1. Why Treat Fungus of the Nails?
For some patients, treatment is advocated to alter the quality of life. Their unsightly nails may socially impair these patients. For others the treatment may be recommended to prevent pain from pressure on the thickened onychomycotic nail. For diabetics and patients with decreased peripheral circulation, treatment may be indicated to decrease the risk of secondary bacterial infection from trauma of adjacent skin by the dystrophic nail. Treatment may also be indicated to prevent spread to other nails or other persons.
2. How do You Diagnoses Onychomycosis?
As only 50% of dystrophic nails have a fungal cause, it is important to accurately diagnose fungus in the nail. The simplest procedure is direct microscopic examination using potassium hydroxide (10% to 15% potassium hydroxide [KOH] solution) to dissolve the keratin in the nail material, which allows the fungal elements to be visualized. To collect the specimen for KOH study, pare the infected part of the nail until the crumbling, white, degenerating portion is reached. Firmly scrape under the free edge of the nail and collect any white keratin debris. The greater the quantity of specimen, the greater is the chance of obtaining a positive result. The KOH prep may take 1 to 2 hours to dissolve the keratin for reading.
Culture of the nail is another option. Fungal growth in the culture media takes 7 to 10 days. Although culture may be accepted as the best method for confirming the diagnosis, the yield of positive culture is often disappointing. This particularly high failure rate may be due to taking the sample from the distal part of the nail where, although fungal elements are still visible on microscopy, the fungus is no longer viable and will not grow in culture. It is often necessary to repeat the culture to be sure that there is truly no fungus infection in the nail.
When direct microscopic examination by KOH preparation and fungal culture fail to arrive at a diagnosis, submission of the nail plate for histologic analysis is an option. Mehregan et al.  demonstrated that direct examination by routine histology methods may be more sensitive than fungal culture. In addition, other reasons for nail dystrophy (such as psoriasis and lichen planus) may ultimately be diagnosed from a nail biopsy specimen.
3. What Diseases Mimic Onychomycosis?
Any process that causes dystrophic nails (thickened, misshaped, pitted) or onycholysis (separation of the nail from the nail bed) may be mistaken for onychomycosis. Dystrophic nails or onycholysis may also be caused by trauma. Numerous diseases such as lichen planus, psoriasis, alopecia areata, and pityriasis rubra pilaris may be mistaken for onychomycosis. Genetic diseases of the nail such as Darier’s disease, hydrotic ectodermal dysplasia, dyskeratosis congenita, and pachyonychia congenita may also resemble onychomycosis.
Nail changes in lichen planus are less common than psoriasis but are almost always accompanied by typical skin (purple, polygonal, papules) changes or buccal mucosal (white, reticulated, lace-like) lesions. The nail alterations may vary from simple longitudinal ridging and furrowing to total shedding of the nails with scarring and no regrowth.
Nail changes in psoriasis are common. Although loss of nails may occur, the three most common changes are pitting of the nail plate, lysis or separation of the nail plate from the nail bed, and subungual hyperkeratosis and crumbling of the nail plate. Nail defects are associated with alopecia areata in 10–20% of cases. The more extensive the disease, as in alopecia universalis, the more likely is nail involvement. Characteristically the nail is pitted in regular horizontal and/or vertical rows. The nail changes are considerably less consistent and less profound than in psoriasis. The nails in pityriasis rubra pilaris are often dull, thickened, and may show transverse striations. The characteristic widespread follicular papules and the hyperkeratotic palms and soles would point to pityriasis rubra pilaris rather than a fungal origin of the nail dystrophy.
4. Can Nail Fungus be Treated Topically?
Generally, nail fungus does not respond well to topical treatment. Antifungal drugs poorly penetrate the nail plate and have had only limited use. In minimally infected nails one may cut back the involved portion of the nail and apply topical antifungals with some success. Total nail removal is rarely used as mono therapy.
The new lacquer antifungals such as Ciclopirox (trade name Penlac) found complete cure rates in toenail onychomycosis of 5.5% to 8.5% after 48 weeks . However, in white superficial onychomycosis the nail lacquer is very effective when combined with gentle scraping of the nail. The lacquer is applied over the entire nail plate once a day until clear, usually 1 to 4 months in white superficial onychomycosis. Additionally the nail surface should be gently scraped periodically to remove the more superficial white masses of fungal filaments.
5. What are the Patterns of Nail Infection?
Distal and Lateral Subungual Onychomycosis
This is the most common pattern and usually involves Trichophyton rubrum and T. mentagrophytes. The fungus invades the distal nail bed and the lateral nail groove, and hyperkeratosis of the nail bed follows, resulting in a thickened, discolored nail.
White Superficial Onychomycosis (Leukonychia Dystrophica)
This is less common and frequently caused by T. mentagrophytes but occasionally Cephalosporium, Aspergillus spp., and Fusarium oxysporum . Primarily an invasion of the surface of the nail plate, white superficial onychomycosis is characterized by soft white spots on the surface, then punctuated by colonies that gradually enlarge. They may coalesce to involve the entire surface. Masses of fungal filaments may be easily scraped away.
Proximal Subungual Onychomycosis
Though rare, this is most common in persons infected with HIV. The organism, usually T. rubrum, invades under the cuticle and infects the proximal nail bed. Transverse white bands begin at the proximal nail plate and advance distally with the outward nail growth.
Candida of the Nails
Nail candida may be classified as 1) candidal paronychia in which nail dystrophy is a subsequent process, or 2) onychomycosis due to Candida. Nail plate invasion may occur in chronic mucocutaneous candidiasis. Additionally, some patients may develop nail plate invasion and destruction particularly if there is underlying Cushing’s syndrome or Raynaud’s disease. True invasion of a nail by yeast is characterized by the appearance under light microscopy of yeast in its pseudomycelium growth phase with moniliform filament and lateral blastoconidia. Budding yeast cells merely reflect pockets of saprophytic colonization in nails.
6. What Oral Treatments are Available?
Terbinafine and itraconazole are the treatment of choice for fungal nail infections.
Fluconazole may also be used. Systemic treatments with griseofulvin and ketoconazole have limited use. Griseofulvin has a low cure rate; 15–30% for toenails and 50–70% for fingernails, high recurrence rate, and requires a prolonged course of treatment (12 months or greater for toe nails) . Although ketoconazole demonstrates a higher cure rate than griseofulvin, (21% vs 17%) , ketoconazole also requires prolonged therapy, 12 months or more for toenails, has a high relapse rate, carries a significant risk of drug interactions and serious adverse effects such as heptotoxicity. What dosage options are there?
- 200mg, 300mg, or 450 mg once weekly
- Duration 6 to 12 months, until the nails have regrown
- Intermittent cycles of 200 mg twice daily for 1 week per month
- Duration 2 months for fingernails, 3 to 4 months for toenails
- Itraconazole should be taken after a full meal or with an acidic beverage and not within 2 hours of antacids or H2-receptor antagonists
- 250 mg once daily
- Duration 6 weeks for fingernails, 12 weeks for toenails.
- Alternatively, one may also pulse dose terbinafine
- Intermittent cycles of 500 mg daily for 1 week per month
- Duration 2 months for fingernails, 4 months for toenails 
The concentration of both itraconazole and terbinafine in the nails 90 days after a 7-day course greatly exceeds the minimum inhibitory concentration of common dermatophytes. It is important to remember that though the nail is not normal at the cessation of therapy with either itraconazole or terbinafine, it should continue to grow free of fungus because of the continued presence of these agents in the nail.
7. What are Some of the Side Effects of Itraconazole, Fluconazole, and Terbinafine?
The more common side effects are gastrointestinal (nausea, abdominal pain, dyspepsia, diarrhea, flatulence), headache, and dermatological symptoms (rash, pruritus, urticaria).
Rare cases of serious liver problems including liver failure, transplantation, and death have been associated with the use of terbinafine and itraconazole.
With the use of terbinafine, the incidence of severe neutropenia including agranulocytosis is 1:400,000. The frequency of thrombocytopenia is 1:200,000 .
8. Can Itraconazole be Used in Patients With Congestive Heart Failure?
No. The recent FDA alert states that with the use of itraconazole there is a small but real risk of developing congestive heart failure (CHF). For this reason it is advisable to avoid itraconazole use in patients with evidence of cardiac dysfunction, such as CHF or a history of CHF .
9. What is the Risk of Liver Toxicity With Terbinafine and Itraconazole?
An estimated incidence of clinically significant hepatobiliary dysfunction is 1:120,000 for terbinafine. With itraconazole, symptomatic hepatitis is reported as approximately 1:500,000 .
The recent FDA alert states: “As of April 2001, FDA has received and reviewed 16 possible Lamisil® (terbinafine)-associated cases of liver failure, including 11 deaths and two liver transplantations.”  As of March 2001, FDA has received and reviewed 24 cases of liver failure possibly associated with Sporanox (itraconazole), including 11 deaths .
10. What About Drug Interactions?
A main concern with the use of itraconazole is its potential for serious drug interactions. Itraconazole and its major metabolite are potent inhibitors of the cytochrome P-450 enzyme system. Use of itraconazole with drugs metabolized by this enzyme system may result in increased plasma concentrations of these drugs and lead to potentially serious or life-threatening events.
Because fluconazole has greater specificity for fungal cytochrome P450 enzymes and because it is excreted largely unmetabolized, it has clinically significant drug interactions less frequently than itraconazole .
Terbinafine is an inhibitor of the CYP2D6 isoform of cytochrome P-450 and thus has potentially fewer drug interactions.
11. Which Drug Has the Highest Cure Rate?
In a large Novartis-administered study (L.I.O.N study), continuous terbinafine therapy at 250 mg for 12 weeks versus pulsed itraconazole therapy at 400mg/day for 1 week, once a month, for 16 weeks showed mycological cure rates at 72 weeks of 75.5% vs 49.1% .
In a terbinafine versus fluconazole study the mycological cure rates were higher (89% vs. 51%) and complete clinical cure greater (67% vs. 32%) for terbinafine . However, the fluconazoloe dosing at 150 mg/wk for 12 to 24 weeks is shorter than the present recommendation for toenails.
When one reviews the multiple clinical trials of these three drugs it is difficult to compare results, as the criteria for cure may be dissimilar. In general, however, terbinafine shows higher cure rates.
12. How do you Minimize Recurrences of Onychomycosis?
- It is imperative to control tinea pedis.
- Wear appropriate foot wear when walking on surfaces that may have a high density of dermatophytes, such as locker rooms, health clubs, gyms, and public showers. Keep feet clean and dry.
- Apply a broad spectrum topical antifungal at the first sign of tinea pedis.
- Use antifungal foot powder such as Zeasorb AF (Stiefel Laboratories, Coral Gables, FL), tolnaftate, or miconazole in shoes.
- Let shoes dry out between use.
1. Mehregan DA, Mehregan DR, Rinker A. Onychomycosis Cutis 1997; 59( 5):247–8.
2. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J AM Acad Dermatol 2000; 43:S70–S80.
3. Sehgal VN, Jain S. Onychomycosis: clinical perspective. Int J Dermatol 2000; 39( 4):241–9.
4. Daniel CR. Traditional management of onychomycosis. J Am Acad Dermatol 1996; 35:S21–5.
5. Hay RJ, Clayton YM, et al. A comparative double blind study of ketoconazole and griseofulvin in dermatophytosis. Br J Dermatol. 1985; 112( 6):691–6.
6. Tosti A, Piraccini BM, Stinchi C, et al. Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole. J Am Acad Dermatol 1996; 34( 4):595–600.
7. Suhonen R, Neuvonen PJ. The tolerability profile of terbinafine. Rev Contemp Pharmacother 1997; 8:373–86.
8. FDA Public Health Advisory May 9, 2001. Full text available at FDA’s MedWatch web site, http://www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.htm
9. Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J AM Acad Dermatol 1993; 29:S50–4.
10. Scher RK, Breneman D, Rich P, et al. Once weekly fluconazole (150,300,450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol 1998; 38:S77–86.
11. Sigurgeirsson B, Billstein S, Rantanen T, et al. L.I.O.N. Study: efficacy and tolerability of continuous terbinafine compared to intermittent itraconazole in the treatment of toenail onychomycosis. Br J Dermatol 1999; 141:5–14.
12. Havu V, Heikkila H, et al. A double blind, randomized study to compare the efficacy and safety of terbinafine with fluconazole in the treatment of onychomycosis. Br J Dermatol 2000; 142( 1):97–102.