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Endonyx toenail onychomycosis caused by Trichophyton rubrum: treatment with photodynamic therapy based on methylene blue dye*
This study shows the effectiveness of photodynamic therapy based on methylene blue dye for the treatment of endonyx toenail onychomycosis. Four patients with endonyx onychomycosis caused by Trichophyton rubrum were treated with 2% methylene blue aqueous solution irradiated with light emission diode at 630 nm and an energy density of 36 J/cm2 for 6 months at 2-week intervals. The preliminary study showed the effectiveness of this therapy in the treatment of endonyx onychomycosis, and also indicated that the disease can be caused by T. rubrum.
Fungal nail infections are classified according to the site of fungal invasion. There are 5 different modes of invasion: distal and lateral subungual onychomycosis, proximal subungual onychomycosis, superficial onychomycosis (white or black), endonyx onychomycosis (EO), and mixed onychomycosis (total dystrophic, secondary, and paronychia-associated).1 EO is characterized by massive fungal invasion of the superficial and deep nail-plate layers with minimal or absent hyperkeratosis.1,2 The nail surface has lamellar-like splits, and the end of the nail plate is often friable and split. Dense opacification of the nail plate with milky-white discoloration is unusual. Endothrix dermatophytes cause the clinical peculiarities of EO, usuallyTrichophyton soudanense and in some cases Trichophyton violaceum.1
Photodynamic therapy (PDT) is a medical modality that combines the use of visible light and a photosensitive compound in the presence of oxygen. It is widely used to treat neoplastic skin lesions.3 PDT has been investigated as a noninvasive treatment for onychomycosis which selectively destroys infectious pathogens.4 Methylene blue (MB) and other dyes of the same class exhibit intense absorption at the 600-660-nm red light region.3 Studies have demonstrated that MB-light emission diode (MBLED)/PDT is effective and safe, with response rates of approximately 85-100%.3,5 Here we investigated the efficacy of MBLED/PDT in patients with toenail EO caused by Trichophyton rubrum.
We conducted a preliminary open clinical trial that included 4 immunocompetent patients with toenail EO with clinical and mycological diagnosis. The inclusion criteria were clinical signs of EO confirmed by direct microscopic examination of nail material with 20% potassium hydroxide and by culture on Sabouraud agar with chloramphenicol-cycloheximide and Sabouraud agar with chloramphenicol. None of the patients showed nail changes associated with skin or systemic diseases, nor had used antifungal medications in the previous 4 months. PDT consisted of 6 months of MBLED sessions with an interval of 15 days between sessions. A 2% aqueous MB solution was applied to the lesion followed by irradiation with red light (630 nm, 36 J/cm2) from an LED device with a light intensity output of 3100 mW/cm2 and optical intensity of 100 mW/cm2 (Multiwaves; Industra, São Carlos, Brazil). Lesions that were not fully penetrated by the dye were treated with nail abrasion, using a rotation abrasive device with a 3-mm diamond tip (Dermoabrasor; Bley Med, Curitiba, Brazil). Patients were evaluated monthly during treatment. The microbiological and clinical outcomes were assessed at the end of treatment. The study was approved by the Ethics Committee of the Montes Claros State University.
Before treatment, all 4 patients were found positive for T. rubrum on mycological examination (Table 1). In 2 patients, a second culture was needed for etiological confirmation. Figure 1A shows nail plate impairment without subungual hyperkeratosis, and the presence of undulation and distal split. Figure 1B shows the rapid clinical response after 8 weeks of treatment and the presence of lamellar scaling and a nail plate distal split. Complete clinical response was evident, with mycological cure in all cases. No patient showed dense opacification of the nail plate (Figure 1). No adverse effects were observed.
This preliminary MBLED/PDT trial showed the effectiveness of the method for treating onychomycosis caused by T. rubrum. EO caused by endothrixdermatophytes (mainly T. soudanense) differs from distal and lateral subungual onychomycosis (mainly caused by T. rubrum), essentially by the absent or minimal subungual hyperkeratosis.1,2 From the genetic standpoint, T. rubrum and T. soudanense are the same species.6 T. rubrum was believed to be exclusively ectothrix but is currently known to be either ectothrix or endothrix.7,8
MB/PDT has been used for several decades for the treatment of cutaneous mycosis.3 Previous clinical trials and in vitro studies have demonstrated the effectiveness of PDT, but indicated the need for adequate energy density and concentration of the photosensitive dye.3,8 The increased energy density used in this study might reduce the number of sessions and the treatment duration due to the increased PDT fungicidal activity.8 The use of macrocyclic molecules with fewer sessions (3 on average), because of the high cost, has resulted in a clinical cure rate lower than that of azole drugs, probably due to the inadequate number of sessions.9,10
In conclusion, onychomycosis remains a therapeutic challenge. The preliminary results of this study confirm that MBLED/PDT is safe and effective, promoting a favorable outcome in the treatment of EO caused by T. rubrum. New clinical studies may indicate the suitable energy density for improving the therapeutic outcome and potential associations with systemic treatments. Finally, this study shows that, besides T. soudanense andT. violaceum, other fungi of the T. rubrum complex can cause endonyx onychomycosis.
* Work performed at the Clemente Faria University Hospital – Montes Claros State University (HUCF – UNIMONTES) – Montes Claros (MG), Brazil.
Financial funding: None
Conflict of interest: None
Device-based therapies for onychomycosis treatment.
Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
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.
Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis.
Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Recent research shows that lasers can inhibit fungal growth and that Nd:YAG 1064-nm lasers can penetrate as deep as the lower nail plate. The aim of this study was to observe the effect of a long-pulse Nd:YAG 1064-nm laser on 154 nails of 33 patients with clinically and mycologically proven onychomycosis.
Thirty-three patients with 154 nails affected by onychomycosis were randomly assigned to two groups, with the 154 nails divided into three sub-groups (II degree, III degree, and IV degree) according to the Scoring Clinical Index of Onychomycosis. The 15 patients (78 nails) in group 1 were given eight sessions with a one-week interval, and the 18 patients (76 nails) in group 2 were given four sessions with a one-week interval.
In group 1, the effective rates at 8 weeks, 16 weeks, and 24 weeks were 63%, 62%, and 51%, respectively, and the effective rates in group 2 were 68%, 67%, and 53% respectively. The treatment effect was not significantly different between any sub-group pair (P > 0.05).
Long pulse Nd:YAG 1064-nm laser was effective for onychomycosis. It is a simple and effective method without significant complications or side effects and is expected to become an alternative or replacement therapy for onychomycosis.
Expert Opin Pharmacother. 2012 Jun;13(8):1131-42. Epub 2012 Apr 25.
New therapeutic options for onychomycosis.
Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. firstname.lastname@example.org
INTRODUCTION: Onychomycosis is a fungal infection of the nail apparatus that affects 10 – 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 – 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment.
AREAS COVERED: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis.
EXPERT OPINION: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices.
J Am Podiatr Med Assoc. 2012 Mar-Apr;102(2):169-71.
Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure: some follow-up observations at 270 days.
Division of Podiatric Surgery, Cambridge Health Alliance, Cambridge, MA, USA. email@example.com
We have previously reported the results of a clinical trial in which the Noveon laser was used to treat onychomycosis. In the 180-day follow-up therein it was noted that positive clinical impact was demonstrable by a clearly measurable decrease in positive fungal culture and a concomitant decrease in positive microscopy with periodic acid-Schiff-stained nail scrapings. Review of 270-day mycological data, which are now available, confirmed that there was further decrease in both measures. Indeed, 38% of the treated population had negative culture and microscopy, qualifying as “mycological cures.” These mycological cures occurred in cases categorized as mild, moderate, and even severe disease.
New concepts in median nail dystrophy, onychomycosis, and hand, foot, and mouth disease nail pathology.
Hoy NY, Leung AK, Metelitsa AI, Adams S.
Faculty of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2R7.
Nails are underutilized as diagnostic tools, despite being involved in many dermatologic conditions. This paper explores new concepts in the treatment of median nail dystrophy (MND), onychomycosis, and the nail pathology of hand, foot, and mouth disease (HFMD). A Pubmed database literature search was conducted for MND treatment, onychomycosis treatment, and HFMD nail pathology. Only papers published after January 2008 were reviewed. The results showed that 0.1% tacrolimus ointment can be an effective treatment for MND. Early studies on laser therapy indicate that it is a safe and efficacious treatment option for onychomycosis, compared to conventional oral antifungal agents. Vicks VapoRub (The Proctor & Gamble Company, Cincinnati, OH) is effective against onychomycosis and is a reasonable option in patients who choose to forgo conventional treatments. Lastly, there is evidence to support a correlation between HFMD and onychomadesis.
Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure.
Division of Podiatric Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.
The Noveon is a unique dual-wavelength near-infrared diode laser used to treat onychomycosis. The device operates at physiologic temperatures that are thermally safe for human tissue. It uses only 870- and 930-nm near-infrared light, wavelengths that have unique photolethal effects on fungal pathogens. These wavelengths lack the teratogenic danger presented by ultraviolet light and the photoablation toxic plume associated with pulsed Nd:YAG lasers.
In this randomized controlled study, treatments followed a predefined protocol and laser parameters and occurred on days 1, 14, 42, and 120. Toes were cultured and evaluated, and measurements were taken from standardized photographs obtained periodically during the 180 day follow-up period.
We treated mycologically confirmed onychomycosis in 26 eligible toes (ten mild, seven moderate, and nine severe). All of the patients were followed-up for 180 days. An independent expert panel, blinded regarding treatment versus control, found that at 180 days, 85% of the eligible treated toenails were improved by clear nail linear extent (P = .0015); 65% showed at least 3 mm and 26% showed at least 4 mm of clear nail growth. Of the 16 toes with moderate to severe involvement, ten (63%) improved, as shown by clear nail growth of at least 3 mm (P = .0112). Simultaneous negative culture and periodic acid-Schiff was noted in 30% at 180 days.
These results indicate a role for this laser in the treatment of onychomycosis, regardless of degree of severity. Ease of delivery and the lack of a need to monitor blood chemistry are attractive attributes.
Photochem Photobiol. 2009 Nov-Dec;85(6):1364-74.
Near-infrared photoinactivation of bacteria and fungi at physiologic temperatures.
Bornstein E, Hermans W, Gridley S, Manni J.
Nomir Medical Technologies, Waltham, MA, USA. firstname.lastname@example.org
We examined a laser system (870 and 930 nm), employing wavelengths that have exhibited cellular photodamage properties in optical traps. In vitro, with 1.5 cm diameter flat-top projections (power density of 5.66 W cm(-2)), at physiologic temperatures, we achieved photoinactivation of Staphylococcus aureus, Escherichia coli, Candida albicans and Trichophyton rubrum. Using nonlethal dosimetry, we measured a decrease in trans-membrane potentials (DeltaPsimt and DeltaPsip) and an increase in reactive oxygen species (ROS) generation in methicillin-resistant S. aureus (MRSA), C. albicans and human embryonic kidney cells. We postulate that these multiplexed wavelengths cause an optically mediated mechano-transduction of cellular redox pathways, decreasing DeltaPsi and increasing ROS. The cellular energetics of prokaryotic and fungal pathogens, along with mammalian cells, are affected in a similar manner when treated with these multiplexed wavelengths at the power densities employed. Following live porcine thermal tolerance skin experiments, we then performed human pilot studies, examining photodamage to MRSA in the nose and fungi in onychomycosis. No observable damage to the nares or the nail matrix was observed, yet photodamage to the pathogens was achieved at physiologic temperatures. The selective aspect of this near-infrared photodamage presents the possibility for its future utilization in human cutaneous antimicrobial therapy.
J Am Podiatr Med Assoc. 2009 Jul-Aug;99(4):348-52.
A review of current research in light-based technologies for treatment of podiatric infectious disease states.
Nomir Medical Technologies, Inc, 307 Waverley Oaks Road, Suite 109, Waltham, MA 02452, USA. email@example.com
Recently, there has been a resurgence of interest in potential phototherapy technologies for the local treatment of bacterial and fungal infection. Currently, onychomycosis is the principle disease that is the target of these phototherapies in podiatric medicine. Some of these technologies are currently undergoing in vitro and in vivo trials approved by institutional review boards. The three light-based technologies are ultraviolet light therapy, near infrared photo-inactivation therapy, and photothermal ablative antisepsis. Each of these technologies have markedly dissimilar mechanisms of action. In this review, each technology will be discussed from the perspectives of history, photobiology, individual mechanism of action, safety, and potential clinical efficacy, with data presented from published material. This review is intended to give podiatric physicians detailed information on state-of-the-art infectious disease phototherapy.
Photochem Photobiol.. [Epub ahead of print]
Direct Antifungal Effect of Femtosecond Laser on Trichophyton rubrum Onychomycosis.
Manevitch Z, Lev D, Palhan M, Lewis A, Enk CD.
Department of Applied Physics, Selim and Rachel Benin School of Engineering and Computer Science, The Hebrew University, Jerusalem, Israel.
Abstract Onychomycosis is caused by dermatophyte infection of the nail. Though laser energy has been shown to eliminate dermatophytes in vitro, direct laser elimination of onychomycosis is not successful due to difficulties in selectively delivering laser energy to the deeper levels of the nail plate without collateral damage. Femtosecond (fsec) infrared titanium sapphire lasers circumvent this problem by the nonlinear interactions of these lasers with biological media. This quality, combined with the deeply penetrating nature of the near-infrared radiation, allows elimination of deeply seeded nail dermatopytes without associated collateral damage. Nail cuttings obtained from patients with onychomycosis caused by Trichophyton rubrum underwent fsec laser irradiation using increasing laser intensities with the focus scanned throughout the whole thickness of the nail specimen. The efficacy of the laser treatment was evaluated by subculture. Scanning electron microscopy was used to determine fsec laser-induced collateral damage. We found that a fsec laser fluence of 7 x 10(31) photons m(-2) s(-1) or above successfully inhibited the growth of the fungus in all samples examined, whereas laser intensities above 1.7 x 10(32) photons m(-2) s(-1) affected the structure of the nail plate. Our findings suggest that T. rubrum-mediated onychomycosis may be treated by fsec laser technology.
Clin Podiatr Med Surg. 1987 Oct;4(4):809-21.
Carbon dioxide laser use for certain diseases of the toenails.
Rothermel E, Apfelberg DB.
Stanford University Medical School, California.
The CO2 laser has facilitated the treatment of many toenail conditions. Satisfactory wound healing and cure rates have been equivalent to current standards of treatment. Pain was markedly diminished as compared with pain in traditional methods of treatment, and time until comfortable ambulation was dramatically shortened. Healing times were consistent with those in other methods of treatment. The protocol for CO2 treatment of nail conditions has been thoroughly described. Evaluation of 50 patients after 4 years from treatment date is tabulated. The CO2 laser must be strongly considered as a treatment modality for toenail pathology. Because of markedly reduced pain, minimal disability, and satisfactory long-term results, the laser is becoming a valuable treatment of choice for pathologic conditions of the nail.