Onychomycosis, or fungal infection of the nail unit, accounts for 50% of nail disorders seen in clinical practice. Population-based studies indicate that its prevalence varies depending on the geographic region, with around 4% in Europe and almost 19% in South America. [1] In most geographic areas, dermatophytes such as T. rubrum and T. interdigitale are responsible for the majority of cases of onychomycosis, although in some areas such as Africa and the Middle East yeasts like C. albicans and C. parapsilosis may be the causative agent. Non-D moulds such as Neoscytalidium, Aspergillus and Fusarium are responsible for only a minority of cases.

• Treatment outcomes are related to a number of factors including the causative pathogen. [2]
• Moreover, drug resistance, both primary (intrinsic) and secondary (acquired), after exposure to an antifungal agent is a problem of increasing concern.
• Onychomycosis is a fungal infection of nails primarily caused by dermatophyte fungi, which are traditionally understood as existing in the environment as planktonic organisms; however, recent advancements in microbiology suggest that fungi can also form biofilms, which are complex sessile microbial communities irreversibly attached to epithelial surfaces by means of an extracellular matrix.
• The extracellular matrix also acts as a protective barrier to the organisms within the biofilm.
• With regards to treatment, a biofilm is surprisingly resistant to injury and may act as a persistent source of infection possibly accounting for antifungal resistance in onychomycosis.
• The clinical factors associated with onychomycosis comprise percentage of nail involvement, lunula involvement, presence of yellow spikes, causative dermatophytoma and the presence of an air gap between the nail plate and nail bed.

• A number of different therapies are used to treat onychomycosis.
• While medical therapies with both topical and systemic antifungal agents are most commonly used, physical/chemical methods may also be of some benefit.
• These include abrasion of the nail plate, etching the nail surface, mechanical debridement, microporation, use of keratolytic agents and penetration enhancers.
• Device-based methods such as photodynamic therapy, lasers and iontophoresis are also utilised.
• Cure may be considered as mycological or complete, and typically rates of the former are higher than the latter.
• Thus, treatment failure typically occurs with antifungals in 20-25% of cases, with recurrence rates up to 50%.

• Several clinical trials are underway with new oral drugs.
• One such molecule is VT-1161, a tetrazole fungal CYP51 inhibitor that blocks the production of ergosterol.
• VT-1161 has broad-spectrum activity against both dermatophytes and Candida species. [3]
• In a phase IIb trial, complete cure was seen in 32-40% of cases, with mycological cure in 61-72% of cases, and low rates of adverse events.
• Fosravuconazole L-lysine ethanol is a new triazole that is in phase III development.
• This agent was associated with complete cure in almost 60% of patients with mycological cure in 82% after 48 weeks of treatment. [4]
• With regards to formulations, several new chemical strategies are under investigation that incorporate chemical compounds into a topical formulation to enhance penetration of drugs through the nail.
• So-called nano formulations, for example, should allow for deep nail penetration, greater stability of the active drug and extended drug delivery times.
• One such formulation is MOB015B (topical formulation of terbinafine) that was investigated in an open, single centre phaseIIa pilot study in 25 patients. [5]
• Highly encouraging results were seen, and phase III studies including approximately 750-800 patients are underway simultaneously in North America and Europe with results expected in 2020.
• Laser treatment to provide selective photothermolysis of fungal chromophores is also being investigated.
• A meta-analysis of controlled trials reported that mycological cure was seen in 70.4% of cases, but with complete cure in only 7.2%. [6]

• Onychomycosis is associated with high rates of treatment failure.
• The relative inefficacy of topical antifungal treatment is related to the difficulty in penetrating the nail.
• Resistance to therapy remains a significant clinical issue.