Letter - Therapy
Terbinafine as a successful treatment in primary cutaneous aspergillosis
Juan-Manuel Morón-Ocaña
, Isabel-María Coronel-Pérez, Elena-Margarita Rodríguez-Rey
Autor para correspondência
Department of Dermatology, Virgen de Valme Hospital, Sevilla, Spain
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2070
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(A) Histopatologia de pele. Coloração de Grocott (40<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>). Hifas septadas, com angulação, vesiculação e pseudo‐hifas. (B) Cultura microbiológica de amostra de pele em ágar dextrose. Colônias com porção central verde‐azulada circundada por borda espumosa esbranquiçada. (C) Microscopia de cultura microbiológica corada com azul de lactofenol. Hifas hialinas septadas com formas de reprodução típicas de <span class="elsevierStyleItalic">Aspergillus fumigatus</span>: cabeças aspergilares, com conidióforos lisos e regulares, e vesículas em forma de bastão, recobertas em seu terço superior por fiálides unisseriadas, originando conídios lisos e globosos.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan‐Manuel Morón Ocaña, Isabel‐María Coronel Pérez, Elena‐Margarita Rodríguez Rey" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Juan‐Manuel" "apellidos" => "Morón Ocaña" ] 1 => array:2 [ "nombre" => "Isabel‐María" "apellidos" => "Coronel Pérez" ] 2 => array:2 [ "nombre" => "Elena‐Margarita" "apellidos" => "Rodríguez Rey" ] ] ] ] ] "idiomaDefecto" => "pt" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0365059624000680" "doi" => "10.1016/j.abd.2023.07.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365059624000680?idApp=UINPBA00008Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2666275224000717?idApp=UINPBA00008Z" "url" => "/26662752/0000009900000004/v1_202406100414/S2666275224000717/v1_202406100414/pt/main.assets" ] ] "itemAnterior" => array:18 [ "pii" => "S0365059624000734" "issn" => "03650596" "doi" => "10.1016/j.abd.2023.05.010" "estado" => "S300" "fechaPublicacion" => "2024-07-01" "aid" => "944" "copyright" => "Sociedade Brasileira de Dermatologia" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter - Therapy</span>" "titulo" => "Successful treatment of rheumatoid neutrophilic panniculitis with tofacitinib" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "644" "paginaFinal" => "647" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1770 "Ancho" => 3008 "Tamanyo" => 351163 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Therapeutic response. (A) Lesion on the left external malleolus with ulceration and infiltrated edges. (B) After 60 days of treatment, the ulceration resolved, but part of the infiltrated edge persisting. (C) Complete resolution after 120 days.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Hiram Larangeira de Almeida Junior, Vitor Dias Furtado, Viviane Siena Issaacson, Ana Letícia Boff" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Hiram Larangeira de" "apellidos" => "Almeida Junior" ] 1 => array:2 [ "nombre" => "Vitor Dias" "apellidos" => "Furtado" ] 2 => array:2 [ "nombre" => "Viviane Siena" "apellidos" => "Issaacson" ] 3 => array:2 [ "nombre" => "Ana Letícia" "apellidos" => "Boff" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S2666275224000766" "doi" => "10.1016/j.abdp.2024.04.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2666275224000766?idApp=UINPBA00008Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365059624000734?idApp=UINPBA00008Z" "url" => "/03650596/0000009900000004/v2_202407191005/S0365059624000734/v2_202407191005/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter - Therapy</span>" "titulo" => "Terbinafine as a successful treatment in primary cutaneous aspergillosis" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "647" "paginaFinal" => "649" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan-Manuel Morón-Ocaña, Isabel-María Coronel-Pérez, Elena-Margarita Rodríguez-Rey" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juan-Manuel" "apellidos" => "Morón-Ocaña" "email" => array:1 [ 0 => "juanm.moron.sspa@juntadeandalucia.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Isabel-María" "apellidos" => "Coronel-Pérez" ] 2 => array:2 [ "nombre" => "Elena-Margarita" "apellidos" => "Rodríguez-Rey" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Dermatology, Virgen de Valme Hospital, Sevilla, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1825 "Ancho" => 2508 "Tamanyo" => 571859 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Physical exploration: (A) Initial physical exploration. Nodules with superficial exulceration in the lower third of the right leg of 0.5‒1 cm, coalescing with each other, forming 4‒5 cm plaques. (B) Physical exploration after 3-months of terbinafine. Residual hyperpigmentation on right left.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Aspergillus is a ubiquitous saprophytic mold in nature and is commonly found in soil water and decaying vegetation. The most common human pathogens include <span class="elsevierStyleItalic">A. fumigatus</span> (85%), <span class="elsevierStyleItalic">A. flavus</span> (5%‒10%) and <span class="elsevierStyleItalic">A. niger</span> (2%‒3%).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Aspergillosis usually occurs in immunocompromised hosts. Primary cutaneous aspergillosis (PCA) is a rare but life-threatening invasive fungal infection of the skin caused by <span class="elsevierStyleItalic">Aspergillus</span>. Due to its clinical heterogeneity, clinical suspicion should be high in immunosuppressed patients.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The literature is replete with reports of PCA, however there is not a single reported case treated with terbinafine in monotherapy.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A 74-year-old man presented for evaluation of a mass in his right leg for a year. He had been under tacrolimus, prednisone, and mycophenolate mofetil treatment since 2012 because of a renal transplant. The patient denied any previous trauma, but he had presented a torpid venous ulcer in the area. Physical examination revealed violaceous and skin-colored subcutaneous nodules with superficial exulceration in the lower third of the right leg (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). A skin biopsy was performed, and samples were sent to the pathology and microbiology labs.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The skin biopsy showed septate hyphae with right angulation and vesiculation (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). These structures corresponded to the growth of colonies composed of <span class="elsevierStyleItalic">Aspergillus fumigatus</span> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B‒C). Blood cultures, galactomannan antigen test, and a chest-abdominal CT scan were performed. The results of all tests were negative. After rejecting systemic involvement, the patient was definitively diagnosed with PCA.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Oral isavuconazole was started but it was suspended because of an important elevation of tacrolimus plasma levels. After that, the patient started terbinafine 250 mg/24h. The lesions disappeared leaving only residual hyperpigmentation after 3 months of treatment (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The presence of two negative cultures separated from each other by 3 months confirmed the resolution of the infection.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Currently, there are four classes of antifungal agents with activity against <span class="elsevierStyleItalic">Aspergillus</span>: 1) The polyenes, such as amphotericin B deoxycholate and nystatin, 2) The triazoles, including itraconazole, voriconazole, isavuconazole; 3) The echinocandins, such as caspofungin and micafungin and 4) The allylamines such as terbinafine.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Until the early 1990s, amphotericin B deoxycholate was the only agent that was available for the management of this infection. However, the significant toxicities associated with this agent made it less attractive with the introduction of newer agents such as the triazoles and the echinocandins, which are much better tolerated.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Among these, isavuconazole proved to be superior in terms of response, toxicity and overall survival.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, triazoles have been found to have inhibitory effects on hepatic cytochrome P450.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The inhibition of the cytochrome P450 can produce an important elevation of plasmatic levels of drugs that are metabolized by this route and can cause significant toxicities, as has happened with the tacrolimus that our patient was taking.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The other antifungals classically effective against <span class="elsevierStyleItalic">A. fumigatus</span> could also have had side effects on our patient. Amphotericin B deoxycholate is highly nephrotoxic and could have increased the nephrotoxicity in a kidney recipient transplant.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> On the other hand, using caspofungin together with tacrolimus may have decreased the plasma levels of tacrolimus,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> increasing the risk of kidney transplant loss.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although it has been well-known for years that terbinafine is effective in vitro in aspergillosis, there are no published cases that have clinically demonstrated its efficacy in vivo. Importantly, because of its poor penetration in deep tissues, terbinafine is almost exclusively indicated for skin and nail infections.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Schmitt et al. demonstrated that concentrations between 0.8‒1.6 μg/mL of terbinafine are sufficient to reach the Minimum Inhibitory and Fungicide Concentration (MIC and MFC) against <span class="elsevierStyleItalic">A. fumigatus</span> in a vitro study.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> As claimed by its fact sheet, a 250 mg single dose of terbinafine (standard dose marketed) is able to reach a serum concentration from 0.8 to 1.5 μg/mL two hours later after ingesting the pill.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Terbinafine can also penetrate excellently from blood to skin according to its pharmacokinetics.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> As the concentration of terbinafine that is reached in plasma is very similar to the MIC of <span class="elsevierStyleItalic">Aspergillus</span>, terbinafine in monotherapy demonstrates good activity against <span class="elsevierStyleItalic">Aspergillus spp.</span> in the skin.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Although further investigation is required, this unique case evidence that PCA could successfully be treated by terbinafine.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0065" class="elsevierStylePara elsevierViewall">None declared.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors’ contributions</span><p id="par0070" class="elsevierStylePara elsevierViewall">Juan Manuel Morón Ocaña: Preparation and writing of the manuscript; critical literature review.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Isabel María Coronel Pérez: Approval of the final version of the manuscript; manuscript critical review.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Elena-Margarita Rodríguez Rey: Approval of the final version of the manuscript; manuscript critical review.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">None declared.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financial support" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Authors’ contributions" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflicts of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-06-15" "fechaAceptado" => "2023-07-10" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "⋆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Study conducted at the Department of Dermatology, Hospital Universitario Virgen de Valme, Sevilla, Spain.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1825 "Ancho" => 2508 "Tamanyo" => 571859 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Physical exploration: (A) Initial physical exploration. Nodules with superficial exulceration in the lower third of the right leg of 0.5‒1 cm, coalescing with each other, forming 4‒5 cm plaques. (B) Physical exploration after 3-months of terbinafine. Residual hyperpigmentation on right left.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1278 "Ancho" => 3341 "Tamanyo" => 774852 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Supplementary tests: (A) Skin biopsy, (Groccot, 40×). Septate hyphae, with right angulation, vesiculation and pseudohyphae. (B) Microbiological culture of skin biopsy on dextrose agar. Colonies composed of a bluish-green central portion surrounded by a whitish foamy edge. (C) Lactophenol blue stained microscopy of microbiological culture. Septate hyaline hyphae were found with typical reproduction forms of <span class="elsevierStyleItalic">Aspergillus fumigatus</span>: aspergilate heads, with smooth and regular conidiophores, club-shaped vesicles covered in their upper third by uniseriad phialides that gave rise to smooth and globose conidia.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aspergillosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B.H. 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| Ano/Mês | Html | Total | |
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