Diagnosing and Treating Onychomycosis

Mark P. Seraly, MD, with Mark L. Fuerst

THE PHYSICIAN AND SPORTSMEDICINE - VOL 26 - NO. 8 - AUGUST 98

In Brief: Onychomycosis is a particular concern for active people because they're exposed to fungi in locker rooms and because hot, sweaty feet enable the infection to flourish. A thorough physical exam and potassium hydroxide exam of debris from the nail plate can help rule out look-alike conditions and provide information that will guide drug therapy. Treatment with the new generation of onychomycosis medications—itraconazole, fluconazole, and terbinafine hydrochloride—is costly but produces impressive cure rates. Active patients need detailed instruction about preventive measures to avoid recurrence.

At one time, onychomycosis was thought of as a nuisance or a cosmetic problem that affected few people. The infection, now thought to be far more widespread, causes discomfort and embarrassment for millions of people and puts them at risk for such complications as bacterial cellulitis and subungual hematoma.

Before new antifungal medications were developed, healthcare professionals clipped and groomed infected nails, and the infection required long-term treatment. The failure rate was high. Now, however, with a correct diagnosis and the use of effective, albeit expensive, oral antifungal agents, onychomycosis can be cured in up to 90% of patients.

Who is at risk for onychomycosis?
By one estimate, onychomycosis occurs in 8.7% of Americans (1), but because of underreporting, the prevalence could be as high as 20% to 25% of the population, especially in patients aged 40 to 60. A number of factors contribute to the infection's increasing prevalence. Onychomycosis is more common in older adults because exposure to trauma increases and immunity decreases with age; the infection is rare among children. People with hyperhidrosis of the feet are at increased risk because of moisture and maceration of the skin.

Immune-suppressed people are also at increased risk of acquiring tinea pedis and onychomycosis; this includes those with solid-organ and bone marrow transplants, those who have human immunodeficiency virus (HIV) infection, and those receiving cancer chemotherapy.

Certain activities put patients at risk for fungal nail infection. Footwear that promotes sweaty feet, such as athletic shoes and boots, presents a risk. Walking barefoot in areas of frequent contamination, such as communal showers, swimming pools, and bathing facilities and on hotel carpets, also can lead to infection. Fitness enthusiasts are at risk on both counts.

What medical and psychological problems are associated with onychomycosis?
Older people who have it are at increased risk of infectious bacterial cellulitis from maceration and skin breakdown, because the skin's resistance against such infections decreases with age. Distorted nail plates may also lead to a risk of bacterial infection. Other medical problems associated with onychomycosis are discomfort from thickened nails, subungual hematoma, allergic urticaria, and eczematous dermatitis—also called a dermatophytid eruption. Also, in older patients who have arthritis, distorted nail plates from onychomycosis may exacerbate pain from underlying joint disease by altering gait patterns.

Onychomycosis also has a psychological impact. Patients may avoid fitness centers or swimming pools because they are embarrassed about the appearance of their feet and concerned about spreading the infection.

What are the signs and symptoms of onychomycosis?
Generally, toenail onychomycosis begins as a result of a chronic tinea pedis infection (athlete's foot, figure 1). Most commonly, the fungus migrates under the distal nail plate, causing a nail-bed infection that causes discoloration at the distal end of the plate and subungual debris or scaling that distorts the nail plate. With time and trauma, the plate can become brittle and crumble, which can make activity painful.

What are the clinical variants of onychomycosis?
There are four classic clinical variants (2). The most common, distal onychomycosis, leads to a subungual infection at the hyponychium, where the nail bed distally attaches to the nail plate (figures 2a and 2b). Once the nail bed is altered by onychomycosis, debris caused directly by fungal infection begins to lift the nail plate, altering the natural protective barrier. This can result in mixed infections with bacteria such as pseudomonads or Proteus organisms, Candida species, and molds such as Aspergillus species, Scopulariopsis brevicaulis, or Scytalidium hyalinum.

The second most common form, white superficial onychomycosis, is often associated with distal onychomycosis. This type generally occurs only when dermatophytes directly invade the dorsal nail. The nail plate becomes white (leukonychia mycotica) and brittle. The toenails are more commonly involved than fingernails.

The third form is proximal subungual onychomycosis. This is the least common variant and is a marker for an HIV infection. The dermatophyte enters the nail plate at the proximal nail fold, creating subungual debris and separating the proximal plate from the nail bed.

The fourth form is Candida onychomycosis, which causes onycholysis, or a separation of the nail plate from the nail bed. This infection causes a yellowish white subungual debris and paronychia, or a boggy, red pustular eruption at the lateral nail fold, which is often confused with a bacterial infection. This type of onychomycosis is more common on the fingernails, particularly among those who do work that keeps their hands wet, such as dish washing.

Another variant is total dystrophic onychomycosis, in which all of the nail plates have been destroyed by dermatophyte. This is most commonly seen among patients who have acquired immune deficiency syndrome with CD4 levels below 450.

How do you differentiate onychomycosis from other nail dystrophies?
Approximately 50% of nail plate dystrophies are caused by fungus. The remaining 50% are caused by a variety of disorders. These include inflammatory skin diseases such as psoriasis and lichen planus; bacterial paronychia that mimics onychomycosis; contact dermatitis, particularly among people who use nail cosmetics with nickel, formaldehyde resin, or acrylic monomers; phototoxic reactions (photo-onycholysis) to oral antibiotics such as tetracycline; and anxiety disorders.

Psoriasis of the nail plate can present as dorsal pitting onycholysis and subungual debris. Looking for characteristic psoriatic plaques on the scalp, elbows, knees, and buttocks helps differentiate onychodystrophy from onychomycosis.

Early in the disease course, lichen planus can be confused with onychomycosis, especially among nondermatologists. Lichen planus of the nail plate is associated with nail plate thinning, longitudinal ridge formation, splitting, and matrix scar formation, which produces an "angel wing" deformity. The presence of violaceous flat-topped papules on the wrists or ankles and white lacy lines (Wickham's striae) on the buccal mucosa helps differentiate lichen planus from fungal onychomycosis.

Onychodystrophy from external irritants typically causes an eczematous dermatosis on the skin surrounding the nail plate, which is generally not seen in patients who have onychomycosis. Photo-onycholysis from tetracycline and tetracycline family members is often painful and acute in onset, unlike Candida onychomycosis, which is asymptomatic and slowly progressive.

What tests are used to diagnose onychomycosis?
Physicians need to document the fungal infection. The simplest, most cost-effective test is the potassium hydroxide (KOH) examination. Using a small curette or No. 15 scalpel or blade, the examiner removes the crumbly subungual debris, then obtains a sample of the scale by firmly scraping the undersurface of the affected nail plate, cutting as close to the leading edge of the infection as possible. It is important to obtain a deep specimen.

The scales are placed on a slide with one drop of 10% to 20% KOH solution for 30 minutes. A variety of KOH preparations with and without dyes are available and can demonstrate the presence of hyphae by direct microscopy. Hyphae with a "boxcar" appearance confirm dermatophyte onychomycosis (figure 3).

Based on recent epidemiologic data (3,4), more than 90% of the fungi that cause onychomycosis are dermatophytes, such as Trichophyton, Epidermophyton, and Microsporum. The most common one is Trichophyton rubrum. About 8% of cases are caused by nondermatophyte molds, and less than 0.07% are caused by yeast (Candida albicans).

A positive KOH test determines that the patient's onychodystrophy is caused by a fungal organism, and no follow-up culture is necessary unless it is required by the patient's insurance provider for reimbursement. If the KOH test is negative, a nail culture is performed to help identify the genus and species of the invading pathogen, which will help guide treatment decisions. Nail cultures help the clinician distinguish dermatophyte-induced onychomycosis from yeast and nondermatophyte-related onychomycosis. This information can be helpful when selecting the most appropriate oral antifungal agent. Nail plate cultures fail to isolate the pathogen in up to 30% of cases. Therefore, if the culture is negative but onychomycosis is strongly suspected, a second culture should be performed. If the second culture is negative and the clinical suspicion is still high, consider doing a nail plate biopsy.

How do you treat onychomycosis?
Two traditional therapies—griseofulvin and ketoconazole—are no longer used because of poor success rates, ranging from 15% to 30% for infected toenails. The two medications (particularly ketoconazole) carry the potential for significant toxicity and are expensive—patients who have toenail onychomycosis require 10 to 18 months of daily therapy for a complete cure.

Currently, three newer oral antifungals—itraconazole, terbinafine hydrochloride, and fluconazole—are suggested (figure 4: not shown). All three are safe and effective. Both itraconazole and terbinafine bind to the keratin in the nail plate, itraconazole for 9 months and terbinafine for 2 to 4 months. In contrast, fluconazole levels drop quickly because the drug does not bind well to lipids or keratin. Patients generally need to be on fluconazole longer than the other two medications, usually until there is complete clinical and onychomycologic cure, which may take 10 to 18 months.

It takes a full month for skin cells to turn over. That is why athlete's foot treatments generally require about 1 month of antifungal creams. Onychomycosis treatment generally takes longer, and can be slower in patients who have poor peripheral circulation.

Itraconazole. Itraconazole has a broad spectrum of activity, being effective against dermatophytes, Candida, and nondermatophyte molds (5). Typical therapy involves 200 mg of itraconazole daily for 12 weeks, or it can be given as pulsed therapy: 400 mg daily for 7 days with a 3-week medication break. Treatment is repeated twice for a total of three pulses for toenails and repeated once for a total of two pulses for fingernails. An efficacy study (6) of 3 months of itraconazole pulse therapy with follow-up at 12 months showed that the drug was effective in the treatment of toenail onychomycosis with complete cure in 64% of patients, marked improvement in 88%, and mycologic cure in 64%.

Used alone, itraconazole is not cardiotoxic, but its use with astemizole, terfenadine, or cisapride can cause high plasma levels of these agents and can cause cardiotoxicity and life-threatening arrhythmias. Other drug interactions are possible when itraconazole is taken with cyclosporine, tacrolimus, digoxin, lovastatin, simvastatin, phenytoin, rifampin, H2 blockers, didanosine, isoniazid, midazolam hydrochloride, triazolam, or diazepam. Itraconazole should be used cautiously in patients who are on sulfonylureas or warfarin.

The most common side effects include elevated liver enzymes, nausea, and rash.

Terbinafine hydrochloride. Terbinafine, shown in clinical studies to be active against T rubrum and T mentagrophytes, is prescribed at 250 mg daily for 12 weeks. In efficacy studies (7-10) of terbinafine 250 mg/d for 12 weeks, between 50% and 74% of patients were completely cured, 71% to 100% had marked improvement, and 76% to 88% were mycologically cured.

There are no major drug interaction concerns with terbinafine and no known interactions that are even clinically significant. Because of this, and because this agent is fungicidal, does not activate the cytochrome P450 system, and does not have active metabolites, it is the treatment of choice.

The most frequently reported side effects include gastrointestinal symptoms, elevated liver enzymes, rashes, urticaria, pruritus, and taste disturbances. Some patients have experienced severe cutaneous reactions from oral terbinafine, including Stevens Johnson syndrome, toxic epidermal necrolysis, and allergic urticaria (11).

Fluconazole. Onychomycosis is an off-label indication for fluconazole, which is indicated for treatment of oropharyngeal and esophageal candidiasis, systemic candidal infections, and cryptococcal pneumonia. In addition to dermatophytes, fluconazole has been shown to be effective against Candida (12,13) and some molds (Bipolaris species and Rhodotorula rubra) (13). As an onychomycosis treatment, fluconazole has no generally accepted standard dose, duration of therapy, or recommendation on pulse therapy vs daily therapy against dermatophytes and Candida.

An study (14) of fluconazole at 150 mg/wk for 3 to 12 months showed that 6 months after stopping therapy, 72% of patients were clinically cured, 87% had marked improvement, and 79% were mycologically cured, with a relapse rate of 11%.

Drug interactions are possible when fluconazole is taken with cisapride, terfenadine, astemizole, phenytoin, rifabutin, rifampin, midazolam, triazolam, or tolbutamide.

The most common side effects of fluconazole include elevated liver enzymes, gastrointestinal complaints, headache, and skin rash.

How do you monitor these patients?
In general, systemic toxicity is uncommon with oral antifungal agents. I order a liver function test (LFT) to screen for hepatotoxicity and bone marrow toxicity. Approximately 1 in 50,000 to 250,000 patients who are treated for onychomycosis with fluconazole or itraconazole has the potential for serious liver toxicity. With terbinafine, the risk of hepatotoxicity is less. Since some drug interactions can occur, it is important to take a good medication history before initiating oral antifungal therapy.

For itraconazole and terbinafine, I do a baseline liver panel, and repeat this at weeks 6 and 12 of treatment. For fluconazole, there is no generally accepted recommendation; for most patients, I follow the same protocol as with the other drugs. If LFTs are abnormal at baseline, I do not initiate oral antifungal therapy. If LFTs become abnormal during the course of therapy, I discontinue the oral antifungal agent.

At the baseline exam, I explain the treatment benefits and risks, including side effects such as headache. Once blood is drawn, I nick the proximal border of the infected nail plate with a scalpel to mark the area of infection. At weeks 6 and 12, I remeasure the distance from the mark to the proximal nail fold adjacent to the cuticle. (Clearing starts where the new nail appears at the proximal nail fold.) I ask about side effects and repeat the blood tests.

I ask patients to return at 9 months for reexamination. At that visit, I emphasize maintenance therapy and review prevention measures. If the infection appears to be recurrent, I reculture the nail plate.

Because of the nature of newer oral antifungals, which bind to the nail plate for at least several months, I don't retest the nail plate or nail bed for infection for at least 6 to 9 months after discontinuation of the oral antifungal.

How successful is treatment?
The treatment failure rate is estimated at 10% to 20%. If the patient has a true positive KOH test and takes the medication as prescribed, the medications generally don't fail. There are no long-term data for any of the oral antifungal agents on the duration of cure following clearance of onychomycosis. Patients who comply with preventive measures reduce their chances of reinfection.

What is the role of topical therapy?
Currently, there are no topical therapies for treating onychomycosis. Some agents are being studied, including amorolfine 5% lacquer. In isolated, single-nail-plate disease, it has shown some efficacy.

The only way to cure onychomycosis is to use oral antifungal agents and to prevent reinfection.

What can patients do to speed healing and prevent recurrences?
There is no generally accepted algorithm on preventing reinfection. I suggest that patients use a topical antifungal cream once a week if they have a history of fungal infection of the toes or toenails. Imidazole cream or terbinafine are fine for maintenance, or I suggest using Zeasorb-AF (Stiefel Laboratories, Coral Gables, Florida), which is a superabsorbent powder that contains miconazole. This is particularly good for athletes who sweat because it keeps moisture off the skin and reduces maceration. Antifungal sprays are helpful to use in boots, shoes, and athletic shoes.

Patients should wear thongs in bathing facilities, gyms, locker rooms, and showers and on hotel carpets. Athletes should wear polypropylene socks under white cotton socks to wick moisture away from the skin. Foot powders can be used to absorb moisture and keep skin clean and dry.

Prevention is important because treatment is expensive. One course of antifungal therapy can cost from $450 to $1,000. Health maintenance organizations will generally cover the cost and treatment of onychomycosis, but many require a positive culture and/or documentation of patient discomfort before allowing antifungal treatment.

References

1. Elewski BE, Charif MA: Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions, letter. Arch Dermatol 1997;133(9):1172-1173
2. Zaias N: The Nail in Health and Disease, ed 2. Norwalk, CT, Appleton & Lange, 1990, pp 106-119
3. Kemna ME, Elewski BE: A U.S. epidemiologic survey of superficial fungal diseases. J Am Acad Dermatol 1996;35(4):539-542
4. Elewski BE: Large-scale epidemiological study of the causal agents of onychomycosis: mycological findings from the Multicenter Onychomycosis Study of Terbinafine, letter. Arch Dermatol 1997;133(10):1317-1318
5. Piérard GE, Arrese JE, De Doncker P: Antifungal activity of itraconazole and terbinafine in human stratum corneum: a comparative study. J Am Acad Dermatol 1995;32(3):429-435
6. De Doncker P, Decroix J, Piérard GE, et al: Antifungal pulse therapy for onychomycosis: a pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1-week pulse therapy with itraconazole. Arch Dermatol 1996;132(1):34-41
7. Arenas R, Dominguez-Cherit J, Fernandez LM: Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol 1995;34(2):138-143
8. Brautigam M, Nolting S, Schopf RE, et al: Randomised double blind comparison of terbinafine and itraconazole for treatment of toenail tinea infection: Seventh Lamisil German Onychomycosis Study Group. BMJ 1995;311(7010):919-922 [published erratum in BMJ 1995;311(7016):1350]
9. Goodfield MJ: Short-duration therapy with terbinafine for dermatophyte onychomycosis: a multicentre trial. Br J Dermatol 1992;126(suppl 39):33-35
10. van der Schroeff JG, Cirkel PK, Crijns MB, et al: A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol 1992;126(suppl 39):36-39
11. Gupta AK, Lynde CW, Lauzon GJ, Mehlmauer MA, et al: Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol 1998;138(3):529-532.
12. Assaf RR, Elewski BE: Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot study. J Am Acad Dermatol 1996;35(2 pt 1):216-219
13. Smith SW, Sealy DP, Schneider E, et al: An evaluation of the safety and efficacy of fluconazole in the treatment of onychomycosis. South Med J 1995;88(12):1217-1220
14. Montero-Gei F, Robles-Soto ME, Schlager H: Fluconazole in the treatment of severe onychomycosis. Int J Dermatol 1996;35(8):587-588

Dr Seraly is an assistant professor and director of clinical services in the department of dermatology at the University of Pittsburgh Medical Center in Pittsburgh. Mr Fuerst is a medical writer in Brooklyn, New York. Address correspondence to Mark P. Seraly, MD, Dept of Dermatology, University of Pittsburgh Medical Center, 190 Lothrop St, Suite 145, Pittsburgh, PA 15213; e-mail to seralymp@msx.upmc.edu.

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