W. Steven Pray, PhD, DPh; Joshua J. Pray, PharmD candidate

Disclosures

US Pharmacist. 2004;29(8) 

Skin diseases often affect both sexes equally. However, there are exceptions, such as the superficial tinea infections. For instance, tinea of the groin preferentially affects males, as does tinea pedis of the feet. In turn, tinea pedis is a risk factor for tinea of the toenails, making males more prone to this troubling condition.[1]

What Is Onychomycosis?

Onychomycosis (fungal toenail infections) may be caused by yeasts, nondermatophyte molds, or superficial dermatophytes that also cause tinea infections of the skin.[2,3,4] More than 90% of toenail fungus cases are caused by Trichophyton rubrum, a common source of superficial dermatological tineas.[3] Onychomycosis caused by superficial dermatophytes is known as tinea unguium. Onychomycosis may be superficial, affecting only the tip of the nail, or it can involve the entire nail.[5]

How Common Is Onychomycosis?

Onychomycosis accounts for 40% to 50% of all nail dystrophies.[2] It has a prevalence in Americans as high as 13%.[3,6,7] It is increasing in incidence; T rubrum on the feet of immigrants to the United States from countries with high infection rates may be the cause.[7] The risk of onychomycosis in adults is 30 times higher than in children.[2,7]

Possible causal factors are peripheral vascular disease, traumatic nail abnormalities, polypharmacy, and poor foot hygiene.[5] Certain activities are linked to onychomycosis. Swimming is a risk factor, perhaps because of prolonged exposure of the nails to moisture, with accompanying cuticle and skin maceration.[8] Further, the floors of locker rooms and swimming facilities are usually heavily contaminated with fungi.[3] Certain medical conditions (e.g., psoriasis, diabetes mellitus, tinea pedis) are risk factors for onchomycosis, as is wearing occlusive or poorly fitting footwear.[7]

Classification of Onychomycosis

Understanding the varying forms and severities of onychomycosis helps the pharmacist refer patients as needed.

Distal/Lateral Subungual Onychomycosis. The most common variant of onychomycosis is distal/lateral subungual onychomycosis, a condition usually caused by T rubrum.[3] The nail is abnormally colored (white or brown) along the lateral edges of the upper distal areas and may be eroded. Unless aggressively treated, the fungus may spread across the entire nail bed. The nail becomes brittle and may disintegrate and flake away with repeated shoe contact. The nail beneath the abnormal area experiences subungual hyperkeratosis with loosening and possible onycholysis (loss of the nail). Thus, the pharmacist must urge the patient to seek treatment from a podiatrist/physician as soon as possible. The pharmacist may suggest concomitant treatment of the surrounding skin, which is also frequently affected with a tinea and can be easily treated with OTC antifungals (i.e., Lotrimin AF, Lamisil AT).

Superficial White Onychomycosis. This uncommon toenail fungus is usually caused by Tinea mentagrophytes.[3] It initially affects the upper nail surface, extending to the nail bed and area beneath the nail.[7] The nail develops small powdery white speckles or patches, with roughening, crumbling, and/or flaking on the surface. Surrounding skin is seldom affected and the nail usually remains intact.

Proximal Subungual Onychomycosis. This toenail fungus involves the proximal area beneath the nail bed; it is most common in immunosuppressed patients and is usually caused by T rubrum.

Candidal Onychomycosis. This may be seen in patients whose feet are constantly wet. With continued water exposure, the cuticle loosens from the nail plate, and microorganisms enter the exposed area. Eventually, the patient develops an overt infection (paronychia). As the cuticle continues to loosen, the organisms penetrate further. To break this cycle, the foot must dry; antibiotics may be needed.

Total Dystrophic Onychomycosis. In this condition, the nail plate is virtually eradicated. If untreated, any of the four variants may proceed to this degree.

What Mimics Onychomycosis?

Toenail fungus may be confused with other nail dystrophies such as traumatic damage, psoriasis, senile ischemia, a tumor of the nail bed, peripheral vascular disease, atopic dermatitis, contact dermatitis, lichen planus, and yellow nail syndrome (i.e., discolored nails, lymphedema, lichen planus).[2,5] Hypoalbuminemia, cirrhosis, and striate leukonychia can induce whitening of the nails resembling a fungus.

Diagnosis

Treatment for onychomycosis should not be initiated solely based on visual examination, as the most common cause for apparent treatment failure is an incorrect diagnosis.[3] Other nail dystrophies resemble onychomycosis too closely to confirm the presence of fungi. Prior to initiating treatment, the podiatrist/physician may choose to rule out nonfungal causes by examining nail scrapings under a microscope.

Complications

Some patients and professionals see onychomycosis as an inconsequential cosmetic problem. However, because the nail supports and protects the toe and helps the foot work, onychomycosis can affect standing, walking, and exercising.[7] It can cause pain, paresthesia, and loss of dexterity, as well as morbidity interfering with work and school. Older men (especially those with diabetes or peripheral vascular disease) have an increased risk of cellulitis and limb loss.

Treatment Guidelines

Treatment of onychomycosis is often unsuccessful. Some therapeutic options require sufficient time for the nail to entirely regrow, which may take as long as 12 months for toenails.[3] Options include oral or topical medications. Although the patient may be satisfied only if the nail can return to a normal appearance, this may not be realistic, since patients may have a nail dystrophy that preceded the fungal pathology. Thus, eradication of fungi may only return the nail to the appearance it had with the original dystrophy.

First-Generation Oral Antifungals. For many years, onychomycosis therapy consisted of griseofulvin or ketoconazole. These first-generation antifungals were unreliable, with relapse rates of 70% to 85%; they required prolonged therapy (as long as 18 months); laboratory monitoring was essential to detect organ damage; and each had numerous adverse effects.[6,7]

Second-Generation Oral Antifungals. The two oral second-generation antifungals currently available in the U.S. are terbinafine and itraconazole. They are more effective than griseofulvin and can cure onychomycosis.[9] Both act by inhibiting ergosterol, a critical component of the fungal cell membrane.[3,6] Both remain in the nail long after they are no longer detectable in plasma, leading to the novel pulse therapy.

Terbinafine (Lamisil) inhibits squalene epoxidase, halting the conversion of squalene to squalene epoxide in the process used by fungi to create ergosterol, causing cell death (a fungicidal effect).[6,10] Squalene accumulation may also be fungicidal.[3] The adult dose for toenail infection is 250 mg orally daily for 12 weeks (six weeks for fingernails).[7] It may also be pulsed at 500 mg orally daily for one week each month for four months for toenails (or two months for fingernails). In most studies, terbinafine is of superior efficacy to continuous itraconazole therapy, with lower relapse rates.[3,6,11,12,13] Even then, failure rates with terbinafine are consistently as high as 20% to 30%.[3] Terbinafine is well tolerated by most patients, although urticaria, erythema multiforme, and hepatotoxicity have been reported.[14]

Itraconazole (Sporanox) inhibits cytochrome P-450, which also affects ergosterol synthesis, slowing cell growth as a fungistatic agent. The adult nonpulse dose for toenails is 200 mg orally daily for 12 weeks. The adult pulse dose for toenails is 200 mg orally twice daily for one week, followed by three treatment-free weeks, and repeated for three pulses.

In July/August 2001, the FDA warned consumers about oral antifungals in FDA Consumer.[15] The agency announced that oral Lamisil and Sporanox were linked to serious liver problems resulting in liver failure, the need for transplantation, and death. New labeling cautioned the consumer that health care professionals should confirm nail fungus through laboratory testing before prescribing the drugs. The FDA also described cardiac events related to drug interactions with Sporanox, announcing that new labeling would warn about the interactions and suggesting that Sporanox not be given to patients with evidence of cardiac dysfunction. The FDA encouraged patients and professionals to report adverse events associated with the drugs to the FDA MedWatch program (phone: 800-332-1088; fax: 800-332-1078; mail: MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857; Web address: www.fda.gov/medwatch).

Topical Antifungals. Ongoing uncertainty about safety of oral antifungals makes a topical agent attractive. A topical nail lacquer (Penlac) containing 8% ciclopirox is the first topical antifungal agent approved by the FDA for onychomycosis.[16,17] Its mechanism may involve chelation of iron and aluminum.[18] Fungal cells degrade intracellular peroxides through metal-dependent enzymatic reactions. When iron and aluminum are unavailable, a lethal accumulation of peroxides may result. In manufacturer-sponsored studies on patients with 20% to 65% involvement of the nail plate of the large toe, Penlac produced a clear nail and negative mycology in 5.5% to 8.5% of patients, and negative mycology alone in 29% to 36% of patients. It is indicated for mild to moderate T rubrum infections that do not involve the lunula. A professional should remove the unattached, infected nails as often as every month. The patient should not take oral antifungal medications concomitantly. Patients should apply Penlac evenly to the entire nail plate and 5 mm of surrounding skin. If the nail is free of the nail bed, the patient should attempt to apply Penlac underneath the nail. During the 48-week therapy, the patient should avoid nail polish and nail cosmetics. Once weekly, the patient should remove accumulated coatings with alcohol and file away loose nail material with an emery board and trim the nails periodically.

Pharmacists should advise all patients with toenail fungus to see a podiatrist or family physician for proper care.

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