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Some topical antifungals, such as ciclopirox olamine, tolnaftate, and undecylenic acid, do not fit well into the major classes and are instead discussed separately.
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Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique structure and mode of action.
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Unlike most other topical antifungals, ciclopirox olamine does not interfere with sterol synthesis.65 Instead, it interrupts active membrane transport of essential cellular precursors, particularly trivalent cations.66 Ultimately, this disrupts cellular function, leading to demise of the fungus. If concentrations of the drug are high enough, the membrane integrity of the fungus may actually be impaired.
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Ciclopirox olamine also has inherent anti-inflammatory activity exerted through inhibition of prostaglandin and leukotriene synthesis within polymorphonuclear cells.67 Broad-spectrum antibacterial properties have also been attributed to ciclopirox olamine. In one study, topical ciclopirox olamine had broader coverage against Gram-positive and Gram-negative organisms than did topical imidazoles or topical allylamines.68
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When applied to the skin, ciclopirox olamine remains in high concentration within the epidermis and upper dermis. Ciclopirox olamine penetrates keratin easily, with cadaveric skin demonstrating concentrations in the epidermis that were 10–15 times the minimum inhibitory concentration for a sensitive species.67 This ability to penetrate keratin recommends use for onychomycosis, as the drug is also capable of penetrating the nail plate material.69 Studies of drug metabolism have demonstrated that, with typical use, approximately 10% of the administered dose is excreted in the urine.70
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Ciclopirox olamine is indicated for the treatment of dermatophytoses and onychomycosis, candidiasis, pityriasis versicolor, seborrheic dermatitis, and even cutaneous infections with unusual saprophytes.71 In tinea pedis, a mycologic cure rate of up to 85% has been observed, and in seborrheic dermatitis, a significantly larger percentage of users had >75% improvement with 2 weeks of use than those using the shampoo vehicle alone.72,73
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Although treatment with ciclopirox olamine for tinea pedis and seborrheic dermatitis has yielded results on par with other modalities, use in onychomycosis has met with more modest success. Often, an assessment of efficacy depends upon whether a mycologic cure (culture-negative) or clinical cure (a disease-free nail) defines success.74 Although a disease-free nail is often the patient's true goal, ciclopirox olamine achieved such a response in just 5.5%–8.5% of those treated with a standard 48-week course.74,75 Two recent trials demonstrated increased efficacy when using oral terbinafine in combination with topical ciclopirox olamine, as opposed to oral terbinafine alone.76,77 Debate regarding the use of ciclopirox olamine as an independent or adjunct treatment for onychomycosis is ongoing.
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Ciclopirox olamine is available in a wide range of forms (see Table 219-1). Cutaneous candidiasis, dermatophytoses, and pityriasis versicolor should be treated twice daily for 2 weeks to 1 month, but treatment for tinea pedis should continue 1 month or longer. When using ciclopirox shampoo for seborrheic dermatitis, treatment may continue twice weekly for an indefinite duration. Improvement is generally noted in 2–4 weeks. Finally, in treating onychomycosis, the nail lacquer is applied daily to the nail and hyponychium for 48 weeks and excess medication is removed weekly with alcohol.
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Risks and Precautions
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Risks associated with use of topical ciclopirox olamine are those inherent to all topical medicaments (see Table 219-4). Allergic contact dermatitis has been reported only rarely, and ciclopirox olamine is considered a weak sensitizer.78 In patients with an allergic reaction to ciclopirox, imidazoles may be used with relative safety because of a markedly different chemical structure.
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Serious complications with topical ciclopirox olamine are few.
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Tolnaftate and undecylenic acid are older agents now available only in over-the-counter products (see Table 219-1). Repeated studies have now demonstrated that they are approximately equal in efficacy,79,80 and that both are less efficacious than topical imidazoles, allylamines, benzylamines, and ciclopirox olamine. Additionally, tolnaftate is ineffective for treating candidiasis. Topical tolnaftate and topical undecylenic acid share the same risks and precautions inherent to all topical medications (see Table 219-4). Additionally, topical forms of undecylenic acid may yield an unpleasant “fishy smell” that further discourages use. Both agents are considered less efficacious than imidazoles.
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Tolnaftate is a thiocarbamate first developed in the 1960s but now contained only in over-the-counter antifungal remedies.
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The precise mechanism of action for tolnaftate is unknown. It is thought to impair ergosterol synthesis via inhibition of squalene epoxidase but in a different manner than that of allylamines and benzylamines.80 Tolnaftate may be fungistatic or fungicidal, depending upon the concentration. No antibacterial properties have been attributed to tolnaftate.
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Little data exists regarding the pharmacokinetics of tolnaftate. Like other topical antifungals, systemic absorption is assumed to be negligible from a clinical standpoint.
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Tolnaftate is indicated for the treatment of dermatophytosis and pityriasis versicolor. Early studies demonstrated a cure rate for tinea pedis as high as 73 percent to 93 percent, but later studies demonstrated lower efficacy, essentially equivalent to undecylenic acid.77,81 Although direct comparisons are lacking, topical tolnaftate is widely considered less effective than topical imidazoles, allylamines, and benzylamines. Tolnaftate is ineffective for candidiasis.
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Tolnaftate is available in a variety formulations (see Table 219-1). Twice-daily use for at least 2 to 4 weeks, and up to 6 weeks on hyperkeratotic skin, is recommended. To diminish the incidence of recurrence, others simply recommend treatment be continued 2 weeks beyond apparent resolution.
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Risks and Precautions
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Risks associated with use of topical tolnaftate are those inherent to all topical medicaments (see Table 219-3). Allergic contact dermatitis has been reported on occasion.82,83
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Serious complications with use of topical tolnaftate are few.
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Despite more than 60 years of use, the mechanism of action for undecylenic acid is largely unknown. It appears that the organic acid interacts with components in the fungal cell wall. In C. albicans, the inhibition of germ tube formation has been recently identified, and a similar effect has been noted in conidia formation in Trichophyton rubrum.84,85
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Undecylenic acid is available as a zinc, calcium, or copper salt. As tissue pH rises, this salt fails to dissociate, and the antifungal properties of the medication diminish.86 The acid is practically insoluble in water, but is miscible in ethanol, water, or ether. With topical use, systemic absorption is negligible. The zinc contained in the zinc undecylenate form, the most common in clinical use, provides some astringent action that may aid in reducing rawness and irritation.
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Topical undecylenic acid is used for the treatment of dermatophytosis and candidiasis. Although early studies indicated a cure rate in excess of 80 percent, subsequent studies demonstrated cure rates of 53 percent or less.87 Undecylenic acid and its salts are widely considered less effective than miconazole, clotrimazole, or tolnaftate in the treatment of tinea pedis.
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A trial of topical undecylenic acid for herpes labialis demonstrated a decreased incidence and duration of viral shedding, with a decrease in pain and tenderness.88 The antiviral effect was of short duration and most pronounced when acid was applied during the prodrome. Other long chain alcohols enjoy specific approval for abbreviation of herpes labialis and appear more effective.89
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Undecylenic acid and its salts are available as a powder, aerosol, cream, and solution. Standard dosing for children and adults is twice-daily for 4 weeks of use.
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Risks and Precautions
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Risks associated with use of topical undecylenic acid are those inherent to all topical medicaments (see Table 219-3). Allergic contact dermatitis has been recently reported, and a protocol for patch testing exists if such an allergy is suspected.90 Topical forms of undecylenic acid may yield an unpleasant “fishy smell” that discourages use.
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Complications with topical undecylenic acid are few. Because undecylenic acid is widely accepted to be less effective than imidazoles, clinical monitoring for treatment failure is indicated.