1Department of Dermatology and STD, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education Research, New Delhi, India
2Consultant Dermatologist, Yashoda Hospital, Ghaziabad, Uttar Pradesh, India
3Department of Dermatology, STD and Leprosy, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
ABSTRACT
Various forms of dermatophytoses have been reported in human population, in both developed and developing countries and an estimated 40 million people suffer from these cutaneous infections. There is a variety of reasons due to which the incidence of dermatophytoses is on the rise; immunosuppression, unscrupulous and unregulated use of over-the-counter topical steroids and change in clothing habits are few of the pertinent ones. Localized infection is usually amenable to topical agents; however, oral antifungal agents may be required for multi-site infection. Various topical antifungal agents have been discussed in detail along with special emphasis on the newer generation antifungal agents.
INTRODUCTION
Dermatophytoses are the most widespread infection amongst the human population with an estimated 40 million people suffering from this cutaneous infection, in developing and underdeveloped countries, in various forms (Figures 1–4).1 The incidence of dermatophytosis is on the rise because of a variety of reasons—some well-understood and some still under evaluation—immunosuppression, unscrupulous and unregulated use of over-the-counter topical steroids and change in clothing habits are among the most prominent factors (Figures 5–7).2
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*Corresponding author
Email: surabhi2310@gmail.com
Antifungal agents can be used both topically and systemically; however, systemic agents are reserved for more widespread or severe fungal infections. Dermatophytoses are usually amenable to topical agents if localized but may need oral antifungals if multisite infection is present or the dermatophytosis is at certain areas like soles, nails, or scalp, etc.3
Topical treatment of fungal infections took a giant leap in the 1960s when specific antifungal agents were introduced; prior to that, only nonspecific agents were in use, e.g., Castellani's paint, Whitfield's ointment, Gentian violet, potassium permanganate, undecylenic acid and selenium sulfide. Most topical antifungals have to be applied twice daily for long duration but certain newer agents now have the advantage of single application daily and shorter duration of treatment.4
Figure 8: A, Pre-treatment tinea faciei in a child; B, Post-treatment improvement in tinea faciei with topical antifungals.
INDICATIONS OF TOPICAL ANTIFUNGALS
Localized dermatophytic infection was previously the main indication of topical antifungal therapy but other important indications include:
- Pregnancy and lactation
- Pediatric dermatophytic infections, especially infants (Figure 8)
- Patients with systemic diseases such as liver, renal or cardiovascular diseases
- Patients on other drugs, which have potential interactions with oral antifungals
- As an adjuvant to systemic therapy
- As adjunctive to systemic therapy
- Prophylactic use to avoid recurrences after adequate oral treatment
- Attempts to shorten, limit or improve systemic antifungal treatment.3
CLASSIFICATION OF TOPICAL ANTIFUNGALS3
The classification of topical antifungals has been shown in Table 1.
MECHANISMS OF ACTION OF VARIOUS ANTIFUNGAL AGENTS
Azoles
This group comprises of two chemically related subgroups which are imidazoles and triazoles. Triazoles have three nitrogen atoms whereas imidazoles have only two atoms in the azole ring.4
The azoles act by inhibition of lanosterol 14α-demethylase of the ergosterol synthesis pathway. This results in the inhibition of conversion of lanosterol to ergosterol. Decreased availability of ergosterol and accumulation of intracellular 14α-methyl sterols result in increased membrane rigidity, increased permeability, and death.
Some of the topical azoles commonly being used nowadays are discussed below:
Eberconazole {1-[2,4-dichloro-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-yl]-1H-imidazole} with a molecular formula C18–H14–Cl2–N2, is a broad-spectrum antifungal agent active against dermatophytes, Candida, Malassezia furfur and gram-positive bacteria.5
It has anti-inflammatory affect akin to aspirin as it can inhibit 5-5- lipooxygenase and cyclooxygenase-2.6 Its anti-inflammatory action and efficacy against gram-positive bacteria can add to its efficacy in inflamed cutaneous mycoses and in secondary infections, favoring the regression of inflammatory symptoms and treatment compliance. Bothiraja et al. used ethyl-cellulose microsponges as a means of drug delivery and found that the levels of eberconazole nitrate were four-fold higher in the stratum corneum as compared to the conventional preparation in use.7 Eberconazole has been marketed as a cream with a characteristic lipophilic-hydrophilic molecular structure for better penetration of fungal cell membrane and prolonged duration of action. The galenic components of this topical azole favor and optimize the drug's action in the skin, fatty acid esters facilitate penetration in the skin and make the cream easy to spread, while polyacrylamides produce a filmogenous effect and facilitate the continuance of the active principle in the skin.
The main side effects observed were mild sensation of coldness and pruritus which resolves on repeated application.5 Eberconazole has been shown to be as effective as and even superior to terbinafine in trials. It has also been shown to have lower MICs than clotrimazole, ketoconazole and miconazole against dermatophytes as well as Candida species, esp. C. krusei and C. glabrata which are usually resistant to triazoles.
Sertaconazole has a unique benzothiophene ring which enhances its lipophilic ability. This imparts it with the ability to bind to nonsterol lipids thus increasing the permeability and also increases dermal retention of the molecule.87 Sertaconazole also inhibits the release of interleukin-2 (IL-2), tumor necrosis factor-α, interferon-α, IL-4 and granulocyte-macrophage colony-stimulating factor, and is also active against gram-positive cocci—thus, responsible for its anti-inflammatory and antibacterial activity. It is also known to kill Trichomonas vaginalis in vitro and to inhibit dimorphic transformation of Candida albicans into its pathogenic form. Contact allergic dermatitis, burning on application, and skin dryness are the possible side effects. It also has antipruritic activity.9
Luliconazole is an R-enantiomer of lanoconazole,10 has an imidazole moiety incorporated into the ketone dithioacetate structure which results in a high potency against dermatophytes with a minimum inhibitory concentration (MIC) levels for Trichophyton rubrum which is 1–4 times lower when compared to terbinafine10 with a strong in vitro activity against C. albicans and Aspergillus fumigatus.3
Efinaconazole, an emerging triazole effective against dermatophytes, Candida, and nondermatophyte molds. Efinaconazole 10% topical solution is used for the topical treatment of toenail onychomycosis caused by T. rubrum and T. mentagrophytes. It reaches the site of infection by transungual penetration. Efinaconazole has better penetration of the nail bed as compared to ciclopirox and amorolfine (14.3% efinaconazole vs. 0.7% and 1.9% for ciclopirox and amorolfine in keratin suspensions, respectively).11
Fenticonazole belongs to the imidazole group and has a broad-spectrum of antimycotic activity against dermatophytes and yeasts. Fenticonazole acts by (1) inhibiting the secretion of protease acid by C. albicans; (2) damaging the cytoplasmic membrane; and (3) by blocking cytochrome oxidases and peroxidases. Fenticonazole also has been shown to have antibacterial activity against the bacteria which are associated with superinfected fungal skin and vaginal infections, and antiparasitic action against the protozoan T. vaginalis. Therefore, fenticonazole may be an ideal topical alternative to multiagent treatment of mixed infections involving mycotic, bacterial, dermatophyte, and/or Trichomonas species. Fenticonazole is the only antifungal to have a single dose dependent suppression of candidal proteinase.
It is well-tolerated topically and the adverse effects most commonly noticed with the application of this drug are burning sensation when applied intravaginally.12
Allylamines
Terbinafine and naftifine are the two important drugs of this group. Allylamines inhibit the formation of squalene epoxidase, which is a precursor of lanosterol and involved in the formation of cell membrane. The accumulation of high levels of squalene leads to increased membrane permeability and disruption of cellular organization.68
Terbinafine
Terbinafine was discovered in 1983 and is different from its parent compound, naftifine, by the presence of a tert-butylacetylene substitution of the phenyl ring on the side chain of the molecule. This confers an additional increase in oral efficacy and increases the in vitro activity 10–100 times that of naftifine.13 Topical terbinafine has been approved by the Food and Drug Administration (FDA) for tinea cruris, athlete's foot, and tinea corporis.6 Choudhary et al. found similar efficacy and side effect profile of 1% terbinafine cream as compared to 1% eberconazole nitrate cream in the management of localized tinea cruris and corporis.14 Terbinafine is also available in newer formulations as transferosome, liposome, liposome film, microemulsion gel, liposome poloxamer gel, liposome ethosome, etc.15
Naftifine
Naftifine, a topical allylamine is effective against dermatophytes, Candida, Aspergillus as well as gram-negative and gram-positive bacteria. Naftifine also acts as an anti-inflammatory agent by blocking the prostaglandin pathway.16 Naftifine 2% gel has been recommended as a treatment for moccasin type tinea pedis by recently conducted randomized controlled trials (RCTs).17 FDA has also approved 2% naftifine cream/gel application once daily for 2 weeks, for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by T. rubrum species.6
Butenafine
Butenafine is a benzylamine derivative and has potent fungicidal activity against Aspergillus, dermatophytes, dimorphic, and dematiaceous fungi with its mechanism of action being similar to the other allylamines. Das et al. found superior efficacy of 1% butenafine cream as compared with 1% terbinafine cream in the treatment of tinea cruris.18 Thaker et al. in a recently conducted RCT found topical 1% butenafine to be more efficacious and equally safe as compared to 2% sertaconazole for the treatment of tinea infections.19
Polyene Antibiotics
Amphotericin B is a broad-spectrum antifungal agent that has been used parenterally. It is still “go to” drug for treatment of disseminated invasive mycoses. It is fungicidal and has a unique structure characterized by both hydrophilic (polyhydroxyl) and hydrophobic (polyene) faces on its long axis. It binds with the ergosterol moiety, forming pores which lead to leakage9 of monovalent ions (K+, Na+, H+, and Cl−) and fungal cell death. Topical formulations of amphotericin B have been studied in cutaneous candidiasis and nondermatophyte mold infections and have been found to be efficacious. There have not been many studies on the use of this drug in dermatophytosis in vivo but a handful of studies in vitro have shown encouraging results.20
Hydroxypyridones
This class of topical antifungal agents has been described as weak acids with broad-spectrum of antimicrobial activity, which is conferred as a result of its unique mechanism of action which is by chelation of trivalent metal cations leading to the inhibition of metal dependent enzymes. This also explains the low level of resistance which has been reported against these agents.21 Ciclopirox, octopirox, and rilopirox are the drugs belonging to this class with ciclopirox being the prototype. Various newer formulations of ciclopirox are available which include lipid diffusion enhancers, isopropyl alcohol, urea, potassium hydroxide and have led to increased permeability and efficacy of the drug in the management of onychomycosis.6
Morpholines
Morpholines act by inhibition of two enzymes, i.e., C-14 sterol reductase and C-8 sterol isomerase, in the pathway for ergosterol synthesis.
Amorolfine is a phenylpropyl-morpholine derivative and is structurally distinct from other commercially available antifungals. Chemically amorolfine (C21H35NO) is cis-4-{3-[4-(1,1-dimethylpropyl)-phenyl]-2-methylpropyl}-2,6-dimethylmorpholine.22 It has been mainly used for the treatment of onychomycosis in a lacquer formulation with its efficacy and safety being comparable to various azoles.6
Oxaboroles
These are a newer class of antifungal agents, which act by blocking protein synthesis by inhibiting leucylaminoacyl transfer RNA (tRNA) synthetase.23
Tavaborole was the first oxaborole and was approved by the FDA in 2014 for the treatment of toenail onychomycosis. Its selectivity for fungal aminoacyl tRNA synthetase (AARS) is 1,000 times more as compared to mammalian AARS. The molecular weight of tavaborole is 152 kDa.6 As a result of this low-molecular weight its permeability within the human nail plate is more as compared to the other antifungal agents.24 Jinna et al. found that 5% tavaborole has a higher penetration than 8% ciclopirox olamine on a cadaveric nail.2510
In a meta-analysis of topical antifungals conducted by Rotta et al., it was concluded that all topical antifungals are better than placebos in treatment of localized dermatophytic infections and there was no statistical difference in the efficacy of azoles versus other antifungal agents.26 However, the mycological cure rates did favor the nonallylamine antifungals but the difference was not statistically significant. Furthermore, it was concluded that azoles are more costeffective as compared to allylamines, and hence, were recommended as first-line antifungal agents with allylamines as the second-line agents in case of failure of azoles.26
The adverse events most commonly reported by patients were burning, stinging, and itching, all confined to the site of application and it was difficult to conclude whether they were actual adverse events related to the application of topical antifungals or were just the manifestations of the disease per se.26
NEWER TOPICAL FORMULATIONS
The molecular weight of the topical antifungal agent as well as its rate of release from the stratum corneum has led to the development of several carriers for these agents.27 Some of them are enlisted below.
Micelle
It is defined as a surfactant dispersed in a liquid with the hydrophilic head aligned toward water and the hydrophobic tail sequestered toward inside. Clotrimazole, fluconazole, and econazole have micellar solutions for the treatment of superficial fungal infections.28
Microemulsion
A mixture of oil and water stabilized by a surfactant with sizes in nanometer range.
Ketoconazole, itraconazole, voriconazole, econazole and fluconazole have been used as microemulsion gels with enhanced percutaneous absorption.27
VESICULAR DRUG DELIVERY UNITS
Vesicles are an assembly of lipid layers which act as depot formulations for the drug in the stratum corneum and also decrease the systemic absorption of the topically applied agent.
These also act in increasing the penetration of the drug into the epidermis as they are lipid soluble.11
Liposomes, ethosomes, niosomes, transferosomes and penetration enhancer vesicles are different types of vesicular drug delivery units.27
Liposomes
Liposomes are vesicles made of concentric lipid bilayers separated by water or aqueous buffer compartments, ranging in size from 10 nm to 20 µm. Liposomes are either adsorbed onto the skin surface or they may also penetrate via the lipid-rich channels.27 They can also form occlusive films leading to an increase in skin hydration and drug penetration into the stratum corneum. Liposomal formulations of ketoconazole and ciclopirox olamine have been found to be more efficacious than the conventional preparations.29
Transferosomes
These have been defined as deformable liposomes and have phospholoipids and an edge activator as their constituents. The edge activator is a surfactant, which can deform the phospholipid layer, and thus, imparts the transferosome the ability to penetrate deeper layers of the skin. Griseofulvin transferosomes have a higher efficacy in treating dermatophyte infection and amphotericin B has also been used topically as a transferosome.27
Ethosomes
These are vesicles which contain ethanol in place of edge activator and the ethanol acts as a penetration enhancer. Ethosomal preparations of clotrimazole and econazole have been used and have been found to be more effective than the liposomal preparations against Candida.27
Niosomes
These are very similar to liposomes but have nonionic surfactants in place of phospholipids. Griseofulvin and ketoconazole have shown enhanced cure rates in niosomal formulations.27 Eberconazole too is available as stable nano particles in niosomal gel formulations for better drug delivery.
Penetration Enhancer Vesicles
These are elastic vesicular systems made from soybean lecithin and can penetrate into the deeper layers of the skin. The commonly used penetration enhancers are oleic acid, Labrasol and Transcutol.2712
SOLID LIPID NANOPARTICLES
The drug is entrapped in a solid lipid core made up of triglycerides, di- and monoglycerides, fatty acids, sterols and waxes.27
CONCLUSION
Topical antifungals have limited but important indications. Although, the older azoles have been there for long, newer ones like luliconazole, eberconazole and sertaconazole work well in the current scenario, with systemic antifungals according to each individual case.
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- Rotta I, Otuki MF, Sanches AC, Correr CJ. Efficacy of topical antifungal drugs in different dermatomycoses: a systematic review with meta-analysis. Rev Assoc Med Bras. 2012;58(3):308–18.
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- Newland JG, Abdel-Rahman SM. Update on terbinafine with a focus on dermatophytoses. Clin Cosmet Investig Dermatol. 2009;2:49–63.
- Choudhary SV, Aghi T, Bisati S. Efficacy and safety of terbinafine hydrochloride 1% cream vs eberconazole nitrate 1% cream in localised tinea corporis and tinea cruris. Indian Dermatol Online J. 2014;5(2):128–31.
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- Polak A, Jäckel A, Noack A, Kappe R. Agar sublimation test for the in vitro determination of the antifungal activity of morpholine derivatives. Mycoses. 2004;47(5-6):184–92.
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- Zane LT, Chanda S, Coronado D, Del Rosso J. Antifungal agents for onychomycosis: new treatment strategies to improve safety. Dermatol Online J. 2016;22(3). pii: 13030/qt8dg124gs.
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