Fiona C. Simpson

Therapies for the treatment of onychomycosis

Onychomycosis treatments include nail avulsion and debridement by chemical or surgical procedures, topical and oral antifungals, and device-based therapies. The advantages, disadvantages, and limitations of the different types of treatments--including the most commonly prescribed topical (ciclopirox) and oral (terbinafine, itraconazole, and fluconazole) treatments for onychomycosis caused by dermatophytes, non-dermatophyte molds, and yeasts--are reviewed. Safety and efficacy data for the healthy adult population and for special populations such as children and diabetic patients have confirmed the importance of proper mycological diagnosis before the initiation of therapy as well as the evaluation of the risks and benefits of the different treatments.

New therapeutic options for onychomycosis

Introduction: Onychomycosis is a fungal infection of the nail apparatus that affects 10 – 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 – 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment. Areas covered: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis. Expert opinion: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices.

Medical devices for the treatment of onychomycosis

Device‐based therapies are the most rapidly expanding area of onychomycosis treatment. Traditional pharmacotherapy of onychomycosis has a low to moderate efficacy and is associated with adverse reactions and drug interactions that limit its use in many patients. These new therapies include laser systems, photodynamic therapy, iontophoresis, and ultrasound. Device‐based therapies are procedures conducted in the clinic by a trained professional, which mitigates the requirement for long‐term patient compliance. In addition, the drug component of these therapies is topical, preventing the adverse events associated with systemic antifungal administration, and potentially allowing for the treatment of individuals who were previously excluded due to drug interactions. Device‐based therapy is a nascent field, so clinical data is still in an emergent stage; however, preliminary clinical trials of laser, photodynamic therapy, and iontophoresis suggest that some devices may have a degree of efficacy. More studies are required to better determine their ability to treat onychomycosis.

New pharmacotherapy for the treatment of onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions. Areas covered: This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development. Expert opinion: The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis.

Do Genetic Mutations and Genotypes Contribute to Onychomycosis

Background: The variability in susceptibility to onychomycosis for individuals exposed to the same environmental risk factors raises the possibility that there may be individuals with a genetic predisposition to dermatophyte infection. Objective: To determine whether there are genetic mutations or genotypes which contribute to onychomycosis. Methods: The PubMed database was searched for examples of immune deficiencies resulting in dermatophyte infections. Results: There are mutations in the innate immune receptors Dectin-1 and its adaptor protein CARD9 which result in familial mucocutaneous infections. There are also specific human leukocyte antigen genotypes that are more common in individuals and families with a high prevalence of onychomycosis. In addition, some patients have been reported with insufficient levels of CD4+CD25+ regulatory T cells. These deficits impair a full innate and adaptive immune response and may result in chronic or recurrent infections. Conclusions: There are documented mutations and genotypes that contribute to familial and individual susceptibility to onychomycosis.

Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis.

Abstract The route of antifungal drug entry into the nail plate and the underlying nail bed plays an important role in determining the efficacy of therapy. Oral antifungal agents reach the nail bed and nail plate by being ingested and achieving antifungal levels in the blood stream that are well in excess of the minimum inhibitory concentration. The reticular circulation at the distal end of the digit enables the drug to reach the nail bed, the proximal matrix and the lateral nail folds. The drug then diffuses into the proximal, ventral and lateral nail plate. The primary route of drug delivery for topical lacquers is transungual, with drug applied to the dorsal aspect of the nail plate and penetrating to the underlying nail bed. The new topical agents approved in the US for the treatment of onychomycosis are solutions with lower viscosity and increased nail penetration characteristics; therefore, these agents penetrate through the transungual route, but also through the space between the nail plate and the nail bed. This subungual route is an important method of drug delivery and is able to in part circumvent the thickness of the nail plate.

Investigational drugs for onychomycosis

Introduction: Onychomycosis is the fungal infection of the nail plate by dermatophytes, yeasts and nondermatophyte molds. The treatment of onychomycosis poses many challenges due to low initial cure rates and a high rate of relapse and recurrence. Oral therapy is limited by adverse events and drug–drug interactions, whereas topical therapy has limited penetrance through the nail plate. Areas covered: New and reformulated drugs are in development for the treatment of onychomycosis. Experimental molecules include both oral and topical azole molecules, topical reformulations of terbinafine, the benzoxaboroles tavaborole and AN2718, the aganocide NVC-422 and the photosensitizer Sylsens B. These drugs are in varying stages of development so results from in vitro studies to Phase III clinical trials are discussed to present a complete picture of the current development pipeline for onychomycosis. Expert opinion: The development of new molecules from familiar and novel classes for both oral and topical administration is encouraging. It is clear that there is currently more emphasis on the development of topical drugs than orals, due to their lower potential for adverse events and drug–drug interactions. The emergence of novel molecular targets is encouraging for the possibility of combination therapy and any future drug-resistant strains of fungi.

Efinaconazole (Jublia) for the treatment of onychomycosis

Efinaconazole 10% nail solution (Jublia®) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14α-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease.