Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream Eun-Hwa Lim, MD,a Hyeong-rae Kim, MD,a Young-Ok Park, PhD,b Young Lee, MD,a Young-Joon Seo, MD,a Chang-Deok Kim, PhD,a Jeung-Hoon Lee, MD,a and Myung Im, MDa Daejeon and Seoul, Korea Background: Traditional pharmacotherapy for onychomycosis has low to moderate efficacy and may be associated with adverse reactions and medication interactions limiting its use in many patients. Objective: We evaluated the clinical efficacy and safety of a fractional carbon-dioxide laser with topical antifungal therapy in the treatment of onychomycosis. Methods: In all, 24 patients were treated with fractional carbon-dioxide laser therapy and a topical antifungal cream. The laser treatment consisted of 3 sessions at 4-week intervals. Efficacy was assessed based on the response rate from standardized photographs, a microscopic examination of subungual debris, and subjective evaluations. Results: Among the patients, 92% showed a clinical response and 50% showed a complete response with a negative microscopic result. The factors that influenced a successful outcome were the type of onychomycosis and the thickness of the nail plate before treatment. The treatment regimen was well tolerated and there was no recurrence 3 months after the last treatment episode. Limitations: The study followed up only 24 patients and there were no relevant treatment controls. Conclusions: Fractional carbon-dioxide laser therapy, combined with a topical antifungal agent, was effective in the treatment of onychomycosis. It should be considered an alternative therapeutic option in patients for whom systemic antifungal agents are contraindicated. ( J Am Acad Dermatol 2014;70:918-23.) Key words: fractional laser; laser therapy; onychomycosis.

nychomycosis is a common fungal infection of the nail. More than just a cosmetic concern, onychomycosis can lead to infections of the toes and cause considerable pain, especially in older, diabetic, or immunocompromised patients.1 The most common therapeutic options are systemic and topical antifungal agents1; however, oral antifungals are associated with adverse effects that can cause patients to discontinue treatment, which may be complicated by the presence of comorbid conditions.1 Furthermore, topical agents have low efficacy because of their limited ability to

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penetrate the nail plate and reach the affected nail bed.1,2 Thus, new therapies that broaden the treatment options and reduce side effects for patients are needed.1,2 Lasers have become a popular option in the treatment of onychomycosis.2 Laser or light systems that have been investigated for this indication include carbon dioxide (CO2),3 neodymium:yttrium-aluminum-garnet,4,5 870/930-nm dual wavelength,6,7 ultraviolet light, and photodynamic therapy.8,9 The CO2 laser system is the oldest of the laser therapies for onychomycosis.3 It is ablative in

From the Department of Dermatology, School of Medicine, Chungnam National University, Daejeona; and Departments of Statistics, College of Business and Economics, Korea University, Seoul.b Supported by a grant from the Korea Ministry of Health and Welfare (A091121). Conflicts of interest: None declared. Accepted for publication January 19, 2014.

Reprint requests: Myung Im, MD, Department of Dermatology, School of Medicine, Chungnam National University, 33-Munhwa-ro, Daejeon, 301-747, Korea. E-mail: im1177@ hanmail.net. Published online March 20, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.01.893

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nature and therefore can serve as a primary treatment were not candidates for oral antifungal therapy for onychomycosis or as an adjunct to topical because of drug interactions with other internal antifungals, providing a means of penetration medicines or a history of liver or kidney disease. In through the nail plate to the nail bed.3,10 However, addition, all patients had failed to improve on only this approach takes considerable time to perform, topical amorolfine cream for several weeks (mean requires a digital block, and is associated with the duration 8 weeks, range 4-17 weeks). Exclusion same postoperative pain as surgical avulsion of the criteria included systemic antifungal treatment durnail.3,10 ing the previous 6 months, and concomitant nail disRecently, the use of a CAPSULE SUMMARY ease, eg, psoriasis, lichen fractional CO2 laser to treat planus, or atopic dermatitis. various dermatologic condiOnychomycosis is difficult to treat and is Demographic data such as tions was investigated, espeassociated with a high rate of age, sex, duration before cially for scar and skin persistence or recurrence. treatment, type of onychoresurfacing.11 This laser Fractional carbon-dioxide laser therapy is mycosis, and medical history creates multiple columns of a promising adjunctive treatment option were collected before destruction in the tissue, for onychomycosis. enrollment in the study. In called microscopic treatment addition, we measured the zones.11 The fractional CO2 This study showed that fractional initial thickness of the laser system has been develcarbon-dioxide laser therapy combined nail plate using a micro oped that uses fractional with a topical cream was efficacious in caliper (Mitutoyo Corp, laser technology to maximize the treatment of onychomycosis. Kawasaki, Japan). This study the effect of ablative laser was approved by the therapies and minimize side Institutional Review Board of Chungnam National effects.11,12 University Hospital, Daejeon, Korea. All subjects The purpose of this study was to evaluate the provided written informed consent before particitreatment of onychomycosis using a fractional CO2 pating in the study. laser and topical antifungal agent. To our knowledge, this is the first report on the efficacy of fractional CO2 lasers for the treatment of Treatment onychomycosis. All patients were treated with an ablative fracd

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METHODS Patients In all, 24 patients were enrolled in this prospective clinical trial. Participants were chosen from patients who had dystrophic nails that were clinically consistent with a fungal infection. To qualify for enrollment, subungual debris from the involved nail plate was obtained by using a small curette and then direct microscopy using 15% potassium hydroxide confirmed the fungal infection. All patients

tional CO2 laser (Mosaic eCO2 Laser, Lutronic Corp, Goyang, Korea) and daily topical amorolfine cream (Loceryl, Galderma, Lausanne, Switzerland). Fractional CO2 laser treatment consisted of 3 sessions at 4-week intervals. After 30 minutes of topical anesthesia (EMLA, AstraZeneca, Wilmington, DE) on periungual skin, treatment was performed with a pulse energy of 160 mJ and a density of 150 spots/ cm2. Treatment parameters were determined by investigator experience. Depending on the severity of the lesions, 2 or 3 passes at the same site were

Fig 1. Nails before (A) and immediately after (B) the first ablative fractional carbon-dioxide laser therapy. The treated nail had multiple pinholes in the infected area.

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Fig 2. Comparison of nails before treatment and at the last visit. There was substantial improvement in the nails after the last treatment episode. In each set of images, one photograph was taken at baseline (left) whereas the other was taken at 3 months after 3 treatment sessions (right). Images of the great toenail, with the following clinical types: total dystrophic onychomycosis (TDO) (A), distolateral subungual onychomycosis (DLSO) (B), and superficial white onychomycosis (SWO) (C). Images of the other toenails, with the following clinical types: TDO (D), DLSO (E), and SWO (F).

performed in static operating mode over the affected area including 1-mm normal-appearing areas close to them (Fig 1). Immediately after laser treatment, the postoperative wounds were managed with ice gauze for 5 to 10 minutes. Finally, patients were instructed to use topical amorolfine cream once a day immediately after laser treatment.

Outcome assessment The treatment efficacy was assessed based on clinical and mycologic improvement. Standardized photographs were obtained at baseline and at 4, 8, 12, and 24 weeks after the start of therapy using a digital single-lens reflex camera (EOS5D, Canon KK, Tokyo, Japan). Images of the affected nail were

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Fig 3. Clinical effect of treatment for onychomycosis. A continuous decrease in the toenail infection was detected at each visit. The relative area of the infected toenail was significantly reduced compared with the baseline area (*P \ .05 vs baseline).

captured and measurements were obtained using IMT i-solution software (IMT i-solution Inc, Vancouver, British Columbia, Canada). The overall treatment efficacy was determined by comparing the infected area at baseline and 12 weeks. It was analyzed in 4 grades as follows: complete response (fully normal-appearing nail measured from the proximal nailfold to involved nail), significant response ([60% normal-appearing nail compared with the area of the initially infected nail), moderate response (20%-60% normal-appearing nail), and no response (\20% normal-appearing nail). If there was a complete response, a direct microscopic examination was performed using potassium hydroxide and fungal culture. Clinical and mycologic evaluations were performed by the same investigators at 3 months after the last treatment. At the end of the study, the patients documented their degree of satisfaction as very satisfied, satisfied, slightly satisfied, or unsatisfied. Patients were also asked to report any treatment side effects and pain scores using 10-cm visual analog scales from 0 (no pain) to 10 (extremely painful). Statistical analysis The data were analyzed using the x 2 test, Fisher exact test, and Mann-Whitney test. P values of less than.05 were considered to be significant.

RESULTS A total of 24 patients (16 female, 8 male) with an average age of 55.79 years (range, 29-68 years) were enrolled in this study. Although all patients had documented fungal infection based on potassium

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hydroxide examination of subungual debris at enrollment, 12 of these patients had samples submitted for fungal culture at enrollment. Cultures revealed 10 cases of Trichophyton rubrum, 1 case of Trichophyton mentagrophytes, and 1 case of Epidermophyton floccosum. The mean duration of the disease was 9.56 years (range, 1.5-19 years). The total number of affected nails was 119, with an average of 4.96 nails per person. The involved nails were divided into 4 infection types: distolateral subungual onychomycosis, total dystrophic onychomycosis, proximal subungual onychomycosis, and superficial white onychomycosis (SWO). Of the 24 patients, 14 presented with distolateral subungual onychomycosis, 6 with total dystrophic onychomycosis, 4 with SWO, and 0 with proximal subungual onychomycosis. The initial thickness of the nail plate was 2.27 mm (range, 1.1-4.4 mm). None of the patients were able to take an oral antifungal because of an underlying systemic disorder, drug interaction, side effects, or breast-feeding. Two patients who did not respond to oral antifungal treatment were also included. Significant clinical improvement was observed. Visually, the appearance of most of the treated nails improved substantially compared with at baseline (Fig 2). In addition, the area of the infected toenail was significantly decreased at each follow-up visit. The mean infected area after the final treatment was reduced to 19.4% compared with baseline (Fig 3). A total of 22 patients (92%) showed a clinical response, whereas 12 patients (50%) showed a complete response with a negative microscopic result. Only 2 patients (8%) showed no improvement after final treatment (Fig 4). In all of the patients showing a complete response, there was no clinical or mycologic recurrence at 3 months after the last treatment. The level of patient satisfaction was similar to the clinical results. Of the patients, 59% were ‘‘very satisfied’’ after treatment; only 8% were ‘‘not satisfied’’ (Fig 5). There was no immediate bleeding or oozing after treatment. The treatments were well tolerated by most patients; the mean visual analog scale score for pain was 2.9. Although some patients experienced mild pain during laser treatment, there were no adverse events reported during the observation period. Factors that influenced treatment outcome were assessed. The 2 most significant factors were the clinical type of onychomycosis and the initial thickness before treatment. The response to therapy showed high variability among different clinical types of onychomycosis. All patients with SWO showed a complete response, but none of the patients with total dystrophic onychomycosis showed a complete response. In terms of the frequency of success according to the thickness of

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Table I. Results of response to the therapy according to influencing factors Total no.

Fig 4. Response rate after the last laser treatment. CR, Complete response; MR, moderate response; NR, no response; SR, significant response.

Age, y \60 $ 60 Sex Male Female Duration, y \10 $ 10 Involved nail, No. Great toenail Other toenail Type of fungus SWO DLSO TDO Initial thickness, mm \2.2 $ 2.2

CR, no.(%)

P value

13 11

8 (61.5) 4 (36.4)

.414

8 16

3 (37.5) 9 (56.3)

.667

12 12

1 (47.1) 4 (57.1)

1.000

40 179

11 (27.5) 61 (34.1)

.423

4 14 6 16 8

4 (100.0) 8 (57.1) — 12 (75.0) —

.005*

.001*

CR, Complete response; DLSO, distolateral subungual onychomycosis; SWO, superficial white onychomycosis; TDO, total dystrophic onychomycosis. *P \ .05.

Fig 5. Subjective evaluation of the treatment results by the patients. NS, Not satisfied; S, satisfied; SS, slightly satisfied; VS, very satisfied.

the nail plate before treatment, 75% of the patients with less than 2.2 mm showed a complete response, whereas none of the patients with more than 2.2 mm showed a complete response (Table I).

DISCUSSION Onychomycosis is difficult to treat, and it has high rates of recurrence.1,2 Treatment options for

onychomycosis have historically included topical and oral antifungals.1 Topical therapies are limited by low efficacy because of subtherapeutic concentrations of antifungal medication reaching the nail bed.1,2 Systemic antifungals are also limited in their use because of drug interactions and systemic adverse reactions.1,2 In recent years, many laser systems have become available to physicians and patients who are interested in improving the appearance of discolored and dystrophic nails secondary to onychomycosis.2 Photodynamic therapy8,9 and the neodymium: yttrium-aluminum-garnet2,4,5,13,14 laser have been evaluated in vivo and ex vivo and have demonstrated some success showing 41% to 95% mycologic cure rate. To our knowledge, there have been no studies to date evaluating the practical efficacy of ablative fractional lasers in the treatment of onychomycosis. Using a standard CO2 laser to totally ablate a nail is little different from nail avulsion followed by topical antifungal treatment.10 Although effective (33%-75% mycologic cure rate),10,15 these approaches require local anesthesia and are painful for weeks after the procedure. The ablative fractional CO2 laser provides short recovery times and decreased pain compared with traditional, continuous CO2 lasers.11 Fractional CO2 laser therapy creates columns of destruction down to

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the dermis, called microscopic treatment zones; therefore, this therapy is usually used for resurfacing to improve the appearance from photoaging, or it is often used to enhance the penetration of topical agents.11,12 The mechanism of action of fractional CO2 laser therapy in onychomycosis is unknown. However, we hypothesize that the tissue ablation process induces direct fungicidal effects and that the multiple columns created by the laser enhance the penetration of topical antifungal agents into the nail bed or matrix. Ablative fractional CO2 laser therapy proved to be efficacious for most patients with onychomycosis included this study. The relative area of the infected toenail decreased significantly at each follow-up visit, and 92% of the patients showed a clinical response. Ultimately, 50% of the patients showed a complete response with a negative microscopic result and no recurrence within 3 months. Puncturing the targeted nails with a fractional CO2 laser is quick, associated with minimal pain during and after the procedure, and required only 3 sessions of treatment to obtain an excellent result in the majority of patients. All of the patients in this study applied the topical anesthetic cream to prevent pain in periungual skin from unexpected injury during treatment for the edge of the nail plate. To understand the patient benefits of fractional CO2 laser therapy, we investigated the factors that influenced the therapeutic efficacy. Our analysis showed that SWO and an initial thickness of less than 2.2 mm were the best predictors of a complete response. Therefore, fractional CO2 laser treatment is very effective for patients with SWO and a thickness of less than 2.2 mm. Our study is limited by lack of controls. However, studies examining monotherapy with topical antifungal cream for onychomycosis have been disappointing except in a very mild case.16 The cure rates among several nail lacquers/solutions available for onychomycosis highly variable (amorolfine monotherapy is 12%-71% and ciclopirox olamine is around 9%-31.3%).16 Our patients also were treated by topical monotherapy before laser treatment. All patients had failed to improve with topical therapy for their onychomycosis, before undergoing combined therapy with fractional CO2 laser and topical amorolfine. To our knowledge, this is the first study of the use of ablative fractional laser therapy for the treatment of onychomycosis. The combination of this laser and a topical antifungal appears to be an effective, safe, and convenient treatment modality for patients in whom oral antifungal treatments are contraindicated or ineffective. A well-designed study with a longer

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follow-up period to compare the effectiveness of monotherapy with topical antifungal, monotherapy with fractionated laser, and the combination of fractionated laser and topical antifungal therapy is warranted at this point. Determination of the optimal settings and duration of treatment will also require further study. REFERENCES 1. Ledon JA, Savas J, Franca K, Chacon A, Nouri K. Laser and light therapy for onychomycosis: a systematic review. Lasers Med Sci doi:10.1007/s10103-012-1232-y. Published online November 20, 2012. 2. Gupta AK, Simpson FC. Medical devices for the treatment of onychomycosis. Dermatol Ther 2012;25:574-81. 3. Apfelberg DB, Rothermel E, Widtfeldt A, Maser MR, Lash H. Preliminary report on use of carbon dioxide laser in podiatry. J Am Podiatry Assoc 1984;74:509-13. 4. Hochman LG. Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd:YAG 1064-nm laser. J Cosmet Laser Ther 2011;13:2-5. 5. Zhang RN, Wang DK, Zhuo FL, Duan XH, Zhang XY, Zhao JY. Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis. Chin Med J 2012;125:3288-91. 6. Landsman AS, Robbins AH, Angelini PF, Wu CC, Cook J, Oster M, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc 2010;100:166-77. 7. Landsman AS, Robbins AH. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure: some follow-up observations at 270 days. J Am Podiatr Med Assoc 2012;102:169-71. 8. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol 2008;59(Suppl):S75-6. 9. Sotiriou E, Koussidou-Eremonti T, Chaidemenos G, Apalla Z, Ioannides D. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: preliminary results of a single-center open trial. Acta Derm Venereol 2010;90:216-7. 10. Baden HP. Treatment of distal onychomycosis with avulsion and topical antifungal agents under occlusion. Arch Dermatol 1994;130:558-9. 11. Tierney EP, Eisen RF, Hanke CW. Fractionated CO2 laser skin rejuvenation. Dermatol Ther 2011;24:41-53. 12. Tierney EP, Hanke CW. Fractionated carbon dioxide laser treatment of photoaging: prospective study in 45 patients and review of the literature. Dermatol Surg 2011;37:1279-90. 13. Choi MJ, Zheng Z, Goo B, Cho SB. Antifungal effects of a 1444-nm neodymium:yttrium-aluminum-garnet laser on onychomycosis: a pilot study. J Dermatolog Treat 2014; 25:294-7. 14. Kimura U, Takeuchi K, Kinoshita A, Takamori K, Hiruma M, Suga Y. Treating onychomycoses of the toenail: clinical efficacy of the sub-millisecond 1,064 nm Nd: YAG laser using a 5 mm spot diameter. J Drugs Dermatol 2012;11:496-504. 15. Grover C, Bansal S, Nanda S, Reddy BS, Kumar V. Combination of surgical avulsion and topical therapy for single nail onychomycosis: a randomized controlled trial. Br J Dermatol 2007;157:364-8. 16. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol 2005;19:21-9.

Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream.

Traditional pharmacotherapy for onychomycosis has low to moderate efficacy and may be associated with adverse reactions and medication interactions li...
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