Pharmacotherapy of onychomycosis

Fungal infections of the nails are frequent in some segments of the population. Dermatophytes, yeasts and moulds are potential pathogens. A series of antifungal treatments are available to the clinician, differing by both their mechanistic nature and mode of administration. The pharmacodynamic and pharmacokinetic properties of each antifungal agent are distinct. This review focuses on the characteristics of amorolfine, bifonazole, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, ravuconazole, R126638 and terbinafine. Single drug treatments and combined therapies are presented. None of the current drug regimens have demonstrated reliable efficacy against all cases of onycho-mycosis. Treatment failures, relapses and reinf-ections remain stubborn pro-blems in the management of onychomycosis.     

Management of toenail onychomycosis.

The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to 40% of all nail disorders and appears to be increasing in frequency. Mycotic nail infections are usually caused by dermatophytes, yeasts, and nondermatophyte molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic nail infections do not always resolve spontaneously and may have a substantial impact on the patient's quality of life. Current treatment modalities for onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery is generally not recommended as first-line therapy. Broad-spectrum topical and oral antifungal agents are the most frequently used treatments. Topical treatment is well tolerated but is usually not effective because of poor patient compliance and inadequate penetration of the nail. Oral antifungals are more successful but carry greater risks. Griseofulvin and ketoconazole have been oral antifungals traditionally used for onychomycosis, but these agents are associated with relatively low cure rates. Itraconazole and terbinafine are both safe and effective first-line agents, with reported overall cure rates of 50-90% for dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may reduce the risk of systemic adverse effects and the cost of therapy; more study of this approach is needed. Oral antifungal agents offer patients with toenail onychomycosis greater likelihood of a cure than topical antifungals, but oral therapy carries greater risks and requires closer monitoring.     

Therapeutic potential of TDT 067 (terbinafine in Transfersome®): a carrier-based dosage form of terbinafine for onychomycosis

Introduction: Current topical treatments for onychomycosis are unsatisfactory. New topical agents that offer efficacy without the potential adverse effects of oral antifungal therapy would benefit patients with this condition and encourage a greater treatment rate. Areas covered: Currently available topical therapies are reviewed, and new approaches for enhancing delivery of the established antifungal terbinafine through the nail are summarized. We focus on the use of ultra-deformable lipid vesicles to facilitate delivery of terbinafine to the nail and surrounding tissue. TDT 067 (terbinafine in Transfersome?) is the only such therapy in development for onychomycosis, and we review published preclinical and clinical studies on this formulation. Expert opinion: TDT 067 offers the use of new technology to deliver an established antifungal, terbinafine. Preclinical data suggest that the Transfersome? accelerates entry of terbinafine released from TDT 067 into fungi and potentiates its antifungal effects, resulting in enhanced activity, compared with conventional terbinafine. This translated into high rates of mycological cure and evidence of clinical effect in a study of TDT 067 administered twice daily for 12 weeks in patients with onychomycosis. An ongoing Phase-III trial involving more than 700 patients treated for 48 weeks is investigating the efficacy and safety of TDT 067.     

A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis.

The newer antifungal agents itraconazole, terbinafine and fluconazole have become available to treat onychomycosis over the last 10 years. During this time period these agents have superseded griseofulvin as the agent of choice for onychomycosis. Unlike griseofulvin, the new agents have a broad spectrum of action that includes dermatophytes, Candida species and nondermatophyte moulds. Each of the 3 oral antifungal agents, terbinafine, itraconazole and fluconazole, is effective against dermatophytes with relatively fewer data being available for the treatment of Candida species and nondermatophyte moulds. Itraconazole is effective against Candida onychomycosis. Terbinafine may be more effective against C. parapsilosis compared with C. albicans; furthermore with Candida species a higher dose of terbinafine or a longer duration of therapy may be required compared with the regimen for dermatophytes. The least amount of experience in treating onychomycosis is with fluconazole. Griseofulvin is not effective against Candida species or the nondermatophyte moulds. The main use of griseo-fulvin currently is to treat tinea capitis. Ketoconazole may be used by some to treat tinea versicolor with the dosage regimens being short and requiring the use of only a few doses. The preferred regimens for the 3 oral antimycotic agents are as follows: itraconazole - pulse therapy with the drug being administered for 1 week with 3 weeks off treatment between successive pulses; terbinafine - continuous once daily therapy; and fluconazole - once weekly treatment. The regimen for the treatment of dermatophyte onychomycosis is: itraconazole - 200mg twice daily for I week per month x 3 pulses; terbinafine - 250 mg/day for 12 weeks; or, fluconazole - 150 mg/wk until the abnormal-appearing nail plate has grown out, typically over a period of 9 to 18 months. For the 3 oral antifungal agents the more common adverse reactions pertain to the following systems, gastrointestinal (for example, nausea, gastrointestinal distress, diarrhoea, abdominal pain), cutaneous eruption, and CNS (for example, headache and malaise). Each of the new antifungal agents is more cost-effective than griseofulvin for the treatment of onychomycosis and is associated with high compliance, in part because of the shorter duration of therapy. The newer antifungal agents are generally well tolerated with drug interactions that are usually predictable.     

Treatment of onychomycosis with oral antifungal agents

Onychomycosis is the most common nail disease and describes the invasion of the nail by fungi. Different clinical patterns of infection depend on the way and the extent by which fungi colonise the nail: distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis and total dystropic onychomycosis. The type of nail invasion depends on both the fungus responsible and on host susceptibility. Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails and the severity of nail involvement. The goals for antifungal therapy are mycological cure and a normal looking nail. In this paper the treatment of onychomycosis with oral antifungal agents will be reviewed.     

Treatment of onychomycosis with oral antifungal agents

Onychomycosis is the most common nail disease and describes the invasion of the nail by fungi. Different clinical patterns of infection depend on the way and the extent by which fungi colonise the nail: distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis and total dystropic onychomycosis. The type of nail invasion depends on both the fungus responsible and on host susceptibility. Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails and the severity of nail involvement. The goals for antifungal therapy are mycological cure and a normal looking nail. In this paper the treatment of onychomycosis with oral antifungal agents will be reviewed.     

3种抗真菌药治疗甲真菌病的成本-效果比较

目的　探讨不同抗真菌药治疗甲真菌病的经济效果。方法　选择 12 0例甲真菌病患者 ,随机分成A、B、C3组 ,分别给予伊曲康唑、特比萘芬、氟康唑口服治疗 ,运用药物经济学的成本 效果分析方法进行评价。结果　A、B、C 3组方案中治疗指甲真菌病 /趾甲真菌病的成本 效果比分别为 10 2 3/ 15 0 7,9 2 1/ 12 .5 6 ,10 6 1/ 15 99;敏感度分析后分别为 9.17/ 13 32、8 2 7/11 14、9 5 8/ 14 2 4。结论　B组方案为治疗甲真菌病的最经济有效方案     

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.     

Onychomycosis in the elderly : drug treatment options

The prevalence of onychomycosis is nearly 20% in patients aged >60 years. In North America, 90% of toenail onychomycosis is caused by dermatophytes (Trichophyton species). Distal-lateral subungual onychomycosis is the most common clinical presentation. The potassium hydroxide test is the most cost-effective diagnostic method. Although nail clipping for histology using periodic acid-Schiff stain is more sensitive, it is much more expensive.Elderly patients have specific risk factors for poor response to therapy for onychomycosis, including frequent nail dystrophy, slow growth of nails and increased prevalence of peripheral vascular disease and diabetes mellitus. Elderly people with diabetes should be treated for onychomycosis to prevent secondary bacterial infections and subsequent complications. Terbinafine is the drug of choice for dermatophyte onychomycosis, with greater mycological cure rates, less serious and fewer drug interactions, and a lower cost than continuous itraconazole therapy. Adjunct debridement may improve the clinical and complete cure rates compared with terbinafine alone. Common adverse effects of terbinafine in the elderly include nausea, sinusitis, arthralgia and hypercholesterolaemia. For onychomycosis caused by Candida or nondermatophyte moulds, there is no superior systemic therapy. In general, topical nail lacquers, amorolfine and ciclopirox are not practical for elderly patients because of the recommended frequency of application, periodic routine debridement of affected nails and long duration of therapy. However, nail lacquers may be a good option as monotherapy for patients with superficial white onychomycosis or in combination with systemic antifungal therapy for patients with predisposing factors for poor response or recurrence.     

Terbinafine. A pharmacoeconomic evaluation of its use in superficial fungal infections

Terbinafine is an orally and topically active allylamine antifungal drug which is an effective and well tolerated therapy for a wide range of superficial dermatophyte infections. In contrast to most other commonly prescribed antifungal agents, terbinafine is fungicidal in vitro and possesses improved pharmacokinetic properties with respect to drug penetration into nail tissue following oral administration. These properties enable terbinafine to achieve high success rates with shortened therapy regimens in the treatment of dermatophyte skin infections and onychomycosis. Pharmacoeconomic analyses have shown that oral terbinafine, with its higher rates of clinical efficacy and lower rates of relapse/reinfection, is less costly and more cost effective than oral griseofulvin, ketoconazole and itraconazole when used as initial therapy in the treatment of onychomycosis. However, some points regarding the clinical efficacy of itraconazole relative to terbinafine and the drug treatment regimens used in these studies need further clarification. In the management of tinea pedis, a cost analysis suggested that initial therapy with terbinafine 1% cream was more costly than initial therapy with miconazole, oxiconazole or clotrimazole. However, in cost-effectiveness studies, terbinafine had a lower cost per disease-free day than ciclopirox, clotrimazole, ketoconazole and miconazole in the treatment of dermatophyte skin infections. In conclusion, available clinical and pharmacoeconomic data support the use of topical terbinafine as first-line treatment of dermatophyte skin infections unless the acquisition cost of terbinafine is markedly greater than that of alternative topical antifungal agents. Oral terbinafine can be recommended as a cost-effective first-line treatment, preferable to oral griseofulvin, ketoconazole and itraconazole, in patients with dermatophyte onychomycosis.     

Onychomycosis in the elderly

Onychomycosis is found more frequently in the elderly, and in more males than females. Onychomycosis of the toes is usually caused by dermatophytes, most commonly Trichophyton rubrum and T. mentagrophytes. The most common clinical presentations are distal and lateral subungual onychomycosis (which usually affects the great/first toe) and white superficial onychomycosis (which generally involves the third/fourth toes). Only about 50% of all abnormal-appearing nails are due to onychomycosis. In the remainder, trauma to the nail, psoriasis and conditions such as lichen planus should be considered in the differential diagnosis. Therefore, the clinical impression of onychomycosis should be confirmed by mycological examination, whenever possible. The management of onychomycosis may include no therapy, palliative treatment with mechanical or chemical debridement, topical antifungal therapy, oral antifungal agents or a combination of treatment modalities. In the US, the only new oral agents approved for treatment of onychomycosis are terbinafine and itraconazole. Fluconazole is approved for onychomycosis in some other countries. Ciclopirox nail lacquer has recently been approved in the US for the treatment of onychomycosis. In some other countries topical agents such as amorolfine are also used. Griseofulvin and ketoconazole are no longer preferred for the treatment of onychomycosis. The new oral antifungal agents are effective and well tolerated in the elderly. Patient selection should be based on the history (including systems review and medication record), examination and baseline monitoring, if indicated. Laboratory monitoring during therapy for onychomycosis varies among physicians. A combination of removal of the diseased nail plate or local measures and oral antifungal therapy may be optimal in certain instances, e.g. when lateral onychomycosis or dermatophytoma are present. For dermatophyte toe onychomycosis the recommended duration of therapy with terbinafine is 250 mg/day for 12 weeks. For itraconazole (pulse) the regimen is 200 mg twice daily for 1 week on, 3 weeks off, repeated for 3 consecutive pulses and with fluconazole the regimen is 150 to 300 mg once weekly given for a usual range of 6 to 12 months or until the nail plate has grown out. In some instances, if extra therapy is required, one suggestion is that 4 weeks of terbinafine or an extra pulse of itraconazole are given between months 6 and 9 from the start of therapy. Once cure has been achieved, it is important to counsel patients on the strategies of reducing recurrence of disease.     

Different physicochemical properties of antimycotic agents are relevant for penetration into and through human nails

This article reports the characterization of the physicochemical properties of two important antifungal topical drugs, amorolfine and ciclopirox. Furthermore, the release of the drugs from commercial lacquer formulations for treatment of onychomycosis was studied using the online FTIR-ATR technique. Based on the physicochemical background of these two drugs and their release from commercial lacquer formulations for treatment of onychomycosis, the suitability of these drugs for optimized local antifungal therapy to human nails is discussed. Amorolfine appears to be more suitable for drug delivery to human nails because it penetrates into the nails via the hydrophilic pathway. Furthermore amorolfine penetrates very well into fungal cells, due to the pH value of the nail, as well as the pKa value of this antimycotic agent and the lipophilic properties of its base form.     

Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail

Efinaconazole 10% topical solution is a new antifungal therapy for the topical treatment of mild to moderate toenail onychomycosis. In vitro and in vivo data have shown significant antifungal activity against dermatophytes, Candida spp. and nondermatophyte molds, and its mechanism of action is through inhibition of fungal lanosterol 14α-demethylase. In two parallel, double-blind, randomized, controlled, Phase III trials, complete cure rates were 17.8 and 15.2%, respectively, and mycological cure rates were 55.2 and 53.4%, respectively, for efinaconazole 10% topical solution, which were superior to vehicle, with minimal adverse events. This drug profile reviews the most recent basic science and clinical data for efinaconazole in the treatment of toenail onychomycosis.     

Tavaborole – a treatment for onychomycosis of the toenails

Introduction: Onychomycosis is a fungal nail infection that accounts for half of all nail diseases. Oral drugs on the market have adverse effects, while it is difficult for traditional topical drugs to penetrate the nail plate to reach the diseased nail bed. Tavaborole is a new drug that addresses the unmet needs of currently available treatments. Tavaborole (5%) is FDA approved for treating toenail onychomycosis and has shown antifungal activities against yeast, moulds and dermatophytes.

Areas covered: The objective of this article is to review the efficacy, pharmacokinetics, pharmacodynamics, and safety of tavaborole for treatment of toenail onychomycosis.

Expert commentary: Tavaborole, with its unique mechanism, may be a good candidate for use in treating children with fungal infections, diabetic individuals, and treating mixed infections. Tavaborole may be paired with other therapies to potentially increase cure rates.     

Emerging therapeutic agents for onychomycosis

Onychomycosis is a frequent disorder that represents the most prevalent fungal infection, particularly among older individuals. Diverse fungi of the dermatophyte, non-dermatophyte mold and yeast families have been reported to be responsible for onychomycosis. The output from the pharmaceutical industry of new antifungals to treat onychomycosis has been limited over the last decade. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes. However, neither of these treatment options provides high cure rates that are durable. At present, azoles and allylamines are keeping the pivotal roles. New derivatives with a favorable risk-benefit ratio and new formulations of older azoles seem to be promising. Thus, ongoing drug development activities have focused on novel delivery technologies to facilitate incorporation of existing antifungal drugs inside the nail plate and the discovery of new active antifungals.     

Onychomycosis: classification and diagnosis

Onychomycosis is a common infection of the nail predominantly caused by anthropophilic dermatophytes, and to a lesser extent by yeasts (Candida species) and non-dermatophyte molds. The treatment of onychomycosis is dependent on several variables, including the type of onychomycosis and the causative organism. Various techniques have been used to accurately diagnose onychomycosis, with microscopy and culture being used most frequently. Histological examination of the distal nail plate can aid in confirming the presence of invasive nail disease, but histological examination should not be limited to the nail plate as it may also be helpful in diagnosing subungual onychomycosis. Nucleic acid-based identification techniques may also be valuable when diagnosing onychomycosis; however, multiple steps may be necessary to determine the causative species. Confocal microscopy may also be a fast and reliable method of diagnosing onychomycosis, though it has very limited ability to distinguish between dermatophyte and mold infections. Prior to treatment an accurate diagnosis can provide guidance about the choice of antifungal agent, especially since the causative organism may vary in its response to the antifungal therapies available.     

Terbinafine-induced lichenoid drug eruption

Drug-induced lichen planus has been induced by antibiotics, anticonvulsants, antidiabetics, antimalarials, antitubercular drugs, antihypertensives, psychiatric drugs, chemotherapeutic agents, diuretic, heavy metals, NSAIDs, etc. Terbinafine, an antifungal agent, is widely used for dermatophyte infections and onychomycosis. Cutaneous adverse effects of terbinafine are rarely reported. Here, we report a case of terbinafine-induced lichenoid drug eruption in a 22-year-old who presented with generalized lichenoid eruption 2 weeks after terbinafine initiation of. The body and lip cleared completely after 8 weeks of drug withdrawal; nail change cleared after 12 weeks.     

Are boosters or supplementation of antifungal drugs of any use for treating onychomycosis?

It is widely accepted that there is a finite failure rate when treating onychomycosis; a case report from the author serves as an example of multiple failures following treatments of varying duration and combinations, including oral-local, then oral-oral therapies. This article discusses the results obtained by authors who have varied the standard duration of therapy, increased the dosage of the oral antifungal agents, or have used two oral drugs in treating this condition.     

Emerging therapeutic agents for onychomycosis

Onychomycosis is a frequent disorder that represents the most prevalent fungal infection, particularly among older individuals. Diverse fungi of the dermatophyte, non-dermatophyte mold and yeast families have been reported to be responsible for onychomycosis. The output from the pharmaceutical industry of new antifungals to treat onychomycosis has been limited over the last decade. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes. However, neither of these treatment options provides high cure rates that are durable. At present, azoles and allylamines are keeping the pivotal roles. New derivatives with a favorable risk-benefit ratio and new formulations of older azoles seem to be promising. Thus, ongoing drug development activities have focused on novel delivery technologies to facilitate incorporation of existing antifungal drugs inside the nail plate and the discovery of new active antifungals.     

How effective is efinaconazole in the management of onychomycosis?

Introduction: Onychomycosis is a fungal nail infection that is difficult to treat due to poor accessibility of drugs into the nail plate. Although oral antifungals can reach the nail apparatus more readily, these therapies may not be suitable or desirable for some patients (e.g., multiple medications or immunocompromised). Efinaconazole 10% solution is a new topical antifungal recently approved and sold in Canada, the United States and Japan for the treatment of mild-to-moderate toenail onychomycosis. Efinaconazole has broad-spectrum antifungal activity against dermatophytes, nondermatophyte molds and yeasts, and high ungual penetration due to its low keratin binding properties.

Areas covered: The objective of this article is to summarize recent data regarding the efficacy, safety and pharmacokinetic properties of efinaconazole in the treatment of onychomycosis.

Expert opinion: Efinaconazole is a safe and effective treatment for onychomycosis that can be used in a wide range of patients due to its broad-spectrum antifungal activity andlow rate of treatment-related adverse events. When incomplete response to oral therapy or devices (e.g. laser therapy) is encountered, efinaconazole could be used in combination to improve success rates. Alternatively, efinaconazole could be used as a ‘closer’ drug, in an effort to provide cure when the initial oral or device therapy has resulted in an incomplete response.