FUNGAL INFECTION OF THE NAIL – ONYCHOMYCOSIS

Onychomycosis, the fungal infection of the nail, is a common nail disorder that faces significant barriers to successful treatment.

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Treatment strategies for onychomycosis with the use of devices

There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are non-invasive procedures that reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies

Onychomycosis is a common nail disorder that faces significant barriers to successful treatment.

Etiologically, fungal pathogens such as dermatophyte fungi, yeasts, and non-dermatophyte moulds invade and colonize the nail plate, bed, and matrix creating an entrenched infection.

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, peripheral vasculopathy, HIV, immunosuppressant, obesity, smoking, and increased age.

Many individuals have sustained infections persisting for months or even years and, hence, they may not be motivated to initiate or complete therapy due to a perception that their condition cannot be treated.

Onychomycosis has traditionally been treated by oral and topical antifungals, which often have low to moderate efficacy. Even when pharmacotherapy initially results in a mycological cure, the relapse and/or re-infection rate ranges from 16 to 25%. 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 reactions that can cause patients to discontinue treatment and therapy may be complicated with the presence of a co-morbid condition.

In addition to this, the extended treatment period may discourage patient compliance, posing a significant detriment to effective therapy. Therefore, the above mentioned factors can contribute to the suboptimal delivery of conventional therapy for onychomycosis.

Device-based therapies are really 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 treatment methods is a non-invasive procedure, which reduces the need for long-term patient compliance. Photodynamic therapy, iontophoresis and ultrasound are used in combination with local pharmacological agents. This promotes the avoidance of adverse effects associated with systemic antifungal therapy

Laser Therapy

Treatment of onychomycosis infections using Laser devices is based on the principle of selective photothermolysis. 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. 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.

Solid State Lasers

Solid state lasers use a solid crystal rod. Among them many of the common commercial lasers are included, such as the neodymium-doped yttrium aluminium garnet – Nd:YAG – and titanium sapphire – Ti:Sapphire – Lasers.

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.

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.

Short Pulse Laser Systems

The first two lasers that were approved by the FDA for the treatment of onychomycosis are both flash lamp pumped short pulse Nd:YAG 1064 nm Lasers.

Q-switched Laser Systems

Q-switched lasers have pulse duration in the nanosecond range and they emit the highest peak power per pulse of all the Nd:YAG lasers. One FDA-approved Q-switched Nd:YAG 1064 nm laser is particularly 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.

Near Infrared Diode Lasers

Diode Lasers use semiconductors for the optical gain medium as an alternative to solid crystals.

The Diode Lasers operate at near infrared wavelengths. Four treatment sessions are necessary with a six-week period between them.

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.

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. Both of these drugs are commercially available for the treatment of actinic keratosis.

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.

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.

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. There are two iontophoresis devices.

Iontophoresis increases the amount of terbinafine accumulated in the nail plate over the uptake from a passive source. Then, the nail plate acts as a reservoir of terbinafine that is then released into the nail bed and matrix over 60–70 days.

Ultrasound Drug Delivery System

The most recent development in device-based treatments for onychomycosis is an ultrasound mediated nail drug delivery system.

Device based treatment strategies seem to be really promising according to various clinical trials including Lasers, Photodynamic Therapy, iontophoresis and ultrasound-based therapy.

Device-based treatments may be advantageous because they only require short-term patient compliance.

Furthermore, these techniques have the potential to reduce adverse events caused by antifungal drugs, as they are highly localized treatments.

Devices may also be an effective alternative 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.

 

Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC

Fiona Simpson, HBSc

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