June 1999
NEW ORLEANS - Although current oral antifungal treatments for dermatomycoses and onychomycoses are effective, resistance is occurring in some areas and physicians are looking at newer, broad-spectrum medications to achieve the desired cure rate of 90% to 95%, said Jan N. Faergemann, MD.
"In the United States, itraconazole [Sporanox, Janssen] and terbinafine HCl [Lamsil, Sandoz] are both approved for treatment of dermatomycoses," noted Faergemann, who is associate professor, department of dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden. However, fluconazole [Diflucan, Pfizer] is only approved for treatment of Candida albicans infection and cryptococcal meningitis.
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An advantage of fluconazole is that it comes in varying doses. "This makes it very easy to give to children because you don't have to break any capsules," said Faergemann.
He reviewed data illustrating both the rapid absorption of fluconazole and the high tissue concentrations of the drug over long periods. "So, once weekly doses of 150 mg are effective in treatment of several dermatomycoses," he said, citing the examples of tinea corporis and tinea cruris, which are treated with four to six weekly 150-mg doses.
Comparative clinical trials support this regimen. For example, Faergemann pointed to a large British study in which researchers compared fluconazole and griseofulvin for t. corporis and t. cruris. Cure rates were highest among 119 subjects given six 150-mg doses of fluconazole at one-week intervals.
In two open comparative studies, fluconazole was similarly effective in treating tinea pedis, tinea versicolor and pityriasis versicolor. Patients with t. pedis were given 150 mg of fluconazole once weekly for four weeks.
Those with t. versicolor and pityriasis versicolor received 150 mg or 300 mg once a week for four weeks, or a single 300-mg dose that was repeated in two weeks.
Cure rates for the three groups ranged from 72% to 87% — similar to those seen with griseofulvin — and were not significantly different. Other studies, including large double-blind, placebo-controlled trials in the United States, found fluconazole is as effective in treating fingernail and toenail infections.
According to the Physicians' Desk Reference (PDR), the safety profile of fluconazole in children has been studied in 577 children age 1 day to 17 years who received doses ranging from 2 mg/kg/day to 15 mg/kg/day for one to 1,616 days. Efficacy in has not been established in infants younger than 6 months. A small number of patients (29) ranging in age from 1 day to 6 months have been safely treated with fluconazole.
For the daily treatment of skin infections, itraconazole is commonly prescribed as 100 mg a day for two to four weeks. "Unfortunately, the cost for this regimen is very high," cautioned Faergemann. However, using pulse therapy can cut the cost in half. For t. versicolor, pityriasis versicolor, t. corporis, and t. cruris, this consists of 200 mg of itraconazole once daily for one week. For t. pedis and tinea manuum, pulse therapy is 200 mg twice daily for one week. Pulse therapy uses short bursts of higher dose treatment with breaks between.
In the treatment of onychomycoses, intraconazole pulse treatment is 200 mg twice daily for one week on two consecutive months. "You do this twice for fingernails and three times for toenails," Faergemann instructed.
Studies have shown that 85% of onychomycoses patients are cured with three itraconazole pulses while, oddly, only 76% are cured with four pulses (a nonsignificant difference). "That's the reason why three pulses has been chosen as the way to use intraconazole for the treatment of onychomycosis of toenails," he said.
Itraconazole can also be used against fungal skin infections. Faergemann cited comparative studies of itraconazole and griseofulvin showing cure rates greater than 80% for t. corporis, t. cruris, t. pedis, and t. manuum in the intraconazole group. In addition, a randomized, double-blind, placebo-controlled study of short-term itraconazole therapy (200 mg once daily for one week) for t. versicolor and pityriasis versicolor found an 89% cure rate. An older study of 30 days of daily itraconazole for tinea capitis showed a 100% cure rate among 20 patients.
For t. corporis, t. cruris, t. pedis and t. capitis, terbinafine should be taken in a dose of 250 mg once daily for two to four weeks. Patients should receive the same 250-mg dose once a day for six weeks for onychomycosis of the fingernails and once a day for 12 weeks for onychomycosis of the toenails.
Six weeks of terbinafine for t. pedis was evaluated in a small double-blind study with a long follow-up of six to 15 months - uncommon in studies of t. pedis therapies, Faergemann noted. Treatment was successful in 15 out of 16 terbinafine recipients. "The numbers here are not so high," he admitted, "but the results are still convincing in favor of terbinafine."
They were somewhat less convincing in another double-blind study looking for the first time at short-term treatment of toenail onychomycosis with terbinafine versus placebo. Subjects included 112 patients who received one 250-mg tablet of terbinafine once daily for 12 weeks (treatment in other studies lasted up to one year). Although the cure rate was 82% in the terbinafine group, many patients did not experience a total cure.
At Faergemann's institution, researchers completed a double-blind study in which subjects with onychomycoses were randomized to 250 mg of terbinafine once daily for 16 weeks or a low dose (500 mg) of griseofulvin once daily for up to one year. Although terbinafine only produced a complete cure rate of 42%, that was far better than the 2% rate for griseofulvin.
According to the PDR, the safety and efficacy of itraconazole have not been established in pediatric patients. A small number of patients age 3 to 16 years habe been treated with 100 mg/kg/day for serious fungal infections and no serious adverse events have been reported. The oral solution (5 mg/kg/day) has been administered to pediatric patients age 6 months to 12 years for as long as two weeks with no serious adverse events.
Pediatric t. capitis can be effectively treated with a half tablet (125 mg) of terbinafine daily for six to eight weeks, suggested an open study in which all 12 children on this regimen were completely cured. In an adult study of 161 cases of t. capitis, there were no statistically significant differences between one, two or four weeks of terbinafine. "This clearly indicates that you can shorten the treatment time," Faergemann said.
He reviewed large and small studies comparing fluconazole, itraconazole, and terbinafine treatment of fungal skin and nail infections. These generally showed few differences between the three drugs in efficacy. In addition, all three were safe in general, with patients rarely developing adverse drug interactions and only about 10% having reversible side effects - most often gastrointestinal events, headache and skin reactions.
For more information:
- Faergemann JN. Treatment with new oral antifungal drugs. Session FOC686. Presented at the 57th Annual Meeting of the American Academy of Dermatology. March 19-24. New Orleans.
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