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Abstract
With the advent of newer drugs and formulations, the armamentarium to combat dermatophytosis is ever-expanding. However, we must be rational and scientific when choosing the drugs. This review is an attempt to summarise the recently approved and upcoming therapeutic options for dermatophytosis.
Keywords: Device-based therapy, formulations, novel, penetration enhancers, super bioavailable itraconazole
Introduction 
We are witnessing an upsurge in difficult-to-treat dermatophytosis cases with atypical clinical presentations, variable therapeutic response, frequent recurrences, and relapses. There is a limited selection of conventional drugs; these act on similar targets, have drug interactions and are of questionable bioavailability. Treatment choices are more experience-based rather than evidence-based. Trichophyton indotineae has emerged as the newest species reaching a near-epidemic scale in our country with an alarming incidence of drug resistance, particularly to terbinafine.[1] All this has led to a pressing demand for newer antifungal formulations and drugs. Ongoing research for drugs with more unique fungal targets explores the potential antifungal properties of other antimicrobials, natural compounds, and device-based physical treatments.
Novel formulations of existing drugs
Much research is in progress to formulate novel preparations of already existing molecules encompassing novel drug delivery systems. Nanotechnology offers promising solutions as it enhances the pharmacological effects of a drug via the use of carriers. Certain carriers, such as magnetic nanoparticles, have inherent and direct fungistatic properties.[2]
Novel topical formulations
A lot of topical antifungal agents have been devised in newer formulations with encouraging results. [Table 1] summarises various novel drug delivery systems used for various conventional antifungal agents.
P-3051 → Ciclopirox 8% hydroxypropyl chitosan (HPCH) lacquer
Onychomycosis is often difficult to treat because the delivery of drugs through the nail plate into the nail bed is challenging. Ciclopirox 8% hydroxypropyl chitosan (HPCH) is a patented drug formulation based on a hydrosoluble semisynthetic amino-polysaccharide biopolymer derivative of chitosan. P-3051 is a novel water-soluble invisible film-forming formulation of ciclopirox oleamine using this technology. The conventional drug is water-insoluble with occlusive properties and lower keratin affinity. This limits the diffusion of the drug through the nail plate, and the film has to be scraped off, which can potentially damage the nail plate. The newer formulation had increased penetration and was found to be more effective than the conventional preparation.[3] It is indicated for mild–moderate onychomycosis without nail matrix involvement. Once daily, application is generally advised for 48 weeks.
P-3058 → Terbinafine trans-ungual HPCH solution
P-3058 is the first terbinafine topical nail solution for onychomycosis treatment made using HPCH technology. Dose-finding studies were conducted in patients having mild to moderate onychomycosis with P-3058. P-3058 10% was found to be efficacious.[4]
TDT-067 → Terbinafine transferosome
TDT-067 is the novel formulation of terbinafine in a transferosome particle for onychomycosis.[5] It has high penetration, and the formulation potentiates its fungicidal activity.
Penetration enhancers
Both physical and chemical permeation enhancers have been patented for use in onychomycosis.[6] An appropriate physical enhancer coupled with an adequate dosage form containing a chemical permeation enhancer and a potent drug in an appropriate delivery system will lead to sustained drug release. JP2010126532A patent provides a solution that comprises terbinafine in combination with a plant essential oil or terpenes. WO2019088005A1 patent is linked to a topical formulation containing an antifungal agent such as efinaconazole or luliconazole along with a permeation enhancer such as ethyl lactate.
Eberconazole ethylcellulose microsponge gel
Ethylcellulose microsponge gel was evaluated for the topical delivery of eberconazole nitrate.[7]In vivo, the deposition study was found to have four-fold retention in the stratum corneum. The formulation was non-irritant with sustained drug release.
Sertraconazole hydrogel and microsponge
An in vivo and in vitro study has evaluated the effect of microemulsion in topical sertraconazole hydrogel and found that the preparation was stable with a threefold higher retention in the stratum corneum.[8] Another study found a sustained drug release with sertraconazole nitrate microsponge.[9]
Econazole foam 1%
A new preparation of topical econazole nitrate 1% foam has been evaluated in a double-blind vehicle-controlled clinical trial for patients of culture-positive interdigital tinea pedis. After one daily application for 4 weeks, the mycological cure was achieved. It was suggested as a novel alternative in patients with tinea pedis.[10]
All these new formulations were designed for fungal infections of a limited extent or affecting the nails. There would be practical problems with their use in the treatment of the characteristically extensive infections observed in the current outbreak of dermatophytosis.
Novel oral formulations
Many strains of T. indotineae display both in vivo and in vitro resistance to terbinafine. The bioavailability of conventional itraconazole (C-ITZ) after oral administration is low. C-ITZ lacks pellet standardisation and has a pH-dependent gastric absorption with a high interindividual variation. Hence, there is a dire need for newer oral therapies to overcome these limitations. SUBA and Meltrex technology are novel advents in this regard.
SUBA technology itraconazole
With the help of SUBA technology, super bioavailable itraconazole (SUBA-ITZ) has been developed. It uses a non-pellet formulation of itraconazole in a pH-dependent matrix of posaconazole phthalate. This leads to intestinal absorption, has about 1.8 times higher bioavailability than conventional itraconazole, and less interindividual variation. SUBA-ITZ has been shown to be non-inferior to conventional form in some dermatophyte infections and can improve patient compliance.[11] It can be a good option for patients who are taking proton pump inhibitors regularly.
Meltrex technology
Likewise, a novel formulation of 200 mg itraconazole developed using the Meltrex technology aids in sustained drug release and improves drug compliance in onychomycosis.[12]
Newer antifungals with broad-spectrum activity
Dermatophytosis often poses a financial burden on the patient, particularly where different medications are used, and there is a prolonged treatment duration. It often leads to incomplete treatment and recurrence. We need affordable drugs with broad-spectrum anti-mycotic activity to increase adherence and treatment outcomes.
NB-002
NB-002 is a novel nanoemulsion formed from highly purified oil, ethanol, polysorbate 20, CPC, and water.[13] It has a broad spectrum, uniform, rapid fungicidal activity against dermatophytes, other filamentous fungi, and Candida albicans. It has also proven active against terbinafine-resistant Trichophyton rubrum isolates. It interacts with the fungal cell wall surface and has not shown any apparent cross-resistance to known antifungals.
PH 151 and PH 153
8-Hydroxyquinolone derivatives have emerged as potential antifungal candidates with broad-spectrum activity. They are lipophilic and act by metal chelation on the cell walls of dermatophytes. After cell entry, the chelate complex dissociates and causes cytotoxicity. The conversion of sulphonic acid into sulphonamides further increases the antifungal effect in PH 151 and PH 153.[14]
Efinaconazole
Efinaconazole, a 10% solution, has been approved by the Food and Drug Administration for onychomycosis in patients aged 6 years and above. It has been found to have higher in vitro activity against dermatophytes. It offers the advantage of increased nail penetration due to low surface tension, poor water solubility, and low keratin affinity. Experts recommend efinaconazole usage in mild toenail onychomycosis, paediatric patients, liver or kidney disease, and maintenance therapy.[15] In growing toenails, vesiculation and dermatitis are some of the local encountered side effects.
Fosravuconazole
Fosravuconazole is a novel oral triazole. It is a prodrug of ravuconazole with potent broad-spectrum and antifungal activity. It has improved lipophilicity and oral absorption compared to ravuconazole. It blocks ergosterol biosynthesis. Moreover, it has a lower inhibitory effect on cytochrome 3A4 than itraconazole and, hence, a better side-effect profile. It is prescribed at a dose of 100 mg/day for 12 weeks for onychomycosis.
Other novel azoles
Posaconazole, voriconazole, and oteseconazole (VT-1611) are other emerging promising therapies for recalcitrant onychomycosis.[16] Posaconazole can be given as a pulse regimen of 800 mg oral solution/day for 1 week per month for 24 weeks or daily 200 mg/day for 24 weeks. Voriconazole is given at a dosage of 200 mg twice daily for 12 weeks. Oteseconazole is given at 300 mg/day (loading dose) × 2 weeks followed by 300 mg/week × 10 weeks (maintenance dose).
Tavabarole
It is a boron-containing new topical antifungal agent that has been approved by the US FDA for onychomycosis in 2014. It inhibits the enzyme leucyl-transfer RNA synthetase, which drives fungal protein synthesis. Nail debridement is not required with tavaborole. It also shows minimal inhibition of cytochrome p450 enzyme, thereby limiting drug interactions.[17]
Newer antifungals with diverse targets
The current range of antifungal drugs generally acts on the ergosterol biosynthesis pathway. There is a need for drugs that act on new fungal targets to overcome drug resistance. An ideal antifungal drug should inhibit virulence factors, disrupt fungal physiology, and act on specific cellular targets.
ME1111
It is a novel inhibitor of the succinate dehydrogenase of Trichophyton species and hence targets the fungal electron transport chain. It offers excellent nail penetration and is being explored as a topical therapy for onychomycosis.[18]
AR-12
This is another novel small molecule with broad-spectrum activity. It is a celecoxib derivative that inhibits the acetyl coenzyme A synthetase enzyme. It has shown high activity against T. rubrum in vitro. Concomitant use of dexpanthenol and PEG400 has been found to increase its trans-ungual permeation.[19]
Compounds with antifungal Properties
Developing a new antifungal drug is both expensive and time-consuming before it becomes available for commercial use. Exploring the antifungal properties of other anti-microbial agents or natural compounds is another way of dealing with this issue and combating drug resistance in dermatophytosis.
Natural compounds
Plant extracts with antifungal properties have been identified. Their potential can be tapped either as directly active as antifungals or as precursors for effective novel antifungal molecules. Traditional medicinal plants have phenolic compounds, flavonoids, tannins, anthocyanins, alkaloids, quinones, and saponins that demonstrate some antifungal effects.[20] Lichen compounds, curcuminoids, and difluorinated curcumin have shown antifungal activity against clinical dermatophyte isolates. Flavonoids inhibit cell wall synthesis and possess antifungal activity.[21] The combination of conventional drugs with natural products such as essential oils has also shown promising results.[21]
Statins
Statins have pleiotropic effects beyond cholesterol lowering, improving endothelial function, regulating inflammation, and potentially exerting anti-microbial effects. They have broad-spectrum anti-mycotic actions and also potentiate the action of other antifungals such as polyenes and azoles.[22] Fluvastatin is the broadest and most potent fungistatic and fungicidal agent.
Calcineurin inhibitors
While immunosuppressive agents are known to increase the risk of fungal infection, research on their antifungal properties has been carried out in recent years with promising results. Calcineurin has been shown to promote hyphae growth, virulence, and drug resistance. Calcineurin inhibitors such as cyclosporine, tacrolimus, and pimecrolimus show synergy or additive effects with azoles in vitro.[22] Alternatively, knowledge of these targets can also be utilised to develop novel antifungal drugs without immunosuppressive effects.
Nitric oxide (NO)
The Nitricil technology platform is composed of polysiloxane-based macromolecules that release therapeutic levels of stable NO. NVN1000 is a product of this technology, which releases NO. It underwent an in vitro assessment, and time-kill assays showed fungicidal activity as early as 4 h. Additionally, NO-releasing drug product formulations were evaluated in an in vitro human nail assay, and all showed inhibition of fungal growth. Thus, they could be potential novel molecules for onychomycosis.[23]
Device-based therapies
The delivery of drugs through the nail plate into the nail bed is particularly challenging in onychomycosis patients. Physical and light therapies can be particularly helpful for these patients.
Photodynamic therapy
Biofilm formation is an important virulence factor that leads to treatment failure. Biofilms consist of an extracellular matrix that limits the contact of drugs with fungal cells. They provide high resistance to traditional therapies. Hence, there is a need for therapies with anti-biofilm activity. One study used an in vitro evaluation of the photodynamic effects of biofilms in onychomycosis.[24] Methylene blue was applied as a photosensitizing agent with LED (635 ± 10 nm, 60 J/cm2) as a light source. This was employed against six strains of T. rubrum, ten strains of T. mentagrophytes and three strains of Microsporum gypseum isolated from clinical specimens. There was highly efficient photodynamic inhibition with a reduction in colony-forming units against biofilms. It appears to be a promising treatment for recalcitrant onychomycosis.
Laser poration
Laser poration utilises a femtosecond pulsed laser to generate pores of 100 micrometres in the nail plate. This enhances topical drug permeation, sequestration and sustained drug release.[25] One study has combined laser poration with the nanocapsule formulation of tioconazole. Porating the nails enhanced tioconazole delivery in single-dose experiments only.[26]
Iontophoresis
Iontophoresis uses electrical current to drive ionizable molecules through biological membranes. Nail hydration, abrasion, avulsion, and keratolytics are used as pre-treatment to enhance permeability. This device has been shown to improve drug permeation by up to 37 times in onychomycotic toenails.[27] It also increases drug loading by tenfold.[28]
Non-thermal plasma
Non-thermal atmospheric plasma (NTAP) has been evaluated in an in vitro human onychomycosis nail. Direct exposure of Candida and Trichophyton mentagrophyte to 12 min of NTAP resulted in complete killing at doses of 39 and 15 k pulses, respectively.[29] It can turn out to be a non-invasive effective therapy and warrants further evaluation.
Advances have been made in antifungal drug development, as evidenced by the above-mentioned therapies. However, it will be a considerable time before most of them are approved and marketed for commercial usage if they reach this stage. The need of the hour is the development of a medical armamentarium of antifungal drugs that are broad-spectrum, cost-effective, with improved patient compliance and a favourable safety profile. Most new approaches have been designed with one target infection in mind: onychomycosis. For practical reasons, the ease of use for extensive skin infections that typify the clinical presentations observed in the current epidemic of dermatophytosis is a key attribute of any new therapeutic agent that could be applied as a treatment for this indication. These drugs should have a reservoir effect and disrupt fungal physiology. The road ahead encompasses further research in five major domains, increasing drug bioavailability, broad-spectrum drugs with novel targets, inhibiting virulence factors, and combating drug resistance. We need a better understanding of fungal pathophysiology, gene structure, and mutations to strategise effective management approaches. We can also explore the untapped potential of natural compounds and devices that could act in synergy with the existing drugs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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