Original article
Analysis of the valproic acid-meropenem interaction in hospitalised patients
Análisis de la interacción ácido valproico-meropenem en pacientes hospitalizados
M. Vélez-Díaz-Pallarés
, E. Delgado Silveira, A.M. Álvarez Díaz, C. Pérez Menéndez-Conde, N. Vicente Oliveros, T. Bermejo Vicedo
Corresponding author
Servicio de Farmacia, Hospital Universitario Ramón y Cajal, Madrid, Spain
Read
11253
Timeswas read the article
1662
Total PDF
9591
Total HTML
Share statistics
array:25 [ "pii" => "S2173580812000107" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2011.03.006" "estado" => "S300" "fechaPublicacion" => "2012-01-01" "aid" => "217" "copyright" => "Sociedad Española de Neurología" "copyrightAnyo" => "2011" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Neurologia. 2012;27:34-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3655 "formatos" => array:3 [ "EPUB" => 67 "HTML" => 2817 "PDF" => 771 ] ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0213485311001423" "issn" => "02134853" "doi" => "10.1016/j.nrl.2011.03.008" "estado" => "S300" "fechaPublicacion" => "2012-01-01" "aid" => "217" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Neurologia. 2012;27:34-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 9052 "formatos" => array:3 [ "EPUB" => 69 "HTML" => 7908 "PDF" => 1075 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original</span>" "titulo" => "Análisis de la interacción ácido valproico-meropenem en pacientes hospitalizados" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "34" "paginaFinal" => "38" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Analysis of the valproic acid-meropenem interaction in hospitalised patients" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "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" => 1233 "Ancho" => 2649 "Tamanyo" => 172809 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Representación de la relación temporal de la interacción entre VPA y meropenem en un paciente ingresado.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Vélez Díaz-Pallarés, E. Delgado Silveira, A.M. Álvarez Díaz, C. Pérez Menéndez-Conde, N. Vicente Oliveros, T. Bermejo Vicedo" "autores" => array:6 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Vélez Díaz-Pallarés" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Delgado Silveira" ] 2 => array:2 [ "nombre" => "A.M." "apellidos" => "Álvarez Díaz" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Pérez Menéndez-Conde" ] 4 => array:2 [ "nombre" => "N." "apellidos" => "Vicente Oliveros" ] 5 => array:2 [ "nombre" => "T." "apellidos" => "Bermejo Vicedo" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173580812000107" "doi" => "10.1016/j.nrleng.2011.03.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000107?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311001423?idApp=UINPBA00004N" "url" => "/02134853/0000002700000001/v1_201305151129/S0213485311001423/v1_201305151129/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2173580812000065" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2010.06.003" "estado" => "S300" "fechaPublicacion" => "2012-01-01" "aid" => "203" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Neurologia. 2012;27:39-45" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2282 "formatos" => array:3 [ "EPUB" => 54 "HTML" => 1660 "PDF" => 568 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Monoclonal antibodies in inflammatory disease of the muscle and peripheral nervous system" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "39" "paginaFinal" => "45" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anticuerpos monoclonales en patología inflamatoria del sistema nervioso periférico y músculo" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.J. Poza Aldea" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J.J." "apellidos" => "Poza Aldea" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485311001009" "doi" => "10.1016/j.nrl.2011.02.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311001009?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000065?idApp=UINPBA00004N" "url" => "/21735808/0000002700000001/v1_201305151316/S2173580812000065/v1_201305151316/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2173580812000119" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2011.03.007" "estado" => "S300" "fechaPublicacion" => "2012-01-01" "aid" => "224" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Neurologia. 2012;27:28-33" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1973 "formatos" => array:3 [ "EPUB" => 44 "HTML" => 1248 "PDF" => 681 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Patients with mild cognitive impairment and a reduced CSF Aβ<span class="elsevierStyleInf">1-42</span> protein progress rapidly to Alzheimer's disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "28" "paginaFinal" => "33" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ<span class="elsevierStyleInf">1-42</span> en LCR evolucionan rápidamente a enfermedad de Alzheimer" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.A. Monge-Argilés, J. Sánchez-Payá, C. Muñoz-Ruiz, A. Pampliega-Pérez, M.J. Gómez-López, E. Rodríguez Borja, J. Montoya-Gutiérrez, C. Leiva-Santana" "autores" => array:8 [ 0 => array:2 [ "nombre" => "J.A." "apellidos" => "Monge-Argilés" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Sánchez-Payá" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Muñoz-Ruiz" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Pampliega-Pérez" ] 4 => array:2 [ "nombre" => "M.J." "apellidos" => "Gómez-López" ] 5 => array:2 [ "nombre" => "E." "apellidos" => "Rodríguez Borja" ] 6 => array:2 [ "nombre" => "J." "apellidos" => "Montoya-Gutiérrez" ] 7 => array:2 [ "nombre" => "C." "apellidos" => "Leiva-Santana" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485311001617" "doi" => "10.1016/j.nrl.2011.03.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311001617?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000119?idApp=UINPBA00004N" "url" => "/21735808/0000002700000001/v1_201305151316/S2173580812000119/v1_201305151316/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Analysis of the valproic acid-meropenem interaction in hospitalised patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "34" "paginaFinal" => "38" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Vélez-Díaz-Pallarés, E. Delgado Silveira, A.M. Álvarez Díaz, C. Pérez Menéndez-Conde, N. Vicente Oliveros, T. Bermejo Vicedo" "autores" => array:6 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Vélez-Díaz-Pallarés" "email" => array:1 [ 0 => "mvelez.hrc@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Delgado Silveira" ] 2 => array:2 [ "nombre" => "A.M." "apellidos" => "Álvarez Díaz" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Pérez Menéndez-Conde" ] 4 => array:2 [ "nombre" => "N." "apellidos" => "Vicente Oliveros" ] 5 => array:2 [ "nombre" => "T." "apellidos" => "Bermejo Vicedo" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Farmacia, Hospital Universitario Ramón y Cajal, Madrid, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis de la interacción ácido valproico-meropenem en pacientes hospitalizados" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1233 "Ancho" => 2628 "Tamanyo" => 163416 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Representation of the temporal relationship of the interaction between valproic acid (VPA) and meropenem in a hospital inpatient.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pharmaceutical intervention (PI) in pharmacotherapeutic monitoring aims to identify and resolve medication-related problems (MRPs). Drug interactions are one of the MRPs in which pharmacists can advise on clinical decision-making to ensure the safest and most effective therapy. In the case of patients with epilepsy, drug interactions have proven to be a major challenge for the maintenance of therapeutic concentrations of anticonvulsant drugs.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Valproic acid (VPA) is one of the most frequently used drugs in the treatment of epilepsy and should be monitored because it has a narrow therapeutic blood margin (50–125<span class="elsevierStyleHsp" style=""></span>μg/ml).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> On the other hand, meropenem is a bactericidal antibiotic with a broad spectrum of activity that is used for a variety of infections in hospitals, for example, in patients with neurological base pathologies, who present respiratory infections requiring broad spectrum antibiotics. These are two drugs whose coincidence in the drug therapy of a single patient is not exceptional and whose interaction is reflected in specific bibliographic sources on this topic.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">This interaction is characterised by a rapid decline in VPA levels within 1–7 days after the start of coadministration with meropenem and their slow recovery after treatment discontinuation (from 3 days to 2 weeks). There are published case series and retrospective studies confirming these data.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–9</span></a> Recent studies point to a combination of the mechanisms of VPA absorption, distribution and metabolism that would explain the interaction.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Avoiding coadministration is the most recent recommendation<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and has been included in the meropenem data sheet.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Meanwhile, Mancl and Gidal<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> recommend in a recent review that, in the absence of an alternative antibiotic therapy, VPA levels should be monitored more frequently and the use of higher doses of VPA should be considered.</p><p id="par0020" class="elsevierStylePara elsevierViewall">After an exhaustive literature review, we found no prospective studies with such a large number of patients that evaluated the interaction between meropenem and VPA. Neither did we find the PI performed in this respect.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study was to analyse the interaction between VPA and meropenem and to evaluate the impact of the PI on the use of these drugs in hospitalised patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">The study was conducted at a tertiary care hospital with 1080 beds in 2 periods: a retrospective and observational study without PI (January to November 2007) and a prospective study with PI (March 2008 to January 2009).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Prescriptions for both drugs were checked daily and a PI was performed in cases of concomitant treatment (during the prospective period). This consisted of contacting the treating physician through online messages and/or telephone calls. The PI included suggestions to change to antibiotic therapy and, if this was not possible, to monitor VPA levels. In addition, we created an electronic alert within the Prescriwin<span class="elsevierStyleSup">®</span> prescribing module of the Hospiwin<span class="elsevierStyleSup">®</span> program, which consisted of having an automatic warning appear when both drugs were prescribed for the same patient, thus reporting about the interaction in real-time.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In both periods we selected admitted patients with assisted electronic prescription, recording age, gender, indication, duration, dose and date of prescription of both drugs, as well as reviewing medical records for the presence of seizures during admission. We recorded VPA levels before, during and after treatment with meropenem. We calculated the drug interaction probability scale (DIPS)<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> for each of the individuals.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We analysed the impact of the PI and the electronic warning for the prescription of both drugs between the two study periods. We compared the number of patients who were prescribed the 2 drugs in each period, the number of days of concomitant treatment and the number of requests for plasma VPA levels, as well as the acceptance of the PI by the physician.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The data were analysed using the “Evaluation of treatments” program, version 1.0.1, developed by the hospital clinical biostatistics unit (<a href="http://www.hrc.es/investigacion/bioest/otras_calculadoras.html">http://www.hrc.es/investigacion/bioest/otras_calculadoras.html</a>), which enabled relative risk reduction and absolute risk reduction. We used a 95% confidence interval.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The main treatment indications for VPA were different types of epilepsy and control of seizures, whereas it was the empirical treatment of aspiration pneumonia in severely ill patients for meropenem. The interaction variables collected between the 2 study periods are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">During the prospective period, pharmacists performed a total of 13 PI and all were reported to the physician responsible for the interaction. In 4 cases, the physician decided to monitor the VPA levels more closely, in 3 the antibiotic was changed to piperacillin-tazobactam, in 2 to levofloxacin and in 4 the prescription of both drugs was maintained.</p><p id="par0065" class="elsevierStylePara elsevierViewall">As a result of the PI, the number of days of concomitant treatment with meropenem was halved (from 10 to 4.7 days) and VPA levels were requested 2.6 times more often per day of concomitant treatment compared with the retrospective period. These differences were statistically significant (95% confidence interval).</p><p id="par0070" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the drug therapy prescribed for the patient who obtained a DIPS score above 8 (very likely). While in hospital, he received meropenem on 2 occasions; in both cases the VPA levels decreased to less than therapeutic values, even though higher doses of the antiepileptic agent were prescribed during those days. On the first occasion, after 2 days of meropenem treatment, it was decided to change the antibiotic to levofloxacin, and on the second to piperacillin-tazobactam, followed in both cases by PI. Once the effect of meropenem was over in this patient, the dose of VPA could be reduced to the initial value and the therapeutic dosage levels were recovered.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Following administration of a single dose of meropenem, 1 of the patients presented seizures that were directly related to the interaction, since less than 24<span class="elsevierStyleHsp" style=""></span>h after the administration of antibiotics, the VPA levels were 28.80<span class="elsevierStyleHsp" style=""></span>μg/ml (infratherapeutic). The antibiotic was then changed to piperacillin-tazobactam.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">From a pharmacokinetic standpoint, the interaction between VPA and meropenem is very complex, since it seems to involve numerous mechanisms that lower antiepileptic agent concentrations.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> A decrease in the absorption of VPA,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> decrease in its enterohepatic recycling,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> a change in distribution volume reducing the free drug proportion<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and, finally, increase in VPA glucuronidation<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> could all justify such abrupt reductions in plasma concentrations of the antiepileptic agent.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Coinciding with other authors, our study found that the interaction between meropenem and VPA was potentially serious, especially due to the speed with which plasma concentration of the antiepileptic agent decreased and the consequences this entailed.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> In our study, 1 of the patients presented epileptic seizures after administration of a single dose of meropenem. Monitoring the antiepileptic revealed a decrease in VPA values to less than therapeutic levels within 24<span class="elsevierStyleHsp" style=""></span>h, so the interaction appears to have a very rapid onset. De Turck et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> found that the half-life of VPA decreased from 15 to 4<span class="elsevierStyleHsp" style=""></span>h, 24<span class="elsevierStyleHsp" style=""></span>h after administration of meropenem.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Haroutiunian et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> found that, during concomitant therapy with meropenem, mean VPA levels were 9.9<span class="elsevierStyleHsp" style=""></span>μg/ml. None of the patients in our study maintained therapeutic levels of VPA and, in addition, the decrease in VPA levels after administration of the first dose of meropenem ranged between 49.1% and 96.3%. Different studies have reported similar declines (from 66% to 90%).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,11,21,22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">For some authors the recovery of VPA levels after discontinuation of the antibiotic is extended from 3 days to 2 weeks.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> However, we were only able to determine it for 2 patients, who recovered their levels 13 and 14 days after discontinuation of meropenem, because the levels were not requested until much later for the remaining patients.</p><p id="par0100" class="elsevierStylePara elsevierViewall">At present there is no consensus regarding the therapeutic approach to be followed with this interaction and, consequently, no agreement as to the PI that must be carried out. Several authors recommend closer monitoring of the antiepileptic agent when both drugs are to be administered, as in those cases where it is not possible to replace either of them.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,9,13,23</span></a> This recommendation also appears in the technical data sheet of VPA.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, other authors are more categorical and suggest that good clinical practice would mean not to administer both drugs together.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,24</span></a> In some countries, such as Japan, health authorities have banned the administration of both drugs at the same time.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The meropenem technical data sheet also reflects that the coadministration of VPA and carbapenem agents is not manageable and should therefore be avoided.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In 2010 the Spanish Agency for Medicines and Health Products issued a warning on the prescription of these drugs, contraindicating their simultaneous use.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In our case, after the PI some physicians chose to carry out more comprehensive monitoring, while others opted for suspending the antibiotic.</p><p id="par0105" class="elsevierStylePara elsevierViewall">As a limitation of the study, we must indicate that we did not include patients admitted to units that did not have assisted electronic prescription (cardiovascular surgery ICU, coronary care unit and paediatric cardiology unit).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Given the results obtained and the literature reviewed, and considering that the effectiveness of anticonvulsant therapy is directly proportional to therapeutic drug levels and the vast antibiotic arsenal at our disposal, we believe the first choice should be not to administer both drugs concomitantly. The declines in VPA levels of up to 90% in different patients in our study, as well as in other published studies, make it very difficult to manage VPA to achieve therapeutic levels without exceeding maximum doses. Therefore, we conclude that the concomitant use of both drugs should be avoided, replacing the antibiotic therapy empirically or according to the resistance patterns of the microorganism being treated in order to maintain the same anticonvulsant therapy.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interests</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres169655" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec157747" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres169654" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec157746" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-01-20" "fechaAceptado" => "2011-03-06" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec157747" "palabras" => array:6 [ 0 => "Valproic acid" 1 => "Epilepsy" 2 => "Drug interactions" 3 => "Pharmaceutical intervention" 4 => "Meropenem" 5 => "Plasma level" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec157746" "palabras" => array:6 [ 0 => "Ácido valproico" 1 => "Epilepsia" 2 => "Interacción farmacocinética" 3 => "Intervención farmacéutica" 4 => "Meropenem" 5 => "Niveles plasmáticos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Published data demonstrate a serious interaction between valproic acid and meropenem. However, recommendations about the management of concomitant treatment are contradictory; some experts recommend closer monitoring of valproic acid serum concentrations and others recommend avoiding concurrent therapy. The purpose of this study is to critically analyse the interaction and to evaluate the impact of pharmaceutical intervention in the use of these drugs in hospitalised patients.</p> <span class="elsevierStyleSectionTitle">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Study of the concomitant prescription of valproic acid and meropenem in a general hospital of 1080 beds divided in to two periods; the first period was retrospective and observational and it was followed by a prospective period involving pharmaceutical intervention. The prescription habits between both periods were compared.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 26 patients received concurrent treatment with valproic acid and meropenem (13 per period) and none of them maintained therapeutic serum levels of the antiepileptic drug. Pharmaceutical intervention modified prescription habits, reducing by half the number of days of concomitant treatment, changing the antibiotherapy and/or monitoring serum concentrations more often.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The interaction between valproic acid and meropenem is serious, especially because of the dramatic decrease in the antiepileptic serum concentrations. The concomitant use of both drugs should be avoided, replacing the antibiotherapy empirically, or according to the resistance profiles of the microorganism and maintaining the same the anti-epileptic treatment.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Existen referencias en la literatura acerca de la gravedad de la interacción entre el ácido valproico y el meropenem. Sin embargo, las recomendaciones en cuanto a su manejo son contradictorias, recomendándose en algunos estudios la monitorización más estrecha del antiepiléptico si se emplean juntos y en otros contraindicando su uso concomitante. El objetivo de este trabajo es analizar la interacción entre el ácido valproico y el meropenem y evaluar el impacto de la intervención farmacéutica sobre la utilización de estos fármacos en pacientes hospitalizados.</p> <span class="elsevierStyleSectionTitle">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio de la prescripción concomitante de ácido valproico y meropenem en un hospital de tercer nivel de 1.080 camas dividido en dos periodos: uno retrospectivo y observacional, el otro prospectivo y con intervención farmacéutica. Se compararon los hábitos de prescripción entre ambos periodos.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Un total de 26 pacientes recibieron ácido valproico y meropenem simultáneamente (13 en cada periodo), no alcanzando ninguno niveles terapéuticos del antiepiléptico durante el tratamiento. La intervención farmacéutica cambió los hábitos de prescripción, disminuyendo a la mitad los días de tratamiento concomitante, cambiando la antibioterapia y/o monitorizando más estrechamente el antiepiléptico.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La interacción entre el ácido valproico y el meropenem es grave, especialmente por la rapidez con la que disminuyen los niveles del antiepiléptico. Se debe evitar el uso concomitante de ambos fármacos, sustituyendo la antibioterapia de manera empírica o según los patrones de resistencia del microorganismo para mantener el mismo tratamiento anticomicial.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Vélez-Díaz-Pallarés M, et al. Análisis de la interacción ácido valproico-meropenem en pacientes hospitalizados. Neurología. 2011;27:34–38.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1233 "Ancho" => 2628 "Tamanyo" => 163416 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Representation of the temporal relationship of the interaction between valproic acid (VPA) and meropenem in a hospital inpatient.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Retrospective \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Prospective \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Number of patients</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Percentage of males</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">DIPS</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Highly probable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Probable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Possible \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Not calculated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Number of study months</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">VPA range during concomitant treatment</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.14–22.76<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.63–43.87<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Decrease in VPA levels</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.6–96.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49.1–88.4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Number of requests for VPA levels during concomitant treatment</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Number of days to recover VPA levels after suspension of meropenem</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264741.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Demographic and pharmacokinetic variables of the interaction.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Assessment of potential drug interactions in patients with epilepsy: impact of age and sex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "B.E. Gidal" 1 => "J.A. French" 2 => "P. Grossman" 3 => "G. Le Teuff" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/01.wnl.0000341789.77291.8d" "Revista" => array:6 [ "tituloSerie" => "Neurology" "fecha" => "2009" "volumen" => "72" "paginaInicial" => "419" "paginaFinal" => "425" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19188572" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ficha técnica del ácido valproico [accessed 27.10.10]. Available from: <a class="elsevierStyleInterRef" href="https://sinaem4.agemed.es/consaem/especialidad.do%3Fmetodo=verFichaWordPdf%26codigo=54470%26formato=pdf%26formulario=FICHAS">https://sinaem4.agemed.es/consaem/especialidad.do?metodo=verFichaWordPdf&codigo=54470&formato=pdf&formulario=FICHAS</a>." ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interacciones farmacológicas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B.K. Stockley" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "edicion" => "2nd ed." "fecha" => "2007" "editorial" => "Pharma editores" "editorialLocalizacion" => "Barcelona" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interacción farmacocinética entre ácido valproico y antibióticos carbapenémicos: descripción de tres casos" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "F. Llinares" 1 => "N. Bosacoma" 2 => "C. Hernández" 3 => "E. Climent" 4 => "J. Selva" 5 => "J.P. Ordovás" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Farm Hosp" "fecha" => "2003" "volumen" => "27" "paginaInicial" => "258" "paginaFinal" => "263" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12966455" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meropenem and valproic acid: a dangerous combination" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Eimil-Ortiz" 1 => "D. Aguirre-Mollehuanca" 2 => "A. Sierra-Limpo" 3 => "C. Fontán-Tirado" 4 => "M.E. Villar-Villar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Neurol" "fecha" => "2008" "volumen" => "46" "paginaInicial" => "124" "paginaFinal" => "125" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18247287" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Seven cases of decreased serum valproic acid concentration during concomitant use of carbapenem antibiotics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.G. Lee" 1 => "J.H. Kim" 2 => "J.Y. Joo" 3 => "O.H. Kwon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3343/kjlm.2007.27.5.338" "Revista" => array:6 [ "tituloSerie" => "Korean J Lab Med" "fecha" => "2007" "volumen" => "27" "paginaInicial" => "338" "paginaFinal" => "343" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18094598" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meropenem–valproic acid interaction in patients with cefepime-associated status epilepticus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "I. Spriet" 1 => "W. Meersseman" 2 => "E. De Troy" 3 => "A. Wilmer" 4 => "M. Casteels" 5 => "L. Willems" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2146/ajhp050512" "Revista" => array:6 [ "tituloSerie" => "Am J Health Syst Pharm" "fecha" => "2007" "volumen" => "64" "paginaInicial" => "54" "paginaFinal" => "58" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17189580" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Seizure worsening caused by decreased serum valproate during meropenem therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Santucci" 1 => "A. Parmeggiani" 2 => "R. Riva" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Child Neurol" "fecha" => "2005" "volumen" => "20" "paginaInicial" => "456" "paginaFinal" => "457" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15968935" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meropenem decreases serum level of valproic acid" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Nacarkucuk" 1 => "H. Saglam" 2 => "M. Okan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pediatrneurol.2004.03.014" "Revista" => array:6 [ "tituloSerie" => "Pediatr Neurol" "fecha" => "2004" "volumen" => "31" "paginaInicial" => "232" "paginaFinal" => "234" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15351028" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction between valproic acid and carbapenem antibiotics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Mori" 1 => "K. Takahashi" 2 => "T. Mizutani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/03602530701690341" "Revista" => array:6 [ "tituloSerie" => "Drug Metab Rev" "fecha" => "2007" "volumen" => "39" "paginaInicial" => "647" "paginaFinal" => "657" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18058328" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Haroutiunian" 1 => "Y. Ratz" 2 => "B. Rabinovich" 3 => "M. Adam" 4 => "A. Hoffman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0091270009334377" "Revista" => array:6 [ "tituloSerie" => "J Clin Pharmacol" "fecha" => "2009" "volumen" => "49" "paginaInicial" => "1363" "paginaFinal" => "1369" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19773524" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ficha técnica del meropenem [accessed 27.10.10]. Available from: <a class="elsevierStyleInterRef" href="https://sinaem4.agemed.es/consaem/especialidad.do%3Fmetodo=verFichaWordPdf%26codigo=60640%26formato=pdf%26formulario=FICHAS">https://sinaem4.agemed.es/consaem/especialidad.do?metodo=verFichaWordPdf&codigo=60640&formato=pdf&formulario=FICHAS</a>." ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of carbapenem antibiotics on plasma concentrations of valproic acid" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.E. Mancl" 1 => "B.E. Gidal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1345/aph.1M296" "Revista" => array:6 [ "tituloSerie" => "Ann Pharmacother" "fecha" => "2009" "volumen" => "43" "paginaInicial" => "2082" "paginaFinal" => "2087" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19934386" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Proposal for a new tool to evaluate drug interaction cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.R. Horn" 1 => "P.D. Hansten" 2 => "L.N. Chan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1345/aph.1H423" "Revista" => array:6 [ "tituloSerie" => "Ann Pharmacother" "fecha" => "2007" "volumen" => "41" "paginaInicial" => "674" "paginaFinal" => "680" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17389673" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carbapenem antibiotics inhibit valproic acid transport in caco-2 cell monolayers" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Torii" 1 => "Y. Takiguchi" 2 => "M. Izumi" 3 => "T. Fukushima" 4 => "M. Yokota" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Pharm" "fecha" => "2002" "volumen" => "233" "paginaInicial" => "253" "paginaFinal" => "256" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11897429" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Yokogawa" 1 => "S. Iwashita" 2 => "A. Kubota" 3 => "Y. Sasaki" 4 => "J. Ishizaki" 5 => "M. Kawahara" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pharm Res" "fecha" => "2001" "volumen" => "18" "paginaInicial" => "1320" "paginaFinal" => "1326" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11683247" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction of valproic acid and carbapenem antibiotics with multidrug-resistance-associated proteins in rat erythrocyte membranes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Ogawa" 1 => "R. Yumoto" 2 => "N. Hamada" 3 => "J. Nagai" 4 => "M. Takano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.eplepsyres.2006.05.016" "Revista" => array:6 [ "tituloSerie" => "Epilepsy Res" "fecha" => "2006" "volumen" => "71" "paginaInicial" => "76" "paginaFinal" => "87" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16806827" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B.T. Ethell" 1 => "G.D. Anderson" 2 => "B. Burchell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Biochem Pharmacol" "fecha" => "2003" "volumen" => "65" "paginaInicial" => "1441" "paginaFinal" => "1449" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12732356" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epileptic seizures caused by low valproic acid levels from an interaction with meropenem" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Fudio" 1 => "A. Carcas" 2 => "E. Piñana" 3 => "R. Ortega" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2710.2006.00743.x" "Revista" => array:6 [ "tituloSerie" => "J Clin Pharm Ther" "fecha" => "2006" "volumen" => "31" "paginaInicial" => "393" "paginaFinal" => "396" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16882111" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute seizures due to a probable interaction between valproic acid and meropenem" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "F.J. Coves-Orts" 1 => "J. Borrás-Blasco" 2 => "A. Navarro-Ruiz" 3 => "A. Murcia-López" 4 => "F. Palacios Ortega" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1345/aph.1E358" "Revista" => array:6 [ "tituloSerie" => "Ann Pharmacother" "fecha" => "2005" "volumen" => "39" "paginaInicial" => "533" "paginaFinal" => "537" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15701769" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.J. De Turck" 1 => "M.W. Diltoer" 2 => "P.J. Cornelis" 3 => "V. Maes" 4 => "H.D. Spapen" 5 => "F. Camu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "1998" "volumen" => "42" "paginaInicial" => "563" "paginaFinal" => "564" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9818768" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction between valproate and meropenem: a retrospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "I. Spriet" 1 => "J. Goyens" 2 => "W. Meersseman" 3 => "A. Wilmer" 4 => "L. Willems" 5 => "W. Van Paesschen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1345/aph.1K079" "Revista" => array:6 [ "tituloSerie" => "Ann Pharmacother" "fecha" => "2007" "volumen" => "41" "paginaInicial" => "1130" "paginaFinal" => "1136" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17609232" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interacción farmacocinética entre ácido valproico y meropenem" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Sala" 1 => "N. Padullés" 2 => "E. Hidalgo" 3 => "S. Clemente" 4 => "M.J. Cabañas" 5 => "M. Oliveras" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2006" "volumen" => "64" "paginaInicial" => "93" "paginaFinal" => "95" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meropenem y ácido valproico: una interacción a recordar" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. San Antonio Arce" 1 => "B. Joyanes Abancens" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2009" "volumen" => "70" "paginaInicial" => "193" "paginaFinal" => "194" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adverse reaction publication 137" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "Welfare Ministry of Japan" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "1996" "editorial" => "Welfare Ministry of Japan" "editorialLocalizacion" => "Tokyo" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Alerta de la AGEMED [accessed 27.10.10]. Available from: <a class="elsevierStyleInterRef" href="http://www.aemps.es/actividad/notaMensual/docs/2010/inforMensual-ene10.pdf">http://www.aemps.es/actividad/notaMensual/docs/2010/inforMensual-ene10.pdf</a>." ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002700000001/v1_201305151316/S2173580812000107/v1_201305151316/en/main.assets" "Apartado" => array:4 [ "identificador" => "9491" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002700000001/v1_201305151316/S2173580812000107/v1_201305151316/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000107?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 41 | 0 | 41 |
| 2024 October | 277 | 16 | 293 |
| 2024 September | 275 | 21 | 296 |
| 2024 August | 198 | 8 | 206 |
| 2024 July | 249 | 14 | 263 |
| 2024 June | 230 | 10 | 240 |
| 2024 May | 280 | 21 | 301 |
| 2024 April | 207 | 10 | 217 |
| 2024 March | 291 | 24 | 315 |
| 2024 February | 186 | 19 | 205 |
| 2024 January | 311 | 12 | 323 |
| 2023 December | 259 | 29 | 288 |
| 2023 November | 328 | 15 | 343 |
| 2023 October | 340 | 50 | 390 |
| 2023 September | 111 | 6 | 117 |
| 2023 August | 113 | 11 | 124 |
| 2023 July | 114 | 7 | 121 |
| 2023 June | 98 | 14 | 112 |
| 2023 May | 164 | 17 | 181 |
| 2023 April | 137 | 17 | 154 |
| 2023 March | 121 | 8 | 129 |
| 2023 February | 97 | 15 | 112 |
| 2023 January | 97 | 19 | 116 |
| 2022 December | 36 | 7 | 43 |
| 2022 November | 62 | 17 | 79 |
| 2022 October | 50 | 15 | 65 |
| 2022 September | 76 | 14 | 90 |
| 2022 August | 77 | 21 | 98 |
| 2022 July | 60 | 17 | 77 |
| 2022 June | 54 | 17 | 71 |
| 2022 May | 68 | 14 | 82 |
| 2022 April | 53 | 16 | 69 |
| 2022 March | 65 | 23 | 88 |
| 2022 February | 65 | 16 | 81 |
| 2022 January | 81 | 11 | 92 |
| 2021 December | 58 | 22 | 80 |
| 2021 November | 61 | 18 | 79 |
| 2021 October | 95 | 30 | 125 |
| 2021 September | 82 | 22 | 104 |
| 2021 August | 88 | 11 | 99 |
| 2021 July | 94 | 26 | 120 |
| 2021 June | 56 | 11 | 67 |
| 2021 May | 70 | 6 | 76 |
| 2021 April | 180 | 19 | 199 |
| 2021 March | 74 | 14 | 88 |
| 2021 February | 63 | 36 | 99 |
| 2021 January | 73 | 20 | 93 |
| 2020 December | 46 | 10 | 56 |
| 2020 November | 64 | 10 | 74 |
| 2020 October | 41 | 9 | 50 |
| 2020 September | 66 | 18 | 84 |
| 2020 August | 64 | 8 | 72 |
| 2020 July | 49 | 11 | 60 |
| 2020 June | 39 | 7 | 46 |
| 2020 May | 34 | 18 | 52 |
| 2020 April | 29 | 2 | 31 |
| 2020 March | 54 | 11 | 65 |
| 2020 February | 45 | 4 | 49 |
| 2020 January | 47 | 15 | 62 |
| 2019 December | 58 | 6 | 64 |
| 2019 November | 30 | 15 | 45 |
| 2019 October | 40 | 7 | 47 |
| 2019 September | 49 | 8 | 57 |
| 2019 August | 42 | 17 | 59 |
| 2019 July | 63 | 15 | 78 |
| 2019 June | 118 | 21 | 139 |
| 2019 May | 234 | 36 | 270 |
| 2019 April | 99 | 15 | 114 |
| 2019 March | 31 | 14 | 45 |
| 2019 February | 40 | 15 | 55 |
| 2019 January | 23 | 7 | 30 |
| 2018 December | 26 | 15 | 41 |
| 2018 November | 38 | 9 | 47 |
| 2018 October | 46 | 3 | 49 |
| 2018 September | 11 | 8 | 19 |
| 2018 August | 25 | 11 | 36 |
| 2018 July | 14 | 7 | 21 |
| 2018 June | 15 | 7 | 22 |
| 2018 May | 9 | 3 | 12 |
| 2018 April | 12 | 2 | 14 |
| 2018 March | 79 | 0 | 79 |
| 2018 February | 18 | 3 | 21 |
| 2018 January | 7 | 5 | 12 |
| 2017 December | 18 | 1 | 19 |
| 2017 November | 15 | 2 | 17 |
| 2017 October | 37 | 2 | 39 |
| 2017 September | 11 | 8 | 19 |
| 2017 August | 22 | 6 | 28 |
| 2017 July | 11 | 2 | 13 |
| 2017 June | 21 | 11 | 32 |
| 2017 May | 24 | 2 | 26 |
| 2017 April | 19 | 5 | 24 |
| 2017 March | 26 | 11 | 37 |
| 2017 February | 17 | 9 | 26 |
| 2017 January | 18 | 5 | 23 |
| 2016 December | 21 | 16 | 37 |
| 2016 November | 42 | 6 | 48 |
| 2016 October | 48 | 15 | 63 |
| 2016 September | 28 | 16 | 44 |
| 2016 August | 15 | 5 | 20 |
| 2016 July | 42 | 3 | 45 |
| 2016 June | 47 | 13 | 60 |
| 2016 May | 30 | 17 | 47 |
| 2016 April | 29 | 16 | 45 |
| 2016 March | 40 | 25 | 65 |
| 2016 February | 28 | 28 | 56 |
| 2016 January | 29 | 13 | 42 |
| 2015 December | 23 | 11 | 34 |
| 2015 November | 27 | 4 | 31 |
| 2015 October | 39 | 8 | 47 |
| 2015 September | 34 | 11 | 45 |
| 2015 August | 48 | 28 | 76 |
| 2015 July | 27 | 7 | 34 |
| 2015 June | 8 | 3 | 11 |
| 2015 May | 20 | 9 | 29 |
| 2015 April | 20 | 12 | 32 |
| 2015 March | 25 | 10 | 35 |
| 2015 February | 21 | 4 | 25 |
| 2015 January | 28 | 9 | 37 |
| 2014 December | 53 | 17 | 70 |
| 2014 November | 27 | 9 | 36 |
| 2014 October | 36 | 11 | 47 |
| 2014 September | 43 | 11 | 54 |
| 2014 August | 45 | 15 | 60 |
| 2014 July | 43 | 9 | 52 |
| 2014 June | 24 | 7 | 31 |
| 2014 May | 19 | 8 | 27 |
| 2014 April | 15 | 5 | 20 |
| 2014 March | 32 | 10 | 42 |
| 2014 February | 18 | 4 | 22 |
| 2014 January | 14 | 8 | 22 |
| 2013 December | 19 | 1 | 20 |
| 2013 November | 44 | 7 | 51 |
| 2013 October | 115 | 6 | 121 |
| 2013 September | 54 | 7 | 61 |
| 2013 August | 44 | 11 | 55 |
| 2013 July | 18 | 5 | 23 |
Show all
