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A Closer Look At Topicals For Tinea Pedis

Given the increasing prevalence of tinea pedis, this author discusses the various forms of the infection, reviews the current literature on topical antifungal therapy and offers perspective on the role of OTC topicals in the overall management of tinea pedis.    The incidence of mycotic infections in the United States continues to rise, especially among older patients.1,2 The overall prevalence of cutaneous fungal infections has been estimated to be between 10 and 20 percent of the United States population. This reportedly translates into approximately 29 to 59 million individuals who will experience at least one fungal infection in any given year.1    The literature suggests that up to 70 percent of the world’s population will experience a cutaneous mycotic infection at some point in their lives.3 Furthermore, 45 percent of those with tinea pedis will have recurrent episodes for more than 10 years.4    Tinea pedis, the most prevalent type of mycotic infection worldwide, is caused by a dermatophyte in more than 90 percent of patients.5 Dermatophytes are pathogenic fungi that produce keratinase, a proteolytic enzyme that breaks down skin, hair and nails by its action on keratin.4,6 The primary organism responsible for causing tinea pedis, both in the U.S. and worldwide, is Trichophyton rubrum.2,5,6 In a large, four-year surveillance study, researchers identified T. rubrum in up to 82.9 percent of isolates from tinea pedis infections.5    The most common form of tinea pedis is interdigital, which occurs in the web spaces between the toes. Interdigital tinea pedis is characterized clinically by maceration, scaling and itching of the skin. Chronic squamous or papulosquamous tinea presents with a moccasin distribution of dry thick scales and fissuring on the plantar surface. Vesicular tinea appears as small vesicles/bullae on the erythematous bases in the arch, interdigital spaces and other non–weightbearing surfaces. Finally, ulcerative tinea pedis is characterized by maceration, denuded tissue, desquamation and foul odor arising from the process of tissue breakdown.7    Effective management of tinea pedis is aided by patient education on the proper use of available treatment options, as well as proper foot care and hygiene. Topical therapies for tinea pedis are generally associated with fewer adverse effects than systemic antifungals. Therefore, topical therapy remains a first-line therapy for uncomplicated dermal dermatophyte infections.4    A number of topical preparations are now available worldwide over the counter (OTC), making it more convenient for patients to access the products. These available topical OTC preparations may also decrease the overall cost of treatment for some patients. Others may benefit from low prescription co-pays.    Although high fungal cure rates are achievable with topical therapy when patients use products as recommended, an important concern is that many patients stop applying the medication at the point of symptom improvement and do not continue using the product as directed on the label.1,4 Patients are more likely to complete a course of topical therapy that involves fewer applications (i.e., less frequent dosing and/or shorter total duration of therapy).    Completion of the full treatment course is one important factor in preventing recurrent infections. Other factors include the efficacy of the active ingredient against the infecting organism and the topical agent’s ability to prevent reinfection.

Emphasizing The Importance Of Timely Diagnosis

   Failure to recognize and fully eradicate a fungal infection early may lead to the development of a more severe, chronic and difficult to treat disease. In addition, it may lead to the spread of the infection to other sites of the body and/or other family members.1 Fungal infections that damage the stratum corneum can result in overgrowth of resident bacteria, leading to a more serious infection (i.e., dermatophytosis complex) characterized clinically by maceration, itching and a foul odor attributable to the antibacterial substances released by fungi. More importantly, the superinfecting bacteria are often resistant to penicillin or other antibiotics.8    The presence of tinea pedis is also highly correlated with the development of onychomycosis.9,10 In one large epidemiological study, the presence of either interdigital or moccasin forms of tinea pedis increased the risk of onychomycosis approximately fourfold.9 In turn, onychomycosis can serve as a reservoir for dermatophytes, which can re-infect the skin. The presence of tinea pedis and/or onychomycosis is also a significant risk factor for acute bacterial cellulitis of the leg as well as diabetes-related foot and leg complications in at-risk individuals.11-13    To diagnose tinea pedis accurately, a thorough clinical history and physical examination are important, especially for patients who come to the physician’s office after they have already tried several treatments. Topics to address in the patient history include: general medical conditions; previous occurrences/duration of the present foot condition; previous/current topical or systemic therapies utilized; the presence of other skin disorders; and occupational or environmental/recreational exposures.14    The clinician should consider differential diagnoses such as atopic or contact dermatitis, eczema, xerosis, psoriasis, Reiter’s syndrome, lichen planus or keratodermas.7 When one suspects tinea pedis, examining a simple potassium hydroxide stain under a light microscope can confirm the presence of dermatophytes. Fungal culture alone can rarely diagnose tinea pedis because the fungi require several weeks to grow and clinical expertise is necessary for the interpretation of the results.    If the diagnosis of a dermatophyte infection is still unclear after office testing or the infection fails to respond to therapy, one may need to submit biopsies with fungal staining (periodic acid-Schiff) to a pathologist for evaluation.15

Patient Education: How Physicians Can Facilitate Optimal Topical Use And Help Prevent Recurrence

   Dermatophytes are located in the stratum corneum, the most superficial layer of the epidermis. Accordingly, topical medications are the primary treatment option for tinea pedis. Many drugs that were formerly available only by prescription are now sold over-the-counter worldwide (see “A Pertinent Overview Of OTC And Prescription Topical Antifungals” to the right). This trend has likely had beneficial effects for patients in terms of convenience. When people use these OTC medications properly, they are as effective as when they are dispensed via prescription.    A patient with uncomplicated tinea pedis can typically recognize this condition and treat it adequately with an OTC product. However, it is important to emphasize that many patients who self-treat lack the benefit of a clinician’s confirmed diagnosis, instruction on proper medication usage and advice on optimal foot care practices.    For patients with recalcitrant and/or recurring tinea pedis that has been difficult to treat with OTC products, there are a number of management issues the podiatrist can address. One may need to consider alternative diagnoses. Diagnostic testing may be necessary to identify the pathogen correctly. If the podiatrist has confirmed the diagnosis of tinea pedis, he or she needs to assess whether the patient was using the OTC medication incorrectly. Examples include premature discontinuation before complete eradication of the fungal infection, skipped days or once-a-day use of a product that requires twice-daily dosing.    Podiatrists can also help their patients clear infections and experience lower rates of recurrence by instructing them on how to take care of their feet properly. Tips DPMs can emphasize with patients include:    • drying between the toes after bathing/showering (including tips for elderly patients who have difficulty reaching their feet);    • maintaining foot dryness through the use of foot powders;    • the importance of changing wet socks and shoes; and    • the best types of socks to wear (absorbent), etc.3,7    Furthermore, instruct patients to avoid going barefoot in public places and to use antifungal powder or spray in shoes at least once per week.16 Advise patients on the importance of discarding old footwear that may harbor fungal spores. Also emphasize wearing shoes of the correct size and fit in order to prevent trauma to nails and pedal skin. Patients should also look for and treat fungal infections elsewhere on the body. They should also encourage self-examination for any family members who may have tinea pedis and/or onychomycosis.1

Key Principles In Recommending Topical Antifungals

   In selecting and instructing patients on the use of topical antifungal agents, it is helpful to be aware of the difference between fungicidal and fungistatic treatments (as highlighted in “A Pertinent Overview Of OTC And Prescription Topical Antifungals” to the right).    Fungistatic agents such as azoles generally require longer treatment durations to eradicate the infection fully. The reason for this is that although azoles limit fungal growth, epidermal turnover is necessary to clear the infection completely.    Therefore, azoles typically require application at least twice a day for two to four weeks, a treatment period that extends considerably beyond the point of symptomatic control. If the patient stops using a fungistatic topical therapy too soon, the organism can simply start to grow again after the residual medication is out of the skin.4,17    Patients are tempted to stop therapy as soon as symptoms resolve. Therefore, the use of agents that cure the infection more quickly has the potential to improve patient adherence (via completion of an entire recommended course of drug treatment), decrease disease transmission to others and reduce the likelihood of relapse.17 Nonadherence to the recommended antifungal treatment regimen is widely recognized as a common cause of antifungal treatment failure.    Furthermore, incomplete treatment maintains an infective reservoir of dermatophytes within the skin, which can lead to relapse. Patients are more likely to adhere to a regimen of topical therapy for tinea pedis that has once-a-day rather than twice-a-day dosing. Once-a-day dosing is especially helpful in allowing patients to use the medication when it is most convenient for them, such as directly before bedtime when feet are uncovered and physical activity is minimal.    It is also important to identify the optimal formulation that best meets the patient’s needs. Since many OTC options are available, it can be difficult for people to sort through all the choices, yet specific preparations may be more appropriate in certain situations.    For example, sprays may be easier for elderly patients to use if they cannot easily reach their feet. Creams are ideal for patients with dry, cracked skin who need a moisturizing component as part of their antifungal therapy. Cooling gels may be preferable for patients particularly bothered by itching or for those with infection in the interdigital spaces where the alcohol base has a drying effect.    Emulsion gels have been available for decades as vehicles for the topical application of drugs. The main benefit of emulsion gels is patient convenience/comfort because some patients would prefer the cooling, rapid drying gel in comparison to a cream. Additionally, the alcohol component of the gel has recently been shown to further enhance drug penetration into the stratum corneum where dermatophytes are located.    The table “What You Should Know About OTC Antifungal Dosing” to the right summarizes the various formulations available for three of the most widely used brands of topical OTC antifungals. This table also includes the labeled dosing of each product for the treatment of either interdigital or whole foot tinea pedis, along with the total number of applications required for a full treatment course of each product. The table clearly demonstrates the greater number of applications required for fungistatic agents.

What The Literature Reveals About Topical Options For Tinea Pedis

   Clotrimazole (Lotrimin AF, Schering-Plough) and miconazole (Monistat, McNeil-PPC), two of the oldest topical antifungals, have for years been the most widely used topical agents for the treatment of uncomplicated tinea pedis.4 Both are effective, showing mycological cure rates similar to those of terbinafine (Lamisil, Novartis) in clinical studies. However, the azoles require four weeks of twice-daily therapy for sufficient treatment of tinea pedis (due to their fungistatic mechanism of action).18-20    In one study, treatment with miconazole 2% cream for four weeks resulted in mycological cure for 97 percent of patients at the end of a six-week study. This was similar to a cure rate of 95 percent for patients treated with terbinafine 1% cream for one week.18 In another six-week study comparing treatment with clotrimazole 1% for four weeks to treatment with terbinafine 1% for one week, cure rates were 84 percent and 97 percent for patients respectively.19    In clinical practice, the more significant issue with the use of imidazoles is convincing patients to complete the full four-week course of treatment. When patients used clotrimazole 1% for only one week for comparison purposes in a clinical study, the mycological cure rate was only 30 percent at the end of the study. This is in comparison to 68 percent for a four-week treatment with clotrimazole or 81 percent for a one-week treatment with terbinafine.18    Although it is not currently available OTC, ciclopirox (Loprox) is another widely used option for topical treatment of tinea pedis that is fungicidal against dermatophytes.21 It is available in generic form and has demonstrated good efficacy against a variety of dermatophytes.21-23 In a study using a 0.77% ciclopirox gel formulation, twice-daily treatment for four weeks resulted in an 85 percent mycological cure rate two weeks after treatment had been completed.22    Another popular topical agent currently available only by prescription is sertaconazole (Ertaczo, Ortho Dermatologics). Sertaconazole is noteworthy in that it is an imidazole agent with fungicidal activity against dermatophytes. It also has antibacterial, anti-inflammatory and antipruritic effects. Accordingly, this treatment option is particularly well suited for fungal infections that are accompanied by marked secondary bacterial colonization and/or symptoms of pruritus.1    An early efficacy trial comparing twice-daily treatment with sertaconazole 2% cream versus miconazole 2% cream reported negative culture test results at day 35 in 98.6 percent versus 91.7 percent of patients respectively.24 A more recent publication of two randomized, double-blind, vehicle-controlled studies reported that twice-daily treatment with sertaconazole for four weeks resulted in mycological cure in 70.3 percent of patients in comparison with 36.7 percent of vehicle-treated patients.25    Butenafine (Lotrimin Ultra, Schering-Plough) is a longer-acting OTC fungicidal agent that patients can apply once daily for four weeks (or twice daily for one week). In clinical studies, butenafine demonstrated a mycological cure rate of 83 to 88 percent when patients used it in a once-daily regimen for four weeks. The twice-daily/one-week butenafine regimen demonstrated a mycological cure rate of 43 percent by the end of treatment. This increased to 74 percent at the end of follow-up.26

Pertinent Insights On The Topical Use Of Terbinafine

   Terbinafine, which is available OTC, is an allylamine with fungicidal activity against dermatophytes. Patients can apply the gel formulation of this agent once daily for seven days. It is the shortest-acting treatment for tinea pedis available. Once-daily administration allows patients the convenience of applying the product just before bedtime.    Moreover, terbinafine has more potent fungicidal activity than many other available agents. In a study by Carillo-Muñoz and colleagues, the in vitro susceptibility of dermatophytes ranged from 94 percent for terbinafine to 87.6 percent for sertaconazole, 86.4 percent for clotrimazole and 73.3 percent for miconazole.27 Following one week of treatment with topical terbinafine, mycological cure rates at six to seven weeks after treatment cessation have been as high as 91 to 97 percent.28    Specifically, in a double-blind, placebo-controlled trial of terbinafine gel administered once-daily for five days, the mycological cure rate was 97 percent versus 22 percent for placebo. In a meta-analysis of 19 studies evaluating topical forms of terbinafine for the treatment of tinea pedis, efficacy was independent of formulation, treatment duration or frequency of application.29 A recent Cochrane review compared various topical treatments for fungal infections of the skin/nails of the foot.30 The review focused on placebo-controlled trials of allylamines and azoles for treatment of tinea pedis. The authors concluded that the most effective topical agent was terbinafine.30    The high efficacy of short courses of treatment with terbinafine is likely the result of a combination of the agent’s high fungicidal potency and its “reservoir effect” in the upper layers of the epidermis. This effect, referring to the accumulation of terbinafine in the stratum corneum, is a direct result of the drug’s high lipophilicity and keratophilic nature. Thus, the drug remains in therapeutic concentrations at the site of infection for several weeks after administration has been discontinued.28    Both the reservoir effect and the greater patient compliance associated with shorter treatment courses may contribute to lower relapse rates of tinea pedis seen with the use of terbinafine. A study comparing terbinafine and clotrimazole in the treatment of interdigital tinea pedis reported that, after a one-week course of terbinafine, relapse/re-infection by week 12 occurred in only 9.3 percent of “cured” patients. This was in contrast to the occurrence of relapse/re-infection in 30 percent of “cured” patients after a four-week course of clotrimazole and 47 percent of patients “cured” after a one-week course of clotrimazole.31    There is also a treatment option currently in development for tinea pedis that may further improve patient adherence and has efficacy equivalent to that of other terbinafine formulations. This is a single application formulation of terbinafine (Lamisil Once), which is not yet available in the U.S. This formulation is a cutaneous solution that the patient applies one time to both feet, covering the entire foot to ensure that even non-visible areas of infection are covered.    As with terbinafine gel, one can apply Lamisil Once directly before bedtime to maximize patient convenience. The ethanol in the solution quickly evaporates, leaving a barely visible film containing the active drug in high concentration (a film-forming solution). The drug stays on the surface of the skin for up to 72 hours and remains in the stratum corneum at fungicidal concentrations for up to 13 days. In a dose-finding study, terbinafine 1% film-forming solution was as effective as higher doses, with an 84.1 percent mycological cure rate six weeks after treatment application.32

In Summary

   Tinea pedis, a widespread problem with a high rate of recurrence, can be associated with serious consequences in at-risk individuals. While one can effectively treat uncomplicated tinea pedis with OTC topical antifungal agents, barriers still exist when it comes to an effective and complete cure.    These barriers include: patient adherence to treatment regimens; patient understanding of the need to finish the complete course of treatment (rather than stopping treatment when symptoms disappear); and proper foot hygiene to help prevent recurrences.    Management considerations for tinea pedis include proper diagnosis, patient education and the selection of therapy that best matches the needs of a particular patient. In general, fungicidal medications are more effective than fungistatic preparations in terms of eradicating an infection quickly and reducing the chance of relapse if a patient stops taking the medication too soon.    Patient adherence to proper treatment regimens is critical in treating this type of infection. Choosing a product that is easy for the patient to use (an agent that requires less frequent dosing and involves a practical duration of therapy) can make an important difference for many people. Dr. Joseph is a consultant in lower extremity infectious diseases and is a Fellow of the Infectious Diseases Society of America. He is affiliated with the Roxborough Memorial Hospital in Philadelphia and is an Attending Podiatrist at Coatesville Veterans Affairs Medical Center in Coatesville, Pa. Editor’s note: Editorial support for this article was provided by Novartis Consumer Health, Inc. The opinions expressed in the article are those of the author. Dr. Joseph received no honoraria or other form of financial support related to the development of this article. Dr. Joseph is a member of the Advisory Board for Pedinol Pharmacal, Inc. For further reading, see “Treating Fungal Infections,” a supplement to the March 2004 issue of Podiatry Today. To access the archives or get reprint information, visit www.podiatrytoday.com.
 

References:

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Warren S. Joseph, DPM, FIDSA
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