Terapia en micosis superficiales

Current concepts in systemic and topical therapy for
superficial mycoses
Larry E. Millikan, MD
Department of Dermatology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Abstract There presently exists a wide selection of choices in the treatment of superficial mycoses. The
main categories of broad-spectrum agents are the allylamines and imidazoles, which have been tried and
proven over more than 2 decades of usage with good safety. Nystatin and griseofulvin have even longer
experience of about 5 decades but have niche usage for yeasts and dermatophytes, respectively.
Although no new therapeutic groups have appeared, extensive development of vehicles and delivery
systems has enhanced therapeutic results and increased patient compliance.
© 2010 Published by Elsevier Inc.
Introduction
In the mid-1970s as a professor at the University of
Missouri, I was invited to speak at the American Academy of
Family Practice Annual Meeting. My talk covered the new
therapies for tinea, and I was rash enough to predict the cure of
dermatophyte infections with the new imidazole topical
antifungals! At the time they supplanted Whitfield's ointment,
Castellani'spaint, undecylenicacid,andthevitaldyes,suchas
carbol fuchsin; griseofulvin, amphotericin B, and nystatin
rounded out the formulary. How things have changed!
I hope this status report is more accurate than the one I
presented 30 years ago—let us start with the currently used
systemic agents.
Systemic agents
Griseofulvin
Because griseofulvin began the revolution in therapy, it
continues to be a mainstay—trends for the microsize and
ultrasize have all but supplanted the original preparation.1
I believe that it is rare in practice to use the recommended
dosages today. In my practice, adjustments are the usual
pattern but vary with the organism and type of tinea, as well as
the geographic area of practice. The usual legend dosages
seem the safest way to start for the infrequent prescriber, but
tinea capitis is the greatest challenge2 because this is largely a
pediatric problem and many of the newer agents have primary
indications and dosages for adults. This is an area where the
generic preparations dominate, and again, the manufacturer's
recommended dose should be the starting dose; hence, I shall
dispense with the dosing schedules in this section.
Little has changed in griseofulvin therapy, although we
have suggestions that resistance is rising, especially in Tri-
chophyton tonsurans infections. Confirmation is available
but not easily obtained. So the usual procedure is to monitor,
and when a question arises, adjust the dosage or switch to an
alternative drug, usually an allylamine (vide infra).
Current concepts in indications
Perhaps, the primary usage of griseofulvin today, is in
pediatric patients, because many of the newer agents do not
have the indications for this age group. This is particularly so
for the treatment of tinea capitis, although the data areE-mail address: millikanmd@gmail.com.
0738-081X/$ – see front matter © 2010 Published by Elsevier Inc.
doi:10.1016/j.clindermatol.2009.12.016
Clinics in Dermatology (2010) 28, 212–216

accumulating for terbinafine use in that indication, when
griseofulvin resistance is suspected.3,4 The more than
4 decades of use also underscores safety; however, the
recommended dosage in most instances is less than I
typically use, and the higher dosing seems to provide, in
my hands, a quicker and higher response rate, without
seeming to increase the adverse effects. This, by no means, is
a dismissal of the approved dosages but merely the use of
experience to determine the circumstances of the treatment
regimen.5 This also includes the allowances for environ-
mental modifiers that are considered by the experienced
clinician, with the higher heat and humidity enhancing the
sweat delivery of griseofulvin in the treatment of dissemi-
nated T corporis as a principle example.
Current concepts in safety
Four decades of treatment underscore the essential
safety of the drug, even in this day of polypharmacy. The
primaryconceptofconcernatpresentistheinteractionprofiles.
Griseofulvin has long been a concern in its interaction with
anticoagulants, hormone replacement therapy agents, seda-
tives, and anticonvulsants. Because many patients are older
and have other health problems, the newer drugs such as
atorvastatin, and likely the whole class of similar drugs should
be a concern—avoid if possible and carefully monitor.
If the statin is necessary, which seems definitely on the
increase with the additional reported benefits of that class of
drugs, tacrolimus, cyclosporine, and now sildenafil and its
group of drugs are implicated in interactions. The list is long
and needs to be frequently updated before prescribing. Drug
interactions are a minor concern in younger tinea patients,
but older patients increasingly are taking these newer,
potentially problematic drugs that require monitoring during
the course of therapy.
Although the long history of use supports safety, when
reactions occur, they can be of serious concern and often
involve the skin, such as erythema multiforme and Stevens-
Johnson syndrome, potentially life-threatening and minor
ones; lichenoid urticarial and erythematous dermatides.
Patients with a history of these reactions from other drugs
may be at higher risk and need careful observation in the first
weeks of therapy.6,7
Imidazoles and triazoles
This group has expanded since the first introduction of
ketoconazole. Even with the early concerns of hepatic
dysfunction, there still seems a very clear role for the drug
with proper evaluation of the patient before therapy. Perhaps
of greater significance in choice of the proper drug is the vast
number of interactions with many drugs commonly used in
older patients, such as the statins.
As a general principle, approval and indications for
different type of tineas in most instances reflected the initial
studies done to achieve United States Food and Drug
Administration (FDA) approval, usually selecting tinea
pedis6 or tinea corporis for ease of both acquisition of
patients and follow-up. Variations may exist in the different
parts of the world, but generally, once approval is received
for a type of tinea, general practices are to use the drug in
nearly all other body sites.
The sole significant variable is the dose and dosing for
onychomycosis, which is unique due to the depot effect of
the drug and nail growth kinetics. This was underscored by
the extensive studies comparing itraconazole and terbinafine
for efficacy and ease of use, resulting in pulse packs seeming
to offer convenience as well as a greater degree of safety.8
With two dosing forms, most treatment protocols are 100 to
200 mg daily or 5 mg/kg daily, excepting the pulse protocols
for the nails.
Although all the antifungals have some hepatotoxic
potential, the imidazoles seem to have a higher incidence;
therefore, it is important to determine liver status before
prescribing. Of greater concern is the large list of
interactions mostly related to cytochrome P450 metabolism,
a very long list of prominent drugs, including the statins;
particularly note the black box warnings for cisapride,
pimozide, and others. Because of the dynamic nature of
new interactions, it is essential to use the latest safety and
interaction warnings when prescribing, which are available
from the pharmacy and the manufacturer, among others.
Several pages could be devoted to the safety issues that
could be out of date by the time of publication. The
imidazoles can be very effective, but the safety issues
mandate care, and caution that the clinician must be
familiar with the latest safety and therapy information
before prescribing.
The only other systemic imidazole is fluconazole, which
has been used off-label for superficial mycoses9 but has the
primary indication of candidosis, not dermatophytes, and is
not discussed here.
Allylamines
Terbinafine, with its perceived greater safety profile,
seems the dominant systemic antifungal at present. Some
differences remain in fungal and yeast sensitivity, which
likely will continue the need for the imidazoles as part of the
necessary formulary.
Several of the types of tinea are amongst the indications,
including tinea corporis, tinea pedis, and tinea cruris, which
will usually clear in 2 weeks of therapy (250 mg/d). In
contrast, special schedules of therapy are necessary for tinea
capitis and tinea unguium. Tinea capitis is generally problem
in pediatric patients, and the three doses used are a 125-mg
tablet, 187.5 granules in the packet, and 250-mg tablets. The
213Current concepts in systemic and topical therapy for superficial mycoses

drug is approved for ages older than 2 years.4 Dosing by
weight, is given once daily for 6 weeks:
• b25 kg, 125 mg
• 25 to 35 kg, 187.5 mg (granules in packet)
• N35 kg, 250 mg
Unguium (onychomycosis)—here again, the reservoir of
drug in the keratin is significant. Dosing by weight for ages
older than 2 years is 12 weeks for toenails, and for 6 weeks
for fingernails:
• b20 kg, 62.5 mg (1/2 tab)
• 20-40 kg, 125 mg
• N40 kg, 250 mg
Currently, only phenothiazines are recognized as contra-
indicated, which have a number of different entities and
previously were the most common ataractics used.
As with all antifungal drugs, liver and renal function are
key areas of concern. Possible reactions are increased in
patients with prior existing abnormalities, and prudent
monitoring is important. The issues of drug interactions are
much less significant with the allylamines.
The other systemic drugs used for yeast and fungal
infections have virtually no role in the treatment of
superficial fungal infections, primarily because they require
parenteral delivery and the adverse effect profile is too great
to be acceptable for non-life-threatening infections.
Topical agents
Some of the very old preparations (undecylenic acid,
iodochloroquinol, and Vioform [Novartis, Basel, Switzer-
land]) have had a rebirth in the over-the-counter (OTC)
market by virtue of newer delivery systems, and some even
have been marketed for treatment in combination with
steroids for intertriginous candidosis and nonspecific inter-
trigo. This is a marketing opportunity rather than a new
concept. Such a shotgun approach has a degree of utility,
primarily for nondermatologists. In most instances, these few
agents that are available in the United States of America
(USA) have generic near-equivalents that eliminate them in
most managed care formularies.
In the treatment field, there remain three groups of topical
agents that are the current treatments of choice
for dermatophytes. Some are distinguished by unique
vehicles such as foams, lacquers, and gels that maintain
their market share and likely will, for the pace of
development of new topical agents has slowed to a trickle,
with very few new characteristics to allow any of the newer
ones to seize a significant advantage and hence increased
market share.
Imidazoles
This group of drugs—the largest worldwide—includes
clotrimazole, ketoconazole, miconazole, oxiconazole, eco-
nazole, sulconazole, and sertaconazole. The imidazoles
inhibit ergosterol synthesis by blocking 14α-demethylation
of lanosterol and are effective against dermatophytes, Ma-
lassezia, and Candida. In this group, there are more data,
unfortunately often anecdotal, for the treatment of many other
molds and yeasts, suggesting a broader usage, but in most
instances this is a very limited usage because these infections
are rare. With the great increase in therapeutic immunosup-
pression due to transplantation and chemotherapy for tumors
and HIV patients, such unusual infections are on the increase.
Several of these agents are now generic, and clotrimazole
has been OTC for many years. It had been long marketed as
Lotrimin (Schering Plough, Memphis, TN), and much
confusion has developed due to the newer agents marketed;
for example, Lotrimin AF is clotrimazole (1% cream, lotion,
or solution) Lotrimin AF spray is miconazole (2% powder,
spray powder, spray solution), and Lotrimin Ultra is
butenafine (1% cream). The busy practitioner is left to the
mercy of the pharmacist.
Miconazole has the largest number of preparations,
among them Micatin Monostat Derm, not to be confused
with Mycostatin (nystatin), Micatin topical (gen), Fungoid
tincture (gen) and Lotrisone AF. Also compounding this
issue is that many of the preparations are just not covered, so
the pharmacist will recommend OTC where substitution is
the rule.
There are few landmark studies to distinguish one
imidazole as being superior to another. Perhaps the only
preferential point can be once-daily application, although
sertaconazole, the newest one marketed in the USA, has
twice-daily dosing and seems to have some anti-inflamma-
tory aspects that are of interest.10 A few have once-daily
indications (butenafine) but for all tinea pedis, application is
twice-daily.
This duplication in names points out that the market is
largely nondermatologist oriented, and the few brand names
seem designed to confuse the generalist. The differences in
vehicles are the area for best administration and possible cure
rate. This is an area that is unfamiliar to the generalist. This
listing is primarily for North America and the list may vary
considerably on other continents.
Allylamines (naftifine) and
benzylamine (butenafine)
This group of drugs, which generally is the newest group,
blocks the squalene epoxidase synthetic step and is effective
against dermatophytes, Malassezia, and Candida. Terbina-
fine, the first drug in this group, has been marketed OTC for
several years but in tablet form is by prescription-only. The
214 L.E. Millikan

indications are for general superficial mycoses. These
antifungals have been characterized by excellent minimum
inhibitory concentrations and are very potent against
dermatophytes. These drugs are less effective against yeasts
and molds.
Polyene (nystatin)
This drug works by binding the cell membrane, resulting
in leakage and permeability issues. It is only effective against
Candida. It is available as a generic (Mycostatin is still
available but the costs determine the use of the generic)
primarily and in cream, ointment, and powder forms. The
indication for any type of vehicle varies with the clinical
presentation, moist, dry, or fissured.
There have been no changes in usage for more than
4 decades, but misuse continues either due to misdiagnosis
(treating a noncandida intertrigo) or incorrect indication (this
drug is not effective against dermatophyte infections).
Nystatin is essentially a generic drug, which allows for
substitution of available generics that may put the patient at
risk for a preservative dermatitis, changing with different
generic sources.
Ciclopirox olamine
This unique drug interferes with membrane transport of
essential macromolecules and subsequent loss of cell
membrane integrity. It is effective against dermatophytes,
yeasts, and some fungal saprophytes, some of which are
possibly involved in onychomycosis.
The sole agent in this group, Loprox, has been available
for some time and is offered in the widest variety of
preparations, including nail lacquers (8%), shampoos
(1%), various gels and creams, and as a suspension
(0.77%). With the many preparations, there are indications
for use from onychomycosis to tinea to seborrheic
dermatitis. The newer formulations have no generic
equivalents; hence, a tier 2 or 3 co-pay, making cost an
issue compared with other agents such as the imidazoles,
for which ample generics are available. The unique
formulations have likely been the major reason for the
continued availability.
As with most topicals, there are few systemic reactions
and little or no drug interactions because of minimal systemic
absorption. The only problem would be irritant or allergic
reactions to constituents in the vehicle or preparation. A
primary allergy to the active ingredient rarely occurs.
Present approach to therapy
For the most part, the major decisions center on safety and
cost. The extent of the skin involved may be a major
determinant in selecting systemic therapy, particularly in
older patients with very extensive tinea corporis where
topical therapy is usually impractical because of the large
area of application and the difficulty of treating areas such as
the back. The extensive involvement in older patients also
implies early decline in cell-mediated immunity, which is an
important consideration for systemic therapy to decrease the
antigen load, which often contributes to its decline.
Another approach has been to use the shampoo as a
soap on widespread tinea corporis in the elderly, at least
partially, to clear the infection before initiating systemic
therapy with its accompanying systemic side effects. The
newer ketoconazole foam can be another approach that thus
far seems to be very effective because of the excellent
percutaneous penetration.
Younger patients and those who have classic and limited
involvement (tinea pedis, tinea cruris, tinea manuum, and
tinea unguium) are usually candidates for the newer topicals
or older generics if cost is a major factor. With topicals,
the major decision and selection can also relate to a given
product on the formulary of the health plan. As noted,
many topicals are not included—some of the rationale being
the number of potent topicals that have made the OTC
switch in the USA (Lamisil, and clotrimazole). Some body
sites have once-daily indications, but essentially, all the
tinea pedis indications are twice-daily application. Again,
it should be emphasized that atypical or extensive or
chronic tinea infections suggest host factors, including
infections, HIV, other viral infections, therapeutic immuno-
suppression in transplant patients, and rarely, the patient
who has a congenital or acquired window of tolerance to
various dermatophytes.
Special considerations
Tinea cruris
Although the diagnosis is very straightforward in some
patients, the decision of cure is sometimes difficult, because
the condition progresses to an irritant allergic dermatitis, or a
common intertrigo. Therapy often continues long after
eradication of the fungus. Careful attention to control of
hyperhidrosis and maceration is necessary to cure it.
Hyperhidrosis and seborrheic dermatitis need to be diag-
nosed and treated, for they can be as much the cause of the
clinical symptoms as the dermatophytosis.
215Current concepts in systemic and topical therapy for superficial mycoses

Tinea capitis
Systemic therapy remains the gold standard of therapy,
but I find some of the newer foam vehicle preparations are
useful at the onset while awaiting culture identification of the
organism, which can take as long as 5 weeks. In addition,
these foam preparations diminish the likelihood of spread to
siblings and playmates.
The question of griseofulvin resistance has been men-
tioned and may be clinically very important in some locales.
As a result, the allylamines may be the best approach to
therapy, but the cost may be a limitation for its use. As
mentioned, the usual dosages recommended by the FDA in
the USA are not my usual treatment, and I use a higher dosing
routine, because the drug generally is very well tolerated as
long as care in administration is taken to ensure optimal
absorption (fatty meals, etc). It seems inner city children are
more likely to have the strains of higher resistance, but this is
a generalization that has many exceptions.
If a 6-week course of therapy is not curative, then the next
step is to use an imidazole or allylamine—the dose varying
with the different agents. Always check the current dosing
guidelines, which are subject to change as experience
increases in the use of these agents in the pediatric age
group. Although adults are infrequently infected, I always
use the allylamines or imidazoles from the beginning. It is
important to evaluate all members of the family or very close
contacts, considering the high level of infectivity especially
with Trichophyton tonsurans.
Tinea unguium-onychomycosis
In contrast to tinea capitis, this is usually at the other end
of the age spectrum, and with aging there are many nail
changes, such as trauma and circulatory dystrophies, that are
not due to dermatophytes; hence, the level of incorrect
diagnosis is significant. Proper culture is essential because
there can be a significant number of false-negative cultures
by clinicians not familiar with the best diagnostic techniques.
Because of cost of therapy and the more serious systemic
side effects, the certainty of diagnosis is essential, and some
insurance plans in the USA require a positive culture
coverage of systemic therapy.
Note
The drugs covered in this chapter represent those that are
FDA-approved and available in the USA and elsewhere in
North America.4 Many other imidazoles may be available
worldwide, some of which have since been discontinued in
the USA but are available elsewhere. The general observa-
tions for the various classes hold for others not covered here.
Topicals have inherent safety and similar indications within
classes. My approach has been that to limit risk. Topicals
should be used first; if there is no response, then a systemic
drug should be carefully considered. With tinea unguium, the
longer therapy raises the inherent risk of systemic adverse
effects, especially hepatic ones.
The problem of interactions and toxicity is of such
potential that current data are essential to determine the risk-
benefit ratio. Any publication like this has the risk of being
out of date at the time of publication, so current guidelines
should always be reviewed before choosing a particular
systemic drug. For yeasts and therapy for immunosuppressed
patients, other agents are at the experimental stage but are not
covered here. With infectious or therapeutically immuno-
suppressed patients with extensive cutaneous mycoses, the
latest guidelines in the literature need careful consideration,
as well as close follow-up. In these cases, each patient can
require an entirely different regimen. These challenging
patients are best cared for with a team approach, including
infectious disease consultation as appropriate.
References
1. Elewski BE, Hay RJ. International summit on cutaneous antifungal
therapy, focus on tinea capitis, Boston, Massachusetts, November
11-13, 1994. Pediatr Dermatol 1996;13:69-77.
2. Del Rosso JQ, Gupta AK. Management of tinea capitis. A status report.
Postgrad Med 1999:38-45.
3. Elewski BE. Tinea capitis: a current perspective. J Am Acad Dermatol
2000;42:1-20 [quiz 1-4].
4. Elewski BE, Caceres HW, DeLeon L, et al. Terbinafine hydrochloride
oral granules versus oral griseofulvin suspension in children with tinea
capitis: results of two randomized, investigator-blinded, multicenter,
international, controlled trials. J Am Acad Dermatol 2008;59:41-54.
5. Gupta AK, Williams JV, Zaman M, Singh J. In vitro pharmacodynamic
characteristics of griseofulvin against dermatophyte isolates of Tri-
chophyton tonsurans from tinea capitis patients. Med Mycol 2009;11:
1-6.
6. Gupta AK, Cooper EA, Bowen JE. Meta-analysis: griseofulvin efficacy
in the treatment of tinea capitis. J Drugs Dermatol 2008;7:369-72.
7. Gupta AK, Chow M, Daniel CR, Aly R. Treatments of tinea pedis.
Dermatol Clin 2003;21:431-62.
8. Gupta AK, Gover MD, Lynde CW. Pulse itraconazole vs. continuous
terbinafine for the treatment of dermatophyte toenail onychomycosis in
patients with diabetes mellitus. J Eur Acad Dermatol Venereol 2006;20:
1188-93.
9. Foster KW, Friedlander SF, Panzer H, Ghannoum MA, Elewski BE. A
randomized controlled trial assessing the efficacy of fluconazole in the
treatment of pediatric tinea capitis. J Am Acad Dermatol 2005;53:
798-809.
10. Sur R, Babad JM, Garay M, Liebel FT, Southall MD. Anti-
inflammatory activity of sertaconazole nitrate is mediated via activation
of a p38-COX-2-PGE2 pathway. J Invest Dermatol 2008;128:336-44.
216 L.E. Millikan

Terapia en micosis superficiales

More Related Content

What's hot

Viewers also liked

Similar to Terapia en micosis superficiales

More from csanoja2020

Recently uploaded

Terapia en micosis superficiales