of transmission to contacts and family members
Regular washing of bed linen (at least once a week)	Minimizes chances of re-infection from infected linen
Avoidance of sharing of fomites like clothes, towels and soaps with others	Reduces transmission to contacts and family members
Avoidance of synthetic tight garments	Prevents occlusion, maceration, friction and barrier dysfunction
Avoidance of wearing bands, threads, draw strings and rings	Reduces chances of re-infection from such infected materials
Regular mopping and cleaning of the house	Reduces chances of persistence of dermatophytes in the environment
Losing weight in obese patients	Reduces chances of intertriginous fungal infections
Avoidance of contact with pets	May reduce zoophilic infection and transmission
Avoidance of application of topical corticosteroids	Reduces chances of unusual presentations, diagnostic difficulty and treatment failure
Strict adherence to treatment	Enhances chances of complete cure and reduces recurrence
Simultaneous treatment of other infected house members and close contacts (prophylactic treatment is not required)	Reduces chances of transmission to each other and recurrence
Avoidance of self-medication, over the counter(OTC) medications and sharing of prescriptions	Reduces chances of inadequate treatment, topical corticosteroid misuse and treatment failure

 

  

Global warming has affected the climate in India in the form of increased maximum temperatures, heat waves and less rainfall. Indian Meteorological department data have shown an increase of 0.6°C in the average temperatures between 1901-10 and 2009-18. The number of days with maximum temperature exceeding 35°C in various cities in India has also increased. A hot and humid climate favors the growth of dermatophytes, while humidity can enhance penetration of fungi. In a study from Kerala done in 2016, 52% of patients with chronic dermatophytosis were manual labourers. About 64% of patients were exposed to the sun for more than 3 hours a day and 68% had reported excessive sweating. In another study, from Tamil Nadu, chronic infection was associated with sun exposure for more than 3 hours daily.

 

Maintenance of personal hygiene is very important to avoid acquiring dermatophytosis and in preventing its spread and persistence. After every bath, the entire body surface, especially the body folds and toe clefts, should be wiped well. Washing of clothes and bed linen in hot water at 60°C and drying them in sunlight inside out may help prevent persistence of infection. Since direct contact and fomites play a significant role in the spread of infection, patients should be advised to avoid sharing of inanimate objects or fomites (e.g., soaps, towels, clothes and bedding) with others, as these can be responsible for transmission of infection. Washing the body surface with soap and water removes fungal elements, emphasizing the need for regular bathing. Use of synthetic tight dresses and occlusive footwear is linked to increased prevalence of dermatophytosis. Tight, restrictive clothing can trap heat and moisture, leading to a conducive environment for the growth of dermatophytes. Hence, patients should be advised to avoid using synthetic or tight clothing and should preferably use loose cotton clothes. Regular mopping and cleaning of the house would also help to reduce the persistence of dermatophytes in the environment.

 

Washing clothes in water at a temperature of 60°C or above eliminates Trichophyton rubrum. Exposure of infected socks to sunlight can reduce fungal contamination as sunlight can act as a good disinfectant. Washing or storing infected and non-infected clothes together can facilitate transmission of infection. Hence the worn clothes of patients should be stored and washed separately in hot water at 60°C and dried inside out in the sun. Similarly, ironing of clothes may also be beneficial. Waistbands, wristbands and threads, which aid the persistence of dermatophytes, are better avoided.

Obese patients should be advised to lose weight to prevent recurrence of infection, especially in intertriginous areas like the groin. The nails should be examined in all patients with dermatophytosis as they may act as a focus for recurrent infection. Contact with pets should be avoided as they can be potential sources of infection, although there appears to be no role of pets in the current scenario.

Abuse of oral or topical corticosteroids frequently leads to diagnostic difficulty (due to atypical presentations of dermatophytosis) and treatment failures. Compliance to treatment is essential to achieve cure as patients often use antifungal drugs irregularly or stop them on getting relief from itching and achieving partial resolution. As infection among other family members is very common in the current scenario, treatment of all infected members simultaneously is necessary to avoid recurrences or persistence of infection. Counseling patients about the course of disease, adherence to treatment and to general measures and avoidance of corticosteroid abuse are essential for treatment to be successful.

To conclude, experts agreed that patients should be educated about personal hygiene, clothing, skin care, corticosteroid abuse, adherence to general measures and compliance to treatment to ensure successful outcome.

 

Pharmacological therapy

Since dermatophytes usually do not penetrate the deeper layers of the skin, the host does not necessarily develop sufficient immunity to ensure spontaneous healing. Spontaneous remission rarely occurs even when the underlying cause has been eliminated. Therefore, every patient with dermatophytosis requires topical and/or systemic antifungal therapy.

Tinea of the glabrous skin has been easily amenable to short courses of standard antifungal agents, terbinafine and itraconazole since the time these drugs were introduced. However, with increasing incidence of inadequate response to treatment, high recurrence rate and chronic infections, an extended duration of therapy is often needed. To ensure compliance, antifungal therapy should be chosen keeping affordability in mind.

 

 

Topical therapy

 

Consensus points on topical therapy in patients with glabrous tinea infections

Consensus point	Justification/comments
Topical therapy can be used as a standalone or an adjuvant therapy	Topical therapy attains high antifungal concentration at the site of infection
Antifungal preparation alone without any corticosteroid or antibacterial component should be used	Corticosteroid application can result in treatment failure and local adverse effects
Topical corticosteroid containing antifungal preparation should be avoided even for an inflammatory lesion	Topical antifungals with anti-inflammatory effect can be used
Keratolytics and Whitfield’s ointment can be used in the treatment of glabrous tinea	Should be avoided if there is local inflammation
Antifungal (with few exceptions) should be applied twice a day	Twice a day application is required to achieve good clinical response
Treatment may be continued for about 2 weeks after clinical resolution	Clinical cure may not correspond with mycological cure
Topical formulation could be chosen according to the site involved	There are advantages of certain preparations; Eg. lotions in hair-bearing area
There is no added advantage in the efficacy of various formulations like lotions and sprays over the creams	Most of these preparations have advantage of being user friendly but not of added efficacy
Various classes of topical antifungals currently available are nearly equipotent	Few studies on head-to-head comparison of topical antifungals are published, but still the evidence is not sufficient to consider one molecule is superior to the other
No role for use of combination of two topical antifungals	No studies to substantiate benefits of such a combination approach and it is not practiced routinely

 

These recommendations are based not entirely on evidence but on consensus for the current scenario of recalcitrant dermatophytosis.

  

Topical antifungal therapy is integral to the management of glabrous tinea especially in the setting of localized infection, pregnancy, and children and in the presence of some co morbidities when systemic antifungals cannot be used. Topical antifungals can be useful adjuvants to systemic antifungals in the current scenario as they may have an additive effect and achieve high local concentration. Reaction at the site of application is rare and is the only significant adverse effect.

The ideal topical antifungal agent should have a high cure rate, low relapse rate and minimal adverse effects. Extensive infection and high cost, especially of the newer topical antifungals, are limitations to topical therapy.

The type of topical formulation could be chosen according to the site involved. Topical agents are available as creams, ointments, lotions, sprays, gels, powders and soaps. Lotion and spray formulations were not considered more effective than creams, although they may be more convenient when larger areas are involved. However, a potential for irritation and high cost are the disadvantages of these products. Antifungal soaps and powders are not recommended in the management of glabrous tinea.

A combination of systemic and topical antifungal drugs is essential in the treatment of glabrous tinea, with the extent of disease being a limiting factor for topicals. There was no consensus regarding the superiority of one topical antifungal over another and whether they should be from the same or different group as the oral antifungal prescribed. As dermatophytes are keratinophilic, moving radially, the topical antifungal should be applied inward, from beyond the margin of the lesion. Application may be continued twice daily until 2 weeks after achieving clinical resolution of lesions. There was no consensus on the routine use of combination of two topical antifungals.

There is no role for corticosteroids alone or in combination with antifungals in the management of dermatophytosis of the glabrous skin including inflammatory tinea. There was no consensus on gradual withdrawal of topical steroid in corticosteroid modified tinea.

In India, topical antifungal, antibacterial and corticosteroid combination creams containing 3-5 components (viz. a potent corticosteroid like clobetasol propionate, ornidazole, ofloxacin and an antifungal agent) are unfortunately freely available over-the-counter. They are often used for the treatment of tinea corporis, tinea cruris and tinea faciei, leading to a variety of adverse effects. Antifungal without any corticosteroid or antibacterial only should be used for the treatment of glabrous tinea. Topical corticosteroids should never be used for tinea corporis, tinea cruris or tinea faciei. Some classes of topical antifungals such as azoles and allylamines have anti-inflammatory properties due to their inhibitory effects on cytokines and may be useful for treating patients with inflammatory lesions and corticosteroid modified tinea.

Keratolytics have been used for the treatment of dermatophytosis, especially hyperkeratotic tinea pedis. Topical keratolytics, such as Whitfield's ointment (3% salicylic acid with 6% benzoic acid), can be used in the treatment of glabrous tinea, but not on the flexures or face or where the lesions are inflamed.

Most topical antifungals need to be applied twice daily, but luliconazole and terbinafine may be applied once daily. Clotrimazole, miconazole, oxiconazole and ketoconazole are relatively less expensive.

 

Topical antifungal preparations available in India

Class	Drug name	Preparations	FDA Pregnancy Category
Imidazoles	Ketoconazole	2 % cream, powder, lotion (with or without1% zinc pyrithione), soap	C
	Miconazole nitrate	2 % cream, gel, powder	C
	Clotrimazole	1 % cream, lotion, powder, soap	B
	Oxiconazole	1 % cream, lotion	B
	Fenticonazole	2 % cream	Not categorized
	Bifonazole	1 % cream	B
	Eberconazole	1 % cream	C
	Sertaconazole nitrate	2 % cream, lotion	C
	Luliconazole	1 % cream, lotion, spray	C
Triazoles	Fluconazole	0.5 % gel, powder	C
Allylamines	Terbinafine hydrochloride	1% cream, gel, powder, lotion	B
Benzylamines	Butenafine	1% cream	B
Morpholenes	Amorolfine hydrochloride	0.25 % cream, 5 % nail lacquer	Not categorized
Hydroxy-pyridinone	Ciclopirox olamine	8% Nail lacquer, 1% cream, 1% shampoo	B
Others	Tolnaftate	Solution(10mg/ml), cream (10mg/g)	Not assigned. To be used if benefits outweigh risk.
	Whitfield’s ointment	3% salicylic acid and 6% benzoic acid in ointment base	C (due to risk of absorption of salicylic acid) WHO allows application, especially if benefits outweigh risks

Specific characteristics of relatively newer select topical antifungals available in India

Drug	Class	Remarks
Terbinafine	Allylamine	Fungicidal antifungal as compared to fungistatic nature of most other antifungals
Butenafine	Benzylamine	Fungicidal antifungal as compared to fungistatic nature of most other antifungals
Bifonazole	Imidazole	Dual mode of action by inhibition of 14α-demethylase and microsomal HMG-CoA-reductase leading to fungicidal effect
Sertaconazole	Imidazole	Anti-inflammatory action. Contains a benzothiophene ring which mimics tryptophan and increases the drug’s ability to form pores in the fungal cell membrane
Eberconazole	Imidazole	Potent anti-inflammatory activity.
Luliconazole	Imidazole	Reservoir effect. Highest antifungal activity against Trichophyton spp. among currently available topical antifungal drugs.
Fenticonazole	Imidazole	Additional action of blocking cytochrome oxidases and peroxidises.
Amorolfine	Morpholine	New class of antifungal with different mechanism of action mediated through inhibition of two different enzymes.
Ciclopirox olamine	Hydroxypyridinone	Acts through chelation of metal ions (Fe3+); inhibits cytochrome oxidase, catalase and peroxidase resulting in intracellular degradation of toxic peroxides; inhibits cellular uptake of essential compounds and alters cell permeability

 

Topical corticosteroid application adversely affects the epidermal barrier function by increasing transepidermal water loss and decreasing the ceramide content of the stratum corneum. Hence, emollient application should be encouraged, particularly in patients with corticosteroid modified tinea, to enhance the barrier function and provide symptomatic relief. Antihistamines can be used to alleviate pruritus. There are a few reports supporting the use of antifungal powders in tinea pedis, but antifungal powders are not recommended for other forms of tinea.

 

Systemic therapy

 

Recommendation of Systemic treatment of glabrous tinea (tinea corporis, tinea cruris and tinea faciei)

Antifungal	Dose		Minimum duration	Precautions
	Children	Adults
Itraconazole	3-5mg/kg/day	Naïve: 100 mg 1 or 2 capsules od	3 weeks	Drug interactions, hepatotoxicity
		CH/SMT/RCL: 100mg bd/ 100 mg 2 od	4 weeks
Terbinafine	10-20 kg - 62.5 mg	Naïve: 250mg/day	4 weeks	Skin rash, hepatotoxicity
	20-40 kg- 125 mg > 40 kg - 250 mg	CH/SMT/RCL: 250 mg bd / day	4 weeks
Griseofulvin	10-20 mg/kg/day	Naïve: 500 mg/day	8 weeks	GI intolerance, head ache
		CH/SMT/RCL: 750 -1000 mg/ day	8 weeks
Fluconazole	3-6 mg/kg/day	Naïve: 50-100 mg/day	4 weeks	Hepatotoxicity
		150-300 once weekly	8 weeks
		CH/SMT/RCL: 100 mg/day	6 weeks
		150 mg /thrice weekly*	8 weeks

Note: Some of the dose schedules in children have been extrapolated from their uses in conditions like tinea capitis. Pediatric dose should not exceed the adult dose. References hold good for some of the drug dosages and not the duration. Duration of therapy is best individualized based on the clinical response. *Dosage in current practice and not evidence based. CH- Chronic; SMT - Steroid modified tinea; RCL -Recalcitrant

 

Consensus recommendation for the various facets of treatment of glabrous tinea

	Comments	Recommendation
Indications
Glabrous tinea	Most cases in the current scenario require systemic therapy	Involvement of multiple sites
		Extensive disease based on clinical judgement
		Chronic dermatophytosis
		Recurrent dermatophytosis
		Steroid modified dermatophytosis/ Tinea incognito
		Failure of topical therapy
		Associated nail and hair involvement vellus hair involvement by dermatoscopic examination
		Immunocompromised states like hematological malignancies and therapy with immunosuppressive drugs
Choice of systemic drug
First line	Best option considering overall efficacy and safety	Itraconazole, Terbinafine,
Alternate drugs	Prolonged duration of treatment required	Griseofulvin, Fluconazole
Complementary topical therapy
Choice and rationale	Topical antifungal without corticosteroid and antibacterial components.	Systemic antifungal therapy should preferably be combined with topical antifungal therapy which may be of same or different class
	There are limited laboratory/clinical studies on the efficacy and utility of combination antifungals (systemic with topical OR two systemic) for dermatophytosis of the glabrous skin
Response
Failure	No improvement or worsening of symptoms and signs at 3 weeks	Assessment of factors responsible for it and if detected to be corrected; if not, antifungal therapy to be changed
Total response	Complete subsidence of symptoms and signs with or without post-inflammatory changes anytime during the treatment	Completion of therapy for the stipulated period or as per the individual response
Partial Response	Partial subsidence of symptoms and signs at the end of 3 weeks	Extended duration of treatment to be considered with appropriate laboratory monitoring; double dosing of terbinafine may be considered
Cure
Clinical cure	Complete subsidence of symptoms and signs with or without post-inflammatory changes at the end of treatment	Follow up must be at 4 weeks after apparent clinical cure to look for recurrence
Mycological cure	Complete subsidence of symptoms and signs with negative mycology reports (direct microscopy with/without culture) at the end of the treatment	Follow up must be at 4 weeks after apparent clinical cure to look for recurrence
Laboratory monitoring
Hepatotoxicity	All systemic antifungals are hepatotoxic	Monitoring hepatic function if the treatment is extended or if the dose is doubled
Renal toxicity	Systemic drugs used in the management of dermatophytosis do not commonly cause renal toxicity	Renal monitoring may be considered if indicated on clinical grounds
Follow up
First follow up visit	To assess clinical response	At 3 weeks, if inadequate response
Final follow up visit	To assess recurrence	At 4 weeks after apparent clinical cure
Special situations
Pregnancy	Teratogenicity of the drugs should be addressed	Topical antifungals with established safety
		Oral terbinafine (routine use should be avoided)
Lactating mother	Safety of the infant should be addressed	Topical antifungals
		Oral fluconazole
Children under 2 years	Safety with respect to hepatotoxicity, GI intolerance and other adverse effects should be addressed	Topical antifungals with established safety
		Oral fluconazole
Children above 2 years	Safety with respect to hepatotoxicity, GI intolerance and other adverse effects should be assessed	Topical antifungals with established safety
		Oral terbinafine, itraconazole, fluconazole and griseofulvin
Hepatic dysfunction	Monitoring of the hepatic function is mandatory	Topical antifungals
		Oral fluconazole
Renal dysfunction	Renal function monitoring if terbinafine is used (dose reduction if creatinine clearance is <50 ml/ min)	Topical antifungals
		Oral itraconazole
Cardiac dysfunction	Cardiotoxicity of drugs should be addressed	Topical antifungals
		Oral terbinafine

 

 

Patients on systemic antifungals should be regularly followed to ensure adherence to treatment and to monitor the therapeutic response. The first follow up visit should be at the end of 3 weeks to assess the clinical response. If there is partial response (i.e. persistent pruritus and incomplete/minimal resolution of lesions), therapy should be continued while reassessing for contributing factors. If there is no response, change of the antifungal drug should be considered. Regular follow up should be continued both during treatment and at least up to 4 weeks after apparent clinical cure.

 

Standard indications for systemic therapy in dermatophytosis are extensive disease, involvement of multiple sites, recurrence, chronicity, failure of topical therapy, nail or hair involvement, vellus hair involvement on dermatoscopy and immunocompromised status. In India, now days, most patients require a combination of systemic and topical antifungal drugs for a longer duration than that is conventionally recommended. This is particularly true for patients with corticosteroid modified, chronic, recurrent or recalcitrant infection. Persistent papules or nodules in a healing or unresponsive lesion may indicate Majocchi granuloma, which also needs prolonged treatment. The duration of treatment may be individualized based on clinical response. The end point of treatment for glabrous tinea should be the achievement of clinical cure.

Terbinafine may be used as first line therapy in treatment-naïve and terbinafine-naïve patients with glabrous tinea. If there is an inadequate response at the end of 3 weeks of terbinafine 250 mg once a day, increasing the dose to 250 mg twice daily may be considered in adult patients, albeit with monitoring of liver function.

 

Terbinafine 250 mg daily or itraconazole 200 mg daily in adults for 4-6 weeks have been recommended for treatment of chronic, widespread dermatophytosis. Griseofulvin 500-1000 mg daily taken after fatty meal until cure (3-6 months) has been mentioned as an alternative drug. Itraconazole and terbinafine are especially useful in sebum rich areas, as the skin pharmacokinetics (pK) are determined predominantly by their lipophilicity.

 

Experts agreed that griseofulvin and fluconazole need to be taken for a longer duration than itraconazole or terbinafine.

 

There have been concerns over increasing instances of failure to terbinafine in tinea corporis, tinea cruris and tinea faciei in the country. Resistance to terbinafine due to mutations in the squalene epoxidase (SQLE) gene of Trichophyton interdigitale and T. rubrum has been documented in studies from Chandigarh and New Delhi. High MIC's (Minimum inhibitory concentration) were observed and a higher dose (250 mg twice daily) or increased duration was found to be more effective in a study, hence the authors concluded that increased exposure to terbinafine, resulting in higher levels of the drug in the stratum corneum, could offset the higher MIC and the effect of SQLE mutation to some degree.

Itraconazole may be used as a first line option or when there is no response to terbinafine and is now the most commonly prescribed oral antifungal agent for dermatophytosis. It should be taken immediately after food or with aerated beverages or acidic juice to improve its bioavailability. While the standard dosage for glabrous tinea is 100 mg once daily for 15 days or 200 mg (as 2 capsules of 100mg taken together or in a BD dose) for 1 week, the current scenario calls for individualization of the duration based on clinical response and continuation of treatment until achieving cure. The experts agreed on not using the unapproved higher dose formulations of itraconazole.

 

Different brands of itraconazole available in India vary in the pellet morphology and thereby the resultant quality and therapeutic effect. The drug-polymer ratio, polymer type, coating thickness, bead size and number determine the dissolution of a capsule of itraconazole. Morphometric analysis of pellets using dermoscopy is a simple method to quantify the quality of a brand of itraconazole. A recent study stated that a pellet count of ≥560 (100 mg capsule) provides a surface area comparable to the innovator brand and may be taken as a cut off for distinguishing poor quality brands. In a compliant patient whose disease is not responsive, changing to a better brand is justified. Since itraconazole follows non-linear pharmacokinetics, a dose higher than 200 mg daily may result in decreased clearance and eventually toxic levels.

In some parts of India, dermatologists have found good therapeutic response to griseofulvin given for 6-8 weeks although not consistently. Since the levels are high in the stratum corneum, this drug could be especially useful in patients prone to increased sweating.

The standard dose of fluconazole in adults is 150-300 mg weekly for 4-6 weeks or 50-100 mg daily 4 weeks. However, it is being commonly prescribed in the dose of 150 mg thrice weekly (extrapolated from the regimen for complicated vulvovaginal candidiasis) in certain parts of India with good results. Skin pharmacokinetic (pK) studies have found that its skin levels are markedly higher with a dose of 100 mg given daily. Notably, fluconazole achieves high levels in stratum corneum, reaching there mainly by way of direct diffusion. Thus, its pathway of reaching the corneum is different from terbinafine and itraconazole which largely depend on sebum secretion and this makes it potentially useful in patients with dry skin and in children who have lesser sebum secretion than adults. However, a disadvantage is that the levels decrease rapidly following treatment discontinuation due to low keratin adherence.

There is paucity of literature with regard to the use of combination of oral antifungals in the treatment of dermatophytosis. Such combinations need to be first assessed in laboratories by checkerboard studies for synergistic activity before considering any clinical utility. Although few studies have proven synergistic effect of combination antifungal therapy against dermatophytes, more evidence is desirable.

Ketoconazole is an imidazole compound with a mechanism of action similar to that of triazoles. It had been used in the management of glabrous tinea in a dose of 200-400 mg daily in adults. It is no longer approved by US FDA for the management of superficial fungal infections because of hepatotoxicity, which may be asymptomatic or can present as acute liver injury. Though available in India, it is not recommended for routine use, but is to be used only as a reserve drug with close monitoring of liver function.

There was no consensus for statements such as use of systemic antifungals in all cases of tinea faciei, initiation of terbinafine in 250 BD dosages, use of fluconazole and griseofulvin as first line therapy or of ketoconazole as a reserve drug. There was also no consensus on updosing of itraconazole and standard fixed duration of therapy for glabrous tinea infection.

Systemic therapy should be continued for another 2 weeks after clinical resolution in recalcitrant cases. Since some systemic antifungal drugs can cause hepatotoxicity, it is advisable to do baseline LFTs to rule out impaired liver function and periodic follow-up, if the treatment duration exceeds 4 weeks, especially in recalcitrant cases, and in the elderly, while it is not mandatory in naïve cases.

 

Special situations

 

Dermatophytosis is now the commonest dermatologic condition seen among outpatients in India. Co morbidities such as diabetes, anemia and immunosuppressive diseases or immunosuppressive therapy, may alter the clinical presentation and predispose such patients to recalcitrant or recurrent infections.

Treatment of dermatophytosis in pregnancy, lactating women, infants, children and geriatric patients has certain limitations.

 

Corticosteroid-modified tinea

 

Corticosteroid-modified tinea and tinea incognito have become common presentations. Some patients tend to apply the topical corticosteroid antibacterial antifungal combination creams continuously or intermittently over weeks to months and present with morphological variants such as tinea pseudoimbricata and breakthrough lesions. Studies have shown that application of more than 50 gm of 0.05% clobetasol propionate per week can result in adrenal suppression. Hence, it is quite understandable that patients may present with Cushingoid features and a low serum cortisol level. Literature states that the recovery of the hypothalamus takes about 14-30 days after cessation of corticosteroids. This explains the delay in clinical response seen in patients with steroid modified dermatophytosis, who will hence require an extended duration of treatment. Patients with steroid modified dermatophytosis with Majocchi granuloma have been shown to achieve clearance with the use of pulse therapy with itraconazole given as 200 mg BD for 7 days followed by drug free period of 14 days (up to 3 pulses).

 

Pregnancy and lactation

 

The ideal management of glabrous tinea during pregnancy is by using only safer topical antifungals. Though oral terbinafine is a FDA pregnancy category B drug, scarce human data precludes its routine use in pregnancy until safety data is available. Itraconazole and griseofulvin, both belong to category C, while fluconazole is a category D drug (except as a 150 mg single dose). Among the topical antifungals, clotrimazole, oxiconazole, bifonazole, terbinafine and ciclopirox olamine belong to Category B, while the newer azoles such as sertaconazole, eberconazole and luliconazole are category C drugs. Systemic absorption is considered to be very low with amorolfine and hence it may be safely used in pregnancy.

All topical antifungals can be used safely during lactation as their secretion in milk is negligible. Cream, gel or liquid products which are water miscible are recommended for application to the skin over the breast because ointments may expose the infant to mineral paraffin while feeding. Data regarding the use of systemic antifungals including terbinafine during lactation is scarce, and therefore they should be avoided as far as possible especially in mothers of preterm infants. However, fluconazole has an acceptable safety profile as its secretion in the breast milk is low. Experts recommend that the decision on treatment should be based on the given clinical scenario.

 

Infants and children

 

Glabrous tinea infections have become common in children in the recent times. There are differences in epidemiology, host biology, predisposing factors and clinical presentation in children as compared to adults. Topical antifungals can be given safely in children since their percutaneous absorption is negligible. Use of topical corticosteroid-antifungal combination creams result in early deleterious effects on the skin of children and persistence of infections and thus is to be avoided.

Localized infection may be treated with topical antifungals alone. However, recurrent, chronic or corticosteroid modified tinea, which is being increasingly observed in children, warrants the use of systemic antifungals. The dosage of systemic antifungals should be based on the body weight. Antifungals like griseofulvin, terbinafine and itraconazole can be used in children above 2 years of age to treat glabrous tinea infections. Considering the safety aspects, fluconazole may be the preferred systemic antifungal in infants and children below 2 years of age. Secretion and distribution pattern of this drug is not dependent on sebum and directly diffuses into the skin.

 

Elderly persons

 

Physiological, psychological and socioeconomic factors, co morbidities (renal, hepatic, cardiac) and influence of polypharmacy should be considered while treating elderly patients. A healthy elderly patient may be treated in the same manner as a young adult. Changes in pharmacokinetics must be considered while deciding an appropriate antifungal drug in elderly patients with altered hepatic or renal functions. It is very important to check for various drug interactions before treating elderly patients on polypharmacy.

 

 

Systemic co morbidities

 

Appropriate laboratory monitoring is mandatory in patients with known hepatic and renal dysfunction while using systemic antifungals. No recommended dose adjustment is available for systemic antifungals in patients with hepatic impairment. Monitoring them regularly is the only option. Fluconazole, as compared to other triazoles, is characterized by high water solubility and the drug is primarily eliminated by the kidneys. Hepatic metabolism does not seem to play an important role in the elimination of the drug. Oral fluconazole with laboratory monitoring can hence be considered as a relatively safer drug in patients with hepatic dysfunction. Itraconazole is eliminated mainly through feces and in lesser amount through the urine. Oral itraconazole is thus a safer drug in patients with renal dysfunction. Itraconazole has however been associated with congestive cardiac failure and must be avoided in patients predisposed to the same. Oral terbinafine is a relatively safer drug in patients with cardiac dysfunction. However, in patients with renal dysfunction, the dose needs modification if creatinine clearance is <50 ml/minute.

 

N.B Topical azoles may be considered for use in pregnancy, whereas all oral antifungals are better avoided, especially in the first two trimesters. Topical azoles and oral fluconazole may be used in lactation. In neonates, topical azoles and oral fluconazole are safely used, whereas in older children, all topical and oral antifungals are safe for use, provided accurate dose adjustment is done.

 

 

Drug interactions

 

Systemic antifungals should be used appropriately in patients on polypharmacy after checking for various drug interactions. Terbinafine has the least drug interactions and is generally the preferred choice of drug in patients on polypharmacy.

 

 

Clinically relevant drug interactions with antifungals

Antifungal drug	Drug level is decreased by	Decreases level of these drugs	Increases level of these drugs
Griseofulvin	Phenobarbital	Anticoagulants, oral contraceptives, Cyclosporin	Potentiates action of alcohol-Disufiram like reaction
Terbinafine	Rifampicin	-	Anti-depressants beta blockers,
			Antiarrthymics class 1c, selective serotonin reuptake inhibitors.
			Caution when used with anticoagulants.
Itraconazole	H2 histamine blockers, proton pump inhibitors, rifampicin, rifabutin, INH, ritonavir, nevirapine, nortriptyline, carbamazepine, phenytoin, phenobarbital	Oral contraceptives	Glibenclamide, phenytoin, warfarin, cyclosporin, tacrolimus, digoxin, lovastatin, midazolam, triazolam, methylprednisolone, Saquinavir
Fluconazole	Rifampicin	Oral contraceptives	Sulfanylurea, nifedipine, theophylline, NSAID, warfarin, cyclosporine

 

 

 

 

 

BRITISH ASSOCIATION OF DERMATOLOGISTS’ GUIDELINES FOR THE MANAGEMENT OF TINEA CAPITIS 2014

 

Definition

Tinea capitis is an infection of scalp hair follicles and the surrounding skin, caused by dermatophyte fungi, usually species in the genera Microsporum and Trichophyton.

Epidemiology and etiology

Tinea capitis is predominantly a disorder of prepubertal children. Although Microsporum canis remains the most commonly involved organism, a shift towards anthropophilic species continues to be observed. Trichophyton tonsurans is reported to account for 50–90% of dermatophyte scalp isolates in the U.K. This rise in anthropophilic dermatophyte infections is attributed to immigration and travel patterns.

 

Laboratory diagnosis of tinea capitis

Although the clinical diagnosis of tinea capitis is often relatively accurate, when considered, laboratory investigations to confirm the diagnosis are advisable to isolate the causal organism and direct the choice of systemic therapy. Post-treatment samples should be sent to ensure clearance.

 

Taking specimens

Suspected tinea capitis lesions should be sampled either by plucking hairs, using a blunt scalpel to remove hair and scalp scale, or by taking scalp brushings. In cases of tinea capitis caused by M. canis, affected hairs identified by fluorescence under a Wood’s lamp may be plucked and constitute an appropriate specimen. Specimens should be collected in paper or card packs. A disadvantage of brush sampling is that it does not enable the laboratory to examine the specimen microscopically and permits only culture. Friedlander et al. have demonstrated that gauze swabs make an equally effective and often more convenient sampling method. It is considered that sampling the edge of scalp lesions may provide higher yields of causal fungus. Sampling of kerions may be problematic, and culture is often negative. A swab of the lesion may provide the most appropriate specimen.

Scalp lesions in suspected cases of tinea capitis should be sampled by scalpel scraping, hair pluck, brush or swab as appropriate to the lesion.

 

Laboratory investigations

Microscopy should be carried out on all scalp scrapings and plucked hairs, by mounting in 10–30% potassium hydroxide with or without calcofluor, and examination by light. The presence of hyphae and/or arthroconidia should be reported.  Where possible it should be determined whether the arrangement of arthroconidia is endothrix or ectothrix, but this is often difficult. All specimens should be cultured on Sabouraud agar with at least one agar plate containing cycloheximide to inhibit nondermatophyte mould growth. Plates should be incubated for at least 2 weeks. Where exposure to cattle is documented and an infection caused by T. verrucosum is suspected, plates should be incubated for up to 3 weeks and examined very carefully at the end of this period for the presence of the slow-growing and inconspicuous colonies of this species. Any dermatophytes growing should be identified and reported. 

All specimens from cases of tinea capitis should be processed for microscopy and culture where possible, and the causal agent fully identified where isolated. Susceptibility testing is not indicated.

 

Management

The aims of treatment are eradication of the organism, resulting in both a clinical and mycological cure as quickly and safely as possible; alleviation of symptoms; prevention of scarring and reduction of transmission to others. Oral therapy is generally required to achieve these goals. 

 

When to start treatment

Ideally one should wait for confirmation of the presence of fungus, either by conducting microscopy at the patient side or waiting for culture. However, in high-risk populations, awaiting results increases delay (as culture results may take 2–4 weeks to be available) and may further increase spread. So, in the presence of a kerion or when the diagnosis of a fungal infection is strongly suspected clinically based on the presence of very typical features of scaling, lymphadenopathy or alopecia, it is reasonable to start therapy immediately, as these are strong predictive factors for tinea capitis.

 

Topical therapy

Topical therapy alone is not recommended for the management of tinea capitis. However, topical agents such as povidone–iodine, ketoconazole 2% and selenium sulfide 1% shampoos are used to reduce transmission of spores. 

 

Oral therapy

It is reasonable to begin treatment on the basis of one or more cardinal signs, while awaiting confirmatory mycology.  Treatment protocols should be based on the most likely culprit organism. A prolonged course or a change of agent may be required in cases of treatment failures, or if an unexpected fungus is identified on culture. Although griseofulvin remains the only licensed treatment for tinea capitis in children, cumulative evidence now demonstrates that newer antifungal agents have higher response rates, and are safe and more cost-effective.

 

Choice of drug according to organism isolated

Trichophyton tonsurans:  Terbinafine

Trichophyton violaceum, soudanense:  Terbinafine

Microsporum canis:  Griseofulvin or itraconazole

Microsporum audouinii:  Griseofulvin or itraconazole

 

Griseofulvin

Griseofulvin is a fungistatic drug that inhibits nucleic acid synthesis, arrests cell division at metaphase and impairs synthesis of the cell wall.  It is available in several forms (micronized, ultra micronized and suspension). 

The standard licensed treatment protocol for those aged > 1 month is 1 g in children weighing > 50 kg, or 15– 20 mg/ kg daily in single or divided doses for 6–8 weeks if < 50 kg. Taking the drug with fatty food may increase absorption and improve bioavailability. Dosage recommendations vary according to the type of formulation used and how easily it is absorbed. It may be necessary to use doses up to 25 mg/ kg daily for more prolonged periods in resistant cases. 

Side-effects occur in 20% of cases, mostly gastrointestinal upset, in particular diarrhea, rashes and headache. The drug is contraindicated in pregnancy and men are cautioned against fathering a child for 6 months after treatment.

Advantages: extensive experience; suspension more palatable to children and allows more accurate dosage adjustments.

Disadvantages: increasingly expensive; prolonged treatment required with potential to affect compliance.

Contraindications: lupus erythematosus, porphyria, severe liver disease.

Drug interactions: include warfarin, ciclosporin and the oral contraceptive pill.

 

Terbinafine

Terbinafine is an allylamine that acts on the cell membrane and is fungicidal. It shows activity against all dermatophytes, but has much higher efficacy against Trichophyton species than Microsporum.  Additionally, terbinafine is not excreted in the sweat or sebum of prepubertal children, and cannot be incorporated into the hair shaft in children, so does not effectively reach the scalp surface where the arthroconidia are located in Microsporum infections, accounting for its relative inefficacy. In contrast, meta-analysis of RCTs shows that 2–4 weeks of terbinafine is at least as effective as 6–8 weeks of griseofulvin in T. tonsurans infections. Terbinafine may now be considered the optimal choice, when cost-efficiency and compliance are taken into account.  

Pharmacokinetic studies of terbinafine show that children require significantly weight-normalized doses to approximate the equivalent drug levels needed for efficacy in adults. Terbinafine appears well tolerated in children.

Side-effects include gastrointestinal disturbances and rashes in < 8%.

Advantages: fungicidal; shorter treatment regimens, so potential to improve compliance; cost; safety.

Disadvantages: no suspension formulation 

Drug interactions: plasma concentration is decreased by rifampicin and increased by cimetidine.

 

Itraconazole

The primary mode of action of Itraconazole is fungistatic, through depletion of cell-membrane ergosterols, which interferes with membrane permeability. A dose of 50–100 mg daily for 4 weeks or 5 mg/ kg daily for 2–4 weeks is used. Itraconazole is now the preferred agent as it has activity against both Microsporum and Trichophyton species. The drug is well tolerated and has been shown to be safe for use in the first year of life.

Intermittent dosing regimens are effective and may be preferred.  Advantages: pulsed regimes; shorter treatment protocols; available in liquid form.

Drug interactions: enhanced toxicity of warfarin, some antihistamines (specifically terfenadine, astemizole), antipsychotics (sertindole), anxiolytics (midazolam), digoxin, cisapride, ciclosporin and simvastatin (increased risk of myopathy); decreased efficacy with concomitant H2 blockers, phenytoin and rifampicin.

 

Fluconazole

Fluconazole has been used in the treatment of tinea capitis and has been advocated as an alternative to terbinafine.  Once-weekly dosing regimens have been used and appear well tolerated.

 

Additional measures

Exclusion from school

Although the potential risk of transmission of infection to unaffected classmates has led some authorities to recommend exclusion from school, most experts consider this impractical and suggest that children receiving appropriate systemic and adjunctive topical therapy should be allowed to attend school.

Family screening

Index cases due to the anthropophilic T. tonsurans are highly infectious. More than 50% of family members (including adults) may be affected, often with occult disease. Failure to treat the whole family will result in high recurrence rates. Therefore we recommend screening of all family members and treating those found positive.

 

Cleansing of fomites

Viable spores have been isolated from hairbrushes and combs. For all anthropophilic species, these should be cleansed with disinfectant. This has particular implications for barbers, who need to ensure that appropriate measures are taken to disinfect multiuser equipment. Disinfectants commonly used are simple bleach or a 2% aqueous solution of sodium hypochlorite containing 16.5% salt.

Steroids

The use of corticosteroids (both oral and topical) for inflammatory varieties of tinea capitis (e.g. kerion and severe id reactions) may reduce itching and general discomfort, but is controversial. Historically, oral steroids were thought to reduce scarring, but studies show that, compared with oral antifungal therapy alone, they do not reduce the time to clearance, and therefore confer no long-term advantage, so are not recommended.  Scarring is rare in T. tonsurans infection, and hair usually fully regrows after effective oral antifungal therapy alone.

Treatment failure

Some individuals are not clear at follow-up. The reasons for this include (i) lack of compliance – especially in long treatment courses; (ii) suboptimal absorption of drug; (iii) relative insensitivity of the organism; and (iv) reinfection. If fungi can still be isolated at the end of treatment, but the clinical signs have improved, it is reasonable to continue therapy for a further 2–4 weeks. However, if there has been no clinical response, it is imperative to ensure that the antifungal therapy is appropriate for the causal organism identified on culture. If so, the options then are (i) to increase the dose or duration of the original drug; or (ii) to change to an alternative agent, for example griseofulvin to itraconazole (for M. canis); terbinafine to itraconazole (for T. tonsurans); or itraconazole to terbinafine (for T. tonsurans). 

Carriers

In asymptomatic carriers (i.e. those individuals without overt clinical infection who are culture positive) with a high spore load, oral therapy is usually justified. If the spore load is low, carriage may be eradicated with topical treatment alone, but close follow-up is needed, with repeat mycology, to ensure that treatment has been effective.

Follow-up

The definitive end point for adequate treatment must be mycological cure, rather than clinical response. Therefore, follow-up with repeat mycology sampling is recommended at the end of the standard treatment period and then monthly until mycological clearance is documented. Treatment should therefore be tailored to each individual patient according to response.

 

 

SUMMARY OF TREATMENT CHOICE

Laboratory diagnosis

Scalp lesions in suspected cases should be sampled via scalpel scraping, hair pluck, brush or swab. All specimens should be processed for microscopy and culture, where possible. Susceptibility testing is not indicated.

 

Treatment

In the presence of a kerion or where one or more of the cardinal clinical signs is present (scale, lymphadenopathy, alopecia) it is reasonable to commence treatment while awaiting confirmatory mycology.

Topical therapy alone is not recommended for the treatment of tinea capitis. Oral therapy is generally indicated to achieve both clinical and mycological cure. Choice of systemic therapy should be directed by causative dermatophyte.

First-line therapy

Both griseofulvin and terbinafine have good evidence of efficacy and remain the most widely used first-line treatments. As a general rule, terbinafine is more efficacious against Trichophyton species (T. tonsurans, T. violaceum, T. soudanense), and griseofulvin more effective against Microsporum species (M. canis, M. audouinii). Terbinafine requires a shorter course of treatment, which may increase compliance.

Griseofulvin dose by body weight

< 50 kg 15–20 mg /kg per day (single or divided dose) for 6–8 weeks

> 50 kg 1 g per day (single or divided dose) for 6–8 weeks

Doses up to 25 mg/kg per day may be required in some cases

Terbinafine dose by body weight

< 20 kg 62.5 mg per day for 2–4 weeks

20–40 kg 125 mg per day for 2–4 weeks

> 40 kg 250 mg per day for 2–4 weeks

Treatment failure

Initially consider lack of compliance, suboptimal absorption of drug, relative insensitivity of the organism and reinfection. In cases of clinical improvement but ongoing positive mycology, continue current therapy for a further 2–4 weeks. If there has been no initial clinical improvement, proceed to second-line therapy below

Second-line therapy

Itraconazole is safe, effective and has activity against both Trichophyton and Microsporum species. If itraconazole has been selected as first-line therapy, convert to terbinafine second line for Trichophyton infections or griseofulvin for Microsporum species, at standard dosing regimens.

Itraconazole, 50–100 mg per day for 4 weeks, or 5 mg/ kg per day for 2–4 weeks

Alternative agents

For cases refractory to the above regimens, other modalities to be considered in exceptional circumstances include fluconazole.

Additional measures

Children receiving appropriate therapy should be allowed to attend school.

Index cases due to T. tonsurans warrant screening of all family members and close contacts and treatment for those positive cases.

In asymptomatic carriers (no clinical infection, culture positive) with a high spore load, systemic treatment is generally justified.

The end point of treatment is mycological rather than clinical cure; therefore repeat mycology sampling is recommended until mycological clearance is achieved.