Antifungal Therapy for the Skin, Hair, and Nails

Dermatophytoses are fungal infections of the skin, hair, and nails caused by fungi called dermatophytes. The causative fungi in fungal infections of the skin are Trichophyton, Microsporum, and Epidermophyton.¹

Fungal infections are named according to the part of the body affected by the infection. Tinea pedis is a fungal infection of the foot; tinea capitis, the scalp; tinea corporis/cruris, the body/groin area; and tinea unguium, the nail.

Conditions promoting dermatophyte or fungal growth include moisture, dead keratin, and occlusion. These conditions lead to inflammation, desquamation, and pruritus, which cause a raised annular appearance of the skin commonly known as ringworm.²

Antifungal Therapy

Antifungal agents are available as oral and topical treatments. Oral agents include griseofulvin, ketoconazole (Nizoral), itraconazole (Sporanox), fluconazole (Diflucan), and terbinafine (Lamisil). Topical-agent categories include keratolytic/miscellaneous antifungals, antiseptic compounds, synthetic agents, imidazole derivatives, and allylamine derivatives.

Oral Agents

Griseofulvin. Griseofulvin is an oral agent with fungistatic activity against species of Trichophyton, Microsporum, and Epidermophyton that cause fungal infections of the feet, hair, and nails. Griseofulvin is deposited in keratin precursor cells, which are then replaced by noninfected tissue.³

Drug interactions are possible with anticoagulants and could result in decreased hypoprothrombinemic activity, loss of oral contraceptive efficacy, reduced cyclosporine levels, and decreased salicylate levels. Griseofulvin induces hepatic microsomal enzymes. Side effects may include photosensitivity, skin rashes, cross-sensitivity with penicillin, and lupus-like syndrome or exacerbations. Griseofulvin is in pregnancy category C, and it should not be administered to pregnant women or women contemplating pregnancy. For dosing, see Table 1.⁴

Ketoconazole. Ketoconazole is an oral fungistatic imidazole-class antifungal agent used for infections not responding to griseofulvin that require systemic treatment. Ketoconazole impairs the synthesis of ergosterol, a sterol in fungal cell membranes, resulting in increased permeability and leakage of cellular components.

Ketoconazole dosing for skin infections is 200 mg daily for 4 weeks. If clinical response is insufficient, the dose can be increased to 400 mg daily.

Drug interactions with isoniazid, rifampin, carbamazepine, and phenytoin have been documented. Drug interactions with protease inhibitors?such as indinavir, ritonavir, and saquinavir? involve increased protease concentration. Warfarin coadministration results in increased anticoagulant response.

A hepatotoxicity risk or warning exists with ketoconazole. Antacids decrease the absorption of ketoconazole.³ Ketoconazole is in pregnancy category C and is not recommended for pregnant or lactating women.³

Itraconazole. Itraconazole is an oral triazole-class fungistatic antifungal agent approved for the treatment of onychomycosis (tinea unguium). It impairs cytochrome P-450-dependent metabolism of ergosterol, a major component of fungal cell membranes.

Itraconazole dosing for fingernail infections is 200 mg twice daily for 1 week, then 3 weeks without itraconazole, followed by 200 mg twice daily for 1 week. Itraconazole dosing for toenail infections, with or without fingernail involvement, is 200 mg daily for 12 weeks.

Itraconazole coadministration is contraindicated with quinidine, dofetilide, triazolam, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins; eg, lovastatin, simvastatin), and ergot alkaloids. This drug should be used with caution in patients taking cilostazol and eletriptan due to elevated plasma concentrations.

Side effects include hepatotoxicity, dermatologic rash, congestive heart failure, hypertension, nausea, vomiting, dizziness, and headache. Itraconazole is in pregnancy category C; it should not be administered to pregnant women or women contemplating pregnancy.³

Fluconazole. Fluconazole also is a triazole-class antifungal agent that has been used for the treatment of onychomycosis. Regimens of 150, 300, and 450 mg weekly have been compared, showing efficacy.

Fluconazole is a cytochrome P-450 enzyme inhibitor. It should be used with caution with drugs metabolized by this enzyme system. Drugs metabolized by cytochrome P-450 include warfarin, carbamazepine, rifampin, statins, and protease inhibitors.⁵

Terbinafine. Terbinafine is an oral synthetic allylamine-class antifungal agent with fungicidal activity approved for the treatment of onychomycosis (tinea unguium). It inhibits squalene epoxidase, an enzyme responsible for ergosterol synthesis, a component of fungal cell membranes. Increased squalene within fungal cells results in cell death.³

Terbinafine dosing for fingernail infections is 250 mg daily for 6 weeks. Dosing for toenail infections is 250 mg daily for 12 weeks.³

Terbinafine inhibits the enzyme CYP2D6. Tricyclic antidepressants, - blockers, selective serotonin reuptake inhibitors, and monoamine oxidase type B inhibitors are metabolized by this enzyme. Terbinafine clearance is decreased by cimetidine and increased 100% by rifampin.

Side effects may include hepatotoxicity, dermatologic rash, ophthalmic changes, and hematologic neutropenia. Terbinafine is in pregnancy category B, and therefore it is not recommended for the treatment of pregnant and lactating women.³

Topical Agents

Keratolytic and miscellaneous antifungals include salicylic acid, boric acid, and undecylenic acid. Salicylic acid is a keratolytic agent used for tinea pedis infections. It causes exfoliation of the stratum corneum layer of the skin, resulting in the removal of dead, infected skin.

Boric acid and undecylenic acid are agents with fungistatic activity that prevent dermatophyte growth. They are available in OTC products for the treatment of tinea pedis infections.

Antiseptic agents include clioquinol, aluminum salts, and carbol-fuchsin, which possess antimicrobial activity and weak antifungal activity. These agents are applied topically to reduce the wet form of tinea pedis.² Keratolytic and antiseptic compounds are used topically, but their use is limited due to burning of the skin (in keratolytic therapy) and weak antifungal activity with antiseptic agents.²

The synthetic agents tolnaftate and ciclopirox are used primarily for tinea pedis infections. Tolnaftate inhibits fungal growth by interfering with fungal hyphae. It is applied twice a day for 2 to 3 weeks, up to 4 to 6 weeks if the skin is thickened.

Ciclopirox has fungicidal activity, and its mechanism of action is chelation and the inhibition of metal-dependent enzymes responsible for the degradation of peroxides within fungal cells. It is applied twice a day for 4 weeks. Shampoo is available for tinea capitis infections. Ciclopirox nail lacquer is applied daily at bedtime to the nail, the nail bed, and under the nail, and it should be removed once every 7 days. Monthly visits to a health care professional are required to assess the duration of treatment (usually >9 months).²

Imidazole derivatives are topical fungicidal antifungals that impair the synthesis of ergosterol, a sterol in fungal cell membranes. This process results in increased permeability and leakage of cellular components² (Table 2⁴).

Allylamine-derivative topical antifungals?such as naftifine, terbinafine, and butenafine?interfere with the formation of ergosterol in the cell membrane by inhibiting the enzyme squalene epoxidase, resulting in fungicidal activity. Naftifine cream is applied daily, whereas the gel is applied twice daily, for 4 weeks for the treatment of tinea pedis, cruris, or corporis.

Terbinafine is applied twice daily for a minimum of 1 week, but not to exceed 4 weeks, for the treatment of tinea pedis or corporis. Butenafine cream is applied daily for 2 weeks for the treatment of tinea pedis or corporis. For tinea cruris infections, it is applied twice a day for 7 days or daily for 4 weeks.³

Final Words

Tinea pedis is the most common type of dermatophytosis. Topical agents are the treatment of choice. Treatment of fungal infections at other body sites may require oral medication and longer duration of treatment.²

Dr. Ambrosini is a pharmaceutical consultant based in Flushing, NY.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an e-mail request to: arybovic@ascendmedia.com.