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Fluconazole for the treatment of tinea capitis in children
274
Journal of the American Academy of Dermatology August 1997
Brief communications
Fluconazole for the treatment of tinea capitis in children Barry A. Solomon, MD, JD, a Riva Collins, MD, a Roopali Sharma, PharmD, b Nanette Silverberg, MD, a Asha R. Jain, MD, c John Sedgh, a and Teresita A. Laude, MD a, c
Brooklyn, New York
Fluconazole, a water soluble bis-triazole, is a highly selective inhibitor of fungal cytochrome P450 and sterol 14-alpha demethylation. It has good bioavailability, low protein binding, and a long half-life. After oral administration it rapidly distributes to the subcutaneous tissues and epidermis, where it accumulates. Favorable results have been obtained with fluconazole in the treatment of various systemic mycoses, candidiasis, and dermatophyte infections. We studied the efficacy of fluconazole in the treatment of tinea capitis in children. MATERIAL
AND METHODS
Forty-one children were entered into an open-label study of fluconazole tablets or suspension for the treatment of noninflammatory tinea capitis. Twenty-seven patients, 15 girls and 13 boys between the ages of 2 and 15 years, completed the study. Patients were randomly assigned to receive one of three doses for 20 days. Eight patients completed the 1.5 mg/kg per day regimen; 10 received 3 mg/kg per day, and nine received 6 mg/kg daily. A common protocol, approved by the Institutional Review Board, was used for all patients. Inclusion criteria consisted of (1) mycologic confirmation of infection before initiation of therapy; (2) children from 2 to 15 years of age; (3) normal complete blood cell count with differential, liver function test, and SMA-7; and (4) parental consent. Exclusion criteria included (1) patients who had received antimycotic therapy within 2 weeks of the initial visit; (2) a history of kidney or liver disease; (3) patients with a history of hypersensitivity reaction to any of the ingredients of fluconazole; (4) patients receiving interactive medications within the preceding 30
From the Departments of Dermatology, a Pharmacy? and Pediatrics,c State University of New York Health Science Center at Brooklyn. Reprint requests: Barry A. Solomon, MD, Department of Dermatology, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave., Brooklyn, NY 11203. J Am Acad Dermatol 1997;37:274-5. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0
16/54/82788
I. Summary of clinical results: Fluconazole for tinea capitis in children Table
Dosage (mg/kg)
No. of patients
No. of patients cured
1.5 3.0 6.0
8 10 9
2 6 8
Mycologically cured at 20 days 6 wk 4 mo
25 60 89
25 60 89
25 60 89
days; (5) patients with a coexisting immunosuppressive disease; and (6) patients with inflammatory tinea capitis. Clinical and mycologic evaluations were performed before patients entered into the study, at day 20 of treatment, and at 6 weeks and 4 months after treatment was completed. Efficacy was determined by evaluation of signs and symptoms, as well as mycologic evidence at each visit. Routine laboratory studies were performed before initiation of therapy, on the 20th day of treatment, and at 6 weeks and 4 months after treatment was discontinued. No adjunctive care was prescribed during the treatment period. RESULTS Of the 41 patients who entered the study, 27 (66%) completed the study. All had a Trichophyton tonsurans infection. Thirteen patients were lost to follow-up. Table I summarizes our results. Patients were placed into one of three dosing groups. Of the 1.5 mg/kg group, two of eight patients (25%) responded to therapy by the 20th day of treatment. At 6 weeks and 4 months after therapy was discontinued, the two patients were still clinically and mycologically cured. Clinically, six of the eight patients presented with a seborrheic type tinea and two with black dot tinea. In the 3 mg/kg group, 6 of the 10 patients (60%) responded to therapy by the 20th day of treatment. All six patients were clinically and mycologically cured 6 weeks and 4 months after therapy was discontinued. No correlation could be made between the type of tinea and whether therapy was effective.
Journal of the AmericanAcademyof Dermatology Volume 37, Number 2, Part 1
In the 6 mg/kg group, eight of nine patients (89%) responded to therapy by the 20th day of treatment. All patients remained clinically and mycologically cured 6 weeks and 4 months after therapy was discontinued. Six patients had seborrheic type tinea and three had black dot tinea. Clinical improvement was noted on average by the 12th day in the 6 mg/kg group, the 16th day in the 3 mg/kg group, and the 17th day in the 1.5 mg/kg group. There was no intolerance to the medication, and no patient was removed from the study for medication reactions. No laboratory values were abnormal at any follow-up time. DISCUSSION Tinea capitis is a dermatophyte infection of the scalp that primarily affects children. It occurs worldwide, as well as throughout the United States. The disease varies from a mild scalp infection to an inflammatory disease that can lead to alopecia. Commonly, T. tonsurans, an endophytic dermatophyte, is the cause of tinea capitis in the United States, especially in urban centers. 1 Topical treatment alone is usually not efficacious. Treatment requires systemic antifungals. Reported effective medications include griseofulvin, itraconazole, and ketoconazole. The standard treatment is griseofulvin on a daily basis for up to 8 weeks. 1 This rigorous schedule often leads to noncompliance that can lead to continued infection for the patient, reinfection of other children, and drug resistance. Fluconazole is a bis-triazole antifungal agent with a broad spectrum of activity against a variety of dermatophytes and candidal infections2-6 (also personal communication to J. S. From Casilda Luck, Pfizer, Inc., Sept. 13, 1995). Case reports have proved the efficacy of fluconazole for tinea capitis at doses of 50 to 150 mg/day for approximately 20 days 7 (personal communication, Casilda Luck [see above]). No study has been conducted to assess the efficacy of fluconazole for pediatric tinea capitis nor to determine the minimum concentration necessary for treatment. The
Brief communications
275
pediatric population poses an additional obstacle related to the volume of distribution and rate of elimination of fluconazole.8 We undertook an open-label clinical therapeutic pilot study to evaluate the efficacy and safety of fluconazole for noninflammatory tinea capitis in children and to determine the minimal effective dose for this condition. Our results suggest that in children fluconazole at 6 mg/kg for 20 days is effective and safe in the treatment of tinea capitis caused by T. tonsurans. In our study 89% of patients had a clinical and mycologic cure for 4 months after discontinuation of treatment. This phenomenon may be a result of the continuing levels of fluconazole in the scalp and hair. At 3 mg/kg, 60% of patients responded to treatment without adjunctive care. This percentage may increase with such care. With the lower dosage of fluconazole (1.5 mg/kg), only 25% were cured. This was interesting because the case reports that prompted this study used the lower dosage regimen to cure tinea capitis. REFERENCES 1. Laude TA, Shah BR, Lynfield Y. Tinea capitis in Brooklyn.Am J Dis Child 1982;136:1047-50. 2. Montero-GeiF, Perera A. Therapy with fluconazolefor tinea corporis, tinea cruris, and tinea pedis. Clin Infect Dis 1992;14(Suppl):577-81. 3. Naeyaert MJ, de Bersaques J, de Cyper C, et al. Fluconazole (UK-49,858) a novel oral antifungalin the treatment of skin infections: results of an open study in 43 patients. In: Fromtling RA, editor. Recent trends in the discovery,developmentand evaluationof antifungal agents. Barcelona: J.R. Prous Science Publishers; 1987. p. 157-61. 4. HanekiE. Fluconazole levels in human epidermis and blister fluid. Br J Derrnatol 1990;123:273-4. 5. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990;12(Suppl):53318-26. 6. GrantSM, ClissoldSR Fluconazole:a review of its pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39:877916. 7. GattiS, Marinaro C, BianchiL, et al. Treatmentof kerion with fluconazole[letter]. Lancet 1991;338:1156. 8. BrammerKW, Coates PE. Pharmacokineticsof fluconazole in pediatricpatients. Eur J Clin MicrobiolInfectDis 1994;13:325-9.
Journal of the American Academy of Dermatology August 1997
Brief communications
Fluconazole for the treatment of tinea capitis in children Barry A. Solomon, MD, JD, a Riva Collins, MD, a Roopali Sharma, PharmD, b Nanette Silverberg, MD, a Asha R. Jain, MD, c John Sedgh, a and Teresita A. Laude, MD a, c
Brooklyn, New York
Fluconazole, a water soluble bis-triazole, is a highly selective inhibitor of fungal cytochrome P450 and sterol 14-alpha demethylation. It has good bioavailability, low protein binding, and a long half-life. After oral administration it rapidly distributes to the subcutaneous tissues and epidermis, where it accumulates. Favorable results have been obtained with fluconazole in the treatment of various systemic mycoses, candidiasis, and dermatophyte infections. We studied the efficacy of fluconazole in the treatment of tinea capitis in children. MATERIAL
AND METHODS
Forty-one children were entered into an open-label study of fluconazole tablets or suspension for the treatment of noninflammatory tinea capitis. Twenty-seven patients, 15 girls and 13 boys between the ages of 2 and 15 years, completed the study. Patients were randomly assigned to receive one of three doses for 20 days. Eight patients completed the 1.5 mg/kg per day regimen; 10 received 3 mg/kg per day, and nine received 6 mg/kg daily. A common protocol, approved by the Institutional Review Board, was used for all patients. Inclusion criteria consisted of (1) mycologic confirmation of infection before initiation of therapy; (2) children from 2 to 15 years of age; (3) normal complete blood cell count with differential, liver function test, and SMA-7; and (4) parental consent. Exclusion criteria included (1) patients who had received antimycotic therapy within 2 weeks of the initial visit; (2) a history of kidney or liver disease; (3) patients with a history of hypersensitivity reaction to any of the ingredients of fluconazole; (4) patients receiving interactive medications within the preceding 30
From the Departments of Dermatology, a Pharmacy? and Pediatrics,c State University of New York Health Science Center at Brooklyn. Reprint requests: Barry A. Solomon, MD, Department of Dermatology, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave., Brooklyn, NY 11203. J Am Acad Dermatol 1997;37:274-5. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0
16/54/82788
I. Summary of clinical results: Fluconazole for tinea capitis in children Table
Dosage (mg/kg)
No. of patients
No. of patients cured
1.5 3.0 6.0
8 10 9
2 6 8
Mycologically cured at 20 days 6 wk 4 mo
25 60 89
25 60 89
25 60 89
days; (5) patients with a coexisting immunosuppressive disease; and (6) patients with inflammatory tinea capitis. Clinical and mycologic evaluations were performed before patients entered into the study, at day 20 of treatment, and at 6 weeks and 4 months after treatment was completed. Efficacy was determined by evaluation of signs and symptoms, as well as mycologic evidence at each visit. Routine laboratory studies were performed before initiation of therapy, on the 20th day of treatment, and at 6 weeks and 4 months after treatment was discontinued. No adjunctive care was prescribed during the treatment period. RESULTS Of the 41 patients who entered the study, 27 (66%) completed the study. All had a Trichophyton tonsurans infection. Thirteen patients were lost to follow-up. Table I summarizes our results. Patients were placed into one of three dosing groups. Of the 1.5 mg/kg group, two of eight patients (25%) responded to therapy by the 20th day of treatment. At 6 weeks and 4 months after therapy was discontinued, the two patients were still clinically and mycologically cured. Clinically, six of the eight patients presented with a seborrheic type tinea and two with black dot tinea. In the 3 mg/kg group, 6 of the 10 patients (60%) responded to therapy by the 20th day of treatment. All six patients were clinically and mycologically cured 6 weeks and 4 months after therapy was discontinued. No correlation could be made between the type of tinea and whether therapy was effective.
Journal of the AmericanAcademyof Dermatology Volume 37, Number 2, Part 1
In the 6 mg/kg group, eight of nine patients (89%) responded to therapy by the 20th day of treatment. All patients remained clinically and mycologically cured 6 weeks and 4 months after therapy was discontinued. Six patients had seborrheic type tinea and three had black dot tinea. Clinical improvement was noted on average by the 12th day in the 6 mg/kg group, the 16th day in the 3 mg/kg group, and the 17th day in the 1.5 mg/kg group. There was no intolerance to the medication, and no patient was removed from the study for medication reactions. No laboratory values were abnormal at any follow-up time. DISCUSSION Tinea capitis is a dermatophyte infection of the scalp that primarily affects children. It occurs worldwide, as well as throughout the United States. The disease varies from a mild scalp infection to an inflammatory disease that can lead to alopecia. Commonly, T. tonsurans, an endophytic dermatophyte, is the cause of tinea capitis in the United States, especially in urban centers. 1 Topical treatment alone is usually not efficacious. Treatment requires systemic antifungals. Reported effective medications include griseofulvin, itraconazole, and ketoconazole. The standard treatment is griseofulvin on a daily basis for up to 8 weeks. 1 This rigorous schedule often leads to noncompliance that can lead to continued infection for the patient, reinfection of other children, and drug resistance. Fluconazole is a bis-triazole antifungal agent with a broad spectrum of activity against a variety of dermatophytes and candidal infections2-6 (also personal communication to J. S. From Casilda Luck, Pfizer, Inc., Sept. 13, 1995). Case reports have proved the efficacy of fluconazole for tinea capitis at doses of 50 to 150 mg/day for approximately 20 days 7 (personal communication, Casilda Luck [see above]). No study has been conducted to assess the efficacy of fluconazole for pediatric tinea capitis nor to determine the minimum concentration necessary for treatment. The
Brief communications
275
pediatric population poses an additional obstacle related to the volume of distribution and rate of elimination of fluconazole.8 We undertook an open-label clinical therapeutic pilot study to evaluate the efficacy and safety of fluconazole for noninflammatory tinea capitis in children and to determine the minimal effective dose for this condition. Our results suggest that in children fluconazole at 6 mg/kg for 20 days is effective and safe in the treatment of tinea capitis caused by T. tonsurans. In our study 89% of patients had a clinical and mycologic cure for 4 months after discontinuation of treatment. This phenomenon may be a result of the continuing levels of fluconazole in the scalp and hair. At 3 mg/kg, 60% of patients responded to treatment without adjunctive care. This percentage may increase with such care. With the lower dosage of fluconazole (1.5 mg/kg), only 25% were cured. This was interesting because the case reports that prompted this study used the lower dosage regimen to cure tinea capitis. REFERENCES 1. Laude TA, Shah BR, Lynfield Y. Tinea capitis in Brooklyn.Am J Dis Child 1982;136:1047-50. 2. Montero-GeiF, Perera A. Therapy with fluconazolefor tinea corporis, tinea cruris, and tinea pedis. Clin Infect Dis 1992;14(Suppl):577-81. 3. Naeyaert MJ, de Bersaques J, de Cyper C, et al. Fluconazole (UK-49,858) a novel oral antifungalin the treatment of skin infections: results of an open study in 43 patients. In: Fromtling RA, editor. Recent trends in the discovery,developmentand evaluationof antifungal agents. Barcelona: J.R. Prous Science Publishers; 1987. p. 157-61. 4. HanekiE. Fluconazole levels in human epidermis and blister fluid. Br J Derrnatol 1990;123:273-4. 5. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990;12(Suppl):53318-26. 6. GrantSM, ClissoldSR Fluconazole:a review of its pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39:877916. 7. GattiS, Marinaro C, BianchiL, et al. Treatmentof kerion with fluconazole[letter]. Lancet 1991;338:1156. 8. BrammerKW, Coates PE. Pharmacokineticsof fluconazole in pediatricpatients. Eur J Clin MicrobiolInfectDis 1994;13:325-9.