Chapter 219. Topical Antifungal Agents

Superficial fungal infections, including dermatophytoses, candidiasis, and pityriasis versicolor, are most often restricted to the epidermis. In treating these infections, the clinician must select between topical or systemic management. Factors guiding management include, but are not limited to, the:

• extent and severity of the infection,
• site of involvement,
• comorbid conditions or potential drug interactions, if any,
• anticipated efficacy of treatment,
• cost and access to medication, and
• ease of use.

Patients with limited fungal infections confined to glabrous skin are usually best treated with topical agents. Conversely, those with extensive or recalcitrant disease, or with involvement of terminal hair or nails, may be better suited for systemic management. In some cases, either treatment option may be reasonably chosen.

Treatment with topical antifungal therapy enjoys several advantages over systemic management, including:

• fewer side effects,
• fewer drug interactions,
• localization of treatment, and
• generally lower cost.

Numerous topical antifungal medications are available (Table 219-1). For the most part, specific antifungal agents have replaced nonspecific topical treatments, such as keratolytics (salicylic acid) or antiseptics (gentian violet or Castellani paint), which were once the cornerstones of management.

The “ideal” topical antifungal is easily defined (Table 219-2), and is in sum, efficacious, inexpensive, well tolerated, and has low resistance within targeted fungi. Despite widespread availability, few topical antifungal agents have been directly compared with one another in clinical trials. Studies sponsored by the manufacturer often compare just the active agent to the vehicle. Extrapolation between studies is further complicated due to differences in study design, duration of therapy, site of infection, selection methodology, or treatment endpoint.

Most topical antifungals belong to one of three classes: (1) imidazoles, (2) allylamines and benzylamines, and (3) polyenes. Agents that do not fit well into this schema are discussed separately.

Imidazoles represent a broad class of antifungal medications. Certain of these, such as clotrimazole, have been around for decades, while others, such as sertaconazole, have only become available recently.

Mechanism of Action

Imidazoles impede synthesis of a component of the fungal cell wall through inhibition of lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme, which converts lanosterol to ergosterol.1 Depletion of ergosterol results in membrane instability and hyperpermeability; changes incompatible with growth and survival of the fungus. Imidazoles are considered fungistatic in practical application, with the possible exception of sertaconazole when used to treat some Candida species.2 While all imidazoles possess the same mechanism of action, in-vitro studies demonstrate that not all dermatophytes are uniformly susceptible to an imidazole at an equivalent concentration, and this may explain some treatment failures.3–5

Topical imidazoles possess anti-inflammatory activity via inhibition of neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes and prostaglandins, and histamine release from mast cells.6–8 Some agents, such as ketoconazole, yield anti-inflammatory effects equivalent to 1% hydrocortisone.9 Topical imidazoles also demonstrate limited antibacterial properties, particularly with respect to Gram-positive organisms.10,11

Pharmacokinetics

All marketed imidazoles demonstrate excellent penetration of the stratum corneum with strong keratinophilic behavior. Sulconazole may be detected in the stratum corneum up to 96 hours after application.12 Similarly, sertaconazole, the newest of all marketed imidazoles, has a half-life within the stratum corneum of more than 60 hours.13 Because of this high affinity for keratin, systemic absorption of imidazoles is low, with urinary excretion usually in the range of 0.3%–1.0% of the applied dose. Even when applied to inflamed skin, absorption of imidazoles does not usually exceed 4% of the applied dose. Again, sulconazole is unique in that percutaneous absorption in the range of 8%–11% of the applied dose exceeds that of all other imidazoles.12

Indications

Indications for topical imidazole use are detailed in Table 219-3. Because of inherent antibacterial activity, some topical imidazoles have demonstrated modest efficacy in treating erythrasma, impetigo, and ecthyma. Because there are more potent antibacterial agents, this is not a preferred indication for imidazole use.9,14,15

Cure rates for superficial fungal infection treated with imidazoles are variable and often depend upon study design. For example, topical miconazole has demonstrated a 63%–100% cure rate, depending upon the study quoted. A thorough review of the literature provides no compelling evidence that significant differences in cure or relapse exist among the various topical imidazoles; however, other considerations may dictate selection of a particular imidazole.

Topical imidazoles are available as a cream or lotion. Although lotions are better suited for use over large areas or upon hair-bearing skin, limited studies suggest a cream may be marginally more effective. In studies performed by the manufacturer, oxiconazole cream yielded a clinical and mycologic cure in 52% of tinea pedis cases while the lotion yielded the same cure in just 41% of cases. Additionally, the potential for irritancy must be considered. In one study of topical clotrimazole for treatment of tinea cruris, erosive reactions developed in 4 of 27 patients while sulconazole did not cause any erosions in the same population.16 Similarly, in a second study, severe irritant reactions were reported with miconazole use but not with sulconazole use.17 Until formal studies of irritancy are performed, we often recommend use of sulconazole in sensitive areas such as the groin. Finally, ease of use may be a factor to consider, as some imidazoles are specifically approved for once-daily dosing (see Section “Dosing Regimen”).

Dosing Regimen

Topical imidazoles are available in a multitude of forms (see Table 219-1). Econazole, ketoconazole, and oxiconazole are approved for once-daily dosing but twice-daily dosing is recommended for the remainder. Nevertheless, although twice-daily dosing is recommended for sulconazole, a study comparing once-daily to twice-daily dosing in tinea corporis and tinea cruris reported an identical rate of cure.16 This might have been predicted based upon the 60-hour half-life within the stratum corneum.13 Application of all topical antifungals, including imidazoles, should include normal skin for a radius of 2 cm beyond the affected area. Duration of treatment with imidazoles has varied. In general, tinea corporis and tinea cruris require treatment for approximately 2 weeks, whereas tinea pedis may require treatment for up to 4 weeks.18 Treatment should be continued for at least 1 week after all symptoms have abated.19

Risks and Precautions

Risks associated with the use of topical imidazoles include those inherent to all topical medications (Table 219-4), and consist chiefly of irritant and allergic reactions. Additionally, clotrimazole is marketed in combination with the topical glucocorticoid, betamethasone dipropionate. It was assumed that the addition of the steroid would more rapidly relieve inflammation, scaling, and pruritus. Early studies demonstrated the combination was indeed more effective than clotrimazole alone in alleviating symptoms.20,21 However, betamethasone dipropionate is a potent topical steroid, and striae and other cutaneous side effects from the steroid component may occur.22 Longer term studies also reported a higher relapse rate (36%) with the combination product.23,24

This combination product may comprise 50% or more of antifungal prescriptions by primary care providers, compared to less than 7% among dermatologists.25 It is likely that overuse by nonspecialists occurs because of the mistaken assumption either that the steroid agent is mild, or that the combination will be a “better choice” when the differential diagnosis is unresolved.26 The US Food and Drug Administration has twice revised the product warnings for clotrimazole-betamethasone dipropionate, discouraging use on thin skin, for prolonged periods, or when the diagnosis is in doubt.

Complications

Use of topical imidazoles is associated with few complications. Because of low systemic absorption, drug reactions with topical imidazoles are rare. Nevertheless, in a single study, increased serum tacrolimus levels were observed in renal transplant recipients who used clotrimazole troches for mucocutaneous candidiasis.27 For this reason, use of nystatin may be preferred when treating thrush in transplant patients using tacrolimus.

Concerns of resistance must also be considered. Resistance of Candida albicans to clotrimazole has been described in human immunodeficiency virus-positive patients with mucocutaneous candidiasis.28 Low levels of in-vitro resistance of various Candida species to other topical imidazoles has also been documented.29 Often, this resistance is associated with resistance to oral fluconazole.

Allylamines and benzylamines are closely related compounds. Currently, two topical allylamines and single topical benzylamine are marketed in the United States (see Table 219-1).

Mechanism of Action

Allylamines and benzylamines share impede synthesis of ergosterol through inhibition of squalene epoxidase, an enzyme that converts squalene to squalene oxide.30 Depletion of ergosterol results in membrane instability and hyperpermeability. Allylamines and benzylamines are considered fungicidal because the accumulation of intracellular squalene leads directly to cell death. The clinical significance of this cidal action is unclear. Unlike imidazoles, the activity of allylamines and benzylamines is independent of the cytochrome P450 enzyme system. When compared to naftifine, terbinafine demonstrates a 10–100-fold increased potency in vitro, although this does not appear to be relevant in clinical use.

Like imidazoles, allylamines, and benzylamines demonstrate anti-inflammatory activity.6,31 Naftifine inhibits adhesion of polymorphonuclear cells to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase proinflammatory pathway.32,33 It is assumed that terbinafine and butenafine yield anti-inflammatory effects through similar mechanisms. Allylamines and benzylamines also demonstrate limited antibacterial properties. A recent study showed lowered minimum inhibitory concentrations for both bacteria and fungi when terbinafine was used in combination with benzoyl peroxide.34

Pharmacokinetics

Allylamines and benzylamines are highly lipid soluble and efficiently penetrate the stratum corneum, where they may persist for extended durations.35 Butenafine has been detected within the stratum corneum at minimum inhibitory concentration for at least 72 hours after application,36 and terbinafine may persist at a similar level for up to 7 days after application.37 Systemic absorption of these agents is quite low, with typical urinary excretion in the range of 3%–5% of the applied dose.37

Indications

Indications for the use of topical allylamines and topical benzylamines are detailed in Table 219-5. Despite antibacterial properties, terbinafine has proven inferior to mupirocin for treatment of impetigo,38 and a traditional antibacterial agent should be used. Similarly, although allylamines and benzylamines do demonstrate activity against fungi involved in systemic infection, such as Sporothrix schenckii, Blastomyces dermatitidis, and Histoplasmosis capsulatum, topical therapy is inappropriate.

Limited evidence suggests that topical allylamines or benzylamines may be preferred over topical imidazoles for certain dermatophyte infections. Some trials for tinea pedis indicate that 1 week of topical terbinafine is as effective as 4 weeks of topical imidazoles, with cure resulting in 53%–95% of cases.39–42 Use of this abbreviated treatment with terbinafine has been confirmed in trials using the active agent versus vehicle alone.43 In some instances, resolution of tinea pedis using terbinafine has occurred with as few as three doses.44

Generic terbinafine 1% cream is more expensive than an equivalent amount of clotrimazole 1%,45 but considering the frequency of application, the amount of medication required, the likelihood of patient compliance and ease of use, and the rapidity of results, some experts recommend topical terbinafine over topical imidazoles for tinea pedis.46–48

Dosing Regimen

Topical allylamines and benzylamines are available in a number of forms (see Table 219-1). Each agent has a slightly different dosing regimen based upon the formulation and the location and severity of infection (Table 219-6).

Risks and Precautions

Risks associated with use of topical allylamines and benzylamines are those inherent to all topical medicaments (see Table 219-4).

Complications

A recent case report highlighted a possible interaction between topical terbinafine and acenocoumarol, and speculated this might be due to high protein binding of terbinafine, with displacement of the anticoagulant,49 but this is likely exceptional; complications arising from use of topical allylamines or benzylamines are few.

Polyenes were among the first agents discovered to possess specific antifungal properties. The two major topical polyene antifungals are nystatin and amphotericin B. Only topical nystatin is actively marketed in the United States (see Table 219-1).

Mechanism of Action

Like all polyenes, nystatin binds irreversibly to membrane sterols present in susceptible species of Candida.50 The polyene molecules demonstrate a higher affinity for fungal sterols, including ergosterol, than for human sterols, yielding imperfect selective toxicity. This irreversible binding alters membrane permeability, causing leakage of essential intracellular components and fungal death. In low concentrations, nystatin is fungistatic, but, at high concentrations, it may be fungicidal.51

Pharmacokinetics

Nystatin is insoluble in water and is not absorbed from intact skin, the gastrointestinal tract, or the vagina.52

Indications

Topical nystatin is used to treat mucocutaneous candidiasis caused by C. albicans, and other susceptible species such as C. parapsilosis, C. krusei, and C. tropicalis. Repeated studies have demonstrated that topical imidazoles are more effective than nystatin in treating vulvovaginal candidiasis, and use of nystatin for this indication has diminished in recent years.53,54 Nystatin is not effective against dermatophytes or Pityrosporum; and hence, it is not indicated for treatment of tinea or pityriasis versicolor.

Dosing Regimen

Nystatin is available as a powder, cream, ointment, suspension, and pastille. To treat oral candidiasis (thrush), the suspension or pastille is used four to five times daily, usually for 2 weeks. To treat cutaneous infection, the powder, cream, and ointment are used twice daily for approximately 2 weeks.

Risks and Precautions

Risks associated with use of topical nystatin are those inherent to all topical medicaments (see Table 219-4). A significant number of cases of allergic contact dermatitis attributed to nystatin alone have been reported. These reactions have been reported with topical and oral use.55,56 Anaphylaxis has been described with use of nystatin-containing vaginal suppositories but the reaction was attributed to ingredients other than nystatin.57

A combination agent consisting of nystatin and triamcinolone acetonide is widely marketed. The addition of triamcinolone may provide additional benefit over nystatin alone during the first few days of treatment when inflammation is maximal.58 After this initial period, the manufacturer recommends a transition to nystatin alone or to other topical antifungal agents. Although triamcinolone acetonide is only a midpotency agent, cutaneous sequelae, including striae, skin atrophy, and steroid-induced acne, have been reported.59 Because candidiasis often involves thin and fragile skin, such as that of the intertriginous areas, the risk of damage is likely potentiated. Finally, many of the combined formulations contained, or may still contain, ethylenediamine, a sensitizer that may cause allergic contact dermatitis.60 As with clotrimazole-betamethasone dipropionate, the combination agent of nystatintriamcinolone acetonide is more often prescribed by nondermatologists.

Complications

Complications with topical polyenes are few. Nystatin resistance may be encountered in some Candida sp.61,62 This resistance may either be seen in wild strains (primary type) or it may be induced during therapy (secondary type). Although C. albicans maintains a low rate of spontaneous resistance to nystatin,63 particularly in comparison to resistance to imidazoles,64 other species, such as C. tropicalis, C. guilliermondi, C. krusei, and C. stellatoides, rapidly acquire resistance upon exposure to nystatin.

Some topical antifungals, such as ciclopirox olamine, tolnaftate, and undecylenic acid, do not fit well into the major classes and are instead discussed separately.

Ciclopirox Olamine

Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique structure and mode of action.

Mechanism of Action

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.

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

Pharmacokinetics

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

Indications

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

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.

Dosing Regimen

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.

Risks and Precautions

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.

Complications

Serious complications with topical ciclopirox olamine are few.

Older Agents

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.

Tolnaftate

Tolnaftate is a thiocarbamate first developed in the 1960s but now contained only in over-the-counter antifungal remedies.

Mechanism of Action

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.

Pharmacokinetics

Little data exists regarding the pharmacokinetics of tolnaftate. Like other topical antifungals, systemic absorption is assumed to be negligible from a clinical standpoint.

Indications

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.

Dosing Regimen

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.

Risks and Precautions

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

Complications

Serious complications with use of topical tolnaftate are few.

Undecylenic Acid

Mechanism of Action

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

Pharmacokinetics

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.

Indications

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.

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

Dosing Regimen

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.

Risks and Precautions

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.

Complications

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.

Amorolfine is a morpholine derivative unapproved for use in the United States. Elsewhere in the world, it is approved for use as a 5% nail lacquer. Amorolfine is fungicidal against most dermatophytes, yeasts, and some molds. With 6 months of biweekly use, amorolfine 5% nail lacquer resulted in complete cure in up to 54% of patients.91 Side effects were similar to those of ciclopirox nail lacquer. Also, similar to ciclopirox olamine, a recent study using amorolfine lacquer and oral terbinafine in combination resulted in a significantly higher cure rate and lower cost per patient cured.92 In the future, approval of amorolfine in the United States may be pursued.

Benzoxaboroles, derivatives of boronic acid, represent a burgeoning new class of topical antifungal agents. The most explored of these compounds, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), inhibits an aminoacyl–transfer RNA (tRNA) synthetase that catalyzes attachment of the correct amino acid to corresponding tRNA during translation of the genetic code, blocking protein synthesis.93 The active agent penetrated well the nail plate when applied in an ethanol/propylene glycol vehicle, leading to considered use in onychomycosis.94 Future discovery with regard to this new class of antifungal agents is anticipated.

Because of relatively low cost, acceptable efficacy, ease of use, and low potential for side effects, complications, or drug interactions, topical antifungals are preferred for most superficial fungal infections of limited extent. Alternatively, use of a systemic agent is justified when a superficial fungal infection covers a large surface area, involves terminal hair or nails, or has proven recalcitrant to prior topical management. Imidazoles provide a reasonable balance of efficacy and affordability and are indicated for treatment of dermatophytoses, mucocutaneous candidiasis, and pityriasis versicolor. Despite higher cost, allylamines and benzylamines may be advantageous in some cases of tinea pedis, due to shorter treatment courses. Ciclopirox olamine is a topical antifungal with a unique mechanism of action and a broad range of indications. Topical nystatin is useful in treating mucocutaneous candidiasis, but is ineffective for dermatophyte infections. Use of tolnaftate and undecylenic acid is decreasing due to lower efficacy compared with other available agents. New topical agents for treatment of onychomycosis are being pursued.