Scientific Letter
Successful treatment of Panton–Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus pneumonia with high doses of linezolid administered in continuous infusion
Tratamiento eficaz de una neumonia comunitaria producida por un Staphylococcus aureus resitente a meticilina leucocidina Panton-Valantin con altas dosis de linezolid en perfusión continua
F. Álvarez-Lermaa,
, R. Muñoz-Bermúdeza, M.A. Samper-Sáncheza, M.P. Gracia Arnillaa, S. Graub, S. Luqueb
Corresponding author
a Service of Intensive Care Medicine, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain
b Service of Hospital Pharmacy, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain
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"apellidos" => "Álvarez-Lerma" "email" => array:1 [ 0 => "Falvarez@parcdesalutmar.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "R." "apellidos" => "Muñoz-Bermúdez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "M.A." "apellidos" => "Samper-Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "M.P." "apellidos" => "Gracia Arnilla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "S." "apellidos" => "Grau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "S." "apellidos" => "Luque" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Service of Intensive Care Medicine, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Service of Hospital Pharmacy, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento eficaz de una neumonia comunitaria producida por un <span class="elsevierStyleItalic">Staphylococcus aureus</span> resitente a meticilina leucocidina Panton-Valantin con altas dosis de linezolid en perfusión continua" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1093 "Ancho" => 1501 "Tamanyo" => 274767 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Thoracic CT scan at day 7 after hospital admission showing multiple cavities and important necrotic areas in the upper lobes compatible with pneumatoceles and bronchiectasis.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Pneumonia caused by methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> (MRSA) strains producing a cytotoxin known as Panton–Valentin leukocidin (PVL) is a severe and difficult to treat disease.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–4</span></a> Linezolid has excellent epithelial lining fluid (ELF) penetration rates but drug concentrations in critically ill patients are highly variable.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5-8</span></a> We describe the clinical case of a patient with septic shock secondary to a community-acquired PVL-secreting MRSA pneumonia, in which linezolid plasma concentration within the therapeutic range were only reached with the use of higher than recommended doses (600<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h) administered in continuous infusion.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 56-year-old Caucasian man was admitted on February 2, 2015 with a 4-day history of dyspnea, mucopurulent expectoration, and fever (>38<span class="elsevierStyleHsp" style=""></span>°C). His weight was 80<span class="elsevierStyleHsp" style=""></span>kg (body mass index [BMI] 27.7<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span>), smoked 2–3 cigarettes a day, and consumed approximately 7 standard drinks daily. Physical examination revealed sinus tachycardia (160<span class="elsevierStyleHsp" style=""></span>beats/min), diaphoresis, hypertension (blood pressure [BP] 154/92<span class="elsevierStyleHsp" style=""></span>mmHg), and marked respiratory distress as well as bilateral crackles and disperse rhonchi up to the apex on lung auscultation. This caused a hypoxemic respiratory insufficiency with an initial PaO<span class="elsevierStyleInf">2</span> of 55<span class="elsevierStyleHsp" style=""></span>mmHg that did not improve despite an elevated inspired oxygen fraction (FiO<span class="elsevierStyleInf">2</span> 0.5) and noninvasive mechanical ventilation, for which he needed orotracheal intubation and ICU admission. Blood urea nitrogen was 32<span class="elsevierStyleHsp" style=""></span>mg/dL, serum creatinine 0.88<span class="elsevierStyleHsp" style=""></span>mg/dL, and glomerular filtration rate (Cockcroft–Gault equation) 106<span class="elsevierStyleHsp" style=""></span>mL/min, C-reactive protein 25.6<span class="elsevierStyleHsp" style=""></span>mg/L, procalcitonin 24.17<span class="elsevierStyleHsp" style=""></span>ng/mL, and lactic acid 5<span class="elsevierStyleHsp" style=""></span>mmol/L. Other laboratory data were unrevealing. Chest radiography revealed bilateral alveolar and interstitial infiltrates and alveolar condensation in the right upper lobe. The patient was tentatively diagnosed with CAP and was treated empirically with intravenous ceftriaxone (2<span class="elsevierStyleHsp" style=""></span>g every 24<span class="elsevierStyleHsp" style=""></span>h), intravenous levofloxacin (0.5<span class="elsevierStyleHsp" style=""></span>g every 12<span class="elsevierStyleHsp" style=""></span>h) (positive urinary detection of pneumococcal antigen), and oseltamivir (positive PCR assay detection of influenza A and B viruses in oropharyngeal swabs). During the first 24<span class="elsevierStyleHsp" style=""></span>h of ICU admission, the patient's condition deteriorated, with secondary septic shock and need of vasoactive drugs (norepinephrine 0.2 ¿g/kg/min). Microbiologically, a MRSA was isolated in cultures from bronchial aspirates and in four blood culture bottles (linezolid minimum inhibitory concentration [MIC]<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mg/L) on the day of admission. Each MRSA isolate carried the PVL genes. The MRSA strain was sent to the National Microbiology Center (Institute of Health Carlos III, Madrid). The initial empirical antibiotic treatment was discontinued and linezolid at a standard dose (600<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h infused over 60<span class="elsevierStyleHsp" style=""></span>min) was administered.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Treatment with linezolid was maintained and the remaining antimicrobials were discontinued. Steady state plasma concentrations of linezolid were determined from the third day of treatment using a high-performance liquid chromatography technique, with a minimum plasma concentration state (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span>) (or pre-dose) of 0.8<span class="elsevierStyleHsp" style=""></span>mg/L and maximum (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span><span class="elsevierStyleSup">ss</span>) (at the end of infusion) of 4.8<span class="elsevierStyleHsp" style=""></span>mg/L, which were considered subtherapeutic (therapeutic range <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mg/L). Although blood cultures became negative on the fifth day of treatment, the patient showed a protracted respiratory clinical course with worsening of radiographic images, and according to drug susceptibility testing, antimicrobial coverage was expanded with intravenous clindamycin (600<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h) and ciprofloxacin (400<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h). In addition, the dosing interval of linezolid as well as the duration of the time of infusion were modified on several occasions based on results of plasma drug concentrations in order to achieve an optimal pharmacokinetic (PK) and pharmacodynamic (PD) ratio (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Seventeen days after starting treatment with linezolid, therapeutic levels were reached with a regimen of 600<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h administered in continuous infusion, which coincided with eradication of PVL producing MRSA in pulmonary samples. Thoracic computed tomographic (CT) scans performed over the course of treatment revealing extensive involvement of the pulmonary parenchyma with multiple cavities and important necrotic areas in the upper lobes compatible with pneumatoceles and bronchiectasis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient required mechanical ventilation during 73 days (with tracheostomy) with procedural sedation, analgesia, and prolonged muscle relaxation. After 5 weeks of treatment with linezolid, the patient was successfully weaned. Linezolid was administered for a total of 35 days, clindamycin for 29 days and ciprofloxacin for 19 days. He was discharged after a 3-month hospitalization. At the present time, his oxygen saturation on room air is >95%.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Mortality related to PVL-secreting MRSA pneumonia is around 70% despite the use of appropriate antimicrobials according to results of susceptibility testing.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> A combination of antimicrobials active against MRSA and with adequate penetration in the pulmonary parenchyma should be selected. Linezolid is a synthetic antibiotic belonging to the oxazolidinone family especially active against Gram-positive bacteria, including multiresistant pathogens, with 100% diffusion in the ELF.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Although in the technical specifications of linezolid, a standard dose of 600<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h administered in 60-min intermittent infusion is recommended, recent pharmacokinetic studies have shown that the administration of this fixed dose in some population groups did not allow to reach an optimal predictive pharmacokinetic/pharmacodynamic (pk/pd) ratio of clinical efficacy of the drug (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>2–4<span class="elsevierStyleHsp" style=""></span>mg/L), whereas it has also been related to overexposure (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg/L) and higher risk of hematologic toxicity.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> These circumstances are frequent in ICU patients with severe sepsis or septic shock, in whom most factors associated with underexposure or overexposure to linezolid may be present.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Subtherapeutic linezolid concentrations have been related to glomerular filtration rates greater than 80<span class="elsevierStyleHsp" style=""></span>mL/min,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> which is frequent in septic patients treated with vasoactive drugs as was in our patient.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Strategies for optimizing linezolid plasma levels include an increase in the total dose, by-reducing the dosing interval from 12<span class="elsevierStyleHsp" style=""></span>h to every 8 or 6<span class="elsevierStyleHsp" style=""></span>h, or extending the duration of infusion to 2–4<span class="elsevierStyleHsp" style=""></span>h (extended infusion) or using a continuous infusion.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Our patient in whom glomerular filtration rates >200<span class="elsevierStyleHsp" style=""></span>mL/min were recorded, a <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg/L were only obtained with the administration of a linezolid dose of 600<span class="elsevierStyleHsp" style=""></span>mg every 6–8<span class="elsevierStyleHsp" style=""></span>h in continuous infusion, which coincided with negativization of pulmonary exudate cultures. This high dose, between 1.5 and 2-fold higher than the standard recommended dose was well tolerated, without signs of toxicity, particularly without a decrease in platelet count or hemoglobin levels.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In ICU patients with severe infections and increased renal clearance, linezolid should be administered at high doses and in continuous infusion with close monitorization of plasma drug levels.</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Source of funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">None declared.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">None declared.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Source of funding" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "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" => 1093 "Ancho" => 1501 "Tamanyo" => 274767 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Thoracic CT scan at day 7 after hospital admission showing multiple cavities and important necrotic areas in the upper lobes compatible with pneumatoceles and bronchiectasis.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">GFR: glomerular filtration rate.</p>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Day of sampling \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose (mg) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosing interval doses \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type and duration of infusion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GFR (mL/min) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span> (mg/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Platelet count (×10<span class="elsevierStyleSup">9</span>/L) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">February 13, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermittent (60<span class="elsevierStyleHsp" style=""></span>min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">176 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">112 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">February 17, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermittent (60<span class="elsevierStyleHsp" style=""></span>min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">239 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">85 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">February 23, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extended (2<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">345 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">456 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">February 24, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extended (2<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">267 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">531 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">February 26, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extended (2<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">301 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">540 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1358385.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Day of sampling \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose (mg) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosing interval doses \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type and duration of infusion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GFR (mL/min) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleSup">ss</span> (mg/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="char" valign="top" scope="col" style="border-bottom: 2px solid black">Platelet count (×10<span class="elsevierStyleSup">9</span>/L) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">March 2, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous (6<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">301 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">544 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">March 6, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous (8<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">275 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">527 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">March 9, 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous (8<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">333 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">467 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1358386.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Changes in doses, intervals between doses, forms of administration, and plasma concentrations of linezolid during the patient's stay in the ICU.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Emergence of community-acquired methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> USA 300 clone as the predominant cause of skin and soft-tissue infections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.D. King" 1 => "B.J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 2 | 8 |
| 2024 October | 117 | 61 | 178 |
| 2024 September | 120 | 34 | 154 |
| 2024 August | 143 | 38 | 181 |
| 2024 July | 152 | 28 | 180 |
| 2024 June | 150 | 68 | 218 |
| 2024 May | 134 | 36 | 170 |
| 2024 April | 100 | 46 | 146 |
| 2024 March | 103 | 37 | 140 |
| 2024 February | 97 | 43 | 140 |
| 2024 January | 171 | 46 | 217 |
| 2023 December | 207 | 44 | 251 |
| 2023 November | 179 | 41 | 220 |
| 2023 October | 161 | 33 | 194 |
| 2023 September | 119 | 32 | 151 |
| 2023 August | 96 | 17 | 113 |
| 2023 July | 88 | 25 | 113 |
| 2023 June | 124 | 23 | 147 |
| 2023 May | 138 | 42 | 180 |
| 2023 April | 96 | 29 | 125 |
| 2023 March | 162 | 33 | 195 |
| 2023 February | 184 | 45 | 229 |
| 2023 January | 172 | 37 | 209 |
| 2022 December | 128 | 42 | 170 |
| 2022 November | 156 | 39 | 195 |
| 2022 October | 173 | 42 | 215 |
| 2022 September | 124 | 48 | 172 |
| 2022 August | 107 | 44 | 151 |
| 2022 July | 84 | 49 | 133 |
| 2022 June | 98 | 32 | 130 |
| 2022 May | 108 | 41 | 149 |
| 2022 April | 98 | 45 | 143 |
| 2022 March | 161 | 51 | 212 |
| 2022 February | 132 | 38 | 170 |
| 2022 January | 143 | 39 | 182 |
| 2021 December | 120 | 85 | 205 |
| 2021 November | 99 | 43 | 142 |
| 2021 October | 241 | 74 | 315 |
| 2021 September | 152 | 41 | 193 |
| 2021 August | 282 | 58 | 340 |
| 2021 July | 151 | 39 | 190 |
| 2021 June | 139 | 50 | 189 |
| 2021 May | 158 | 61 | 219 |
| 2021 April | 296 | 96 | 392 |
| 2021 March | 239 | 35 | 274 |
| 2021 February | 196 | 38 | 234 |
| 2021 January | 195 | 36 | 231 |
| 2020 December | 140 | 28 | 168 |
| 2020 November | 149 | 30 | 179 |
| 2020 October | 168 | 33 | 201 |
| 2020 September | 176 | 13 | 189 |
| 2020 August | 163 | 22 | 185 |
| 2020 July | 161 | 33 | 194 |
| 2020 June | 152 | 28 | 180 |
| 2020 May | 132 | 16 | 148 |
| 2020 April | 96 | 13 | 109 |
| 2020 March | 66 | 18 | 84 |
| 2020 February | 190 | 37 | 227 |
| 2020 January | 80 | 28 | 108 |
| 2019 December | 111 | 29 | 140 |
| 2019 November | 49 | 28 | 77 |
| 2019 October | 76 | 19 | 95 |
| 2019 September | 63 | 22 | 85 |
| 2019 August | 61 | 17 | 78 |
| 2019 July | 55 | 23 | 78 |
| 2019 June | 53 | 14 | 67 |
| 2019 May | 71 | 26 | 97 |
| 2019 April | 58 | 23 | 81 |
| 2019 March | 58 | 28 | 86 |
| 2019 February | 55 | 21 | 76 |
| 2019 January | 53 | 31 | 84 |
| 2018 December | 63 | 15 | 78 |
| 2018 November | 79 | 64 | 143 |
| 2018 October | 60 | 19 | 79 |
| 2018 September | 26 | 4 | 30 |
| 2018 August | 21 | 3 | 24 |
| 2018 July | 17 | 5 | 22 |
| 2018 June | 25 | 8 | 33 |
| 2018 May | 7 | 4 | 11 |
| 2018 April | 26 | 5 | 31 |
| 2018 March | 18 | 4 | 22 |
| 2018 February | 11 | 6 | 17 |
| 2018 January | 28 | 9 | 37 |
| 2017 December | 24 | 4 | 28 |
| 2017 November | 17 | 10 | 27 |
| 2017 October | 23 | 7 | 30 |
| 2017 September | 19 | 9 | 28 |
| 2017 August | 20 | 10 | 30 |
| 2017 July | 15 | 6 | 21 |
| 2017 June | 16 | 6 | 22 |
| 2017 May | 10 | 9 | 19 |
| 2017 April | 23 | 1 | 24 |
| 2017 March | 0 | 1 | 1 |
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