Pharmacokinetics of micafungin in patients with pre-existing liver dysfunction: A safe option for treating invasive fungal infections | Enfermedades Infecciosas y Microbiología Clínica

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It has previously been shown to be non-inferior to both liposomal amphotericin B and caspofungin for the treatment of invasive candidiasis and candidemia and it has demonstrated efficacy for the prophylaxis of invasive fungal infections<a class="elsevierStyleCrossRefs" href="#bib0100">5,6</a> and the treatment of esophageal candidiasis.<a class="elsevierStyleCrossRef" href="#bib0110">7</a> Potential hepatotoxicity is an adverse event reported for the different antifungal families, with pooled estimates of the percentage of patients with elevated liver enzymes requiring stopping treatment of 3.0% for MCF, 7% for caspofungin, 9.3% for fluconazole, 14.1% for amphotericin B formulations, 17.4% for itraconazole, and 19.7% for voriconazole.<a class="elsevierStyleCrossRef" href="#bib0115">8</a> MCF displays linear pharmacokinetics (PK)<a class="elsevierStyleCrossRef" href="#bib0120">9</a> and preliminary studies in subjects with hepatic impairment indicates that dose adjustment is not required.<a class="elsevierStyleCrossRef" href="#bib0125">10</a>MethodsA prospective, observational study was designed to assess the potential drug-induced liver injury of MCF during its clinical use in routine daily practice, and to evaluate a possible linear correlation between baseline liver function tests and MCF plasma levels. The study population consisted of 12 hospitalized patients with proven or suspected invasive fungal infections treated with MCF. Plasma levels of MCF were measured at steady state (at least 4 days after starting MCF treatment) using a validated highly performed liquid chromatography (HPLC) method (Waters Alliance Systems). Two determinations of MCF plasma levels per patient were performed (Cmaxss or peak and Cminss or trough). Data recorded were age; sex; body mass index (BMI); liver function tests, including serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, and Child-Pugh score at the beginning and at the end of MCF treatment; MCF-related data, including daily dose, dose/kg actual body weight, duration of treatment (days), Cmaxss and Cminss; concomitant use of other hepatotoxic and cholestatic drugs; MCF withdrawal due to drug-induced liver disease; and crude mortality during treatment with MCF. In this study, liver toxicity was defined as the presence of serum levels of AST and ALT more than five times the upper limit of the normal range, alkaline phosphatase levels more than two-fold the upper limit of the normal range, and total bilirubin more than three times the upper limit of the normal range and/or a value >2.5mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0130">11,12</a> Bivariate correlations between liver function tests at the beginning and at the end of MCF treatment as well as MCF levels at steady state were analyzed using the Spearman's rho coefficient.ResultsThere were 6 men and 6 women, with a mean (standard deviation, SD) age of 62.2 (15.6) years, and a mean BMI of 25.4 (4.9) kg/m2. The clinical and pharmacokinetic characteristics of these patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. History of liver disease was recorded in 6 (50%) patients. The majority of patients (83.3%) were treated with a daily dose of MCF of 100mg. The mean duration of treatment was 14.4 (8.7) days. The mean Cmaxss was 8.94 (2.94) mg/L and the mean Cminss 1.51 (0.58) mg/L. As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, there were 8 (66.7%) patients with altered liver function tests at the beginning of MCF treatment as compared with 5 patients at the end of it, although all of these 5 patients had been concomitantly treated with other drugs that can induce cholestasis, such as paracetamol, linezolid, imipenem, ceftriaxone, cloxacillin, erythromycin, and others. No linear correlation was observed between MCF plasma levels (Cmaxss nor Cminss) and the values of different liver parameters (AST, ALT, total bilirubin and alkaline phosphatase) at the beginning of treatment (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). At the end of treatment with MCF, serum levels of alkaline phosphatase correlated inversely with Cminss and ALT values with Cmaxss, with a correlation coefficient (rho) of −0.803 (P=0.009) and −0.683 (P=0.042), respectively (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Also, there were no differences in Cmaxss and Cminss between patients with and without altered liver function tests at the beginning of MCF treatment as well as between patients with and without altered liver function tests at the end of MCF treatment (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The crude mortality was 16.7% (n=2). One patient (8.3%) died during MCF treatment. The cause of death was hemodynamic instability with severe metabolic acidosis and cardiorespiratory arrest. Also, MCF discontinuation was necessary due to drug-induced adverse event (increase in bilirubin level of 19mg/dL) in one patient. This patient showed persistent positive culture for Candida spp. After withdrawal of MCF, anidulafungin was administered but serum bilirubin levels continued to increase up to 47.7mg/dL. In none of the patients worsening of liver function parameters was observed, with the exception of this patient with increased bilirubin level.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionThis prospective observational study carried out in a small clinical series of 12 patients, 8 (66.7%) of which had altered function tests at the beginning of MCF treatment, shows that MCF is a safe option for the treatment of invasive fungal infection, even for those patients with pre-existing liver function impairment. Liver function remained stable or even improved in all but one MCF-treated patients. In only one patient MCF was discontinued due to liver toxicity. However, this patient with invasive candidiasis showed persistent positive blood cultures for Candida and elevated serum bilirubin levels that even increased after discontinuation of MCF and switching to treatment with anidulafungin. Data from randomized double blind clinical trials performed in patients with baseline normal liver function tests have reported elevations of alkaline phosphatase, AST and ALT in only 2.7, 2.3 and 2.0 of the patients, respectively.<a class="elsevierStyleCrossRef" href="#bib0140">13</a> A favorable clinical safety profile for MCF similar to other echinocandins has been demonstrated in different studies, including analysis a large database (a pooled clinical trial data set of 3028 patients that received at least one dose of MCF).<a class="elsevierStyleCrossRef" href="#bib0145">14</a>In a recent study of the pharmacokinetics of MCF in 8 healthy volunteers and 8 patients with severe liver dysfunction treated with a single dose of MCF of 100mg, pharmacokinetic parameters were lower in subjects with severe hepatic dysfunction, except for clearance, which was higher in these subjects. However, the magnitude of the differences was not considered to be clinically meaningful.<a class="elsevierStyleCrossRef" href="#bib0150">15</a>In this study, MCF plasma levels at steady state showed no correlation with hepatic parameters at the beginning of MCF treatment. Also, Cmaxss and Cminss were similar in patients with and without altered liver function tests both at starting and at the end of MCF treatment. These data support the usefulness of MCF in patients with liver dysfunction and invasive fungal infections.FundingNone.Conflict of interestThe authors declare no conflict of interest." 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Liver function remained stable or even improved in all patients, except in one in which MCF was discontinued due to liver toxicity." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Se trata de un estudio prospectivo observacional en 12 pacientes ingresados en un hospital con sospecha o infección fúngica confirmada tratados con micafungina (MCF) durante una media de 14 días, 8 de los cuales con presencia de alteración hepática preexistente. Los niveles plasmáticos de MCF en el estado estacionario no se correlacionaron con los valores basales de las pruebas hepáticas al inicio del tratamiento. La función hepática permaneció estable o incluso mejoró en todos los pacientes excepto en uno de ellos en el que el tratamiento con MCF fue interrumpido debido a la presencia de toxicidad hepática." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Data expressed as patients and percentages (in parenthesis) unless otherwise stated." "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">Variables \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">Patients (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Men/women \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6/6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age, years, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.2 (15.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BMI, kg/m2, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25.4 (4.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Previous or on admission hepatobiliary disease, no. (%)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">MCF, daily dose, mg, no. (%)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (83.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">MCF dose/body weight, mg/kg, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.5 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Duration of treatment, days, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.4 (8.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cmaxss, mg/L, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.94 (2.94) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cminss, mg/L, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.51 (0.58) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1270958.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="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Altered liver function tests</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">At the start of MCF therapy \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">At the end of MCF therapy \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Patients, no. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (66.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">AST, IU/L>5 upper normal limit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (8.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ALT, IU/L>5 upper normal limit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Alkaline phosphatase, IU/L, >2 upper normal limit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total bilirubin, mg/dL, >3 upper normal limit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Child-Pugh A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Child-Pugh B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (58.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Child-Pugh C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1270959.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Acute pancreatitis and biliary lithiasis (n=1); acute pancreatitis and acute cholangitis (n=1); Biliary lithiasis (gallbladder and common duct) (n=1); HCV chronic infection (genotype A1) (n=1); Alcohol-related liver cirrhosis Child-Pugh C (n=1); HCV-related cirrhosis Child-Pugh B, hepatocellular carcinoma BCLC A4 (n=1)." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of 12 patients with proven or suspected invasive fungal infection treated with micafungin (MCF)." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 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">MCF plasma level \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">At the beginning of treatment with MCF</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">At the end of treatment with MCF</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Liver function test \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">rho<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \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">P value \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">Liver function test \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">rho<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \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">P value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cminss \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.175 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.607 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.316 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.407 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.495 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.121 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.232 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.756 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alkaline phosphatase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.571 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.085 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alkaline phosphatase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.803 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.431 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.185 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.084 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.831 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cmaxss \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.302 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.340 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.049 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.894 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.441 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.683 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.042 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alkaline phosphatase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.689 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alkaline phosphatase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.345 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.328 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.438 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.155 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.455 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.187 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1270960.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Spearman's correlation coefficient." ] ] ] "descripcion" => array:1 [ "en" => "Results of correlation analysis between MCF plasma levels and liver functions tests at the beginning and at the end of treatment." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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">MCF plasma levels \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Altered liver function tests at the start of MCF treatment</th><th class="td" title="table-head " align="left" valign="top" scope="col">P value \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Present \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">Absent \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cmaxss, mg/L, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.5 (7.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.3 (8.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.660<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cminss, mg/L, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.47 (1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.56 (1.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.792<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1270961.png" ] ] 1 => 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valign="top">1.58 (1.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.648<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1270957.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Student's t test." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "Mann-Whitney U test." ] ] ] "descripcion" => array:1 [ "en" => "Differences in plasma levels of MCF between patients with and without altered liver function tests either at the beginning or at the end of MCF treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/0213005X/0000003400000010/v1_201612040021/S0213005X15001019/v1_201612040021/en/main.assets" "Apartado" => array:4 [ "identificador" => "8684" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Original breve" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/0213005X/0000003400000010/v1_201612040021/S0213005X15001019/v1_201612040021/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X15001019?idApp=UINPBA00004N"]

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Pharmacokinetics of micafungin in patients with pre-existing liver dysfunction: A safe option for treating invasive fungal infections

Farmacocinética de micafungina en pacientes con alteración del perfil hepático basal: una opción segura para el tratamiento de la infección fúngica invasora

Sonia Luquea,b, Nuria Campilloa, Francisco Álvarez-Lermac, Olivia Ferrándeza, Juan Pablo Horcajadad, Santiago Graua,b,e,

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sgrau@parcdesalutmar.cat

Corresponding author.

a Pharmacy Department, Hospital-del-Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain

b Institut Hospital del Mar d’ Investigacions Mèdiques (IMIM), Barcelona, Spain

c Intensive Care Medicine Department, Hospital-del-Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain

d Infectious Diseases Department, Hospital-del-Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain

e Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Invasive fungal infections in hospitalized patients are a major source of mortality and morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Widespread and prolonged use of fluconazole has been associated with an increase of nosocomial non-albicans <span class="elsevierStyleItalic">Candida</span> spp&#46; bloodstream infections<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> and conventional amphotericin B with nephrotoxicity and severe adverse events&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#44;4</span></a> Micafungin &#40;MCF&#41; is an echinocandin antifungal agent that inhibits the synthesis of 1&#44;3-&#946;-<span class="elsevierStyleSmallCaps">d</span>-glucan with activity against <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Aspergillus</span> species&#46; It has previously been shown to be non-inferior to both liposomal amphotericin B and caspofungin for the treatment of invasive candidiasis and candidemia and it has demonstrated efficacy for the prophylaxis of invasive fungal infections<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">5&#44;6</span></a> and the treatment of esophageal candidiasis&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> Potential hepatotoxicity is an adverse event reported for the different antifungal families&#44; with pooled estimates of the percentage of patients with elevated liver enzymes requiring stopping treatment of 3&#46;0&#37; for MCF&#44; 7&#37; for caspofungin&#44; 9&#46;3&#37; for fluconazole&#44; 14&#46;1&#37; for amphotericin B formulations&#44; 17&#46;4&#37; for itraconazole&#44; and 19&#46;7&#37; for voriconazole&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> MCF displays linear pharmacokinetics &#40;PK&#41;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> and preliminary studies in subjects with hepatic impairment indicates that dose adjustment is not required&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">A prospective&#44; observational study was designed to assess the potential drug-induced liver injury of MCF during its clinical use in routine daily practice&#44; and to evaluate a possible linear correlation between baseline liver function tests and MCF plasma levels&#46; The study population consisted of 12 hospitalized patients with proven or suspected invasive fungal infections treated with MCF&#46; Plasma levels of MCF were measured at steady state &#40;at least 4 days after starting MCF treatment&#41; using a validated highly performed liquid chromatography &#40;HPLC&#41; method &#40;Waters Alliance Systems&#41;&#46; Two determinations of MCF plasma levels per patient were performed &#40;Cmax<span class="elsevierStyleInf">ss</span> or peak and Cmin<span class="elsevierStyleInf">ss</span> or trough&#41;&#46; Data recorded were age&#59; sex&#59; body mass index &#40;BMI&#41;&#59; liver function tests&#44; including serum levels of aspartate aminotransferase &#40;AST&#41;&#44; alanine aminotransferase &#40;ALT&#41;&#44; total bilirubin&#44; alkaline phosphatase&#44; and Child-Pugh score at the beginning and at the end of MCF treatment&#59; MCF-related data&#44; including daily dose&#44; dose&#47;kg actual body weight&#44; duration of treatment &#40;days&#41;&#44; Cmax<span class="elsevierStyleInf">ss</span> and Cmin<span class="elsevierStyleInf">ss</span>&#59; concomitant use of other hepatotoxic and cholestatic drugs&#59; MCF withdrawal due to drug-induced liver disease&#59; and crude mortality during treatment with MCF&#46; In this study&#44; liver toxicity was defined as the presence of serum levels of AST and ALT more than five times the upper limit of the normal range&#44; alkaline phosphatase levels more than two-fold the upper limit of the normal range&#44; and total bilirubin more than three times the upper limit of the normal range and&#47;or a value &#62;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">11&#44;12</span></a> Bivariate correlations between liver function tests at the beginning and at the end of MCF treatment as well as MCF levels at steady state were analyzed using the Spearman&#39;s rho coefficient&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="par0015" class="elsevierStylePara elsevierViewall">There were 6 men and 6 women&#44; with a mean &#40;standard deviation&#44; SD&#41; age of 62&#46;2 &#40;15&#46;6&#41; years&#44; and a mean BMI of 25&#46;4 &#40;4&#46;9&#41; kg&#47;m<span class="elsevierStyleSup">2</span>&#46; The clinical and pharmacokinetic characteristics of these patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; History of liver disease was recorded in 6 &#40;50&#37;&#41; patients&#46; The majority of patients &#40;83&#46;3&#37;&#41; were treated with a daily dose of MCF of 100<span class="elsevierStyleHsp" style=""></span>mg&#46; The mean duration of treatment was 14&#46;4 &#40;8&#46;7&#41; days&#46; The mean Cmax<span class="elsevierStyleInf">ss</span> was 8&#46;94 &#40;2&#46;94&#41; mg&#47;L and the mean Cmin<span class="elsevierStyleInf">ss</span> 1&#46;51 &#40;0&#46;58&#41; mg&#47;L&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; there were 8 &#40;66&#46;7&#37;&#41; patients with altered liver function tests at the beginning of MCF treatment as compared with 5 patients at the end of it&#44; although all of these 5 patients had been concomitantly treated with other drugs that can induce cholestasis&#44; such as paracetamol&#44; linezolid&#44; imipenem&#44; ceftriaxone&#44; cloxacillin&#44; erythromycin&#44; and others&#46; No linear correlation was observed between MCF plasma levels &#40;Cmax<span class="elsevierStyleInf">ss</span> nor Cmin<span class="elsevierStyleInf">ss</span>&#41; and the values of different liver parameters &#40;AST&#44; ALT&#44; total bilirubin and alkaline phosphatase&#41; at the beginning of treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; At the end of treatment with MCF&#44; serum levels of alkaline phosphatase correlated inversely with Cmin<span class="elsevierStyleInf">ss</span> and ALT values with Cmax<span class="elsevierStyleInf">ss</span>&#44; with a correlation coefficient &#40;rho&#41; of &#8722;0&#46;803 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41; and &#8722;0&#46;683 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Also&#44; there were no differences in Cmax<span class="elsevierStyleInf">ss</span> and Cmin<span class="elsevierStyleInf">ss</span> between patients with and without altered liver function tests at the beginning of MCF treatment as well as between patients with and without altered liver function tests at the end of MCF treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The crude mortality was 16&#46;7&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; One patient &#40;8&#46;3&#37;&#41; died during MCF treatment&#46; The cause of death was hemodynamic instability with severe metabolic acidosis and cardiorespiratory arrest&#46; Also&#44; MCF discontinuation was necessary due to drug-induced adverse event &#40;increase in bilirubin level of 19<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; in one patient&#46; This patient showed persistent positive culture for <span class="elsevierStyleItalic">Candida</span> spp&#46; After withdrawal of MCF&#44; anidulafungin was administered but serum bilirubin levels continued to increase up to 47&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; In none of the patients worsening of liver function parameters was observed&#44; with the exception of this patient with increased bilirubin level&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">This prospective observational study carried out in a small clinical series of 12 patients&#44; 8 &#40;66&#46;7&#37;&#41; of which had altered function tests at the beginning of MCF treatment&#44; shows that MCF is a safe option for the treatment of invasive fungal infection&#44; even for those patients with pre-existing liver function impairment&#46; Liver function remained stable or even improved in all but one MCF-treated patients&#46; In only one patient MCF was discontinued due to liver toxicity&#46; However&#44; this patient with invasive candidiasis showed persistent positive blood cultures for <span class="elsevierStyleItalic">Candida</span> and elevated serum bilirubin levels that even increased after discontinuation of MCF and switching to treatment with anidulafungin&#46; Data from randomized double blind clinical trials performed in patients with baseline normal liver function tests have reported elevations of alkaline phosphatase&#44; AST and ALT in only 2&#46;7&#44; 2&#46;3 and 2&#46;0 of the patients&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> A favorable clinical safety profile for MCF similar to other echinocandins has been demonstrated in different studies&#44; including analysis a large database &#40;a pooled clinical trial data set of 3028 patients that received at least one dose of MCF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In a recent study of the pharmacokinetics of MCF in 8 healthy volunteers and 8 patients with severe liver dysfunction treated with a single dose of MCF of 100<span class="elsevierStyleHsp" style=""></span>mg&#44; pharmacokinetic parameters were lower in subjects with severe hepatic dysfunction&#44; except for clearance&#44; which was higher in these subjects&#46; However&#44; the magnitude of the differences was not considered to be clinically meaningful&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In this study&#44; MCF plasma levels at steady state showed no correlation with hepatic parameters at the beginning of MCF treatment&#46; Also&#44; Cmax<span class="elsevierStyleInf">ss</span> and Cmin<span class="elsevierStyleInf">ss</span> were similar in patients with and without altered liver function tests both at starting and at the end of MCF treatment&#46; These data support the usefulness of MCF in patients with liver dysfunction and invasive fungal infections&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Funding</span><p id="par0040" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec769072"
          "palabras" => array:3 [
            0 => "Micafungina"
            1 => "Hepatotoxicidad"
            2 => "Monitorizaci&#243;n farmacocin&#233;tica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In this prospective observational study performed in 12 hospitalized patients with proven or suspected invasive fungal infection treated for a mean of 14 days with micafungin &#40;MCF&#41;&#44; 8 of whom with pre-existing liver function impairment&#44; plasma levels of MCF at steady state were not correlated with liver function tests at the beginning of treatment&#46; Liver function remained stable or even improved in all patients&#44; except in one in which MCF was discontinued due to liver toxicity&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio prospectivo observacional en 12 pacientes ingresados en un hospital con sospecha o infecci&#243;n f&#250;ngica confirmada tratados con micafungina &#40;MCF&#41; durante una media de 14 d&#237;as&#44; 8 de los cuales con presencia de alteraci&#243;n hep&#225;tica preexistente&#46; Los niveles plasm&#225;ticos de MCF en el estado estacionario no se correlacionaron con los valores basales de las pruebas hep&#225;ticas al inicio del tratamiento&#46; La funci&#243;n hep&#225;tica permaneci&#243; estable o incluso mejor&#243; en todos los pacientes excepto en uno de ellos en el que el tratamiento con MCF fue interrumpido debido a la presencia de toxicidad hep&#225;tica&#46;</p></span>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Data expressed as patients and percentages &#40;in parenthesis&#41; unless otherwise stated&#46;</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">Variables&nbsp;\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">Patients &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Men&#47;women&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Age&#44; years&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;2 &#40;15&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">BMI&#44; kg&#47;m<span class="elsevierStyleSup">2</span>&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#46;4 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Previous or on admission hepatobiliary disease&#44; no&#46; &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top">MCF&#44; daily dose&#44; mg&#44; no&#46; &#40;&#37;&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;83&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>150&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">MCF dose&#47;body weight&#44; mg&#47;kg&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Duration of treatment&#44; days&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#46;4 &#40;8&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Cmax<span class="elsevierStyleInf">ss</span>&#44; mg&#47;L&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;94 &#40;2&#46;94&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Cmin<span class="elsevierStyleInf">ss</span>&#44; mg&#47;L&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;51 &#40;0&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1270958.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="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Altered liver function tests</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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">At the start of MCF therapy&nbsp;\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">At the end of MCF therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Patients&#44; no&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">AST&#44; IU&#47;L<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5 upper normal limit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">ALT&#44; IU&#47;L<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5 upper normal limit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Alkaline phosphatase&#44; IU&#47;L&#44; &#62;2 upper normal limit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Total bilirubin&#44; mg&#47;dL&#44; &#62;3 upper normal limit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Child-Pugh A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Child-Pugh B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Child-Pugh C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1270959.png"
              ]
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          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Acute pancreatitis and biliary lithiasis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#59; acute pancreatitis and acute cholangitis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#59; Biliary lithiasis &#40;gallbladder and common duct&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#59; HCV chronic infection &#40;genotype A1&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#59; Alcohol-related liver cirrhosis Child-Pugh C &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#59; HCV-related cirrhosis Child-Pugh B&#44; hepatocellular carcinoma BCLC A4 &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Characteristics of 12 patients with proven or suspected invasive fungal infection treated with micafungin &#40;MCF&#41;&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            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">MCF plasma level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">At the beginning of treatment with MCF</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">At the end of treatment with MCF</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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">Liver function test&nbsp;\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">rho<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">P</span> value&nbsp;\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">Liver function test&nbsp;\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">rho<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">P</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Cmin<span class="elsevierStyleInf">ss</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;175&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;607&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;407&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;495&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;121&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;232&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;756&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alkaline phosphatase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;571&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;085&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alkaline phosphatase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;803&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total bilirubin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;431&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;185&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total bilirubin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;084&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;831&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Cmax<span class="elsevierStyleInf">ss</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;302&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;340&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;049&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;894&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;441&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;683&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;042&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;328&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;187&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 0213005X
Original language: English

DOI:10.1016/j.eimc.2015.02.021

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Year/Month	Html	Pdf	Total

2024 October	15	10	25
2024 September	59	18	77
2024 August	38	19	57
2024 July	56	30	86
2024 June	59	18	77
2024 May	58	23	81
2024 April	48	30	78
2024 March	66	21	87
2024 February	70	26	96
2024 January	109	34	143
2023 December	88	34	122
2023 November	108	36	144
2023 October	108	50	158
2023 September	52	31	83
2023 August	63	16	79
2023 July	74	48	122
2023 June	57	21	78
2023 May	56	17	73
2023 April	52	10	62
2023 March	50	8	58
2023 February	45	11	56
2023 January	45	14	59
2022 December	33	20	53
2022 November	62	31	93
2022 October	59	18	77
2022 September	42	12	54
2022 August	71	27	98
2022 July	40	7	47
2022 June	52	25	77
2022 May	59	21	80
2022 April	83	28	111
2022 March	86	18	104
2022 February	59	15	74
2022 January	67	12	79
2021 December	41	17	58
2021 November	61	12	73
2021 October	66	14	80
2021 September	56	21	77
2021 August	62	15	77
2021 July	40	15	55
2021 June	48	34	82
2021 May	47	20	67
2021 April	94	35	129
2021 March	67	8	75
2021 February	51	15	66
2021 January	42	19	61
2020 December	43	11	54
2020 November	42	16	58
2020 October	35	11	46
2020 September	66	17	83
2020 August	46	22	68
2020 July	37	6	43
2020 June	42	21	63
2020 May	56	25	81
2020 April	40	18	58
2020 March	48	22	70
2020 February	45	12	57
2020 January	57	16	73
2019 December	74	36	110
2019 November	29	10	39
2019 October	45	12	57
2019 September	46	12	58
2019 August	39	12	51
2019 July	36	21	57
2019 June	64	26	90
2019 May	129	59	188
2019 April	59	47	106
2019 March	21	3	24
2019 February	24	14	38
2019 January	19	3	22
2018 December	16	6	22
2018 November	23	8	31
2018 October	30	16	46
2018 September	29	4	33
2018 August	13	7	20
2018 July	3	6	9
2018 June	9	1	10
2018 May	12	10	22
2018 April	11	3	14
2018 March	6	2	8
2018 February	9	4	13
2018 January	4	3	7
2017 December	12	3	15
2017 November	16	6	22
2017 October	23	6	29
2017 September	22	4	26
2017 August	18	3	21
2017 July	12	4	16
2017 June	17	2	19
2017 May	1	0	1
2017 March	4	0	4
2017 February	32	3	35
2017 January	54	4	58
2016 December	71	9	80
2016 November	3	2	5
2016 October	6	4	10
2016 September	3	4	7
2016 August	2	2	4
2016 July	1	0	1

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