Antifungal Agents

ANTIFUNGAL AGENTS

The treatment of superficial fungal infections caused by dermato-phytic fungi may be accomplished (1) with topical antifungal agents, eg, clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, sulconazole, sertaconazole, ciclopirox olamine, nafti-fine, terbinafine, butenafine, and tolnaftate; or (2) with orally administered agents, ie, griseofulvin, terbinafine, ketoconazole, fluconazole, and itraconazole. Superficial infections caused by candida species may be treated with topical applications of clotri-mazole, miconazole, econazole, ketoconazole, oxiconazole, ciclopirox olamine, nystatin, or amphotericin B. Chronic general-ized mucocutaneous candidiasis is responsive to long-term therapy with oral ketoconazole.

TOPICAL ANTIFUNGAL PREPARATIONS

TOPICAL AZOLE DERIVATIVES

The topical imidazoles, which currently include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, and sertaconazole, have a wide range of activity against dermato-phytes (epidermophyton, microsporum, and trichophyton) and yeasts, including Candida albicans and Pityrosporum orbiculare .

Miconazole (Monistat, Micatin) is available for topical applica-tion as a cream or lotion and as vaginal cream or suppositories for use in vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex) is available for topical application to the skin as a cream or lotion and as vaginal cream and tablets for use in vulvovaginal candidia-sis. Econazole (Spectazole) is available as a cream for topical appli-cation. Oxiconazole (Oxistat) is available as a cream and lotion for topical use. Ketoconazole (Nizoral) is available as a cream for topical treatment of dermatophytosis and candidiasis and as a shampoo or foam for the treatment of seborrheic dermatitis. Sulconazole (Exelderm) is available as a cream or solution. Sertaconazole (Ertaczo) is available as a cream. Topical antifungal-corticosteroid fixed combinations have been introduced on the basis of providing more rapid symptomatic improvement than an antifungal agent alone. Clotrimazole-betamethasone dipropionate cream (Lotrisone) is one such combination.

Once- or twice-daily application to the affected area will gen-erally result in clearing of superficial dermatophyte infections in 2–3 weeks, although the medication should be continued until eradication of the organism is confirmed. Paronychial and inter-triginous candidiasis can be treated effectively by any of these agents when applied three or four times daily. Seborrheic derma-titis should be treated with twice-daily applications of ketocon-azole until clinical clearing is obtained.

Adverse local reactions to the imidazoles may include stinging, pruritus, erythema, and local irritation. Allergic contact dermatitis is uncommon.

CICLOPIROX OLAMINE

Ciclopirox olamine is a synthetic broad-spectrum antimycotic agent with inhibitory activity against dermatophytes, candida spe-cies, and P orbiculare. This agent appears to inhibit the uptake of precursors of macromolecular synthesis; the site of action is prob-ably the fungal cell membrane.

Pharmacokinetic studies indicate that 1–2% of the dose is absorbed when applied as a solution on the back under an occlu-sive dressing. Ciclopirox olamine is available as a 1% cream and lotion (Loprox) for the topical treatment of dermatomycosis, can-didiasis, and tinea versicolor. The incidence of adverse reactions has been low. Pruritus and worsening of clinical disease have been reported. The potential for allergic contact dermatitis is small.

Topical 8% ciclopirox olamine (Penlac nail lacquer) has been approved for the treatment of mild to moderate onychomycosis of fingernails and toenails. Although well tolerated with minimal side effects, the overall cure rates in clinical trials are less than 12%.

ALLYLAMINES: NAFTIFINE & TERBINAFINE

Naftifine hydrochloride and terbinafine (Lamisil) are allylamines that are highly active against dermatophytes but less active against yeasts. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48–1).

They are available as 1% creams and other forms for the topical treatment of dermatophytosis, to be applied on a twice-daily dos-ing schedule. Adverse reactions include local irritation, burning sensation, and erythema. Contact with mucous membranes should be avoided.

BUTENAFINE

Butenafine hydrochloride (Mentax) is a benzylamine that is struc-turally related to the allylamines. As with the allylamines, buten-afine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes. Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis.

TOLNAFTATE

Tolnaftate is a synthetic antifungal compound that is effective topically against dermatophyte infections caused by epidermophy-ton, microsporum, and trichophyton. It is also active against Porbiculare but not against candida.

Tolnaftate (Aftate, Tinactin) is available as a cream, solution, powder, or powder aerosol for application twice daily to infected areas. Recurrences following cessation of therapy are common, and infections of the palms, soles, and nails are usually unrespon-sive to tolnaftate alone. The powder or powder aerosol may be used chronically following initial treatment in patients susceptible to tinea infections. Tolnaftate is generally well tolerated and rarely causes irritation or allergic contact dermatitis.

NYSTATIN & AMPHOTERICIN B

Nystatin and amphotericin B are useful in the topical therapy of Calbicans infections but ineffective against dermatophytes. Nystatin islimited to topical treatment of cutaneous and mucosal candida infec-tions because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration. Amphotericin B has a broader antifungal spectrum and is used intravenously in the treatment of many systemic mycoses  and to a lesser extent in the treatment of cutaneous candida infections.

The recommended dosage for topical preparations of nystatin in treating paronychial and intertriginous candidiasis is applica-tion two or three times a day. Oral candidiasis (thrush) is treated by holding 5 mL (infants, 2 mL) of nystatin oral suspension in the mouth for several minutes four times daily before swallowing. An alternative therapy for thrush is to retain a vaginal tablet in the mouth until dissolved four times daily. Recurrent or recalcitrant perianal, vaginal, vulvar, and diaper area candidiasis may respond to oral nystatin, 0.5–1 million units in adults (100,000 units in children) four times daily in addition to local therapy. Vulvovaginal candidiasis may be treated by insertion of 1 vaginal tablet twice daily for 14 days, then nightly for an additional 14–21 days.

Amphotericin B (Fungizone) is available for topical use in cream and lotion form. The recommended dosage in the treat-ment of paronychial and intertriginous candidiasis is application two to four times daily to the affected area.

Adverse effects associated with oral administration of nystatin include mild nausea, diarrhea, and occasional vomiting. Topical appli-cation is nonirritating, and allergic contact hypersensitivity is exceed-ingly uncommon. Topical amphotericin B is well tolerated and only occasionally locally irritating. The drug may cause a temporary yellow staining of the skin, especially when the cream vehicle is used.