Simon Murray, MD: Diagnosis and Treatment of Onychomycosis

Onychomycosis is a common nail disorder caused by dermatophytes, non-dermatophytes, and yeasts and other molds. It is a disease more common in adults with a North American incidence of 3%-7% and may be rising.

Dermatophytes are the most common type of organism affecting the toe nail with 45% of the organisms being Trichophyton rubrum. Candida albicans is the most common organism causing infection in finger nails. Non-dermatophyte and yeast infections are uncommon in toenails.

The major clinical presentations include distal lateral subungual onychomycosis, white superficial onychomycosis, and proximal subungual onychomycosis. Other presentations include infections limited to the nail plate and sparing the nail bed and total dystrophic onychomycosis.

Risk factors include advanced age, swimming, tinea pedis, psoriasis, diabetes, cohabitation with others who are infected, and genetic predisposition.

Nail infections may be painful, may predispose to infections particularly in immunocompromised patients such people with diabetes. Newer treatments are expensive and not without risk, so it is important to accurately diagnose onychomycosis prior to treatment.

At the 2019 American Academy of Dermatology Annual Meeting in Washington, DC, Molly Hinshaw, MD, reported that up to 50% of diagnosed nail infections were in fact not nail infections and she stressed the importance of accurate diagnosis prior to treatment. Clinical diagnosis may suggest fungal infection, but laboratory evidence is necessary to confirm.

There are a number of nail lesions that mimic fungal infections including skin cancer, psoriasis, onychogryphosis, lichen planus, yellow nail syndrome, and other onychodytrophies. Sometimes these conditions coexist with onychomycosis. The diagnosis is clearly easy to miss on clinical grounds.

Several diagnostic tools are available, including:

1. KOH with or without DMSO can be done in the office, has a fairly high specificity. Sensitivity approaches 80% and sensitivity 72% (Weinberg JM et al, JAAD 2003;49 193-7) KOH does not provide speciation or assessment of fungal viability. The test is limited by the skill of the user, but most primary care providers can easily learn to do the procedure and perform it accurately in their office.
2. PAS staining involves taking nail clippings placing in formalin then stained with PAS. Sensitivity 92%, specificity 72% (Weinberg JM et al, JAAD 2003;49 193-7) PAS staining has the higher sensitivity than KOH or culture.
3. Cultures are inexpensive and are approximately 50 % sensitive but can take up to 4 weeks to get results. They can provide speciation and identification of fungal agents. One third of all cultures are false negative so repeat cultures should be done on all suspected cases of onychomycosis based on clinical grounds with a negative culture. The cultures occasionally report non-dermatophyte molds which may be contamination or true pathogens so repeat cultures are necessary before assuming that yeast is the cause of toe nail infection.
4. Molecular diagnosis: PCR employs direct ID of DNA in nail versus the use of morphology and other methods. The technology is probably the choice of the future but is currently not widely employed.

Having made a diagnosis, the treatment decision will involve oral, topical, or mechanical therapy.

Oral: the oral therapies available to treat nail infection in the US, include Ketoconazole, Griseofulvin, Fluconazole, Itraconazole, and Terbinafine.

1. Ketoconazole is no longer recommended as oral therapy for nail infections because of the possibility of life-threatening liver toxicity.
2. Griseofulvin, invented in 1951, is rarely used because it requires a very long duration of therapy and greater risk of side effects. Clinical studies have suggested it may be as effective as Terbinafine in inducing mycologic cures.
3. Fluconazole, given weekly in doses of 150 mg to 450 mg, may be effective in fingernail infections if used for 3 months and for toenail infections for 6 months. Head to head comparisons show it to be inferior to Terbinafine to induce complete cure. As the dose increases the cure rates increase from 37% with 150 mg/week to 48% at 450 mg/week. Pulse dosing of fluconazole is not FDA-approved but is superior to continuous therapy.
4. Itraconazole is an effective treatment but considered second line because of side effects and drug to drug interactions. It is not as effective as Terbinafine with mycologic cure rates of 26%. It carries a black box warning for congestive heart failure. (Gupta,K et al, Am J Derm 2014: 15: 488)
5. Terbinafine is the drug of choice for moderate and severe nail infections. It can be co-administered with topical agents. Cure rates appear to better with pulsed therapy and approach 49% after 3 pulses and 54% after 4 pulses. These are the highest cure rates of any other agent. Formerly the drug’s use was limited by high cost, but it has become as cheap as $10 per course since going generic. It is currently the oral drug of choice. It can be given on a daily basis for 6 weeks for finger nail infections, and up to 12 weeks for toes nails. Liver functions must be checked after 6 weeks. Liver toxicity is not common but does occur.

Topical treatment options include: Efinaconazole, Tavaborole, and Ciclopirox.

1. High quality head to head trials are lacking comparing the efficacy of these agents and all are generally not highly effective for onychomycosis due to poor nail penetration into the nail plate. These topical agents are reserved for more mild infections. (Gupta, K et Am J Derm 2014: 15: 488)
2. Efinaconazole is the newest agent, applied daily as a nail lacquer on a daily basis for up to a year or longer. Cure rates in mild infections with dermatophytes, or with candida involving less than 25% of the nail achieved cure rates of 15 %. One drop of the solution is applied by brush over the nail surface at night, with an additional drop applied at the tip of the nail.
3. Tavaborole 5% solution is applied for 48 weeks. Patient treated in trials had 20% to 60% of the nail involved, and lacked any evidence of dermatophyte involvement. Cure rates ranged from 7% to 15%. Side effects included local skin exfoliation and ingrown toe nail. (Gupta, K et al, Am J Derm 2014: 15: 488)
4. Ciclopirox is active against dermatophytes, yeasts, and molds. Treatment for 48 weeks showed complete cure rates of 7% in nails that were 20% to 65% involved. When combined with oral Terbinafine no increased cure rates were observed greater than Terbinafine alone. (Gupta, K et al, Am J Derm 2014: 15: 488)

Mechanical treatment options:

1. Laser treatment is not indicated to treat nail infections other than to produce a temporary clear appearance, but not cure.
2. Other devices and treatments are in development, but none approved or widely used. Photodynamic therapy (PDT), and surgical removal of the nail are other treatment options.

In summary, onychomycosis is a common medical problem that may lead to coinfections and can be painful. Diagnosis prior to treatment is essential. Topical and oral treatments are widely available, but relapse is common. Newer agents are in the pipeline for use but is unclear if the FDA will approve for nail infection.