Please see Table 1 for a glossary of unfamiliar terms.
|Allylamine||Class of antifungal molecules used to treat skin and nails. Examples include butenafine and terbinafine|
|Azole||Class of antifungal compounds used to treat skin and nails, characterised by a 5-membered nitrogen heterocyclic ring. Examples include ketoconazole and fluconazole|
|Benzoxaborole||Class of small molecules characterised by a boron atom. The antifungal tavaborole is a member of this class|
|Cross-contamination||Unintentional transfer of a micro-organism from 1 object or person to another|
|Dermatophytes||Infectious fungi that feed on the keratin present in the skin, hair, and nails, which usually cause an inflammatory response at the site of infection|
|Distal||Away from the cuticle, toward the end of the nail|
|Dystrophic||Progressive damage or deformity characterised by the wasting away of tissue or both|
|Fungicidal||To kill fungal cells|
|Fungistatic||To impede the growth and reproduction of fungal cells|
|Hydroxypyridone||Class of compounds with antifungal properties used to treat skin and nails. Example: ciclopirox|
|Hyponychium||The skin beneath the distal free edge of the nail|
|Iontophoresis||A method whereby ionic medicinal compounds are introduced into the body by applying an electrical current to the skin|
|keratin||A key protein in the structure of skin, hair, and nails|
|Lateral||To the sides (of the nail)|
|Proximal||Close to (the cuticle)|
|Metalloproteases||Enzymes in the body that break down proteins and contain a metal ion to aid in this process|
|Morpholine derivative||An antifungal based on the organic compound morpholine. Example: amorolfine|
|Nail apparatus||Refers to the nail and associated underlying structures (Figure 1)|
|Onycholysis||Detachment of the nail from the nail bed|
|Subungual||Underneath the nail|
|Synthetase||A biological enzyme that acts in the body to combine molecules or compounds together|
|Tinea pedis||Also known as "athlete's foot", an infection of skin of the feet typically caused by dermatophytes|
Description of the condition
Onychomycosis is a fungal infection of the nail apparatus (Zaias 1972). It is primarily caused by dermatophytes, which are Infectious fungi that feed on the keratin present in the skin, hair, and nails, that usually cause an inflammatory response at the site of infection (Welsh 2010). Yeasts and non-dermatophyte moulds can also cause onychomycosis either alone or in combination with dermatophytes (Gupta 2012; Welsh 2010). Many people seek treatment for cosmetic purposes, but onychomycosis is an infectious condition, so it is critical that it is treated to prevent cross-contamination and secondary complications (Szepietowski 2006). Patients with onychomycosis report decreased quality of life and may restrict their activities because of embarrassment about the aesthetic appearance of their nails (Reich 2011).
Onychomycosis has several clinical presentations, including distal and lateral subungual (under the nail) onychomycosis (DLSO), proximal subungual onychomycosis, superficial white onychomycosis, and total dystrophic onychomycosis (Hay 2011). DLSO is the most common form of onychomycosis and often presents secondary to tinea pedis (Hay 2011). DLSO affects the nail plate; nail bed; and hyponychium, which is the skin beneath the distal free edge of the nail, and may present with streaks of pigmentation in the nail and uneven borders, which distinguishes it from simple onycholysis, where the nail detaches from the nail bed (Hay 2011). Proximal subungual onychomycosis is initiated at the proximal nail fold and is usually whitish in colour, while superficial white onychomycosis is localised to the centre of the nail plate with a white, chalky appearance (Hay 2011). Total dystrophic onychomycosis is the most severe form of onychomycosis; it affects the entire nail plate and results in nail thickening along with complete loss of normal nail architecture (Hay 2011).
Figure 1 presents the anatomy of the nail, including the distal, lateral, and proximal areas of the nail.
Onychomycosis accounts for approximately 50% of reported nail disorders (Faergemann 2003). A recent systematic review, Sigurgeirsson 2014, reported the population-based prevalence of onychomycosis as 4.3% in Europe and North America and found it was more prevalent in men in North America and Europe and women in South America. The review reported that onychomycosis was more common in toenails than fingernails, and the primary causative organism was Trichophyton rubrum (44.9%), followed by yeasts (21.2%) and moulds (13.3%).
Onychomycosis is associated with a number of medical conditions and advancing age (Baran 2011). For example, there is an increased prevalence of onychomycosis in individuals with psoriasis, diabetes, immunosuppression, peripheral vascular disease, and obesity (Baran 2011; Döner 2011; Gupta 1997; Gupta 2000). It is critical to treat onychomycosis in individuals with these conditions, as they are at an increased risk of secondary complications. These patients may also have contraindications for the oral antifungals terbinafine and itraconazole due to drug-drug interactions or a higher risk of adverse events (Baran 2008; Barber 2006).
Description of the intervention
Topical drugs for onychomycosis generally come in the form of lacquers or solutions directly applied to the surface of the nail (Gupta 2013). Device-based therapies may include, but are not limited to, laser systems, iontophoresis, photodynamic therapy, and ultrasound (Gupta 2013). We will consider device-based therapies with a topical component or in combination with a topical therapy. Oral treatments for fungal infections of the toenails are also commonly used (Gupta 2015); however, they are outside the scope of this review.
How the intervention might work
Antifungal drugs can either be fungistatic, preventing further growth of fungal cells, or fungicidal, killing fungal cells entirely. Most antifungal drugs inhibit cell membrane synthesis, but others target protein translation and fungal proteases (Gupta 2013). Topical drugs are usually applied daily for six months or longer in order to allow the normal nail to grow and replace the regions damaged by infection (Gupta 2014b). Drugs formulated for topical application in onychomycosis include those from the allylamine, azole, hydroxypyridone, morpholine-derivative, and benzoxaborole classes (Gupta 2013; Gupta 2014). The azoles, allylamines, and morpholine-derivative drugs inhibit ergosterol biosynthesis, an essential component of the cell wall (Gupta 1994). The hydroxypyridone-class drug ciclopirox inhibits metalloproteases by binding metal ions (Valeant 2004). The benzoxaborole-class drugs inhibit protein translation by inhibiting the fungal leucine transfer ribonucleic acid (tRNA) synthetase (Rock 2007).
Devices have diverse mechanisms of action. Laser device systems are thought to act via selective photothermolysis, which is the conversion of light energy into heat energy that is confined to a specific target (Anderson 1983). Iontophoresis devices use an electrical current to increase the penetration of a topically applied drug into the nail plate (Amichai 2010). Photodynamic therapy uses a narrow-spectrum light source to activate topically applied photosensitisers (Piraccini 2008). This Cochrane Review may also identify new devices with novel mechanisms of action.
Why it is important to do this review
A Cochrane review on dermatophyte infections of the feet and nails was published in 2007 (Crawford 2007). Since then, a substantial amount of research on topical drugs and device-based therapies for the treatment of onychomycosis has emerged in the scientific literature, warranting a review exclusively on toenails. Topical drugs and devices are important therapeutic options for mild to moderate onychomycosis. The advantage of effective topical therapies for onychomycosis is that they are not distributed throughout the body systemically so may mean there is less likelihood of drug interactions or adverse events.
As these categories of therapies increase, it is important that healthcare professionals have accurate information about the optimal dosage and treatment regimens, so they can effectively treat patients with new drugs and devices.