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    "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&#46; The most common human pathogens include <span class="elsevierStyleItalic">A&#46; fumigatus</span> &#40;85&#37;&#41;&#44; <span class="elsevierStyleItalic">A&#46; flavus</span> &#40;5&#37;&#8210;10&#37;&#41; and <span class="elsevierStyleItalic">A&#46; niger</span> &#40;2&#37;&#8210;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Aspergillosis usually occurs in immunocompromised hosts&#46; Primary cutaneous aspergillosis &#40;PCA&#41; is a rare but life-threatening invasive fungal infection of the skin caused by <span class="elsevierStyleItalic">Aspergillus</span>&#46; Due to its clinical heterogeneity&#44; clinical suspicion should be high in immunosuppressed patients&#46;<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&#44; however there is not a single reported case treated with terbinafine in monotherapy&#46;</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&#46; He had been under tacrolimus&#44; prednisone&#44; and mycophenolate mofetil treatment since 2012 because of a renal transplant&#46; The patient denied any previous trauma&#44; but he had presented a torpid venous ulcer in the area&#46; Physical examination revealed violaceous and skin-colored subcutaneous nodules with superficial exulceration in the lower third of the right leg &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A skin biopsy was performed&#44; and samples were sent to the pathology and microbiology labs&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The skin biopsy showed septate hyphae with right angulation and vesiculation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; These structures corresponded to the growth of colonies composed of <span class="elsevierStyleItalic">Aspergillus fumigatus</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8210;C&#41;&#46; Blood cultures&#44; galactomannan antigen test&#44; and a chest-abdominal CT scan were performed&#46; The results of all tests were negative&#46; After rejecting systemic involvement&#44; the patient was definitively diagnosed with PCA&#46;</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&#46; After that&#44; the patient started terbinafine 250&#8239;mg&#47;24h&#46; The lesions disappeared leaving only residual hyperpigmentation after 3 months of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The presence of two negative cultures separated from each other by 3 months confirmed the resolution of the infection&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Currently&#44; there are four classes of antifungal agents with activity against <span class="elsevierStyleItalic">Aspergillus</span>&#58; 1&#41; The polyenes&#44; such as amphotericin B deoxycholate and nystatin&#44; 2&#41; The triazoles&#44; including itraconazole&#44; voriconazole&#44; isavuconazole&#59; 3&#41; The echinocandins&#44; such as caspofungin and micafungin and 4&#41; The allylamines such as terbinafine&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Until the early 1990s&#44; amphotericin B deoxycholate was the only agent that was available for the management of this infection&#46; However&#44; the significant toxicities associated with this agent made it less attractive with the introduction of newer agents such as the triazoles and the echinocandins&#44; which are much better tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Among these&#44; isavuconazole proved to be superior in terms of response&#44; toxicity and overall survival&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; triazoles have been found to have inhibitory effects on hepatic cytochrome P450&#46;<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&#44; as has happened with the tacrolimus that our patient was taking&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The other antifungals classically effective against <span class="elsevierStyleItalic">A&#46; fumigatus</span> could also have had side effects on our patient&#46; Amphotericin B deoxycholate is highly nephrotoxic and could have increased the nephrotoxicity in a kidney recipient transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> On the other hand&#44; using caspofungin together with tacrolimus may have decreased the plasma levels of tacrolimus&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> increasing the risk of kidney transplant loss&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although it has been well-known for years that terbinafine is effective in vitro in aspergillosis&#44; there are no published cases that have clinically demonstrated its efficacy in vivo&#46; Importantly&#44; because of its poor penetration in deep tissues&#44; terbinafine is almost exclusively indicated for skin and nail infections&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Schmitt et al&#46; demonstrated that concentrations between 0&#46;8&#8210;1&#46;6&#8239;&#956;g&#47;mL of terbinafine are sufficient to reach the Minimum Inhibitory and Fungicide Concentration &#40;MIC and MFC&#41; against <span class="elsevierStyleItalic">A&#46; fumigatus</span> in a vitro study&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> As claimed by its fact sheet&#44; a 250&#8239;mg single dose of terbinafine &#40;standard dose marketed&#41; is able to reach a serum concentration from 0&#46;8 to 1&#46;5&#8239;&#956;g&#47;mL two hours later after ingesting the pill&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Terbinafine can also penetrate excellently from blood to skin according to its pharmacokinetics&#46;<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>&#44; terbinafine in monotherapy demonstrates good activity against <span class="elsevierStyleItalic">Aspergillus spp&#46;</span> in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Although further investigation is required&#44; this unique case evidence that PCA could successfully be treated by terbinafine&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0065" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#8217; contributions</span><p id="par0070" class="elsevierStylePara elsevierViewall">Juan Manuel Mor&#243;n Oca&#241;a&#58; Preparation and writing of the manuscript&#59; critical literature review&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Isabel Mar&#237;a Coronel P&#233;rez&#58; Approval of the final version of the manuscript&#59; manuscript critical review&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Elena-Margarita Rodr&#237;guez Rey&#58; Approval of the final version of the manuscript&#59; manuscript critical review&#46;</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&#46;</p></span></span>"
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Letter - Therapy
Terbinafine as a successful treatment in primary cutaneous aspergillosis
Juan-Manuel Morón-Ocaña
Corresponding author
, Isabel-María Coronel-Pérez, Elena-Margarita Rodríguez-Rey
Department of Dermatology, Virgen de Valme Hospital, Sevilla, Spain
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    "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&#46; The most common human pathogens include <span class="elsevierStyleItalic">A&#46; fumigatus</span> &#40;85&#37;&#41;&#44; <span class="elsevierStyleItalic">A&#46; flavus</span> &#40;5&#37;&#8210;10&#37;&#41; and <span class="elsevierStyleItalic">A&#46; niger</span> &#40;2&#37;&#8210;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Aspergillosis usually occurs in immunocompromised hosts&#46; Primary cutaneous aspergillosis &#40;PCA&#41; is a rare but life-threatening invasive fungal infection of the skin caused by <span class="elsevierStyleItalic">Aspergillus</span>&#46; Due to its clinical heterogeneity&#44; clinical suspicion should be high in immunosuppressed patients&#46;<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&#44; however there is not a single reported case treated with terbinafine in monotherapy&#46;</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&#46; He had been under tacrolimus&#44; prednisone&#44; and mycophenolate mofetil treatment since 2012 because of a renal transplant&#46; The patient denied any previous trauma&#44; but he had presented a torpid venous ulcer in the area&#46; Physical examination revealed violaceous and skin-colored subcutaneous nodules with superficial exulceration in the lower third of the right leg &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A skin biopsy was performed&#44; and samples were sent to the pathology and microbiology labs&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The skin biopsy showed septate hyphae with right angulation and vesiculation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; These structures corresponded to the growth of colonies composed of <span class="elsevierStyleItalic">Aspergillus fumigatus</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8210;C&#41;&#46; Blood cultures&#44; galactomannan antigen test&#44; and a chest-abdominal CT scan were performed&#46; The results of all tests were negative&#46; After rejecting systemic involvement&#44; the patient was definitively diagnosed with PCA&#46;</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&#46; After that&#44; the patient started terbinafine 250&#8239;mg&#47;24h&#46; The lesions disappeared leaving only residual hyperpigmentation after 3 months of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The presence of two negative cultures separated from each other by 3 months confirmed the resolution of the infection&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Currently&#44; there are four classes of antifungal agents with activity against <span class="elsevierStyleItalic">Aspergillus</span>&#58; 1&#41; The polyenes&#44; such as amphotericin B deoxycholate and nystatin&#44; 2&#41; The triazoles&#44; including itraconazole&#44; voriconazole&#44; isavuconazole&#59; 3&#41; The echinocandins&#44; such as caspofungin and micafungin and 4&#41; The allylamines such as terbinafine&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Until the early 1990s&#44; amphotericin B deoxycholate was the only agent that was available for the management of this infection&#46; However&#44; the significant toxicities associated with this agent made it less attractive with the introduction of newer agents such as the triazoles and the echinocandins&#44; which are much better tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Among these&#44; isavuconazole proved to be superior in terms of response&#44; toxicity and overall survival&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; triazoles have been found to have inhibitory effects on hepatic cytochrome P450&#46;<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&#44; as has happened with the tacrolimus that our patient was taking&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The other antifungals classically effective against <span class="elsevierStyleItalic">A&#46; fumigatus</span> could also have had side effects on our patient&#46; Amphotericin B deoxycholate is highly nephrotoxic and could have increased the nephrotoxicity in a kidney recipient transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> On the other hand&#44; using caspofungin together with tacrolimus may have decreased the plasma levels of tacrolimus&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> increasing the risk of kidney transplant loss&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although it has been well-known for years that terbinafine is effective in vitro in aspergillosis&#44; there are no published cases that have clinically demonstrated its efficacy in vivo&#46; Importantly&#44; because of its poor penetration in deep tissues&#44; terbinafine is almost exclusively indicated for skin and nail infections&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Schmitt et al&#46; demonstrated that concentrations between 0&#46;8&#8210;1&#46;6&#8239;&#956;g&#47;mL of terbinafine are sufficient to reach the Minimum Inhibitory and Fungicide Concentration &#40;MIC and MFC&#41; against <span class="elsevierStyleItalic">A&#46; fumigatus</span> in a vitro study&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> As claimed by its fact sheet&#44; a 250&#8239;mg single dose of terbinafine &#40;standard dose marketed&#41; is able to reach a serum concentration from 0&#46;8 to 1&#46;5&#8239;&#956;g&#47;mL two hours later after ingesting the pill&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Terbinafine can also penetrate excellently from blood to skin according to its pharmacokinetics&#46;<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>&#44; terbinafine in monotherapy demonstrates good activity against <span class="elsevierStyleItalic">Aspergillus spp&#46;</span> in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Although further investigation is required&#44; this unique case evidence that PCA could successfully be treated by terbinafine&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0065" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#8217; contributions</span><p id="par0070" class="elsevierStylePara elsevierViewall">Juan Manuel Mor&#243;n Oca&#241;a&#58; Preparation and writing of the manuscript&#59; critical literature review&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Isabel Mar&#237;a Coronel P&#233;rez&#58; Approval of the final version of the manuscript&#59; manuscript critical review&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Elena-Margarita Rodr&#237;guez Rey&#58; Approval of the final version of the manuscript&#59; manuscript critical review&#46;</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&#46;</p></span></span>"
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ISSN: 03650596
Original language: English
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