Step Up Your Approach to Fungal Infections

Fungi—yeasts, dermatophytes, molds—existed long before humans, and there's a chance they'll eventually out-live us. Coexistence is a necessity and not always a detriment, as any mushroom lover can attest. But when fungi invade the skin and nails, few people are willing to endure the situation for long. Thankfully, dermatologists have at their disposal numerous therapeutic approaches to eliminate fungal infestations and relieve associated symptoms. To optimize the clinical approach to fungal infections, specialists offer their recommendations and share clinical pearls below.

TOPICAL THERAPY POINTERS
Boni Elewski, MD, Vice-chair and Professor of Dermatology at University of Alabama, Birmingham, uses and advocates an individualized approach to topical therapeutic selection based on the presentation and the patient's specific needs and concerns. Start by considering the infective organism and choose an active agent with the necessary activity. Allylamines are active against dermatophytes, while ketoconazole targets yeasts (particularly Malassezia), and the imidazoles have broad action against mixed presentations (and perhaps some benefit in presentations that may have a bacterial component).

With an ideal agent identified, the next consideration is the vehicle. Dr. Elewski notes that gels are particularly useful for application to the nail, may be suited for application to the face, ears, or scalp, and could be used for the feet or axillae. Foams are ideal for application to hair-bearing areas and to the face and ears, but they can also be applied to other sites, such as the feet or axillae. Creams are best when some moisturization is desired, including for use on the feet, and may be used on the face or axillae, though they are not generally useful for the scalp or hair-bearing skin.

TINEAS
For dermatophyte infestations, an allylamine, such as naftifine or terbinafine, is generally indicated. "Naftifine is an excellent drug. Like terbinafine, it is fungicidal and has a broad spectrum of activity," Dr. Elewski observes. Naftifine in a gel formulation may be especially useful for application to the nail, Dr. Elewski suggests.

William Abramovits, MD, Professor of Dermatology at Baylor University Medical Center, prescribes naftifine gel for tinea pedis. "Although other allylamines have gone OTC and patients come having tried some—usually for insufficient periods to provide long-term benefits," he says an appropriate course of the topical prescription gel can be effective. The vehicle is well suited to application to the feet.

Another option for tineas is sertoconazole, which may be particularly beneficial for a mixed presentation—candida and dermatophytes—and even if there is erythrasma, Dr. Elewski suggests. The broad-spectrum antifungal may be used in a manner similar to a predecessor, econazole.

Although there aren't many US publications on sertoconazole, there are numerous international studies, including many in Europe, where the drug has been available for some time. "This is an old -azole with the properties of most of them and then some proven anti-inflammatory effects," Dr. Abramovits explains. "In spite of the advent of some allylamines and oxolamines with faster clearances in some indications, I still find it of use on some tineas."

Ketoconazole foam "may be also of value in T. pedis, as it goes dry instantly, making it comfortable to use between toes," Dr. Abramovits says. Although it may not be a first-line option, it is helpful in some cases, he notes.

In the case of tinea versicolor (or pityriasis versicolor), ketoconazole foam (Extina, Stiefel) is an attractive option because it permits easy application to larger body areas. "The foam is quick, clean, and easy," Dr. Elewski says. The versatility of a foam can be beneficial if there is more than one site of involvement—perhaps the abdomen and the scalp or the back and chest, as it is suitable for application to multiple body sites. This allows the patient to use one therapy and pay one co-pay, versus purchasing two or more different formulations, Dr. Elewski points out.

Dr. Abramovits also uses ketoconazole foam for "limited forms of tinea versicolor," as well as "for dermatitis of the inframammary folds of—usually elder—women with pendulous breasts; this may or not be colonized with Candida. Similarly for the infra-abdominal folds of both men and women with a pendulous abdomen over the pubic area." He notes that there may be better alternatives for these presentations, but urges clinicians not to overlook these possible uses for ketoconazole.

SEBORRHEIC DERMATITIS
There has been some interest in using topical calcineurin inhibitors (TCIs), particularly pimecrolimus, for the management of SD.^1,2 One recent study compared pimecrolimus cream 1% to ketoconazole cream 2% for the management of SD, finding comparable efficacy for the two agents.³ There was a higher incidence of side effects with pimecrolimus. Dr. Abramovits observes that combination therapy with a TCI and an antifungal would have the potential benefit of offering two different methods of action and urges further study.

Dr. Elewski sees a potential role for pimecrolimus in SD management (tacrolimus would probably work, as well, she notes, but the ointment vehicle in not conducive to facial application). She maintains that to address the underlying cause of SD, it's essential to target the fungus, and ketoconazole remains the first-line agent. "Sometimes that doesn't work alone. A course of ketoconazole is not going to clear seborrheic dermatitis in everyone; you need to have a back-up plan, " she says.

When SD is persistent, it could be time to add on a TCI or a low-potency corticosteroid, such as hydrocortisone or desonide. One benefit of a TCI is that it does not pose certain risks associated with corticosteroids, including rebound, cutaneous atrophy, thinning of the skin, and rosacea-like side effects. However, unlike the corticosteroids, there are no generic TCIs, thus treatment may be more costly. "Starting with the combination is a nice way to go," in some cases, Dr. Elewski says, "or you could add a topical steroid or pimecrolimus if necessary."

Severe SD may warrant oral therapy, suggests Boaz Amichai, MD, Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel, who recently studied the systemic treatment approach with a team of colleagues.⁴ "This treatment is advised only in severe cases of SD because of the potential systemic side effects of the medication," he says. "Only in severe cases, my recommendations are oral itraconazole, initially 200mg/day for a week, followed by a maintenance therapy of a single dose of 200mg every two weeks."

ONYCHOMYCOSIS
Terbinafine has been proven effective in the management of onychomycosis. Based on an analysis of data on available oral agents in which Dr. Elewski participated, it is a first line option for most patients with onychomycosis.⁵ It's "a great drug," Dr. Elewski acknowledges, pointing out that a 30-day supply of generic terbinafine costs just $10 or less through many prescription plans, making the typical three-month course of therapy an affordable $30. Ninety consecutive days of terbinafine therapy may not provide clearance in all cases, so longer courses may be indicated, Dr. Elewski says.

As with topical therapy selection, it is important to choose oral therapy with the patient's needs in mind. For example, Dr. Elewski says she recently saw an older patient with onychomycosis who was already taking seven pills each morning and six pills each evening for various other indications. Although there were no known interactions between terbinafine and any of the drugs he was already taking, the patient did not wish to add another daily pill to his regimen. He was willing, however, to take one extra pill per week, so Dr. Elewski prescribed fluconazole 200mg/week. She notes that this is an off-label indication for fluconazole. Studies confirm its efficacy.⁶

Changes in the nail, generally, and onychomycosis, specifically, may be associated with certain other medical conditions. Dr. Amichai and colleagues recently investigated nail changes in a cohort of 312 psoriasis patients, and found that 21.5 percent had experienced nail changes. Of these, 23 were related to onychomycosis.⁷ "Indeed, one of the major problems of psoriasis, especially on exposed body sites like face and hand or nails, is the cosmetic aspect that leads to psychological distress," he says. In psoriatic patients, Dr. Amichai summarizes, nail abnormalities may be due to:

1. Nail psoriasis.
2. Fungal infection.
3. Induced by systemic treatment. (Etretinate may cause paronychia. Methotrexate slows down nail growth and may alter the immune status and can aggravate onychomycosis.)
4. A combination of the first three factors.

"I think [the combination] is the most common," he says. "Unfortunately only biological treatments have been reported to be effective in the treatment of nail psoriasis, but this treatment is usually given to patients suffering from severe psoriasis," Dr. Amichai says, noting potential side effects and high costs. But biologics are not effective against onychomycosis.

"Since in most of the patients, nail abnormalities are due to combination of factors, combination of biological treatment and systemic antifungal treatment may lead to a temporary relief," he speculates. Due to the price of biological treatment and potential severe side effects of combination therapy, though, he says he's "not sure if this treatment is logical."

Onychomycosis in patients with diabetes is a particular concern that Dr. Elewski and colleagues recently addressed.⁸ Nail disease in diabetics poses particular challenges. For example, patients with diabetic neuropathy may not feel pain associated with onychomycosis. "Treat onychomycosis aggressively until cured," Dr. Elewski advises, suggesting extended courses of systemic therapy, if needed. It's best to implement treatment at the first sign of infection. Importantly, all patients with diabetes should be counseled on proper foot care, which can be useful not only to help prevent infections but also to identify infections as early as possible. "I try to keep the patient's feet in the most pristine health that we can," she says.

Finally, there is the issue of artificial nails. Amichai et al. confirmed onychomycosis in a significant proportion of patients presenting with paronychia following removal of artificial nails.⁹

Dr. Amichai summarizes the following concerns associated with artificial nails (ANs):

1. Onychomycosis.
2. Contact dermatitis, both irritant and allergic (clinical manifestations include onycholysis, paronychia, and hand eczema).
3. Several cases in which ANs were the accidental cause of foreign body in palate, larynx, and aspiration in patients have been reported.
4. Bacterial and fungal infections are the most common side effect with a severe potential hazard of infections transferred by health care personnel.

"Unfortunately, it is impossible to prevent fungal or baterial infection associated with ANs," Dr. Amichai says. "Only after removing the ANs, onychomycosis can be diagnosed." To minimize risk of transfer of bacterial and fungal infections, he says, health care personnel and workers in the food industry should avoid the use of ANs.

1. Tatlican S, Eren C, Oktay B, Eskioglu F, Durmazlar PK. Experience with repetitive use of pimecrolimus: Exploring the effective and safe use in the treatment of relapsing seborrheic dermatitis. J Dermatolog Treat. 2009 Jan 1:1-3
2. Cook BA, Warshaw EM.Role of topical calcineurin inhibitors in the treatment of seborrheic dermatitis: a review of pathophysiology, safety, and efficacy. Am J Clin Dermatol. 2009;10(2):103-18.
3. Koc E, Arca E, Kose O, Akar A. An open, randomized, prospective, comparative study of topical pimecrolimus 1% cream and topical ketoconazole 2% cream in the treatment of seborrheic dermatitis. J Dermatolog Treat. 2009;20(1):4-9.
4. Shemer A, Kaplan B, Nathansohn N, Grunwald MH, Amichai B, Trau H. Treatment of moderate to severe facial seborrheic dermatitis with itraconazole: an open non-comparative study. Isr Med Assoc J. 2008 Jun;10(6):417-8.
5. Elewski B, Tavakkol A. Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther Clin Risk Manag. 2005 Dec;1(4):299-306.
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7. Shemer A, Trau H, Davidovici B, Grunwald MH, Amichai B. Onychomycosis in psoriatic patients - rationalization of systemic treatment. Mycoses. 2009 May 29.
8. Cathcart S, Cantrell W, Elewski B.Onychomycosis and diabetes. J Eur Acad Dermatol Venereol. 2009 Mar 4.
9. Shemer A, Trau H, Davidovici B, Grunwald MH, Amichai B.Onycomycosis due to artificial nails. J Eur Acad Dermatol Venereol. 2008 Aug;22(8):998-1000.