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Treatment of dermatophyte nail infections: An open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy
CLINICAl, AND LABORATORY STUDIES II
IIII
III
Treatment of dermatophyte nail infections: An open randomized study comparing intermittent terbinafine therapy with continuous terbinafme treatment and intenmttent itraconazole therapy AntoneUa Tosti, MD, a Bianca Mafia Piraccini, M~D, a Caterina Stinchi, MD, a Nicola Venturo, MD, a Federico Bardazzi, MD, a and Maria Delia Colombo, M D b
Bologna, Italy Background: Terbinafine persists in the nail at effective concentrations for several weeks after discontinuation of treatment.
Objective: Our purpose was to verify whether intermittent terbinafine therapy is effective in dermatophytic onychomycosis and to compare the results of intermittent terbinafine with those of intermittent itraconazole and continuous terbinafine treatment. Methods: An open, randomized study of 63 patients was performed with three treatment regimens: terbinafine, 250 mg daily (21 patients); terbinafine, 500 mg daily for 1 week every month (21 patients); or itraconazole, 400 mg daily for 1 week every month (21 patients). Treatment was continued for 4 months in toenail infections (60 patients) and 2 months in fingemail infections (3 patients). Results: At the end of the follow-up period (6 months after discontinuation of treatment) 16 of 17 patients (94.1%) with toenail onychomycosis were mycologicaUy cured in the terbinafine 250 mg group, 16 of 20 (80%) in the terbinafme 500 mg group, and 15 of 20 (75%) in the itraconazole group. Conclusion: The percentage of patients who were mycologicaUy cured was higher in the continuous terbinafine group than in the intermittent terbinafme and itraconazole groups, but statistical analysis did not reveal any significant difference between these cure rates. (J AM ACADDERMATOL1996;34:595-600.)
Terbinafine is an allylamine derivative with fungicidal properties against dermatophytes, l Studies have shown that terbinafine is more effective than griseofulvin in the treatment of onychomycosis caused by dermatophytes. 2-4 Terbinafine reaches the distal nail 1 week after initiation o f therapy and persists in the nail plate for 2 to 3 months after treatment is stopped. 5' 6 Terbinafine at a dosage of 250 mg daily produced cure rates of more than 80% in fingemail and toenail infections in 6 and 12 weeks, respectively.3, 7, 8
Intermittent administration of itraconazole has been proposed for the treatment of onychomycosis. 9 Itraconazole, 400 mg daily, taken for 1 week a month for 3 to 4 months produced mycologic cure rotes ranging from 64% to 72%. 1° The aim of this study was to verify whether intermittent therapy with terbinafine is effective in the treatment of dermatophytic nail infections and to compare the results of intermittent terbinafine treatment with those of intermittent itraconazole treatment and continuous terbinafine treatment. MATERIAL AND METHODS
From the Department of Dermatology, University of Bologna, and the Medical Department, Sandoz P.F., Italy? Supported in part by Sandoz PF, Milan, Italy. Accepted for publication Aug. 15, 1995. Reprint requests: Prof. Antonella Tosti, Department of Dermatology, University of Bologna Via Massarenti, 1; 40138 Bologna, Italy. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/1/68602
The trial was carded out according to the principles of the Declaration of Helsinki as well as of the subsequent amendments of Tokyo in 1975, Venice in 1983, and Hong Kong in 1989. The experimental design was open and randomized. Patients were given (1) terbinafine, 250 rag, one tablet daily; (2) terbinafine, 250 mg, two tablets daily for I week 595
596
Journal of the American Academy of Dermatology April 1996
Tos~etaL
Table L
Site of infection and causative dermatophytes in the different treatment groups
I T'meapedis ] Drop-outs (No.of (No.of Treatment
Terbinafine 250 mg (21 pts)
Site of infection (No.)
Toenails (16) Toenails and fingernails (3) Fingernails (2)
Terbinafine 500 mg (21 pts) Itraconazole 400 mg (21 pts)
Toenails (17) Toenails and fingemails (4) Toenails (18) Toenails and fingernails (2) Fingernails (1)
every month; or (3) itraconazole, 400 mg daily for 1 week every month. All patients were instructed to take the drug with a meal. Duration of treatment was 4 months for toenail infections and 2 months for fingernail infections. Patients were assigned sequentially to the treatment. The selection of the experimental design was obligatory. It was not possible to perform a double-blind study; a placebo-controlled double-blind study deemed likely to cause compliance problems. Patients who had taken systemic antifungal agents in the previous 6 weeks were excluded, as were patients with severe liver, renal, or cardiovascular disease and pregnant women. All patients were examined monthly up to 6 months after discontinuation of lreatment. At each visit, mycologic (direct microscopic examination and cultures) and clinical evaluation were performed. Clinical assessment of onycholysis, subungual hyperkeratosis, and nail discoloration was made on a 4-point scale (0=absent, 1 = mild, 2 = moderate, 3 = severe). Routine laboratory studies were performed at baseline and at the end of treatment. At the end of the follow-up period ( 10 months after the beginning of Ireatment for toenail infections and after 8 months for fingernail infections), patients were assigned to one of three categories: not mycologically cured, mycologically cured with residual nail malformation, and mycologically cured without residual nail malformation. Mycologic cure was defined as a negative culture and negative microscopic preparation. All patients who started treatment were considered able to be evaluated even if they withdrew the first day because of adverse events (intention to treat). The percentage of cured patients at the end of the follow-up period was compared between groups by the Fisher exact test. The
Causative dermatophyte
patients)
Trichophyton rubrurn (13) T. mentagrophytes (1) T. soudanense (2) T. rubrum (3) T. rubrum (!) Microsporum canis (1) T. rubrum (13) T. mentagrophytes (4) T. rubrum (4) T. rubrum (16) T. mentagrophytes (2) T. rubrum (2) T. rubrum ( 1)
6
patients)
2 4
5 1
severity of clinical signs was compared separately by Student's t test. RESULTS Sixty-three patients (31 men, 32 women; 27 to 60 years of age [mean 47.3 years]) entered the study; these included 51 patients with only toenail infection, nine patients with toenail and fingernail infection, and three patients with only fingernail infection (two in the terbinafine 250 mg group and one in the itmconazole group). The dermatophytes isolated in the three treatment groups, as well as the sites of the infection, are given in Table I. The statistical analysis showed no differences in the severity of onychomycosis between the three groups of patients. Three patients had to discontinue treatment in the first month of therapy because of factors not related to treatment and were considered as drop-outs (two in the terbinafine 250 mg group, one in the terbinafine 500 mg group). Therefore the statistical analysis of toenail infections is based on 57 patients: 48 with toenail and 9 with toenail plus fingernail onychomycosis.
Mycologic examination After 4 months of treatment, mycologic examination was negative in 13 of 17 patients (76.5%) with toenail onychomycosis treated with terbinafme, 250 mg; in 16 of 20 patients (80%) with toenail onychomycosis treated with terbinaflne, 500 mg; and in 13 of 20 patients (65%) with toenail onychomycosis treated with itraconazole, 400 mg.
Journal of the American Academy of Dermatology Volume 34, Number 4
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597
A Fig. 1. Distal subungual onychomycosis before (A) and 6 months after (B) terbinafme 500 mg/day, 1 week per month for 4 months. Table II. Final assessment of patients at the end of the follow-up period Results
250 mg
500 mg
Itraconazole 400 mg
Failure MycologicaUycured with nail deformities Mycologicallycured without nail deformities$
1/19" (5.2%) 3/19" (15.8%) 15/19" (78.9%)
4/20 (20%) 6/20 (30%) 10/20 (50%)
5/215- (23.8%) 8/21t (38.1%) 8/215"(38.1%)
Terbinafine
1
Terbinaflne
*Including two patients with exclusive fingernail infection. tIncluding one patient with exclusive fingernail infection. SFisher exact test is significant (p = 0.013) between the terbinafine 250 mg group and the itraconazole group.
At the end of the follow-up period 16 of 17 patients (94.1%) with toenail onychomycosis were mycologicaUy cured in the terbinafine 250 mg group, 16 of 20 (80%) in the terbinafine 500 mg group, and 15 of 20 (75%) in the itraconazole 400 mg group. All three patients with only fingernail infection were mycologically cured at the end of the 2-month treatment period with terbinafine, 250 mg (two patients), and itraconazole, 400 mg (one patient). Final assessment Final assessment of patients at the end of the follow-up period is reported in Table II. In the terbinafine 250 mg group, 13 of 17 patients (76.5%) with toenail infections were cured without residual malformation. The two patients with only fingernail infection were also cured. Two of the three patients
with residual nail malformation had nail abnormalities unrelated to onychomycosis: splinter hemorrhages (one patient) and traumatic onycholysis (one patient). The remaining patient had a small band of residual distal subungual hyperkemtosis. In the terbinafine 500 mg group, 10 of 20 patients with toenail infections (50%) were cured without residual malformation (Fig. 1). Two of six patients with residual nail malformation had traumatic nail deformities not related to onychomycosis: "pincernail" deformity (one patient) and traumatic onycholysis (one patient). Three patients had a small band of residual distal subungual hyperkeratosis and onycholysis. The remaining patient had mild distal subungual hyperkemtosis associated with a longitudinal white streak. In the itraconazole 400 mg group, 7 of the 20 patients with toenail infections were cured with-
598 Tosti et al:,
Journal of the American Academy of Dermatology April 1996
malformation (one in the terbinafine 500 mg group and one in the itraconazole group).
Tolerability Drug-related adverse effects were reported in two patients while taking 250 mg of terbinafme (one patient with itch) and 500 mg of terbinafine (one patient with diarrhea). No significant laboratory abnormalities were observed. DISCUSSION
A
Fig. 2. Distal subungual onychomycosis before (A) and 6 months after (B) itraconazole treatment. Residual nail abnormalities are traumatic; they are not related to infection.
out residual malformation (35%). The patient with an exclusive fingernail infection was also cured without malformation. Six of eight patients with residual nail malformation had nail abnormalities unrelated to onychomycosis: splinter hemorrhages (one patient), Beau's lines (one patient), nail bed hematoma (one patient), onychogryphosis (one patient), traumatic onycholysis (one patient), melanonychia (one patient). Two patients had linear subungual hyperkeratosis extending to the proximal nail plate. The fingernails of the nine patients with toenail and fingernail infection (terbinafine 250 mg group, t~ee patients; terbinafine 500 mg group, four patients; itraconazole 400 mg group, two patients) were all mycologicaUy and crmically cured, even in patients whose toenails failed to respond to treatment (one in the terbinafine 250 mg group and one in the itmconazole group), or were cured with residual nail
This study confirms the efficacy of terbinafine and itraconazole in the treamaent of dermatophyfic nail infections. Continuous terbinafine cured 94% of patients with toenail onychomycosis, and intermittent terbinafine cured 80%. Our results also indicate that intermittent terbinafine treatment is as effective as intermittent itraconazole treatment for dermatophytic nail infections. All three treatment regimens were well tolerated and no serious side effects were seen. Although the percentage of patients who were mycologically cured was higher in the continuous terbinafine group (94%) than in the intermittent terbinafme (80%) and itraconazole (75%) groups, statistical analysis did not reveal any significant difference between the cure rates with the three different regimens. Clinical evaluation at the end of the follow-up period revealed completely healthy nails in only 30 of 47 patients with toenail onychomycosis who were mycologicaUy cured. The percentage of patients who were mycologically cured without nail deformities was significantly higher in the continuous terbinafine group than in the intermittent iWaconazole group (Fisher's exact test, p = 0.013). Examination of the 17 patients with residual nail abnormalities revealed traumatic nail lesions in 10 patients (Fig. 2). Although these abnormalities were not due to persistence of fimgi in the nail, it is possible they could be a predisposing factor for future reinfection. In four of the remaining seven patients (three in the terbinafine 500 mg group and one in the terbinafine 250 mg group) the nail abnormalities consisted of a distal band of residual subungual hyperkeratosis and onycholysis. Sequential clinical photographs show that this band was progressively moving distally every month. This indicates that the follow-up period (10 months) was not long enough to obtain complete regrowth of the toenail. In all patients the onychomycosis involved the entire nail plate before treatment.
•Journal of the AmericanAcademyof Dermatology Volume 34, Number4
A
Tosti et aL
599
B
Fig. 3. Distal subungual onychomycosis before (A) and 6 months after (B) terbinafine 500 rag. Note persistent linear band of infection along lateral nail plate. The other three patients (two in the itraconazole group and one in the terbinafine 500 mg group) had nail changes that were difficult to interpret at the final assessment because their clinical features were suggestive of persistence of onychomycosis although microscopic examinations and cultures were repeatedly negative. Treatment failures Despite the high efficacy of new antifungal agents, a considerable number of patients with onychomycosis still fail to respond to treatment. Ten of the 57 patients (17.5%) with toenail onychomycosis who completed the study still had positive cultures at the end of the follow-up period. Two of these patients had a concomitant fingernail infection that was cured. Failures were more common in patients treated with intermittent regimens (either terbinafine or itraconazole) than in patients treated with continuous terbinafine. Patients unresponsive to treatment were not significantly different from those who responded regarding duration of onychomycosis, presence of proximal nail plate invasion, and the causative species. The retrospective analysis of the clinical data and examination of the clinical features did not offer any clue to predict which patients would be a treatment failure. Clinically, patients who were not cured can be di-
vided into three groups. In 4 of 10 patients, treatment produced clearing of onychomycosis only in some affected nails (two patients) or in some areas but not in other areas of the same nail (two patients). Fungi frequently persisted only along narrow linear streaks that apparently followed the longitudinally oriented nail bed epidermal ridges (Fig. 3). This could possibly reflect poor distribution of the drug in some areas of the nail that remained infected during treatment and became a source of reinfection a few months after treatment was stopped. Baran believes that the persistence of a linear band of infection along the lateral edge of the nail occurs because the nail plate does not adhere to the nail bed there (unpublished data). Because itraconazole and terbinafine mainly diffuse to the nail plate through the nail bed, these drugs might not reach therapeutic concentrations in such sites. TM12 In five patients, treatment did not produce any clinical alleviation of the onychomycosis, which persisted unchanged or even worsened during therapy. Failure in these cases could be caused by poor penetration of the drug in the nail. We have not been able to verify this by monitoring the anfifungal levels in the nails of these patients during and after treatment. The remaining patient (itraconazole group) had an unexpected previously reported response to treatment,7 she had complete clearing of her nails
600
Journal of the American Academy of Dermatology April 1996
Tosti et aL
a l t h o u g h Trichophyton r u b r u m w a s constantly isolated f r o m h e r nails during treatment a n d follow-up. L o n g - t e r m f o l l o w - u p will possibly clarify w h e t h e r T. r u b r u m is acting as a c o m m e n s a l rather than as a p a t h o g e n as has b e e n suggested b y others. 13 REFERENCES
1. Balfour JA, Faulds D. Terbinafine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drags 1992;43:259-84. 2. Haneke E, Tausch I, Brautigam M, et al. Short-duration treatment of fingernail dermatophytosis: a randomized, double-blind study with terbinafine and griseofulvin. J AM ACAD Dm~ATOL 1995;32:72-7. 3. La Plata M Jr, Stinchi C, Venturo N, et al. Terbinafine vs griseofulvin in the treatment of onychomycosis due to dermatophytes. G Ital Dermatol Venereol 1994;129:19-22. 4. Villars B, Jones TC. Present status of efficacy and tolerabitity of terbinafine ~ s i l ) used systemically in the treatment of dermatomycosis of skin and nails. J Dermatol Treat 1990;l(suppl 2):33-8. 5. Faergemarm J, Zehender H, Millerioux L. Levels of terbinafine in plasma, stratum comeum, dermis-epidermis (without stratum comeum), sebum, hair and nails during
6. 7. 8. 9. 10. 1 I. 12.
13.
and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol 1994;19:121-6. Dykes PJ, Thomas R, Finlay AY. Determination of terbinafine in nail samples during systemic treatment of onychomycosis. Br J Dermatol 1990;123:481-6. Cribier B, Grosshans E. Efficacit6 et tol6rance de la terbinafine (Lamisil®) dans une s6rie de 50 onychomycoses dermatophytes. Ann Derm Venereol 1994; 121:15-20. Goodfields MJD. Short-duration therapy with terbinafme for dermatophyte onychomycosis: a multicentre trial. Br J Dermatol 1992;126(suppl 39):33-5. Roseeuw D, De Doncker P. New approaches to the treatment of onychomycosis, J AM ACAD DERMATOL 1993; 29:545-50. De Doncker P, Decroix J, Pierard G, et al. Antifungal pulse therapy for onychomycosis. Arch Dermatol On press.) Munro CS, Shuster S. The route of rapid access of drugs to the distal nail plate. Acta Derm Venereol (Stockh) 1992;72:387-8. Matthieu L, De Doncker P, Cauwenbergh G, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed - an investigation in onychomycosis. Clin Exp Dermatol 1991; 16:374-6. Baran R, Badillet G. Un dermatophyte ungu6al est-il n6cessairement pathog6ne? Ann Dermatoi Venereol 1983; I 10:629-31.
IIII
III
Treatment of dermatophyte nail infections: An open randomized study comparing intermittent terbinafine therapy with continuous terbinafme treatment and intenmttent itraconazole therapy AntoneUa Tosti, MD, a Bianca Mafia Piraccini, M~D, a Caterina Stinchi, MD, a Nicola Venturo, MD, a Federico Bardazzi, MD, a and Maria Delia Colombo, M D b
Bologna, Italy Background: Terbinafine persists in the nail at effective concentrations for several weeks after discontinuation of treatment.
Objective: Our purpose was to verify whether intermittent terbinafine therapy is effective in dermatophytic onychomycosis and to compare the results of intermittent terbinafine with those of intermittent itraconazole and continuous terbinafine treatment. Methods: An open, randomized study of 63 patients was performed with three treatment regimens: terbinafine, 250 mg daily (21 patients); terbinafine, 500 mg daily for 1 week every month (21 patients); or itraconazole, 400 mg daily for 1 week every month (21 patients). Treatment was continued for 4 months in toenail infections (60 patients) and 2 months in fingemail infections (3 patients). Results: At the end of the follow-up period (6 months after discontinuation of treatment) 16 of 17 patients (94.1%) with toenail onychomycosis were mycologicaUy cured in the terbinafine 250 mg group, 16 of 20 (80%) in the terbinafme 500 mg group, and 15 of 20 (75%) in the itraconazole group. Conclusion: The percentage of patients who were mycologicaUy cured was higher in the continuous terbinafine group than in the intermittent terbinafme and itraconazole groups, but statistical analysis did not reveal any significant difference between these cure rates. (J AM ACADDERMATOL1996;34:595-600.)
Terbinafine is an allylamine derivative with fungicidal properties against dermatophytes, l Studies have shown that terbinafine is more effective than griseofulvin in the treatment of onychomycosis caused by dermatophytes. 2-4 Terbinafine reaches the distal nail 1 week after initiation o f therapy and persists in the nail plate for 2 to 3 months after treatment is stopped. 5' 6 Terbinafine at a dosage of 250 mg daily produced cure rates of more than 80% in fingemail and toenail infections in 6 and 12 weeks, respectively.3, 7, 8
Intermittent administration of itraconazole has been proposed for the treatment of onychomycosis. 9 Itraconazole, 400 mg daily, taken for 1 week a month for 3 to 4 months produced mycologic cure rotes ranging from 64% to 72%. 1° The aim of this study was to verify whether intermittent therapy with terbinafine is effective in the treatment of dermatophytic nail infections and to compare the results of intermittent terbinafine treatment with those of intermittent itraconazole treatment and continuous terbinafine treatment. MATERIAL AND METHODS
From the Department of Dermatology, University of Bologna, and the Medical Department, Sandoz P.F., Italy? Supported in part by Sandoz PF, Milan, Italy. Accepted for publication Aug. 15, 1995. Reprint requests: Prof. Antonella Tosti, Department of Dermatology, University of Bologna Via Massarenti, 1; 40138 Bologna, Italy. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/1/68602
The trial was carded out according to the principles of the Declaration of Helsinki as well as of the subsequent amendments of Tokyo in 1975, Venice in 1983, and Hong Kong in 1989. The experimental design was open and randomized. Patients were given (1) terbinafine, 250 rag, one tablet daily; (2) terbinafine, 250 mg, two tablets daily for I week 595
596
Journal of the American Academy of Dermatology April 1996
Tos~etaL
Table L
Site of infection and causative dermatophytes in the different treatment groups
I T'meapedis ] Drop-outs (No.of (No.of Treatment
Terbinafine 250 mg (21 pts)
Site of infection (No.)
Toenails (16) Toenails and fingernails (3) Fingernails (2)
Terbinafine 500 mg (21 pts) Itraconazole 400 mg (21 pts)
Toenails (17) Toenails and fingemails (4) Toenails (18) Toenails and fingernails (2) Fingernails (1)
every month; or (3) itraconazole, 400 mg daily for 1 week every month. All patients were instructed to take the drug with a meal. Duration of treatment was 4 months for toenail infections and 2 months for fingernail infections. Patients were assigned sequentially to the treatment. The selection of the experimental design was obligatory. It was not possible to perform a double-blind study; a placebo-controlled double-blind study deemed likely to cause compliance problems. Patients who had taken systemic antifungal agents in the previous 6 weeks were excluded, as were patients with severe liver, renal, or cardiovascular disease and pregnant women. All patients were examined monthly up to 6 months after discontinuation of lreatment. At each visit, mycologic (direct microscopic examination and cultures) and clinical evaluation were performed. Clinical assessment of onycholysis, subungual hyperkeratosis, and nail discoloration was made on a 4-point scale (0=absent, 1 = mild, 2 = moderate, 3 = severe). Routine laboratory studies were performed at baseline and at the end of treatment. At the end of the follow-up period ( 10 months after the beginning of Ireatment for toenail infections and after 8 months for fingernail infections), patients were assigned to one of three categories: not mycologically cured, mycologically cured with residual nail malformation, and mycologically cured without residual nail malformation. Mycologic cure was defined as a negative culture and negative microscopic preparation. All patients who started treatment were considered able to be evaluated even if they withdrew the first day because of adverse events (intention to treat). The percentage of cured patients at the end of the follow-up period was compared between groups by the Fisher exact test. The
Causative dermatophyte
patients)
Trichophyton rubrurn (13) T. mentagrophytes (1) T. soudanense (2) T. rubrum (3) T. rubrum (!) Microsporum canis (1) T. rubrum (13) T. mentagrophytes (4) T. rubrum (4) T. rubrum (16) T. mentagrophytes (2) T. rubrum (2) T. rubrum ( 1)
6
patients)
2 4
5 1
severity of clinical signs was compared separately by Student's t test. RESULTS Sixty-three patients (31 men, 32 women; 27 to 60 years of age [mean 47.3 years]) entered the study; these included 51 patients with only toenail infection, nine patients with toenail and fingernail infection, and three patients with only fingernail infection (two in the terbinafine 250 mg group and one in the itmconazole group). The dermatophytes isolated in the three treatment groups, as well as the sites of the infection, are given in Table I. The statistical analysis showed no differences in the severity of onychomycosis between the three groups of patients. Three patients had to discontinue treatment in the first month of therapy because of factors not related to treatment and were considered as drop-outs (two in the terbinafine 250 mg group, one in the terbinafine 500 mg group). Therefore the statistical analysis of toenail infections is based on 57 patients: 48 with toenail and 9 with toenail plus fingernail onychomycosis.
Mycologic examination After 4 months of treatment, mycologic examination was negative in 13 of 17 patients (76.5%) with toenail onychomycosis treated with terbinafme, 250 mg; in 16 of 20 patients (80%) with toenail onychomycosis treated with terbinaflne, 500 mg; and in 13 of 20 patients (65%) with toenail onychomycosis treated with itraconazole, 400 mg.
Journal of the American Academy of Dermatology Volume 34, Number 4
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597
A Fig. 1. Distal subungual onychomycosis before (A) and 6 months after (B) terbinafme 500 mg/day, 1 week per month for 4 months. Table II. Final assessment of patients at the end of the follow-up period Results
250 mg
500 mg
Itraconazole 400 mg
Failure MycologicaUycured with nail deformities Mycologicallycured without nail deformities$
1/19" (5.2%) 3/19" (15.8%) 15/19" (78.9%)
4/20 (20%) 6/20 (30%) 10/20 (50%)
5/215- (23.8%) 8/21t (38.1%) 8/215"(38.1%)
Terbinafine
1
Terbinaflne
*Including two patients with exclusive fingernail infection. tIncluding one patient with exclusive fingernail infection. SFisher exact test is significant (p = 0.013) between the terbinafine 250 mg group and the itraconazole group.
At the end of the follow-up period 16 of 17 patients (94.1%) with toenail onychomycosis were mycologicaUy cured in the terbinafine 250 mg group, 16 of 20 (80%) in the terbinafine 500 mg group, and 15 of 20 (75%) in the itraconazole 400 mg group. All three patients with only fingernail infection were mycologically cured at the end of the 2-month treatment period with terbinafine, 250 mg (two patients), and itraconazole, 400 mg (one patient). Final assessment Final assessment of patients at the end of the follow-up period is reported in Table II. In the terbinafine 250 mg group, 13 of 17 patients (76.5%) with toenail infections were cured without residual malformation. The two patients with only fingernail infection were also cured. Two of the three patients
with residual nail malformation had nail abnormalities unrelated to onychomycosis: splinter hemorrhages (one patient) and traumatic onycholysis (one patient). The remaining patient had a small band of residual distal subungual hyperkemtosis. In the terbinafine 500 mg group, 10 of 20 patients with toenail infections (50%) were cured without residual malformation (Fig. 1). Two of six patients with residual nail malformation had traumatic nail deformities not related to onychomycosis: "pincernail" deformity (one patient) and traumatic onycholysis (one patient). Three patients had a small band of residual distal subungual hyperkeratosis and onycholysis. The remaining patient had mild distal subungual hyperkemtosis associated with a longitudinal white streak. In the itraconazole 400 mg group, 7 of the 20 patients with toenail infections were cured with-
598 Tosti et al:,
Journal of the American Academy of Dermatology April 1996
malformation (one in the terbinafine 500 mg group and one in the itraconazole group).
Tolerability Drug-related adverse effects were reported in two patients while taking 250 mg of terbinafme (one patient with itch) and 500 mg of terbinafine (one patient with diarrhea). No significant laboratory abnormalities were observed. DISCUSSION
A
Fig. 2. Distal subungual onychomycosis before (A) and 6 months after (B) itraconazole treatment. Residual nail abnormalities are traumatic; they are not related to infection.
out residual malformation (35%). The patient with an exclusive fingernail infection was also cured without malformation. Six of eight patients with residual nail malformation had nail abnormalities unrelated to onychomycosis: splinter hemorrhages (one patient), Beau's lines (one patient), nail bed hematoma (one patient), onychogryphosis (one patient), traumatic onycholysis (one patient), melanonychia (one patient). Two patients had linear subungual hyperkeratosis extending to the proximal nail plate. The fingernails of the nine patients with toenail and fingernail infection (terbinafine 250 mg group, t~ee patients; terbinafine 500 mg group, four patients; itraconazole 400 mg group, two patients) were all mycologicaUy and crmically cured, even in patients whose toenails failed to respond to treatment (one in the terbinafine 250 mg group and one in the itmconazole group), or were cured with residual nail
This study confirms the efficacy of terbinafine and itraconazole in the treamaent of dermatophyfic nail infections. Continuous terbinafine cured 94% of patients with toenail onychomycosis, and intermittent terbinafine cured 80%. Our results also indicate that intermittent terbinafine treatment is as effective as intermittent itraconazole treatment for dermatophytic nail infections. All three treatment regimens were well tolerated and no serious side effects were seen. Although the percentage of patients who were mycologically cured was higher in the continuous terbinafine group (94%) than in the intermittent terbinafme (80%) and itraconazole (75%) groups, statistical analysis did not reveal any significant difference between the cure rates with the three different regimens. Clinical evaluation at the end of the follow-up period revealed completely healthy nails in only 30 of 47 patients with toenail onychomycosis who were mycologicaUy cured. The percentage of patients who were mycologically cured without nail deformities was significantly higher in the continuous terbinafine group than in the intermittent iWaconazole group (Fisher's exact test, p = 0.013). Examination of the 17 patients with residual nail abnormalities revealed traumatic nail lesions in 10 patients (Fig. 2). Although these abnormalities were not due to persistence of fimgi in the nail, it is possible they could be a predisposing factor for future reinfection. In four of the remaining seven patients (three in the terbinafine 500 mg group and one in the terbinafine 250 mg group) the nail abnormalities consisted of a distal band of residual subungual hyperkeratosis and onycholysis. Sequential clinical photographs show that this band was progressively moving distally every month. This indicates that the follow-up period (10 months) was not long enough to obtain complete regrowth of the toenail. In all patients the onychomycosis involved the entire nail plate before treatment.
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Fig. 3. Distal subungual onychomycosis before (A) and 6 months after (B) terbinafine 500 rag. Note persistent linear band of infection along lateral nail plate. The other three patients (two in the itraconazole group and one in the terbinafine 500 mg group) had nail changes that were difficult to interpret at the final assessment because their clinical features were suggestive of persistence of onychomycosis although microscopic examinations and cultures were repeatedly negative. Treatment failures Despite the high efficacy of new antifungal agents, a considerable number of patients with onychomycosis still fail to respond to treatment. Ten of the 57 patients (17.5%) with toenail onychomycosis who completed the study still had positive cultures at the end of the follow-up period. Two of these patients had a concomitant fingernail infection that was cured. Failures were more common in patients treated with intermittent regimens (either terbinafine or itraconazole) than in patients treated with continuous terbinafine. Patients unresponsive to treatment were not significantly different from those who responded regarding duration of onychomycosis, presence of proximal nail plate invasion, and the causative species. The retrospective analysis of the clinical data and examination of the clinical features did not offer any clue to predict which patients would be a treatment failure. Clinically, patients who were not cured can be di-
vided into three groups. In 4 of 10 patients, treatment produced clearing of onychomycosis only in some affected nails (two patients) or in some areas but not in other areas of the same nail (two patients). Fungi frequently persisted only along narrow linear streaks that apparently followed the longitudinally oriented nail bed epidermal ridges (Fig. 3). This could possibly reflect poor distribution of the drug in some areas of the nail that remained infected during treatment and became a source of reinfection a few months after treatment was stopped. Baran believes that the persistence of a linear band of infection along the lateral edge of the nail occurs because the nail plate does not adhere to the nail bed there (unpublished data). Because itraconazole and terbinafine mainly diffuse to the nail plate through the nail bed, these drugs might not reach therapeutic concentrations in such sites. TM12 In five patients, treatment did not produce any clinical alleviation of the onychomycosis, which persisted unchanged or even worsened during therapy. Failure in these cases could be caused by poor penetration of the drug in the nail. We have not been able to verify this by monitoring the anfifungal levels in the nails of these patients during and after treatment. The remaining patient (itraconazole group) had an unexpected previously reported response to treatment,7 she had complete clearing of her nails
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a l t h o u g h Trichophyton r u b r u m w a s constantly isolated f r o m h e r nails during treatment a n d follow-up. L o n g - t e r m f o l l o w - u p will possibly clarify w h e t h e r T. r u b r u m is acting as a c o m m e n s a l rather than as a p a t h o g e n as has b e e n suggested b y others. 13 REFERENCES
1. Balfour JA, Faulds D. Terbinafine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drags 1992;43:259-84. 2. Haneke E, Tausch I, Brautigam M, et al. Short-duration treatment of fingernail dermatophytosis: a randomized, double-blind study with terbinafine and griseofulvin. J AM ACAD Dm~ATOL 1995;32:72-7. 3. La Plata M Jr, Stinchi C, Venturo N, et al. Terbinafine vs griseofulvin in the treatment of onychomycosis due to dermatophytes. G Ital Dermatol Venereol 1994;129:19-22. 4. Villars B, Jones TC. Present status of efficacy and tolerabitity of terbinafine ~ s i l ) used systemically in the treatment of dermatomycosis of skin and nails. J Dermatol Treat 1990;l(suppl 2):33-8. 5. Faergemarm J, Zehender H, Millerioux L. Levels of terbinafine in plasma, stratum comeum, dermis-epidermis (without stratum comeum), sebum, hair and nails during
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and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol 1994;19:121-6. Dykes PJ, Thomas R, Finlay AY. Determination of terbinafine in nail samples during systemic treatment of onychomycosis. Br J Dermatol 1990;123:481-6. Cribier B, Grosshans E. Efficacit6 et tol6rance de la terbinafine (Lamisil®) dans une s6rie de 50 onychomycoses dermatophytes. Ann Derm Venereol 1994; 121:15-20. Goodfields MJD. Short-duration therapy with terbinafme for dermatophyte onychomycosis: a multicentre trial. Br J Dermatol 1992;126(suppl 39):33-5. Roseeuw D, De Doncker P. New approaches to the treatment of onychomycosis, J AM ACAD DERMATOL 1993; 29:545-50. De Doncker P, Decroix J, Pierard G, et al. Antifungal pulse therapy for onychomycosis. Arch Dermatol On press.) Munro CS, Shuster S. The route of rapid access of drugs to the distal nail plate. Acta Derm Venereol (Stockh) 1992;72:387-8. Matthieu L, De Doncker P, Cauwenbergh G, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed - an investigation in onychomycosis. Clin Exp Dermatol 1991; 16:374-6. Baran R, Badillet G. Un dermatophyte ungu6al est-il n6cessairement pathog6ne? Ann Dermatoi Venereol 1983; I 10:629-31.