ARTICLE
Definition and epidemiology of dermatomycoses
Mycosis is defined as an infection with fungi, be they dermatophytes,
yeasts or moulds. Dermatomycosis is an infection with fungi related to
the skin: glabrous skin, hair and/or nails. Onychomycosis in particular
is an infection with fungi of the finger- or more often of the toenails.
Fungal skin disease is most often due to dermatophyte infection. Such
a type of skin disease is called dermatophytosis or tinea.
Among the relevant pathogens Trichophyton rubrum is the most
common cause world-wide of tinea pedis, onychomycosis, tinea cruris, and
tinea corporis. Although the incidence of tinea capitis is decreasing
in highly developed countries, it is still a problem in Eastern Europe,
Africa, Asia, and South America. The main pathogenic agent of tinea capitis
is Microsporum canis in highly developed countries and Trichophyton
violaceum in other parts of the world [1]. Among the various fungal
infections of the skin onychomycosis is the one most difficult to treat,
followed by the hyperkeratotic variant of tinea pedis. In Europe there
seems to be an average frequency of fungal nail disease amounting to 2
to 5% [2] with a higher prevalence in older people. Mycoses have significant
negative social, psychological, occupational, and health effects. Treatment
of dermatomycoses in general and onychomycoses in particular is not merely
for aesthetic reasons. Pertinent infections can compromise the quality
of life to a remarkable extent [3].
Diagnostics of dermatomycoses
Before therapy, the diagnosis of fungal skin disease must be established
on clinical and laboratory grounds. The first step is the microscopic
examination of sample material after one hour's incubation in 15 to 20%
potassium hydroxide (KOH) solution in a wet chamber. In the case of an
infection mycelial material can be seen. Sensitivity of the procedure
can be enhanced by the addition of a blancophore and the use of fluorescence
microscopy. The second step is the cultural differentiation of the pathogen
at species level by macroscopic and microscopic inspection assessing growth
form, surface, colour, macro- and microconidia and further parameters
whose assessment is based on subcultures [4].
Treatment of dermatomycoses: general
aspects
Before the introduction of griseofulvin in 1959 cutaneous mycoses were
treated topically. For a long time griseofulvin was virtually the only
available systemic antimycotic agent. The development of imidazoles and
triazoles meant the next big step forward. In addition to these azole
agents the allylamine terbinafine has recently been introduced as an antimycotic
agent with extraordinarily high activity against dermatophytes in vitro
[5].
In the planning of therapy for cutaneous fungal infections, many different
criteria must be taken into account. Especially, the following questions
must be asked :
* Is there just a suspicion of infection or has a cutaneous mycosis
been proven?
* Is the infectious agent culturally identified on species level?
* Which parts of the body are affected?
* How severe is the affection?
* Is it a primary infection or a relapse?
* Are there underlying illnesses compromising the immune situation of
the host?
* Does the patient take other drugs?
In many cases the therapy of cutaneous mycoses will be primarily a topical
one. This in particular applies to non-severe cases of dermatophytosis
of glabrous skin, where hyphae are only present in the stratum corneum.
For topical therapy, among others the azoles bifonazole, clotrimazole,
econazole, ketoconazole, miconazole, and sertaconazole, the morpholine
amorolfine, the allylamines naftifine and terbinafine and the hydroxypyridone
ciclopiroxolamine, are available.
With respect to therapy for superficial fungal skin infections terbinafine
cream and sertaconazole cream have been proven superior to others on the
list [6, 7]. With the use of topical agents the type of vehicle plays
an important role, too. e.g., liposomal encapsulation seems to
influence the efficacy of a conventional agent such as econazole [8].
With respect to some types of fungal skin disease, however, it appears
wise to start with systemic therapy right away.
This is the case in the following contexts:
* Extensive forms of tinea of glabrous skin, in which topical therapy
would fail
* Hyperkeratotic tinea (affecting palms and soles)
* Onychomycosis affecting > 30% of the nail plate
* Relapse of disease following topical treatment.
Onychomycosis especially is a prime indication for the primary use of
systemic antimycotics. With an affection of less than 30% of the nail
plate topical therapy can be successful. In other cases a systemic therapy
should be chosen from the start [9] (Table
I). This applies particularly to the most common type, distal
subungual onychomycosis (DSO). In addition to onychomycosis hyperkeratotic
tinea affecting the soles and palms often causes therapeutic problems
with topical therapy. For this indication a systemic treatment should
be chosen, if topical treatment fails or if it is likely that topical
treatment would fail.
Griseofulvin
Griseofulvin is a compound synthesised by some Penicillium spec.
It has been used for treatment of cutaneous mycoses and onychomycoses
since 1959. The only route of application is peroral. The in vitro
activity of griseofulvin is limited to dermatophytes. With time griseofulvin
has ceased to be the gold standard for systemic therapy. Since the introduction
of the newer systemic azoles it is rarely used in the western world. It
initiates a fungistatic mechanism of action due to interaction with microtubuli
associated proteins and through that, inhibition of fungal cell mitosis
(Table II). With the ultramicrosize
preparation the highest rate of absorption can be found [10]. Even with
this best absorbed preparation the cure rates for toenail onychomycoses
are lower than 40% despite treatment periods of one year and more [11]
(Table III).
Ketoconazole
Ketoconazole has been used since the eighties in the systemic therapy
of onychomycoses and severe tinea of glabrous skin. The cure rates in
most cases are similar to those following griseofulvin. Over time it became
clear that ketoconazole can induce hepatitis due to idiosyncrasy, with
fatal outcome. For that reason ketoconazole is no longer used for onychomycosis.
The approval for systemic application for onychomycoses has been revoked.
However it can still be used for skin and hair disease if topical treatment
is not effective (Table III).
Itraconazole
Itraconazole belongs to the newer antifungal drugs and is one of the
most important drugs at present for peroral administration in the given
context. It is a triazole derivate. In vitro its activity is directed
against a variety of different fungi, including dermatophytes, yeasts
and some moulds [12] (Table III).
The mode of action is an inhibition of the biosynthesis of ergosterol,
which is essential for generating the fungal cell wall. In vivo
itraconazole acts as a fungistatic agent. It has a high affinity to fungal
cytochrome-p-450 isoenzymes, which is much higher than the one to human
congeners. After peroral administration it can be detected within 24 hours
in sweat. The active ingredient accumulates in the stratum corneum, nail
material, sebum and vaginal mucosa [13]. 99.8% of itraconazole is bound
to plasma proteins. Within one week 35 and 54% respectively are excreted
by urine and faeces [12]. Itraconazole has a high affinity to keratin
and is highly incorporated into the nail matrix and the nail bed [14].
Effective concentrations of the drug remain present in the nail material
for some months. Consequently there is further improvement of the clinical
state after discontinuation of the drug. This is the rationale for the
option of pulse therapy. Pulse therapy means application of the drug just
for one week per month. The result is a lower amount of the applied drug,
with similar efficacy. For onychomycosis itraconazole can be given continuously
at a dose of 200 mg/d for three months or as pulse therapy with 400 mg/d
in two daily doses of 200 mg for one week per month for three to four
months.
Terbinafine
The allylamine terbinafine belongs to the newer antifungal agents as
well. It exhibits a primarily fungicidal mode of action. In vitro
its activity is directed against a broad range of dermatophytes and moulds
as well (Table III). It
has a lower activity against yeasts. Its in vitro activity against
dermatophytes is by more than one order of magnitude higher than the one
of other antifungal agents (Fig.
1) [15]. Terbinafine prevents fungal ergosterol biosynthesis by
specific and selective inhibition of fungal squalene epoxidase [16]. This
inhibition is followed by a destruction of the fungal cell wall due to
the enrichment of toxic squalene. The affinity of terbinafine to cytochrome-p-450
is low in contrast to the azoles. This is one reason for a lower rate
of interactions of terbinafine with co-medication in comparison to the
azoles.
After peroral application terbinafine is bound to plasma proteins for
the most part, and maximal plasma concentrations are reached within two
hours. The mean terminal plasma half life (t 1/2) after 4 weeks of terbinafine
is about three weeks. In the distal part of the nail plate it can be detected
within one week [17].
The usual dose of peroral terbinafine is 250 mg/d. For tinea corporis
or cruris infections it can be given for 2 to 4 weeks, in tinea pedis
for 2 to 6 weeks and in onychomycosis for 6 to 12 weeks.
Fluconazole
Fluconazole is a newer, bis-triazole antifungal drug and suitable for
peroral and parenteral administration. It has been used in oropharyngeal
and esophageal candidosis or other indications with great success in immunocompromised
patients for years. Recently the use of fluconazole has been evaluated
for tinea of glabrous skin and onychomycosis [18]. The in vitro
activity appears sufficient with a wide variety of fungi encompassing
not only yeasts but also dermatophytes. So far very little data are available
on the efficacy of fluconazole on mycoses of keratinised tissue, and experience
with this therapy is limited.
Fluconazole is well absorbed after peroral application. In contrast
to itraconazole, gastric acid, food and antacids or H-2-receptor blocking
agents do not influence absorption [19]. After absorption only 11% are
bound to plasma proteins, the rest can be found as unbound free molecules.
Fluconazole shows a long plasma half life (t 1/2) of 30 hrs. In hair and
toenails it can be detected for four to five months after termination
of peroral therapy [20] (Fig.
2). Fluconazole is eliminated as unchanged drug through renal
excretion. Because of limited data a standard dosage for onychomycosis
cannot yet be given. 150 mg/d or 300 mg/d once a week might turn out as
the preferred dose in the near future [21]. For tinea of glabrous skin
50 mg/d for two to seven weeks is recommended [22] (Table
III).
Adverse effects
Some minor side effects including nausea, abdominal pain, vomiting,
diarrhoea, headache, dizziness, rash and pruritus may appear with all
the systemic antimycotics discussed here.
Itraconazole is an azole derivate as is ketoconazole, but severe hepatic
toxicity is not a major concern. Adverse effects reported in case reports
are debilitating edema and acute generalised exanthematous pustulosis
(AGEP) [23].
With terbinafine, over time, some reports on severe unwanted side effects
have been published. They comprise erythema multiforme, Stevens-Johnson
syndrome as well as toxic epidermal necrolysis. Fortunately none of these
severe effects has been lethal so far. As a non-severe side effect, taste
disturbances or dysgeusia occur in about 0.6% of patients; women tend
to be more often affected. The unwanted effect may last up to one month
after termination of therapy.
With fluconazole very few data on side effects in the context of therapy
of tinea are available. With other indications such as HIV-infection-related
fungal disease patients take a large variety of drugs additionally and
side effects cannot be easily differentiated between fluconazole and co-medication.
Anyhow, no severe side effects have been reported with respect to monotherapy
with fluconazole.
Outlook
With the newer antifungal agents, itraconazole, terbinafine and fluconazole,
much higher cure rates can be reached in comparison to griseofulvin or
topical therapy. The clinical results of treatment with itraconazole,
fluconazole and terbinafine are satisfactory. This is relevant especially
in more difficult indications such as onychomycosis and hyperkeratotic
tinea. The future will show which of these drugs offers better efficacy
in a given indication, and which induces less unwanted effects, and thus
commands a better benefit to risk ratio [24]. The role of fluconazole
for tinea unguium in particular awaits further elucidation.
Article accepted on 12/4/99
REFERENCES
1. Aly R. Ecology and epidemiology of dermatophyte infections.
J Am Acad Dermatol 1994; 31: S21-5.
2. Williams HC. The epidemiology of onychomycosis in Britain.
Br J Dermatol 1993; 129: 101-9.
3. Drake LA, Scher RK, Smith EB, et al. Effect of onychomycosis
on quality of life. J Am Acad Dermatol 1998; 38: 702-4.
4. Meinhof W. Isolierung und Identifizierung von Dermatophyten
(in German). Zbl Bakt 1990; 273: 229-45.
5. Korting HC, Ollert M, Abeck D. Results of German multicenter
study of antimicrobial susceptibilities of Trichophyton rubrum
and Trichophyton mentagrophytes strains causing tinea unguium.
Antimicrob Agents Chemother 1995; 39: 1206-8.
6. Elewski B, Bergstresser PR, Hanifin J, et al. Long-term
outcome of patients with interdigital tinea pedis treated with terbinafine
or clotrimazole. J Am Acad Dermatol 1995; 32: 290-2.
7. Alomar C et al.. Multi-centre double-blind trial on
the efficacy and safety of sertaconazole 2% cream in comparison with miconazole
2% cream on patients suffering from cutaneous mycoses. Drug Res
1992; 42: 767-71.
8. Korting HC, Klövekorn W, Klövekorn G. Comparative
efficacy and tolerability of econazole liposomal gel 1%, branded econazole
conventional cream 1% and generic clotrimazole cream 1% in tinea pedis.
Clin Drug Invest 1997; 14: 286-93.
9. Abeck D, Gruseck E, Korting HC, Ring J. Onychomykose: Epidemiologie,
Pathogenese, Klinik, Mikrobiologie und Therapie (in German). Dt Ärztebl
1996; 93: A-2027-32.
10. Schäfer-Korting M, Korting HC, Mutschler E. Human plasma
and skin blister fluid levels of griseofulvin after its repeated administration.
Eur J Clin Pharmacol 1985; 29: 351-4.
11. Korting HC, Schäfer-Korting M. Is tinea unguium still
widely incurable? Arch Dermatol 1992; 128: 243-8.
12. Haria M, Bryson HM, Goa KL. Itraconazole: a reappraisal of
its pharmacological properties and therapeutic use in the management of
superficial fungal infections. Drugs 1996; 51: 585-620.
13. Cauwenbergh G, Degreef H, Heykants J, et al. Pharmacokinetic
profile of orally administered itraconazole in human skin. J Am Acad
Dermatol 1988; 18: 263-8.
14. Willemsen N, De Doncker P, Willems J. Posttreatment itraconazole
levels in nail. New implications for the treatment of onychomycosis. J
Am Acad Dermatol 1992; 26: 731-5.
15. Niewerth M, Splanemann V, Korting HC, et al. Antimicrobial
susceptibility testing of dermatophytes comparison of the agar
macrodilution and broth microdilution tests. Chemotherapy 1998;
44: 31-5.
16. Balfour JA, Faulds D. Terbinafine: a review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic potential in superficial
mycoses. Drugs 1992; 43: 259-84.
17. Gupta AK, Shear NH. Terbinafine: an update. J Am Acad
Dermatol. 1997; 37: 979-88.
18. Smith SW, Sealy DP, Schneider E, et al. An evaluation
of the safety and efficacy of fluconazole in the treatment of onychomycosis.
Southern Med J 1995; 88: 1217-20.
19. Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic potential in superficial
and systemic mycoses. Drugs 1990; 39: 877-916.
20. Wildfeuer A, Faergemann J, Laufen H, et al. Bioavailability
of fluconazole in the skin after oral medication. Mycoses 1994;
37: 127-30.
21. Scher RK. A placebo-controlled, randomized, double-blind
trial of once-weekly fluconazole (150, 300, or 450 mg) in the treatment
of distal subungual onychomycosis of the toenail. 37th ICAAC, Toronto,
Ontario, Canada, 1997, September 28-October 1.
22. Rote Liste 1998 (in German). Aulendorf: Editio Cantor, 1998:
21.001-148.
23. Süss R, Korting HC. Generalised pustular drug rash.
Eur J Dermatol 1994; 5: 351-3.
24. Gupta AK, De Doncker P, Heenen M. An overview and assessment
of the use of the antifungal agents itraconazole, terbinafine, and fluconazole
in dermatology. In: Korting HC, Schäfer-Korting M, eds. The benefit/risk
ratio. Boca Raton: CRC Press LLC, 1999: 263-85.
25. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview.
Part II. J Am Acad Dermatol 1994; 30: 911-33.
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