ORAL ANTIFUNGAL AGENTS
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
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.
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.
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.
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.
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
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.
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.
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.
(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.