ARTICLE
Tinea
pedis, commonly known as athlete's foot, is the most frequent dermatophytosis.
It is caused by a series of Dermatophytes, with worldwide predominance of
Trichophyton rubrum as the main causal agent. It is a cosmopolitan
condition seen most often in adults. It may have three different clinical
presentations, the most frequent one being the interdigital form, followed
by the plantar hyperkeratotic one, also known as moccasin-type, and the
inflammatory or vesiculobullous variety, which is the least common one.
It is important to state that these varieties may coexist, particularly
plantar hyperkeratotic and interdigital tinea pedis [1, 3].
Treatment of tinea pedis is usually variable. There is a series of medications
available in various presentations (creams, solutions, powders). The best-known
antifungal agents are imidazoles: clotrimazole, miconazole, ketoconazole,
etc., as well as alilamines: terbinafine and naftifine. In general, good
outcomes are obtained with most topical treatments. However, systemic
antifungal agents like itraconazole and terbinafine, lead to better results
and contribute to reduce the length of treatment [2, 3]. With the safe
use of itraconazole pulses, equivalent to 400 mg/day for one week, the
treatment period is short (one week) and proper itraconazole levels are
achieved in the stratum corneum for over two months. This treatment has
been used with appropriate clinical and mycologic results [4, 5].
Methods
A prospective, open-design, non-comparative clinical trial was conducted
at the Dermatology Service, General Hospital of Mexico. This study included
initially 58 patients, only 44 of whom completed all the phases of the
study and met all the criteria. The age range of those 44 patients was
18-65 years. All of them had clinically and mycologically proven interdigital
or mild hyperkeratotic tinea pedis, or both, without onychomycosis. Patients
were consecutively screened and enrolled in the study if they met the
following inclusion criteria: no use of topical antifungal agents 30 days
prior to enrolment; no use of systemic antifungal agents during the 2
months prior to the study. Patients with chronic processes or conditions
were excluded (like gastric, liver and hematological disorders, immunosupression,
etc.), as well as women of childbearing age, pregnant and lactating women.
Patients with known hypersensitivity to itraconazole or taking drugs with
known interactions were also excluded [6].
Before drug administration, the major clinical signs and symptoms were
evaluated. Tinea pedis was confirmed through direct examinations with
potassium hydroxide (KOH) and the isolation of the causal agent in the
usual Sabouraud dextrose agar and Mycosel agar (Sabouraud media + cloramphenicol
& cicloheximidie). Treatment consisted of the oral administration
of 400 mg/day of itraconazole for 7 days, distributed in two daily doses
(200 mg or 2 capsules) after breakfast and dinner; this is equivalent
to one pulse of itraconazole. Clinical and mycologic control exams were
conducted at baseline (B = baseline) and upon completion of treatment
(F); two follow-up visits were scheduled at 30 and 60 days after the end
of treatment. Probable side effects were evaluated. In case of a serious
adverse reaction, medication should be discontinued.
Results
The study included 44 patients, 27 males and 17 females; the youngest
patient was 18 years old, the oldest was 65, mean age was 32.1 years.
Table I summarizes most
of the demographic data. All patients presented with clinically and mycologically
proven tinea pedis that was not associated with onychomycosis. According
to the clinical classification, 11 (25%) cases had interdigital (intertriginous)
tinea pedis and 7 (16%) had the mild hyperkeratotic type; most of them,
26 (59%), had both types.
From the aetiologic standpoint, T. rubrum was isolated in 41/44
patients (93%), most of the times as the single causal agent, and it was
found in combination with C. albicans in two patients (4.5%). The
second most common causal agent was T. interdigitale, found in
3/44 isolates (6.8%).
Table II shows the clinical
efficacy results. Cure represents the clinical and mycologic cure; improvement
means clinical changes and a positive KOH, and failure means a few clinical
changes as well as combined positive KOH and culture. Three assessments
were made, upon completion of treatment, and at the one- and two-month
follow-up visits. The final result of the evaluation (at 60 days of follow-up)
was 2 failures (4.5%), 5 improvements (11.3%), and 37 cures (84.4%) (Fig.
1). The two failures corresponded to mixed tineas (interdigital plus
hyperkeratotic) with T. rubrum as causal agent. Of the cases that
improved, 4 were mixed tineas and one was hyperkeratotic tinea, with T.
rubrum as the causal agent. Two patients who also had tinea of the
hands (palmar) achieved clinical and mycologic cure in both locations.
Concerning adverse events, 3 cases were reported (6.6%). One of them
was a moderate headache in the middle of the treatment period; the other
two had moderate dyspepsia. None of the 3 cases needed to discontinue
the medication and were therefore evaluated for treatment efficacy. Cure
was achieved in 2/3 cases and the third one improved.
Discussion
Itraconazole may be administered to treat tinea pedis according to three
different treatment regimens: 100 mg/day for 4 weeks; 200 mg/day for 2
weeks or the regimen used in this study, consisting of one 400 mg/day
pulse for one week. All three regimens result in a similar cumulative
dose, that is, a total of 2.8 g of itraconazole. However, other studies
report even better results with the latter regimen. For instance, in a
multicenter trial Gupta et al. [4] obtained the following cure
rates: 67% with the first regimen, 65% with the second one, and 85% with
the third. The latter outcome is very similar to what we obtained in our
study and is comparable to what other authors have reported [7-9]. Tausch
et al. [10] obtained a higher cure rate in a study comparing one
week of itraconazole therapy 400 mg/day (one pulse) versus two weeks of
terbinafine 250 mg/day. Cure rates were 93% and 91% respectively, without
any significant differences.
Itraconazole is a triazole derivative with a high affinity for keratinized
tissues. It is mostly excreted through the sebaceous glands and moderately
by the sweat glands. It is important to emphasize that the stratum corneum
in the palms and soles is 30-50 times thicker, without any sebaceous excretion
and only a limited sweat excretion. This is why at higher doses, itraconazole
reaches higher concentrations in the stratum corneum and, according to
its pharmacokinetics, at such concentrations it behaves like a "reservoir"
drug whose levels continue to increase even after the treatment has been
discontinued. In fact, Table
II shows that a clinical and mycologic cure rate of only 27% is obtained
at the end of treatment; however, by the final follow-up visit it had
increased to 84%, reflecting the influence of the incorporation of the
itraconazole into the basal cells of the epidermis and migration during
the normal turnover of keratinocytes (keratopoiesis) [4, 9-11].
In general, this study included only patients with interdigital and
hyperkeratotic tinea or with a combination of both (75%). No cases of
inflammatory vesiculobullous tinea were included, since the treatment
criteria that apply to this variety are different from the ones used here.
The predominance of hyperkeratotic tineas is important because this variety
is thought to require more than one systemic therapy, unlike the interdigital
variety, which usually responds well to both types of therapy [1, 2, 12].
Our objective was not to assess the effectiveness of this medication in
the treatment of palmar tinea, which was not an exclusion criterion. The
two patients who presented with the classical syndrome of "both feet and
one hand" had an appropriate treatment response; this has been previously
reported in the literature [13]. The cure rate at 60 day follow-up was
of 37 patients (84.4%) compared to 41 patients (93.1%) at 30 day follow-up;
this decrease is difficult to explain, but we believe that the increase
in follow-up period allows re-infection or relapse. Concerning the aetiology
(Table I), a clear predominance
of T. rubrum was observed (89%), followed by T. interdigitale.
This is consistent with the causal agents reported in the literature.
Mixed cases of T. rubrum and C. albicans, which were 2 in
the study, are relatively frequent. However, since itraconazole is a broad-spectrum
agent and is also effective against Candida-type of yeast, this
makes no difference from the therapeutic viewpoint. It is important to
stress that our efficacy results are preliminary as a placebo-controlled
study, and could be compared with studies with terbinane at doses of 250
mg/day for two weeks [10].
It is important to point out that one of the
exclusion criteria was onychomycosis, because a single pulse of itraconazole
(one week) is insufficient to cure onychomycosis and the latter would
therefore represent a source of reinfection of patients. In fact, this
study resulted from the investigation of pulse administration of itraconazole
[14], since after one week and at the one-month follow-up patients with
interdigital and hyperkeratotic tinea had virtually reached clinical cure.
Overall the study was safe, since only 3 cases with side effects attributable
to itraconazole were reported (6.6%). All of them were minor and did not
require the discontinuation of the medication. Not only is the number
of side effects not increased when pulse therapy with itraconazole is
used, particularly in cases of onychomycosis, but their number is even
decreased when compared with continuous therapy. In a recent review of
this dosage, adverse effects were reported in only 5% of cases, with the
most important ones being: nausea, abdominal pain, headache and dyspepsia
[5]. Side effects reported in our study were one moderate headache and
two cases of dyspepsia.
CONCLUSION
The treatment of interdigital or plantar hyperkeratotic tinea pedis or
the combination of both with one pulse of itraconazole, or 400 mg/day,
for one week, led to clinical and mycologic cure rates of 84%. This regimen
was safe, with few side effects. We think it is the shortest and most
effective therapy for most cases of tinea pedis.
Article accepted on 13/12/01
REFERENCES
1. Leyden JL. Tinea pedis pathophysiology and treatment. J
Am Acad Dermatol 1994; 31: S31-3.
2. Brooks KE, Bender JF. Tinea pedis: diagnosis and treatment.
Clin Podiatr Med Surg 1996; 13: 31-46.
3. Lambert J, Richert B, Dezfoulian B, et al. Epidemiology,
physiopathology and treatment of a frequent ailment of tinea pedis. Rev
Med Liege 2000; 55: 161-168.
4. Gupta AK, De Doncker P, Heremans A, et al. Itraconazole
for the treatment of tinea pedis: a dosage of 400 mg/day given for a week
is similar in efficacy to 100 or 200 mg/day given for 2 to 4 weeks.
J Am Acad Dermatol 1997; 36: 789-792.
5. Gupta AK, Lambert J, Revuz J, Shear L. Update on the safety
of itraconazole pulse therapy in onychomycosis and dermatomycoses.
Eur J Dermatol 2001; 11: 6-10.
6. Katz HI. Drug interactions of the newer oral antifungal agents.
Br J Dermatol 1999; suppl. 56: 26-32.
7. Svejgaard E, Avntorp C, Wanscher B, et al. Efficacy
and safety of short-term itraconazole in tinea pedis: a double-blind,
randomized, placebo-controlled trial. Dermatology 1998; 197: 368-72.
8. Schuller J, Remme JJ, Rampen FH, Van Neer FC. Itraconazole
in the treatment of tinea pedis and tinea manuum: a comparison of two
treatment schedules. Mycoses 1998; 41: 515-20.
9. Decroix J. Tinea pedis (mocassin-type) treated with itraconazole.
Int J Dermatol 1995; 34: 122-4.
10. Tausch I, Decroix J, Gwiezdzinski Z, et al. Short-term
itraconazole versus terbinafine in the treatment of tinea pedis and manus.
Int J Dermatol 1998; 37: 140-2.
11. Cauwenberg G, Degreef H, Heykants J, et al. Pharmacokinetic
profile of orally administered itraconazole in human skin. J Am Acad
Dermatol 1988; 18: 263-8.
12. Tanuma H. Pathogenesis and treatment of hyperkeratotic tinea
pedis in Japan. Mycoses 1999; 42: 21-8.
13. Seeburger J, Scher RK. Long-term remission of two feet-one
hand syndrome. Cutis 1998; 61: 149-51.
14. Bonifaz A, Carrasco-Gerard E, Saúl A. Itraconazole
in onychomycosis: intermittent dose schedule. Int J Dermatol 1997;
36: 70-2.
|
Printable version
