¹Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Introduction

Onychomycosis is a common nail disorder for which successful treatment can be clinically challenging. The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also increase the risk of co-morbid onychomycosis infection including diabetes, peripheral vascular disease, HIV, immunosupression, obesity, smoking, and increased age.^1-5 Onychomycosis has traditionally been treated by oral and topical antifungals that often yield low to moderate efficacy.⁶ Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^7-8 Efinaconazole, a sterol 14α-demethylase inhibitor, is an emerging antifungal therapy for the topical treatment of onychomycosis, which has shown greater efficacy in vitro than terbinafine, itraconazole, ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds.⁹ Further, it may be a useful adjunct to oral and device-based therapies, during the main course of treatment, and as a subsequent maintenance therapy to prevent reinfection.

Background

• Onychomycosis is a fungal infection of the nail apparatus.¹⁰ It is primarily caused by dermatophytes, yeasts and non-dermatophyte molds.
• Keratinolytic dermatophytes infect and colonize the nail plate, bed, and matrix.¹¹ This may cause symptoms such as onycholysis, discoloration, and thickening of the nail plate.¹¹
• Onychomycosis needs to be treated for both cosmetic and medical purposes. Left untreated, the infection can spread to other nails and potentially cause further complications, especially in at-risk populations like diabetics and the immunosuppressed.^2,12
• The treatment of onychomycosis poses a number of challenges due to the nail plate’s lack of intrinsic immune function and the poor accessibility of drugs into the nail plate.
• The current gold standard therapy for onychomycosis is oral antifungals because their systemic distribution allows them to penetrate the nail apparatus and to a certain extent, the nail plate via the circulatory system.¹³
• Problematically, all of the oral drugs suffer from a potential for systemic adverse events and drug interactions.¹⁴
• This potential for negative side effects and drug interactions is often higher in the very populations who are at the greatest risk for onychomycosis, such as diabetics and the immunosuppressed; however, these individuals are the most susceptible to health complications if left untreated.
• Existing topical antifungals are not associated with adverse events to the same extent as oral therapy, as they rarely penetrate the systemic circulation and gain a significant concentration in the body.
• The topical antifungals available in the past were less widely used because their poor penetrance into the nail plate results in correspondingly poor mycological and complete cure rates.¹⁵
• The ideal topical antifungal would have a higher nail plate penetrance than existing drugs but maintain the advantage of minimal systemic uptake.^15,16

Diagnosis of Onychomycosis Caused by Dermatophytes

• • Diagnosing onychomycosis on clinical grounds alone is challenging; therefore, correlation with mycological evidence remains critical for an accurate diagnosis.¹⁷
  • Definitive laboratory criteria include positive microscopic evidence of septate hyphae and/or arthroconidia (KOH preparation, Calcofluor white, Sigma-Aldrich, St Louis, Mo), periodic acid Schiff, and/or biopsy, and positive fungal culture findings for dermatophytes (Trichophyton, Epidermophyton, or Microsporum species) or certain nondermatophyte nail pathogens (eg, Scytalidium dimidiatum and S hyalinum).¹⁷
  • The primary criteria for clinical diagnosis are:¹⁷
    • White/yellow or orange/brown patches or streaks
  • Secondary criteria are*
    • Onycholysis
    • Subungual hyperkeratosis/debris
    • Nail-plate thickening

* Tinea pedis often occurs concomitantly with pedal onychomycosis, and tinea manuum with infected fingernails.

• Laboratory diagnostic criteria are:¹⁷
  • Positive microscopic evidence
  • Positive culture of dermatophyte
• If onychomycosis is suggested based on clinical observation, diagnostic laboratory tests should be performed. If these produce negative findings, they should be repeated.

Treatment

• The primary aim of treatment is to eradicate the organism as evidenced on microscopy and culture.¹⁸

Oral Therapies Approved in Canada

• There are two oral therapies currently approved for use in Canada:
  1. Terbinafine 250mg/day for 12 weeks
  2. Itraconazole pulse therapy: for dermatophyte onychomycosis
     • 1 pulse = 200mg twice daily for 1 week on, 3 weeks off.
     • 3 pulses are standard for toenail onychomycosis.
• Oral therapies provide access to the nail bed and matrix of all toes; both terbinafine and itraconazole may persist in nails for long periods after treatment.
• Oral therapy can also treat concomitant skin infections such as tinea pedis.
• Current prescribing information should be consulted for contraindications and monitoring requirements.
• Liver function testing should be done prior to therapy, and periodically during therapy.

Topical Therapies Approved in Canada

• Ciclopirox nail lacquer 8%, once daily for 48 weeks.¹⁰
• Adverse events are few, with mild localized reactions at the application site.
• It may not provide adequate penetration where nails are thick or severe onycholysis is present.
• Efinaconazole 10% topical triazole antifungal was approved by Health Canada in October 2013.

Efinaconazole, A New Topic Antifungal

• Efinaconazole is a topical triazole antifungal developed specifically for the topical treatment of distal and lateral subungual onychomycosis (DLSO).¹⁹
• Efinaconazole expands on the success of the existing triazole antifungals, while being intentionally formulated to more effectively penetrate the nail plate.²⁰
• Additionally, because it is a solution, there is no product build-up and removal time.

In Vitro Efficacy

• Efinaconazole is an inhibitor of sterol 14α-demethylase (14-DM).²¹
• In broth dilution tests in vitro against reference strains, efinaconazole was more potent than terbinafine, ciclopirox, itraconazole and amorolfine.⁹
• The efficacy of efinaconazole was comparable in clinical isolates of T. mentagrophytes and T. rubrum from Canada, the USA and Japan.
• The high in vitro efficacy of efinaconazole against the reference strains suggests that the agent would be effective in onychomycosis should the formulation provide sufficient nail penetrance.

Clinical Efficacy

• A randomized, parallel-group, double-blind, vehicle-controlled, Phase II clinical trial of efinaconazole was conducted at 11 sites in Mexico.²² This initial trial compared the use of 10% solution, 5% solution and 10% solution with semi-occlusion in a 2:2:2:1 ratio with placebo. The treatment period was 36 weeks with a 4 week wash-out period prior to the evaluation of the outcome measures.
• The efficacy variables reported were mycological cure, complete cure, clinical efficacy, and effective treatment (Table 1). Efinaconazole 10% solution without semi-occlusion was the most effective treatment for all outcomes measured.
• Recently, two parallel, double-blind, randomized, controlled, Phase III trials of efinaconazole 10% nail solution (ENS) were completed.¹⁹ Trial participants applied ENS daily for 48 weeks followed by a 4-week wash-out period. Trial outcome measures were evaluated at week 52. Results demonstrated that ENS was superior to vehicle for all outcome measures. The primary outcome measure, complete cure for efinaconazole, was 17.8% and 15.2% respectively in the two parallel studies.
• The mycological cure rates were 55.2% and 53.4% respectively. Table 1 shows a comparison of the mycological cure rates for efinaconazole, itraconazole, terbinafine and ciclopirox.^22-24 The mycological and complete cure rates for efinaconazole were comparable to oral itraconazole.

Safety and Adverse Events

• In Phase II, 76.9% of the ENS group experienced treatment associated adverse events (TEAEs) compared with 63.6% of vehicle.²²
• The main TEAEs associated with efinaconazole were blisters, contact dermatitis, erythema and ingrown nail, none of which resulted in study discontinuation.
• In the duplicate Phase III studies, the reporting rates for a single adverse event during treatment with efinaconazole were comparable to vehicle (S1: 66.0% vs. 61.0%; S2: 64.5% vs. 58.5%).²⁰
• The reported primary TEAEs were application site dermatitis and vesicles; however, the rates for localized skin reactions were comparable to vehicle.
• Discontinuation as a result of TEAEs was low, with 3.2% and 1.9% vs. 0.5% and 0% of participants in the efinaconazole and vehicle groups respectively.
• Overall, efinaconazole showed low rates of treatment emergent adverse events.

Other Therapies

• Mechanical or chemical debridement lessens the burden of infection and may benefit any degree of onychomycosis; it can be performed in office, or by other healthcare professionals.

Combination Therapy

• Dual therapies: oral/topical, oral/debridement, or topical/ debridement.²⁶
• Triple therapies: oral/topical/debridement: Oral therapy combined with topical therapy can provide penetration of the nail plate from inside and out, which may increase the overall amount of antifungal medication reaching the infection, particularly where the nail is thickened, shows extensive onycholysis, has lateral or matrix involvement, or is a dermatophytoma.²⁶
• Debridement may increase access to the infection by topical medications.

Clinical Variables Affecting Treatment and Outcomes

Nail Disease Variables

• Number of nails affected
• Percentage of affected nail plate area
• Is it DLSO or another presentation?
• Infection confirmed as dermatophyte? (i.e., Trichophyton sp., Microsporum sp., or Epidermophyton sp.)
• Thickness of nails
• Is matrix (proximal nail fold) area involved in infection?
• Are lateral streaks or central spikes (dermatophytoma) present?

Patient Variables

• Presence of peripheral vascular disease
• Diabetes
• Age of patient
• Obesity
• Other co-morbid conditions, e.g., liver disease
• Oral drugs patient is using
• Compliance
• Drug insurance status
• Patient preference

Criteria for Onychomycosis Mycological and Complete Cures

• Criteria for a mycological cure are eradication of the fungus as confirmed by negative fungal culture and negative KOH examination.²⁷
• Criteria for a complete cure are mycological cure plus complete clearance.²⁸

Factors Affecting Treatment Failure and Recurrence29

• Poor adherence
• Poor absorption
• Immunosuppression
• Dermatophyte resistance
• Zero nail growth
• Concomitant disease
• Age >60 years
• Trauma/faulty biomechanics
• Moisture exposure
• Poor patient hygiene/footwear

Recurrence

• Patient education on recurrence is recommended, specifically:³⁰
  • One course of treatment may not produce the optimum results.
  • May require multiple courses of antifungals.
• Recurrence of onychomycosis is very common.
• If the patient experiences any signs of onychomycosis recurrence or tinea pedis, they should be treated immediately.
• Proper foot care may minimize the chance of recurrence.
• Due to the high rate of recurrence and relapse, even in completely cured individuals, long-term topical therapy is often recommended concurrently or following oral therapy.^7,8,31

Foot Care & Maintenance³²

• Wear footwear and cotton socks that minimize humidity.
• Replace or sanitize shoes and socks as they can be contaminated with the microorganism.
• Dry feet and interdigital spaces thoroughly after washing.
• Use footwear to avoid fungal transmission from shared public spaces such as swimming pools.
• Keep nails clean and cut short.
• Avoid sharing nail clippers or footwear.
• Bring their own nail clippers, files, and emery boards to the salon.
• Prevent further trauma to toenails (nonrestrictive footwear or orthotics).
• Wear rubber gloves with cotton liners to protect the fingernails in those persons who have hands immersed in water for long periods of time.
• Apply emollients on cracked skin to reduce further entry points for fungus.
• Control chronic health conditions such as diabetes mellitus or peripheral vascular disease.

Table 2: Simple treatment algorithm for dermatophyte toenail onychomycosis

Conclusion

Efinaconazole 10% solution is a significant advancement in the efficacy of topical therapy for onychomycosis. It has demonstrated good tolerability and as such, the increase in efficacy is not met with the increase in complications observed with oral drugs. The safety profile for participants treated with efinaconazole is good, with minimal and transient TEAEs that ceased upon conclusion of treatment and minimal contact sensitization. Used either as monotherapy or in addition to device-based or oral therapy, it offers a promising addition to the clinical management of onychomycosis.

References

1. Gupta AK, Gupta MA, Summerbell RC, et al. J Eur Acad Dermatol Venereol. 2000;
   14:466-469.
2. Gupta AK, Taborda P, Taborda V, et al. Int J Dermatol. 2000;39:746-753.
3. Gulec AT, Demirbilek M, Seckin D, et al. J Am Acad Dermatol. 2003;49:187-192.
4. Baran R. Clin Dermatol. 2011;29:54-60.
5. Döner N, Yasar S, Ekmekçi TR. Turk Derm. 2011;45:146-151.
6. Gupta AK, Uro M, Cooper EA. J Drug Dermatol. 2010;9:1109-1113.
7. Scher RK, Baran R. Br. J. Dermatol. 2003;149 Suppl 65:5- 9.
8. Tosti A, Piraccini BM, Stinchi C, et al. Dermatology (Basel). 1998;197:162-166.
9. Jo Siu WJ, Tatsumi Y, Senda H, et al. Antimicrob. Agents Chemother. 2013;[Epub ahead of print].
10. Zaias N. Onychomycosis. Arch Dermatol. 1972;105:263-274.
11. Welsh O, Vera-Cabrera L, Welsh E. Clin. Dermatol. 2010;28:151-159.
12. Gupta AK, Humke S. Eur J Dermatol. 2000;10:379-384.
13. Gupta AK, Paquet M, Simpson F, et al. Journal of the European Academy of Dermatology and Venereology: JEADV. 2013;27:267-272.
14. Shear N, Drake L, Gupta AK, et al. Dermatology. 2000;201:196-203.
15. Murdan S. Expert Opin Drug Deliv. 2007;4:453-455.
16. Murdan S. Expert Opin Drug Deliv. 2008;5:1267-1282.
17. Scher RK, Tavakkol A, Sigurgeirsson B, et al. J Am Acad Dermatol 2007;56:939-944.
18. Roberts DT, Taylor WD, Boyle J. Brit J. Dermatol, 2003; 148: 402-410
19. Elewski BE, Rich P, Pollak R, et al. J Am Acad Dermatol. 2012;[Epub ahead of print].
20. Suguira K, Sugimoto N, Hosaka S, et al. Antimicrob Agents Chemother. 2014;58: 3837-3842
21. Tatsumi Y, Nagashima M, Shibanushi T, et al. Antimicrob. Agents Chemother. 2013; 57:2405.
22. Tschen EH, Bucko AD, Oizumi N, et al. J Drugs Dermatol. 2013;12:186-192.
23. Janssen Pharma. SPORANOX® (itraconazole) Capsules. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf.
24. Novartis. LAMISIL (terbinafine hydrochloride) Tablets, 250 mg. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf. Accessed March 15, 2013.
25. Valeant. Penlac® Nail Lacquer (ciclopirox) Topical Solution, 8%. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21022s004lbl.pdf. Accessed March 15, 2013.
26. Gupta AK, Lynch LE. Cutis. 2004;74(1 Suppl):5-9.
27. Gupta MA. Gupta AK. Intl J of Derm. 2003;4:833-842
28. CRC Press. Onychomycosis: The Current Approach to Diagnosis and Therapy: Baran R, Hay R, Haneke E, Tosti A. 1999. 0000415385792: 405.
29. Westerberg DP, Voyack MJ. Am Fam Physician. 2013;88:771-772.
30. Pariser D, Scher RK, Elewski B, et al. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S13-14
31. Arrese JE, Piérard GE. Dermatology. 2003;207:255-260.
32. Miller P. Skin Disorders: Fungal Nail Infections. Available at: https://www.etherapeutics.ca/ Accessed June 10 2014.

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest: Dr. Gupta has served as a clinical trials investigator for Valeant Pharmaceuticals Inc.
ABSTRACT

Efinaconazole is an emerging antifungal therapy for the topical treatment of onychomycosis. Efinaconazole is an inhibitor of sterol 14α-demethylase and is more effective in vitro than terbinafine, itraconazole, ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds. Phase II studies indicate that efinaconazole 10% nail solution is more effective than either the 5% strength or 10% solution with semi-occlusion. In duplicate Phase III clinical trials, complete cure rates of 17.8% and 15.2% were demonstrated. The mean mycological cure rate for efinaconazole is similar to the oral antifungal itraconazole and exceeds the efficacy of topical ciclopirox. Efinaconazole showed minimal localized adverse events, which ceased upon stopping treatment. Overall, efinaconazole 10% nail solution is an effective topical monotherapy for distal and lateral subungual onychomycosis (<65% nail involvement, excluding the matrix) that shows further potential use as an adjunct to oral and device-based therapies.

Key Words:
antifungal agent, efinaconazole, fungal nail infection, onychomycosis, topical triazole

Introduction

Onychomycosis is a fungal infection of the nail apparatus¹ caused primarily by dermatophytes, yeasts, and non-dermatophyte molds. Keratinolytic dermatophytes infect and colonize the nail plate, bed, and matrix,² resulting in symptoms such as onycholysis, discoloration, and thickening of the nail plate.² Onychomycosis warrants treatment for both cosmetic and medical purposes. Left untreated, the infection can spread to other nails and potentially cause further complications, especially in at-risk populations such as diabetic and immunosuppressed patients.^3,4

The treatment of onychomycosis poses a number of challenges due to the nail plate’s lack of intrinsic immune function and the poor accessibility of drugs into the nail plate. The current gold standard therapy for onychomycosis is oral antifungals because their systemic distribution allows them to penetrate the nail apparatus and, to a certain extent, the nail plate via the circulatory system.⁵ Problematically, all of the oral drugs suffer from potential systemic adverse events and drug interactions.⁶ This potential for negative side effects and drug interactions is often higher in the very populations who are at the greatest risk for onychomycosis, such as diabetics and the immunosuppressed; however, if left untreated, these individuals are the most susceptible to health complications. The existing topical antifungals are not associated with dangerous adverse events, as they rarely penetrate the systemic circulation and gain a significant concentration in the body. Topicals are less widely used for onychomycosis because their poor penetrance into the nail plate results in correspondingly poor mycological and complete cure rates.⁷ Hence, the ideal scenario would be to develop topicals that have a higher nail plate penetrance compared with existing drugs, but maintain the advantage of minimal systemic uptake.^7,8

A Novel Topical Triazole Antifungal

Efinaconazole is a triazole antifungal that has been developed specifically for the topical treatment of distal and lateral subungual onychomycosis (DLSO).⁹ Efinaconazole expands on the success of existing triazole antifungals, itraconazole and fluconazole, and is specifically formulated to more effectively penetrate the nail plate. In addition, the solution formulation avoids product build-up and removal time associated with the use of lacquers.

In Vitro Efficacy

Efinaconazole is an inhibitor of sterol 14α-demethylase (14-DM).¹⁰ In broth dilution tests in vitro against reference strains, it was more potent than terbinafine, ciclopirox, itraconazole, and amorolfine.¹¹ The efficacy of efinaconazole was comparable in clinical isolates of Trichophyton mentagrophytes (T. mentagrophytes) and Trichophyton rubrum (T. rubrum) from Canada, the US, and Japan (Table 1). The high in vitro efficacy of efinaconazole against the reference strains suggests that the agent would be effective in onychomycosis, providing the formulation renders sufficient nail penetrance.

Clinical Efficacy

The randomized, parallel-group, double-blind, vehicle-controlled Phase II clinical trial of efinaconazole was conducted at 11 sites in Mexico.¹² This initial trial compared the use of 10% solution, 5% solution, 10% solution with semi-occlusion, and placebo in a 2:2:2:1 ratio. The treatment period was 36 weeks with a four week wash-out period prior to the evaluation of the outcome measures. The efficacy variables reported were mycological cure, complete cure, clinical efficacy, and effective treatment (Table 2). Efinaconazole 10% solution without semi-occlusion was the most effective treatment for all outcomes measured.

Efinaconazole 10% nail solution (ENS) has recently completed two parallel, double-blind, randomized, controlled, Phase III trials.⁹ Trial participants applied ENS daily for 48 weeks followed by a four week wash-out period. The trial outcome measures were evaluated at week 52 and results from these evaluations demonstrated that ENS was superior to vehicle for all outcome measures (Table 3). The primary outcome measure, complete cure, was 17.8% and 15.2% for efinaconazole. The mycological cure rate was 55.2% and 53.4%. Table 4 shows a comparison of the mycological cure rates for efinaconazole, itraconazole, terbinafine, and ciclopirox.^13-15 The mycological cure rate for 48 weeks of topical efinaconazole was comparable to 12 weeks of oral itraconazole.

Safety and Adverse Events

In a Phase II trial, 76.9% of participants in the efinaconazole 10% group experienced treatment associated adverse events (TEAEs) compared with 63.6% of vehicle.¹² The main TEAEs associated with efinaconazole were blisters, contact dermatitis, erythema and ingrown nail, none of which resulted in study discontinuation. In two identical Phase III studies, the reported rates for a single adverse event during treatment with efinaconazole were comparable to vehicle (study 1: 66% vs. 61%; study 2: 64.5% vs. 58.5%).⁹ The primary TEAEs reported were application site dermatitis and vesicles; however, the rates for localized skin reactions were comparable to vehicle. Discontinuation as a result of TEAEs was low, with 3.2% and 1.9% vs. 0.5% and 0% of participants in the efinaconazole groups vs. the vehicle groups, respectively. Overall, efinaconazole showed low rates of treatment emergent adverse events.

An additional study was conducted to determine if efinaconazole was associated with contact sensitization.¹⁶ Healthy participants (n=239) were treated nine times each with efinaconazole 10% solution or its vehicle in occlusive patches over a three week period. A subsequent 48-hour challenge to a naïve site occurred three weeks later. Participants who showed signs of contact sensitization were then re-challenged and evaluated at 48, 72, and 96 hours after patch application. An additional re-challenge was evaluated on the forearm in addition to the back. These evaluations resulted in mild irritation scores of 0 or 0.5 in 67.8% and 91.6%, respectively, in efinaconazole exposures. Vehicle produced a similar result with 71% scoring 0 and 95% scoring 0.5. The highest reported score, indicating bright-red erythema with or without edema, petechiae, or papules, was observed in two efinaconazole and four vehicle treated participants. An additional 21-day cumulative irritation test was conducted in 37 individuals. Each individual was exposed to efinaconazole and vehicle solutions for three weeks. The cumulative irritation scores were comparable to the vehicle solution.

Discussion

Efinaconazole 10% solution represents a significant advancement in improving the efficacy of topical therapy for onychomycosis. In assessing the Phase III results for existing oral therapeutics, efinaconazole exhibits a similar mycological and complete cure rate compared to oral itraconazole. Efinaconazole shows significantly improved cure rates over topical ciclopirox and does not require additional nail debridement. Furthermore, all three studies reported efinaconazole therapy was well-tolerated, therefore, demonstrating that the improved efficacy is not necessarily accompanied by an increase in complications, as is associated with oral drugs. A Phase II investigation of the 10% solution reported a treatment completion rate of 86.7%, and rates of 87.7% and 85.4% in Phase III studies.^9,12 These exceed the completion rates for vehicle, which were 81%, 87.4%, and 79.2%, respectively.^9,12 The safety profile for participants treated with efinaconazole was favorable, with minimal or transient TEAEs (e.g., contact sensitization) that resolved upon cessation of treatment.

Although efinaconazole may primarily be intended for monotherapy, it could also serve as an excellent adjunct for oral or device-based therapies. Due to the high rate of recurrence and relapse in DLSO, even for completely cured individuals, long-term topical therapy is often recommended concurrently or following oral therapy.^17-19 Adjunctive treatment may also be desirable with newer therapeutic modalities such as lasers, in order to promote sustained cure. Thus, the addition of efinaconazole may be ideal for these situations as it demonstrates the potential for prolonged efficacy and tolerability, as well as safety for long-term use.

Efinaconazole 10% nail solution is an effective and safe emerging topical treatment of DLSO. It shows promise in comparison to the currently available topical prescription and over-the-counter options. The first regulatory approval of efinaconazole (Jublia®) as a topical monotherapy was recently granted by Health Canada in October 2013 and marketing authorization is pending in several other countries. In addition to its usefulness as a single agent therapy, efinaconazole may be a useful adjunct to oral and device-based therapies, both during the main course of treatment and as subsequent maintenance therapy to prevent reinfection.

References

1. Zaias N. Onychomycosis. Arch Dermatol. 1972 Feb;105(2):263-74.
2. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
3. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000 Jul-Aug;10(5):379-84.
4. Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol. 2000 Oct; 39(10):746-53.
5. Gupta AK, Paquet M, Simpson F, et al. Terbinafine in the treatment of dermatophyte toenail onychomycosis: a meta-analysis of efficacy for continuous and intermittent regimens. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):267-72.
6. Shear N, Drake L, Gupta AK, et al. The implications and management of drug interactions with itraconazole, fluconazole and terbinafine. Dermatology. 2000;201(3):196-203.
7. Murdan S. 1st meeting on topical drug delivery to the nail. Expert Opin Drug Deliv. 2007 Jul;4(4):453-5.
8. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008 Nov;5(11):1267-82.
9. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, doubleblind studies. J Am Acad Dermatol. 2013 Apr;68(4):600-8.
10. Tatsumi Y, Nagashima M, Shibanushi T, et al. Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother. 2013 May;57(5):2405-9.
11. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
12. Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013 Feb;12(2):186-92.
13. Sporanox® (itraconazole) capsules [package insert]. Revised April 2012. Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ.
14. Lamisil® (terbinafine hydrochloride) tablets, 250 mg [package insert]. March 2011. Novartis Pharmaceuticals Corporation, East Hanover, NJ.
15. Penlac® nail lacquer (ciclopirox) topical solution, 8% [package insert]. July 2006. Dermik Laboratories/ sanofi-aventis U.S. LLC, Bridgewater, NJ. Available at: http://products.sanofi.us/penlac/Penlac.pdf. Accessed November 24, 2013.
16. Del Rosso JQ, Reece B, Smith K, et al. Efinaconazole 10% solution: a new topical treatment for onychomycosis: contact sensitization and skin irritation potential. J Clin Aesthet Dermatol. 2013 Mar;6(3):20-4.
17. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
18. Tosti A, Piraccini BM, Stinchi C, et al. Relapses of onychomycosis after successful treatment with systemic antifungals: a three-year follow-up. Dermatology. 1998;197(2):162-6.
19. Arrese JE, Pierard GE. Treatment failures and relapses in onychomycosis: a stubborn clinical problem. Dermatology. 2003;207(3):255-60.

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

ABSTRACT

Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals, reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies.

Key Words:
antifungal, iontophoresis, laser devices, nails, onychomycosis, photodynamic therapy, ultrasound

Introduction

Onychomycosis is a common nail disorder that faces significant barriers to successful treatment. Etiologically, fungal pathogens such dermatophyte fungi, yeasts, and non-dermatophyte molds invade and colonize the nail plate, bed, and matrix creating an entrenched infection.^1-10 The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also confer an increased risk of co-morbid onychomycosis infection including diabetes,¹¹ peripheral vascular disease,¹¹ HIV,¹² immunosupression,^13,14 obesity,¹⁵ smoking,¹¹ and increased age.¹⁴ Many individuals have sustained infections persisting for months or years and, hence, they may not be motivated to initiate or complete therapy due to a perception that their condition is untreatable.

Onychomycosis has traditionally been treated by oral and topical antifungals¹⁶ that often yield low to moderate efficacy. Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^17,18 Successful treatment for onychomycosis requires antifungal drugs to penetrate the nail plate and nail bed, but incomplete dissemination to the lesion is a problem for both oral and topical agents. Antifungal drugs may be associated with adverse events that can cause patients to discontinue treatment and therapy may be complicated with the presence of a co-morbid condition.^19,20 Additionally, the extended course of treatment may discourage patient compliance, which poses a significant detriment to effective therapy. Thus, these factors can contribute to the suboptimal delivery of conventional therapy for onychomycosis.

Device-based therapies are promising solutions for the treatment of onychomycosis because they can mitigate some of the negative factors that contribute to treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis and ultrasound. Each of these techniques is a noninvasive procedure conducted by a medical professional, which reduces the need for long-term patient compliance. Photodynamic therapy, iontophoresis and ultrasound are used in combination with local pharmacological agents, thereby avoiding adverse effects associated with systemic antifungal therapy.

Laser Therapy

Laser treatment of onychomycosis infections uses the principle of selective photothermolysis.^21,22 Laser therapy is intended to exploit the differences in laser energy absorption and thermal conductivity between the fungal infection and the surrounding tissue. The absorption of light energy by the fungi results in the conversion of the energy into heat or mechanical energy.^21,22 Fungi are heat sensitive above 55°C, so absorption of laser energy that results in sustained photothermal heating of the mycelium (10+ minutes) is likely to result in fungicidal effects.^23,24 However, heating dermal tissue to temperatures above 40°C results in pain and necrosis; therefore, the laser energy format must either be pulsed to allow the dissipation of heat by the tissue through its superior thermal conduction or delivered at a moderate energetic level to prevent tissue damage. The exact mechanism of laser therapy is still under investigation, but it may combine direct fungicidal effects of the laser with induced modifications in the immune system or changes in the local microenvironment.

Laser therapy for onychomycosis is currently being studied in vitro and in vivo. In addition, at the time of this writing, the following lasers have been granted FDA marketing approval for the treatment of onychomycosis: PinPointe™ FootLaser™ (PinPointe USA, Inc.),²⁵ Cutera GenesisPlus™ (Cutera, Inc.),²⁶ Q-Clear™ (Light Age, Inc.),²⁷ CoolTouch VARIA™ (CoolTouch, Inc.),²⁸ and JOULE ClearSense™ (Sciton, Inc.).²⁹ The parameters of lasers that have been FDA cleared or tested and supported by publications for onychomycosis are summarized in Table 1. It is important to note that regulatory clearance of device systems are made on the basis of “substantial equivalence” to the technical specifications of pre-existing devices approved for marketing for onychomycosis, not on the basis of clinical trials data, so these systems cannot be directly compared to pharmacologic therapies.

Solid State Lasers

Solid state lasers use a solid crystal rod and they include many of the common commercial lasers such as the neodymium-doped yttrium aluminum garnet (Nd:YAG) and titanium sapphire (Ti:Sapphire) lasers. Solid state lasers may be built for use as continuous lasers or as pulsed lasers with pulse durations in the millisecond, microsecond, nanosecond, or femtosecond ranges. The maximum pulse energy increases as the pulse length decreases, so different pulse formats may result in greater nonspecific heating of the nail plate, or require longer treatment lengths to produce a fungicidal effect. The lasers that have been approved for the treatment of onychomycosis in North America have all been Nd:YAG lasers.

Long Pulse Laser Systems

Long pulse Nd:YAG lasers have received CE Marking in Europe (the mandatory conformity designation for marketed products in the European Economic Area), but they have not yet been approved to treat onychomycosis in North America.³⁰ The pulse duration for these lasers is in the millisecond range. These lasers can cause a high degree of non-specific heating and may need to be operated in the presence of a dedicated cooling system. The largest study of millisecond Nd:YAG lasers was conducted using the Fotona Dualis SP™ laser on 162 participants in Serbia.^31,32 Fungal infections in both fingernails and toenails were identified by potassium hydroxide (KOH) microscopy.³¹ Participants were treated with a 30-40 J/cm² energy fluence with a spot size of 4 mm and a pulse duration of 35 ms in the presence of cold air cooling.³¹ The nail plate was treated in a spiral pattern. A 2 minute wait period was observed before repeating the laser treatment.³¹ Participants received 4 treatments at 1 week intervals and they were followed after therapy from 12-30+ months. A completely clear nail plate was achieved by 93.5% of participants.³² The Fotona Dynamis™ family of laser systems has the same technical parameters as the laser used in the studies described above and has received marketing clearance in Europe.

Short Pulse Laser Systems

The first two lasers that were sanctioned by the FDA for the treatment of onychomycosis (PinPointe™ FootLaser™ and Cutera GenesisPlus™) are both flashlamp pumped short pulse Nd:YAG 1064 nm lasers.^25,26 The CoolTouch VARIA™ laser is the most recent addition to this class of devices.²⁸ These lasers emit 100-3000 µs pulses with an energy fluence of 25.5 J/cm² for a 1 mm spot size.^25,26,28 The PinPointe™ FootLaser™ was used in an initial phase I/II clinical trial.³³ Seventeen participants demonstrating great toenails afflicted with onychomycosis were enrolled and randomized into treated (n=11) or untreated (n=6) groups. Participants received a single treatment and were followed-up at 3 and 6 months. At the 6 month time period, 11 of 14 treated toes showed improvement in clear linear nail growth. Clinicaltrials.gov reports that a phase III clinical trial for the PinPointe™ laser (NCT00935649) was completed on November 29, 2010, but the data from this study remains unpublished.³⁴ Cutera has released a white paper on the GenesisPlus™ laser³⁵ that reported a 70% improvement rate in the 7 participants treated with 2 sessions of laser therapy. The JOULE ClearSense™ laser was tested in an initial trial of 21 patients.³⁶ Onychomycosis was confirmed by culture and periodic-acid schiff (PAS) microscopy. Patients were treated 4 times, at 1 week intervals with a pulse length of 0.3 ms, an energy fluence of 13 J/cm², and a repetition rate of 6 Hz. Follow-up mycological culture was negative in 95% of patients.³⁶ Clinical trials data for the CoolTouch™ laser has not yet been released.

An additional clinical study was published by Hochman et al. using a short pulse Nd:YAG laser system that has not been FDA cleared for onychomycosis.³⁷ This study confirmed active fungal infections in toenails and fingernails by culture or PAS stain. Participants were treated with a 223 J/cm² energy fluence with a 2 mm spot size for ≤45 seconds. Each subject received 2-3 treatments spaced at least 3 weeks apart. Antifungal cream was used daily where anatomically possible during this study. The efficacy of treatment was followed for between 4-6 months after therapy. Treatment resulted in negative mycological culture in 7 of 8 participants.

CoolTouch, Inc. is also conducting a clinical trial with a 1320 nm Nd:YAG laser (NCT01498393).³⁸ The CoolTouch CT3 Plus™ with the CoolBreeze Zoom handpiece can be operated in short pulse (450 µs) or continuous mode.³⁹ The handpiece has a pre-set temperature threshold that employs a cryogen cooling system.⁴⁰ Duration of the trial is 6 months and the inclusion criteria require patients to have a fungal infection on both great toenails.

Q-switched Laser Systems

Q-switched lasers have a pulse duration in the nanosecond range and they emit the highest peak power per pulse of all the Nd:YAG lasers. In vitro, an energy fluence of 4 J/cm² optimally inhibited Trichophyton rubrum (T. rubrum) colony growth.⁴¹ The Light Age Q-Clear™ is a FDA-cleared Q-switched Nd:YAG 1064 nm laser.²⁷ The FDA 510(k) summary for this laser device states that “Light Age, Inc.’s study of 100 randomized subjects of both genders,including Caucasian, Asian, African American, and Latino, has demonstrated substantially effective clearance of dystrophic toenails having a clinically apparent diagnosis of onychomycosis. Statistical analysis of results indicates significant apparent clearing in 95% of the subjects with an average clearance of affected areas of 56 ± 7% at 98% level of confidence.”²⁷

Modelocked Laser Systems

A modelocked femtosecond pulsed Ti:Sapphire laser tuned to 800 nm was used in an in vitro study on T. rubrum.⁴² Nail clippings were obtained from participants with onychomycosis and the fungal infection was confirmed by culture (n=99). The cultures were irradiated with a Ti:Sapphire laser that was pumped by a solid-state laser, which emitted 200 fs pulses at a frequency of 76 MHz through a variety of numerical apertures from 0.12 to 0.45. Treatment with energy above 7×10³¹ photons m^-2 s^-1 resulted in a 100% fungicidal effect.

Near Infrared Diode Lasers

Diode lasers use semiconductors for the optical gain medium as an alternative to solid crystals. The diode lasers that are currently under investigation for onychomycosis operate at near infrared wavelengths. The Noveon® laser (Nomir Medical Technologies) is an 870 nm and 930 nm dual wavelength diode laser.⁴³ In vitro studies have shown that 870 nm and 930 nm wavelengths photoinactivate T. rubrum and Candida albicans, and have a minimal negative effect on cultured fibroblasts.⁴⁴ Preliminary trials for the Noveon® laser have been conducted.⁴² Distal and lateral subungual onychomycosis was confirmed by culture or PAS stain and each participant received 4 treatments on days 1, 14, 42 and 120. Each treatment comprised 4 minutes of dual wavelength therapy, followed by 2 minutes of 930 nm treatment. At 180 days, the participants showed an 85% improvement of infection in 26 toes treated.⁴³ The status of the phase II and II/III trials for the Noveon® laser in onychomycosis (NCT00771732 and NCT00776464) remains unknown.^45,46

ConBio Inc. has registered a single assignment, open label clinical trial (NCT01452490) for a near infrared diode laser.⁴⁷ The V-Raser® laser is a 980 nm near infrared diode laser that has previously been marketed for the removal of vascular lesions. The study aims to enroll 50 participants at two podiatric practices in the United States. Participants will receive 4 laser treatments at 6 week intervals.⁴⁷

Photodynamic Therapy

Photodynamic therapy (PDT) uses visible spectrum light to activate a topically applied photosensitizing agent, which generates reactive oxygen species that initiate apoptosis. Photodynamic therapy was originally optimized for actinic keratosis, but photosensitizers can also be absorbed by fungi.^48,49 The effects of various photosensitizing agents have been studied in vitro and in vivo. These include 5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), and 5,10,15-tris (4-methylpyridiuium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B).

Heme Biosynthesis Intermediates – ALA and MAL

ALA and its methyl ester MAL are heme precursors. They cause a build-up of protoporphyrin IX (PpIX), which is a photodynamically active molecule. In the presence of the correct spectrum of light, PpIX generates reactive oxygen species that initiate apoptosis.⁵⁰ Both of these drugs are commercially available for the treatment of actinic keratosis. Several studies have tested these formulations in small studies on participants with onychomycosis (Table 2).^51-54 These studies are heterogeneous, preventing any form of direct comparison; however, these investigations have shown promising initial results, but their small sample sizes (n>30) limit our ability to draw conclusions on the efficacy of this mode of therapy. The protocols developed for these studies indicate that the nail plate should be pre-treated with urea ointment to soften the nail plate prior to application of the photosensitizer.

Non-Heme Porphyrins – Sylsens B

Sylsens B is a non-heme porphyrin that has been used for in vitro studies on T. rubrum. PDT with Sylsens B is fungicidal in T. rubrum suspensions of both hyphae and microconidia at concentrations above 10 µM.^49,55,56 PDT with Sylsens B is also fungicidal when T. rubrum is adhered to keratinized structures.⁵⁷ In vitro experiments determined that ultraviolet-A (UVA-1) light is fungicidal in commercial strains and clinical isolates of T. rubrum, so it was an ideal excitatory light source for PDT.⁵⁸ The clinically isolated strain required a higher dose of Syslens B (9 µM) than the commercial strain (1 µM) using a UVA-1 energy fluence of 18 J/cm².⁵⁸ Sylsens B has not yet been tested in vivo.

Iontophoresis

Iontophoresis is a technique that uses a low level electrical current to increase the transport of drugs across semi-permeable barriers. The limitation of many topical treatments for onychomycosis is their inability to fully penetrate the nail plate.⁵⁹ This technique may be more successful in incorporating the drug into the nail plate and passing it through the plate to ensure that it penetrates the nail bed and matrix. Iontophoresis is currently being optimized for terbinafine, because it has the highest antifungal effect on dermatophytes in vitro.⁶⁰ There are two iontophoresis devices currently in clinical trials.

Iontophoresis increases the amount of terbinafine accumulated in the nail plate over the uptake from a passive source.^61-67 The nail plate then acts as a reservoir of terbinafine that is then released into the nail bed and matrix over 60-70 days.^62-65,67 The drug uptake during iontophoresis can be enhanced after removal of the dorsal layer of the nail plate, or in the presence of keratolysis.⁶⁴ The devices by NB Therapeutics were effective at targeting the nail plate exclusively and both the nail plate and surrounding skin.⁶³ The iontophretic device (Electrokinetic Transungual System) by Transport Pharmaceuticals was registered in a phase I clinical trial (NCT00768768) that has since been completed, but the data remains unpublished.⁶⁸ A phase II clinical trial is also ongoing in North America (NCT01484145).⁶⁹

The Power Paper iontophoretic patch device was used in a single preliminary trial of 38 participants.⁶¹ Infections were confirmed by both KOH examination and mycological culture. The participants were randomized into two groups for the treatment of a single great toenail. The first group received terbinafine iontophoresis with a current density of 100 µA/cm². The second was treated with the terbinafine gel patch without iontophoresis. The participants wore the patch overnight, every day for 4 weeks. After the initial visit, two further iontophoresis treatments were conducted. Follow-up occurred at 8 weeks and 12 weeks. At the final follow-up, 84% of participants demonstrated a mycological cure confirmed by KOH microscopy.

Ultrasound Drug Delivery System

The most recent development in device-based treatments for onychomycosis is an ultrasound mediated nail drug delivery system.⁷⁰ This system has been tested in a canine nail model. The intent was to determine which period of 1.5 W/cm² ultrasound treatment increased the nail uptake of a blue dye. Findings showed that the 120 second period was the most effective, increasing dye permeability by 1.5 fold. Further studies will be required to determine if this technique is suitable for existing antifungal drugs.

Conclusion

Device-based therapies for onychomycosis show promise in initial clinical studies involving lasers, photodynamic therapy, iontophoresis, and ultrasound-based therapy. Device-based treatments may be advantageous because they are conducted in the clinic and only require short-term patient compliance. These modalities also have the potential to reduce adverse events caused by antifungal drugs, as they are highly localized treatments. Devices may also be alternatives for patients whose susceptibility to onychomycosis infection arises from a co-morbidity, as these therapies do not interact with the drugs involved in the management of such conditions.^{65, 66} In order to substantiate the efficacy of device-based therapies for onychomycosis, randomized controlled trials with mycological evaluation and long-term follow-up are required. We believe this therapeutic area will continue to expand and hope that broader clinical investigations will result in new options for practitioners.

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