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Topical Antifungal Agents


Questions

  • Q42.1 What are primary examples of topical antifungal agents from the following categories: (1) polyenes, (2) azoles, (3) allylamines, (4) benzylamines, and (5) hydroxypyridones? (Pg. 480, Table 42.1 )

  • Q42.2 Although azole and allylamine antifungals both block ergosterol synthesis, how do they differ in their mechanism of action? (Pgs. 481, 486, Table 42.2 )

  • Q42.3 How does tavaborole differ from other antifungals in its mechanism of action? (Pg. 486, Table 42.2 )

  • Q42.4 What is the mechanism of action for ciclopirox olamine as an antifungal agent? (Pg. 487)

  • Q42.5 How do terbinafine and naftifine compare in dermatophyte activity in vitro? (Pg. 488x2)

  • Q42.6 Which group of antifungal agents demonstrates the most potent in vitro and clinical activity against dermatophytes? (Pg. 489)

  • Q42.7 Based on in vitro and clinical data, are the azole antifungals or the allylamine antifungals more efficacious for cutaneous candidiasis? (Pg. 490x2)

  • Q42.8 Which class of topical antifungal agents possesses the most potent anti-inflammatory activity? (Pg. 490)

  • Q42.9 Which class of topical antifungal agents has the most significant and most varied antibacterial activity? (Pg. 491)

  • Q42.10 What are the pros and cons of treating vulvovaginal candidiasis during pregnancy with topical azole products? (Pg. 491)

Abbreviations used in this chapter

AE

Adverse effect/event

HETE

Hydroxyeicosatetraenoic (acid)

KOH

Potassium Hydroxide

MFC

Minimum fungicidal concentration

MIC

Minimum inhibitory concentration

PMN

Polymorphonuclear neutrophil

UVB

Ultraviolet B

Acknowledgment

The authors would like to acknowledge Dr. Rhea M. Phillips and Dr. Theodore Rosen for their contributions to the previous edition of this chapter.

Introduction

Fungal infections are among the most common diseases of the skin and, taken all together, are second only to acne as the most common condition prompting dermatologic care. Topical antifungals ( Fig. 42.1 ) are generally considered first-line therapy for uncomplicated, superficial dermatomycoses owing to their high efficacy and low potential for systemic adverse effects (AE).

Fig. 42.1, Chemical structure of topical antifungal agents (naftifine, terbinafine, tavaborole, miconazole, efinaconazole).

In the 1830s, Robert Remak and Johann Schonlein first identified fungi as the etiologic agent of human dermatomycoses and revealed the infectious nature of these microorganisms. David Gruby and Raimond Sabouraud, two influential mycologists, later published extensive research on the clinical, microscopic, and culture techniques relating to fungi that cause human disease. These developments marked the beginning of scientific medical mycology. Effective therapies for human dermatomycoses were slow to evolve, and it was not until 100 years after Remak and Schonlein’s initial findings that the first treatments demonstrating specific antimycotic actions were developed.

World War II marked a pivotal point in the development of antifungal medications. Before the 1940s, antifungal therapy was limited to Castellini’s paint, Whitfield’s ointment, and Gentian violet. These nonspecific agents were generally irritating, staining, and minimally effective. The explosive increase in fungal infections, and recurring treatment failures during World War II, led to a more aggressive search for improved therapeutic measures and prompted the development of new training facilities, research institutions, and federal agencies specializing in medical mycology.

There are now multiple modern topical antifungal agents capable of achieving clinical and mycologic eradication of human dermatomycoses. Q42.1 The most commonly employed topical antifungal agents belong to three main classes: (1) polyenes, (2) azoles, and (3) allylamines/benzylamines. Other topical antifungal agents, not among these major drug classes, include the hydroxypyridone antifungal agent ciclopirox olamine, the oxaborole antifungal tavaborole, and selenium sulfide ( Table 42.1 ). Properties of these various classes are summarized in Table 42.2 .

Table 42.1
Topical Antifungal Agents
Generic Name Trade Name Manufacturer Generic Cream Ointment Special Formulations PPS
Polyenes
Nystatin Mycostatin, Nilstat, Various Yes Cream a Yes a Powder, suspension B
Nystop, others
Amphotericin B Fungizone Bristol-Myers Squibb Yes No No Oral suspension 100 mg/mL (Also IV) B
Azoles
Miconazole Monistat-Derm, Micatin Ortho Yes 2% cream Yes Spray, powder, solution, gel (also IV) B
Clotrimazole Lotrimin Schering-Plough Yes 1% cream No 1% solution/lotion B
Oral troches (Mycelex)
Ketoconazole Nizoral McNeill Yes 2% cream No 1%, b 2% shampoos (also oral) B
Oxiconazole Oxistat Glaxo Wellcome Yes 1% cream No 1% lotion B
Econazole Spectazole
Ecoza		 Ortho
Chemo Research SL		 Yes
No		 1% cream No 1% foam C
Sulconazole Exelderm Journey Yes 1% cream No 1% solution B
Sertaconazole Ertaczo Bausch Health Yes 2% cream No None C
Luliconazole Luzu Medicis Yes 1% cream No None C
Efinaconazole Jublia Bausch Health Yes No No 10% solution C
Allylamines and Benzylamines
Naftifine Naftin Sebelus Yes 2% cream No 1% cream, 1%, 2% gel B
Terbinafine Lamisil AT Novartis Yes 1% cream No 1% spray (Also oral) B
Butenafine c Mentax Bertek Yes 1% cream No None B
Other Antifungal Agents
Ciclopirox Loprox Medicis Yes 0.77% cream No 0.77% gel, 1% shampoo, 8% solution B
Selenium sulfide Selsun, Exsel, others Allergan, Ross Yes No No 1%, 2.5% lotion, shampoos C
Tavaborole Kerydin Sandoz No No No 5% solution C
IV, Intravenous; PPS, pregnancy prescribing status—US Food and Drug Administration.
See Chapter 65 for newer ‘Pregnancy Summary Rating’ for most topical antifungals.

a Not expressed as a percentage; 100,000 United States Pharmacopeia (USP) units/g.

b Over-the-counter (OTC) strength for ketoconazole products.

c Butenafine is a benzylamine.

Table 42.2
In Vitro and in Vivo Activity of Common Antifungal Agents
Class Drug Name Mechanism of Action Organisms Treated
Polyene antibiotics Nystatin Binds to cell membrane sterols causing cell leakage and permeability changes Yeast ( Candida )
Azoles Miconazole Inhibits ergosterol synthesis blocking 14α-demethylation of lanosterol Dermatophytes, Malassezia furfur, Candida
Clotrimazole
Ketoconazole
Econazole
Oxiconazole
Sulconazole
Azoles (subset) Luliconazole
Efinaconazole		 Same as azoles above Dermatophytes, Candida a
Allylamines Naftifine Inhibits ergosterol synthesis by blocking action of squalene epoxidase Dermatophytes (both drugs)
Terbinafine Candida b (only terbinafine)
Benzylamines Butenafine Same as allylamines above Dermatophytes, Candida b
Oxaborole Tavaborole Inhibits protein synthesis by binding to leucyl-tRNA synthetase Dermatophytes, Candida

a Activity against Candida species is relatively weak compared with the other azole antifungal agents.

b Activity against Candida species is relatively weak compared with the azole antifungal agents.

Polyenes

Developed in the late 1950s, polyene antifungal agents were the first agents to have specific antifungal properties. Polyene antifungals are characterized by a macrolide ring of carbon atoms containing a number of conjugated double bonds (C=C–C=C), hence the name polyene . The polyene macrolide ring is closed by an internal ester or lactose. The two clinically significant and readily available polyenes are nystatin and amphotericin B. Only nystatin is covered in this chapter.

Nystatin

Nystatin (Mycostatin, Mytrex, Nystop) was the first specific antimycotic to become available for human use and was discovered in 1949 by Hazen and Brown in the New York State Health Laboratory, hence the name, nystatin .

Pharmacology

Nystatin is a polyene antibiotic produced by Streptomyces noursei and Streptomyces albidus . It is a tetraene antibiotic with both a conjugated diene and a conjugated tetraene moiety in the molecule. It also contains a sugar moiety, mycosamine, as part of its composition. It has a structure and mode of action similar to that of amphotericin B but associated systemic toxicity has limited nystatin’s use to topical applications. Nystatin is essentially insoluble in water and not absorbed from intact skin, the gastrointestinal tract, or the vagina.

Mechanism of Action

Nystatin is an antifungal agent with both fungistatic and fungicidal activity in vitro. It acts by binding irreversibly to membrane sterols of susceptible species of Candida , resulting in a change in membrane permeability and the subsequent leakage of essential intracellular components (see Table 42.2 ).

Clinical Use

Indications

Nystatin is a topical antifungal agent that is clinically and mycologically effective in the treatment of cutaneous or mucocutaneous mycotic infections caused by Candida albicans and other susceptible candidal species; however, nystatin is clinically ineffective in the treatment of dermatophyte infections. Nystatin shows no appreciable activity against bacteria, protozoa, or viruses. Nystatin is available in cream, ointment, and powder formulations for twice-daily cutaneous application. Nystatin is also available in suspension and slowly dissolving pastille formulations for the treatment of oral candidiasis (thrush). Four to five times daily use is recommended in the latter situation.

Adverse Effects

Nystatin is well tolerated by patients, with <0.1% of patients reporting AE; the more common AE include burning, pruritus, rash, eczema, and pain on application. Very rare occurrences of hypersensitivity reactions have been reported.

Azoles

Azole antifungal agents presented a new class of compounds with a broader spectrum of activity, including action against the common dermatophytes that were not susceptible to the polyenes. Q42.2 Azoles act by blocking the biosynthesis of ergosterol, the primary sterol derivative of the fungal cell membrane. Depletion of ergosterol results in improper membrane function (see below) incompatible with fungal growth and survival. Azoles interfere with the cytochrome P-450-dependent enzyme, lanosterol 14α-demethylase, which catalyzes the conversion of lanosterol to ergosterol (see Table 42.2 ). The binding of the azoles proceeds primarily by a direct link of an azole nitrogen to the heme iron located in a binding domain of the cytochrome P-450 molecule. These antifungals bind to the heme iron of the cytochrome at the same site where oxygen is bound. In this manner, the azole compounds compete with oxygen and inhibit its binding and activation. This results in inhibition of the cytochrome P-450 catalysis of lanosterol to ergosterol. Decreased availability of ergosterol and accumulation of intracellular 14α-methylsterols result in increased membrane rigidity, membrane permeability changes, alterations in critical membrane-bound enzymes, inhibition of growth, and ultimately cell death.

The human skin is an efficient barrier to most azole compounds. On intact skin, percutaneous absorption is generally less than 1%. The absorption may be increased up to 4% on inflamed or damaged skin, which can be mimicked by abrasion or tape stripping of the stratum corneum. In general, there is a very low sensitizing potential associated with all the azole antifungals.

Miconazole

Pharmacology

Miconazole (Monistat-Derm, Micatin) is a synthetic β-substituted 1-phenethyl imidazole derivative. It is very slightly soluble in water, and is slightly soluble in most common organic solvents and diluted inorganic acids. Miconazole penetrates the stratum corneum well, and can be detected there up to 4 days after a single application. Systemic absorption is minimal: less than 1% of the drug is absorbed following topical application.

Clinical Use

Indications

Miconazole is active in vitro against the common dermatophytes, Trichophyton rubrum , Trichophyton mentagrophytes , and Epidermophyton floccosum . It also has inhibitory activity against C. albicans and Malassezia furfur/Pityrosporum ovale . Miconazole cream is effective in the treatment of tinea pedis, tinea corporis, tinea cruris, pityriasis (tinea) versicolor, and cutaneous candidiasis. Miconazole also demonstrates activity against some Gram-positive bacteria; it has proved modestly effective in the treatment of erythrasma, impetigo, and ecthyma caused by group A β-hemolytic streptococci or pathogenic staphylococci. However, antibacterial activity is not sufficient to make this agent a drug of choice for such infections. Twice-daily application is recommended in all clinical situations except pityriasis versicolor, in which once-daily application is effective.

Adverse Effects

Topical application of miconazole is well tolerated, with rare AE including irritation, burning, maceration, and allergic dermatitis at application sites.

Clotrimazole

Pharmacology

First synthesized in 1967, clotrimazole (Lotrimin, Fungoid, Mycelex Troches) is a broad-spectrum imidazole antifungal agent. After topical application of clotrimazole 1% cream and clotrimazole 1% solution to intact and acutely inflamed skin, the concentration of clotrimazole was measured as 100 mg/cm 3 in the stratum corneum, 0.5 to 1 mg/cm 3 in the dermis, and 0.1 mg/cm 3 in the subcutis. During routine topical application, systemic absorption of clotrimazole is extremely low; after topical application of clotrimazole cream and solution under occlusive dressing for 48 hours, no measurable amount of clotrimazole was found in the serum and only 0.5% or less of the applied product was recovered in the urine.

Clinical Use

Indications

In vitro clotrimazole exhibits a broad spectrum of activity against most strains of Trichophyton , Epidermophyton , and Microsporum species. It is also active against Gram-positive bacteria and exhibits efficacy near, although slightly less than, that of nystatin in Candida inhibition. Clotrimazole is effective in the treatment of tinea pedis, tinea corporis, tinea cruris, tinea versicolor, and cutaneous candidiasis.

The agent is available in cream, lotion, and solution formulations for twice-daily application. It is also used in the treatment of oropharyngeal (troches) and vaginal (intravaginal tablet, cream) candidiasis. Oral troches are designed to slowly dissolve in the mouth and should be administered four to five times daily for 2 weeks. Intravaginal clotrimazole may be effective following once-daily tablet insertion for 1 to 2 days.

Adverse Effects

Clotrimazole is generally well tolerated, with isolated reports of erythema, burning, irritation, stinging, peeling, blistering edema, pruritus, and urticaria at the site of application.

Ketoconazole

Pharmacology

Ketoconazole (Nizoral) is a water-soluble imidazole derivative. First synthesized in 1977, ketoconazole is a synthetic antimycotic with a broad spectrum of activity against dermatophytes and yeasts.

After a single topical application to the trunk and upper extremities of healthy volunteers, there were no detectable plasma levels of ketoconazole at a sensitivity level of 5 mg/L over a 72-hour period following application. In infants treated with topical ketoconazole to the scalp, no plasma levels were detected over a 10-day treatment period.

Clinical Use

Indications

Ketoconazole is a broad-spectrum antifungal agent that exhibits a wide spectrum of activity against dermatophytes, C. albicans , and M. furfur in vitro. In clinical trials, ketoconazole 2% cream has demonstrated efficacy in the treatment of tinea pedis, tinea cruris, and tinea corporis. Lester reported that 82% of patients with tinea pedis, tinea cruris, or tinea corporis had an excellent response to 4 weeks of therapy with once-daily applications of topical ketoconazole. Ketoconazole cream is also effective in the treatment of cutaneous candidiasis and pityriasis versicolor. Ketoconazole cream, 2% shampoo, and 2% foam have also been shown to be effective in the treatment of seborrheic dermatitis, owing to the role M. furfur in causation. In one study, 78.9% of patients with infantile seborrheic dermatitis achieved a good to excellent response after 10 days of ketoconazole application. Comparable success can be expected in adults. A 1% shampoo formulation is approved for over-the-counter use in the ongoing management of seborrheic dermatitis.

Adverse Effects

In clinical trials during which 905 patients were treated with ketoconazole 2% cream, 5% of the patients reported AE including irritation, pruritus, and stinging. One of these patients developed a painful allergic reaction at the site of application. In worldwide postmarketing experience, rare reports of contact dermatitis have been associated with ketoconazole cream or one of its ingredients, namely sodium sulfite or propylene glycol.

Oxiconazole

First approved for use in the United States in 1989 for the topical treatment of human dermatophyte infections, oxiconazole (Oxistat) was the first topical antifungal agent to be approved for once-daily application.

Pharmacology

Oxiconazole nitrate is an acetophenone-oxime derivative of the basic imidazole structural unit (substituted heterocyclic ring with a nitrogen in the 3-position). Topical oxiconazole is rapidly absorbed into the stratum corneum. Fungicidal concentrations of oxiconazole are found in the epidermis within 5 hours of topical application, reach maximum concentrations as early as 100 minutes following application, and in animal studies have persisted in the stratum corneum for up to 96 hours after a single application. Oxiconazole persists in the epidermis at therapeutic levels for 7 days, allowing for once-daily dosing. Systemic absorption of oxiconazole is negligible; in clinical trials, less than 0.3% was recovered in the urine of volunteer patients up to 5 days after application of oxiconazole cream, and none was recovered from the feces.

Clinical Use

Indications

Oxiconazole lotion applied topically once daily was safe and significantly superior to the vehicle for treatment of tinea pedis, including the hyperkeratotic plantar and interdigital subtypes. In a multicenter, double-blind, parallel-group study, 153 patients with mycologically confirmed tinea pedis were treated with once- or twice-daily applications of either oxiconazole cream or an inactive vehicle cream. At the 2-week follow-up visit, a mycological cure (negative KOH preparation and negative fungal culture) was achieved in 80% of the once-daily treatment group and 75% of patients treated twice daily with oxiconazole cream, compared with 34% of those receiving inactive vehicle cream. In clinical trials in Europe, the United States, Latin America, and Japan, oxiconazole has proved highly efficacious in the treatment of superficial fungal infections. Oxiconazole is commercially available in 1% cream and 1% lotion formulations, the latter being useful for large or hairy areas (the trunk and back).

Adverse Effects

Topical application of oxiconazole is well tolerated. Of 955 patients treated in US clinical trials, 41 patients experienced drug-related AE, including pruritus (1.6%), burning (1.4%), irritation (0.4%), erythema (0.2%), maceration (0.1%), and fissuring (0.1%).

Econazole

Pharmacology

First synthesized in 1969, econazole (Spectazole) is a deschloro derivative of miconazole. Absolute concentrations of econazole in the human stratum corneum after local application far exceed the minimal inhibitory concentration (MIC) for dermatophytes, and inhibitory concentrations are detected as deep as the mid-dermis. Systemic absorption after topical application of econazole is low, with less than 1% recovered in the urine and feces.

Clinical Use

Indications

In vitro, econazole inhibits most strains of Trichophyton , Microsporum , and Epidermophyton , C. albicans , and M. furfur . Topical econazole is effective in the treatment of tinea pedis, tinea cruris, and tinea corporis caused by dermatophytes, as well as pityriasis versicolor caused by M. furfur and cutaneous candidiasis caused by C. albicans . Econazole 1% cream has been shown to be as effective as clotrimazole 1% cream in the treatment of tinea infections and cutaneous candidiasis, but with a more rapid onset of activity in patients treated with econazole. Econazole has also shown activity against some Gram-positive and Gram-negative bacterial organisms. Econazole (Ecoza) is available in an oil-in-water emulsion base to treat interdigital tinea pedis. This 1% foam produced a complete cure rate of 24.3% versus 3.6% placebo 2 weeks following once-daily application for 4 weeks. Econazole foam specifically alleviated pruritus and improved patient quality of life.

Adverse Effects

Topical application of econazole is well tolerated with rare AE; in clinical trials, 3% of the patients treated with econazole experienced AE, including erythema, burning, stinging, and pruritus. During clinical trials with econazole 1% foam, the most common AE were application site reactions, occurring in less than 1% of patients.

Sulconazole

Pharmacology

Sulconazole is similar to other azole compounds previously discussed. Sulconazole differs from the other azole compounds by having a sulfide (thiol) bond between constituent rings. Sulconazole may be detected in the stratum corneum for up to 96 hours after application. Human percutaneous absorption of sulconazole exceeds that of other azole compounds, being of the order of 8% to 11%. The clinical significance, if any, of this phenomenon is unknown. In addition to lanosterol 14α-demethylase inhibition, sulconazole also demonstrates modest antibacterial activity against Gram-positive bacteria.

Clinical Use

Indications

Sulconazole (Exelderm) offers little advantage over azole compounds discussed previously. It has proved effective in the treatment of dermatophytosis caused by common organisms, pityriasis versicolor, and cutaneous candidiasis. Sulconazole is available as 1% cream and 1% solution formulations. Sulconazole is applied one to two times daily until clinical resolution, generally within 2 to 4 weeks. Clinical responses are equivalent to other azoles, although some reports suggest more rapid response when sulconazole is compared with miconazole or clotrimazole. Sulconazole has been reported an effective therapy for impetigo and ecthyma caused by group A β-hemolytic streptococci and staphylococci when applied twice daily for 14 days. However, it is not a first-line choice for these infections.

Adverse Effects

Sulconazole is well tolerated, although there have been a few reports of allergic contact dermatitis likely caused by vehicle ingredients.

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