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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 Keywords Tinea capitis  Tinea corporis  Tinea
agents are available for the treatment of superficial cruris  Tinea pedis  Onychomycosis  Topical
fungal infections caused by dermatophytes. This review antifungals
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 Introduction
armamentarium, with terbinafine, itraconazole, and
fluconazole still in widespread use, albeit for generally Dermatophytoses are superficial fungal infections
more severe or recalcitrant infections. Griseofulvin is caused by dermatophytes that affect the skin, hair,
used in the treatment of tinea capitis. Oral ketoconazole and nails [1]. There are three main classes of
has fallen out of favor in many jurisdictions due to risks dermatophytes that cause fungal infections on the
of hepatotoxicity. Topical antifungals, applied once or body: Epidermophyton, Trichophyton, and Microspo-
twice daily, are the primary treatment for tinea pedis, rum [1]. Hair, skin, and nails are common targets as
tinea corporis/tinea cruris, and mild cases of tinea keratin is a food source for these organisms [1].
unguium. Newer topical antifungal agents introduced Sources of dermatophytes can include environmental
include the azoles, efinaconazole, luliconazole, and sources (e.g., soil) or transmission via contact with
sertaconazole, and the oxaborole, tavaborole. Research infected humans or animals [2]. The majority of
is focused on developing formulations of existing dermatophyte infections are caused by Trichophyton
topical antifungals that utilize novel delivery systems rubrum [3]; however, Microsporum canis is a common
in order to enhance treatment efficacy and compliance. 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].
A. K. Gupta
Department of Medicine, University of Toronto, Fungal infections can be an economical burden
Toronto, Canada with approximately $1.67 billion spent on treatments
[7]. Dermatophytes are the main cause of fungal
A. K. Gupta (&)  K. A. Foley  S. G. Versteeg
infections in North America [8]. The American
Mediprobe Research Inc., 645 Windermere Road,
London, ON, Canada Academy of Dermatology has estimated that there
e-mail: publications@mediproberesearch.com have been over 29.4 million cases of cutaneous fungal

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Mycopathologia

infections with over 51 million physician visits in the There are numerous treatment options for tinea
USA alone [7, 9]. The prevalence of dermatophyte pedis. Topical treatments are first-line therapy, with
infections in European countries can range from 2.6 % oral antifungals recommended when the infection is
(Spain and the UK) to 8.4 % (Finland) [10–12]. With extensive and/or the use of topical antifungals is not
20–25 % prevalence worldwide, successful treatments feasible [20]. Bacterial superinfections might co-occur
are necessary to address this health issue [13]. with these types of infections; thus, it is beneficial for
There are numerous treatment options for dermato- antifungal agents to have antibacterial activity or to
phyte infections. For the most part, similar antifungal use concomitant antibacterial therapy. Treatment
treatments are used worldwide; however, there are options that include this additional antibacterial
some variations and country-specific guidelines activity are miconazole nitrate, ciclopirox olamine,
should be consulted. Historically, imidazoles (e.g., naftifine hydrochloride, and sulconazole nitrate [20].
bifonazole, clotrimazole, miconazole) were the most Patient compliance can be an issue when treating tinea
commonly used antifungal drugs for treatment of pedis. Patients have a tendency to cease treatment
superficial cutaneous fungal infections [9]. These have before the full regimen is completed, often terminating
been joined by the triazoles (e.g., fluconazole, itra- treatment when clinical symptoms have improved/
conazole, efinaconazole), allylamines (e.g., bute- resolved [16]. This contributes to reinfection or
nafine, naftifine, terbinafine), and others (e.g., relapse.
amorolfine, ciclopirox, tavaborole). This review sum-
marizes the main antifungal treatments used to treat Oral Therapy
dermatophytoses that are cited in the literature with an
emphasis on newer agents. Oral ketoconazole is no Oral antifungals are used in severe cases of tinea
longer recommended for superficial fungal infections pedis or where topical treatment is ineffective, with
and has been excluded from this review [14]. Systemic use being off-label in some parts of the world (e.g.,
(oral) antifungals are recommended for tinea capitis USA). Terbinafine (Fig. 1) can inhibit fungal ergos-
and for serious cases of tinea corporis/tinea cruris, terol synthesis through squalene epoxidase as well as
tinea pedis, and onychomycosis. Topical antifungals influence human host cytochromes (e.g., CYP 2D6)
are recommended for localized tinea corporis and [20]. Terbinafine is administered once daily
tinea pedis and mild-to-moderate cases of onychomy-
cosis [5]. Combinations of oral and topical antifungals
may also effectively treat fungal infections [5].

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 with an effective treatment rate (mycological cure
superficial fungal infections, although it is used off- with no tinea pedis symptoms) of 48.6 % [41].
label in some places for tinea pedis (e.g., Canada). Recent clinical trials have demonstrated the effi-
FDA approved for the treatment of tinea pedis caused cacy of the gel formulation of naftifine hydrochloride
by T. rubrum, T. interdigitale, E. floccosum, and M. in treating moccasin tinea pedis [17]. Naftifine has
canis [31], and ciclopirox disrupts fungal metabolism antifungal, antibacterial, and anti-inflammatory activ-
by inhibiting iron-dependent enzymes, preventing the ity [17, 42, 43]. Most topical antifungal clinical trials
chelation of heavy metal irons (e.g., iron or alu- study interdigital tinea pedis, and the moccasin form
minum) [32–34]. Ciclopirox (0.77 %) cream or gel is considered too severe. A post hoc analysis of two
formulation is usually applied twice daily for four phase III clinical trials (double-blind, randomized,
weeks [20]. Clinical cure rates and mycological cure vehicle controlled, multicenter, parallel group) with
rates after 8 weeks of treatment with ciclopirox daily application of naftifine gel for 2 weeks showed
(0.77 % gel formulation) twice daily for tinea pedis a complete cure rate of 19.2 % (mycological cure
were 51.4 and 80.8 %, respectively [35]. All adverse and absence of erythema, scaling, pruritus) and a
events recorded were not significantly different from mycological cure rate of 65.8 % at 4 weeks post-
placebo group [35]. treatment [17]. Only 1.2 % of participants experi-
Sertaconazole and luliconazole represent newer enced treatment-emergent adverse events related to
additions to the armory of topical antifungals. Serta- study treatment such as site pruritus, rash, and
conazole 2 % cream is FDA approved for treatment of hypersensitivity [17].
tinea pedis caused by T. rubrum, T. interdigitale, and A meta-analysis of 65 randomized trials that
E. floccosum in individuals 12 years of age and older included 16 topical antifungal agents (e.g., bifonazole,
[36] and is approved for use in the EU [37]. clotrimazole, naftifine) in the treatment of tinea pedis
Sertaconazole should be applied twice daily for found no statistically significant differences in myco-
4 weeks [36]. Both the solution and cream formula- logical cure rates [44]. Butenafine was more effica-
tions of sertaconazole have been evaluated, with both cious than azoles (clotrimazole, oxiconazole, and
producing high efficacy rates (solution: 90.6 %; sertaconazole) [44], and oral terbinafine was found
cream: 88.9 %) and no adverse effects in patients to be more efficacious than itraconazole and griseo-
with tinea pedis [38]. fulvin [45]. There are several drugs currently in
Luliconazole 1 % cream is FDA approved for development (e.g., phase II and phase III clinical
treatment of tinea pedis caused by T. rubrum and E. trials) for the treatment of tinea pedis that include VT-
floccosum [39]. Luliconazole is able to remain phar- 1161, Drug 33525, LAS41003, and nitric oxide.
maceutically active in the presence of keratin and
inhibits 14a-demethylase causing fungal ergosterol Prevention of Tinea Pedis
biosynthesis to be disrupted [39]. Phase 3 clinical trials
reported complete clearance of tinea pedis occurring Tinea pedis is both contagious (via infected skin cells)
in 26.4 % of patients 28 days post-treatment when and recurrent [46]. Approximately, 70 % of the
luliconazole was applied once a day for 14 days [40]. population has been or will be infected with tinea
Research into new formulations that can enhance pedis in their lifetime [16]. Taking precautions are
the efficacy and potentially compliance of topical necessary in order to avoid transmitting and contract-
antifungals has been a priority. Econazole nitrate 1 % ing this infection. Preventative methods can include
cream has been used for 20 years, yet a new foam 1 % proper hygiene practices, avoiding communal areas
formulation was recently FDA approved. The novel (e.g., swimming pool, showers), and drying feet
water–lipid delivery system aims to deliver drug and appropriately [20]. Choosing antimicrobial fabrics
help restore damaged skin [41]. Foam formulations over textiles could also help to control dermatophyte
may be seen as more attractive to patients, being easier infections [47]. Health education programs have also
to apply and more esthetically pleasing than creams. been evaluated as possible preventative measures. A
Econazole 1 % foam is applied only once, not twice, reduction in the severity of tinea pedis and increase in
per day. Phase III clinical trials (daily application for symptom-free patients were observed following an
4 weeks) showed a mycological cure rate of 67.6 % educational program for diabetic patients whose goal

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was to prevent diabetic foot ulcerations, a possible corporis/tinea cruris (and tinea pedis) caused by T.
complication of tinea pedis [48]. rubrum and E. floccosum. Application to the affected
area and immediate surrounding skin once a day for
one week may encourage patient compliance com-
Tinea Corporis/Tinea Cruris pared to topical antifungals that require application
multiple times daily for 2 or more weeks [59]. A large-
Tinea corporis and tinea cruris are common superficial scale phase 3 clinical trial evaluated one week of
fungal infections, predominantly caused by T. rubrum, luliconazole treatment for tinea cruris in patients
T. mentagrophytes, and M. canis [49]. Affecting the C12 years of age. Clinical signs and symptoms were
trunk, tinea corporis is generally found in children and resolved and mycological cure obtained at 28 days,
young adults. Interaction with animals is often a demonstrating superiority of luliconazole to vehicle
source of transmission of M. canis in children [49, 50]. cream [60].
Tinea cruris affects the groin and is generally found New head-to-head clinical studies have compared
more frequently in men. Excessive perspiration and topical antifungals in the treatment of tinea corporis/
restrictive clothing are predisposing factors for these tinea cruris. An open-label pilot study compared
infections in adults [49, 50]. luliconazole 1 % cream (once daily for 2 weeks) to
Both topical and oral antifungals can be used to treat sertaconazole 2 % cream (twice daily for 4 weeks)
tinea corporis/tinea cruris. Oral antifungal agents are and terbinafine 1 % cream (once daily for 2 weeks)
used off-label where daily application of topical anti- [61]. At the end of treatment, the reduction in mean
fungals may be cumbersome, for example, in severe composite score of clinical signs and symptoms
cases involving large parts of the body. Terbinafine (pruritus, erythema, vesicles, and desquamation) was
(250 mg/day for 2–4 weeks), itraconazole (200 mg/day greater in the sertaconazole group (97 %) compared to
for 1 week), and fluconazole (150–300 mg/week for luliconazole (93 %) and terbinafine (91 %) [61]. All
2–4 weeks) have been shown to be effective [49]. treatments were effective and well tolerated. An
Topical antifungals include terbinafine, butenafine, additional trial comparing use of topical antifungals
naftifine, clotrimazole, econazole, ketoconazole, for one week (tinea corporis/tinea cruris) or two weeks
miconazole, sulconazole, and ciclopirox. Evidence (tinea pedis) showed that luliconazole, sertaconazole,
from a Cochrane review suggests that azoles provide amorolfine, and terbinafine significantly reduced signs
therapeutic benefit, with pooled results of studies with and symptoms of tinea infections by 4 weeks, whereas
each of terbinafine and naftifine showing significant eberconazole did not [62]. Eberconazole, however,
benefit over placebo [51]. Older, widely available has been shown to be as effective as terbinafine in
treatments for tinea corporis/tinea cruris include Whit- treating tinea corporis/tinea cruris. A small compar-
field’s ointment and tolnaftate. Topical corticosteroid ison trial using longer treatment regimens (twice daily
use for tinea corporis/tinea cruris is contentious; while for 3 weeks) produced complete cure (clinical and
use may decrease inflammation, other complications mycological) in all patients receiving eberconazole or
may occur [52–54]. terbinafine [63].
Sertaconazole 2 % cream is FDA approved for
tinea pedis, with sertaconazole used in the EU for
many superficial fungal infections, including tinea Tinea Capitis
corporis/tinea cruris. Twice-daily application for
3 weeks of sertaconazole showed a reduction in Tinea capitis is a superficial dermatophyte infection
clinical signs and symptoms that was greater than that that is located primarily in hair follicles as well as
of clotrimazole in patients with tinea corporis and surrounding skin. Common characteristics of this
similar to terbinafine in patients with tinea corporis/ infection include: hair loss (with or without broken
tinea cruris [55, 56]. Novel delivery systems are under hairs), scaling (diffuse or focal), erythema, inflamma-
development to enhance the efficacy of sertaconazole tion of the scalp, and lesions [64, 65]. In the last
[57, 58]. 30 years, there has been a significant increase in the
Luliconazole 1 % cream is a more recent imidazole number of reported cases of tinea capitis [66–68].
that is FDA approved (2013) for the treatment of tinea Tinea capitis is typically caused by Trichophyton and

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Microsporum species [66–68]. There are both non- Terbinafine is used worldwide with FDA approval
inflammatory and inflammatory variants of tinea of granule formulations (125 or 187.5 mg) for use in
capitis depending on type of organism causing the children 4 years of age and older [65, 78]. Granules
infection [65]. Non-inflammatory variants include can be added to non-acidic foods (e.g., pudding or
gray patch (Microsporum infection), black dot (Tri- mashed potatoes) to ease administration [78]. Treat-
chophyton infection), and diffuse scaling of the scalp ment is usually 6 weeks in length, and there is a
[65]. Inflammatory variants include diffuse pustular significant reduction in clearance of terbinafine that
(patchy alopecia), kerion (development of plaques and occurs with age which requires children to be given
associated alopecia), and favus (T. schoenleinii infec- larger weight-normalized doses than adults [81].
tion) [65]. Efficacy rates of terbinafine and griseofulvin are
Tinea capitis commonly occurs in children under influenced by the causal dermatophyte. Terbinafine
the age of 10 years [69–72]. Although rare, adults can (47.7–56.1 %) has higher complete cure rates for tinea
also suffer from tinea capitis, accounting for approx- capitis caused by T. tonsurans when compared to
imately 20.6 % of cases [64]. Individuals who have a griseofulvin (34.4–36.5 %) [78]. Griseofulvin, how-
high risk of infection include the immunocompro- ever, has higher complete cure rates for tinea capitis
mised and postmenopausal women [73, 74]. Addi- caused by M. canis (35.1–51.1 %) as compared to
tionally, evidence to support a male bias in young terbinafine (23.8–30.6 %) [78].
children with tinea capitis has been reported [68]. Itraconazole can also be used to effectively treat
A Canadian survey of family physician practices in an tinea capitis. It is not FDA approved for the treatment
urban community found that approximately 210 new of tinea capitis. There are multiple formulations
cases of tinea capitis occur every year in children available: capsule (100 mg) and liquid (10 mg/mL).
living in a high-risk neighborhood (e.g., low income, The liquid form is generally restricted to immunosup-
crowded) [75]. pressed patients and for prevention of systemic
The goals for successful treatment include symp- mycoses [82]. Itraconazole using pulse therapy may
tom alleviation, mycological and clinical cure, and be effective and promote compliance in children.
preventing infection transmission [65, 76]. Due to Itraconazole was given to children with tinea capitis at
follicle involvement, oral treatments are required for 5 mg/kg/day for 1 week, and a second or third pulse
mycological cure, and scarring can occur if tinea was given if clinically necessary with two weeks
capitis is left untreated [20, 77]. If compliance is a between pulses. Complete (clinical and mycological
concern, granule formulations can be used and added cure) cure was 100 % 12 weeks after therapy was
to non-acidic foods (e.g., peanut butter) to increase commenced [83].
compliance [65, 78]. There are also multiple formulations of fluconazole
with suggested treatment duration of 4 weeks: tablets
Oral Therapy (50, 100, 150, and 200 mg) and suspension (200 and
50 mg/5 ml) formulation [65, 84]. Like itraconazole,
There are several antifungal agents that have been fluconazole is not FDA approved for the treatment of
used for years to treat tinea capitis such as terbinafine, tinea capitis. One study reported that 8.04 weeks of
griseofulvin, fluconazole, and itraconazole. Treatment treatment with fluconazole at a dose of 6 mg/kg per
options for tinea capitis can differ depending on age day was required to achieve a clinical cure, while
and weight, and between countries (Table 1). Grise- 12 weeks of treatment at a dose of 4 mg/kg per day
ofulvin is not available in Canada and many other was required for clinical cure [85].
countries; however, it is listed on the WHO Model of Time required to achieve a complete cure can also
essential medicines (April 2015) and is FDA approved vary between treatments [67]. Terbinafine has a
for treating tinea capitis [79, 80]. In the UK, for shorter treatment duration required to obtain complete
example, griseofulvin is available for children with cure when compared to griseofulvin (4 vs. 8 weeks,
tinea capitis with suggested treatment duration of respectively), especially for Trichophyton tonsurans
8 weeks [65]. Griseofulvin has efficacy rates ranging [67]. Short-term treatment (4–6 weeks) is desired as
from 88 to 100 %, and could be considered an long-term treatment can lead to poor patient compli-
effective antifungal in treating tinea capitis [20]. ance and increased drop-out rates [67].

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

Shampoos individuals were clinically diagnosed with tinea


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

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

123
Mycopathologia

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

yeasts, although this has yet to be confirmed with strategies can be taken to limit the risk of recurrence/
clinical studies. With these newly approved solutions, reinfection. Prophylactic treatment with topical anti-
application is not only to the nail plate itself, but also fungals has been suggested as a way to maintain
to the nail folds, hyponychium, and the undersurface complete cure after standard treatment protocols.
of the nail plate. This may aid in drug delivery to the Evidence suggests that the topical antifungals amor-
site of infection, as both transungual and subungual olfine, efinaconazole, and tavaborole all remain in the
routes of delivery are utilized [108]. Post hoc analyses nail plate at concentrations above the minimum
from phase 3 clinical trials suggest that efinaconazole inhibitory concentration (MIC) values for dermato-
may be efficacious in difficult to treat sub-populations phytes for up to 28 days or longer following treatment
of onychomycosis (summarized in [108]). For exam- [100, 101, 111, 112]. Recurrence and/or reinfection, if
ple, no difference in clinical efficacy of efinaconazole occurring, will do so likely within 3 years of treatment
was found between patients with and without diabetes. completion [101]. Following attainment of complete
Additionally, the importance of treating concomitant cure, prophylactic treatment (once every 2 weeks for
tinea pedis was demonstrated, with efinaconazole cure 3 years) with amorolfine delayed recurrence by almost
rates significantly higher if patients with onychomy- 200 days as compared to patients who attained
cosis were treated for concomitant tinea pedis. complete cure and did not undergo a prophylactic
Tavaborole 5 % solution employs a unique mech- regimen [101].
anism of action as its boron-based structure targets
leucyl-tRNA synthetase to inhibit protein synthesis, Combination Therapy
and thus fungal cell growth, whereas most existing
antifungals target ergosterol synthesis [109]. This may There are few published clinical trials of treatment
be relevant for treatment of dermatophytoses if the combinations. Standard treatment combinations have
concern of antifungal resistance to azoles continues to not been established; however, combinations of oral
develop. Daily application of tavaborole for 48 weeks treatments and oral/topical treatments have been
is approved in the USA for the treatment of toenail studied (i.e., terbinafine/itraconazole, amorolfine, or
onychomycosis caused by T. rubrum and T. interdig- ciclopirox with an oral antifungal) [113, 114]. A
itale. Complete cure rates were reported to be combination of amorolfine and terbinafine produced a
6.5–9.0 %, mycological cure rates were 31–36 %, significantly higher success rate as compared to
and clinical improvement (negative mycology terbinafine alone (59 vs. 45 % in treating onychomy-
and B10 % nail involvement) was 15–18 % in phase cosis with matrix involvement) [115]. It has been
3 clinical trials [98]. Like efinaconazole, tavaborole suggested that parallel combination treatment may be
also shows broad-spectrum activity in vitro against suitable for those likely to fail therapy, whereas
dermatophytes, non-dermatophyte molds, and yeasts sequential combination treatment may be effective in
[109]; again, clinical efficacy has not been demon- poor responders (positive microscopy after 6-month
strated with the latter two. treatment) [113]. Of interest for the future will be
Research into new formulations of existing anti- investigation of the efficacy of topical antifungals
fungals may provide the most promising break- combined with devices.
throughs in the coming years for treatment of
onychomycosis. Developing vehicles that can allow
topical antifungals to penetrate the nail plate and Discussion
accumulate in the nail bed are of interest. Apart from
ciclopirox HPCH (P-3051), P-3058, a terbinafine film- Accurately diagnosing superficial fungal infections is
forming solution utilizing HPCH technology has been a key step in achieving successful treatment. Using
investigated in clinical trials; likewise, liposomal antifungal agents against dermatophytes that are not
formulations and UV-curable gels have been investi- actually present can lead to frustration for patients and
gated, and ME-1111 is currently undergoing clinical perceived treatment failures. However, timely treat-
evaluation [110]. ment is also important as dermatophyte infections are
Recurrence or reinfection is common, and reports communicable. Treatment of tinea capitis in
range from 10 to 53 % of cases [100]. Multiple schoolchildren is particularly important in order to

123
Mycopathologia

not only prevent transmission to other children, but consideration for onychomycosis in particular. Many
also prevent potential scarring. drugs in development exhibit in vitro broad-spectrum
The number of antifungal treatments has expanded, activity against dermatophytes. This does not neces-
although this has been limited to topical therapy. The sarily translate to clinical studies when antifungals are
gold standard of oral antifungal therapy is still required to penetrate the nail plate. Rather than
terbinafine, with griseofulvin persisting in some areas formulate novel agents, much research has focused
of the world. Ketoconazole should no longer be consid- on technological advances that can enhance the
ered as first-line therapy to treat superficial fungal efficacy of currently existing antifungals. HPCH
infections due to potential adverse effects (e.g., fatal liver technology has improved the efficacy of ciclopirox
injury, adrenal gland problems, and drug–drug interac- in treating onychomycosis and shows promise in
tions) [14]. These antifungals are effective against many improving terbinafine, which in its current form, is not
dermatophyte species and in clinical studies, produce an effective topical antifungal for onychomycosis.
higher cure rates than topical agents. Concern regarding Foam or gel formulations may improve patient
hepatotoxicity and drug–drug interactions with use of compliance if they are easier to apply and less messy
oral antifungals has increased [94]. As such, oral than cream or solutions. Econazole foam and naftifine
antifungal therapy continues to be considered where gel have been developed to treat tinea pedis. Lastly,
infections are severe, covering large parts of the body, or novel delivery systems are being developed for
recurring, the exception being tinea capitis. sertaconazole [57, 58], but perhaps these technologies
Since the publication of the first special issue on can be extended to other antifungals. There are
Dermatophytosis [20], new topical antifungals have potential antifungal agents undergoing clinical inves-
been developed. Trials documenting the efficacy of tigation (VT-1161, Drug 33525, LAS41003, ME-
sertaconazole in treating tinea pedis and tinea cor- 1111), and we await the results of those investigations.
poris/tinea cruris have been published, with treatment In the short term, the most effective way to combat
success similar to topical terbinafine. Luliconazole dermatophyte infections may be to educate patients on
was recently FDA approved for treatment of tinea preventative measures to be undertaken in conjunction
pedis and can be effective in treating tinea corporis/ with antifungal treatment. With less than perfect cure
tinea cruris as well. The indication for luliconazole rates, preventative measures are critical to limiting
specifies once-a-day application for 2 weeks. This relapse and reinfection. Treating asymptomatic carri-
may encourage compliance as most other topical for ers in families with children with tinea capitis and
tinea pedis are indicated for twice daily application for treating family members for possible tinea pedis in
4 weeks. Treatment for onychomycosis has also households where tinea pedis and onychomycosis is
expanded with the FDA approval of efinaconazole present may help in decreasing transmission of
and tavaborole. Efinaconazole may be effective in dermatophyte infections and decrease the chance of
treating patients that may otherwise not consider recurrence/reinfection in patients completing antifun-
topical antifungal therapy (e.g., diabetics, dermato- gal therapy. Additionally, maintaining personal
phytoma) [108]. Tavaborole is the first in a new class hygiene, wearing loose-fitting clothing and shoes,
of drugs, the oxaboroles, whose unique mechanism of and keeping skin clean and dry may improve treatment
action is intriguing as most other antifungals operate outcomes [100].
similarly. Additionally, use of prophylactic topical
antifungals has been discussed in the treatment of
onychomycosis and there are some data to suggest a
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