I know....what in tarnation am I talking about? For those who don't know me personally, I am a registered drug dealer (AKA pharmacist) by trade. I gave up the retail rat race thirteen years ago after suffering in that environment for fourteen years. In my current role within a PBM (pharmacy benefit company), I still am required to keep my pharmacy license up. Which means thirty hours of continuing education every two years.
I thought I'd do something new with the blog. I have created
On the Mend entries before, but now wanted to bring to you first hand information on various topics that you might have interest in. Such as tinea pedis, commonly known as athlete’s foot. And if you have been hanging around locker rooms as long as I have...you probably have experienced a bout of this fungus among us.
If you like this concept, let me know. I'll continue to post if something of interest comes along. Or if you have a topic you'd like covered, I will track down the information....keeping your request anonymous. Oh, and by the way, I use Lotrimin for my little foot affliction.
Lotrimin AF Antifungal Cream for Athlete's Foot, .85-Ounce Tubes (Pack of 2)
Here we go.......
OVERVIEW OF TINEA PEDIS AND RELATED CONDITIONS
Prevalence
Between 10% and 20% of the world population is infected with a dermatophyte, a fungus that affects the skin and skin derivatives. Within their lifetime, up to 70% of adults will have tinea pedis, commonly known as athlete’s foot; it is the most common of all dermatophytic infections. Dermatophytes can infect many other skin surfaces and are usually classified by the affected body area; tinea means fungal infection of the skin. For example, tinea capitis means fungal infection of the scalp. Other possible sites of infection include the following: tinea unguium (onychomycosis, fungal nail infection), tinea cruris (ringworm of the groin), and tinea corporis (ringworm of the body and face). Between 1995 and 2004, there were over 750,000 outpatient medical visits with tinea pedis as the diagnosis code. It was the third most common dermatophyte diagnosis reported and comprised 18.8% of all diagnoses. However, this report does not include the patients who self‐treated their tinea pedis. Most of the patients were male (64.4%) and were 1.62 times more likely to be between 25 and 44 years of age.
Etiology
Dermatophytes are fungi that can invade and infect the upper layer of the skin, hair, or nails. They are not like pathogenic yeasts; they do not disseminate and they are not lethal. In the United States (U.S.), tinea pedis is most commonly caused by either Trichophyton rubrum or Trichophyton interdigitale. The organism Epidermophyton floccosum is another possible cause, but this occurs less frequently. All of these fungi are spread between humans and have been found on surfaces or items that commonly come in contact with bare feet (e.g., showers or baths, pool decks, locker rooms, shoes, bath towels, and socks).
Patients who wear occlusive shoes are more likely to develop tinea pedis. Occlusive footwear may increase perspiration and decrease aeration; this moist environment promotes fungal growth. There is little information in the literature describing why men are more commonly diagnosed with tinea pedis. One explanation is that women wear sandals and open‐toe shoes more frequently than men. Studies have shown that up to 70% of athletes are affected by tinea pedis. Athletes are at increased risk of exposure to foot trauma, communal showers, pool decks, and they wear closed footwear more frequently, which promotes sweating. Perspiration removes the protective antifungal surface lipids, softens the top layer of the dermis, and increases softening of the skin. Foot injury can compromise the skin’s barrier and increase infection risks, and communal showers and pool decks are commonly infected with dermatophytes. Swimming and running, compared with other sports, are associated with an increased incidence of tinea pedis.
Diagnosis
Tinea pedis can be subclinical and unnoticed by patients until it is diagnosed during a routine medical examination. The classic symptoms of tinea pedis are pruritus, peeling, and flaky skin. Symptomatic tinea pedis is divided into 3 categories: interdigital, moccasin‐distributed, and acute vesicular tinea pedis.
Interdigital tinea pedis, between the toes, is the most common location for a dermatophytic infection of the foot. Trichophyton rubrum, Trichophyton interdigitale, and Epidermophyton floccosum are frequently the pathogens. The space between the fourth and fifth (smallest) toes is the most common area, but it can also affect areas between any of the other toes.(Figure 1) The skin within the toe web may appear macerated and soggy or scaly with dry fissures. Patients may complain of mild‐to‐severe itching in the infected area(s). Deep fissures can be painful. It is common for the infection to spread to other parts of the foot. Bacterial superinfections of the organisms can develop, causing inflammation and foul odor.
Figure 1. Interdigital Tinea Pedis
Hyperkeratotic moccasin‐distributed tinea pedis occurs when a tinea affects the part of the foot covered by a moccasin‐style shoe (i.e., soles, heals, and sides). (Figure 2) The skin typically appears hyperkeratotic (darker), scaly, flaky, reddened, somewhat thickened, and the usual organism involved is Trichophyton rubrum. Patients usually complain of intense pruritus. Unfortunately, this type of tinea pedis responds to treatment slower than other forms of the condition.
Figure 2. Hyperkeratotic Moccasin‐Distributed Tinea Pedis
Acute vesicular tinea pedis, the least common type, typically erupts secondary to a more chronic web infection.(Figure 3) Vesicles rapidly develop on the sole of the foot, and they may rise to the surface, fuse into larger blisters, or remain under the surface of the sole. If vesicles rupture, they can be sites for secondary bacterial infection. Acute vesicular tinea pedis is seen more often in patients who wear occlusive shoes and is most often caused by Trichophyton interdigitale. The inflammation is usually severely pruritic.
Figure 3. Acute Vesicular Tinea Pedis
The clinical history and physical exam are critical for the diagnosis of tinea pedis. The diagnosis is confirmed by either microscopic examination or culture results. A scraping from the edge of the infected area is soaked and softened in 10% to 20% potassium hydroxide then examined under a microscope. Scrapings can also be sent for culture; however, test results take at least 2 weeks.
Related Conditions and Complications
Tinea unguium (onychomycosis, fungal nail infection) is often detected and recorded in codiagnosis with tinea pedis; in fact, onychomycosis may be the reason for recurrent tinea pedis. The risk factors for onychomycosis are as follows: increasing age, positive family history, history of nail trauma, diabetes, immunosuppression, smoking, and poor circulation. The most common cause of onychomycosis is Trichophyton rubrum, but Trichophyton interdigitale, Epidermaphyton floccosum, and Candida species have also been observed. Presentation differs depending upon the infecting agent. Typically the nail thickens and a white, yellow, or brown discoloration occurs. Occasionally, pitting and small fissures are present. Topical and oral antifungal ointments and creams may be used, but treatment is complicated by a long duration and a high recurrence rate. Debridement of the infected nail removes most of the invading fungi and will hasten clinical resolution. Patients should be informed that long‐term therapy is necessary and that, even with effective treatment, the nail may not be restored to its original appearance.
Patients with a tinea may occasionally develop an autoeczematization reaction (also known as an id reaction or a dermatophytid). The id reaction is an immunologic dermatologic response to various infectious and inflammatory cutaneous conditions. Although it is not only associated with a tinea, an autoeczematization reaction is more commonly associated with the acute vesicular type of tinea pedis than with the interdigitale or the moccasin‐type tinea pedis. The rash is typically generalized, diffuse, pruritic, and sterile. The exact prevalence of a dermatophytid is unknown; treatment of the underlying infection is critical and symptomatic therapy with systemic or topical steroids and/or antihistamines may also be indicated—the application of wet compresses may also be helpful. Another complication of tinea pedis is the transfer of this fungal infection to another body part. A common clinical scenario is 2 foot–1 hand syndrome. This occurs when patients scratch their tinea pedis and then the infection spreads to the hand. Trichophyton rubrum is the most common isolate identified in this syndrome. Untreated prolonged tinea pedis can create an environment for secondary bacterial infections. In one prospective case‐control study, the odds of tinea interdigitale were 3.72 times higher in patients with cellulitis than it was in case controls.
NONPHARMACOLOGICAL TREATMENT
Avoiding the conditions that promote fungal growth is the most important nonpharmacologic treatment; and keeping feet dry, as often as possible, is vital to achieving a cure. After activities during which the foot perspires, the patient must change their shoes and socks and wash their feet as soon as possible. Feet should be dried thoroughly, especially between the toes. Until the treatment course is over, patients should use a different towel to dry their feet to avoid spreading the infection to another body part; towels should not be shared with others. Additionally, shoes should be aired out and the insides should be dusted with antifungal powder or sprayed with antifungal agents. A study showed that wiping the insides with a wet towel and/or pouring cold or boiling water into sandals or sneakers reduced dermatophyte passage. In addition, wiping the insides of boots with a wet towel or rinsing with boiling water proved effective in reducing the transfer of fungus. Socks should be washed in hot water prior to being worn again. When using communal showers or bathrooms, patients should wear shower shoes to avoid direct contact with surfaces that may be infected with fungi. Nonocculsive footwear should be worn as often as possible; runners and other athletes should exercise in ventilated shoes. The majority of placebo‐controlled trials showed that placebo treatment has a failure rate of more than 65%. Given this information, it is obvious that antifungal drug therapy must accompany lifestyle modification.
There are numerous alternative medications and home remedies that patients may use to treat their athlete’s foot infection. Soaking in a solution of vinegar, baking soda, boric acid, or bleach are recommendations found on many layperson Web sites. Formulations with any of these substances would result in a pH that may be toxic to the organisms commonly causing tinea pedis. However, there are no published clinical studies of these products; therefore, there are no data documenting their safety and efficacy. In addition, the requirements indicating frequency of use or duration of therapy are also unknown. Tea tree oil and Solanum chrysotrichum are 2 herbal remedies that are frequently recommended for the treatment of tinea pedis. There is some evidence that a 50% topical solution of tea tree oil reduced symptoms in substantially more patients (64% versus 31%) and had a higher cure rate (72% versus 39%) than placebo.16 However, a meta‐analysis of all randomized trials involving tea tree oil suggests that it is ineffective for the treatment of dermatophyte infections. Topical Solanum chrysotrichum is a Mexican herbal medication that has been shown to have comparable efficacy to topical ketoconazole in a controlled, randomized, double‐blind study (N = 101). However, the safety, potency, and purity of available preparations cannot be guaranteed because these are not U.S. Food and Drug Administration (FDA)‐regulated products.
PHARMACOLOGICAL APPROACHES
Topical
Topical and systemic treatment for tinea pedis is common. Most clinicians will try a topical therapy initially, especially if the infection doesn’t appear to have invaded deep into the keratinous tissue. Deep‐seated infections will likely require a systemic therapy. Topical agents are generally effective, well‐tolerated, and relatively inexpensive.
Topical Azole Antifungals
These agents are fungistatic and are only fungicidal when used at very high concentrations. Azoles selectively interfere with the natural synthesis of ergosterol, a critical fungal sterol of the cell wall, and serve to prevent the growth and duplication of fungi. None of the topical azoles is significantly absorbed through the skin. All azoles are active against Trichophyton, Epidermophyton, and Microsporum species. Clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, and sulconazole are the azole antifungals that are currently approved by the FDA for the treatment of tinea pedis. Over‐the‐counter (OTC)‐brand extension is common with many of the antifungal agents. For example, Lotrimin® brand products can contain clotrimazole, butenafine, or miconazole. Therefore, it is important to recommend treatment according to the active ingredients rather than just the brand name.
Randomized, controlled trials have shown that all of the azole antifungal agents are superior to placebo for treating tinea pedis.9,19 One trial initiating the twice‐daily application of clotrimazole 1% cream, or solution, for 4 to 6 weeks reported cure rates between 56% and 86%.9 In another study, the once‐daily topical application of 1% econazole cream resulted in a culture and microscopic cure for approximately 73% of participants. In addition, ketoconazole 2% cream applied once‐or twice‐daily for 4 weeks demonstrated a cure rate between 77% and 87%. Similarly, 4 weeks of the twice‐daily application of miconazole 2% cured tinea pedis in 60% to 95% of subjects. Oxiconazole 1% applied once‐ or twice‐daily has been shown to cure tinea pedis in up to 76% of patients. Applying sertaconazole 2% cream twice‐daily for 4 weeks yielded cure rates between 46% and 66% in one study. In another study, 57% of patients treated with twice‐daily applications of sulconazole 1% cream were cured of tinea pedis. The results of a meta‐analysis suggested that there is little difference in efficacy rates among the various topical azoles; however, duration of therapy does improve outcomes. One week of treatment with a topical azole is inferior to 4 weeks of therapy. This may be because azoles are only fungistatic against dermatophytes and a longer duration of treatment is needed to completely eradicate the organism from layers of skin.
Allylamines and Benzylamine
Terbinafine and naftifine are allylamines, and butenafine is a benzylamine. The 2 classes have a similar mechanism of action and antifungal spectrum of activity. These drugs inhibit ergosterol synthesis and stop fungal growth and division. They are fungicidal to dermatophytes but only fungistatic to Candida. All 3 agents are active against the common organisms that cause tinea pedis. Terbinafine and butenafine topical formulations are available without a prescription, but topical naftifine requires a prescription; terbinafine is also available orally with a prescription. Systemic absorption of these agents after topical application is minimal. Data from 2 studies indicated that treatment with twice‐daily naftifine 1% gel resulted in fungal cure rates of 63% and 66% after 4 weeks. In another study, terbinafine 1% cured tinea pedis in 91% of participants after 7 days of treatment. When patients were treated with 1% butenafine cream, 91% of them experienced a cure from their tinea after 4 weeks of therapy.
A meta‐analysis of randomized, controlled trials found that there was no difference in the failure rates between the allylamines (terbinafine and naftifine) and butenafine. However, the same review found naftifine and terbinafine were generally more effective than azoles in direct comparison trials. In a double‐blind, randomized trial involving 193 participants, investigators compared the efficacy of terbinafine with that of clotrimazole, after both 1 and 4 weeks of treatment: 1 week of treatment with terbinafine cured 81% of patients, while 1 week of clotrimazole yielded a 30% cure rate; after 4 weeks of treatment, 85% of those using terbinafine were cured as compared with 68% of the participants randomized to treatment with clotrimazole. At the 18‐month follow‐up, participants from the terbinafine group had a lower rate of tinea pedis recurrence when compared with those from the clotrimazole group. Terbinafine’s higher efficacy after shorter courses of treatment may be a result of its fungicidal activity and its ability to accumulate in the upper layers of epidermis. Therapeutic concentrations of terbinafine have been observed in the stratum corneum for several weeks after application has been discontinued. Treatment with once‐daily or twice‐daily naftifine 1% cream was compared with treatment using twice‐daily clotrimazole 1% cream in a randomized trial: After 6 weeks of therapy, 81% of those treated with naftifine and 58% of participants using clotrimazole achieved a cure. There was no difference in effectiveness observed between once‐daily and twice‐daily naftifine therapy. In fact, therapy with naftifine 1% for 1 week was compared with treatment using a clotrimazole‐betamethasone formulation and resulted in a cure for tinea pedis at a rate of 33% and 24%, respectively. After 4 weeks of therapy for tinea pedis, the cure rate increased to 68% for naftifine and 50% for those using the clotrimazole‐betamethasone formulation. These data indicate that 4 weeks of naftifine therapy is an effective treatment for tinea pedis. Another study indicated that 1 week of treatment with butenafine 1% cream, applied twice‐daily, resolved tinea pedis in 43% of subjects, but 4 weeks of therapy cured 78% to 94% of participants.
Polyenes
Nystatin is not effective against dermatophytes and should not be used to treat tinea pedis.
Other Agents
Ciclopirox does not interfere with ergosterol synthesis; instead, it creates a large polyvalent complex by binding cations like Fe3+ and Al3+. These complexes inhibit important enzymes, like cytochromes, and interfere with mitochondrial electron transport and energy production. Ciclopirox also impairs the integrity of fungal cell membranes. Ciclopirox has broad‐spectrum activity against dermatophytes, Candida species, and various other fungi, including Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, and Aspergillus. It also has some activity against gram‐positive and gram‐negative bacteria, which may make it a good alternative for treating tinea pedis when a secondary bacterial infection is present. It is only used topically and is only available with a prescription. In a clinical trial, ciclopirox 0.77% cream cured a fungal infection in 85% of patients after 4 weeks of twice‐daily therapy.
Tolnaftate has been used to treat athlete’s foot for decades. Its exact mechanism of action is unknown; it is also believed to disrupt ergosterol synthesis, but by a different means than azole antifungals. Tolnaftate is effective against Trichophyton rubrum, Trichophyton interdigitale, and Epidermophyton floccosum, but it is ineffective against Candida. In one clinical trial, using tolnaftate 1% cream twice daily for 4 weeks cured 85% of patients treated. Undecylenic acid is another antifungal used to treat tinea pedis, and has been on the market longer than many other treatment options. It is available in various formulations and strengths ranging from 10% to 25%. The mechanism of action for undecylenic acid has not been detected and it has been shown to be more effective than placebo, but it demonstrates a relatively low cure rate.
ORAL ANTIFUNGAL AGENTS
Typically, athlete’s foot can be effectively treated with topical therapy; however, there are times when topical therapy may not be effective and treatment with an oral antifungal agent may be necessary. Many times hyperkeratotic tinea pedis will require oral therapy for a complete cure. Itraconazole, terbinafine, and fluconazole are not FDA‐approved for the treatment of athlete’s foot, but they are used for treatment of chronic tinea pedis typically after topical therapy has failed. Oral terbinafine, 125 mg administered every day for 4 weeks, cured 95% of participants with tinea pedis, according to one study. In another trial, patients were treated with terbinafine 250 mg/day for 1 week; in an 8‐week follow‐up they were evaluated for a full and clinical cure of their fungal infection. If their infection was not resolved, a second course of therapy was prescribed. The final cure rate was 89.3% and the percentages of patients requiring a second round of therapy differed according to the type of tinea, as follows: 20.9% of the patients with interdigital and 54.5% those with moccasin‐ distributed tinea required a second treatment. Treatment with traconazole, 400 mg administered once daily or 200 mg given twice daily for 1 week, resulted in clearance rates of 63% and 75%, as reported by 2 different studies. Treatment with itraconazole, 100 mg administered once daily for 4 weeks, cured tinea pedis in 75% of patients. Fluconazole, prescribed at 150 mg/week or 50 mg/day and until a cure is achieved or for up to 6 weeks, was administered to patients with tinea pedis. Investigators observed a 79% overall positive clinical response for patients administered fluconazole once weekly, and the success rate was 93% for those receiving treatment once daily. Griseofulvin is a traditional antifungal agent that has been used since the 1960s. Its exact mechanism of action is unknown, but it is thought to inhibit fungal cell mitosis and nucleic acid synthesis. This agent has fungistatic activity against Trichophyton species, Epidermophyton species, and Microsporum species. Griseofulvin is not as effective for the treatment of tinea pedis as the other oral antifungals.
STRATEGIES TO ENHANCE ADHERENCE
Education
Since many patients will have to make lifestyle modifications to prevent reinfection or relapse, it is important to understand the etiology and risk factors associated with tinea pedis. Take a moment to explain to each patient how the organism infects the foot and to describe the environments known to harbour dermatophytes (e.g., communal showers and baths, pool decks). Patients should be informed that the type of fungus causing this infection is not the same type of fungus that causes diaper rashes or vaginal yeast infections and, therefore, the treatment may not be the same. Keeping the foot dry is a critical preventive measure that should be strongly emphasized. Individuals, like those working in construction, who wear occlusive footwear and work in environments where perspiring is likely, should change socks frequently throughout the day. When at home, these individuals should wear open shoes. Athletes should adhere to these same recommendations, as well as consider the following: After playing sports, they should change their shoes as soon as possible; spray the inside of their footwear with antifungal agents; or sprinkle antifungal powder on the inside of footwear to reduce fungal transfer and to prevent reinfections. Shoes should be ventilated and fit properly; shoes that are too small may increase perspiration. Swimmers should make sure they wear shower shoes on deck and in bathrooms. Tinea pedis has also been known to infect other family members, especially if showers and baths are not disinfected between users; it is important to disinfect surface areas in shared rooms to avoid spreading the infection. If recurrence is a problem for 1 family member, the other household members should be examined for signs of an infection that may be presenting subclinically.
Feet infected with a dermatophyte should be washed at least once a day. Patients should dry the foot thoroughly, especially between the toes. For this process, it is a good idea to use a separate, clean towel for drying the feet to avoid spreading the infection to other parts of the body. In addition, it is important to tell teenage athletes not to share towels with others or to use a towel that is not their own, clean towel. Any towels or clothing that is in contact with infected areas should be washed in hot water and bed sheets should be washed in hot water every 2 to 3 days until the infection is cleared.
Since tinea pedis is often self‐diagnosed and self‐treated, many patients will use nonprescription products. Fortunately, there are many effective and safe topical agents available without a prescription. Patients should clean and thoroughly dry the infected area and then apply and massage the agent of choice into the infection, which includes the skin 1 to 2 inches beyond the border of the infected area. They should wash their hands after application. It is better to use a gel or powder formulation between toes because of the drying effects of these preparations. Terbinafine‐containing topical products should be applied for 1 week; all other topical products require at least 4 weeks of treatment. Not completing the course of therapy significantly reduces the efficacy and increases the occurrence of a relapse. Therefore, it’s essential to stress the need for adherence to the entire duration of therapy.
When recommending an agent for the treatment of athlete’s foot, efficacy, safety, and patient adherence are the most important factors to be considered. Topical terbinafine has been shown to be more effective than azole antifungals. The topical agents have minimal adverse effects, but patients should be instructed to report any worsening of rash or itching after application. Patient adherence is critical to the success of any antimicrobial therapy; nonadherence is the most common cause of treatment failure. Frequency of administration and duration of therapy are inversely correlated with adherence rates. Therefore, to increase the chances of treatment success, products with the fewest applications, the lowest frequency, and the shortest duration should be recommended.
Monitoring
Topical agents are generally well‐tolerated and they have minimal adverse effects. Local irritation, pruritus, and a rash may occur at the application site and contact dermatitis is possible. Patients should be instructed to seek additional medical care if the initial tinea pedis rash worsens or another type of rash develops.
Although oral antifungal agents are also generally safe, they are only available with a prescription, and they have contraindications that must be considered. Terbinafine has been reported to cause gastrointestinal upset, abnormal liver function tests, rashes, and taste disturbances. Typically, these events were mild and transient. Rare cases of liver failure have been reported after treatment with terbinafine, in patients with and those without liver disease prior to therapy initiation, and many of these patients reported severe comorbidities at baseline. Therefore, testing liver function is routinely recommended during therapy longer than 6 weeks. Terbinafine should not be used in patients with pre‐existing liver disease. Patients should be instructed to report any signs of liver disease (e.g., jaundice, upper‐right quadrant abdominal pain, dark urine).
Although rare, the most common adverse events resulting from itraconazole therapy are nausea, diarrhea, dyspepsia, and abdominal pain. Itraconazole has rarely been associated with liver failure, and will only require the monitoring of liver enzymes after therapy lasting longer than 1 month. It cannot be used for long‐term treatment in patients with heart failure. Additionally, it is a potent inhibitor of cytochrome P450 (CYP) and, be cautioned, coadministration is contraindicated with many agents (e.g., alprazolam, simvastatin, lovastatin, nisoldipine, cyclosporine). Fluconazole’s most common adverse events are nausea and vomiting. About 1% of patients studied experienced an unwanted increase, of more than 8 times the upper limits of normal, on their liver function tests. Patients should be instructed to report signs and symptoms of liver dysfunction.
Conclusion
Tinea pedis is a common dermatophytic infection of the foot that causes itchy, scaly, and peeling skin. Trichophyton rubrum, Trichophyton interdigitale, and Epidermophyton floccosum are the organisms that typically cause athlete’s foot. The most frequent site of infection is between the toes (interdigitale tinea pedis) but the soles and the sides of the foot can also be infected (moccasin‐distributed tinea pedis). Moccasin‐distributed tinea pedis is the most difficult type of tinea to treat and, often, requires oral therapy. Pruritic vesicles on the soles of the foot characterize the least common type of tinea pedis (acute vesicular). Topical therapy with nonprescription products containing azole antifungals, terbinafine, or butenafine is effective. Topical terbinafine has been shown to be more effective than topical azole antifungals and has the advantage of only requiring 1 week of therapy, while still exhibiting a comparable cure rate. Patient education is crucial to the success of therapy and lifestyle modifications are necessary because keeping the feet clean and dry will promote healing and prevent reinfection. Maintaining adherence to therapy is critical and completing the course of therapy is essential for a complete eradication of the organism, symptom resolution, and relapse prevention.
Gina J. Ryan PharmD, BCPS, CDE
Mercer University College of Pharmacy and Health Sciences
Atlanta, Georgia
Michael Cantrell, DPM
Instructor of Medicine
Emory University School of Medicine
