ARTICLE
The treatment for tinea corporis and tinea cruris is extremely
varied; current treatment schemes include topic imidazoles such as clotrimazole,
miconazole, ketoconazole and others, which achieve high cure rates but
require diverse treatment times ranging from 2 to 6 weeks. Terbinafine,
a wide range synthetic allylamine particularly active against most dermatophytes,
can be administered systemically or topically. The topical formulation
has been extensively employed in short-term treatment periods (usually,
once daily for a week) in the 1% cream presentation, obtaining high cure
rates (80-90%) [1-6]. Recently, two novel terbinafine formulations have
been specifically created for application in extensive skin areas and
hairy parts of the body [7]: a 1% solution and a 1% emulsion-gel (Derm-gel).
Faergemann et al [8] have demonstrated that application of the
emulsion-gel presentation results in a high concentration of the drug
in the skin, including the stratum corneum, reaching concentrations well
above the minimal inhibitory concentration for most dermatophytes. Moreover,
its slow elimination half-life allows terbinafine to retain its action
for an additional 2 to 3 weeks after only one week of topical application.
Methods
An open, comparative, prospective study including 65 patients between
the ages of 12-79 years from the Dermatology Service of the General Hospital
of Mexico was performed. All patients presented clinically and mycologically-confirmed
tinea corporis and tinea cruris. Patients were enrolled
in the study and randomly assigned to one of 2 treatment groups: one arm
received 1% terbinafine emulsion-gel, while the other was given 2% ketoconazole
cream. Patients had been without topical antifungal treatment for the
previous 15 days and systemic antimycotics during the previous 2 months.
Patients presenting chronic diseases or processes (such as haematological
or hepatic alterations, immunosuppression, etc.), pregnant or lactating
women and patients with known hypersensitivity to terbinafine, ketoconazole
or any of the formula components, were excluded from the study.
Treatment for the terbinafine arm included a once daily application
with 1% emulsion-gel for 1 week (7 days), whereas patients in the ketoconazole
arm were administered a once daily application with 2% cream during 2
weeks (14 days). Complete clinical assessments of the main signs and symptoms
and mycological tests (KOH and cultures) were performed at visit 1 (baseline),
at the corresponding end-of-treatment visit (either 7 or 14 days, for
the terbinafine or the ketoconazole arms, respectively), and 15 days after
the last application of the trial drugs (follow-up). Probable adverse
events, tolerability and cosmetic acceptance were recorded at each visit.
Statistical analyses at the end of the study included the following: Fisher's
exact test (X2) and Conhran-Mantel-Haenszel (XM-H)
for the qualitative variables, and Student's t test (t) and Wilcoxon's
score ranges (z) for the quantitative variables.
Results
The study population (n = 65) included 39 male and 26 female patients,
the youngest being 12 and the oldest 79 years old, with a mean age of
37.1 years. Both study groups were demographically similar, the only exception
being gender, since the ketoconazole arm presented a predominance of males
(24/32). Table I summarises the most relevant demographic data,
as well as the etiological agents isolated from the cultures from the
samples obtained at the baseline visit. Both groups presented a clear
predominance of Trichophyton rubrum as the most frequently isolated
infective agent; it occurred in 72.8% of the 1% terbinafine emulsion-gel
group and in 84.4% of the 2% ketoconazole cream group. The distribution
of tinea corporis and tinea cruris (35/30) was very similar.
An evaluation of all the relevant clinical signs and symptoms was performed;
no significant difference was observed between the groups (p = 0.088).
The mycological assessment, however, did show a statistically significant
difference (p = 0.027) favouring terbinafine over ketoconazole; the same
was true (p = 0.002) for the overall assessment, which is the sum of the
clinical plus the mycological data. At the end-of-treatment evaluation
the following mycological results were obtained: the terbinafine emulsion-gel
arm presented 6 positive KOH examinations and 3 positive cultures (2 Microsporum
canis and 1 Candida albicans) and the ketoconazole arm had
11 positive KOH results and 7 positive cultures (all of them T. rubrum).
At the end of the follow-up period (15 days after the last application
of either study medication), 2 positive KOH results and 1 positive culture
(M. canis) were obtained in the terbinafine group, whereas the
ketoconazole group presented 9 positive KOH examinations and 5 positive
cultures (T. rubrum); this difference was demonstrated to be statistically
significant (p = 0.027).
Although only one adverse event occurred in the terbinafine emulsion-gel
group (3%) compared to 3 in the ketoconazole cream group (9%), this difference
was not statistically relevant. The adverse events reported were all contact
dermatitis phenomena, related to the study medications or their formulations;
all were classified as mild, and only one required treatment discontinuation.
As determined by the patients themselves, the tolerability of the study
medication was evaluated as excellent by 32/33 (97%) and as moderate by
1/33 (3%) of the patients in the terbinafine group. In contrast, 21/32
(65%) of the patients in the ketoconazole group considered the trial drug
to be excellent, 7/32 (22%) good, 3/32 (9%) moderate and 1/32 (4%) poor.
As a whole, terbinafine emulsion-gel was significantly better tolerated
(p = 0.003) than ketoconazole cream.
Discussion
The present study showed terbinafine emulsion-gel to be significantly
more effective than ketoconazole cream, despite the fact that the former
was only applied for 1 week and the latter for 2 weeks. We decided to
compare terbinafine emulsion-gel to ketoconazole cream for two main reasons:
terbinafine has been previously described as a very effective short-term
treatment topical antifungal [4, 5, 7], and ketoconazole, particularly
the topical presentation, is considered by many researchers to be the
"gold standard" drug.
The decrease of tinea signs and symptoms in both arms of the study was
similar and without any significant differences; both groups showed a
decrease of more than 50% of the clinical variables by the middle of the
study period. This decrease was apparent within a shorter period in the
terbinafine group, probably due to its shorter treatment time. Although
the demographic data of the 2 study arms were similar, there was a clear
predominance of male patients in the ketoconazole group; we consider this
to be irrelevant to the interpretation of the results, since the type
of tinea encountered in each group (corporis and cruris)
was uniformly distributed among the study arms (Table
I).
The first clinical trials performed with the terbinafine emulsion-gel
presentation were for the treatment of pityriasis versicolor, where good
cure rates and tolerability were achieved [9]. Two studies [10, 11] similar
to this one have recently published results which correlate with those
obtained by us; for example, Heerden et al [11] reported a mycological
cure rate of 85% and a complete cure in 59% of the cases studied; we obtained
slightly better results, finding 94% and 72%, respectively (Table
II). Regarding etiological agents, it is noteworthy that both
groups were comparable, T. rubrum being the most frequently isolated
agent, followed by M. canis. At the follow-up evaluation, 5 positive
T. rubrum cultures were obtained in the ketoconazole group and
only one M. canis in the terbinafine one. The statistically significant
differences indicated that terbinafine was more effective than ketoconazole
in the control of T. rubrum infection, and a little less so in
the treatment of M. canis mycoses. In fact, terbinafine has been
demonstrated to be less effective against the latter etiological agent
[12], particularly in tinea capitis, for which we propose the use
of terbinafine gel for double the recommended treatment time, a measure
that might result in an increased probability of eradicating this dermatophyte.
We believe the excellent effectivity resulting from the short-term treatment
scheme with the terbinafine emulsion-gel presentation, better than the
one obtained with the cream and gel formulations [4, 6, 7], lies in its
broad spectrum of activity and its capacity to penetrate rapidly and remain
in keratinized tissues.
Terbinafine was generally well tolerated and cosmetically accepted.
One patient on terbinafine emulsion presented a contact dermatitis reaction
as an adverse event; this had not been reported previously [9-11]. It
is noteworthy that this patient was under concomitant treatment with carbamazepine,
a drug that in our experience elicits contact dermatitis-like collateral
events when administered with diverse topical antimycotics, as well as
a cutaneous pigmentation when combined with terbinafine cream and systemic
azoles (fluconazole and itraconazole). We therefore assume that the collateral
event observed was probably elicited by carbamazepine. In contrast, ketoconazole
cream generated 3 cases of dermatitis; a situation that some authors suggest
is caused by the vehicle rather than by the active principle itself. Unfortunately
we are unable to discuss issues such as cost/cure or the economic advantage
of one over the other since terbinafine emulsion-gel is as yet commercially
unavailable.
CONCLUSION
We conclude that 1 week of treatment with 1% terbinafine emulsion-gel
applied once daily is significantly more effective for the control of
tinea corporis and tinea cruris than 2% ketoconazole applied
once daily for 2 weeks, both in terms of clinical and mycological cure
rates. Both medications were generally well tolerated. Terbinafine was
superior to ketoconazole in cosmetic terms. Both drugs presented few collateral
events of the contact dermatitis type; the majority of these were found
in the ketoconazole group (3/4).
Article accepted on 18/11/99
REFERENCES
1. Gupta AK, Saunder D, Shear NH. Antifungal agents: an overview.
Part I. J Am Acad Dermatol 1994; 30: 677-98.
2. Clynton YM. In vitro activity of terbinafine. Clin
Exp Dermatol 1989; 14: 101-3.
3. Villars V, Jones TC. Clinical efficacy and tolerability of
terbinafine (Lamisil). A new topical and systemic fungicidal drug for
treatment of dermatomycoses. Clin Exp Dermatol 1989; 14: 124-7.
4. Zaias N, Berman B, Cordero CN, et al. Efficacy of a
1-week, once-daily regimen terbinafine 1% cream in the treatment of tinea
cruris and tinea corporis. J Am Acad Dermatol 1993;
29: 646-8.
5. Evans EG, Seaman RA, James IG. Short-duration therapy with
terbinafine 1% cream in dermatophyte skin infections. Br J Dermatol
1994; 130: 83-7.
6. Greer DL, Jolly HW. Treatment of tinea cruris with
topical terbinafine. J Am Acad Dermatol 1990; 23: 800-4.
7. Evans EGV. Topical terbinafine (Lamisil) for superficial mycoses:
High cure rates in short treatment times. J Dermatol Treat 1998;
9 (suppl. 1): S13-6.
8. Faergemann J, Zehender H, Boukhabza A, et al. Comparison
of terbinafine levels in stratum corneum and dermis-epidermis (without
stratum corneum) after topical or topical combined with oral therapy in
healthy volunteers. J Eur Acad Derm Vener 1995; 5 (suppl.1): S94
(abs. 016).
9. Faergemann J, Hersle K, Nordin P. Pityriasis versicolor: clinical
experience with lamisil cream and lamisil derm-gel. Dermatology
1997; 194 (suppl 1): 19-21.
10. Lebwohl M, Hall ML. Terbinafine (1%) solution and emulsion
gel: two new formulations in one-week treatment of tinea pedis
and tinea corporis/cruris. Abstracts. World Congress of Dermatology.
Sydney, 1997, (P-5177).
11. Van Heerden JS, Vismer HF. Tinea corporis/cruris:
New treatment options. Dermatology 1997; 194 (suppl. 1): 14-8.
12. Gupta AK, Shear NH. Terbinafine an update. J Am Acad Dermatol
1997; 37: 979-88.
|
Printable version
