Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy

Abstract

To the Editor: Onychomycosis by nondermatophyte molds (NDM) is uncommon with prevalence rates ranging from 1.45% to 17.6%.1Tosti A. Piraccini B.M. Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases.J Am Acad Dermatol. 2000; 42: 217-224Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Moreover, NDM onychomycosis is especially difficult to cure using standard topical or systemic antifungal therapy.2Baudraz-Rosselet F. Ruffieux C. Lurati M. Bontems O. Monod M. Onychomycosis insensitive to systemic terbinafine and azole treatments reveals non-dermatophyte moulds as infectious agents.Dermatology. 2010; 220: 164-168Crossref PubMed Scopus (61) Google Scholar We present two cases of refractory NDM fingernail onychomycosis that were completely cured by methylaminolevulinate (MAL)-photodynamic therapy (PDT).Case 1. A 44-year-old woman presented with onychomycosis of her left hand fourth fingernail for more than 2 years. She had been treated with amorolfine and ciclopirox lacquers as well as oral terbinafine and itraconazole without success (Fig 1, A). Four nail samples were taken and Fusarium oxysporum was isolated from all of them.Case 2. A 60-year-old woman, with medical history of left hemiplegia, had onychomycosis on her 5 right fingernails for the last 5 years (Fig 2, A). She had been treated several times with topical and oral antifungal drugs without improvement. Six different samples were taken during those years and Aspergillus terreus was recovered from all of them.Fig 2White onychomycosis of left hand nails caused by Aspergillus terreus. Before (A) and 6 months after (B) treatment (3 sessions, 2 weeks apart of photodynamic therapy with methylaminolevulinate and Aktilite [Photocure ASA, Oslo, Norway; 37 J/cm2]): resolution of infection.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The diagnosis of NDM onychomycosis was made based on the criteria proposed by Tosti et al.1Tosti A. Piraccini B.M. Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases.J Am Acad Dermatol. 2000; 42: 217-224Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar No dermatophytes were isolated from any of the nail samples.Considering the failure of conventional therapy for onychomycosis, we proposed the use of PDT and followed the modified protocol of Piraccini et al3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar (Table I). First of all, the nail plate was softened with 40% ointment urea under occlusion for 12 hours. Next MAL 16% cream (Metvix, Galderma, La Défense Cedex, France) was applied on the nail plate and the periungual areas under an occlusive dressing (Tegaderm, 3M Healthcare, St. Paul, MN) and protected from the light for 4 hours. The Wood lamp showed light red fluorescence only on paronychia areas. After that, the nails were illuminated using a 635-nm LED (Aktilite, Photocure ASA, Oslo, Norway; 37 J/cm2). No side effects were observed except for pain in one session during illumination, probably caused by the accidental application of urea ointment on the periungual skin allowing a higher penetration of MAL. After the first session, clinical improvement was remarkable and cultures were negative; nevertheless, two more sessions, 2 weeks apart were administered. Six months later, the patients were clinically and microbiologically cured according to the standard criteria4Scher R.K. Tavakkol A. Sigurgeirsson B. Hay R.J. Joseph W.S. Tosti A. et al.Onychomycosis: diagnosis and definition of cure.J Am Acad Dermatol. 2007; 56: 939-944Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar (Fig 1, B) except for minimal clinical yellowish discoloration persisting in the fourth and fifth fingernails of case 2 (Fig 2, B). After 6 months of follow-up, recurrences were not detected.Table IMethylaminolevulinate–photodynamic therapy protocol for fingernail onychomycosis1. 40% Urea ointment was applied under occlusion for 12 h (if intense hyperkeratosis is present, this process can be performed several nights before photodynamic therapy)2. Alcohol cleaning3. Apply Metvix (Galderma, La Défense Cedex, France) on nail plate and periungual areas under occlusive dressing (Tegaderm, 3M Healthcare, St. Paul, MN)4. Protect from light and incubate for 4 h5. Illuminate with LED 635 nm (Aktilite, Photocure ASA, Oslo, Norway) with fluence of 37 J/cm26. Protect area from light for 24 h7. Same protocol is repeated 3 times every 2 wk Open table in a new tab Although PDT with MAL has been previously shown to be effective in toenail tinea unguium,3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar cases of NDM onychomycosis treated with PDT have not been reported. The fact that MAL-PDT has not been proved to be active in vitro against molds adds value to our clinical report. Related to the mechanism of action of MAL-PDT in onychomycosis, it has been proved that the application of topical aminolevulinic acid (ALA) in occlusion on the nail surface leads to a significant concentration on its ventral side.5Donnelly R.F. McCarron P.A. Lightowler J.M. Woolfson A.D. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis.J Control Release. 2005; 103: 381-392Crossref PubMed Scopus (99) Google Scholar However, clinical results obtained by ALA-PDT in tinea unguium have not been so satisfactory, perhaps because of the short ALA incubation time (3 hours).6Watanabe D. Kawamura C. Masuda Y. Akita Y. Tamada Y. Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy.Arch Dermatol. 2008; 144: 19-21Crossref PubMed Scopus (90) Google Scholar, 7Sotiriou E. Koussidou-Ermonti 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: 216-217Crossref PubMed Scopus (105) Google ScholarIn conclusion, our experience supports the use of MAL-PDT for NDM onychomycosis, because of its efficacy and lack of significant side effects. We are proposing a modification of the protocol of Piraccini et al3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar for the treatment of fingernail NDM onychomycosis. However, clinical trials are needed to confirm these findings and establish a standard protocol. To the Editor: Onychomycosis by nondermatophyte molds (NDM) is uncommon with prevalence rates ranging from 1.45% to 17.6%.1Tosti A. Piraccini B.M. Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases.J Am Acad Dermatol. 2000; 42: 217-224Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Moreover, NDM onychomycosis is especially difficult to cure using standard topical or systemic antifungal therapy.2Baudraz-Rosselet F. Ruffieux C. Lurati M. Bontems O. Monod M. Onychomycosis insensitive to systemic terbinafine and azole treatments reveals non-dermatophyte moulds as infectious agents.Dermatology. 2010; 220: 164-168Crossref PubMed Scopus (61) Google Scholar We present two cases of refractory NDM fingernail onychomycosis that were completely cured by methylaminolevulinate (MAL)-photodynamic therapy (PDT). Case 1. A 44-year-old woman presented with onychomycosis of her left hand fourth fingernail for more than 2 years. She had been treated with amorolfine and ciclopirox lacquers as well as oral terbinafine and itraconazole without success (Fig 1, A). Four nail samples were taken and Fusarium oxysporum was isolated from all of them. Case 2. A 60-year-old woman, with medical history of left hemiplegia, had onychomycosis on her 5 right fingernails for the last 5 years (Fig 2, A). She had been treated several times with topical and oral antifungal drugs without improvement. Six different samples were taken during those years and Aspergillus terreus was recovered from all of them. The diagnosis of NDM onychomycosis was made based on the criteria proposed by Tosti et al.1Tosti A. Piraccini B.M. Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases.J Am Acad Dermatol. 2000; 42: 217-224Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar No dermatophytes were isolated from any of the nail samples. Considering the failure of conventional therapy for onychomycosis, we proposed the use of PDT and followed the modified protocol of Piraccini et al3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar (Table I). First of all, the nail plate was softened with 40% ointment urea under occlusion for 12 hours. Next MAL 16% cream (Metvix, Galderma, La Défense Cedex, France) was applied on the nail plate and the periungual areas under an occlusive dressing (Tegaderm, 3M Healthcare, St. Paul, MN) and protected from the light for 4 hours. The Wood lamp showed light red fluorescence only on paronychia areas. After that, the nails were illuminated using a 635-nm LED (Aktilite, Photocure ASA, Oslo, Norway; 37 J/cm2). No side effects were observed except for pain in one session during illumination, probably caused by the accidental application of urea ointment on the periungual skin allowing a higher penetration of MAL. After the first session, clinical improvement was remarkable and cultures were negative; nevertheless, two more sessions, 2 weeks apart were administered. Six months later, the patients were clinically and microbiologically cured according to the standard criteria4Scher R.K. Tavakkol A. Sigurgeirsson B. Hay R.J. Joseph W.S. Tosti A. et al.Onychomycosis: diagnosis and definition of cure.J Am Acad Dermatol. 2007; 56: 939-944Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar (Fig 1, B) except for minimal clinical yellowish discoloration persisting in the fourth and fifth fingernails of case 2 (Fig 2, B). After 6 months of follow-up, recurrences were not detected. Although PDT with MAL has been previously shown to be effective in toenail tinea unguium,3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar cases of NDM onychomycosis treated with PDT have not been reported. The fact that MAL-PDT has not been proved to be active in vitro against molds adds value to our clinical report. Related to the mechanism of action of MAL-PDT in onychomycosis, it has been proved that the application of topical aminolevulinic acid (ALA) in occlusion on the nail surface leads to a significant concentration on its ventral side.5Donnelly R.F. McCarron P.A. Lightowler J.M. Woolfson A.D. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis.J Control Release. 2005; 103: 381-392Crossref PubMed Scopus (99) Google Scholar However, clinical results obtained by ALA-PDT in tinea unguium have not been so satisfactory, perhaps because of the short ALA incubation time (3 hours).6Watanabe D. Kawamura C. Masuda Y. Akita Y. Tamada Y. Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy.Arch Dermatol. 2008; 144: 19-21Crossref PubMed Scopus (90) Google Scholar, 7Sotiriou E. Koussidou-Ermonti 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: 216-217Crossref PubMed Scopus (105) Google Scholar In conclusion, our experience supports the use of MAL-PDT for NDM onychomycosis, because of its efficacy and lack of significant side effects. We are proposing a modification of the protocol of Piraccini et al3Piraccini B.M. Rech G. Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum.J Am Acad Dermatol. 2008; 59: S75-S76Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar for the treatment of fingernail NDM onychomycosis. However, clinical trials are needed to confirm these findings and establish a standard protocol.