Toenail fungus is an infection that gets in your nails. The nail infection with fungus is called onychomycosis. The term „onychomycosis“ is derived from the Greek words „onyx“ meaning nail and „mykes“ meaning fungus. The hard part of the nail, the nail plate is made of keratin protein. The nail gets infected by keratinophilic fungi that parasitize keratinized tissue such as nails, which means that the fungi feed on keratin.
Traditional treatment options for toenail fungus are toenail debridement, i.e. trimming and smoothing of thick toenails and systemic, i.e. oral, and topical, i.e. directly applied, pharmacological therapies. Onychomycosis is associated with digital deformity. Perhaps onychomycosis develops as a result of repetitive friction and pressure sustained by the nail in association with digital deformity. Through the mechanical insults on the nail the integrity of the nail is impaired making it susceptable for being invaded by pathologic microorganism such as fungi. Abrading the nail surface can enhance the ability of dermatophytes to infect. Fungi are microorganisms that thrive in moist, dark places, such as shoes.
Fungal infection of the toenails has a prevalence of 2 – 5,5% depending on country. The prevalence increases with age with an increase in prevalence of onychomycosis in the older population. In elderly people, epidemiological studies have found prevalences of around 35% to 46.5% with those in their sixth decade being the most prevalent age group. Individuals with diabetes are highly susceptible to mycotic disease of their toenails. 26% of people with diabetes get onychomycosis. The prevalence of mycotic toenails is rising, because of longer life expectancy, use of occlusive modern footwear, increased prevalence of obesity, and increased urbanisation.
The aging of the skin and its associated structures leads to structural changes that facilitate the entry of microorganisms such as fungi. With progressing age, the nails, mainly the toenails, thicken and suffer traumas even with shoes, providing a favorable environment for the development of fungal toenail infections.
Predisposing factors of toenail fungus include fungal infection elsewhere on the body in particular, tinea pedis, a fungal skin infection that usually begins between the toes. Further predisposing factors are chronic paronychia, a skin infection around the toenails, previous onychomycosis, wearing of occlusive and tight shoes, hyperhidrosis, participation in sports or fitness activities, nail trauma, poor nail grooming, use of commercial swimming pools, communal bathing, living with family members with fungal infection, poor health, genetic factors, immunodeficiency (in particular, acquired immune deficiency syndrome and transplant patients), diabetes mellitus, obesity, Down syndrome, psoriasis, smoking, peripheral vascular disease, venous insufficiency, hallux valgus, and asymmetric gait nail unit syndrome, AGNUS, which is the result of asymmetric shoe pressure on the toes and foot caused by ubiquitous uneven flat feet that affect the gait.
Risk factors for toenail fungal infections are occlusive footwear or warm, damp conditions. Compressions and microtraumas are the main triggers of onychomycosis of the toes which are frequent in diabetics and immunocompromised individuals, as well as in those suffering peripheral arterial diseases. Occlusive footwear and socks generate environmental conditions in which frequent minor injuries to the nail bed are likely. Vascular disease often promote dystrophic or thickened nails. The treatment of onychomycosis of the toenails is hindered not only by the concomitant thickening of the nail, which slows or even prevents the penetration of topical antifungals, but also by the poor vascularization of the toes.
Over time, the fungal toenail infection causes discoloration and distortion of the toenail unit. Typically, onychomycosis presents as a white or yellow-brown discoloration of the toenail. Other clinical manifestations include subungual hyperkeratosis, detachment of the nail from the nail bed (onycholysis) and thickening of the nail plate (onychauxis). Dermatophytoma, a unique characteristic of onychomycosis, presenting as linear, single or multiple white, yellow, orange or brown bands on the toenail plate is specific for onychomycosis.
The big toenails are most often affected. Distal lateral subungual onychomycosis is the most common clinical subtype. In distal lateral subungual onychomycosis, the fungal invasion begins at the hyponychium and then progresses to involve the distal toenail bed and subsequently the toenail plate. The fungus then migrates proximally through the nail plate, causing linear channels or „spikes“. This clinical subtype is usually caused by Trichophyton rubrum. Clinically, distal lateral subungual onychomycosis presents as yellowish, whitish, or brownish discoloration of a distal corner of a nail. Distal subungual hyperkeratosis, detachment of the toenail from the toenail bed and thickening of the toenail plate of the lateral and distal aspects of the toenail plate are common.
A diagnosis of onychomycosis can be strongly suspected based on the typical clinical features such as toenail discoloration, subungual hyperkeratosis/debris, detachment of the toenail from the toenail bed and thickening of the toenail plate. Howver, the gold standard for diagnosis of onychomycosis is the mycological culture.
For a fungal culture debris from the diseased toenail is scratched off and subsequently incubated in a petri dish for the fungus to grow in colonies on a special nutrient medium such as for example dextrose agar if it is present. Colonies of Trichophyton rubrum are white and cottony on the surface and have a reverse side that ranges from yellow-brown to wine-red. Most cultures have been identified to be granular strains, which include numerous microconidia and small spores produced from asexual reproduction.
Onychomycosis is a chronic fungal infection of nails, commonly caused by dermatophyte fungi. Dermatophyt fungi are fungi that require keratin for growth. Trichophytons are the primary species of dermatophyt fungi. Tricho- comes from the greek word thrix that means hair. Phyton derives from the greek word phyton for plant. Trichophyton fungi are molds characterized by the development of both smooth-walled macro- and microconidia. A conidium is a type of asexual reproductive spore of fungi usually produced at the tip or side of hyphae or on special spore-producing structures called conidiophores. Hyphae are filaments that make up the body of a typical fungus. The spores detach when mature. Conidia vary widely in shape, colour, and size. Relatively large and complex conidia are called macroconidia, small more simple ones, microconidia.
A conidium is an asexual, non-motile spore of a fungus.
A spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of fungi. Fungi commonly produce spores during sexual and asexual reproduction. Many fungal species are actively dispersed by forcible ejection from their reproductive structures. After ejection spores can travel through the air over long distances. The term spore derives from the an ancient Greek word that means „seed, sowing“.
A hypha is a long, branching, filamentous structure of a fungus. Hyphae are comprised of hypha, which are the long filamentous branches found in fungi. Hyphae are important structures required for growth. Each hypha is comprised of at least one cell encapsulated by a protective cell wall.
Of the Trichophytons Trichophyton rubrum causes most chronic human dermatophyte infections. Trichophyton rubrum is especially suited to survive on the nail surface. Trichophyton rubrum is not especially aggressive compared with other dermatophytes. By remaining in the stratum corneum, it may evade immune surveillance, and may evade white blood cells that would attack the organism if it tried to invade into viable epidermis.
Toenail invasion by Trichophyton rubrum tends to be restricted to the underside of the nail plate and is characterized by the formation of white plaques on the lunula that can spread to the entire nail. The toenail often thickens and becomes brittle, turns brown or black. Infections by Trichophyton rubrum are frequently chronic, remaining limited to the nails of only one or two digits for many years without progression.
T. rubrum can survive off the human body as a spore. Its life cycle apparently lets spores desquamate and, thereby, remain plentiful in many human habitats. If a spore finds a warm, moist area of skin, it can crowd out normal flora and grow within the stratum corneum. T. rubrum’s ability to infect and its ubiquitous presence account for the high incidence of infections. This, plus the ability of T. rubrum to evade host defenses, accounts for the high prevalence of infections with this fungus. Almost all chronic dermatophyte infections of skin involve the anthropophilic, attracted to humans as a source of food, fungus Trichophyton rubrum.
Trichophyton rubrum, is the most common causitive agent of dermatophytosis. T. rubrum is a keratinophilic filamentous fungus. It forms a filamentous structure known as hyphae. These are multicellular structures with branching. Most of these hyphae extend in 3 dimensions through whatever they are growing in. Specialised hyphae are produced to allow vegetative (non-sexual) reproduction with spores.
T. rubrum is an anthropophilic – preferring a human over another animal – fungus capable of the invading the stratum corneum of nails. Infections typically are largely asymptomatic and may be chronic or recurrent. In order to infect stratum corneum, an organism first must adhere to it. Organisms that are better able to adhere to corneocytes are more likely to cause infections. The mere binding of a spore of a dermatophyte to the surface of the stratum corneum, the outer layer of a nail alone is not sufficient to establish infection. In most cases, if a fungal spore binds to the nail, it is likely to be shed by the process of desquamation before invasion can occur.
Hydration is an important factor. A macerated, sopping-wet foot may be an environment that dermatophytes may chronically inhabit. Fungal infections occur under occlusive clothing such as shoes. Hyperkeratosis, abundant aberrant stratum comeum, is infected more easily by dermatophytic fungi. The immune system fights off dermatophytic fungi. Cell-mediated immunity is the major immunologic defense against dermatophytic fungi. A specific cell-mediated immune response normally is induced after infections with dermatophytes, usually within 1 month. A cell-mediated immune response in the dermis may rid dermatophytes from the stratum corneum. The absence of cell-mediated immunity to dermatophyte antigens corresponds to widespread and chronic infections with T. rubrum.
Toe-nail fungal infections are difficult to cure, as judged by their persistence despite therapy and by their prompt recurrence when antifungal therapy is discontinued. Infections usually recur at exactly the same site. Once spores have adhered to the nail, they must invade into it. To accomplish this, dermatophytes secrete keratinase, a type of proteolytic enzyme capable of hydrolyzing keratin. The cell walls of T. rubrum consist of the mannoprotein called mannan.
Mannan is a complex glycoprotein containing mannose polymers and oligomers attached to a peptide “back bone”. Mannan may be immunoinhibitory and may be secreted by fungi to inhibit the immune response. Mannans from T. rubrum reduce lymphocyte proliferation in response to specific antigens. Mannans act on the antigen-presenting cells and interfere with processes necessary for lymphocyte activation. Acute or chronic focal nail trauma, peripheral vascular disease, and peripheral neuropathy compromise the immune response to fungal infection.
Onychomycosis is acquired through direct contact of the nail with dermatophytes, non-dermatophyte molds, or yeasts. Because the nail unit does not have effective cell-mediated immunity, it is susceptible to fungal infection. Fungal production of enzymes that have proteolytic, keratinolytic, and lipolytic activities help to degrade the keratin in the nail plate and facilitate fungal invasion of the nail. In addition the formation of fungal biofilms allows the fungi to evade current antifungal therapies.
Most fungi produce biofilms. Biofilms are sessile microbial communities that attach irreversibly to the epithelial surfaces such as the toenail plate by means of an extracellular matrix. The extracellular matrix acts as a protective barrier to the organism such as a fungus within the biofilm. As such, biofilms increase fungal resistance to antifungal agents by reducing penetration of these agents, along with protection from host defenses.
Onychomycosis is often considered only an aesthetic problem being unsightly and socially embarrassing. However, if left untreated, onychomycosis may cause nail deformities such as transverse overcurvature, difficulties in trimming thick nail plates, difficulties in fitting shoes, and low self-esteem.
Without treatment, mycotic toenails usually become thick, onycholytic, and irregularly shaped, and associated with hyperkeratotic nail fold and bed tissue, making routine nail trimming and hygienic maintenance difficult. Self-care for mycotic toenails can be particularly difficult for individuals with conditions that impair eyesight, manual dexterity, or the ability to adequately reach the toes.
Periodic toenail debridement has been established as the standard therapy for onychomycosis. Although toenail debridement can be achieved with topical keratolytic agents, it is generally considered a podiatric procedure that requires periodic mechanical removal of the abnormal portions of the nail plate.
Mechanical debridement of mycotic toenails is typically well tolerated and it is usually performed by podiatrists, who focus their attention on direct removal of grossly infected portions of the involved toenails, including those portions that are discolored, lytic, thickened, or deformed. However, although debridement can improve the appearance of the nail by reducing hypertrophy and pain and preventing development of adjacent cutaneous compromise, it does not cure the fungal infection. For the cure of mycotic toenails pharmacologic antimycotic treatmemt in addition to the mechnical debridement is necessary. Antifungal agents such as itraconazole and terbinafine combined with toenail debridement are the gold standard of treatment of mycotic toenails with healing rates of between 40 and 80%. Terbinafine is the preferred drug for oral treatment of dermatophytosis, because it inhibits all genera of dermatophytes. However, oral antifungals have general adverse effects, including gastrointestinal complaints. It can take between 6 and 18 months of antifungal treatment for the appearance of the affected toenail to return to normal. However, since antifungals show a range of adverse effects patients may stop the treatment before the affected toenail returns to normal. The treatment of onychomycosis remains a challenge to patients and professionals, because of the difficulty in attaining a definitive cure and the high recurrence rate.
Toenail debridement service entails complete removal of all grossly infected, onycholytic, flaking and/or crumbling nail plate, subungual debris, and hyperkeratotic toenail bed. Toenail debridement is accomplished with nippers, curettes, rasps, scalpel or chisel blades, and/or electronic rotary burrs. Debridement of mycotic toenails improves patients’ subjective foot-related quality of life. The addition of topical antifungal toenail lacquer to a regimen of toenail debridement provides a reasonable likelihood of curing the toenail fungal infection.
Topical antifungal agents such as for example ciclopirox can be used in conjunction with mechanical debridement for the treatment of mycotic toenails. Ciclopirox is a synthetic hydroxy-pyridone antifungal agent. The antifungal mechanism of action of ciclopirox is primarily chelation of trivalent cations, such as Fe+++, and resultant inhibition of metal-dependent enzymes that are responsible for the degradation of toxic metabolites in the fungal cell. This disrupts a wide range of intracellular metabolic pathways, including respiratory and energy-producing processes, making ciclopirox fungicidal against dermatophytes as well as yeast and nondermatophyte molds. Topical pharmacologic compounds are recommended especially for mild-to-moderate nail involvement in distal onychomycosis. The topical route of administration is preferred over the systemic. The medication is applied directly on the affected area, minimizing possible interactions with other drugs.
Ciclopirox 8% is available as a topical nail lacquer (Penlac; Dermik Laboratories, Sanofi-Aventis US, LLC, Bridgewater, NJ) and has been approved by the US Food and Drug Admin- istration (FDA) for treatment of mild-to-moderate cases of toenail onychomycosis due to Trichophyton rubrum without involvement of the lunula in immunocompetent patients.
Ciclopirox 8% topical antifungal nail lacquer (TANL), moreover, has been shown to penetrate the nail plate and display activity in the nail bed after a single application. The addition of ciclopirox 8% nail lacquer to mycotic toenail debridement can result in a prevalence of mycological cure of 76.74%. One study showed that a combination of oral terbinafine and topical ciclopirox 8% nail lacquer resulted in a cure rate of 88%. Combined topical and oral treatments are recommended when there is a generalized involvement of the nail. However, thorough debridement of mycotic toenails is a prerequisite to mycological cure. Nail abrasion, trimming, and debridement is performed to enhance topical penetration of antifungal agents and reduce fungal load.
Removal of the unattached, infected nail, as frequently as monthly, by a health care professional, weekly trimming by the patient, and daily application of the medication are all integral parts of the topical fungal therapy with the antifungal nail lacquer Penlac. Trimming of onycholytic toenails, and filing of excess horny material should be performed by professionals trained in treatment of toenail disorders. Penlac should be applied once daily to all affected nails evenly distributed over the entire nail plate, to the nail bed, the hyponychium, and the under surface of the nail plate when it is free of the nail bed with the applicator brush provided. Daily applications should be made over the previous coat and removed with alcohol every seven days.
Propolis is a well-known resinous material collected by bees from bud and exudates of the plants, mixed with bee enzymes, pollen and wax. The Greek word ‘propo- lis’ reveals its use by bees in the hive: pro = for or in defence and polis = the city, meaning ‘defence of the hive’. Bees use propolis to smooth out internal walls, seal holes in their honeycombs, and to cover carcasses of intruders who died inside the hive, avoiding their decomposition. In general, propolis in natura is composed of 30% wax, 50% resin and vegetable balsam, 10% essential and aromatic oils, 5% pollen and other substances. However, propolis composition is dependent upon the source plant and local flora. The active substances in a propolis ethanol extract are chiefly the phenolic substances, which are responsible for the anti-inflammatory, antimicrobial, and in particular antifungal activity of propolis.
Propolis is a topical treatment with an adhesive resinous compound produced by honeybees by mixing salivary secretions and beeswax with exudate gathered from plants that is efficient against the biofilm formed by Trichophyton. Propolis is able to penetrate the human nail without cytotoxicity and to reach the deep layers of the nail by itself.
A study by Veiga et al. showed that 6 months after treatment with a 10% ethanol propolis extract 56.25% of the patients with fungal toenail infection showed a complete cure, with total recovery of the initial appearance of the nail and absence of fungi in the sample. Participating in the study were patients with mild-to-moderate toenail onychomycosis with up to approximately 60% involvement of the toenail and the distal lateral lesions being the most common clinical manifestation.
The patients were instructed to clean their nails with soap, water, and a brush daily and to polish the affected areas of the nails weekly. Thereafter, they were to apply two drops of the 10% ethanol propolis extract on the affected area of their toenail twice a day. None of the patients treated with propolis extract reported side effects even with long-term use. Therefore, the extract of propolis is a potent therapeutic agent for the topical treatment of Trichophyton onychomycosis.