Introduction
Topical application of an antifungal cream, gel or paint remains the most popular way to treat fungal foot infections of the skin. In the UK, we have a range of topical drugs including terbinafine, clotrimazole, miconazole, bifonazole and ketoconazole. Most of these have been discussed in an earlier blog post (click here) but across the globe there are other topical drugs which are licenced elsewhere but currently not available for in the United Kingdom. Sometimes we feel that the grass is always greener on the other side. So, what are we potentially missing here in the fight against fungus? This article looks at some of the (newer) drugs we cannot currently obtain or use legally in this country and assesses the evidence for their use.
The Imidazoles
The imidazoles are a large, well established group of antifungal agents which we have long been using in the UK for treating athletes’ foot and nail infection in various formulations. We all know and love miconazole and clotrimazole amongst others but globally, there are other newer members of the family including luliconazole, efinaconazole and more recently dapconazole.
Luliconazole (Luzu®), has been available in Japan since 2005 and latterly entered the United States as a topical 1% cream indicated for interdigital tinea pedis (cream) and onychomycosis (as a nail paint). The pivotal study for the drug in the USA was published in 2014, examining its effectiveness against interdigital tinea pedis where it was set against a placebo vehicle – applied once daily for two weeks as a double-blind, multi-centre, randomised controlled trial. After 2 weeks of topical application, patients were reassessed at day 42 and luliconazole patients showed a 15% cure rate versus just 2% with the placebo vehicle cream (1). Its effectiveness was subsequently confirmed by a meta-analysis (2) which also showed it to be potentially superior to miconazole, clotrimazole and terbinafine. In the US, its currently available as a cream and nail application. The drug itself has shown the ability to remain active in keratin longer than older azole drugs.
Efinaconazole 10% (Jublia®) has also been licenced in the USA and Japan. A triazole agent, similar to itraconazole, this is currently marketed as a solution for the topical treatment of onychomycosis, and like luliconazole it has a broad spectrum against a range of dermatophyte and non-dermatophyte moulds and does not bind to keratin making more of the drug available for delivery through the nail (3). The drug is specifically marketed for distal and lateral onychomycosis. The Phase three trials for once daily efinaconazole showed in two studies a complete cure rate (mycological & clinical) of 55% versus just 15% for the control vehicle (4). This was closely matched by a follow up study showing results of 56% mycological cure rate versus 17% in the placebo group (5).
Sertaconazole (Ertaczo®) is another imidazole drug available in the United States. Most imidazoles are a twice a day application as a treatment for tinea, as a result of them being primarily fungistatic and not fungicidal, like terbinafine. However, sertaconazole bucks this trend as it is fungicidal in action. In a 179-patient study of sertaconazole versus terbinafine, both drugs showed similar cure rates in skin dermatophytosis (89%-93% clinical cure) at four weeks (6).
Dapanazole tosylate 2% (Zilt®) is the latest addition to the azole family used clinically in the treatment of tinea pedis. The drug, available in Brazil, has been tested against topical ketoconazole 2% in a cohort of 48 adults with interdigital tinea pedis. Twice daily application was ensured as it was applied by the researcher. One way to ensure compliance! The two creams were applied to the same patient (one on the left, the other on the right). Both the researcher and patient were blind to the application). Participants were paid to take part – another way to ensure compliance. After two weeks of daily application the cure rates on each pair of feet was examined and both ketoconazole (66%) and dapanazole (68%) had very good cure rates and very few adverse effects (7).
Other Newer Drugs
As a podiatrist or chiropodist of a certain age you may remember a good old remedy – “Phytex” paint. A closer look at the box and you will see it contains Boric acid (3%). As new drugs are developed a new class of boron-based drug has appeared. It was said to have been developed as a nail treatment, particularly as nail penetration of topical agents had been poor and ultimately cure rates with topical nail treatments alone had been disappointing. Tavaborole (Keradyn®), an oxaborole, specifically blocks protein synthesis via inhibition of leucyl-aminoacyl transfer RNA (tRNA) synthetase (8). Two studies were undertaken comparing it against a placebo vehicle. At week 52, subjects were assessed, and 31-36% of tavaborole patients were negative on mycology versus just 7-12% with placebo. Complete cure was achieved 6.5% & 9% versus 0.5% & 1.5% with the placebo (9).
So are we missing anything here in the UK?
After reading through the studies and clinical papers discussing these drugs, the question is are we missing something or falling behind? Developing new drugs to compete in an already busy market is an expensive business and to give them a good chance, they need to offer something new. On the basis of the evidence, they all appear to be able to do a job but whether it’s a better job than our currently available medications is really difficult to tell. A systematic review in 2012, made this point after reviewing 16 antifungal agents and it could not discern a clearly superior topical agent (10).
On the face of it, efinaconazole is a broad-spectrum antifungal probably as good as terbinafine as it also provides cover against the less common yeasts with which terbinafine struggles but then again, they are only occasionally found the foot. Tavaborole as a nail treatment certainly does seem to show it is able to work well in the hard keratin of the nail but clinical results at this stage are still not far different from other agents we already have. Moreover, all of these new topicals still cannot achieve the 80% mycological cure rates enjoyed by oral antifungal agents. Topically, terbinafine remains a strong candidate for tinea pedis, with the exception that its is not effective against Candida albicans (which is unusual on the foot as a sole infection), but like all the others it is still very safe. So for now, lets keep using what we have. The grass maybe just as green on this side.....for now.
References
1. Draelos ZD, Vlahovic TC, Gold MH, Parish LC, Korotzer A. A Randomized, Double-blind, Vehicle-controlled Trial of Luliconazole Cream 1% in the Treatment of Interdigital Tinea Pedis. The Journal of clinical and aesthetic dermatology. 2014;7(10):20-7.
2. Feng X, Xie J, Zhuang K, Ran Y. Efficacy and tolerability of luliconazole cream 1% for dermatophytoses: A Meta-analysis. The Journal of Dermatology. 2014;41(9):779-82.
3. Sugiura K, Sugimoto N, Hosaka S, Katafuchi-Nagashima M, Arakawa Y, Tatsumi Y, et al. Efinaconazole: low keratin affinity contributes to nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014.
4. Elewski BE, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, 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(4):600-8.
5. Joseph WS, Vlahovic TC, Pillai R, Olin JT. Efinaconazole 10% Solution in the Treatment of Onychomycosis of the Toenails. J Am Podiatr Med Assoc. 2014;104(5):479-85.
6. Chatterjee D, Ghosh SK, Sen S, Sarkar S, Hazra A, De R. Efficacy and tolerability of topical sertaconazole versus topical terbinafine in localized dermatophytosis: A randomized, observer-blind, parallel group study. Indian journal of pharmacology. 2016;48(6):659-64.
7. Gobbato AAM, Gobbato C, Moreno RA, Antunes NJ, De Nucci G. Dapaconazole versus ketoconazole in the treatment of interdigital tinea pedis. Int J Clin Pharmacol Ther. 2018;56(1):31-3.
8. Markham A. Tavaborole: first global approval. Drugs. 2014;74(13):1555-8.
9. Elewski BE, Aly R, Baldwin SL, González Soto RF, Rich P, Weisfeld M, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73(1):62-9.
10. Rotta I, Sanchez A, Gonçalves PR, Otuki MF, Correr CJ. Efficacy and safety of topical antifungals in the treatment of dermatomycosis: a systematic review. Br J Dermatol. 2012;166(5):927-33.