Mycopathologia
DOI 10.1007/s11046-016-0045-0
New Antifungal Agents and New Formulations
Against Dermatophytes
Aditya K. Gupta . Kelly A. Foley .
Sarah G. Versteeg
Received: 4 July 2016 / Accepted: 26 July 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A variety of oral and topical antifungal
agents are available for the treatment of superficial
fungal infections caused by dermatophytes. This review
builds on the antifungal therapy update published in this
journal for the first special issue on Dermatophytosis
(Gupta and Cooper 2008;166:353–67). Since 2008,
there have not been additions to the oral antifungal
armamentarium, with terbinafine, itraconazole, and
fluconazole still in widespread use, albeit for generally
more severe or recalcitrant infections. Griseofulvin is
used in the treatment of tinea capitis. Oral ketoconazole
has fallen out of favor in many jurisdictions due to risks
of hepatotoxicity. Topical antifungals, applied once or
twice daily, are the primary treatment for tinea pedis,
tinea corporis/tinea cruris, and mild cases of tinea
unguium. Newer topical antifungal agents introduced
include the azoles, efinaconazole, luliconazole, and
sertaconazole, and the oxaborole, tavaborole. Research
is focused on developing formulations of existing
topical antifungals that utilize novel delivery systems
in order to enhance treatment efficacy and compliance.
A. K. Gupta
Department of Medicine, University of Toronto,
Toronto, Canada
A. K. Gupta (&)
K. A. Foley
S. G. Versteeg
Mediprobe Research Inc., 645 Windermere Road,
London, ON, Canada
e-mail: publications@mediproberesearch.com
Keywords Tinea capitis
Tinea corporis
Tinea
cruris
Tinea pedis
Onychomycosis
Topical
antifungals
Introduction
Dermatophytoses are superficial fungal infections
caused by dermatophytes that affect the skin, hair,
and nails [1]. There are three main classes of
dermatophytes that cause fungal infections on the
body: Epidermophyton, Trichophyton, and Microspo-
rum [1]. Hair, skin, and nails are common targets as
keratin is a food source for these organisms [1].
Sources of dermatophytes can include environmental
sources (e.g., soil) or transmission via contact with
infected humans or animals [2]. The majority of
dermatophyte infections are caused by Trichophyton
rubrum [3]; however, Microsporum canis is a common
dermatophyte that can be found in both pets (e.g., cats
and dogs) and humans [4]. Improper hygiene, socioe-
conomic status, occlusive footwear, diabetes mellitus,
age, genetics, and immunocompromised status can
increase the likelihood of infection [1, 5, 6].
Fungal infections can be an economical burden
with approximately $1.67 billion spent on treatments
[7]. Dermatophytes are the main cause of fungal
infections in North America [8]. The American
Academy of Dermatology has estimated that there
have been over 29.4 million cases of cutaneous fungal
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infections with over 51 million physician visits in the
USA alone [7, 9]. The prevalence of dermatophyte
infections in European countries can range from 2.6 %
(Spain and the UK) to 8.4 % (Finland) [10–12]. With
20–25 % prevalence worldwide, successful treatments
are necessary to address this health issue [13].
There are numerous treatment options for dermato-
phyte infections. For the most part, similar antifungal
treatments are used worldwide; however, there are
some variations and country-specific guidelines
should be consulted. Historically, imidazoles (e.g.,
bifonazole, clotrimazole, miconazole) were the most
commonly used antifungal drugs for treatment of
superficial cutaneous fungal infections [9]. These have
been joined by the triazoles (e.g., fluconazole, itra-
conazole, efinaconazole), allylamines (e.g., bute-
nafine, naftifine, terbinafine), and others (e.g.,
amorolfine, ciclopirox, tavaborole). This review sum-
marizes the main antifungal treatments used to treat
dermatophytoses that are cited in the literature with an
emphasis on newer agents. Oral ketoconazole is no
longer recommended for superficial fungal infections
and has been excluded from this review [14]. Systemic
(oral) antifungals are recommended for tinea capitis
and for serious cases of tinea corporis/tinea cruris,
tinea pedis, and onychomycosis. Topical antifungals
are recommended for localized tinea corporis and
tinea pedis and mild-to-moderate cases of onychomy-
cosis [5]. Combinations of oral and topical antifungals
may also effectively treat fungal infections [5].
There are numerous treatment options for tinea
pedis. Topical treatments are first-line therapy, with
oral antifungals recommended when the infection is
extensive and/or the use of topical antifungals is not
feasible [20]. Bacterial superinfections might co-occur
with these types of infections; thus, it is beneficial for
antifungal agents to have antibacterial activity or to
use concomitant antibacterial therapy. Treatment
options that include this additional antibacterial
activity are miconazole nitrate, ciclopirox olamine,
naftifine hydrochloride, and sulconazole nitrate [20].
Patient compliance can be an issue when treating tinea
pedis. Patients have a tendency to cease treatment
before the full regimen is completed, often terminating
treatment when clinical symptoms have improved/
resolved [16]. This contributes to reinfection or
relapse.
Oral Therapy
Oral antifungals are used in severe cases of tinea
pedis or where topical treatment is ineffective, with
use being off-label in some parts of the world (e.g.,
USA). Terbinafine (Fig. 1) can inhibit fungal ergos-
terol synthesis through squalene epoxidase as well as
influence human host cytochromes (e.g., CYP 2D6)
[20]. Terbinafine is administered once daily

Tinea Pedis

Tinea pedis is a fungal infection of the foot and can be

classified based on location of the infection: sole of the
foot (vesicular), lateral aspects of the foot (moccasin),
and between the toes (interdigital) [15]. The most
severe and chronic form of tinea pedis is the moccasin
classification, and the most common is interdigital
tinea pedis [15, 16]. Leading causes of tinea pedis
include T. rubrum, T. interdigitale, and E. floccosum
[17]. Moisture accumulation (e.g., hot humid climates
or sporting activities) can be a risk factor associated
with this fungal infection [18]. Tinea pedis can lead to
health complications if left untreated such as cellulitis
(bacterial infection), secondary immunological reac-
tions, and perifollicular granulomatous inflammation
[16, 19]. Fig. 1 Chemical structure of terbinafine [26]

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Mycopathologia

(250 mg) for 2–6 weeks [20]. High cure rates can be
found with oral terbinafine as seen in 75–85 % of
dermatophyte infection studies [21] and, following
6 weeks of treatment, mycological cure rates ranged
from 77 to 83 % [22]. Side effects reported with oral
terbinafine can include actions on the central nervous
system (e.g., headaches, concentration difficulties),
gastrointestinal system (e.g., diarrhea, dyspepsia,
nausea), and cutaneous system (e.g., erythema,
pruritus) [20, 22].
Itraconazole (Fig. 2) prevents the synthesis of
fungal ergosterol by inhibiting C-14a-demethylation
of lanosterol, disrupting fungal cell membranes [20].
Oral treatment consists of 200 mg twice daily for
7 days [20]. Phase 3 clinical trials reported high
mycological cure rates (79 %) and clinical responses
(healed or markedly improved) (93 %) following
7 days of itraconazole (200 mg twice a day) [23].
Itraconazole also has effects on the central nervous
system (e.g., headache, dizziness), gastrointestinal
system (e.g., diarrhea, dyspepsia, abdominal pain),
and cutaneous system (e.g., rash) [20].
In North America, fluconazole (Fig. 3) is used off-
label for treatment of tinea pedis. Available in 50 mg Fig. 3 Chemical structure of fluconazole [28]
and 100 mg tablets [24], fluconazole also inhibits the
C-14a-demethylation of lanosterol and has the poten-
tial to inhibit human host cytochromes (e.g., CYP2C9 terbinafine and itraconazole, including headache,
and CYP2C19) [20]. A typical regime consists of nausea, and skin rash [20].
150 mg per week for 2–6 weeks [20]. High clinical
responses with fluconazole taken daily (50 mg) and Topical Therapy
weekly (150 mg) for 6 weeks in treating tinea pedis
have been reported, with a mycological cure rate of There are several topical agents that can be used for
93 % and marked improvement rate of 79 % [25]. treating tinea pedis, such as terbinafine, butenafine,
Fluconazole can produce similar side effects as naftifine, ciclopirox, clotrimazole, econazole, micona-
zole, sertaconazole, and luliconazole. Most treatments
are classified as azoles or allylamines, which typically
inhibit ergosterol synthesis and disrupt fungal growth
[29] Terbinafine spray and cream formulations are
available, and cream is available over-the-counter in
some areas (e.g., USA) [30]. High mycological and
effective treatment (mycological cure and no signs of
infection) rates were achieved when 1 % terbinafine
cream was used to treat tinea pedis, 67–95 % and
60–80 %, respectively [22]. Terbinafine (1 %) in
spray formulation had mycological cure rates of
85 % (1-week treatment) to 92 % (2-week treatment)
and effective treatment (mycological cure and no signs
Fig. 2 Chemical structure of itraconazole [27] of infection) rates of 66–83 % in the treatment of tinea
pedis [22].

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Ciclopirox is used worldwide for treatment of
superficial fungal infections, although it is used off-
label in some places for tinea pedis (e.g., Canada).
FDA approved for the treatment of tinea pedis caused
by T. rubrum, T. interdigitale, E. floccosum, and M.
canis [31], and ciclopirox disrupts fungal metabolism
by inhibiting iron-dependent enzymes, preventing the
chelation of heavy metal irons (e.g., iron or alu-
minum) [32–34]. Ciclopirox (0.77 %) cream or gel
formulation is usually applied twice daily for four
weeks [20]. Clinical cure rates and mycological cure
rates after 8 weeks of treatment with ciclopirox
(0.77 % gel formulation) twice daily for tinea pedis
were 51.4 and 80.8 %, respectively [35]. All adverse
events recorded were not significantly different from
placebo group [35].
Sertaconazole and luliconazole represent newer
additions to the armory of topical antifungals. Serta-
conazole 2 % cream is FDA approved for treatment of
tinea pedis caused by T. rubrum, T. interdigitale, and
E. floccosum in individuals 12 years of age and older
[36] and is approved for use in the EU [37].
Sertaconazole should be applied twice daily for
4 weeks [36]. Both the solution and cream formula-
tions of sertaconazole have been evaluated, with both
producing high efficacy rates (solution: 90.6 %;
cream: 88.9 %) and no adverse effects in patients
with tinea pedis [38].
Luliconazole 1 % cream is FDA approved for
treatment of tinea pedis caused by T. rubrum and E.
floccosum [39]. Luliconazole is able to remain phar-
maceutically active in the presence of keratin and
inhibits 14a-demethylase causing fungal ergosterol
biosynthesis to be disrupted [39]. Phase 3 clinical trials
reported complete clearance of tinea pedis occurring
in 26.4 % of patients 28 days post-treatment when
luliconazole was applied once a day for 14 days [40].
Research into new formulations that can enhance
the efficacy and potentially compliance of topical
antifungals has been a priority. Econazole nitrate 1 %
cream has been used for 20 years, yet a new foam 1 %
formulation was recently FDA approved. The novel
water–lipid delivery system aims to deliver drug and
help restore damaged skin [41]. Foam formulations
may be seen as more attractive to patients, being easier
to apply and more esthetically pleasing than creams.
Econazole 1 % foam is applied only once, not twice,
per day. Phase III clinical trials (daily application for
4 weeks) showed a mycological cure rate of 67.6 %
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Mycopathologia
with an effective treatment rate (mycological cure
with no tinea pedis symptoms) of 48.6 % [41].
Recent clinical trials have demonstrated the effi-
cacy of the gel formulation of naftifine hydrochloride
in treating moccasin tinea pedis [17]. Naftifine has
antifungal, antibacterial, and anti-inflammatory activ-
ity [17, 42, 43]. Most topical antifungal clinical trials
study interdigital tinea pedis, and the moccasin form
is considered too severe. A post hoc analysis of two
phase III clinical trials (double-blind, randomized,
vehicle controlled, multicenter, parallel group) with
daily application of naftifine gel for 2 weeks showed
a complete cure rate of 19.2 % (mycological cure
and absence of erythema, scaling, pruritus) and a
mycological cure rate of 65.8 % at 4 weeks post-
treatment [17]. Only 1.2 % of participants experi-
enced treatment-emergent adverse events related to
study treatment such as site pruritus, rash, and
hypersensitivity [17].
A meta-analysis of 65 randomized trials that
included 16 topical antifungal agents (e.g., bifonazole,
clotrimazole, naftifine) in the treatment of tinea pedis
found no statistically significant differences in myco-
logical cure rates [44]. Butenafine was more effica-
cious than azoles (clotrimazole, oxiconazole, and
sertaconazole) [44], and oral terbinafine was found
to be more efficacious than itraconazole and griseo-
fulvin [45]. There are several drugs currently in
development (e.g., phase II and phase III clinical
trials) for the treatment of tinea pedis that include VT-
1161, Drug 33525, LAS41003, and nitric oxide.
Prevention of Tinea Pedis
Tinea pedis is both contagious (via infected skin cells)
and recurrent [46]. Approximately, 70 % of the
population has been or will be infected with tinea
pedis in their lifetime [16]. Taking precautions are
necessary in order to avoid transmitting and contract-
ing this infection. Preventative methods can include
proper hygiene practices, avoiding communal areas
(e.g., swimming pool, showers), and drying feet
appropriately [20]. Choosing antimicrobial fabrics
over textiles could also help to control dermatophyte
infections [47]. Health education programs have also
been evaluated as possible preventative measures. A
reduction in the severity of tinea pedis and increase in
symptom-free patients were observed following an
educational program for diabetic patients whose goal
Mycopathologia
was to prevent diabetic foot ulcerations, a possible
complication of tinea pedis [48].
Tinea Corporis/Tinea Cruris
Tinea corporis and tinea cruris are common superficial
fungal infections, predominantly caused by T. rubrum,
T. mentagrophytes, and M. canis [49]. Affecting the
trunk, tinea corporis is generally found in children and
young adults. Interaction with animals is often a
source of transmission of M. canis in children [49, 50].
Tinea cruris affects the groin and is generally found
more frequently in men. Excessive perspiration and
restrictive clothing are predisposing factors for these
infections in adults [49, 50].
Both topical and oral antifungals can be used to treat
tinea corporis/tinea cruris. Oral antifungal agents are
used off-label where daily application of topical anti-
fungals may be cumbersome, for example, in severe
cases involving large parts of the body. Terbinafine
(250 mg/day for 2–4 weeks), itraconazole (200 mg/day
for 1 week), and fluconazole (150–300 mg/week for
2–4 weeks) have been shown to be effective [49].
Topical antifungals include terbinafine, butenafine,
naftifine, clotrimazole, econazole, ketoconazole,
miconazole, sulconazole, and ciclopirox. Evidence
from a Cochrane review suggests that azoles provide
therapeutic benefit, with pooled results of studies with
each of terbinafine and naftifine showing significant
benefit over placebo [51]. Older, widely available
treatments for tinea corporis/tinea cruris include Whit-
field’s ointment and tolnaftate. Topical corticosteroid
use for tinea corporis/tinea cruris is contentious; while
use may decrease inflammation, other complications
may occur [52–54].
Sertaconazole 2 % cream is FDA approved for
tinea pedis, with sertaconazole used in the EU for
many superficial fungal infections, including tinea
corporis/tinea cruris. Twice-daily application for
3 weeks of sertaconazole showed a reduction in
clinical signs and symptoms that was greater than that
of clotrimazole in patients with tinea corporis and
similar to terbinafine in patients with tinea corporis/
tinea cruris [55, 56]. Novel delivery systems are under
development to enhance the efficacy of sertaconazole
[57, 58].
Luliconazole 1 % cream is a more recent imidazole
that is FDA approved (2013) for the treatment of tinea
corporis/tinea cruris (and tinea pedis) caused by T.
rubrum and E. floccosum. Application to the affected
area and immediate surrounding skin once a day for
one week may encourage patient compliance com-
pared to topical antifungals that require application
multiple times daily for 2 or more weeks [59]. A large-
scale phase 3 clinical trial evaluated one week of
luliconazole treatment for tinea cruris in patients
C12 years of age. Clinical signs and symptoms were
resolved and mycological cure obtained at 28 days,
demonstrating superiority of luliconazole to vehicle
cream [60].
New head-to-head clinical studies have compared
topical antifungals in the treatment of tinea corporis/
tinea cruris. An open-label pilot study compared
luliconazole 1 % cream (once daily for 2 weeks) to
sertaconazole 2 % cream (twice daily for 4 weeks)
and terbinafine 1 % cream (once daily for 2 weeks)
[61]. At the end of treatment, the reduction in mean
composite score of clinical signs and symptoms
(pruritus, erythema, vesicles, and desquamation) was
greater in the sertaconazole group (97 %) compared to
luliconazole (93 %) and terbinafine (91 %) [61]. All
treatments were effective and well tolerated. An
additional trial comparing use of topical antifungals
for one week (tinea corporis/tinea cruris) or two weeks
(tinea pedis) showed that luliconazole, sertaconazole,
amorolfine, and terbinafine significantly reduced signs
and symptoms of tinea infections by 4 weeks, whereas
eberconazole did not [62]. Eberconazole, however,
has been shown to be as effective as terbinafine in
treating tinea corporis/tinea cruris. A small compar-
ison trial using longer treatment regimens (twice daily
for 3 weeks) produced complete cure (clinical and
mycological) in all patients receiving eberconazole or
terbinafine [63].
Tinea Capitis
Tinea capitis is a superficial dermatophyte infection
that is located primarily in hair follicles as well as
surrounding skin. Common characteristics of this
infection include: hair loss (with or without broken
hairs), scaling (diffuse or focal), erythema, inflamma-
tion of the scalp, and lesions [64, 65]. In the last
30 years, there has been a significant increase in the
number of reported cases of tinea capitis [66–68].
Tinea capitis is typically caused by Trichophyton and
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Microsporum species [66–68]. There are both non-
inflammatory and inflammatory variants of tinea
capitis depending on type of organism causing the
infection [65]. Non-inflammatory variants include
gray patch (Microsporum infection), black dot (Tri-
chophyton infection), and diffuse scaling of the scalp
[65]. Inflammatory variants include diffuse pustular
(patchy alopecia), kerion (development of plaques and
associated alopecia), and favus (T. schoenleinii infec-
tion) [65].
Tinea capitis commonly occurs in children under
the age of 10 years [69–72]. Although rare, adults can
also suffer from tinea capitis, accounting for approx-
imately 20.6 % of cases [64]. Individuals who have a
high risk of infection include the immunocompro-
mised and postmenopausal women [73, 74]. Addi-
tionally, evidence to support a male bias in young
children with tinea capitis has been reported [68].
A Canadian survey of family physician practices in an
urban community found that approximately 210 new
cases of tinea capitis occur every year in children
living in a high-risk neighborhood (e.g., low income,
crowded) [75].
The goals for successful treatment include symp-
tom alleviation, mycological and clinical cure, and
preventing infection transmission [65, 76]. Due to
follicle involvement, oral treatments are required for
mycological cure, and scarring can occur if tinea
capitis is left untreated [20, 77]. If compliance is a
concern, granule formulations can be used and added
to non-acidic foods (e.g., peanut butter) to increase
compliance [65, 78].
Oral Therapy
There are several antifungal agents that have been
used for years to treat tinea capitis such as terbinafine,
griseofulvin, fluconazole, and itraconazole. Treatment
options for tinea capitis can differ depending on age
and weight, and between countries (Table 1). Grise-
ofulvin is not available in Canada and many other
countries; however, it is listed on the WHO Model of
essential medicines (April 2015) and is FDA approved
for treating tinea capitis [79, 80]. In the UK, for
example, griseofulvin is available for children with
tinea capitis with suggested treatment duration of
8 weeks [65]. Griseofulvin has efficacy rates ranging
from 88 to 100 %, and could be considered an
effective antifungal in treating tinea capitis [20].
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Mycopathologia
Terbinafine is used worldwide with FDA approval
of granule formulations (125 or 187.5 mg) for use in
children 4 years of age and older [65, 78]. Granules
can be added to non-acidic foods (e.g., pudding or
mashed potatoes) to ease administration [78]. Treat-
ment is usually 6 weeks in length, and there is a
significant reduction in clearance of terbinafine that
occurs with age which requires children to be given
larger weight-normalized doses than adults [81].
Efficacy rates of terbinafine and griseofulvin are
influenced by the causal dermatophyte. Terbinafine
(47.7–56.1 %) has higher complete cure rates for tinea
capitis caused by T. tonsurans when compared to
griseofulvin (34.4–36.5 %) [78]. Griseofulvin, how-
ever, has higher complete cure rates for tinea capitis
caused by M. canis (35.1–51.1 %) as compared to
terbinafine (23.8–30.6 %) [78].
Itraconazole can also be used to effectively treat
tinea capitis. It is not FDA approved for the treatment
of tinea capitis. There are multiple formulations
available: capsule (100 mg) and liquid (10 mg/mL).
The liquid form is generally restricted to immunosup-
pressed patients and for prevention of systemic
mycoses [82]. Itraconazole using pulse therapy may
be effective and promote compliance in children.
Itraconazole was given to children with tinea capitis at
5 mg/kg/day for 1 week, and a second or third pulse
was given if clinically necessary with two weeks
between pulses. Complete (clinical and mycological
cure) cure was 100 % 12 weeks after therapy was
commenced [83].
There are also multiple formulations of fluconazole
with suggested treatment duration of 4 weeks: tablets
(50, 100, 150, and 200 mg) and suspension (200 and
50 mg/5 ml) formulation [65, 84]. Like itraconazole,
fluconazole is not FDA approved for the treatment of
tinea capitis. One study reported that 8.04 weeks of
treatment with fluconazole at a dose of 6 mg/kg per
day was required to achieve a clinical cure, while
12 weeks of treatment at a dose of 4 mg/kg per day
was required for clinical cure [85].
Time required to achieve a complete cure can also
vary between treatments [67]. Terbinafine has a
shorter treatment duration required to obtain complete
cure when compared to griseofulvin (4 vs. 8 weeks,
respectively), especially for Trichophyton tonsurans
[67]. Short-term treatment (4–6 weeks) is desired as
long-term treatment can lead to poor patient compli-
ance and increased drop-out rates [67].
Mycopathologia

Table 1 Approved oral antifungal agents that are used for treatment of tinea capitis*
Antifungal Agent Dosage recommendations
Children Adults (FDA approved) Children (British Association of
(FDA approved) Dermatologists’ Guidelines)

Terbinafine [65, 78, 82]
Fluconazole [65, 69, 82] [65]
[66] [65]
Itraconazole [65, 82, 87]
Griseofulvin [20, 65]
* Disclaimer: For countries not listed, please see individual guidelines for approval and recommendations
\25 kg 250 mg/day for 4–6 weeks 150 mg/day for 4 weeks
125 mg/day
25–35 kg
187.5 mg/day
[35 kg
250 mg/day
3 to 5 mg/kg/day 50 mg/day for 4–7 weeks or 150 mg/week 150 mg/week for 4 weeks
for 4–8 weeks
3–5 mg/kg/day 100–200 mg/day for 4 weeks 100 mg/day for 4 weeks
Ultramicrosize: 125–250 mg 200–300 mg/day for 8 weeks

Shampoos individuals were clinically diagnosed with tinea

Antifungal shampoos can be used in combination with
oral antifungal therapy and as a preventative measure
or to treat asymptomatic carriers [20]. Antifungal
ingredients for shampoos include selenium sulfide,
povidone iodine, ciclopirox, and zinc pyrithione with
administration twice weekly for durations dependent
on the antifungal ingredient [82].
Selenium sulfide is a heavy metal that can denature
fungal cells [76]. When selenium sulfide is added in
combination with an oral treatment (griseofulvin), a
decrease in spore counts occurs faster than using oral
monotherapy [86]. However, due to its strong odor,
patients may not prefer selenium sulfide shampoos
[86]. A less odorous alternative is ciclopirox shampoo.
This antifungal agent is a hydroxypyridone that
inhibits degradation of peroxides in fungi [76].
Ciclopirox (1 %) is comparable to selenium sulfide
(1 %) with no differences in mycological cure rates
between ciclopirox (95.2 %) and selenium sulfide
(91.7 %) [76].
Prevention of Tinea Capitis
Transmission of tinea capitis can occur by physical
contact of infected patients or animals (pets), via
spores, or by asymptomatic carriers [20]. Infections
caused by Trichophyton tonsurans can be highly
contagious. Out of 209 households, 7.2 % of
capitis and 44.5 % were asymptomatic carriers (no
visible symptoms of tinea capitis, but dermatophytes
were evident in scalp brushing) [88]. To avoid
transmission, shared items (e.g., hats, brushes) should
be limited and bleach used to disinfect [20]. Children
can be free to attend school once treatment is
commenced as it was reported that after 10 days of
antifungal treatment, over 75 % of patients with tinea
capitis were no longer contagious [20, 89].
Tinea Unguium (Onychomycosis)
Onychomycosis is a fungal infection of the nail plate
that can be characterized by nail thickening, onychol-
ysis, and subungual hyperkeratosis. It is particularly
difficult to treat infection with high recurrence rates.
Most infections are caused by T. rubrum and T.
interdigitale. As much as 12–13 % of the population
may be affected by fungal nail infections [11, 12, 90].
Distal-lateral subungual onychomycosis is the most
common presentation. Certain populations are more
susceptible to onychomycosis, including the elderly
and those with comorbid medical conditions (e.g.,
diabetes, psoriasis). Treatment success, in part,
depends on nail growth. Fingernails grow faster and
often have shorter treatment durations and higher
success rates than toenails, which may take
12–18 months to grow [20, 91].

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Treatment options for onychomycosis include oral
and topical antifungals. Nail debridement may aid
with the success of antifungal therapy, although it is
specifically not required with newer topical agents.
Avulsion with urea in combination with bifonazole is
also a treatment option and is more attractive than
undergoing surgical nail removal [91]. The oral
antifungals in widespread use are terbinafine, itra-
conazole, and fluconazole, with the drug VT-1161 in
early development (in vitro). Terbinafine and itra-
conazole are initially prescribed for 12 weeks for
toenail infection; in the case of fluconazole, once-
weekly treatment is administered until the nail plate
grows out, typically 9–18 months for toenails [92].
Topical antifungals are applied to nails daily for up to
48 weeks, with some suggestion that application
should continue to occur until healthy nail growth is
complete.
Duration of therapy with oral antifungals is not only
shorter than that of topical antifungals, but cure rates
are higher, with clinical cure ranging from 40 to 80 %
for oral antifungals [92, 93]. The caveat to this is that
oral antifungals may not be appropriate for some
patients; for example, the immunocompromised, dia-
betic, or those on polypharmacy (drug–drug interac-
tions via CYP enzymes). In recent years, there has
been growing concern about hepatotoxicity with
terbinafine and itraconazole [94]. While the risk of
experiencing complications is small, this information
may produce reservations surrounding use of oral
antifungals. In cases of severe ([60 % nail involve-
ment) or recurring onychomycosis, oral antifungal
therapy is likely warranted.
Topical antifungal therapy is commonly used for
mild-to-moderate cases of onychomycosis, or for
single affected digits. There are minimal adverse
effects with topical antifungals, limited to site-appli-
cation reactions [95–98]. Little to no systemic absorp-
tion with topical antifungal application also eliminates
the possibility of drug–drug interactions. Amorolfine
and ciclopirox are the main topical agents used in
Europe, with efinaconazole and tavaborole recently
introduced in North America. Amorolfine is not
available in North America. Topical terbinafine cream
or solution, effective treatment for other superficial
fungal infections, is not efficacious in the treatment of
onychomycosis.
Following completion of treatment, there are mea-
sures that can be taken to help prevent recurrence and
123
Mycopathologia
reinfection. Fungi can be transmitted to other clothing
during laundering. Sixteen percent of fungal matter
remained in the rinse cycle of a 30 °C wash. Laun-
dering socks in a 60 °C wash for at least 45 min may
aid in destroying residual fungal matter [99]. Main-
taining proper foot and nail hygiene (e.g., nails short,
absorbent, and dry socks), avoiding ill-fitting foot-
wear, treating concurrent tinea pedis, and treating
family members for onychomycosis may also decrease
risk of recurrence/reinfection [100]. There is evidence
to suggest that prophylactic use of topical antifungals
can delay recurrence [101].
Oral Therapy
Terbinafine, itraconazole, and fluconazole are the main
oral antifungal treatments for onychomycosis, having
replaced the older antifungal, griseofulvin. Treatment
regimens are either continuous (daily terbinafine)
250 mg/day for 12 weeks (FDA approved) or pulse
therapy (1 week on, 3 weeks off for itraconazole) for
about 12 weeks. A recent network meta-analysis
concluded that 250 mg daily terbinafine and 400 mg
pulse therapy with itraconazole were superior to
fluconazole and topical therapies [102].
There are multiple pulse regimens of terbinafine
that have been clinically investigated. A meta-analysis
evaluating continuous versus pulse regimens supports
the superiority of continuous terbinafine. However, for
complete cure, some pulse regimens were equivalent
to continuous terbinafine. The pulsed regimen that was
most comparable to continuous terbinafine was 2
pulses of 250 mg/day for 4 weeks on/4 weeks off
[103]. Terbinafine may also be used in cases of non-
dermatophyte mold and mixed dermatophyte/non-
dermatophyte mold infections [104].
Itraconazole has been shown to be effective using a
continuous regimen 200 mg/day for 12 weeks or pulse
regimen of 200 mg twice daily (400 mg/day) for
1 week, followed by 3 weeks off [105]. The contin-
uous regimen is approved in the USA. In Canada, both
the continuous and pulse regimens are approved. This
is repeated 3 times for toenails and 2 times for
fingernails. Itraconazole may also successfully treat
non-dermatophyte mold and mixed dermatophyte/
non-dermatophyte mold infections [104].
Fluconazole is not approved in all countries for
treatment of dermatophyte onychomycosis. Adminis-
tration of 150–300 mg weekly for about 6 months is
Mycopathologia

the most frequent regimens of fluconazole reported.
Treatment should generally continue until the diseased
nail has grown out, which may be 6–9 months for
finger nails and 9–18 months for toenails. Fluconazole
was found to be superior to topical treatments for
onychomycosis, but not as efficacious as terbinafine or
itraconazole [20, 102]. There are limited data sup-
porting the use of fluconazole for the management of
dermatophyte molds [104].
Topical Therapy
For over 10 years, amorolfine 5 % and ciclopirox 8 %
nail lacquers were the only efficacious topical treat-
ments for onychomycosis. Even then, cure rates
remained lower than those for oral antifungals
(Table 2). Prior to application of these lacquers, nail
debridement and removal of previously applied
lacquer are required. Soluble solutions that can be
applied daily to affected nails are desirable. Such a
water-soluble formulation of ciclopirox, ciclopirox
8 % HPCH (P-3051) has been developed and used in
many countries. In 2014, efinaconazole 10 % and
tavaborole 5 % solutions were approved by the FDA.
Efinaconazole is used in Canada, the USA, and Japan;
tavaborole is used in the USA.
Ciclopirox 8 % HPCH (P-3051) is a hydrolacquer
based on hydroxypropyl chitosan (HPCH) technology.
P-3051 is water soluble and forms a film over the nail.
Overnight application of the hydrolacquer allows
ciclopirox to penetrate the nail plate prior to removal
of the film through daily washing and does not require
debridement [106]. Clinical studies have shown once
daily treatment for 48 weeks of P-3051 to produce
significantly higher complete and mycological cure
rates than amorolfine 5 % lacquer and ciclopirox 8 %
lacquer (Table 2). At 60 weeks, complete cure was
12.7 % for P-3051, compared to 5.8 % for ciclopirox
8 % lacquer (p \ 0.05) and 1.3 % for vehicle
(p \ 0.01) [107]. Clinical improvement, defined as
mycological cure and B10 % nail involvement, was
significantly higher at 60 weeks with P-3051 treat-
ment (28.7 %) as compared to ciclopirox 8 % lacquer
(17.3 %, p \ 0.05) and vehicle (14.7 %, p \ 0.05)
[107]. P-3051 was also more efficacious than amor-
olfine 5 % lacquer at 48 weeks, as assessed by cure
rates and number needed to treat (NNT) analyses
[106]. The NNT was calculated from complete cure
rates for P-3051 (NNT = 3, 95 % CI 2–5) and
amorolfine (NNT = 11, 95 % CI 5–88) [106].
Efinaconazole 10 % solution was approved for the
treatment of toenail onychomycosis caused by T.
rubrum and T. interdigitale. In phase 3 clinical trials
conducted in North America and Japan, complete
cure, mycological cure, and clinical improvement
(\10 % nail involvement) rates were 15–18 %,
53–55 %, and 31–36 %, respectively [97]. Efinacona-
zole is applied once daily for 48 weeks and while
approved for use against dermatophytes, it may also
have efficacy against non-dermatophyte molds and

Table 2 Efficacy rates for Complete cure (%) Mycological cure (%) Clinical improvement (%)
topical treatments for
onychomycosis Treatment Vehicle Treatment Vehicle Treatment Vehicle
(48–52 weeks)
Amorolfine [95] – – 52 – 41 –
Ciclopirox [96]
Trial 1 5.5 0.9 29** 11 6.5* 0.9
Trial 2 8.5** 0 36*** 9 12** 0.9
Ciclopirox HPCH
Study 1 [107] 5.7* 0 89.1*** 69.1 24*** 6.4
Study 2a [106] 35*** 11.7 100*** 81.7 58.3*** 26.7
Efinaconazole [97]
* p \ 0.05, ** p \ 0.01,
Trial 1 17.8*** 3.3 55.2*** 16.8 35.7*** 11.7
*** p \ 0.001
a Trial 2 15.2*** 5.5 53.4*** 16.9 31*** 11.9
Amorolfine was used as a
comparator to ciclopirox Tavaborole [98]
HPCH in Study 2, and Trial 1 6.5** 0.5 31.1*** 7.2 15.3*** 1.5
vehicle cure rates indicate Trial 2 9.1*** 1.5 35.9*** 12.2 17.9*** 3.9
amorolfine cure rates

123

yeasts, although this has yet to be confirmed with
clinical studies. With these newly approved solutions,
application is not only to the nail plate itself, but also
to the nail folds, hyponychium, and the undersurface
of the nail plate. This may aid in drug delivery to the
site of infection, as both transungual and subungual
routes of delivery are utilized [108]. Post hoc analyses
from phase 3 clinical trials suggest that efinaconazole
may be efficacious in difficult to treat sub-populations
of onychomycosis (summarized in [108]). For exam-
ple, no difference in clinical efficacy of efinaconazole
was found between patients with and without diabetes.
Additionally, the importance of treating concomitant
tinea pedis was demonstrated, with efinaconazole cure
rates significantly higher if patients with onychomy-
cosis were treated for concomitant tinea pedis.
Tavaborole 5 % solution employs a unique mech-
anism of action as its boron-based structure targets
leucyl-tRNA synthetase to inhibit protein synthesis,
and thus fungal cell growth, whereas most existing
antifungals target ergosterol synthesis [109]. This may
be relevant for treatment of dermatophytoses if the
concern of antifungal resistance to azoles continues to
develop. Daily application of tavaborole for 48 weeks
is approved in the USA for the treatment of toenail
onychomycosis caused by T. rubrum and T. interdig-
itale. Complete cure rates were reported to be
6.5–9.0 %, mycological cure rates were 31–36 %,
and clinical improvement (negative mycology
and B10 % nail involvement) was 15–18 % in phase
3 clinical trials [98]. Like efinaconazole, tavaborole
also shows broad-spectrum activity in vitro against
dermatophytes, non-dermatophyte molds, and yeasts
[109]; again, clinical efficacy has not been demon-
strated with the latter two.
Research into new formulations of existing anti-
fungals may provide the most promising break-
throughs in the coming years for treatment of
onychomycosis. Developing vehicles that can allow
topical antifungals to penetrate the nail plate and
accumulate in the nail bed are of interest. Apart from
ciclopirox HPCH (P-3051), P-3058, a terbinafine film-
forming solution utilizing HPCH technology has been
investigated in clinical trials; likewise, liposomal
formulations and UV-curable gels have been investi-
gated, and ME-1111 is currently undergoing clinical
evaluation [110].
Recurrence or reinfection is common, and reports
range from 10 to 53 % of cases [100]. Multiple
123
Mycopathologia
strategies can be taken to limit the risk of recurrence/
reinfection. Prophylactic treatment with topical anti-
fungals has been suggested as a way to maintain
complete cure after standard treatment protocols.
Evidence suggests that the topical antifungals amor-
olfine, efinaconazole, and tavaborole all remain in the
nail plate at concentrations above the minimum
inhibitory concentration (MIC) values for dermato-
phytes for up to 28 days or longer following treatment
[100, 101, 111, 112]. Recurrence and/or reinfection, if
occurring, will do so likely within 3 years of treatment
completion [101]. Following attainment of complete
cure, prophylactic treatment (once every 2 weeks for
3 years) with amorolfine delayed recurrence by almost
200 days as compared to patients who attained
complete cure and did not undergo a prophylactic
regimen [101].
Combination Therapy
There are few published clinical trials of treatment
combinations. Standard treatment combinations have
not been established; however, combinations of oral
treatments and oral/topical treatments have been
studied (i.e., terbinafine/itraconazole, amorolfine, or
ciclopirox with an oral antifungal) [113, 114]. A
combination of amorolfine and terbinafine produced a
significantly higher success rate as compared to
terbinafine alone (59 vs. 45 % in treating onychomy-
cosis with matrix involvement) [115]. It has been
suggested that parallel combination treatment may be
suitable for those likely to fail therapy, whereas
sequential combination treatment may be effective in
poor responders (positive microscopy after 6-month
treatment) [113]. Of interest for the future will be
investigation of the efficacy of topical antifungals
combined with devices.
Discussion
Accurately diagnosing superficial fungal infections is
a key step in achieving successful treatment. Using
antifungal agents against dermatophytes that are not
actually present can lead to frustration for patients and
perceived treatment failures. However, timely treat-
ment is also important as dermatophyte infections are
communicable. Treatment of tinea capitis in
schoolchildren is particularly important in order to
Mycopathologia
not only prevent transmission to other children, but
also prevent potential scarring.
The number of antifungal treatments has expanded,
although this has been limited to topical therapy. The
gold standard of oral antifungal therapy is still
terbinafine, with griseofulvin persisting in some areas
of the world. Ketoconazole should no longer be consid-
ered as first-line therapy to treat superficial fungal
infections due to potential adverse effects (e.g., fatal liver
injury, adrenal gland problems, and drug–drug interac-
tions) [14]. These antifungals are effective against many
dermatophyte species and in clinical studies, produce
higher cure rates than topical agents. Concern regarding
hepatotoxicity and drug–drug interactions with use of
oral antifungals has increased [94]. As such, oral
antifungal therapy continues to be considered where
infections are severe, covering large parts of the body, or
recurring, the exception being tinea capitis.
Since the publication of the first special issue on
Dermatophytosis [20], new topical antifungals have
been developed. Trials documenting the efficacy of
sertaconazole in treating tinea pedis and tinea cor-
poris/tinea cruris have been published, with treatment
success similar to topical terbinafine. Luliconazole
was recently FDA approved for treatment of tinea
pedis and can be effective in treating tinea corporis/
tinea cruris as well. The indication for luliconazole
specifies once-a-day application for 2 weeks. This
may encourage compliance as most other topical for
tinea pedis are indicated for twice daily application for
4 weeks. Treatment for onychomycosis has also
expanded with the FDA approval of efinaconazole
and tavaborole. Efinaconazole may be effective in
treating patients that may otherwise not consider
topical antifungal therapy (e.g., diabetics, dermato-
phytoma) [108]. Tavaborole is the first in a new class
of drugs, the oxaboroles, whose unique mechanism of
action is intriguing as most other antifungals operate
similarly. Additionally, use of prophylactic topical
antifungals has been discussed in the treatment of
onychomycosis and there are some data to suggest a
prophylactic amorolfine regimen can delay recurrence
[100, 101]. Further clinical research is required to
develop effective protocols, and the arrival of efina-
conazole and tavaborole to the treatment landscape
may aid in this development.
One of the challenges with topical antifungal drug
development is formulating antifungals that can
penetrate the skin, hair, and nails. This is a
consideration for onychomycosis in particular. Many
drugs in development exhibit in vitro broad-spectrum
activity against dermatophytes. This does not neces-
sarily translate to clinical studies when antifungals are
required to penetrate the nail plate. Rather than
formulate novel agents, much research has focused
on technological advances that can enhance the
efficacy of currently existing antifungals. HPCH
technology has improved the efficacy of ciclopirox
in treating onychomycosis and shows promise in
improving terbinafine, which in its current form, is not
an effective topical antifungal for onychomycosis.
Foam or gel formulations may improve patient
compliance if they are easier to apply and less messy
than cream or solutions. Econazole foam and naftifine
gel have been developed to treat tinea pedis. Lastly,
novel delivery systems are being developed for
sertaconazole [57, 58], but perhaps these technologies
can be extended to other antifungals. There are
potential antifungal agents undergoing clinical inves-
tigation (VT-1161, Drug 33525, LAS41003, ME-
1111), and we await the results of those investigations.
In the short term, the most effective way to combat
dermatophyte infections may be to educate patients on
preventative measures to be undertaken in conjunction
with antifungal treatment. With less than perfect cure
rates, preventative measures are critical to limiting
relapse and reinfection. Treating asymptomatic carri-
ers in families with children with tinea capitis and
treating family members for possible tinea pedis in
households where tinea pedis and onychomycosis is
present may help in decreasing transmission of
dermatophyte infections and decrease the chance of
recurrence/reinfection in patients completing antifun-
gal therapy. Additionally, maintaining personal
hygiene, wearing loose-fitting clothing and shoes,
and keeping skin clean and dry may improve treatment
outcomes [100].
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