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"subdocumento" => "crp" "cita" => "Enferm Infecc Microbiol Clin. 2016;34:536-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3116 "formatos" => array:3 [ "EPUB" => 37 "HTML" => 2334 "PDF" => 745 ] ] "es" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Carta científica</span>" "titulo" => "Meropenem y ácido valproico: interacción farmacológica clínicamente relevante" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "536" "paginaFinal" => "537" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Meropenem and valproic acid: A clinically relevant drug-drug interaction" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1086 "Ancho" => 1738 "Tamanyo" => 145114 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Evolución de las dosis (mg/día) de meropenem y valproato administradas, y de los niveles de ácido valproico (mg/l) detectados.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elena Sánchez-Yáñez, Clara Estaún-Martínez, Guillermo Ojeda Burgos" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Elena" "apellidos" => "Sánchez-Yáñez" ] 1 => array:2 [ "nombre" => "Clara" "apellidos" => "Estaún-Martínez" ] 2 => array:2 [ "nombre" => "Guillermo" "apellidos" => "Ojeda Burgos" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X15003808?idApp=UINPBA00004N" "url" => "/0213005X/0000003400000008/v1_201609231307/S0213005X15003808/v1_201609231307/es/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0213005X15004486" "issn" => "0213005X" "doi" => "10.1016/j.eimc.2015.11.012" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1452" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Enferm Infecc Microbiol Clin. 2016;34:532-4" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1009 "formatos" => array:3 [ "EPUB" => 14 "HTML" => 750 "PDF" => 245 ] ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Autochthonous <span class="elsevierStyleItalic">Cryptosporidium cuniculus</span> infection in Spain: First report in a symptomatic paediatric patient from Madrid" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "532" "paginaFinal" => "534" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Infección autóctona por <span class="elsevierStyleItalic">Cryptosporidium cuniculus</span> en España: primer informe en un paciente pediátrico sintomático del área de Madrid" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 5997 "Ancho" => 6683 "Tamanyo" => 1097053 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Phylogenetic relationships between <span class="elsevierStyleItalic">Cryptosporidium cuniculus</span> and <span class="elsevierStyleItalic">Cryptosporidium</span> spp. sub-genotypes at the <span class="elsevierStyleItalic">GP60</span> locus inferred by a neighbour-joining analysis of the nucleotide sequence covering a 445-bp region (positions 1 to 445 of GenBank accession number GU971645, allele VbA34) of the gene. Empty and filled circles indicate representative <span class="elsevierStyleItalic">C. cuniculus</span> sequences belonging to the sub-genotype families Va and Vb, respectively. Empty triangles and squares indicate representative sequences of the most frequent sub-genotypes of <span class="elsevierStyleItalic">C. hominis</span> and <span class="elsevierStyleItalic">C. parvum</span>, respectively. Bootstrapping values over 50% from 1000 replicates are indicated at the branch points. The evolutionary distances were computed using the Kimura 2-parameter method. The rate variation among sites was modelled with a gamma distribution (shape parameter<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2). <span class="elsevierStyleItalic">C. ubiquitum</span> was used as outgroup taxa.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rocío Martínez-Ruiz, Aida de Lucio, Isabel Fuentes, David Carmena" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Rocío" "apellidos" => "Martínez-Ruiz" ] 1 => array:2 [ "nombre" => "Aida" "apellidos" => "de Lucio" ] 2 => array:2 [ "nombre" => "Isabel" "apellidos" => "Fuentes" ] 3 => array:2 [ "nombre" => "David" "apellidos" => "Carmena" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X15004486?idApp=UINPBA00004N" "url" => "/0213005X/0000003400000008/v1_201609231307/S0213005X15004486/v1_201609231307/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Development of daptomycin resistance during therapy in a patient with methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> endocarditis: A case report" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "534" "paginaFinal" => "535" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Alma Sotillo, José Ramón Paño-Pardo, Beatriz López-Quintana, Rosa Gómez-Gil" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Alma" "apellidos" => "Sotillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "José Ramón" "apellidos" => "Paño-Pardo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Beatriz" "apellidos" => "López-Quintana" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:4 [ "nombre" => "Rosa" "apellidos" => "Gómez-Gil" "email" => array:1 [ 0 => "mrosa.gomezgil@salud.madrid.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Microbiología, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Microbiología Clínica y Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Desarrollo de resistencia a daptomicina durante el tratamiento de un paciente con endocarditis por <span class="elsevierStyleItalic">Staphylococcus aureus</span> resistente a meticilina" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A 69-year-old woman was sent to the emergency room by her cardiologist after a gastrointestinal bleeding episode. She had a history of allergy to amoxicillin-clavulanic acid (rash), type 2 diabetes, hypertension, hypothyroidism, peptic ulcer disease and iron-deficiency anemia. She had a mechanic prosthetic mitral valve placed four years before due to rheumatic mitral stenosis. At that time a tricuspid anuloplasty had been performed. She had atrial fibrillation and severe pulmonary hypertension and was receiving oral anticoagulation, all of which leading to a NYHA class II–III congestive heart failure (CHF) with multiple hospital admissions due to decompensated CHF. Hematocrit was stable and an upper gastrointestinal endoscopy did not show bleeding, ruling out acute gastrointestinal bleed. Elevated creatinine was observed (1.97<span class="elsevierStyleHsp" style=""></span>mg/dL); acute renal failure was considered to be pre-renal, associated to diuretics. On day 5 after hospitalization she presented fever and a painful hematoma around a previous peripheral intravenous line. Blood cultures were obtained and levofloxacin therapy was started. Blood cultures became positive in less than 24<span class="elsevierStyleHsp" style=""></span>h, gram-positive cocci in clusters were observed and identified as <span class="elsevierStyleItalic">Staphylococcus aureus</span> by MALDI-TOF mass spectrometry. Antimicrobial therapy was switched to daptomycin 9<span class="elsevierStyleHsp" style=""></span>mg/kg q48<span class="elsevierStyleHsp" style=""></span>h because her creatinine was rising and her estimated creatinine clearance at that time was 33<span class="elsevierStyleHsp" style=""></span>mL/min. MIC testing was conducted by VITEK<span class="elsevierStyleSup">®</span> and confirmed by Microscan<span class="elsevierStyleSup">®</span> and E-test Biomerieux<span class="elsevierStyleSup">®</span>. The isolate was resistant to methicillin, erythromycin, levofloxacin and tobramycin, and susceptible to trimethoprim-sulfamethoxazole, clindamycin, vancomycin (MIC<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>or<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mg/L), and daptomycin (MIC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.25<span class="elsevierStyleHsp" style=""></span>mg/L). She became afebrile in less than 48<span class="elsevierStyleHsp" style=""></span>h and blood cultures were serially obtained. As part of the initial workup a transesophageal echocardiogram (TEE), which was negative for endocarditis, and an angio-CT scan were performed, disclosing intramuscular hematoma without venous thrombosis and several pulmonary nodules consistent with septic emboli. Blood culture from day 11 was positive, so linezolid (600<span class="elsevierStyleHsp" style=""></span>mg BID iv) was added to daptomycin on day 13. Blood cultures from day 13 continued to be positive for MRSA with the same susceptibility profile as the previous isolates except for daptomycin (MIC of 2<span class="elsevierStyleHsp" style=""></span>mg/L) and vancomycin (MIC of 1<span class="elsevierStyleHsp" style=""></span>mg/L). This was confirmed by E-test<span class="elsevierStyleSup">®</span>. Antimicrobial therapy was switched to teicoplanin (8<span class="elsevierStyleHsp" style=""></span>mg/kg) plus intravenous fosfomycin (4<span class="elsevierStyleHsp" style=""></span>g TID). On day 15 a repeat TEE showed a 7.5<span class="elsevierStyleHsp" style=""></span>mm-long filiform vegetation attached to the auricular side of the prosthetic mitral valve. Thickening of mitro-aortic junction was found too. Cardiac surgery consultation was performed but the patient was not considered a surgical candidate given her baseline dyspnea and severe pulmonary hypertension despite a non-disfunctioning prosthetic valve. She remained afebrile during the whole hospitalization but having dyspnea on minimal physical activity. On day 25 she had a cardiac arrest and died.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Genetic relatedness between the isolates was confirmed by pulsed-field gel electrophoresis (PFGE) with <span class="elsevierStyleItalic">Sma</span>I digestion using the protocol described by Pérez-Vázquez et al. Sequencing of genes reported to be involved in decreased susceptibility to daptomycin (<span class="elsevierStyleItalic">walkA</span>, <span class="elsevierStyleItalic">rpoB, agrA</span> and <span class="elsevierStyleItalic">mprF</span>) showed a G2476A mutation (numbering refers to Genbank entry HM140976) in the <span class="elsevierStyleItalic">mprF</span> gene of the resistant isolate, but not in the susceptible isolate. MLST analysis showed that the <span class="elsevierStyleItalic">S. aureus</span> isolates from days 5 and 13 belonged to ST125. This mutation would translate into a leucine to phenylalanine change in position 826 of the protein sequence (L826F), close to the C-terminus. The <span class="elsevierStyleItalic">walK</span> and <span class="elsevierStyleItalic">agrA</span> genes had no mutations and were identical in the susceptible and resistant isolates.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Discussion</span><p id="par0015" class="elsevierStylePara elsevierViewall">We report a case of treatment failure associated with the development of daptomycin nonsusceptibility during therapy with daptomycin in a patient with acute infective endocarditis due to methicillin-resistant <span class="elsevierStyleItalic">S. aureus</span>.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Treatment options for bacteraemia and endocarditis caused by methicillin-resistant <span class="elsevierStyleItalic">S. aureus</span> (MRSA) are limited. The standard therapy is vancomycin but has been associated with suboptimal outcomes in some cases. Daptomycin is a cyclic lipopeptide antibiotic that has bactericidal activity against a broad spectrum of gram-positive bacteria and an important agent in treating invasive <span class="elsevierStyleItalic">S. aureus</span> infections.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The incidence of daptomycin resistance in clinical isolates is low and the mechanisms of resistance in <span class="elsevierStyleItalic">S. aureus</span> appear to be quite diverse. One of the genes most commonly found to be involved in resistance is the multipeptide resistance factor gene (<span class="elsevierStyleItalic">mprF</span>).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">mprF</span> gene codes for a lysyl-phosphatidylglycerol (L-PG) synthase that transfers lysine residues to phosphatidylglycerol and translocates the resulting lysil-phosphatidylglycerol to the outer membrane leaflet.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> Mutants lacking MprF activity show increased susceptibility to cationic antimicrobial peptides, while mutants associated to daptomycin resistance show increased synthesis or enhanced translocation of lysil-phosphatidylglycerol.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">2</span></a> The resistance has been mapped to the C-terminal portion of MprF, and the L826F mutation has been shown to be causally related to the resistance phenotype in a daptomycin-resistant MRSA clinical isolate.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">There are some reports of development of daptomycin resistance in <span class="elsevierStyleItalic">S. aureus</span> during treatment with daptomycin in patients with endocarditis, and in most cases vancomycin therapy had been used before switching to daptomycin.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4,5</span></a> The emergence of daptomycin resistance in the absence of vancomycin exposure is uncommon.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">6–8</span></a> In our case, daptomycin was the primary therapy, the resistant isolate emerged after 7 days and had a point mutation in <span class="elsevierStyleItalic">mprF</span>. Daptomycin was dosed at 9<span class="elsevierStyleHsp" style=""></span>mg/kg, but given the impaired renal function of the patient the administration interval was adjusted to q48<span class="elsevierStyleHsp" style=""></span>h as recommended, resulting in suboptimal dosing during at least 48<span class="elsevierStyleHsp" style=""></span>h when creatinine clearance increased above the adjustment threshold. Some authors have suggested that a suboptimal dose-regimen may contribute to the emergence of daptomycin resistance.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">7,9</span></a> Two observational studies including patients with impaired renal function receiving daptomycin for MRSA bloodstream infections showed favorable clinical success rates, in spite that a significant proportion of patients received less than 6<span class="elsevierStyleHsp" style=""></span>mg/kg. In these cohorts daptomycin non-susceptible strains emerged in 2/38 and 2/106 patients respectively, all between days 5–7 of daptomycin therapy. Two patients were on hemodialysis and two had mild to moderate renal failure with daptomycin being dosed at 4<span class="elsevierStyleHsp" style=""></span>mg/kg/24<span class="elsevierStyleHsp" style=""></span>h and 8<span class="elsevierStyleHsp" style=""></span>mg/kg. No information about the mechanisms of resistance was provided.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">10,11</span></a> Use of higher dose daptomycin regimens, up to 10–12<span class="elsevierStyleHsp" style=""></span>mg/kg can forestall the emergence of resistance.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">12–14</span></a> This case report underlines the importance of dose interval adjustment in patients with moderately impaired renal function.</p><p id="par0040" class="elsevierStylePara elsevierViewall">We appreciate the collaboration of Dr. Juan de Dios Caballero and Microbiology at the Ramon y Cajal Hospital for performing PFGE.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Discussion" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib0075" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell wall thickening is not a universal accompaniment of the daptomycin nonsusceptibility phenotype in <span class="elsevierStyleItalic">Staphylococcus aureus</span>: evidence for multiple resistance mechanisms" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.-J. Yang" 1 => "C.C. Nast" 2 => "N.N. Mishra" 3 => "M.R. Yeaman" 4 => "P.D. Fey" 5 => "A.S. Bayer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.00122-10" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2010" "volumen" => "54" "paginaInicial" => "3079" "paginaFinal" => "3085" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20498310" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0080" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Causal role of single nucleotide polymorphisms within the mprF gene of <span class="elsevierStyleItalic">Staphylococcus aureus</span> in daptomycin resistance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.-J. Yang" 1 => "N.N. Mishra" 2 => "A. Rubio" 3 => "A.S. Bayer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.01184-13" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2013" "volumen" => "57" "paginaInicial" => "5658" "paginaFinal" => "5664" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24002096" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0085" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "VraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span>" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Mehta" 1 => "A.X. Cuirolo" 2 => "K.B. Plata" 3 => "S. Riosa" 4 => "J.A. Silverman" 5 => "A. Rubio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.00432-10" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2012" "volumen" => "56" "paginaInicial" => "92" "paginaFinal" => "102" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21986832" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0090" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Daptomycin non-susceptible meticillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> USA 300 isolate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.H. Murthy" 1 => "M.E. Olson" 2 => "R.W. Wickert" 3 => "P.D. Fey" 4 => "Z. 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Year/Month | Html | Total | |
---|---|---|---|
2024 October | 7 | 7 | 14 |
2024 September | 36 | 17 | 53 |
2024 August | 18 | 10 | 28 |
2024 July | 9 | 7 | 16 |
2024 June | 14 | 9 | 23 |
2024 May | 17 | 3 | 20 |
2024 April | 11 | 3 | 14 |
2024 March | 20 | 2 | 22 |
2024 February | 18 | 5 | 23 |
2024 January | 21 | 0 | 21 |
2023 December | 15 | 3 | 18 |
2023 November | 23 | 9 | 32 |
2023 October | 22 | 8 | 30 |
2023 September | 14 | 3 | 17 |
2023 August | 11 | 1 | 12 |
2023 July | 25 | 4 | 29 |
2023 June | 23 | 1 | 24 |
2023 May | 12 | 6 | 18 |
2023 April | 31 | 4 | 35 |
2023 March | 29 | 2 | 31 |
2023 February | 19 | 4 | 23 |
2023 January | 10 | 5 | 15 |
2022 December | 17 | 5 | 22 |
2022 November | 31 | 13 | 44 |
2022 October | 12 | 12 | 24 |
2022 September | 29 | 13 | 42 |
2022 August | 23 | 13 | 36 |
2022 July | 34 | 6 | 40 |
2022 June | 18 | 10 | 28 |
2022 May | 34 | 15 | 49 |
2022 April | 24 | 14 | 38 |
2022 March | 35 | 12 | 47 |
2022 February | 24 | 5 | 29 |
2022 January | 32 | 15 | 47 |
2021 December | 48 | 21 | 69 |
2021 November | 33 | 14 | 47 |
2021 October | 42 | 20 | 62 |
2021 September | 37 | 12 | 49 |
2021 August | 28 | 10 | 38 |
2021 July | 38 | 18 | 56 |
2021 June | 20 | 9 | 29 |
2021 May | 23 | 14 | 37 |
2021 April | 37 | 28 | 65 |
2021 March | 35 | 7 | 42 |
2021 February | 38 | 4 | 42 |
2021 January | 26 | 25 | 51 |
2020 December | 19 | 6 | 25 |
2020 November | 21 | 4 | 25 |
2020 October | 18 | 7 | 25 |
2020 September | 32 | 14 | 46 |
2020 August | 19 | 7 | 26 |
2020 July | 13 | 7 | 20 |
2020 June | 24 | 15 | 39 |
2020 May | 22 | 19 | 41 |
2020 April | 24 | 8 | 32 |
2020 March | 18 | 16 | 34 |
2020 February | 16 | 4 | 20 |
2020 January | 27 | 11 | 38 |
2019 December | 24 | 13 | 37 |
2019 November | 20 | 11 | 31 |
2019 October | 28 | 11 | 39 |
2019 September | 16 | 3 | 19 |
2019 August | 19 | 2 | 21 |
2019 July | 30 | 15 | 45 |
2019 June | 47 | 12 | 59 |
2019 May | 138 | 22 | 160 |
2019 April | 70 | 18 | 88 |
2019 March | 16 | 2 | 18 |
2019 February | 20 | 6 | 26 |
2019 January | 11 | 2 | 13 |
2018 December | 12 | 5 | 17 |
2018 November | 23 | 2 | 25 |
2018 October | 24 | 3 | 27 |
2018 September | 25 | 2 | 27 |
2018 August | 32 | 0 | 32 |
2018 July | 7 | 0 | 7 |
2018 June | 10 | 1 | 11 |
2018 May | 24 | 5 | 29 |
2018 April | 24 | 2 | 26 |
2018 March | 7 | 0 | 7 |
2018 February | 40 | 1 | 41 |
2018 January | 24 | 1 | 25 |
2017 December | 36 | 0 | 36 |
2017 November | 21 | 1 | 22 |
2017 October | 10 | 3 | 13 |
2017 September | 19 | 2 | 21 |
2017 August | 12 | 2 | 14 |
2017 July | 20 | 5 | 25 |
2017 June | 20 | 9 | 29 |
2017 May | 11 | 2 | 13 |
2017 April | 17 | 4 | 21 |
2017 March | 3 | 6 | 9 |
2017 February | 23 | 2 | 25 |
2017 January | 55 | 1 | 56 |
2016 December | 139 | 4 | 143 |
2016 November | 711 | 6 | 717 |
2016 October | 100 | 12 | 112 |
2016 September | 30 | 8 | 38 |
2016 August | 3 | 3 | 6 |
2016 July | 1 | 2 | 3 |