Device-Based Therapies for Onychomycosis Treatment

Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC^1,2 and Fiona Simpson, HBSc²

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

ABSTRACT

Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals, reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies.

Key Words:
antifungal, iontophoresis, laser devices, nails, onychomycosis, photodynamic therapy, ultrasound

Introduction

Onychomycosis is a common nail disorder that faces significant barriers to successful treatment. Etiologically, fungal pathogens such dermatophyte fungi, yeasts, and non-dermatophyte molds invade and colonize the nail plate, bed, and matrix creating an entrenched infection.^1-10 The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also confer an increased risk of co-morbid onychomycosis infection including diabetes,¹¹ peripheral vascular disease,¹¹ HIV,¹² immunosupression,^13,14 obesity,¹⁵ smoking,¹¹ and increased age.¹⁴ Many individuals have sustained infections persisting for months or years and, hence, they may not be motivated to initiate or complete therapy due to a perception that their condition is untreatable.

Onychomycosis has traditionally been treated by oral and topical antifungals¹⁶ that often yield low to moderate efficacy. Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^17,18 Successful treatment for onychomycosis requires antifungal drugs to penetrate the nail plate and nail bed, but incomplete dissemination to the lesion is a problem for both oral and topical agents. Antifungal drugs may be associated with adverse events that can cause patients to discontinue treatment and therapy may be complicated with the presence of a co-morbid condition.^19,20 Additionally, the extended course of treatment may discourage patient compliance, which poses a significant detriment to effective therapy. Thus, these factors can contribute to the suboptimal delivery of conventional therapy for onychomycosis.

Device-based therapies are promising solutions for the treatment of onychomycosis because they can mitigate some of the negative factors that contribute to treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis and ultrasound. Each of these techniques is a noninvasive procedure conducted by a medical professional, which reduces the need for long-term patient compliance. Photodynamic therapy, iontophoresis and ultrasound are used in combination with local pharmacological agents, thereby avoiding adverse effects associated with systemic antifungal therapy.

Laser Therapy

Laser treatment of onychomycosis infections uses the principle of selective photothermolysis.^21,22 Laser therapy is intended to exploit the differences in laser energy absorption and thermal conductivity between the fungal infection and the surrounding tissue. The absorption of light energy by the fungi results in the conversion of the energy into heat or mechanical energy.^21,22 Fungi are heat sensitive above 55°C, so absorption of laser energy that results in sustained photothermal heating of the mycelium (10+ minutes) is likely to result in fungicidal effects.^23,24 However, heating dermal tissue to temperatures above 40°C results in pain and necrosis; therefore, the laser energy format must either be pulsed to allow the dissipation of heat by the tissue through its superior thermal conduction or delivered at a moderate energetic level to prevent tissue damage. The exact mechanism of laser therapy is still under investigation, but it may combine direct fungicidal effects of the laser with induced modifications in the immune system or changes in the local microenvironment.

Laser therapy for onychomycosis is currently being studied in vitro and in vivo. In addition, at the time of this writing, the following lasers have been granted FDA marketing approval for the treatment of onychomycosis: PinPointe™ FootLaser™ (PinPointe USA, Inc.),²⁵ Cutera GenesisPlus™ (Cutera, Inc.),²⁶ Q-Clear™ (Light Age, Inc.),²⁷ CoolTouch VARIA™ (CoolTouch, Inc.),²⁸ and JOULE ClearSense™ (Sciton, Inc.).²⁹ The parameters of lasers that have been FDA cleared or tested and supported by publications for onychomycosis are summarized in Table 1. It is important to note that regulatory clearance of device systems are made on the basis of “substantial equivalence” to the technical specifications of pre-existing devices approved for marketing for onychomycosis, not on the basis of clinical trials data, so these systems cannot be directly compared to pharmacologic therapies.

Solid State Lasers

Solid state lasers use a solid crystal rod and they include many of the common commercial lasers such as the neodymium-doped yttrium aluminum garnet (Nd:YAG) and titanium sapphire (Ti:Sapphire) lasers. Solid state lasers may be built for use as continuous lasers or as pulsed lasers with pulse durations in the millisecond, microsecond, nanosecond, or femtosecond ranges. The maximum pulse energy increases as the pulse length decreases, so different pulse formats may result in greater nonspecific heating of the nail plate, or require longer treatment lengths to produce a fungicidal effect. The lasers that have been approved for the treatment of onychomycosis in North America have all been Nd:YAG lasers.

Long Pulse Laser Systems

Long pulse Nd:YAG lasers have received CE Marking in Europe (the mandatory conformity designation for marketed products in the European Economic Area), but they have not yet been approved to treat onychomycosis in North America.³⁰ The pulse duration for these lasers is in the millisecond range. These lasers can cause a high degree of non-specific heating and may need to be operated in the presence of a dedicated cooling system. The largest study of millisecond Nd:YAG lasers was conducted using the Fotona Dualis SP™ laser on 162 participants in Serbia.^31,32 Fungal infections in both fingernails and toenails were identified by potassium hydroxide (KOH) microscopy.³¹ Participants were treated with a 30-40 J/cm² energy fluence with a spot size of 4 mm and a pulse duration of 35 ms in the presence of cold air cooling.³¹ The nail plate was treated in a spiral pattern. A 2 minute wait period was observed before repeating the laser treatment.³¹ Participants received 4 treatments at 1 week intervals and they were followed after therapy from 12-30+ months. A completely clear nail plate was achieved by 93.5% of participants.³² The Fotona Dynamis™ family of laser systems has the same technical parameters as the laser used in the studies described above and has received marketing clearance in Europe.

Short Pulse Laser Systems

The first two lasers that were sanctioned by the FDA for the treatment of onychomycosis (PinPointe™ FootLaser™ and Cutera GenesisPlus™) are both flashlamp pumped short pulse Nd:YAG 1064 nm lasers.^25,26 The CoolTouch VARIA™ laser is the most recent addition to this class of devices.²⁸ These lasers emit 100-3000 µs pulses with an energy fluence of 25.5 J/cm² for a 1 mm spot size.^25,26,28 The PinPointe™ FootLaser™ was used in an initial phase I/II clinical trial.³³ Seventeen participants demonstrating great toenails afflicted with onychomycosis were enrolled and randomized into treated (n=11) or untreated (n=6) groups. Participants received a single treatment and were followed-up at 3 and 6 months. At the 6 month time period, 11 of 14 treated toes showed improvement in clear linear nail growth. Clinicaltrials.gov reports that a phase III clinical trial for the PinPointe™ laser (NCT00935649) was completed on November 29, 2010, but the data from this study remains unpublished.³⁴ Cutera has released a white paper on the GenesisPlus™ laser³⁵ that reported a 70% improvement rate in the 7 participants treated with 2 sessions of laser therapy. The JOULE ClearSense™ laser was tested in an initial trial of 21 patients.³⁶ Onychomycosis was confirmed by culture and periodic-acid schiff (PAS) microscopy. Patients were treated 4 times, at 1 week intervals with a pulse length of 0.3 ms, an energy fluence of 13 J/cm², and a repetition rate of 6 Hz. Follow-up mycological culture was negative in 95% of patients.³⁶ Clinical trials data for the CoolTouch™ laser has not yet been released.

An additional clinical study was published by Hochman et al. using a short pulse Nd:YAG laser system that has not been FDA cleared for onychomycosis.³⁷ This study confirmed active fungal infections in toenails and fingernails by culture or PAS stain. Participants were treated with a 223 J/cm² energy fluence with a 2 mm spot size for ≤45 seconds. Each subject received 2-3 treatments spaced at least 3 weeks apart. Antifungal cream was used daily where anatomically possible during this study. The efficacy of treatment was followed for between 4-6 months after therapy. Treatment resulted in negative mycological culture in 7 of 8 participants.

CoolTouch, Inc. is also conducting a clinical trial with a 1320 nm Nd:YAG laser (NCT01498393).³⁸ The CoolTouch CT3 Plus™ with the CoolBreeze Zoom handpiece can be operated in short pulse (450 µs) or continuous mode.³⁹ The handpiece has a pre-set temperature threshold that employs a cryogen cooling system.⁴⁰ Duration of the trial is 6 months and the inclusion criteria require patients to have a fungal infection on both great toenails.

Q-switched Laser Systems

Q-switched lasers have a pulse duration in the nanosecond range and they emit the highest peak power per pulse of all the Nd:YAG lasers. In vitro, an energy fluence of 4 J/cm² optimally inhibited Trichophyton rubrum (T. rubrum) colony growth.⁴¹ The Light Age Q-Clear™ is a FDA-cleared Q-switched Nd:YAG 1064 nm laser.²⁷ The FDA 510(k) summary for this laser device states that “Light Age, Inc.’s study of 100 randomized subjects of both genders,including Caucasian, Asian, African American, and Latino, has demonstrated substantially effective clearance of dystrophic toenails having a clinically apparent diagnosis of onychomycosis. Statistical analysis of results indicates significant apparent clearing in 95% of the subjects with an average clearance of affected areas of 56 ± 7% at 98% level of confidence.”²⁷

Modelocked Laser Systems

A modelocked femtosecond pulsed Ti:Sapphire laser tuned to 800 nm was used in an in vitro study on T. rubrum.⁴² Nail clippings were obtained from participants with onychomycosis and the fungal infection was confirmed by culture (n=99). The cultures were irradiated with a Ti:Sapphire laser that was pumped by a solid-state laser, which emitted 200 fs pulses at a frequency of 76 MHz through a variety of numerical apertures from 0.12 to 0.45. Treatment with energy above 7×10³¹ photons m^-2 s^-1 resulted in a 100% fungicidal effect.

Near Infrared Diode Lasers

Diode lasers use semiconductors for the optical gain medium as an alternative to solid crystals. The diode lasers that are currently under investigation for onychomycosis operate at near infrared wavelengths. The Noveon® laser (Nomir Medical Technologies) is an 870 nm and 930 nm dual wavelength diode laser.⁴³ In vitro studies have shown that 870 nm and 930 nm wavelengths photoinactivate T. rubrum and Candida albicans, and have a minimal negative effect on cultured fibroblasts.⁴⁴ Preliminary trials for the Noveon® laser have been conducted.⁴² Distal and lateral subungual onychomycosis was confirmed by culture or PAS stain and each participant received 4 treatments on days 1, 14, 42 and 120. Each treatment comprised 4 minutes of dual wavelength therapy, followed by 2 minutes of 930 nm treatment. At 180 days, the participants showed an 85% improvement of infection in 26 toes treated.⁴³ The status of the phase II and II/III trials for the Noveon® laser in onychomycosis (NCT00771732 and NCT00776464) remains unknown.^45,46

ConBio Inc. has registered a single assignment, open label clinical trial (NCT01452490) for a near infrared diode laser.⁴⁷ The V-Raser® laser is a 980 nm near infrared diode laser that has previously been marketed for the removal of vascular lesions. The study aims to enroll 50 participants at two podiatric practices in the United States. Participants will receive 4 laser treatments at 6 week intervals.⁴⁷

Photodynamic Therapy

Photodynamic therapy (PDT) uses visible spectrum light to activate a topically applied photosensitizing agent, which generates reactive oxygen species that initiate apoptosis. Photodynamic therapy was originally optimized for actinic keratosis, but photosensitizers can also be absorbed by fungi.^48,49 The effects of various photosensitizing agents have been studied in vitro and in vivo. These include 5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), and 5,10,15-tris (4-methylpyridiuium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B).

Heme Biosynthesis Intermediates – ALA and MAL

ALA and its methyl ester MAL are heme precursors. They cause a build-up of protoporphyrin IX (PpIX), which is a photodynamically active molecule. In the presence of the correct spectrum of light, PpIX generates reactive oxygen species that initiate apoptosis.⁵⁰ Both of these drugs are commercially available for the treatment of actinic keratosis. Several studies have tested these formulations in small studies on participants with onychomycosis (Table 2).^51-54 These studies are heterogeneous, preventing any form of direct comparison; however, these investigations have shown promising initial results, but their small sample sizes (n>30) limit our ability to draw conclusions on the efficacy of this mode of therapy. The protocols developed for these studies indicate that the nail plate should be pre-treated with urea ointment to soften the nail plate prior to application of the photosensitizer.

Non-Heme Porphyrins – Sylsens B

Sylsens B is a non-heme porphyrin that has been used for in vitro studies on T. rubrum. PDT with Sylsens B is fungicidal in T. rubrum suspensions of both hyphae and microconidia at concentrations above 10 µM.^49,55,56 PDT with Sylsens B is also fungicidal when T. rubrum is adhered to keratinized structures.⁵⁷ In vitro experiments determined that ultraviolet-A (UVA-1) light is fungicidal in commercial strains and clinical isolates of T. rubrum, so it was an ideal excitatory light source for PDT.⁵⁸ The clinically isolated strain required a higher dose of Syslens B (9 µM) than the commercial strain (1 µM) using a UVA-1 energy fluence of 18 J/cm².⁵⁸ Sylsens B has not yet been tested in vivo.

Iontophoresis

Iontophoresis is a technique that uses a low level electrical current to increase the transport of drugs across semi-permeable barriers. The limitation of many topical treatments for onychomycosis is their inability to fully penetrate the nail plate.⁵⁹ This technique may be more successful in incorporating the drug into the nail plate and passing it through the plate to ensure that it penetrates the nail bed and matrix. Iontophoresis is currently being optimized for terbinafine, because it has the highest antifungal effect on dermatophytes in vitro.⁶⁰ There are two iontophoresis devices currently in clinical trials.

Iontophoresis increases the amount of terbinafine accumulated in the nail plate over the uptake from a passive source.^61-67 The nail plate then acts as a reservoir of terbinafine that is then released into the nail bed and matrix over 60-70 days.^62-65,67 The drug uptake during iontophoresis can be enhanced after removal of the dorsal layer of the nail plate, or in the presence of keratolysis.⁶⁴ The devices by NB Therapeutics were effective at targeting the nail plate exclusively and both the nail plate and surrounding skin.⁶³ The iontophretic device (Electrokinetic Transungual System) by Transport Pharmaceuticals was registered in a phase I clinical trial (NCT00768768) that has since been completed, but the data remains unpublished.⁶⁸ A phase II clinical trial is also ongoing in North America (NCT01484145).⁶⁹

The Power Paper iontophoretic patch device was used in a single preliminary trial of 38 participants.⁶¹ Infections were confirmed by both KOH examination and mycological culture. The participants were randomized into two groups for the treatment of a single great toenail. The first group received terbinafine iontophoresis with a current density of 100 µA/cm². The second was treated with the terbinafine gel patch without iontophoresis. The participants wore the patch overnight, every day for 4 weeks. After the initial visit, two further iontophoresis treatments were conducted. Follow-up occurred at 8 weeks and 12 weeks. At the final follow-up, 84% of participants demonstrated a mycological cure confirmed by KOH microscopy.

Ultrasound Drug Delivery System

The most recent development in device-based treatments for onychomycosis is an ultrasound mediated nail drug delivery system.⁷⁰ This system has been tested in a canine nail model. The intent was to determine which period of 1.5 W/cm² ultrasound treatment increased the nail uptake of a blue dye. Findings showed that the 120 second period was the most effective, increasing dye permeability by 1.5 fold. Further studies will be required to determine if this technique is suitable for existing antifungal drugs.

Conclusion

Device-based therapies for onychomycosis show promise in initial clinical studies involving lasers, photodynamic therapy, iontophoresis, and ultrasound-based therapy. Device-based treatments may be advantageous because they are conducted in the clinic and only require short-term patient compliance. These modalities also have the potential to reduce adverse events caused by antifungal drugs, as they are highly localized treatments. Devices may also be alternatives for patients whose susceptibility to onychomycosis infection arises from a co-morbidity, as these therapies do not interact with the drugs involved in the management of such conditions.^{65, 66} In order to substantiate the efficacy of device-based therapies for onychomycosis, randomized controlled trials with mycological evaluation and long-term follow-up are required. We believe this therapeutic area will continue to expand and hope that broader clinical investigations will result in new options for practitioners.

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