Volume 23 Number 4, Part 2 October 1990
4. 5. 6.
7.
terbinafine (Lamisil)-a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp DermatoI1989;14:124-7. Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Larnisil). Clin Exp Dermatol 1989;14:116-9. Davies RR, Everal! J D, Hamilton E. Mycological and clinical evaluation of griseofulvin for chronic onychomycosis. Br Moo J 1967;3:464-8. Nashan D, Knuth VA, Weidinger G, etal. The antimycotic drug terbinafine in contrast to ketoconazole lacksacute effects on the pituitary-testicular function of healthy men: a placebo-controlled double-blind trial. Acta Endocrinol 1988;117:203-4. Heiberg JK, Svejgaard E. Toxic hepatitis during ketoconazole treatment. Br Med J 1981;283:825-6.
Treatment of chronic moccasin-type tinea pedis 8. MacNair AL, Gascoigne E, Heap J, et al. Hepatitis and ketoconazole therapy [Letter]. Br Med J 1981;283:1058. 9. Hay RJ. New oral treatments for dermatophytosis, In: St. Georgiev, ed, Antifungal Drugs. New York: Annals of the New York Academy of Sciences 1988;544:580-5. 10. Lewis JH, Zimmerman HJ, Benson GD, et al. Hepatic injury associated with ketoconazole therapy. Br Med J 1984;86:503-13. 11. Van Dijke CPH, Veerman FR, Haverkamp HCR. Anaphylactic reactions to ketoconazole, Br Med J 1983; 287:1673-6. 12. Kagawa S. Clinical efficacyofterbinafine in 629 Japanese patients with dermatomycosis. Clin Exp DermatoI 1989; 14:114-5.
Oral terbinafine versus griseofulvin in the treatment of moccasin-type tinea pedis Ronald C. Savin, MD New Haven, Connecticut Thesafetyand effectiveness oforal terbinafine, 125 mg twice daily, andgriseofulvin, 250mg twice daily, in patients withmoccasin-type tinea pedis wereexamined in a double-blind randomized trial. At the end ofthe 6-week treatment period, botha clinical and mycologic cure or a mycologic curewith minimal signs of infection was notedin 12(75%) of the 16terbinafine-treated patients compared with only 3 (27%) of the 12 patients treated with griseofulvin. The overall response rate 2 weeks after the completion of treatment was 88% in the terbinafine-treated groupand 45% in the griseofulvin-treated group. When contacted again 6 to 15 monthsaftercompletion ofthestudy, 94% of theterbinafine-treated patients reported sustained clearing oftinea pedis, and 88% ofthose with nailinvolvement at the timeof treatment reportedimprovement. In contrast, tineapedis remained cured in only 30% of the patients whohad received griseofulvin, andonychomycosis improved in only 14%. (J AM ACAD DERMATOL 1990;23:807-9.) For more than 25 years, griseofulvin has been the main oral drug used for the treatment of dermatophyte infections. However, it is fungistatic rather than fungicidal, slow to heal infections, and associated with a high rate of relapse. Terbinafme (Lamisil) is the first orally active member of a new class of antifungal drugs, the allylamines. Unlike griseofulvin, terbinafine is fungicidal, not fungistatic. 1 Topical or oral treatment with terbinafine has been shown to produce rapid clearing with mininal relapse in patients with various
types of dermatomycoses, including tinea cruris, tinea corporis, onychomycosis, and tinea pedis.2·4 No serious side effects and no significant biochemical or hematologic abnormalities have been noted with its use," Moccasin-type tinea pedis is a chronic, severe, hyperkeratotic form of tinea pedis that is relatively resistant to topical therapy. The safety and efficacy of oral terbinafine in the management of this fungal infectionwereevaluated in a comparative study with griseofulvin. The details of this study were previously reported'
From the Department of Dermatology, Yale University School of Medicine.
METHOD
Reprint requests: Ronald C. Savin, MD, 123 York Street, New Haven, CT 06511.
16/0/23523
Participation inthisdouble-blind, randomized trialwas limited to patients withadiagnosis of moccasin-type tinea pedis, confirmed bycultureand microscopic examination
807
J ournal of the American Academy of Dermatology
808 Savin
Table I. Patient characteristics
Antimycotic Activity
ITerbinafine IGriseofulvin ~
100..------------=C:J--I
No. of patients Sex Male Female Mean age (yr) Mean range Causative organism
80
Negative Mycology (% Patients)
60
40
Trichophyson rubrum T. mentagrophytes
20
ol---o--o~:)--o,'--'---'---'---"-----'
o
234
567
16
12
28
11 5
9 3
20 8
38 22-63
13 3
36
37
20-49
20-63
12 0
25
3
From Savin RC. Clin Exp DermatoJ 1989;14;117 (reprinted with permission).
8
Week
Fig. 1. Thirty-six patients were enrolled in a randomized, double-blind study. Patients wereevaluated weekly by mycologic culture and microscopy for 6 weeks during therapy and at follow-up 2 weeks later.
of a KOH preparation. One group of patients was assigned to treatment with 125 mg of oral terbinafine twice daily, and a second groupreceived 250 mgof griseofulvin twice daily. The duration of treatment in both groups was 6 weeks. Changes in erythema, pustules, desquamation, pruritus,and hyperkeratosis wereusedto evaluate the clinical response to terbinafine. The mycologic response was assessed by repeat cultures and KOH preparations, which wereperformed weekly duringthe treatment period and again 2 weeks after treatment was discontinued. Laboratory tests, which included a CBC and blood chemistry studies, wereconducted before the start ofthe study and again after 1 and 6 weeks of treatment. RESULTS
The response to the study medications was evaluated in a total of 28 patients, including 20 men and 8 women, whose ages ranged from 20 to 63 years (Table I). Age and sexdistribution was similar in the terbinafine and griseofulvin treatment group. Trichophyton rubrum was the organism responsible for infection in 13 of the 16 patients assigned to the terbinafine-treated group and in all 12of those assigned to receive griseofulvin. T mentagrophytes accounted for the infection in the remaining three terbinafine-treated patients. The relative effects of terbinafine and griseofulvin on these organisms as determined by microscopy and culture are presented
in Fig. 1. With terbinafine there was a more rapid onset of antimycotic activity, with 80% of patients being mycologically negative by week 5. At the end of the 6-week treatment period, a complete cure, definedas negative mycologyand no signs of infection, was noted in five terbinafinetreated patients (Table II). Another seven terbinafine-treated patients had a mycologiccure and only minimal signs of infection. Thus treatment with terbinafine was considered to be effective in 12 (75%) of the 16patients who receivedthis drug. In contrast, a complete cure or a mycologic cure with minimal clinical involvement was noted in only three (27%) of the 12 patients treated with griseofulvin. By the 2-week follow-up evaluation, seven terbinafine-treated patients were completely cured and an additional seven were mycologically cured with only minimal signs of infection. The overall therapeutic response rate at follow-up in this group was therefore 88%.The response rate in the griseofulvin treatment group was much lower. Only fivepatients (45%) demonstrated either a complete cure (three patients) or a mycologic cure with significant clinical improvement (two patients) at the time of follow-up. Minor signeffectsoccurred in two patients treated with terbinafine. One complained of frequent stools and the other experienceditching and urticaria. Side effects, which included amenorrhea, polymenorrhea, diarrhea, and indigestion, developedin four of the griseofulvin-treated patients. The effect of treatment with terbinafine and griseofulvin on onychomycosis was not monitored during the original study observation period. How-
Volume 23 Number 4, Part 2 October 1990
Oral terbinafine in moccasin-type tinea pedis 809
Table II. Overall evaluation of clinical-mycological response to terbinafine and griseofulvin End of therapy Response
Terbinafine
Effective treatment Completecure (negative mycology, no clinical signs) Mycologic cure with minimal clinical signs Ineffective treatment
I
2-wkFollow-up
I
Placebo
Placebo
Terbinafine
12 (75%) 5
3 (27%) 2
14 (88%) 7
5 (45%) 3
7 4 (25%)
1 8 (73%)
7 2 (12%)
2 6 (55%)
From Savin RC. Clinical Exp Dermatol 1989;14:118 (reprinted with permission).
ever,6 to 15monthsafter completion ofthetrial,the participantswere contacted by telephone and questioned regardingthe effect of the study medication on nail involvement. At this time, 15 of the 16 terbinafine-treated patients (94%) reported sustained clearingofmoccasin-type tinea pedis (TableIII). In addition, seven of the eight patients with nail involvement who received terbinafine (88%) reported improvement in the nail infection. Tinea pedisremainedcured at the timeof followup in onlythree (30%)ofthe 10griseofulvin-treated patientswhowereable to be contacted. Ofthe seven with evidence of onychomycosis at the time of the study, only one noticed improvement (14%). DISCUSSION
Thesefindings indicatethat terbinafine issafeand significantly more effective than griseofulvin for the treatment of moccasin-type tinea pedis. A terbinafinetreatment periodofonly6 weeks was sufficient to produce sustainedimprovement in thisfungalinfection. In contrast, cure persisted at follow-up in only 30% of the griseofulvin-treated patients. In addition to clearing tinea pedis, terbinafine also producedimprovement in patientswithonychomycotic involvement of the nails. The response of the nail infection to terbinafine noted in the patients followed up in this study was similar to that observed in two patientswith severe toe nail onychomycosis treated withoral terbinafine for 14 weeks. These patients were examined at monthlyintervals after the completion oftherapy. A
Table III. Response of tinea pedis and onychomycosis 6 to 15 months after completion of a 6-week course of treatment with terbinafine or griseofulvin Drug
Sustained clearing of tineapedis
Improvement in onychomycosis
Terbinafine Griseofulvin
15/16 (94%) 3/10 (30%)
7/8 (88%) 1/7 (14%)
Reprinted with permission from Savin RC. Clio Exp Dermatol 1989;14:119.
mycologic curewasseen in bothpatients at 5months and a clinical cure was apparent at 8 months. Observations in these two patients provide further evidence that terbinafine continues to exerta therapeuticeffect for a prolonged period, even after a relatively short course of treatment.
REFERENCES I. Stiitz A. Allylamine derivatives-a newclass of active substances in antifungal chemotherapy. Angew Chern 1987; 26:320-8. 2. Kagawa S. Clinical efficacy of terbinafine in 629 Japanese patients with dermatomycosis. Clin Exp Dermatol 1989; 14:114-5. 3. ZaiasN, SerranoL. The successful treatmentoffinger Trichophyton rubrum onychomycosis with oral terbinafine. Clin Exp Dermatol 1989;14:120-l 4. Villars V,Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisilj-s-a new topical and systemic fungicidal drug fortreatmentof dermatomycoses. ClinExpDermatol 1989;14:124-7. 5. SavinR. Successful treatmentof chronic tinea pedis (moccasin type) with terbinafine (Lamisil). ClinExp Derrnato1 1989;14:116-9.
4. 5. 6.
7.
terbinafine (Lamisil)-a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp DermatoI1989;14:124-7. Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Larnisil). Clin Exp Dermatol 1989;14:116-9. Davies RR, Everal! J D, Hamilton E. Mycological and clinical evaluation of griseofulvin for chronic onychomycosis. Br Moo J 1967;3:464-8. Nashan D, Knuth VA, Weidinger G, etal. The antimycotic drug terbinafine in contrast to ketoconazole lacksacute effects on the pituitary-testicular function of healthy men: a placebo-controlled double-blind trial. Acta Endocrinol 1988;117:203-4. Heiberg JK, Svejgaard E. Toxic hepatitis during ketoconazole treatment. Br Med J 1981;283:825-6.
Treatment of chronic moccasin-type tinea pedis 8. MacNair AL, Gascoigne E, Heap J, et al. Hepatitis and ketoconazole therapy [Letter]. Br Med J 1981;283:1058. 9. Hay RJ. New oral treatments for dermatophytosis, In: St. Georgiev, ed, Antifungal Drugs. New York: Annals of the New York Academy of Sciences 1988;544:580-5. 10. Lewis JH, Zimmerman HJ, Benson GD, et al. Hepatic injury associated with ketoconazole therapy. Br Med J 1984;86:503-13. 11. Van Dijke CPH, Veerman FR, Haverkamp HCR. Anaphylactic reactions to ketoconazole, Br Med J 1983; 287:1673-6. 12. Kagawa S. Clinical efficacyofterbinafine in 629 Japanese patients with dermatomycosis. Clin Exp DermatoI 1989; 14:114-5.
Oral terbinafine versus griseofulvin in the treatment of moccasin-type tinea pedis Ronald C. Savin, MD New Haven, Connecticut Thesafetyand effectiveness oforal terbinafine, 125 mg twice daily, andgriseofulvin, 250mg twice daily, in patients withmoccasin-type tinea pedis wereexamined in a double-blind randomized trial. At the end ofthe 6-week treatment period, botha clinical and mycologic cure or a mycologic curewith minimal signs of infection was notedin 12(75%) of the 16terbinafine-treated patients compared with only 3 (27%) of the 12 patients treated with griseofulvin. The overall response rate 2 weeks after the completion of treatment was 88% in the terbinafine-treated groupand 45% in the griseofulvin-treated group. When contacted again 6 to 15 monthsaftercompletion ofthestudy, 94% of theterbinafine-treated patients reported sustained clearing oftinea pedis, and 88% ofthose with nailinvolvement at the timeof treatment reportedimprovement. In contrast, tineapedis remained cured in only 30% of the patients whohad received griseofulvin, andonychomycosis improved in only 14%. (J AM ACAD DERMATOL 1990;23:807-9.) For more than 25 years, griseofulvin has been the main oral drug used for the treatment of dermatophyte infections. However, it is fungistatic rather than fungicidal, slow to heal infections, and associated with a high rate of relapse. Terbinafme (Lamisil) is the first orally active member of a new class of antifungal drugs, the allylamines. Unlike griseofulvin, terbinafine is fungicidal, not fungistatic. 1 Topical or oral treatment with terbinafine has been shown to produce rapid clearing with mininal relapse in patients with various
types of dermatomycoses, including tinea cruris, tinea corporis, onychomycosis, and tinea pedis.2·4 No serious side effects and no significant biochemical or hematologic abnormalities have been noted with its use," Moccasin-type tinea pedis is a chronic, severe, hyperkeratotic form of tinea pedis that is relatively resistant to topical therapy. The safety and efficacy of oral terbinafine in the management of this fungal infectionwereevaluated in a comparative study with griseofulvin. The details of this study were previously reported'
From the Department of Dermatology, Yale University School of Medicine.
METHOD
Reprint requests: Ronald C. Savin, MD, 123 York Street, New Haven, CT 06511.
16/0/23523
Participation inthisdouble-blind, randomized trialwas limited to patients withadiagnosis of moccasin-type tinea pedis, confirmed bycultureand microscopic examination
807
J ournal of the American Academy of Dermatology
808 Savin
Table I. Patient characteristics
Antimycotic Activity
ITerbinafine IGriseofulvin ~
100..------------=C:J--I
No. of patients Sex Male Female Mean age (yr) Mean range Causative organism
80
Negative Mycology (% Patients)
60
40
Trichophyson rubrum T. mentagrophytes
20
ol---o--o~:)--o,'--'---'---'---"-----'
o
234
567
16
12
28
11 5
9 3
20 8
38 22-63
13 3
36
37
20-49
20-63
12 0
25
3
From Savin RC. Clin Exp DermatoJ 1989;14;117 (reprinted with permission).
8
Week
Fig. 1. Thirty-six patients were enrolled in a randomized, double-blind study. Patients wereevaluated weekly by mycologic culture and microscopy for 6 weeks during therapy and at follow-up 2 weeks later.
of a KOH preparation. One group of patients was assigned to treatment with 125 mg of oral terbinafine twice daily, and a second groupreceived 250 mgof griseofulvin twice daily. The duration of treatment in both groups was 6 weeks. Changes in erythema, pustules, desquamation, pruritus,and hyperkeratosis wereusedto evaluate the clinical response to terbinafine. The mycologic response was assessed by repeat cultures and KOH preparations, which wereperformed weekly duringthe treatment period and again 2 weeks after treatment was discontinued. Laboratory tests, which included a CBC and blood chemistry studies, wereconducted before the start ofthe study and again after 1 and 6 weeks of treatment. RESULTS
The response to the study medications was evaluated in a total of 28 patients, including 20 men and 8 women, whose ages ranged from 20 to 63 years (Table I). Age and sexdistribution was similar in the terbinafine and griseofulvin treatment group. Trichophyton rubrum was the organism responsible for infection in 13 of the 16 patients assigned to the terbinafine-treated group and in all 12of those assigned to receive griseofulvin. T mentagrophytes accounted for the infection in the remaining three terbinafine-treated patients. The relative effects of terbinafine and griseofulvin on these organisms as determined by microscopy and culture are presented
in Fig. 1. With terbinafine there was a more rapid onset of antimycotic activity, with 80% of patients being mycologically negative by week 5. At the end of the 6-week treatment period, a complete cure, definedas negative mycologyand no signs of infection, was noted in five terbinafinetreated patients (Table II). Another seven terbinafine-treated patients had a mycologiccure and only minimal signs of infection. Thus treatment with terbinafine was considered to be effective in 12 (75%) of the 16patients who receivedthis drug. In contrast, a complete cure or a mycologic cure with minimal clinical involvement was noted in only three (27%) of the 12 patients treated with griseofulvin. By the 2-week follow-up evaluation, seven terbinafine-treated patients were completely cured and an additional seven were mycologically cured with only minimal signs of infection. The overall therapeutic response rate at follow-up in this group was therefore 88%.The response rate in the griseofulvin treatment group was much lower. Only fivepatients (45%) demonstrated either a complete cure (three patients) or a mycologic cure with significant clinical improvement (two patients) at the time of follow-up. Minor signeffectsoccurred in two patients treated with terbinafine. One complained of frequent stools and the other experienceditching and urticaria. Side effects, which included amenorrhea, polymenorrhea, diarrhea, and indigestion, developedin four of the griseofulvin-treated patients. The effect of treatment with terbinafine and griseofulvin on onychomycosis was not monitored during the original study observation period. How-
Volume 23 Number 4, Part 2 October 1990
Oral terbinafine in moccasin-type tinea pedis 809
Table II. Overall evaluation of clinical-mycological response to terbinafine and griseofulvin End of therapy Response
Terbinafine
Effective treatment Completecure (negative mycology, no clinical signs) Mycologic cure with minimal clinical signs Ineffective treatment
I
2-wkFollow-up
I
Placebo
Placebo
Terbinafine
12 (75%) 5
3 (27%) 2
14 (88%) 7
5 (45%) 3
7 4 (25%)
1 8 (73%)
7 2 (12%)
2 6 (55%)
From Savin RC. Clinical Exp Dermatol 1989;14:118 (reprinted with permission).
ever,6 to 15monthsafter completion ofthetrial,the participantswere contacted by telephone and questioned regardingthe effect of the study medication on nail involvement. At this time, 15 of the 16 terbinafine-treated patients (94%) reported sustained clearingofmoccasin-type tinea pedis (TableIII). In addition, seven of the eight patients with nail involvement who received terbinafine (88%) reported improvement in the nail infection. Tinea pedisremainedcured at the timeof followup in onlythree (30%)ofthe 10griseofulvin-treated patientswhowereable to be contacted. Ofthe seven with evidence of onychomycosis at the time of the study, only one noticed improvement (14%). DISCUSSION
Thesefindings indicatethat terbinafine issafeand significantly more effective than griseofulvin for the treatment of moccasin-type tinea pedis. A terbinafinetreatment periodofonly6 weeks was sufficient to produce sustainedimprovement in thisfungalinfection. In contrast, cure persisted at follow-up in only 30% of the griseofulvin-treated patients. In addition to clearing tinea pedis, terbinafine also producedimprovement in patientswithonychomycotic involvement of the nails. The response of the nail infection to terbinafine noted in the patients followed up in this study was similar to that observed in two patientswith severe toe nail onychomycosis treated withoral terbinafine for 14 weeks. These patients were examined at monthlyintervals after the completion oftherapy. A
Table III. Response of tinea pedis and onychomycosis 6 to 15 months after completion of a 6-week course of treatment with terbinafine or griseofulvin Drug
Sustained clearing of tineapedis
Improvement in onychomycosis
Terbinafine Griseofulvin
15/16 (94%) 3/10 (30%)
7/8 (88%) 1/7 (14%)
Reprinted with permission from Savin RC. Clio Exp Dermatol 1989;14:119.
mycologic curewasseen in bothpatients at 5months and a clinical cure was apparent at 8 months. Observations in these two patients provide further evidence that terbinafine continues to exerta therapeuticeffect for a prolonged period, even after a relatively short course of treatment.
REFERENCES I. Stiitz A. Allylamine derivatives-a newclass of active substances in antifungal chemotherapy. Angew Chern 1987; 26:320-8. 2. Kagawa S. Clinical efficacy of terbinafine in 629 Japanese patients with dermatomycosis. Clin Exp Dermatol 1989; 14:114-5. 3. ZaiasN, SerranoL. The successful treatmentoffinger Trichophyton rubrum onychomycosis with oral terbinafine. Clin Exp Dermatol 1989;14:120-l 4. Villars V,Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisilj-s-a new topical and systemic fungicidal drug fortreatmentof dermatomycoses. ClinExpDermatol 1989;14:124-7. 5. SavinR. Successful treatmentof chronic tinea pedis (moccasin type) with terbinafine (Lamisil). ClinExp Derrnato1 1989;14:116-9.
