Case Letter

Onychomycosis: Current and Investigational Therapies

Cutis. 2014 December;94(6):E21-E24

Onychomycosis is a fungal infection of the nail plate by dermatophytes, yeasts, and nondermatophyte molds. Some patients may have mild asymptomatic cases of onychomycosis and do not inquire about treatment, while many will have more advanced cases, presenting with pain and discomfort, secondary infection, unattractive appearance, or problems performing everyday functions. The goal of onychomycosis treatment is to eliminate the fungus, if possible, which usually restores the nail to its normal state when it fully grows out.

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References

1. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.

2. Heikkila H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol. 1995;133:699-703.

3. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2, suppl 1):S2-S4.

4. Abdullah L, Abbas O. Common nail changes and disorders in older people: diagnosis and management. Can Fam Physician. 2011;57:173-181.

5. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003;149(suppl 65):5-9.

6. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010;28:151-159.

7. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. part II. J Am Acad Dermatol. 1994;30:911-933.

8. 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;27:267-272.

9. Drake LA, Shear NH, Arlette JP, et al. Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol. 1997;37:740-745.

10. Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. the LION Study Group. BMJ. 1999;318:1031-1035.

11. Sporanox [package insert]. Macquarie Park, Australia: Janssen-Cilag Pty Ltd; 2014.

12. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38(6, pt 2):S77-S86.

13. Sigurgeirsson B, van Rossem K, Malahias S, et al. A phase II, randomized, double-blind, placebo-controlled, parallel group, dose-ranging study to investigate the efficacy and safety of 4 dose regimens of oral albaconazole in patients with distal subungual onychomycosis. J Am Acad Dermatol. 2013;69:416-425.

14. Elewski B, Pollak R, Ashton S, et al. A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis. Br J Dermatol. 2012;166:389-398.

15. Gupta AK, Leonardi C, Stoltz RR, et al. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis. J Eur Acad Dermatol Venereol. 2005;19:437-443.

16. Baran R, Sigurgeirsson B, de Berker D, et al. A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement. Br J Dermatol. 2007;157:149-157.

17. Polak A. Preclinical data and mode of action of amorolfine. Dermatology. 1992;184(suppl 1):3-7.

18. Belenky P, Camacho D, Collins JJ. Fungicidal drugs induce a common oxidative-damage cellular death pathway. Cell Rep. 2013;3:350-358.

19. Lee RE, Liu TT, Barker KS, et al. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J Antimicrob Chemother. 2005;55:655-662.

20. Penlac [package insert]. Bridgewater, NJ: sanofi-aventis; 2006.

21. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.

22. Elewski BE, Ghannoum MA, Mayser P, et al. Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs. J Eur Acad Dermatol Venereol. 2013;27:287-294.

23. Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007;316:1759-1761.

24. Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007;96:2622-2631.

25. Elewski BE, Rich P, Wiltz H, et al. Effectiveness and safety of tavaborole, a novel born-based molecule for the treatment of onychomycosis: results from two phase 3 studies. Poster presented at: Women’s & Pediatric Dermatology Seminar; October 4-6, 2013; Newport Beach, CA.

26. The solution study: Topica’s phase 2b/3 clinical trial. Topica Pharmaceuticals Inc Web site. http://www.
topicapharma.com/phase-2b3. Accessed December 2, 2014.

27. Gupta AK, Simpson FC. Medical devices for the treatment of onychomycosis. Dermatol Ther. 2012;25:574-581.

28. Ortiz AE, Avram MM, Wanner MA. A review of lasers and light for the treatment of onychomycosis. Lasers Surg Med. 2014;46:117-124.

29. Vural E, Winfield HL, Shingleton AW, et al. The effects of laser irradiation on Trichophyton rubrum growth. Lasers Med Sci. 2008;23:349-353.

30. Carney C, Cantrell W, Warner J, et al. Treatment of onychomycosis using a submillisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol. 2013;69:578-582.

31. Gupta AK, Daigle D, Paquet M. Therapies for onychomycosis: a systematic review and network meta-analysis of mycological cure [published online ahead of print July 17, 2014]. J Am Podiatr Med Assoc. doi:10.7547/13-110.1.

To the Editor:
Onychomycosis is a fungal infection of the nail plate by dermatophytes, yeasts, and nondermatophyte molds. It is a common problem with a prevalence of 10% to 12% in the United States.^1,2 The clinical presentation of onychomycosis is shown in the Figure. Although some patients may have mild asymptomatic cases of onychomycosis and do not inquire about treatment, many will have more advanced cases, presenting with pain and discomfort, secondary infection, unattractive appearance, or problems performing everyday functions. The goal of onychomycosis treatment is to eliminate the fungus, if possible, which usually restores the nail to its normal state when it fully grows out. Patients should be counseled that it is a long process that may take 6 months or more for fingernails and 12 to 18 months for toenails. These estimates are based on a growth rate of 2 to 3 mm per month for fingernails and 1 to 2 mm per month for toenails.³ Nails grow fastest during the teenaged years and slow down with advancing age.⁴ It should be noted that advanced cases of onychomycosis affecting the nail matrix may cause permanent scarring; therefore, the nail unit may still appear dystrophic after the causative organism is eliminated. The US Food and Drug Administration (FDA) defines a complete cure as negative potassium hydroxide preparation and negative fungal culture plus a completely normal appearance of the nail.

Treatment of onychomycosis poses a number of challenges. First, hyperkeratosis and the fungal mass may limit the delivery of topical and systemic drugs to the source of the infection. In addition, high rates of relapse and reinfection after treatment may be due to residual hyphae or spores.⁵ Furthermore, the extended length of treatment limits patient adherence and many patients are unwilling to forego wearing nail cosmetics during the course of some of the treatments.

^{The clinical presentation of onychomycosis. The great toenail has yellow discoloration of the nail plate, ridging, and subungual hyperkeratosis.}

There are 4 approved classes of antifungal drugs for the treatment of onychomycosis: allylamines, azoles, morpholines, and hydroxypyridinones.⁶ The allylamines (eg, terbinafine) inhibit squalene epoxidase.⁷ Oral terbinafine (250 mg daily) taken for 6 weeks for fingernails and 12 weeks for toenails is considered the current systemic treatment preference in onychomycosis therapy⁸ with complete cure rates in 12-week studies of approximately 38%⁹ and 49%.¹⁰

The second class of drugs is the azoles, which inhibit lanosterol 14a-demethylase, a step in the ergosterol biosynthesis pathway.⁶ Two members of this class that are widely used in treating onychomycosis are oral itraconazole¹¹ and off-label oral fluconazole.¹² The approved dose for oral itraconazole is 200 mg daily for 3 months (or an alternative pulse regimen) with a reported complete cure rate of 14%.¹¹ Although fluconazole is not FDA approved for the treatment of onychomycosis in the United States, it is used extensively in other countries and to some extent off label in the United States. In a study of 362 patients with onychomycosis treated with oral fluconazole, complete cure rates were 48% in patients who received 450 mg weekly, 46% in those who received 300 mg weekly, and 37% in those who received 150 mg weekly for up to 9 months.¹² It should be noted that several oral triazole antifungals, namely albaconazole,¹³ posaconazole,¹⁴ and ravuconazole,¹⁵ have undergone phase 1 and 2 studies for the treatment of onychomycosis and have shown some efficacy.

Another class of antifungals are the morpholines including topical amorolfine, which is approved for use in Europe but not in North America.¹⁶ Amorolfine inhibits D14 reductase and D7-D8 isomerase, thus depleting ergosterol.¹⁷ In one randomized controlled study, the combination of amorolfine nail lacquer and oral terbinafine compared to oral terbinafine alone resulted in a higher clinical cure rate with the combination (59.2% vs 46%); complete cure rate was not reported.¹⁶

Finally, the hydroxypyridinone class includes topical ciclopirox, which has a poorly understood mechanism of action but may involve iron chelation or oxidative damage.^18,19 Ciclopirox nail lacquer 8% was approved by the FDA in 1999 and has reported complete cure rates of 5.5% to 8.5% with monthly nail debridement.²⁰

Based on the poor efficacy of many of the currently available treatments and time-consuming treatment courses, it is clear that there is a need for alternative and novel therapies. There has been a greater emphasis on topical agents due to their more favorable side-effect profile and lower risk for drug-drug interactions. Although there are many agents for the treatment of onychomycosis currently in development, many are in vitro studies or phase 1 and 2 studies. However, we will focus on drugs that are further along in phase 3 studies and those that were recently FDA approved.