CONTINUING MEDICAL EDUCATION

Tinea capitis: A current perspective

Boni Elizabeth Elewski, MD Birmingham, Alabama

During the past 50 years, the predominant etiologic agent of tinea capitis in the United States and in
Western Europe has changed from Microsporum audouinii to Trichophyton tonsurans. This is thought to
be due in part to the sensitivity of M audouinii to griseofulvin treatment and, in part, due to the importing
of T tonsurans by people emigrating from geographic areas where that vector had been the prominent
cause of tinea capitis. With these changes, prospects for newer therapies with the novel antimycotic agents
itraconazole, fluconazole, and terbinafine are reviewed. (J Am Acad Dermatol 2000;42:1-20.)

Learning objective: At the conclusion of this learning activity, participants should be familiar with the
history, epidemiology, and current knowledge of tinea capitis, as well as the newer antifungal agents (ie,
itraconazole, fluconazole, and terbinafine) to treat this infection.

T he increasing incidence of tinea capitis infec-

tions within the United States and elsewhere
in the world has made necessary a review of
current knowledge of the disease and current strate-
gies for treatment. In particular, information con-
cerning the newer antifungal agents (itraconazole,
fluconazole, and terbinafine) is reviewed and sum-
marized.
HISTORY OF TINEA CAPITIS
In an extensive historical review, Sabouraud1 cited
Horace as stating that in Roman times, the word
tinea indicated the insect whose larvae feed on
clothes and books. He also cited Galen that tinea
subsequently came to mean any verminous or para-
sitic infestation of the skin. By the mid 16th century,
the term tinea was used to describe all diseases of
the hairy scalp. The term ringworm came into use at
about the same time and referred to any skin disease
in which the lesions were arranged in rings.2
During the 1830s, various fungi were described as
causative agents of beard and scalp infections, first
by Remak3 and by Schönlein,4 then in a series of
works by Gruby,5-8 which he presented to the
Academy of Sciences in Paris. Although not a derma-
tologist, Gruby described all major types of hair inva-
sion known today, but his accurate microscopic
From the Department of Dermatology, University of Alabama.
Reprint requests: Boni E. Elewski, MD, Department of Dermatology,
University of Alabama, 700 18th St South, Birmingham, AL 35233.
E-mail: beelewski@aol.com.
Copyright © 2000 by the American Academy of Dermatology, Inc.
0190-9622/2000/$12.00 + 0 16/2/102506
observations were overshadowed by his inadequate
and imprecise descriptions of clinical presentations.
Sabouraud1 began his studies of dermatophytes
in 1892 and continued to publish articles on related
works through 1936. Before Gruby’s papers came to
Sabouraud’s attention, he had already independent-
ly rediscovered the main types of tinea capitis. By the
time his dissertation was published in 1894,9 he also
had demonstrated that endothrix tinea capitis was a
disease entity produced by more than a single fungal
species. He described simple culture methods that
were easily reproduced, and by the end of the 19th
century, his methods had been adopted worldwide.
Together with Noiré, he described the treatment of
100 cases of tinea capitis using x-ray epilation and
published the details of this work in 1904.10
There was no effective treatment of tinea capitis
until griseofulvin became available in the 1950s.
Consequently, infection remained a public health
problem until then, with many bizarre treatments
being prescribed, including anointing the head with
grease.
EPIDEMIOLOGY
The dermatophytes are all capable of using ker-
atin for growth, and all keratin-containing body parts
(hair, skin, and nails) can become infected with der-
matophyte species. Clinical manifestations are
named for the area of the body infected: infections
of the hair of the head are termed tinea capitis; infec-
tions of the hair on the face or neck are termed tinea
barbae, whereas infections occurring on the trunk
are termed tinea corporis. Today, almost 100 years
after Sabouraud, we are aware of more than 40

1
2 Elewski J AM ACAD DERMATOL
JANUARY 2000

Table I. Causes of tinea capitis infections the world, and the causal agents of dermatophytoses
Species Type Distribution tend to be reported only in those regions where
there are mycologists to implicate them.
M audouinii* Anthropophilic Sporadic
M canis* Zoophilic Worldwide Types of tinea capitis infections
M gypseum* Geophilic Worldwide When the hair is invaded by dermatophytes, the
M fulvum Geophilic Worldwide infections are classified as favus, endothrix, or
M ferrugineum* Anthropophilic Africa, Asia ectothrix.11 Favus (caused by Trichophyton schoen-
M nanum Zoophilic/geophilic Worldwide
leinii) is inflammatory, characterized by yellow, cup-
M distortum* Zoophilic Australia, New
shaped crusts around the hair shafts (Fig 1). These
Zealand
T mentagrophytes† Anthropophilic, Worldwide keratotic crusts contain fungal hyphae and may be
Zoophilic highly infectious.12 Favus is characterized by produc-
T tonsurans‡ Anthropophilic US, Caribbean, tion of hyphae, which are parallel to the long axis of
Mexico, Europe the hair shaft. Once the hyphae degenerate, long
T violaceum† Anthropophilic Africa, Asia, tunnels are left within the hair shaft. These can be
Europe seen filling with bubbles of air during microscopic
T verrucosum† Zoophilic Worldwide examination of infected hairs, mounted on slides
T schoenleinii§ Anthropophilic Africa, Eurasia with potassium hydroxide (KOH). This is why the
(rarely US) condition was named “favus,” a word derived from
T rubrum‡ Anthropophilic Worldwide
the Latin for honeycomb.
T megninii Anthropophilic Europe
Endothrix hair invasion is produced predomi-
T soudanense‡ Anthropophilic Africa
T yaoundei‡ Anthropophilic Africa nantly by T tonsurans, (Figs 2 and 3), T souda-
nense, and T violaceum (Fig 4). Other endothrix
M canis and M gypseum are the most important of the organisms hair invaders are T gourvilli, T yaoundei, and, occa-
listed above. T tonsurans, T mentagrophytes, T violaceum, and T ver- sionally, T rubrum. Hyphae grow down the hair fol-
rucosum are the organisms most frequently encountered. The inci- licle and then penetrate the hair shaft. The fungus
dence of tinea capitis due to T tonsurans has been increasing. grows completely within the hair shaft, and the cuti-
Despite the prevalence of T rubrum infections worldwide, tinea
capitis due to this organism is uncommon.
cle surface of the hair remains intact. The hyphae
*Produces ectothrix infections. within the hair are converted to arthroconidia
†Produces extothrix infections. (spores) (Fig 5).
‡Produces endothrix infections.
Ectothrix hair invasion is frequently associated
§Produces favus infections.
with infections caused by Microsporum audouinii,
M canis, M distortum, M ferrugineum, M gypseum,
M nanum, and T verrucosum. Hyphae invade the
hair shaft at mid follicle, then grow out of the follicle
species of dermatophytic fungi, only about 12 of and cover the hair surface. Arthroconidia may devel-
which are common causes of human infection (Table op both within and without the hair shaft.13 The
I). Tinea capitis is commonly caused by approxi- arthroconidia that surround the hair have the
mately 6 dermatophytes. Epidermophyton flocco- appearance of a sheath. Ectothrix hair invasion
sum and Trichophyton concentricum, however, do develops in a manner similar to endothrix except
not invade scalp hair and Trichophyton rubrum, that the hyphae destroy the hair cuticle and grow
which is the most common dermatophyte isolated around the exterior of the hair shaft. The hyphae are
worldwide, is not a frequent cause of tinea capitis. subsequently converted into infectious arthroconidi-
al spores.
Geographic distribution
Dermatophytes have 3 major reservoirs and are Changes in geographic distributions of infec-
found in humans (anthropophilic), in animals tious organisms over time
(zoophilic), or in soil (geophilic) (Table I). Although The major etiologic agents of tinea capitis in a
geophilic dermatophytes occur worldwide, anthro- given geographic region can also change over time.
pophilic and some zoophilic species may be geo- During the late 19th and early 20th centuries, M
graphically restricted. The predominant organism(s) audouinii and M canis were the predominant etio-
varies with geographic area, and it is often difficult to logic agents of tinea capitis in Western and
know the precise distribution of a particular der- Mediterranean Europe,14 whereas T schoenleinii
matophyte. Thus the etiologic agents of tinea capitis predominated in Eastern Europe.15 The introduc-
have not been sought or identified in many parts of tion of griseofulvin for treatment of tinea capitis
J AM ACAD DERMATOL Elewski 3
VOLUME 42, NUMBER 1, PART 1

Fig 1. Favus infection caused by T schoenleinii.

infections together with vigilant school surveillance

in the late 1950s and early 1960s has produced a
marked decline throughout Western Europe in the
incidence of tinea capitis caused by Microsporum
spp.14
Current cases of anthropophilic tinea capitis in
Western Europe are due predominantly to T ton-
surans, whereas T violaceum is currently the domi-
nant agent in Eastern Europe.16,17 Likewise, in
Europe, M canis is still the organism isolated in most
laboratories, but anthropophilic infections are
increasing in number in many cities. Similarly, in the
United States, T tonsurans has supplanted M
audouinii and M canis as the primary etiologic
agent of ringworm of the scalp.18
As a result, we are experiencing new clinical pat-
terns of disease that invalidate older diagnostic
methods. With M audouinii, an ectothrix-producing
organism, Wood’s light (filtered ultraviolet light) pro-
duces a characteristic yellow-green fluorescence that Fig 2. Colony of T tonsurans. Note suede-like texture, flat
is diagnostic for the organism. Other organisms that and yellow-to-brown color that diffuses slightly into the
fluoresce yellow-green with Wood’s light include M medium.
canis, M distortum (M canis var distortum), M fer-
rugineum, and occasionally M gypseum.19,20 T
schoenleinii may fluoresce blue-white with Wood’s Age and sexual predilections
light examination. Tinea capitis is overwhelmingly a scourge of child-
However, Wood’s light is useless with T tonsurans, hood; the predominant age range affected is
an endothrix-producing organism, and we must now between 3 and 7 years of age.17-26 The incidence of
rely upon microscopic screening examinations of tinea capitis may also vary by sex, depending on the
KOH-treated hair and scalp scrapings and, ultimately, causative organism. When the etiologic agent is M
upon culture methods to make a proper diagnosis. audouinii, the ratio of infected boys to infected girls
4 Elewski J AM ACAD DERMATOL
JANUARY 2000

Fig 3. Macroconidia of T tonsurans.

Fig 4. Colony of T violaceum. Note violet color.

is as high as 5:1.27 With M canis, the ratio varies con-
siderably, but the infection rate in boys is usually
higher.28 Although tinea capitis is predominantly a
disease of prepubescent children, adults do become
infected from time to time. Thus Trichophyton infec-
tions of the scalp affect girls and boys equally, where-
as in adults, women are infected more frequently
than men.27
SOURCES OF INFECTION
Surveys within the United States suggest that
large family size, crowded living conditions, and low
J AM ACAD DERMATOL Elewski 5
VOLUME 42, NUMBER 1, PART 1

Fig 5. Direct microscopy of hair shaft shows endothrix tinea capitis with spores (arthroconi-
dia) inside hair shaft. T tonsurans is the pathogen.

Image available only in print edition

Fig 6. “Black dot” tinea capitis caused by T tonsurans. (From Elewski BE. Cutaneous fungal
infections. Malden (MA): Blackwell Sciences; 1998. p. 264. Reprinted by permission of
Blackwell Sciences, Inc.)

socioeconomic situations may contribute to the ed hairs, and select animal vectors. Spread of tinea
increased incidence of tinea capitis caused by T ton- capitis by fomites (contaminated barbershop instru-
surans in some urban populations.21 Tinea capitis ments, hairbrushes, combs, and shared hats) is also
can be transmitted via infected persons, fallen infect- common. T tonsurans has been isolated from
6 Elewski
Fig 7. Dry, noninflammatory tinea capitis caused by T
tonsurans in a 9-year-old child.
combs, hairbrushes, bedding, and clothing.29 M
audouinii has been isolated from infected hair,
clothing, furniture in the home, and from the back of
seats in movie theaters.30 These data suggest that
infectious fungal particles are viable in fomites for
many months. T violaceum and T schoenleinii can
be transmitted from person to person by sharing
clothing or towels. Infection due to these dermato-
phytes has also been perpetuated within families
from one generation to another through a low-grade
infection of the scalp or by asymptomatic carriers.30
Humans may become infected with zoophilic der-
matophytes by direct contact with family pets or with
wild animals.31 Cats and dogs are the major sources
of M canis. In rural areas, farmers may acquire a T
verrucosum infection when handling infected cattle.
Humans may also acquire infections of M gypseum
when working with soil containing this organism.32
CLINICAL APPEARANCE OF TINEA
CAPITIS
There are several different clinical patterns of
J AM ACAD DERMATOL
JANUARY 2000
tinea capitis infection, including a seborrheic der-
matitis–like pattern, “black dot” (Fig 6), which refers
to the breakage of hairs at the scalp (leaving behind
a pattern of black dots); alopecia areata–like pattern
(Fig 7); inflammation or kerion (Fig 8); and favus
(Fig 1). In 1985, Laude33 published an epidemiologi-
cal study on tinea capitis indicating that approxi-
mately 60% of cases of tinea capitis caused by T ton-
surans manifest as the “seborrheic” type character-
ized by diffuse scaling, otherwise known as dandruff.
This may occur with or without discrete patches of
hair loss. In the “black dot” pattern, there are well-
demarcated areas of hair loss, with hairs broken off
at the follicular orifice, giving the characteristic
appearance of black dots. However, it is important
not to use the term black dot in the narrow sense of
the term. Blond hairs that break off at the follicular
orifice will produce a “blond dot” pattern and red
hairs will produce a “red dot” pattern. Inflammatory
forms of tinea capitis may develop pustules, abscess-
es, or kerions that are edematous nodules with or
without pustules (Fig 8).33 Favus is a rare type of
tinea capitis infection, which produces crusts or scu-
tula formations that are hairs matted together with
dermatophyte hyphae and keratin debris. Some
patients have features of all the aforementioned clin-
ical patterns.
A prominent cervical or occipital lymphadenopa-
thy occurs in all types of tinea capitis and is an
important clinical clue to the proper diagnosis of the
disease. Without adenopathy, the diagnosis of tinea
capitis should be questioned because it is seldom
associated with other noninfectious causes of hair
loss.
Widespread dermatophytid (“id”) reaction often
accompanies treatment (Fig 9). Caution must be
exercised to avoid confusion with a reaction to med-
ication. The id reaction is a nonfungal, generally pru-
ritic, papular or vesicular eruption, often follicular,
that typically begins on the face and then spreads to
the trunk. It may be a result of a cell-mediated
immune response by the patient to the dermato-
phyte after effective therapy has been initiated.
Consequently, systemic antimycotic treatment does
not need to be altered or discontinued. However, if
necessary, topical steroids can be used to minimize
symptoms. A drug eruption, on the other hand, is
generally morbilliform and often begins on the
trunk. Kerions have also been associated with ery-
thema nodosum.19
If tinea capitis infections go untreated, scarring
alopecia may occur. Unlike infections caused by M
canis and M audouinii, tinea capitis caused by T
tonsurans does not necessarily resolve after patients
go through puberty.
J AM ACAD DERMATOL Elewski 7
VOLUME 42, NUMBER 1, PART 1

Fig 8. Kerion infection caused by T tonsurans in an 8-year-old child.

Fig 9. Typical dermatophytid or “id” eruption shows lichenoid papules on forehead develop-
ing after initiation of antifungal therapy.

LABORATORY DIAGNOSIS AND
MYCOLOGY
Visual screening examination of microscopic
mounts and isolation by culture are the preferred
methods used for diagnosing ringworm infection of
the scalp. Children complaining of an itchy, scaly scalp
and any child with alopecia should be carefully exam-
ined for evidence of tinea capitis. Examination with
Wood’s ultraviolet light will fail with Trichophyton
spp, such as T tonsurans, because this endothrix
infection does not produce the characteristic yellow-
green fluorescence seen with ectothrix organisms,
8 Elewski
Fig 10. Macroconidia of M canis. Note spindle-shaped echinulate wall.
such as M audouinii and M canis. Scalp examination
should include a search for broken-off hairs or black
dots. These should be collected with a forceps and
the scaly area scraped to transfer scales to a glass
slide. Scales and hair are mixed with 10% to 15% KOH
solution, the slide gently heated, and examined
microscopically for evidence of fungal hyphae and
spores (see Fig 5). Such mounts may be difficult to
interpret, especially in early or inflammatory lesions.
Therefore the ultimate diagnosis of tinea capitis is
obtained by fungal cultures.
Cultures are best obtained by using a sterile
toothbrush that is run over the scalp about 10 times
to collect infected scales and hair debris.
Alternatively, saline-moistened cotton swabs or
gauze pads can be rubbed over the infected area.
The sampled scrapings are placed on a suitable fun-
gal medium such as Sabouraud’s dextrose agar or
Mycosel (Mycobiotic) agar containing cycloheximide
and chloramphenicol to suppress the growth of
common saprophytic and bacterial contaminants,
respectively. Dermatophyte Test Medium (DTM) is
another commonly used culture medium and is sim-
ilar to Mycosel (Mycobiotic) agar, but contains a
color indicator that changes from yellow to red in
the presence of dermatophyte fungi. False-positive
cultures may occur, so caution must be exercised in
interpretation. In addition, the color change pre-
cludes identification of organisms based on colonial
morphology because it obscures salient features
used to distinguish various dermatophytes.
J AM ACAD DERMATOL
JANUARY 2000
Cultures are incubated at 25°C to 30°C. Positive
cultures will usually show signs of growth within 7 to
10 days, but they should be incubated for up to 30
days before declaring cultures to be negative.
Microscopic features of a fungal colony are used for
identification (Figs 3 and 10). It is now more impor-
tant than ever to precisely identify the pathogen
because of varied susceptibilities of certain fungi to
the new oral antifungal agents. For example,
terbinafine is extremely effective in T tonsurans
infection but less effective in M canis infection. It is
likely that other susceptibility discrepancies will be
noted with current and future antimycotic agents.
THE ASYMPTOMATIC CARRIER STATE
We define an asymptomatic carrier as a person
with no signs or symptoms of tinea capitis but from
whom positive scalp cultures can be isolated.20,25,33
Mackenzie, Burrows, and Wallby34 were early in rec-
ognizing this state in tinea capitis. They described
many of its features during their study of an out-
break of tinea capitis caused by T tonsurans in a
boarding school in Northern Ireland. Positive fungal
cultures were obtained from the hairbrushes and
clothing of several children who were “not ostensi-
bly infected.” They also noted “exceptional difficulty
in detecting infection” in some cases in which 8 or 9
examinations were needed before establishing a
diagnosis of tinea capitis. They concluded: “Perhaps
the greatest single factor which has prevented com-
plete elimination of the pathogen is the inability to
J AM ACAD DERMATOL
VOLUME 42, NUMBER 1, PART 1
detect infection, particularly that of the scalp. In our
opinion, it is almost impossible to detect what is vir-
tually a carrier phase…”34 (page 1058)
Subsequent studies35-38 using cotton swabs,
toothbrushes, or scalp massage brushes have con-
firmed such asymptomatic carriage. This has led to a
growing awareness that asymptomatic carriers con-
stitute a major reservoir of infectious organisms that
produce tinea capitis.
Asymptomatic carriage seems to be somewhat
organism specific. Almost all reports of high rates of
asymptomatic carriage have been due to anthro-
pophilic organisms, usually either T tonsurans or T
violaceum. The signs of overt infection with these
organisms vary, but they generally produce a sebor-
rheic dermatitis–like tinea capitis with only a mild or
absent inflammatory response. This relative lack of
host response is what may enable these organisms to
escape detection, thus making them good candi-
dates for asymptomatic carriage.39 In contrast,
zoophilic organisms, such as M canis or T menta-
grophytes, cause a brisk inflammatory response in
nearly all those infected and so are less likely to have
an asymptomatic carrier state.
EPIDEMIOLOGY OF THE CARRIER STATE
Risk factors for the carrier state closely parallel
those of overt infection. Most cases involve African-
American, Afro-Caribbean, and black children in
Africa.35,36,40,41 The prevalence of asymptomatic carri-
ers varies considerably, but it generally correlates well
with the incidence of tinea capitis in the community.
In Spain, where tinea capitis has been relatively rare,
the prevalence of scalp carriage in one study of unse-
lected school children was 0.2%.42 A similar study
conducted in Italy revealed a carriage rate of 0.3%.43
In marked contrast, in the Cape Peninsula of South
Africa, where T violaceum tinea capitis is endemic,
the rates of asymptomatic carriage have been report-
ed to be as high as 49%.36 Despite these extremes, the
majority of studies that examine the at-risk popula-
tion of children (those in school or a community
where tinea capitis is common) have found point-
prevalence rates for asymptomatic carriage of approx-
imately 15%,17,26,35,40,44,45 although some studies
demonstrate rates of 25% or more.36,40
Both adults and children living with an index case
of tinea capitis have been shown to carry dermato-
phytes without showing any symptoms. Babel and
Baughman27 determined that 30% of caretakers
(mostly women) had T tonsurans present in their
scalps with no evidence of disease. Raubitschek46
discovered an asymptomatic T violaceum carrier
rate of 21% in adult family members of infected chil-
dren. Vargo and Cohen35 examined not only adult
Elewski 9
family members, but also siblings within the same
family and found asymptomatic scalp carriage rates
of T tonsurans in 12% of adults and 44% of siblings.
Such high rates of positive cultures among unaffect-
ed family members suggest that homes, as well as
schools, are likely sources of tinea capitis infections
in children.
PROGNOSIS AND TREATMENT OF
CARRIERS
Although only a few studies have examined the
prognosis of the carrier state, studies of actual treat-
ment are even more rare. Williams et al26 studied a
primary school in Philadelphia and determined a
14% rate of asymptomatic carriage. With no treat-
ment and an average of 2.3 months of follow-up, 4%
of carriers had symptoms develop, 58% remained
culture positive, and 38% became culture negative.
Ive40 studied 19 carriers of M audouinii, noting that
after 4 months, 21% became symptomatic, 42% were
culture positive, whereas 37% became culture nega-
tive. Neil et al36 found that T violaceum persisted in
25% of asymptomatic carriers for a period of 6 weeks
to 6 months.
Shampoos and oral antimycotic therapy have
been advocated for eradication of the carrier state. In
1982, McGinley and Leyden47 demonstrated that
shampoos containing 2.5% selenium sulfide or 1% to
2% zinc pyrithione inhibited the growth of a wide
range of fungi. In 1982, Allen et al48 also tested sele-
nium sulfide and other products in a study involving
44 children who were being treated with oral griseo-
fulvin. Of 16 children who received griseofulvin and
who shampooed biweekly with 2.5% selenium sul-
fide, 15 had negative scalp cultures after just 2
weeks, whereas 1 child remained culture positive for
4 weeks. This compared favorably with the other
children in the study who were treated with griseo-
fulvin and nonselenium shampoos and who main-
tained positive cultures at 2 to 8 weeks.
Givens, Murray, and Baker49 compared 1% and
2.5% selenium sulfide shampoos and found them
equally effective in reducing positive cultures from
infected children. Neil et al36 compared 4 shampoos:
econazole, selenium sulfide, povidone-iodine, and
Johnson’s Baby Shampoo. All treatments were applied
twice weekly for 15 minutes on 4 successive weeks by
supervisors at 4 different child care institutions.
Povidone-iodine was found to be significantly
more effective than the other shampoos, resulting in
94% culture negativity after 4 weeks of use. The
other 3 shampoos gave response rates of about 50%.
The latter rate probably can be attributed to the ten-
dency for spontaneous clearing of the carrier state
and an increase in the rate and duration of sham-
10 Elewski
pooing, compared with normal community prac-
tices. Although these results imply that povidone-
iodine may be useful in the topical treatment of the
carrier state of tinea capitis, it remains unknown
whether the response with T tonsurans would be
the same as seen with T violaceum in the study by
Neil et al.36 In addition, the study by Neil et al was
marred by inclusion of only female patients in the
2.5% selenium sulfide study arm and only male
patients in the other study arms. Furthermore, the
female patients were less likely to complete the
entire course of therapy. Nevertheless, both povi-
done-iodine and selenium shampoos merit further
study for the control of spore loads in both infected
children and those suspected to be infected as well
as proven asymptomatic carriers.
IMPLICATIONS FOR SCHOOL
ATTENDANCE
In 1973, a concerned and well-intentioned
Philadelphia public school system decided that any
child with tinea capitis would not be allowed back into
school until regrowth of hair had occurred. In addi-
tion, the head nurse was to receive data showing that
an infected child receiving antimycotic therapy was no
longer contagious (Frieden IJ, personal communica-
tion, October 1998). Compare this public stance with
the current recommendations of the Committee on
Infectious Diseases of the American Academy of
Pediatrics: “Children receiving treatment for tinea
capitis may attend school. Haircuts, shaving of the
head, or wearing a cap during treatment are not nec-
essary.”50 The latter, less restrictive position seems jus-
tified in terms of the information presented herein.
Let us consider some conclusions that can be
drawn from our current knowledge of tinea capitis:
1. It is quite impractical to keep children with tinea
capitis out of the schools because shedding of
spores can continue for months despite active
therapies.
2. Asymptomatic carriers both at school and at
home may be more important vectors of tinea
capitis infections than index cases themselves.
Because such carriers are undetected, the poten-
tial exists for large numbers of spores to be shed
over long periods (6 weeks-8 months).
3. Measures to eradicate, prevent, or control the
asymptomatic carrier state might be expected to
have a beneficial effect in settings in which tinea
capitis is present. To date, however, available
measures, such as shampoos together with
antimycotic therapy, are too draconian to be rou-
tinely applied on a mass scale.
4. When assessing a school outbreak of tinea capi-
tis, one must evaluate
J AM ACAD DERMATOL
JANUARY 2000
a. Classrooms with the youngest children
(kindergarten through 2nd grade). These chil-
dren are most susceptible because their nor-
mal school work and play activities lead to
close contacts and a greater risk of disease
transmission.
b. Adults and siblings in the family unit: asympto-
matic carriers may be a continuing source of
infection and may also require active treatment
to cure persistent or intransigent infections.
c. Playmates in close physical contact and who
share toys or other personal objects (combs
and hairbrushes) can spread tinea capitis
organisms from one to another and can trans-
port infectious organisms to different classes
within the same or different schools.
d.Fomites: shared facilities and objects may
promote the spread of infections both within
the classroom and within the home environ
ment.
Many practical questions remain unaddressed or
unanswered. The manner in which one deals with
schoolmates, susceptible siblings, and other house-
hold members is unclear. Should cultures be
obtained from them and therapy initiated when pos-
itive cultures are obtained? How does one manage
asymptomatic carriers, be they classmates, play-
mates, siblings, or adults? How can we deal with
viable spores in the environment? Are there practical
and economically reasonable methods to rid the
household or classroom of infective spores, and is it
desirable to do so? Perhaps future research will shed
additional light on such questions that baffle us at
present.
SOCIETAL AND SOCIAL ASPECTS OF
TINEA CAPITIS
Besides the medical issues that we have been dis-
cussing, 3 societal and social aspects of tinea capitis
are also worth considering.
Within the United States, the changeover of tinea
capitis agents from M audouinii to T tonsurans dur-
ing the past half century is attributed by some to the
success of griseofulvin treatment in the virtual eradi-
cation of M audouinii on the US mainland. On the
other hand, it has also been suggested that immi-
grants from Mexico and South America may have
brought their endemic vector, T tonsurans, with
them to the United States incidental to their migra-
tion. Similar arguments have been made concerning
the switch of pathogens found after immigrations of
African peoples into Spain42 and of Eastern European
and Mediterranean peoples into Western Europe.51
Surveys have demonstrated that the incidence of
tinea capitis caused by T tonsurans within the
J AM ACAD DERMATOL
VOLUME 42, NUMBER 1, PART 1
Table II. Oral drugs used to treat tinea capitis in children
Drug Dose
Griseofulvin 20-25 mg/kg/d
Itraconazole 5 mg/kg/d
5 mg/kg/d
Fluconazole 5 mg/kg/d
6 mg/kg/d
8 mg/kg/once weekly
Terbinafine Weight 10-20 kg 62.5 mg/d
Weight 20-40 kg 125 mg/d
Weight >40 kg 250 mg/d
*Longer duration may be necessary for M canis.
United States correlates with large family size,
crowded living conditions, and low socioeconomic
situations in some urban populations.21 Certain cul-
turally dictated grooming habits practiced by African
Americans, such as the use of pomades and the plait-
ing of hair into tight rows, may also increase the inci-
dence of tinea capitis by providing more favorable
conditions for the establishment of infections.
The effects of tinea capitis on young children can
be stark and tragic. Victims of itchy scalp and hair loss
can be ridiculed and bullied, sometimes viciously, by
classmates and playmates. This can lead to social
ostracism and feelings of inadequacy and low self-
esteem. Recommendations by school teachers and
health personnel of the necessity for treatment as well
as the initiation of medical interventions and thera-
pies by health professionals can also contribute to the
feelings of “being different” and “singled out for spe-
cial attention.” Such circumstances can sometimes be
difficult for adults to handle; for vulnerable, unpre-
pared children, it can be a devastating experience. A
deliberately developed and practiced bedside manner
that soothes and allays fears can be of enormous emo-
tional benefit to these young patients.
CURRENT STATUS OF TINEA CAPITIS
Evidence continues to accumulate indicating that
tinea capitis poses an increasing public health con-
cern. In the United States and throughout the world,
tinea capitis is the most common pediatric dermato-
phyte infection. Prevalence in the United States is
generally estimated to be between 3% and 8% of the
pediatric population, with carriers occurring in as
many as 34% of household contacts of infected per-
sons.21,26,44,52
Lobato, Vugia, and Frieden53 found a marked ele-
vation in the occurrence of tinea capitis in California
from 1983 through 1994. This heightened incidence
Elewski 11
Duration
6-8 wk
4-6 wk
In 1-wk treatment intervals for 2 to
3 consecutive mo80,81
4-6 wk86,87
20 days
4-6 wk86,87
2-4 wk*
2-4 wk*
2-4 wk*
was most striking among African Americans who suf-
fered an increase of more than 200% during the 10-
year interval studied.
In 1996, Hay et al17 found a new epidemiologic
pattern of tinea capitis in southeast London where
the incidence of infections caused by T tonsurans
had increased dramatically. Moreover, child-to-child
transmission had assumed increasing importance in
the epidemiology of the disease, as did the finding of
an asymptomatic carrier state found within the class-
room that is a potentially important source of dis-
ease transmission.
Fungal infections of the scalp are more common
than other pediatric fungal infections and appear to
be increasingly difficult to eradicate. Abdel-Rahman,
Nahata, and Powell54 documented that the initial
response rate to griseofulvin therapy in pediatric
patients with tinea capitis at their institution was
only 60%. This compares with the 80% to 90%
response rate that has been reported in previous
controlled studies.
Such findings suggest that the incidence of tinea
capitis is growing and that the current pathogens
may be less sensitive to griseofulvin. This suggestion
is further substantiated by the recommendations of
the Infectious Diseases Committee of the American
Academy of Pediatrics. Specifically, over the past
decade, the Committee has called for the increasing
dosage and longer duration of treatment (Table II).50
CURRENT APPROACHES TO TINEA
CAPITIS THERAPY
Griseofulvin is the “gold standard” for treatment
of dermatophyte infections in children. Introduced
in 1958, this drug has exhibited an excellent safety
profile and has been widely used for the treatment of
dermatophyte infections in both adults and children.
Known side effects include headaches and gastroin-
12 Elewski
testinal disturbances, but overall griseofulvin is
generally safe and well tolerated. According to the
package insert, oral griseofulvin was found to be
embryotoxic and teratogenic to pregnant rats and,
therefore, should not be prescribed to pregnant
patients or women comtemplating pregnancy.
Although dosages of 10 mg/kg per day for 4 weeks
were previously considered effective for the treatment
of tinea capitis, most specialists now use doses of 20 to
25 mg/kg per day for 6 to 8 weeks. Because numerous
treatment failures have been reported, patients often
receive even more prolonged therapy.55 Extended
therapy increases the risk of noncompliance, so some
treatment failures may be caused by poor compliance
in taking medication rather than lack of effectiveness
of the drug. Moreover, drug resistance is difficult to
document in dermatophytes. Despite many attempts,
no widely accepted standardized method of antimy-
cotic susceptibility testing of organisms is available. In
addition, when such attempts have been made, con-
siderable interlaboratory and intralaboratory variability
has been noted.
These considerations emphasize the need to
develop safe, inexpensive, effective, and, ideally,
“short-course” alternatives to current antifungal ther-
apy for the treatment of tinea capitis. Newer antifun-
gal agents (Table II) possess pharmacologic and phar-
macokinetic characteristics that suggest they may be
reasonable therapeutic alternatives to griseofulvin.
Such drugs have already been shown to be effective in
the treatment of fungal infections of the skin and nails
of adults.56 They concentrate in hair, skin, and nails,
leading to a reservoir or depot effect that maintains
therapeutic drug levels in these tissues long after
drug dosing has been discontinued.
In evaluating any new agent for clinical use, it is
essential that the risks and benefits of the drug be
assessed. Safety, tolerability, efficacy, and cost must be
considered when evaluating potential new clinical
drug therapies. The discussion that follows compares
the pharmacokinetics, efficacy, safety, and cost data
thus far collected for these newer antifungal agents.
PHARMACOKINETIC CHARACTERISTICS
OF ORAL ANTIFUNGAL AGENTS
Griseofulvin
Griseofulvin was originally isolated in 1939 as a
metabolite that accumulated in cultures of the mold
Penicillium griseofulvum,57 but it was not until
1958 that the compound was reported to be effec-
tive in the treatment of experimental fungal infec-
tions in animals and in human dermatophyte infec-
tions.58 Since then, it has become the drug of
choice for treating dermatophyte infections in
infants and children.59
J AM ACAD DERMATOL
JANUARY 2000
Griseofulvin is rather poorly absorbed after oral
dosage. Absorption is highly dependent on dietary
fat intake and the dissolution rate of different prepa-
rations. Micronized and ultramicronized prepara-
tions exhibit better absorption characteristics than
the original preparation, especially when dispersed
in a polyethylene glycol vehicle.59,60 With micronized
preparations, peak serum concentrations occur at
approximately 4 hours after oral dosing. Overall
bioavailability, however, is highly variable and ranges
from 25% to 70% of the administered dose.61
Within the skin, a concentration gradient is estab-
lished over time with the highest concentrations
developing in the outermost layer of the skin, the
stratum corneum. The drug is carried to the skin by
sweat and through transepidermal fluid loss.62 This
concentrating of the drug within the skin is consid-
ered analogous to a “wick effect,” which in normal
volunteers is thought to be due to griseofulvin-con-
taining sweat constantly bathing the outermost layers
of the stratum corneum. Investigations have shown
that the concentration of griseofulvin in skin is sensi-
tive to the rate of eccrine sweat production.62 In dis-
eased skin, this does not occur because in many
instances sweat ducts and sebaceous glands are
obstructed within the diseased skin area, rendering
them ineffective in sweating and consequent drug
delivery. When the drug reaches the stratum
corneum, reversible protein binding and lipid solubil-
ity result in its concentration in the horny cell layer.
Once drug dosing is discontinued, the drug is cleared
from the skin by a variety of dispersal mechanisms.
Griseofulvin is eliminated from the body through
various metabolic pathways, with demethylation and
glucuronidation serving as the primary routes. Fecal
elimination accounts for almost 36% of the dose,
whereas virtually all drug excreted in the urine con-
sists of various metabolites.60 Elimination of griseo-
fulvin is biphasic, with a T ⁄ (β) = 0.7 to 1.7 hours
1
2
and T ⁄ (γ) = 9.5 to 21 hours.61 This long terminal
1
2
elimination half-life is thought to support once-daily
dosing. Because the drug is rapidly cleared from the
site of infection once dosing is terminated, treat-
ment must be continued until all the hair within the
affected area has been replaced by new growth.
One of the most attractive features of griseofulvin
is its safety profile.60,63 Side effects are infrequent,
especially when the drug is taken with meals. Of the
side effects that do occur, headaches are among the
most common, but these tend to disappear as thera-
py continues. Other side effects that occur infre-
quently involve the skin, the gastrointestinal tract,
and the nervous, genitourinary, and musculoskeletal
systems (Table III). Despite its derivation from the
mold Penicillium, there is no well-documented,
J AM ACAD DERMATOL
VOLUME 42, NUMBER 1, PART 1
cross-reactivity of griseofulvin with penicillin.64
Overall, griseofulvin has been shown to be a safe and
effective drug for treating pediatric tinea capitis and
similar dermatophyte infections. Its successful clini-
cal use over several decades serves as a yardstick
against which the efficacy and safety of all newer
antifungal agents must be measured.
Ketoconazole
Ketoconazole was the first orally administered
broad-spectrum antifungal compound of the azole
group with activity against anthropophilic dermato-
phytes.63,65 In the presence of normal gastric acidity,
it is generally well absorbed and achieves peak plas-
ma concentrations in 2 to 3 hours, with steady state
concentrations being achieved in 3 to 4 days. Only
1% of the drug exists free in plasma with the remain-
der bound to plasma proteins. Because it is
hydrophilic, the drug is widely distributed through-
out body tissues (but is not present in cerebrospinal
fluid). Delivery to the skin is accomplished through
normal blood circulation and sweat. There is also
some excretion into sebum and subsequent incor-
poration into the epidermal basal layer.66-68 Very
high concentrations of the drug develop within the
skin, thus making ketoconazole potentially useful for
treating superficial fungal infections.
Oral ketoconazole experiences a large first-pass
metabolic effect with scission of the imidazole and
piperazine rings.65 The drug is extensively metabo-
lized; this includes oxidation and degradation of the
imidazole ring, O-dealkylation, oxidative degradation
of the piperazine ring, and aromatic hydroxylation.
None of the metabolites possesses any activity, leav-
ing the untransformed ketoconazole as the sole
active antifungal compound.61
Despite such active metabolism, up to 65% of
administered ketoconazole is eliminated unchanged,
primarily through biliary excretion. The half-life is
dose dependent, and elimination is biphasic with T ⁄ 1
2
(beta) = 1.5 to 2.7 hours and T ⁄ (gamma) = 6.5 to
1
2
9.6 hours.65 The long gamma elimination half-life is
thought to support once-daily dosing. Because of its
rapid metabolism and biliary excretion, dosage
adjustment is not required in patients with renal
impairment.
Side effects of ketoconazole occur predominant-
ly in the gastrointestinal system61; the most com-
mon are nausea and vomiting. However, there is
also a significant incidence of idiosyncratic hepatic
toxicity noted in 1 of 15,000 reports.69 Hepatic man-
ifestations usually appear only after 8 to 10 weeks of
drug therapy and require weeks to resolve. Other
adverse events are found within the central nervous
system, endocrine system, and genitourinary sys-
Elewski 13
Table III. Side effects of griseofulvin*
System Symptoms
Cutaneous Photosensitivity
Precipitation or exacerbation of
lupus, petechiae, pruritus, urticaria,
etc
Gastrointestinal Nausea, vomiting, heartburn, cramps,
flatulence, dysgeusia, angular stom-
atitis, thrush, black and furred
tongue
Genitourinary Enuresis, frequency
Musculoskeletal Arthralgia, serum sickness
Nervous Blurred vision, vertigo, depression,
nightmares, insomnia, ataxia, pares-
thesia, fatigue, syncope
Miscellaneous Fever, epistaxis, estrogen-like effects,
sore throat, menstrual irregularities
*Data from Gupta AK, Sauder DN, Shear NH. Antifungal agents: an
overview. Part I. J Am Acad Dermatol 1994;30:677-98.
tem along with some dermatologic and hematolog-
ic disturbances.
Despite the detailed pharmacokinetic and phar-
macodynamic studies that have been performed
with ketoconazole, virtually no data are available
concerning the biodisposition and metabolism of
this drug in infants and in children. No liquid formu-
lations exist, and no systematic evaluation of keto-
conazole tablet preparations has been done with
pediatric patients of any age for this indication.
However, the hepatic toxicity noted with adults pre-
cludes the use of this drug in children who may be
even more susceptible to liver toxicity.
Itraconazole
Itraconazole is one of two new triazole antifungal
drugs that have potential use for the treatment of
superficial pediatric dermatophyte infections.69 This
drug is poorly water soluble, but its bioavailability is
improved when it is taken with a fatty meal. After
oral administration, peak plasma concentrations
occur within about 4 hours, but absorption appears
to be dose dependent,63,70 so higher doses result in
disproportionately higher plasma concentrations.
Absorbed itraconazole has a very large apparent
volume of distribution, equaling 17 L/kg,63,70 and
exists in the circulation bound almost completely
(99.8%) to plasma proteins. Most of this binding is to
plasma albumin, but some is associated with red
blood cells. Because this agent is very lipophilic, it is
found in highest concentrations in fat, omentum,
vaginal and cervical tissues, and within skin and
nails.71 Skin concentrations may be 3- to 10-fold
14 Elewski
higher than those occurring simultaneously in plas-
ma, and antimycotically significant concentrations
may persist within skin up to 4 weeks after cessation
of drug administration.72
Itraconazole is converted to more than 30 inactive
metabolites. One metabolite that is pharmacologi-
cally active, hydroxyitraconazole, is pharmacokineti-
cally similar to its parent compound.70 Itraconazole
has a terminal elimination half-life of 20 to 60 hours.
This suggests that steady-state concentrations are
reached only after at least 2 weeks of daily drug
administration.73 Because of its large molecular size
and high molecular weight, one would expect signif-
icant biliary excretion of itraconazole and its metabo-
lites. Elimination of the drug is balanced, with
approximately 65% being excreted in feces and 35%
in urine, virtually all in the form of metabolites. No
dosage adjustment is indicated for impaired hepatic
or renal functions.
Itraconazole appears to be a relatively safe drug
with only minor side effects noted in 7% to 12% of
recipients.71 The frequency of side effects appears to
depend upon duration of therapy. Nausea and vom-
iting occur with greatest frequency, but abnormali-
ties in laboratory tests of liver functions can occur in
more than 1% of patients.
Itraconazole has significantly greater selectivity for
inhibiting fungal enzymes than does ketoconazole.
Fluconazole
Fluconazole is another triazole compound, but
unlike itraconazole, it is relatively water soluble and is
extremely well absorbed on ingestion.70,74 Its high
bioavailability is not influenced by food intake or gas-
tric acidity. Peak plasma concentrations are reached
within 1 to 2 hours after oral dosing, and there is min-
imal binding to plasma proteins. The drug is widely
distributed to body tissues and fluids, including the
cerebrospinal fluid, where it may reach concentra-
tions as high as, or higher than, plasma concentra-
tions. Fluconazole has a long half-life of 22 to 30 hours
in adults, and steady-state levels are reached within 6
to 10 days after therapy is initiated.70
The biodisposition of fluconazole has been studied
in children infected with HIV who required the drug
for prevention and treatment of systemic fungal infec-
tions.75 The data obtained (at 2 mg/kg, mean = 27.22
hours; at 8 mg/kg, mean = 33.02 hours) are quite sim-
ilar to data obtained with adults, including a long ter-
minal half-life that supports once-daily dosing.
There is little hepatic metabolism of fluconazole,
and most of the drug is excreted unchanged in the
urine. Fluconazole appears to be eliminated more
slowly from the skin than from plasma, so there may
be a continued therapeutic benefit against superfi-
J AM ACAD DERMATOL
JANUARY 2000
cial fungal infections even after dosage has been dis-
continued.63,70 Because elimination of the drug is
mainly by the renal route, dosage adjustment would
be required in cases of renal impairment.
Adverse events occur in about 16% of patients
who receive the drug for longer than 7 days, but
most of these are mild and are reversed when the
drug is discontinued. The most common side effects
are nausea and vomiting, but liver function test
abnormalities are also found. In general, fluconazole
appears to be an efficacious antifungal agent that is
safe for use in children. However, additional clinical
research will be necessary to determine proper pedi-
atric dosage and duration of therapy for the treat-
ment of tinea capitis in children.
Terbinafine
Terbinafine is an allylamine with antifungal prop-
erties.76 It is well absorbed after oral dosage, reach-
ing peak plasma concentrations in about 2 hours,
and it has a bioavailability of 70% to 80%. There is
strong binding to plasma proteins, with about 8%
bound to red blood cells.70 In addition, terbinafine
becomes associated with chylomicrons. As such, it
has a large lymphatic distribution. Its preferential
uptake into fat ultimately results in relatively high
concentrations in skin and skin structures.77,78
During the first 2 weeks of therapy, concentrations
within the stratum corneum increase to 75 times
plasma concentrations. When administration ceases,
the concentration of terbinafine in the stratum
corneum remains well above that required for
inhibiting fungal growth for 2 months after plasma
concentrations have been depleted. This protracted
presence of drug within the skin has led to the
design of short courses of terbinafine therapy.
Terbinafine is highly metabolized after ingestion,
and more than 15 inactive metabolites have been
identified. Most metabolization occurs through N-
demethylation and aromatic ring oxidation.76
Elimination of terbinafine is triphasic with T ⁄ 1
2
(beta) = 1.1 hours, T ⁄ (gamma) = 16 hours, and T ⁄
1
2
1
2
(delta) = > 100 hours. About 80% of the adminis-
tered dose is eliminated as urinary metabolites.
Dosage adjustment is required in patients with
severe renal or hepatic dysfunction.70,76
Several studies have compared the pharmacoki-
netics of terbinafine in both children and
adults.79,80 Such data indicate that in children there
is a significantly larger steady-state apparent volume
of distribution and area under the plasma concen-
tration-time curve. In children, there is a signifi-
cantly longer first phase of drug elimination and a
significantly shorter second phase. However, when
the values for clearance and volume of distribution
J AM ACAD DERMATOL
VOLUME 42, NUMBER 1, PART 1
are normalized for body weight, these differences
disappear, suggesting that there are no great dis-
parities between children and adults in the biodis-
position of terbinafine.79
A low incidence (about 10%) of adverse events
occurs with terbinafine, with gastrointestinal
episodes being most common.71 These appear gen-
erally during the first week of dosage, but subside
with continuing therapy. Some rare cutaneous reac-
tions have been reported, such as toxic epidermal
necrolysis and Stevens-Johnson syndrome.
Terbinafine has recently been shown to be a
potent inhibitor of the cytochrome P-450 isoform
CYP2D6. This enzyme is responsible for the bio-
transformation of several pharmacological agents by
way of O-demethylation. Terbinafine produced in
vitro inhibition of O-demethylation of dextrometh-
orphan by human hepatic microsomes with an
inhibitory rate constant ranging from 25 to 50
nmol/L, which is dimensionally in agreement with
those observed for quinidine, a well-known and well-
characterized potent inhibitor of CYP2D6.81 In vivo
inhibition of CYP2D6 by terbinafine has also been
demonstrated, but the clinical significance of this is
still unknown.82
MECHANISMS OF ACTION OF
ANTIFUNGAL AGENTS AND ANTIFUNGAL
EFFICACY
Griseofulvin
Griseofulvin appears to function by inhibiting fun-
gal microtubule assembly that is essential for mitosis
during cell division, and so ultimately inhibits cell
replication.60,63 Although it is merely fungistatic in its
activity,61 it is quite effective in curing tinea capitis
infections caused by M audouinii and M canis and
almost as effective against T tonsurans.
Azoles and triazoles
The azoles are fungistatic and act by inhibiting the
14α-demethylase that converts lanosterol to 14-
demethyl-lanosterol in the middle portion of the
ergosterol biosynthetic pathway. Ergosterol is an
essential structural component of the cell mem-
branes of most fungi, and interference with its for-
mation and availability has a major impact on hyphal
replication and survival. Unfortunately, the fungal 14-
α-demethylase is a cytochrome P-450 enzyme that is
quite similar to the human cytochrome P-450 3A4, so
the potential exists for adverse drug-drug interac-
tions in using these antifungal agents.83
Because of the safety and therapeutic concerns
mentioned earlier, ketoconazole is not considered
appropriate therapy for pediatric tinea capitis. The
results of several clinical trials with itraconazole have
Elewski 15
been reported, but inconsistent outcomes were
obtained. One study that included 15 children, most-
ly with T tonsurans infections, reported 100% cure
rates when 1 to 3 pulses of itraconazole were used
(only 5 children required 3 pulses).84,85 The pulse
schedule used was itraconazole 5 mg/kg per day for
1 week, then 2 weeks with no drug, followed by 1
week with drug. When a third pulse was required, 3
weeks elapsed between the second and third drug
treatments.
A larger, open-label study by Elewski55 involved
120 children who had been treated unsuccessfully
with griseofulvin, and who were subsequently
switched to itraconazole 3 to 5 mg/day for 4 to 6
weeks. This report indicated that itraconazole was
both a safe and efficacious alternative to griseofulvin
for the treatment of tinea capitis. In contrast, other
studies suggest a poor therapeutic response from
itraconazole.
Abdel-Rahman, Powell, and Nahata86 evaluated
the cases of 25 Ohio children with tinea capitis
caused by T tonsurans. Itraconazole, 100 mg/day,
was administered for 4 weeks, but only 40% were
considered cured at 6 weeks. A high drop-out rate
was reported; of the 54 children originally enrolled
in the study, only 25 were able to be evaluated.
Furthermore, all children were given the same
dosage, that is, the dose was not adjusted for body
weight. In a double-blind study that compared itra-
conazole with griseofulvin, 34 children (91% of
whom were infected with M canis) were evaluat-
ed, but no substantial differences were found in
efficacy between the two drugs. Itraconazole and
terbinafine had an 88% clinical cure rate and a 76%
and 78% mycologic cure rate, respectively.87 Such
data raise concerns about efficacy and illustrate
the need for additional trials to compare these
newer agents with the current standard of care,
griseofulvin.
Although there is a liquid formulation of itracona-
zole available, according to the Physicians’ Drug
Reference, it is not to be used interchangeably with
the capsule formula because of the cyclodextrin
vehicle.
Few data are available about the efficacy of flu-
conazole for the treatment of tinea capitis. The first
report was of a single patient with inflammatory
tinea capitis who was successfully treated with 50 mg
of fluconazole daily for 20 days.88 Based on this sin-
gle case, a larger study was conducted, exploring 1.5,
3.0, and 6.0 mg/kg doses for 20 days. There was an
89% cure rate in the 6.0 mg/kg group. The authors
concluded that a 20-day regimen at 6 mg/kg was
effective.89 A third study used a dose of 5 mg/kg for
30 days with excellent results.90 Finally, a small study
16 Elewski
by Montero91 showed that once-weekly dosing of flu-
conazole at 8 mg/kg for 4 to 6 weeks may be effec-
tive. Fluconazole is approved by the Food and Drug
Administration (FDA) for usage in children older
than 6 months, and it is available in a pleasant-tasting
liquid formula (10 and 40 mg/mL).
Terbinafine
The allylamines, including terbinafine, appear to
function by inhibiting the enzyme squalene epoxi-
dase that is also a key enzyme of ergosterol biosyn-
thesis. Such inhibition results in the intracellular
accumulation of squalene, which is lipid-soluble and
toxic to the fungus at higher concentrations. Thus
allylamines are fungicidal, at least in vitro.76
Jones80 reviewed experience to date with
terbinafine for fungal infections in children and found
high cure rates for all dermatophyte infections. Most
clinical trials evaluating terbinafine have used a stan-
dard dosing regimen based on body weight: < 20 kg
= 62.5 mg/day, 20 to 40 kg = 125 mg/day, and > 40 kg
= 250 mg/day (the usual adult dose). The pharmaco-
kinetic data collected by Nejjam et al79 support this
dosing regimen. For young children, tablets may be
split and hidden in foods such as applesauce or
peanut butter (crushing is not recommended as the
formulation is not palatable).
At least 4 comparative studies have been done
with terbinafine. Alvi et al92 conducted a trial with
105 Pakistani children, 87% of whom were infected
with T violaceum. Patients were treated either with
terbinafine (by weight) for 4 weeks or with griseoful-
vin (6 to 12 mg/kg per day) for 8 weeks. Four weeks
after the study was concluded, the authors found
that 93% of the terbinafine group were completely
cured, compared with 80% (clinical) and 88% (myco-
logic) of the griseofulvin group.
Haroon et al93 performed a comparative trial
using terbinafine for 1, 2, and 4 weeks of therapy in
patients predominantly (71%) infected with T vio-
laceum. The cure rate after week 1 was 74%; after
week 2 it was 80%, and after 4 weeks it was 86%.
There was no statistical difference among these
groups, but the trend was that longer duration was
correlated with higher cure rates.
Jahangir et al94 conducted a randomized, double-
blind study to compare the safety and efficacy of
terbinafine and itraconazole, each given for 2 weeks,
in patients primarily infected with T violaceum.
Results showed that 2 weeks of therapy with either
drug is effective in eradicating this infection. The
final evaluation at week 12 showed a cure rate of
77.8% for terbinafine and 85.7% for itraconazole.
Rademaker95 reported that 4 weeks of terbinafine
therapy was as efficacious as 8 weeks of griseofulvin
J AM ACAD DERMATOL
JANUARY 2000
treatment, but complete clinical and mycologic data
for end-of-study and follow-up time points were not
provided. Caceres et al96 evaluated 50 Peruvian chil-
dren, 74% of whom were infected with T tonsurans.
Half were treated with terbinafine (by weight) for 4
weeks, and the other half received griseofulvin, 15
mg/kg per day for 8 weeks. At the termination of the
study, 76% of the terbinafine group and 80% of the
griseofulvin group were considered cured. However,
at a subsequent follow-up 4 weeks later, the 76%
cure rate of the terbinafine group was sustained,
whereas the cure rate of the griseofulvin group
decreased to 64%. This illustrates the importance of
long-term follow-up in determining therapeutic effi-
cacy in dermatophyte infections.
Gupta and Adam97 reported a 92% cure rate in 13
children who were treated with terbinafine pulse
therapy, 6 mg/kg for 1 week followed by 2 weeks of
no therapy, repeated 3 times with 3 weeks of no ther-
apy during the third pulse. Results from one study
deviated from those mentioned heretofore.
Dragos and Lunder98 evaluated 22 Slovenian chil-
dren with tinea capitis due to M canis. The patients
were treated with terbinafine (by weight) for 6 weeks
and were followed up for another 8 weeks, at which
time a cure rate of only 32% was reported. It appears
that terbinafine is not as efficacious for M canis
infections as it is for those caused by T tonsurans.
Nonetheless, additional controlled studies will be
needed to confirm this suspicion. This may extend
to other Microsporum spp as well.
SAFETY ISSUES
Neither fluconazole nor terbinafine seems to
possess clinically significant carcinogenic potential.
Although both agents have been demonstrated to
produce liver tumors in male rats, this occurs only
at doses that far exceed the maximal recommended
therapeutic human doses. Itraconazole has been
associated with several abnormalities, including
soft-tissue sarcomas, bone defects, and hypocellu-
lar tooth pulp. All these abnormalities were report-
ed with doses that exceeded normal human expo-
sure. It should be noted that cyclodextrin, a com-
ponent of the liquid formulation of itraconazole,
has been shown to produce pancreatic adenocarci-
nomas in rats at doses similar to human exposure.
Although the significance of this is presently uncer-
tain, it is probably prudent to administer only the
capsule form of this drug to children until this issue
is clarified.
The triazoles fluconazole and itraconazole both
affect the cytochrome P-450 system, so the poten-
tial for drug-drug interactions is present.83 Possible
drug-drug interactions are listed in Table IV.83 In
J AM ACAD DERMATOL Elewski 17
VOLUME 42, NUMBER 1, PART 1

particular, the simultaneous use of itraconazole Table IV. Potential cytochrome P-450-mediated
with nonsedating antihistamines (astemizole, terfe- drug-drug interactions with newer antifungal
nadine) is absolutely contraindicated. Significant agents*
interactions may also occur with lovastatin, simvas- Fluconazole Itraconazole Terbinafine
tatin, and midazolam. Drug interactions are not as
great a concern with terbinafine, which does not Astemizole Antacids Carbamazepine
affect the same subset of cytochrome P-450 Cyclosporine Astemizole Cimetidine
enzymes.83 Nevertheless, cimetidine, cyclosporine, Digoxin Carbamazepine Cyclosporine
rifampin, and terfenadine may affect the plasma Hydrochlorothiazide Cimetidine Rifampin
level of terbinafine if used concurrently, but con- Hypoglycemics (oral) Cyclosporine Terfenadine
Midazolam Digoxin
current use is not contraindicated. There has been
Phenytoin Hypoglycemics
a report of increased levels of carbamazepine with
(oral)
concurrent terbinafine use, but the clinical signifi- Rifampin Isoniazid
cance of this finding is uncertain (Friedlander A, Terfenadine Lovastatin
personal communication, October 1998). Theophylline Midazolam
The incidence of adverse reactions is low with all Warfarin Phenytoin
3 drugs.80,85,99 The most common are gastrointesti- Zidovudine Protease
nal disturbances and cutaneous reactions. Abnormal inhibitors
liver function laboratory tests have been noted with Rifampin
all 3 drugs but are not very common. Neutropenia Simvastatin
and thrombocytopenia have been reported with the Terfenadine
Triazolam
azoles and with terbinafine, but were infrequent and
Viagra
were not noted in a postmarketing surveillance of
Warfarin
nearly 26,000 patients.99
*Data from Albengres E, Le Louët H, Tillement J-P. Drug Safety
COST CONSIDERATIONS 1998;18:83-97; Abdel-Rahman SM, Marcucci K, Boge T, et al. Clin
Costs of all medical treatments are becoming Pharmacol Ther 1999;65(2):135 [abstract]; Abdel-Rahman SM,
increasingly important in the delivery of health care Gotschall RR, Kauffman RE, et al. Clin Pharmacol Ther 1999b;
65(2):135 [abstract].
and should properly play a role in the therapeutic
decision process if safety and efficacy factors can pin-
point acceptable therapeutic options. A cost com-
parison of griseofulvin and the newer antifungal the “gold standard” in the treatment of tinea capi-
agents is presented in Table V. The indicated dosing tis should be questioned.
regimens are those that are currently most com- Itraconazole, fluconazole, and terbinafine all pos-
monly used by specialists in the field. The calculation sess desirable pharmacokinetic and pharmacodynam-
of costs is based on the capsule or tablet form for ic properties that make them excellent candidates for
itraconazole and terbinafine and on the liquid for- the treatment of tinea capitis. Thus far, however, few
mulation for fluconazole using the average whole- randomized, double-blind, controlled studies with
sale drug prices. Terbinafine is significantly more these agents have been published. Of those studies
economical than the other two new antifungals, that have appeared in print, many are incomplete in
especially for short courses of therapy. one or more respects, and the results of some studies
seem to contradict the results obtained with other
SUMMARY investigations using the same drug.
During the past decade, tinea capitis has again The best available data strongly support the effi-
become a major public health concern in the cacy and safety of the new antifungal agents for the
United States and elsewhere. Not only is there evi- treatment of tinea capitis. However, none of these
dence of increasing incidence of the disease, the agents has yet been officially approved for this indi-
sometimes subtle, nonspecific clinical presentation cation by the FDA; all current use is strictly off-label.
of tinea capitis may mask its true incidence and can Fluconazole is the only antimycotic agent that is cur-
confound proper diagnosis. Moreover, the appar- rently approved by the FDA for use in children.
ent development of tolerance or resistance to Safety and cost data currently favor terbinafine for
griseofulvin therapy has led to the need for alter- the treatment of T tonsurans infections. It is possi-
native drug therapies that are safe, efficacious, and ble that M canis infections respond better to itra-
inexpensive, and that work relatively rapidly. conazole therapy, but adequately controlled studies
Because of these factors, the role of griseofulvin as needed to confirm this speculation have not yet
18 Elewski J AM ACAD DERMATOL
JANUARY 2000

Table V. Cost to treat tinea capitis in a child weighing 20 kg (based on average wholesale drug prices)
Total No.
Dose/ mL(mg)/ No. dose Bottle Formula Price/ bottles Total
Drug Mg/kg/day day day days (mL) size (mg/mL) unit ($) (units) cost ($)

Griseofulvin 20 400 16 56 896 4 oz 125 20.80 8 166.40

Griseovulvin 20 400 16 84 1344 4 oz 125 20.80 11 228.80
Itraconazole 5 100 (100) 28 – 100 mg cap 5.00 (28) 140.00
Fluconazole 6 120 3 20 60 35 mL 40 mg/mL 102.13 1.5 153.20
Fluconazole 6 125 (125) 20 – – 100 mg tab 6.87 (25) 171.75
Terbinafine N/A 125 (125) 14 – – 1
⁄2 (250 mg) tab 5.64 (7) 39.48
Terbinafine N/A 125 (125) 28 – – 1
⁄2 (250 mg) tab 5.64 (14) 78.96

cap, Capsule; tab, tablet.

been reported. Short-course and pulse dosings are
exciting options that could decrease cost and lower
the risk of adverse events. Additional useful informa-
tion will, no doubt, be forthcoming from future clin-
ical trials, especially if proper initial identifications of
etiologic agents are made, standardized definitions
are used to establish what is a “cure,” and long-term
follow-up evaluations of clinical and mycologic cures
are properly carried out with all patients enrolled in
the trials.
Some present obstacles to conducting appropri-
ate clinical trials include the lack of oral pediatric for-
mulations for some of the newer antifungal drugs
and uncertainty as to proper dosage and duration of
therapy with the newer agents. The need for long-
term therapies with these drugs, whether continu-
ous or intermittent, poses a significant compliance
challenge. It is likely that the drugs currently avail-
able will not require daily dosing, but intermittent
dosing strategies may prove even more difficult to
execute faithfully. With the new millenium, we need
to turn our attention to rapid diagnostic techniques
for tinea capitis and more effective therapies that
offer patients safe treatment alternatives.
The cost of color reproductions has been covered by
Novartis Pharmaceuticals Corp, East Hanover, New Jersey.
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