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.     

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.     

New antifungal therapies for the treatment of onychomycosis

Onychomycosis is a common disorder of nails caused by diverse spectrum of fungi ranging from dermatophytes to nondermatophyte molds and yeasts. Presently, oral and topical therapies are the mainstay of treatment with oral therapies yielding somewhat better results. Though various treatment options are available to treat onychomycosis, search for a convenient, cost effective agent with high and long-lasting cure rates is continuing. Currently, many new therapies for onychomycosis are under investigation which includes new formulations of azoles, improvement of existing topical treatments through addition of ungual enhancers and new drugs with better nail permeation.     

Antifungal azoles for skin disorders

The output from the pharmaceutical industry of new antifungals to treat superficial infections over the last decade has been limited. Notwithstanding the fact that the need to combat life-threatening deep fungal infections is of great importance, there remains an unmet need for compounds to treat superficial infections, especially chronic ones such as onychomycosis and tinea capitis. Azoles still have a pivotal role to fulfill. Both new azole derivatives, with a favourable risk–benefit ratio, and new formulations of older azoles are currently under development in various companies. In the search for novel properties to make azoles attractive, special attention has been paid to mechanisms of action ancillary to the well known ergosterol biosynthesis inhibition and broadened the activity spectrum, including other microorganisms, more favourable pharmacokinetics, fewer drug–drug interactions and more acceptable irritation profiles for drugs intended for topical application. The most recent list of new azoles in early and late clinical development is given in this review, preceded by an overview of presently used medications to treat fungal infections of the skin.     

Recent progress on the topical therapy of onychomycosis

Onychomycosis is a fungal infection of the fingernails and toenails that results in thickening, discoloration, splitting of the nails and lifting of the nail from the nail bed. The disease is caused by dermatophytes and has a high incidence within the general population, especially among older individuals. 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. The difficulty in treating onychomycosis results from the deep-seated nature of the infection within the nail unit (nail plate, nail bed and surrounding tissue) and the inability of drugs to effectively reach all sites. Ongoing drug development activities have focused on novel delivery technologies to facilitate penetration of existing antifungal drugs through the nail plate and on the discovery of inherently penetrable antifungals. AN-2690 represents an oxaborole antifungal that is designed to penetrate the nail plate and is showing promising results in clinical trials.     

Recent progress on the topical therapy of onychomycosis

Onychomycosis is a fungal infection of the fingernails and toenails that results in thickening, discoloration, splitting of the nails and lifting of the nail from the nail bed. The disease is caused by dermatophytes and has a high incidence within the general population, especially among older individuals. 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. The difficulty in treating onychomycosis results from the deep-seated nature of the infection within the nail unit (nail plate, nail bed and surrounding tissue) and the inability of drugs to effectively reach all sites. Ongoing drug development activities have focused on novel delivery technologies to facilitate penetration of existing antifungal drugs through the nail plate and on the discovery of inherently penetrable antifungals. AN-2690 represents an oxaborole antifungal that is designed to penetrate the nail plate and is showing promising results in clinical trials.     

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.     

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.     

Which antifungal agent for onychomycosis? A pharmacoeconomic analysis.

The incidence of fungal nail infections is increasing and this is possibly because of several factors: better methods of detection, a growing population of immunocompromised patients who have a greater susceptibility to such infections, the increased use of immunosuppressive drugs, the increasing number of elderly people, worldwide travel, and the use of communal bathing facilities. Onychomycosis is a fungal infection of the fingernails and toenails that accounts for about 30% of all superficial fungal infections. It is characterised by nail discoloration, thickening and ultimately destruction of the nail plate. Management of this disease has improved significantly and treatment patterns have dramatically changed in recent years as a result of advances in new treatment options (e.g. oral antifungal agents) and changes in treatment regimens (e.g. pulse therapy). Also, newer drugs for onychomycosis have improved tolerability profiles compared with older agents. The overall costs of treating onychomycosis are substantial, and it has been estimated that direct cost for US Medicare patients with the disease is 43 million US dollars per year (year of costing not available). Pharmacoeconomic studies help in the decision-making process when selecting the most cost-effective antifungal agents to treat onychomycosis. To date there have been a number of national and international economic studies aimed at effectively assessing the efficacy and costs of the treatment options available to cure onychomycosis. The objectives of this paper are to (i) review the published findings regarding the epidemiology of onychomycosis; (ii) summarise the original pharmacoeconomic studies that describe the economic impact of the disease; and (iii) address the impact of the disease on patients' health-related quality of life.     

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.     

New antifungal agents and preparations

In neutropenic patients amphotericin B remains the drug of choice for the treatment of systemic fungal infections. On the basis of a superior efficacy in combination with a lower toxicity, the triazoles have superseded the older azoles. Regularly, amphotericin B and a triazole are used simultaneously without any evidence from clinical trials that such a strategy is safe and efficacious. Liposomal preparation, lipid complex or colloidal dispersion of amphotericin B have been produced successfully to reduce toxicity. However, there is only one small randomised study that hints at the superiority of liposomal amphotericin B over amphotericin B deoxycholate. Promising new agents like candins, sordarins, high dose oral terbinafine, the third generation azoles, and liposomal nystatin are under development. The first phase II study on voriconazole in the treatment of pulmonary aspergillosis has produced encouraging results. The major promise of the new candins lies in the activity against Candida species, including those resistant to the azoles and polyenes, and in a mechanism of action totally different from the established antifungals. Cytokines and colony stimulating factors are theoretically very promising but there are no clinical studies that warrant routine use.     

Options for the Management of Mucosal Candidiasis in Patients with AIDS and HIV Infection

Oropharyngeal candidiasis may be the first manifestation of human immunodeficiency viral (HIV) infection, and more than 90% of patients with the acquired immunodeficiency syndrome (AIDS) develop the disease. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole), have largely replaced older topical antifungals (gentian violet, nystatin) in the management of the disease in these patients. A concern in these patients is clinical relapse, which appears to be dependent on degree of immunosuppression and is more common with clotrimazole and ketoconazole than with fluconazole or itraconazole. Candida esophagitis is also of concern, since it occurs in more than 10% of patients with AIDS. Fluconazole is an integral part of management. A cyclodextrin oral solution formulation of itraconazole has similar clinical response rates as fluconazole and is an effective alternative. In patients with fluconazole-resistant mucocutaneous candidiasis, treatment options include itraconazole and amphotericin B oral suspension and parenteral preparation.     

Treating chromoblastomycosis with systemic antifungals

Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi ), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 - 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.     

Dacomitinib,a new therapy for the treatment of non-small cell lung cancer

Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 – 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.     

Clinical impact of drug-drug interactions with systemic azole antifungals

The number of drug-drug interactions is remarkably high among hospitalized patients receiving systemic azole antifungal agents. Recent estimates suggest that as many as 95% of hospitalized patients treated with azole antifungals may receive medications capable of producing a major or moderate pharmacokinetic interaction. The antifungal properties of the azoles stem from their propensity to inhibit fungal cytochrome P-450 enzymes. In humans, however, azole antifungals also interfere with several hepatic and intestinal cytochrome P-450 isoenzymes responsible for the metabolism of numerous drugs. As a result, the azole antifungals have drug-drug interactions with a plethora of drug classes, including H(1)-antihistamines, antineoplastics, steroids, antimicrobials, antiretrovirals, opioids, long acting barbiturates, cardiovascular agents, psychotropics and oral contraceptives. These interactions are so numerous that it is extremely difficult to remember them all and would be even harder to prospectively predict their consequences in an individual patient. In fact, any drug that shares the same cytochrome P-450 isoenzymes for metabolism may potentially to give rise to drug-drug interactions in vivo. Patients with specific polymorphisms are probably at especially high risk. Certain drug combinations with azoles should be absolutely avoided, while other combinations may be prescribed provided monitoring of drug levels is undertaken, dosage reduction of one or more of the drugs is made (as appropriate) and/or careful monitoring of clinical parameters is performed.     

Antifolates as antimycotics?: Connection between the folic acid cycle and the ergosterol biosynthesis pathway in Candida albicans

The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance have encouraged the search for new antifungal agents or effective combinations of existing drugs. Infections due to Candida albicans are usually treated with azole antifungals such as fluconazole, ketoconazole or itraconazole. Whilst azoles may have little or no toxicity, they generally offer rather poor fungicidal activity. Even in the absence of resistance, treatment failures or recurrent infections are not uncommon, especially in immunocompromised individuals. Here we demonstrate that the non-classical antifolate pyrimethamine shows synergy with azole antifungal compounds and interferes with the ergosterol biosynthesis pathway in C. albicans. By disturbing folate metabolism in this fungus, pyrimethamine can inhibit ergosterol production. The molecular connection between the folic acid cycle and the ergosterol biosynthesis pathway is discussed and we show that the filamentous form of this fungus is more susceptible to methotrexate than the yeast form because the drug is more effectively transported through the membrane of the filamentous form. When used to treat the hyphal form, methotrexate showed synergy with other antifungals such as azoles and terbinafine. This finding could have important clinical applications, as a combination of azoles with antifolates and/or inhibitors of folic acid synthesis could represent an attractive alternative for the treatment of C. albicans infections.     

Recent advances in antifungal chemotherapy

For over 50 years, amphotericin B deoxycholate (AmBD) has been the 'gold standard' in antifungal chemotherapy, despite its frequent toxicities. However, improved treatment options for invasive fungal infections (IFIs) have been developed during the last 15 years. Newer antifungal agents, including less toxic lipid preparations of AmBD, triazoles and the echinocandins, have been added to our armamentarium against IFIs. Some of these newer drugs can now replace AmBD as primary therapy (e.g. caspofungin for candidiasis, voriconazole for aspergillosis), whilst others offer new therapeutic options for difficult-to-treat IFIs (e.g. posaconazole for zygomycosis, fusariosis and chromoblastomycosis). It is interesting that extended use of newer antifungals such as fluconazole, despite decreasing the mortality attributed to candidiasis, resulted in selection of species resistant to several antifungals (Candida krusei, Candida glabrata); whilst several publications suggest that prolonged use of voriconazole may expose severely immunocompromised patients to the risk of zygomycosis (breakthrough). On the other hand, the differences in the mode of action of newer antifungals such as echinocandins raise the question whether combination antifungal therapy is more effective than monotherapy. Finally, the availability of an oral formulation with excellent biosafety of several newer antifungals (e.g. posaconazole) makes them candidates for prophylactic or prolonged maintenance therapy.     

Treatment of drug-resistant Aspergillus infection

Triazole antifungals are frontline drugs for the treatment and prophylaxis of infections due to Aspergillus species. Azole resistance is an emerging problem and is associated with treatment failure in several case series. The management of azole-resistant invasive aspergillosis remains a challenge and there are no guidelines with appropriate recommendations. The current clinical practice suggests that liposomal amphotericin B or a combination of voriconazole or posaconazole with an echinocandin may be effective. Although cross-resistance within the azoles seems to be common, the role of azoles in the management of azole-resistant aspergillosis remains unclear, but optimizing drug exposure is critical for treatment success.     

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.     

Treatment of invasive candidiasis in immunocompromised pediatric patients

In the last 3 decades, systemic candidiasis has become increasingly recognized as a major source of morbidity and mortality in immunocompromised pediatric patients. As the number of children receiving chemotherapy and bone marrow transplantations continue to increase, clinicians should expect that invasive infections from Candida spp. will also increase in these vulnerable hosts. Fortunately, in the past 15 years, the evolution of older antifungals coupled with the discovery of new classes of antifungal agents has equipped physicians with reasonable options for treating these otherwise life-threatening infections.This review aims to familiarize the reader with the evolving epidemiology of candidiasis in immunocompromised children as well as discuss therapeutic options from each class of antifungal agents. Mechanisms of action, pharmacokinetics, toxicities, resistance patterns, chemotherapy interactions, and clinical relevance in immunocompromised children are reviewed for polyenes, flucytosine (5-fluorocytosine), azoles, and echinocandins.