Onychomycosis Diagnosis and Emerging Therapy

Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC^1,2 and Fiona C. Simpson, HBSc²

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.