Review of antifungal therapy and the severity index for assessing onychomycosis: part I

This review outlines recent data on treatment modalities and outcomes with antifungal therapy in onychomycosis. Included are topical, mechanical, chemical and systemic treatments or a combination thereof. Topical treatments, or transungual drug delivery systems (TUDDS), including ciclopirox and amorolfine were shown to be effective if used alone for mild-moderate nail involvement. Specifically, superficial white onychomycosis (SWO) restricted to the dorsum of the nail plate and moderate distal lateral subungual onychomycosis (DLSO). Mechanical treatments were mostly effective as adjuncts to topical therapy which include nail avulsion and abrasion. In particular, partial nail avulsion aids topical therapy in DLSO and partial subungual onychomycosis for a more effective therapy. Chemical avulsion is a painless method of debridement which uses a keratinolysis formula that is effective only in limited and early disease. Systemic therapies have been shown to be effective with terbinafine and itraconazole is suggested as being the most cost-effective therapy. Systemic therapies require consideration of side effects and monitoring by both patient and physician prior to treatment application. An effective suggestion is the use of a topical with debridement for mild-moderate onychomycosis and systemic (terbinafine) plus topical for severe onychomycosis. Most treatment modalities will require long-term use from 3 to 9 months to be most effective, with strategies presented in Part II of this review.     

Onychomycosis Does Not Always Require Systemic Treatment for Cure: A Trial Using Topical Therapy

Standard teaching dictates that systemic therapy is required for treatment of onychomycosis. It is unknown whether topical antifungal therapy is effective for pediatric nail infections. This prospective, randomized, double‐blind, vehicle‐controlled study was conducted in the Pediatric Dermatology Research Unit at Rady Children's Hospital to determine whether topical antifungal therapy is efficacious for pediatric onychomycosis. Forty patients ages 2 to 16 years with nonmatrix onychomycosis were randomized 1:3 to ciclopirox lacquer or vehicle lacquer. Ciclopirox lacquer or vehicle was applied daily for 32 weeks, with weekly removal of the lacquer and mechanical trimming. Those with poor response were crossed over to active drug at week 12. Thirty‐seven patients completed the 32‐week study, and follow‐up data were collected 1 year after completion of the study from 24 patients. Mycologic cure, effective treatment, and complete cure were assessed, as well as adverse events and effect on quality of life. Mycologic cure was 70% in the treated group and 20% in the vehicle arm (p = 0.03) at week 12. At end of the study (week 32), 77% of treated patients achieved mycologic cure and 71% effective treatment, compared with 22% of the control group. Ninety‐two percent of those who were cured and followed for 1 year remained clear. Topical antifungal lacquer (ciclopirox) can be an effective option for children with nonmatrix onychomycosis. Pediatric onychomycosis does not always require systemic therapy and responds better to topical therapy than does adult disease.     

The use of topical therapies to treat onychomycosis

The management of onychomycosis using topical agents has improved with the introduction of ciclopirox and amorolfine nail lacquers; other topical agents may be less effective. The combination of a nail lacquer with an oral antifungal agent may further improve efficacy rates in certain clinical presentations (eg, among those individuals with severe onychomycosis). Topical agents have a favorable adverse events profile. Further studies are required on the treatment of onychomycosis with nail lacquers.     

Therapeutic strategies in onychomycosis

Objective: This paper reviews current advantages and limits of modern topical antifungal agents (amorolfine, ciclopirox nail lacquer, bifonazole/urea ointment) and oral antimycotic drugs (itraconazole, terbinafine) in the treatment of onychomycosis, taking into account the results of clinical trials.Results: Clinical studies show that both topical and oral antimycotic therapy are effective in treating onychomycosis. However, topical antimycotic treatment produces high efficacy only in superficial and minor distal subungual onychomycosis. The newer oral antifungal drugs have been relatively well tolerated so far. Nevertheless, if oral antimycotic treatment schedules of several months are used, liver function should be monitored.Conclusion: Knowledge of the advantages and limits of both topical and systemic antimycotic treatment of onychomycosis is a prerequisite for a reasonable and effective therapy. Consequently, a therapeutic strategy in onychomycosis is useful to aid physicians choose a suitable treatment.     

Canadian perspectives on antifungal treatment for onychomycosis

Onychomycosis is a common nail disease caused by dermatophytes, yeasts, and nondermatophyte molds affecting approximately 6.5% of the Canadian population. Approved therapies for onychomycosis in Canada are terbinafine 250 mg once daily for 6 to 12 weeks; itraconazole 200 mg twice daily given for two to three pulses (one pulse = 200 mg daily for 1 week, with 3 weeks off the drug before the next pulse); and ciclopirox nail lacquer 8% used once daily for up to 48 weeks. These medications can be used for dermatophyte onychomycosis of toenails or fingernails. Liver enzyme monitoring should be performed when prescribing the oral medications. Ciclopirox is one of the newest antifungal agents and is the only topical therapy specifically indicated for onychomycosis in Canada. Topical therapy for onychomycosis provides an advantage over oral treatment in safety and cost, giving ciclopirox wide potential for use. It remains to be seen what future role ciclopirox will have in the Canadian onychomycosis spectrum.     

Labeled use of efinaconazole topical solution 10% in treating onychomycosis in children and a review of the management of pediatric onychomycosis

Onychomycosis is a difficult to treat condition whose prevalence is increasing. Until recently, there was no FDA approved antifungal agent for the treatment of onychomycosis in children. Although systemic antifungal agents are effective, their use is restricted by the potential adverse events and drug‐drug interactions. There is evidence regarding the safety and efficacy of topical antifungal agents for pediatric onychomycosis. We have summarized the results of a recently published study using efinaconazole topical solution 10% to treat onychomycosis in children and discuss management of pediatric onychomycosis. In a multicenter, open‐label phase 4 study, efinaconazole 10% solution was applied topically once daily in children aged 6 to 16 years with mild to severe, culture positive, distal and lateral subungual onychomycosis. Treatment was for 48 weeks with a follow‐up at week 52. Pharmacokinetics was performed in a subset of patients. There were 62 patients enrolled in the study. At week 52, the efficacy was mycological cure rate 65% and complete cure rate 40%. All treatment‐emergent adverse events (TEAE) were mild to moderate in severity with none resulting in study discontinuation. The only treatment‐related TEAE was ingrown toenail. Efinaconazole was detected at low levels in plasma. Efinaconazole topical solution 10% is effective and safe in treating onychomycosis in children age 6 to 16 years and was recently FDA‐approved for this indication. The on‐label use of other topical agents, tavaborole solution 5% and ciclopirox nail lacquer solution 8% is reviewed. We also briefly discuss the use of oral agents, terbinafine, itraconazole, and fluconazole in pediatric onychomycosis.     

Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy

BACKGROUND: Onychomycosis is a relatively common disease accounting for up to 50% of all nail disorders and its prevalence rises with age. As onychomycosis is an important medical disorder affecting both patient's health and quality of life, it requires prompt and effective treatment. OBJECTIVE: Topical antifungal nail lacquers have been formulated to provide efficient delivery to the nail unit. As both amorolfine and ciclopirox have proved useful as monotherapy for onychomycosis that does not involve the nail matrix area, the purpose of this article is to check if, when combined with oral agents, the effectiveness and scope of treatment can be improved further. METHODS: Combining data for mycological cure with clinical success (nail morphology) provides a more exacting efficacy measure. RESULTS: Clinical investigations have shown that the combination of oral therapies with antifungal nail lacquer can confer considerable advantage over monotherapy with either drug type. CONCLUSION: The improved effectiveness and economic advantages of combined topical/oral therapies benefit both patients and health providers; these treatment regimens therefore have an important role to play in the modern management of onychomycosis.     

Brief treatment guide for onychomycosis

Most onychomycosis infections result from dermatophyte organisms and present as distal lateral subungual onychomycosis (DLSO). Mild to moderate infections may be effectively treated with topical lacquer medications; however, there is no general consensus on what constitutes mild infection. In general, mild infections involve relatively small areas of the nail plate without infection of the nail matrix or lunula. Characteristics such as nail thickness, the number of nails affected, and the degree of onycholysis will also be taken into account in the categorization of nail severity and may increase the severity to moderate or severe even where nail plate area involvement is low. Similarly, although an infection may be mild, for patients with underlying health issues such as diabetes or immunodeficiency, oral therapy may be recommended as it typically provides the higher treatment efficacy required by these conditions. Severe infections may be treated with oral antifungal agents or combinations of oral agents and oral antifungals or oral and topical lacquer antifungals. Débridement is a technique that may be used in nearly any degree of infection to aid treatment efficacy by reducing the burden of fungal infection. Other treatment issues discussed include superficial white onychomycosis, nondermatophyte mold infection, and infection prophylaxis. Treatment is discussed considering a dermatophyte infection of DLSO presentation, unless otherwise stated. Infections should be confirmed by laboratory culture to eliminate any other diagnosis. Therapy recommendations concentrate on those agents approved in Canada for onychomycosis: oral terbinafine, oral itraconazole, and ciclopirox 8% nail lacquer.     

Ciclopirox nail lacquer 8% for the treatment of onychomycosis: a Canadian perspective

Onychomycosis is prevalent in the Canadian population, and risk factors, such as old age and diabetes, are increasing. This condition has traditionally been treated using oral antifungal agents with varying degrees of success. Recently, ciclopirox nail lacquer 8% solution became the first topical agent approved in Canada for onychomycosis. Ciclopirox nail lacquer may be safe and effective for the treatment of onychomycosis, and certain candidates may benefit from therapy. Ciclopirox may be implicated for prophylactic use in order to prevent recurrent infection and may be used in combination with oral agents.     

Efficacy and tolerability of amorolfine 5% nail lacquer in combination with systemic antifungal agents for onychomycosis: A meta‐analysis and systematic review

The efficacy and safety of amorolfine 5% nail lacquer in combination with systemic antifungal agents in the treatment of the onychomycosis were evaluated. According to our meta‐analysis, combination treatment of amorolfine 5% nail lacquer and systemic antifungals can result in higher percentage of complete clearance of onychomycosis. It showed that the experimental combination group was more effective than monotherapy of the systemic antifungals [OR (odds ratio) = 1.97, 95%CI (95% confidence interval) = 1.44–2.69], and no more adverse events happened with the addition of amorolfine 5% nail lacquer (OR = .96, 95%CI = .56–1.63, p = .95). This effect strengthens the fact that amorolfine 5% nail lacquer in combination with systemic antifungal agents was better than the monotherapy of systemic antifungals like itraconazole and terbinafine.     

Determination of the subungual antifungal activity of amorolfine after 1 month's treatment in patients with onychomycosis: comparison of two nail lacquer formulations

Onychomycosis is common worldwide, about 10% of all dermatomycosis being fungal infections of the nails.¹ Up until now no satisfactory topical treatment has been available. Therefore, the development of any new antifungal gives rise to high expectations with regard to its effectiveness in onychomycosis. Amorolfine is a phenylpropyl morpholine derivative which has been found to be more effective than imidazole derivatives and polyene antibiotics both in vitro and in experimental infections against dermatophytes and yeasts.^2,3
Amorolfine possesses two properties which give rise to hopes that it may be used to treat onychomycosis. First, it is effective at low concentrations,² and secondly, studies of in-vitro penetration on human nails show the presence of amorolfine in sufficient concentrations in the nail plate and the nail bed to give fungistatic and fungicidal levels.⁴ Furthermore, the persistence of amorolfine in the subungual keratin for 7 days⁵ would allow physicians to reduce the frequency of application.
Two different lacquer formulations, one methylene chloride-based and the other ethanol based, were developed as vehicles for amorolfine for treating onychomycosis with one or two applications per week. This study was carried out in order to test the bioequivalence of the two different lacquer formulations and to see whether the antifungal activity of amorolfine in the subungual area would last longer than 7 days, as shown in a previous study.⁵ The measurement of the antifungal activity in the subungual area will be taken as one of the criteria for penetration of amorolfine through the human nail.     

Onychocola canadensis Sigler bei Onychomykose

Moulds or non-dermatophyte moulds (NDM) are being increasingly isolated as causative agent of onychomycoses. Known causes of a NDM-OM are Scopulariopsis brevicaulis, Fusarium, Aspergillus, Acremonium, Neoscytalidium dimidiatum, Arthrographis kalrae, and Chaetomium. In this article, 5 patients with suspected nail infection due to Onychocola canadensis are reported for the first time in Germany. Systemic antifungal agents are not considered to be effective in NDM onychomycosis. In individual cases, however, terbinafine seems to be effective in Onychocola canadensis infection of the nails. Treatment of choice represents, however, nontraumatic nail avulsion using 40?% urea ointment followed by antifungal nail lacquer with ciclopirox olamine or amorolfine.     

Pharmacoeconomic assessment of ciclopirox topical solution, 8%, oral terbinafine, and oral itraconazole for onychomycosis

Most pharmacoeconomic data available for antifungal agents are based on US or European cost parameters. Similar data have not been reported in a Canadian health care system. A pharmacoeconomic analysis was performed considering the costs of drug acquisition and medical management, which were representative of the Canadian health care system, for each of the therapies approved for use in toenail onychomycosis in Canada: continuous oral terbinafine, oral pulse itraconazole, and topical ciclopirox 8% nail lacquer. A survey of provincial fee schedules was conducted to determine the representative costs of parameters relating to onychomycosis treatment, such as consultation visit cost, return visit cost, mycology testing, liver function testing, and complete blood count analysis. Manufacturers' costs were used to calculate representative drug acquisition costs. Meta-analysis was used to determine the average mycologic cure rates of each therapy, and the medical literature was consulted to determine the relapse rates for each therapy. Ciclopirox nail lacquer had the lowest drug acquisition costs compared with continuous terbinafine and pulse itraconazole ($197.89 vs $311.39 and $323.40, respectively). Using the pharmacoeconomic model with three 1-year treatment phases, in which failures or relapses were re-treated with the primary drug, the expected cost per patient was $601.52 with ciclopirox nail lacquer, $746.72 with oral terbinafine, and $938.42 with itraconazole. The main analysis assumed that two bottles of ciclopirox nail lacquer were required per treatment. The cost for the ciclopirox lacquer exceeded continuous terbinafine but remained lower than pulse itraconazole when three bottles of ciclopirox nail lacquer were considered in the calculation of cost per mycological cure. A variety of relapse rates were tested, and ciclopirox using two or fewer bottles remained cost-effective compared with continuous terbinafine or pulse itraconazole, regardless of the relapse rate. Where three bottles are required, the cost-effectiveness of ciclopirox nail lacquer is less than that of continuous terbinafine but more cost-effective than that of pulse itraconazole.     

Mycology – an update Part 3: Dermatomycoses: topical and systemic therapy

Treatment of dermatophyte infections is based on the clinical picture and mycological detection of the causative pathogen. Based on the appropriate indication, onychomycosis can be treated topically using an antimycotic nail lacquer. Atraumatic nail abrasion with 40 % urea ointment has a beneficial effect on healing. Continuous treatment of onychomycosis with terbinafine represents the most effective systemic therapy. Terbinafine or itraconazole are the safest and most effective antimycotic agents for the treatment of onychomycosis in children. For laser therapy of onychomycosis, only a few studies on clinical efficacy are available. Regarding tinea capitis, targeted species‐specific therapy of dermatophytosis of the scalp is currently recommended. Terbinafine, yet also itraconazole and fluconazole, are effective in tinea capitis caused by Trichophyton species. Microsporum infections of the scalp are preferably treated with griseofulvin, alternatively with itraconazole or fluconazole. Terbinafine is less effective. Candidal intertrigo are topically treated with nystatin, but azoles or ciclopirox olamine are also suitable candidates. Systemically, fluconazole or itraconazole are used. Topical and systemic antimycotics are equivalent forms of therapy in acute vulvovaginal mycosis. Fluconazole is the drug of choice in chronic recurrent vulvovaginal mycosis caused by Candida albicans. Ketoconazole shows very good efficacy in tinea versicolor. With respect to systemic treatment of severe and widespread tinea versicolor, itraconazole is the drug of choice.     

Combination of surgical avulsion and topical therapy for single nail onychomycosis: a randomized controlled trial

BACKGROUND: Conventional therapy of onychomycosis is prolonged and often frustrating, which is why combination therapy involving topical, oral and surgical measures has been advocated as the treatment of choice. There are no controlled studies evaluating the efficacy of nail avulsion followed by topical antifungal therapy. OBJECTIVES: To evaluate the efficacy of combined surgical and topical therapy for onychomycosis. METHODS: Forty patients with single nail onychomycosis [28 with distal and lateral subungual onychomycosis, seven with total dystrophic onychomycosis (TDO) and five with proximal subungual onychomycosis] were randomly assigned to four treatment groups. Each group received avulsion of the involved nail, followed by ketoconazole 2% cream without (group I) or with occlusion (group II), or oxiconazole 1% cream without (group III) or with occlusion (group IV). Topical therapies were applied twice daily. The patients were reviewed monthly and treatment was continued until the regrowth of completely normal nail (mycologically negative). In cured cases, further monthly review was carried out for at least 6 months, without any form of therapy. At each visit direct microscopic examination was repeated. RESULTS: There was a high dropout rate, with seven patients (group I), six patients (group II), six patients (group III) and eight patients (group IV) completing the treatment protocol. Out of these, mycological cure was achieved in three (43%) patients in group I, four (67%) in group II, two (33%) in group III and six (75%) in group IV. All the cases of TDO failed to respond to this therapy. Overall, 15 of 27 (56%) patients were cured with this approach. On further follow up, recurrence of onychomycosis was recorded in two patients in group I. No side-effects or long-term complications of the nail avulsion were encountered. Important limitations encountered in the present study included a small sample size, a high dropout rate (32%) and poor patient compliance. CONCLUSIONS: Contrary to earlier reports, surgical nail avulsion with topical antifungal agents was not found to be a very encouraging modality for the treatment of onychomycosis. Both oxiconazole and ketoconazole delivered comparable results. Occlusion improved the treatment outcome, although the difference was not statistically significant. As a subtype, TDO showed poorest response. Surgical nail avulsion followed by topical antifungal therapy cannot be generally recommended for the treatment of onychomycosis.     

An innovative water-soluble biopolymer improves efficacy of ciclopirox nail lacquer in the management of onychomycosis

Background  A new 8% ciclopirox-medicated nail lacquer (P-3051), based on a new technology, revealed superior properties in terms of affinity to keratin, nail permeation, and ease of use.
Objective  This study aims to assess the efficacy and safety of P-3051 vs. the market 8% ciclopirox nail lacquer.
Methods  This is a multicentre, randomized, three-arm, placebo-controlled, parallel groups, evaluator-blinded study. Overall, 467 patients with onychomycosis of at least one big toenail were randomized to receive P-3051, the reference drug or placebo in a 2 : 2 : 1 ratio for a 48-week treatment by daily application, followed by a 12-week follow-up.
Results  The study satisfied its objective by demonstrating that P-3051 was both superior to placebo and non-inferior to reference in the complete cure rate after a 48-week active treatment period. Switching the non-inferiority to superiority hypothesis, the superiority of P-3051 vs. reference was nearly significant at week 48 (confirmed at week 52), and it was significant at week 60 (cure rate for P-3051 is 119% higher than reference; P  < 0.05). Altogether, the results on primary endpoint exceed expectations; superiority test was performed also on secondary endpoints to confirm the superiority trend of the study. At the end of follow-up, percentages of patients who achieved the endpoint 'responder' in the P-3051 group were 66% higher than reference ( P  < 0.05), and those who achieved the endpoint 'decrease of diseased nail' were 40% higher ( P  < 0.05).
Conclusion  Ciclopirox 8% hydrolacquer is more active than reference ciclopirox nail lacquer in the treatment of onychomycosis.

Conflicts of interest

None declared.     

Einsatz und Bedeutung von Ciclopirox‐Lack

Summary: Onychomycosis is a common disease all over the world. Epidemiological surveys estimate the share of nail fungi at 30 % in superficial mycoses. Patients regard this disease as annoying and restrictive with regard to daily activities and social contacts. Since the beginning of the 1990ies modern treatment strategies have been developed. Among oral drugs topical lacquers like ciclopirox 8 % nail lacquer – which is approved in 45 countries of the world – play an important role in the treatment of onychomycosis. Ciclopirox nail lacquer is approved for the treatment of all types of onychomycosis. Its mode of action is fungicidal and sporocidal. The efficacy has been proven in numerous studies including all potential fungi responsible for the infection of the nail plate and in different patient populations. Due to the different mode of action compared to the azoles – ciclopirox does not impact the ergosterole synthesis – ciclopirox is an ideal combination partner for oral antimycotics. Ciclopirox nail lacquer is applied with a brush. This makes it easy to use. Adverse events were rarely reported and are of local nature.     

Collection of fungi samples from nails: comparative study of curettage and drilling techniques

Background Onychomycosis is a common problem. Obtaining a positive laboratory test before treatment is important in clinical practice because the treatment of onychomycosis requires expensive oral antifungal therapy with potentially serious side‐effects. Objective The purpose of this study was to compare curettage and subungual drilling techniques of nail sampling in the diagnosis of onychomycosis. Methods We evaluated 194 patients suffering from distal and lateral subungual onychomycosis and lateral subungual onychomycosis using curettage and subungual drilling sampling techniques. Nail samples were obtained in each case from proximal, medial and distal parts of the nail. KOH examination and fungal culture were used for detection and identification of fungal infection. Results With each technique, the culture sensitivity improved as the location of the sample was more proximal (drilling proximal vs. distal, χ² = 5.15, P = 0.023; curettage proximal vs. distal, χ² = 4.2, P = 0.041). In each sample location, the drilling technique has a better culture sensitivity (drilling vs. curettage proximal, χ² = 11.9, P = 0.001; drill vs. curettage distal, χ² = 13.7, P < 0.0001). Trichophyton rubrum was by far the most common pathogen detected by both techniques from all sampling sites. Conclusion The drilling technique was found to be statistically better than curettage at each site of sampling. With each technique, we found that the culture sensitivity improved as the location of the sample was more proximal. More types of pathogens were detected in samples taken by both methods from proximal parts of the affected nails.     

Review of treatment for onychomycosis: consideration for special populations

This article provides a brief discussion of onychomycosis treatment in special populations such as children, the elderly, and patients with diabetes, human immunodeficiency virus (HIV), or Down syndrome. These subjects are generally not included in clinical trials, and few data on antifungal therapy are available in the literature. Issues with onychomycosis infection and treatment affecting each group are discussed, and where treatment reports exist, efficacy and safety data are presented. The discussion is restricted to agents approved for use in onychomycosis in Canada: oral terbinafine, oral itraconazole, and ciclopirox 8% nail lacquer. Although sparse, the literature demonstrates that onychomycosis therapies can be used safely and effectively in these special populations, although it is likely that the appropriateness of such treatment would have to be assessed on a case-by-case basis. Typically, oral medications are used reluctantly in these groups as the potential for adverse liver or kidney effects and medication interactions may be significant. Ciclopirox nail lacquer has recently become available for use and may offer an alternative to oral therapy in the future for mild to moderate cases of onychomycosis; however, the efficacy in these patients has not typically been reported. It remains to be seen what impact this medication will have for special populations. More knowledge of treatment in special populations must be accumulated in the literature before more formal treatment guidelines may be formulated.     

Nail sampling in onychomycosis: comparative study of curettage from three sites of the infected nail

Background: Onychomycosis is a common problem.Obtaining accurate laboratory test results before treatment is important in clinical practice since the treatment of onychomycosis requires expensive oral antifungal therapy with potentially serious side‐effects. The purpose of this study was to compare results of curettage technique of nail sampling in the diagnosis of onychomycosis from three different sites of the affected nail to establish the best location of sampling. Patients and Methods: We evaluated 194 patients suffering from distal and lateral subungual onychomycosis (DLSO) and lateral subungual onychomycosis (LSO) using curettage technique. KOH examination and fungal culture were used for detection and identification of fungal infection. Results: The culture sensitivity improves significantly as the location of the sample is more proximal. Trichophyton rubrum was by far the most common pathogen detected from all sampling sites. Conclusions: We found that the culture sensitivity improved as the location of the sample was more proximal. More types of pathogens were detected in samples taken from proximal parts of the affected nails.