Oral Antifungal Agents

ORAL ANTIFUNGAL AGENTS

ORAL AZOLE DERIVATIVES

Azole derivatives currently available for oral treatment of systemic mycosis include fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and others. As discussed,  midazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell.

Patients with chronic mucocutaneous candidiasis respond well to a once-daily dose of 200 mg of ketoconazole, with a median clearing time of 16 weeks. Most patients require long-term main-tenance therapy. Variable results have been reported in treatment of chromomycosis.

Ketoconazole is effective in the therapy of cutaneous infections caused by epidermophyton, microsporum, and trichophyton spe-cies. Infections of the glabrous skin often respond within 2–3 weeks to a once-daily oral dose of 200 mg. Palmar-plantar skin is slower to respond, often taking 4–6 weeks at a dosage of 200 mg twice daily. Infections of the hair and nails may take even longer before resolv-ing, with low cure rates noted for tinea capitis. Tinea versicolor is responsive to short courses of a once-daily dose of 200 mg.

Nausea or pruritus occurs in approximately 3% of patients tak-ing ketoconazole. More significant adverse effects include gyneco-mastia, elevations of hepatic enzyme levels, and hepatitis. Caution is advised when using ketoconazole in patients with a history of hepatitis. Routine evaluation of hepatic function is advisable for patients on prolonged therapy.

Fluconazole is well absorbed following oral administration, with a plasma half-life of 30 hours. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous can-didiasis; alternate-day doses are sufficient for dermatophyte infec-tions. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomyco-sis in a dosage of 200 mg daily taken with food to ensure maxi-mum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treat-ment of onychomycosis in patients with ventricular dysfunction. Additionally, routine evaluation of hepatic function is recom-mended for patients receiving itraconazole for onychomycosis.

Administration of oral azoles with midazolam or triazolam has resulted in elevated plasma concentrations and may potentiate and prolong hypnotic and sedative effects of these agents. Administration with HMG-CoA reductase inhibitors has been shown to cause a significant risk of rhabdomyolysis. Therefore,administration of the oral azoles with midazolam, triazolam, or HMG-CoA inhibitors is contraindicated.

GRISEOFULVIN

Griseofulvin is effective orally against dermatophyte infections caused by epidermophyton, microsporum, and trichophyton. It is ineffective against candida and P orbiculare. Griseofulvin’s mecha-nism of antifungal action is not fully understood, but it is active only against growing cells.

Following the oral administration of 1 g of micronized griseoful-vin, drug can be detected in the stratum corneum 4–8 hours later. Reducing the particle size of the medication greatly increases absorption of the drug. Formulations that contain the smallest particle size are labeled “ultramicronized.” Ultramicronized griseofulvin achieves bioequivalent plasma levels with half the dose of micronized drug. In addition, solubilizing griseofulvin in polyethylene glycol enhances absorption even further. Micronized griseofulvin is available as 250 mg and 500 mg tablets, and ultramicronized drug is available as 125 mg, 165 mg, 250 mg, and 330 mg tablets and as 250 mg capsules.

The usual adult dosage of the micronized (“microsize”) form of the drug is 500 mg daily in single or divided doses with meals; occasion-ally, 1 g/d is indicated in the treatment of recalcitrant infections. The pediatric dosage is 10 mg/kg of body weight daily in single or divided doses with meals. An oral suspension is available for use in children.

Griseofulvin is most effective in treating tinea infections of the scalp and glabrous (nonhairy) skin. In general, infections of the scalp respond to treatment in 4–6 weeks, and infections of gla-brous skin will respond in 3–4 weeks. Dermatophyte infections of the nails respond only to prolonged administration of griseoful-vin. Fingernails may respond to 6 months of therapy, whereas toenails are quite recalcitrant to treatment and may require 8–18 months of therapy; relapse almost invariably occurs.

Adverse effects seen with griseofulvin therapy include head-aches, nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis, and occasionally mental confusion. Griseofulvin is derived from a penicillium mold, and cross-sensitivity with penicillin may occur. It is contraindicated in patients with porphyria or hepatic failure or those who have had hypersensitivity reactions to it in the past. Its safety in pregnant patients has not been established. Leukopenia and proteinuria have occasionally been reported. Therefore, in patients undergoing prolonged therapy, routine evaluation of the hepatic, renal, and hematopoietic systems is advisable. Coumarin anticoagulant activity may be altered by griseofulvin, and anticoagulant dosage may require adjustment.

TERBINAFINE

Terbinafine (described above) is quite effective given orally for the treatment of onychomycosis. Recommended oral dosage is 250 mg daily for 6 weeks for fingernail infections and 12 weeks for toenail infections. Patients receiving terbinafine for onychomycosis should be monitored closely with periodic laboratory evaluations for pos-sible hepatic dysfunction.