e-Case Report
Photodynamic Therapy With Methylene Blue for Skin Ulcers Infected With Pseudomonas aeruginosa and Fusarium spp.
Terapia fotodinámica con azul de metileno en úlceras cutáneas infectadas con Pseudomonas aeruginosa y Fusarium spp.
a Sección de Microbiología, Hospital Royo Villanova, Zaragoza, España
b Servicio de Medicina Interna, Hospital Royo Villanova, Zaragoza, España
c Servicio de Medicina Interna/Unidad de Enfermedades Infecciosas, Hospital Royo Villanova, Zaragoza, España
d Servicio de Dermatología, Hospital San Jorge, Huesca, España
e Instituto Aragonés de Ciencias de la Salud, Zaragoza, España
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Images A and C correspond to the beginning of the process and images B and D to after treatment, with the lesions resolving.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Photodynamic therapy (PDT) is a therapeutic modality based on photooxidation of biological materials induced by a photosensitizer, which is selectively located in some cells which are destroyed on irradiation with a certain wavelength of light.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">PDT has an approved indication for the treatment of keratinocyte skin cancer, although it can have other applications.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">1,2</span></a> In addition to acting on tumor cells, antimicrobial effects of PDT have been known for more than 100 years.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> The advantages of antimicrobial PDT (aPDT) include the possibility to use in mixed infections (not just for different bacteria, whatever their resistance profile, but also for combinations of bacteria, fungi, virus, and even parasites).<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">1,2</span></a> It can therefore serve as a complement to conventional antimicrobial agents.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Given aPDT has a direct local action, it is used above all in accessible areas such as skin lesions and it constitutes a safe therapy with few side effects.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Colonized and/or infected skin ulcers are an important concern, both from the clinical standpoint (recalcitrant, slow healing, painful, antiesthetic, source of infection) and the epidemiological one (reservoir of multiresistant bacteria and hard-to-treat fungi), not to mention the extra costs associated with expensive treatments.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">PDT has other actions in addition to the improvement that may result from a decrease, or disappearance, of the microbial load.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> It can stimulate healing and skin epithelialization through immunoregulatory and regenerative processes, such as increased hydroxyproline content, improved angiogenesis, and modulation of collagen (attenuating its degradation and mediating remodelling).<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">5–7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Practical experience in the use of aPDT in the management of ulcers is limited, although 2 clinical trials have been published with promising results.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8,9</span></a> Our group has experience with the resolution of a complex case of recalcitrant ulcerative cutaneous sporotrichosis, treated with PDT with intralesional methylene blue (MB) in combination with a systemic antifungal agent.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">We present 2 cases of superinfected nonhealing leg ulcers that resolved with the help of PDT in its 2 modalities: conventional application (with the Aktilite lamp) and with exposure to daylight.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case Histories</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Case 1</span><p id="par0040" class="elsevierStylePara elsevierViewall">A 76-year-old woman was admitted to the internal medicine department with chronic malodorous grade <span class="elsevierStyleSmallCaps">iv</span> varicose vein ulcer on the right leg. The course of the lesion was nonhealing and extending with suppuration and necrosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a><span class="elsevierStyleHsp" style=""></span>A). <span class="elsevierStyleItalic">Fusarium</span> species and <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> grew rapidly in the cultures. Surgical debridement was performed and the patient treated empirically with linezolid and piperacillin-tazobactam <span class="elsevierStyleSmallCaps">iv</span>. After the findings of the culture were available, treatment was switched to ciprofloxacin and voriconazole was added. The lesion was very refractory to treatment, with multiple complications (urinary sepsis and stroke) and new concurrent treatments were initiated (anticoagulants, ceftazidime, and amikacin). In the face of this clinical course, and after obtaining informed consent from the patient, PDT was applied with 1% MB solution (30<span class="elsevierStyleHsp" style=""></span>min of incubation under occlusion) and, after rinsing away any excess MB, irradiation with the Aktilite lamp (Galderma SL, France; fluence of 37<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>). Three sessions were administered in the first week and 2 in the second and third weeks (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a><span class="elsevierStyleHsp" style=""></span>B). The improvement was notable and the patient discharged. She continued with 2 weekly sessions of PDT with daylight at home (MB application and exposure to daylight for 30<span class="elsevierStyleHsp" style=""></span>min daily, with fortnightly follow-up). Late follow-up revealed methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> (MRSA) in the culture. This was considered a colony of little pathogenic importance, although topical mupirocin was applied and home PDT continued. The bacterium was not detected in the next microbiological control. After 6 months of treatment, complete healing of the lesion was achieved (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a><span class="elsevierStyleHsp" style=""></span>C).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Case 2</span><p id="par0045" class="elsevierStylePara elsevierViewall">A 38-year-old woman with a combined kidney and pancreas transplant, in treatment with tacrolimus and prednisone, suffered symmetric burns to the calf area during a surgical procedure for eventration. On visual inspection, 2 symmetric ulcers were observed of 9<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>cm, which initially were covered by a blackish sore (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> A and C). <span class="elsevierStyleItalic">Corynebacterium striatum</span> and <span class="elsevierStyleItalic">Fusarium oxysporum</span> were isolated repeatedly from the lesions. The patient was treated with oral ciprofloxacin for a week and PDT was initiated with 1% MB solution according to the protocol described above. One session weekly was administered, and culture at 8 weeks was negative for bacteria and fungi. After 2 months, healing of the right side was observed, whereas MSRA was isolated from the left side. PDT with MB was restarted with mupirocin administered between sessions. Culture was negative for MRSA after 3 weeks. After 3 months, the 2 lesions had healed (<a class="elsevierStyleCrossRef" href="#fig0010">Figs. 2</a> B and D).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">During the course of infection, cultures became negative in both cases and there was a gradual decrease in microbial load (bacteria and fungi). The perception of the patients was very positive, with the therapy being subjectively assessed as very effective and painless. The only side effect reported was the intense blue coloration of the treated area and, occasionally, of urine.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discussion and Conclusion</span><p id="par0055" class="elsevierStylePara elsevierViewall">PDT with MB was effective in the management of 2 non-healing ulcers superinfected with <span class="elsevierStyleItalic">Fusarium</span> species, <span class="elsevierStyleItalic">Pseudomonas</span> and other difficult-to-treat bacteria. The 2 patients achieved healing and epithelization of the ulcers without the need for costly therapies that are not free of interactions and adverse effects and that may require parenteral administration.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The presence of <span class="elsevierStyleItalic">Fusarium</span> species in both cases and of <span class="elsevierStyleItalic">P aeruginosa</span> in the first patient represents a paradigm of microorganisms that are difficult to treat with anti-microbial agents. <span class="elsevierStyleItalic">P aeruginosa</span> in particular is currently a therapeutic challenge because of its increasing multiresistance. In addition, MRSA was isolated in both cases during the clinical course of the lesion but systemic treatment was not required and the infection could be treated with topical mupirocin and PDT itself. PDT can be considered a safe, simple, and inexpensive adjuvant therapy that, in addition, does not lead to resistance, has a broad spectrum of action, and may have an effect on the biofilm.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> The phenomenon of biofilm or biolayer formation appears to play a role in delayed wound healing. The process consists of the formation of aggregated bacterial communities covered by an extracellular matrix of polysaccharides that protects against antibiotics and the patient's immune system.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> PDT complements antimicrobial treatments, with which it may have synergistic effects,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> avoids expensive and aggressive therapies for the microbiota of the patients, and is free of interactions, and so can be particularly useful in immunosuppressed patients, patients with diabetes, and multimedicated elderly patients, as described here.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a> Moreover, when applied to skin ulcers, PDT appears to reduce the microbial load and substantially promote healing.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Biopsy was not performed in either of the patients as, given the natural course of the lesions, there were no grounds for clinical suspicion of another cause (for example, pyoderma gangrenosum).</p><p id="par0070" class="elsevierStylePara elsevierViewall">No approved photosensitizers are available on the market for aPDT. Different in vitro and in vivo studies show that MB has an excellent profile with activity against gram-positive and gram-negative bacteria and fungi.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> In the case of <span class="elsevierStyleItalic">Pseudomonas</span>, there are several reports of successful application of PDT for skin lesions, both in in vitro and in animal models.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">14–16</span></a> The cases presented here are the first experience in the use of PDT with MB in <span class="elsevierStyleItalic">Fusarium</span> species.</p><p id="par0075" class="elsevierStylePara elsevierViewall">MB is indicated for human use with intravenous administration, and so it is safe. It is also cheap and already available in the hospital. Nevertheless, precautions are necessary, even when used topically in aPDT, for example, in the case of pregnancy and patients treated with serotonergic psychiatric drugs (<a href="http://www.fda.gov/Drugs/DrugSafety/ucm267886.htm">http://www.fda.gov/Drugs/DrugSafety/ucm267886.htm</a>).</p><p id="par0080" class="elsevierStylePara elsevierViewall">aPDT acts only when the photosensitizer is photoactivated, and as soon as there is no light source, it is no longer active. For this reason, we recommend that patients continue to activate MB that persists in the ulcer for several days after application through exposure to sunlight. This enables a daily dose of PDT to be applied.</p><p id="par0085" class="elsevierStylePara elsevierViewall">In conclusion, the cases presented are an example of how aPDT can be a therapeutic alternative with a promising future in the management of chronic skin ulcers. Use of this technique can help overcome multiple resistance and antimicrobial agents can be reserved for patients with infections that can be effectively treated with such agents and that are at sites where PDT is not effective.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects.</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data.</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare that they have followed their hospital's protocol on the publication of data concerning patients.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent.</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors received the support of the Ministry of Economy, Industry and Competitiveness in their investigation into photodynamic therapy through the Spanish National Plan for Scientific and Technical Research and Innovation CTQ2013-48767-C3-2-R. They also received support from the Government of Aragon through participation in the B-85 Research Group.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres858624" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec852778" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres858625" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec852777" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Case Histories" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 2" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion and Conclusion" ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of human and animal subjects." ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data." ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent." ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of Interest" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "xack287835" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec852778" "palabras" => array:5 [ 0 => "Photodynamic therapy" 1 => "Methylene blue" 2 => "Ulcers" 3 => "<span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>" 4 => "<span class="elsevierStyleItalic">Fusarium</span> spp." ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec852777" "palabras" => array:5 [ 0 => "Terapia fotodinámica" 1 => "Azul de metileno" 2 => "Úlceras" 3 => "<span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>" 4 => "<span class="elsevierStyleItalic">Fusarium</span> spp." ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Photodynamic therapy (PDT) is a therapeutic modality with significant antimicrobial activity. We present 2 cases of chronic lower limb ulcers in which fungal and bacterial superinfection complicated management. PDT with methylene blue as the photosensitizer led to clinical and microbiological cure with no significant adverse effects. PDT with methylene blue is a valid option for the management of superinfected chronic ulcers, reducing the use of antibiotics and the induction of resistance.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La terapia fotodinámica tiene una importante acción antimicrobiana. Se presentan 2 casos clínicos de úlceras crónicas en las extremidades inferiores sobreinfectadas por hongos y bacterias de difícil manejo, en los que el tratamiento fotodinámico con azul de metileno como fotosensibilizante resultó en la curación clínica y microbiológica. No se presentaron efectos adversos reseñables. La posibilidad de utilizar la terapia fotodinámica con azul de metileno en el manejo de las úlceras crónicas sobreinfectadas constituye una interesante alternativa para reducir el uso de antibióticos y disminuir la aparición de resistencias.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Aspiroz C, Sevil M, Toyas C, Gilaberte Y. Terapia fotodinámica con azul de metileno en úlceras cutáneas infectadas con <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> y <span class="elsevierStyleItalic">Fusarium</span> spp. Actas Dermosifiliogr. 2017;108:e45–e48.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2232 "Ancho" => 1625 "Tamanyo" => 616823 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Course of an ulcer on the leg of patient 1. <span class="elsevierStyleItalic">Fusarium</span> species and <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> were repeatedly isolated from the lesion. The images correspond to the following dates: October 2012 (A), January 2013 (B), and April 2013 (C).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1066 "Ancho" => 1399 "Tamanyo" => 142394 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Course of an ulcer on the leg of patient 2. <span class="elsevierStyleItalic">Fusarium oxysporum</span> (and <span class="elsevierStyleItalic">Corynebacterium ulcerans</span>) were repeatedly isolated from the lesion. Images A and C correspond to the beginning of the process and images B and D to after treatment, with the lesions resolving.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Terapia fotodinámica antimicrobiana en dermatología" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Y. Gilaberte" 1 => "M.P. Paz-Cristóbal" 2 => "A. Rezusta" 3 => "C. 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Vrahas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.01652-12" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2013" "volumen" => "57" "paginaInicial" => "1238" "paginaFinal" => "1245" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23262998" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0160" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial blue light inactivation of <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> by photo-excitation of endogenous porphyrins: In vitro and in vivo studies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.M. Amin" 1 => "B. Bhayana" 2 => "M.R. Hamblin" 3 => "T. Dai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/lsm.22474" "Revista" => array:6 [ "tituloSerie" => "Lasers Surg Med" "fecha" => "2016" "volumen" => "48" "paginaInicial" => "562" "paginaFinal" => "568" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26891084" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack287835" "titulo" => "Acknowledgments" "texto" => "<p id="par0115" class="elsevierStylePara elsevierViewall">The authors would like to express their thanks to Dr. Antonio Rezusta for his collaboration and guidance.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010800000006/v1_201706300050/S157821901730152X/v1_201706300050/en/main.assets" "Apartado" => array:4 [ "identificador" => "34944" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "e- Case Report" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010800000006/v1_201706300050/S157821901730152X/v1_201706300050/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157821901730152X?idApp=UINPBA000044" ]
| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 12 | 13 | 25 |
| 2024 Octubre | 96 | 48 | 144 |
| 2024 Septiembre | 117 | 56 | 173 |
| 2024 Agosto | 136 | 68 | 204 |
| 2024 Julio | 134 | 49 | 183 |
| 2024 Junio | 127 | 52 | 179 |
| 2024 Mayo | 117 | 36 | 153 |
| 2024 Abril | 89 | 35 | 124 |
| 2024 Marzo | 88 | 27 | 115 |
| 2024 Febrero | 81 | 41 | 122 |
| 2024 Enero | 76 | 41 | 117 |
| 2023 Diciembre | 88 | 29 | 117 |
| 2023 Noviembre | 82 | 42 | 124 |
| 2023 Octubre | 84 | 37 | 121 |
| 2023 Septiembre | 112 | 54 | 166 |
| 2023 Agosto | 97 | 19 | 116 |
| 2023 Julio | 117 | 41 | 158 |
| 2023 Junio | 128 | 30 | 158 |
| 2023 Mayo | 119 | 33 | 152 |
| 2023 Abril | 92 | 28 | 120 |
| 2023 Marzo | 140 | 42 | 182 |
| 2023 Febrero | 98 | 32 | 130 |
| 2023 Enero | 97 | 40 | 137 |
| 2022 Diciembre | 83 | 38 | 121 |
| 2022 Noviembre | 65 | 36 | 101 |
| 2022 Octubre | 51 | 25 | 76 |
| 2022 Septiembre | 18 | 39 | 57 |
| 2022 Agosto | 24 | 29 | 53 |
| 2022 Julio | 22 | 37 | 59 |
| 2022 Junio | 41 | 34 | 75 |
| 2022 Mayo | 75 | 46 | 121 |
| 2022 Abril | 90 | 48 | 138 |
| 2022 Marzo | 75 | 54 | 129 |
| 2022 Febrero | 63 | 40 | 103 |
| 2022 Enero | 110 | 64 | 174 |
| 2021 Diciembre | 96 | 57 | 153 |
| 2021 Noviembre | 87 | 59 | 146 |
| 2021 Octubre | 84 | 70 | 154 |
| 2021 Septiembre | 67 | 49 | 116 |
| 2021 Agosto | 67 | 51 | 118 |
| 2021 Julio | 74 | 46 | 120 |
| 2021 Junio | 74 | 47 | 121 |
| 2021 Mayo | 65 | 70 | 135 |
| 2021 Abril | 136 | 115 | 251 |
| 2021 Marzo | 110 | 52 | 162 |
| 2021 Febrero | 111 | 56 | 167 |
| 2021 Enero | 84 | 49 | 133 |
| 2020 Diciembre | 109 | 34 | 143 |
| 2020 Noviembre | 82 | 54 | 136 |
| 2020 Octubre | 42 | 94 | 136 |
| 2020 Septiembre | 71 | 902 | 973 |
| 2020 Agosto | 43 | 24 | 67 |
| 2020 Julio | 60 | 27 | 87 |
| 2020 Junio | 61 | 36 | 97 |
| 2020 Mayo | 34 | 29 | 63 |
| 2020 Abril | 44 | 24 | 68 |
| 2020 Marzo | 33 | 11 | 44 |
| 2020 Febrero | 5 | 0 | 5 |
| 2020 Enero | 2 | 0 | 2 |
| 2019 Diciembre | 4 | 0 | 4 |
| 2019 Noviembre | 5 | 1 | 6 |
| 2019 Octubre | 1 | 0 | 1 |
| 2019 Septiembre | 8 | 0 | 8 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 0 | 4 |
| 2019 Junio | 3 | 0 | 3 |
| 2019 Mayo | 5 | 1 | 6 |
| 2019 Abril | 2 | 0 | 2 |
| 2019 Febrero | 1 | 0 | 1 |
| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 6 | 0 | 6 |
| 2018 Noviembre | 3 | 0 | 3 |
| 2018 Octubre | 1 | 0 | 1 |
| 2018 Septiembre | 3 | 0 | 3 |
| 2018 Mayo | 1 | 0 | 1 |
| 2018 Febrero | 40 | 6 | 46 |
| 2018 Enero | 77 | 10 | 87 |
| 2017 Diciembre | 66 | 11 | 77 |
| 2017 Noviembre | 49 | 8 | 57 |
| 2017 Octubre | 45 | 13 | 58 |
| 2017 Septiembre | 39 | 22 | 61 |
| 2017 Agosto | 47 | 26 | 73 |
| 2017 Julio | 63 | 24 | 87 |
| 2017 Junio | 18 | 20 | 38 |
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