Antibiotic dose optimization in critically ill patients

array:23 ["pii" => "S2173572715000727" "issn" => "21735727" "doi" => "10.1016/j.medine.2015.07.001" "estado" => "S300" "fechaPublicacion" => "2015-12-01" "aid" => "827" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "copyrightAnyo" => "2015" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Intensiva. 2015;39:563-72" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5850 "formatos" => array:3 [ "EPUB" => 189 "HTML" => 3477 "PDF" => 2184 ] ] "itemSiguiente" => array:19 [ "pii" => "S2173572715000648" "issn" => "21735727" "doi" => "10.1016/j.medine.2015.06.001" "estado" => "S300" "fechaPublicacion" => "2015-12-01" "aid" => "824" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Intensiva. 2015;39:573-4" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2399 "formatos" => array:3 [ "EPUB" => 188 "HTML" => 1474 "PDF" => 737 ] ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Point of view" "titulo" => "Does early versus late tracheotomy afford benefits in ventilated patients?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "573" "paginaFinal" => "574" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Aporta beneficios la traqueotomía precoz frente a la tardía en el enfermo ventilado?" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.M. Añón" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J.M." "apellidos" => "Añón" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210569115001667" "doi" => "10.1016/j.medin.2015.06.007" "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/S0210569115001667?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000648?idApp=WMIE" "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000648/v2_201703210124/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173572715000703" "issn" => "21735727" "doi" => "10.1016/j.medine.2015.05.005" "estado" => "S300" "fechaPublicacion" => "2015-12-01" "aid" => "807" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Intensiva. 2015;39:552-62" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4202 "formatos" => array:3 [ "EPUB" => 173 "HTML" => 3025 "PDF" => 1004 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "552" "paginaFinal" => "562" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Foro de debate: seguridad de las alternativas a la transfusión alogénica en el paciente quirúrgico y/o crítico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Muñoz Gómez, E. Bisbe Vives, M. Basora Macaya, J.A. García Erce, A. Gómez Luque, S.R. Leal-Noval, M.J. Colomina, J. Comin Colet, E. Contreras Barbeta, J. Cuenca Espiérrez, A. Garcia de Lorenzo y Mateos, F. Gomollón García, M. Izuel Ramí, M.V. Moral García, J.B. Montoro Ronsano, J.A. Páramo Fernández, A. Pereira Saavedra, M. Quintana Diaz, Á. Remacha Sevilla, R. Salinas Argente, C. Sánchez Pérez, G. Tirado Anglés, P. Torrabadella de Reinoso" "autores" => array:23 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Muñoz Gómez" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Bisbe Vives" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Basora Macaya" ] 3 => array:2 [ "nombre" => "J.A." "apellidos" => "García Erce" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Gómez Luque" ] 5 => array:2 [ "nombre" => "S.R." "apellidos" => "Leal-Noval" ] 6 => array:2 [ "nombre" => "M.J." "apellidos" => "Colomina" ] 7 => array:2 [ "nombre" => "J." "apellidos" => "Comin Colet" ] 8 => array:2 [ "nombre" => "E." "apellidos" => "Contreras Barbeta" ] 9 => array:2 [ "nombre" => "J." "apellidos" => "Cuenca Espiérrez" ] 10 => array:2 [ "nombre" => "A." "apellidos" => "Garcia de Lorenzo y Mateos" ] 11 => array:2 [ "nombre" => "F." "apellidos" => "Gomollón García" ] 12 => array:2 [ "nombre" => "M." "apellidos" => "Izuel Ramí" ] 13 => array:2 [ "nombre" => "M.V." "apellidos" => "Moral García" ] 14 => array:2 [ "nombre" => "J.B." "apellidos" => "Montoro Ronsano" ] 15 => array:2 [ "nombre" => "J.A." "apellidos" => "Páramo Fernández" ] 16 => array:2 [ "nombre" => "A." "apellidos" => "Pereira Saavedra" ] 17 => array:2 [ "nombre" => "M." "apellidos" => "Quintana Diaz" ] 18 => array:2 [ "nombre" => "Á." "apellidos" => "Remacha Sevilla" ] 19 => array:2 [ "nombre" => "R." "apellidos" => "Salinas Argente" ] 20 => array:2 [ "nombre" => "C." "apellidos" => "Sánchez Pérez" ] 21 => array:2 [ "nombre" => "G." "apellidos" => "Tirado Anglés" ] 22 => array:2 [ "nombre" => "P." "apellidos" => "Torrabadella de Reinoso" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210569115001175" "doi" => "10.1016/j.medin.2015.05.006" "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/S0210569115001175?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000703?idApp=WMIE" "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000703/v2_201703210124/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Antibiotic dose optimization in critically ill patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "563" "paginaFinal" => "572" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.O. Cotta, J.A. Roberts, J. Lipman" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M.O." "apellidos" => "Cotta" "email" => array:1 [ 0 => "meninocotta@gmail.com" ] "referencia" => array:5 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.A." "apellidos" => "Roberts" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Lipman" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Burns Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Optimización de la dosis de antibióticos en pacientes críticamente enfermos" ] ] "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" => 1532 "Ancho" => 2257 "Tamanyo" => 181514 ] ] "descripcion" => array:1 [ "en" => "Initial pathophysiology of severe sepsis/septic shock and its impact on antibiotic pharmacokinetics." ] ] ] "textoCompleto" => "IntroductionGiven an era of accelerating bacterial resistance and dwindling antimicrobial resources, optimization of existing antibiotic therapy is an increasingly important consideration for clinicians worldwide. There is perhaps added significance among intensive care unit (ICU) patients, as these patients are at high risk of infection-related mortality.<a class="elsevierStyleCrossRef" href="#bib0465">1</a> They are also more prone to acute and often marked changes in pathophysiology and are subject to invasive intervention, both of which have the potential to significantly alter drug exposure.<a class="elsevierStyleCrossRef" href="#bib0470">2</a>Antibiotics are one of the most commonly prescribed drug classes in the ICU and they have the ability to dramatically improve patient outcomes.<a class="elsevierStyleCrossRefs" href="#bib0475">3,4</a> Therefore, it stands to reason that maximizing the likelihood of eradicating infection whilst lowering the risk of unwanted effects should be the end goal for all prescribed antibiotic therapy. This is perhaps why determining the relationship between exposure of antibiotics in vivo (i.e. pharmacokinetics, PK) and what clinical response it elicits (pharmacodynamics, PD) has gained much prominence in critical care literature. The purpose of this review is to discuss variations in PK that commonly occur among the critically ill, through both existing pathophysiology as well as associated interventions, and to offer insights on how antibiotic therapy can be tailored accordingly so as to optimize desired PD effects.Severe sepsis and septic shockSepsis is a common occurrence within the ICU and is defined as a systemic inflammatory response to infection, which can be complicated by organ dysfunction (‘severe sepsis’) or persistent hypotension refractory to fluid resuscitation (‘septic shock’).<a class="elsevierStyleCrossRef" href="#bib0485">5</a> Although the incidence of sepsis worldwide is currently unknown, extrapolations from United States data conservatively estimate an occurrence of 19 million cases annually.<a class="elsevierStyleCrossRefs" href="#bib0490">6,7</a> Added to this high burden are reports indicating a severe sepsis mortality rate of nearly 30% in developed countries.<a class="elsevierStyleCrossRefs" href="#bib0500">8,9</a>Initial pathophysiology and its impact on antibiotic pharmacokinetics (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>)One of the first clinical observations during severe sepsis and septic shock is significant fluid shift from the intravascular compartment (i.e. blood vessels) into interstitial space due to endothelial damage and increased capillary leak.<a class="elsevierStyleCrossRef" href="#bib0510">10</a> The resultant hypotension is often fulminant, requiring urgent and aggressive delivery of intravenous resuscitation fluid, which in turn can further increase interstitial volume. Depending on the physiochemical properties of the antibiotic, these large amounts of extravascular fluid may have a significant impact on drug distribution and hence dosing strategies. For example, initial doses of hydrophilic antibiotics (i.e. that concentrate more in blood and interstitial fluid of tissues) will need to take into account these increased volumes. In this case, due to the greater volume of distribution (Vd) noted for these drugs, use of loading doses should be considered to ensure early achievement of therapeutic concentrations.<a class="elsevierStyleCrossRefs" href="#bib0515">11,12</a> Lipophilic antibiotics (i.e. that concentrate intra-cellularly and in adipose tissue), on the other hand, are not greatly influenced by changes in fluid volume and may not require alterations in initial dosing.<a class="elsevierStyleCrossRef" href="#bib0525">13</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>A main element of the systemic inflammatory response during sepsis is that initial vasodilation is associated with a hyperdynamic cardiovascular state.<a class="elsevierStyleCrossRef" href="#bib0530">14</a> Increased cardiac output is further driven by use of resuscitation fluid and vasopressors, resulting in increased blood flow to major organs including the kidneys. Although the exact mechanism has not been fully elucidated, the end result may be that of increased renal blood blow and glomerular filtration leading to enhanced renal drug elimination, termed ‘augmented renal clearance’ (ARC). ARC has previously been defined as a creatinine clearance ≥ 130mL/min/1.73m2.<a class="elsevierStyleCrossRef" href="#bib0535">15</a> There are now numerous reports of the prevalence of ARC in septic as well as other groups of critically ill patients.<a class="elsevierStyleCrossRefs" href="#bib0540">16–18</a>Mathematical formulae to estimate glomerular filtration rate have all been derived from outside of the ICU and so have limited applicability in determining this increased renal clearance.<a class="elsevierStyleCrossRef" href="#bib0555">19</a> Additionally, serum creatinine concentrations are not sensitive enough to identify patients with ARC and so a measured urine creatinine clearance collection over a specified period remains the preferred method for clinical use.<a class="elsevierStyleCrossRef" href="#bib0545">17</a> Recent data suggests that a 2-hour creatinine clearance may be a suitable substitute for longer collection times, such as the standard 24-hour creatinine clearance,<a class="elsevierStyleCrossRef" href="#bib0560">20</a> though the importance of accuracy of sample collection is required with shorter collection times. Although generally not applicable for determining initial antibiotic dosing regimens, it may be an important consideration in some patients, particularly younger males,<a class="elsevierStyleCrossRef" href="#bib0565">21</a> with severe sepsis and septic shock, as important data is accumulating that ARC is associated with subtherapeutic exposure to renally cleared antibiotics such as the β-lactams.<a class="elsevierStyleCrossRef" href="#bib0570">22</a>Another common phenomenon soon after the initial phase of severe sepsis and septic shock is the pronounced reduction in serum albumin concentrations (hypoalbuminemia).<a class="elsevierStyleCrossRef" href="#bib0575">23</a> Albumin constitutes nearly two-thirds of all human serum proteins and is the primary protein responsible for drug-protein binding.<a class="elsevierStyleCrossRef" href="#bib0580">24</a> Previously defined as a serum albumin concentration less than 25g/L,<a class="elsevierStyleCrossRef" href="#bib0585">25</a> hypoalbuminemia has a direct impact on the PK of antibiotics, particularly on those antibiotics that are highly protein bound.<a class="elsevierStyleCrossRef" href="#bib0590">26</a> Firstly, it increases the unbound or ‘free’ fraction of drug. This is important given that it is only the unbound drug that can exert a pharmacodynamic effect. As hypoalbuminemic states can increase the amount of drug that distributes into tissues, this is likely to have a direct effect on the Vd of an antibiotic. Finally, as only the unbound drug in the intravascular compartment is available for metabolism and elimination, low serum albumin concentrations may mean that there is higher proportion of unbound drug available for clearance leading to low concentrations toward the end of the dosing interval.Now that the main considerations for altered drug pharmacokinetics during the initial phase of severe sepsis and septic shock have been described, the next step is to apply this knowledge when formulating dosing strategies for antibiotics based on their pathogen-exposure relationship, also known as the pharmacokinetic/pharmacodynamic (PK/PD) index (see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> for summary of PK/PD index of antibiotic classes).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Time-dependent antibioticsAntibiotics that belong to this category exhibit maximum bactericidal activity when unbound concentrations of the drug exceed the minimum inhibitory concentration (MIC) of the bacterial pathogen (fT>MIC). The main classes of antibiotics in this group include β-lactams (penicillins, cephalosporins, carbapenems, monobactams) and lincosamides (clindamycin and lincomycin).From these, the broad-spectrum β-lactams are perhaps the most important group in the critical care setting. Particularly for Gram-negative infections, the maximal effect of bacterial killing and suppression of resistance emergence for β-lactams has previously been shown to be when the unbound trough drug concentration to MIC ratio is four to six.<a class="elsevierStyleCrossRefs" href="#bib0595">27–29</a> Increasing MICs among bacterial isolates from hospital ICUs has meant that aggressive dosing of β-lactams is a fundamental consideration in the setting of severe sepsis and septic shock. Added to this, the hydrophilicity of these agents means that they are not only prone to the effects of an increased Vd, but also increased clearance in those patients exhibiting ARC.It is for these reasons that use of continuous or extended infusions with front-loading doses, as opposed to traditional intermittent bolus doses, have gained prominence when administering β-lactams in the ICU.<a class="elsevierStyleCrossRef" href="#bib0610">30</a> Although some studies have shown favorable results in terms of continuous infusions attaining higher plasma β-lactam concentrations and increased rates of clinical cure when compared to intermittent bolus administration,<a class="elsevierStyleCrossRefs" href="#bib0615">31,32</a> a large randomized controlled trial is still required to confirm differences, if any, in patient outcomes.Another important consideration in the optimization of β-lactam therapy in the ICU is the use of therapeutic drug monitoring (TDM). Measuring trough concentrations of the free fraction of β-lactams in plasma is a useful tool in ensuring that PK/PD targets for efficacy are being met. Use of TDM may be particularly important when faced with the conundrum of treating multi-resistant pathogens with high MICs to β-lactams in the setting of patients with potentially increased renal clearance.<a class="elsevierStyleCrossRef" href="#bib0625">33</a> A trough fT>MIC ratio of one is generally recommended when administering intermittent bolus or extended infusions, whilst for continuous infusions, a steady-state fT>MIC ratio of between four to six is recommended.<a class="elsevierStyleCrossRef" href="#bib0630">34</a> There is, however, scope for more robust studies that better define optimal β-lactam PK/PD targets.<a class="elsevierStyleCrossRef" href="#bib0635">35</a>Lincosamides represent the other main antibiotic class demonstrating primarily a time-dependent PK/PD index. Being more lipophilic than the β-lactams, the Vd of lincosamides such as lincomycin and clindamycin are less likely to be affected by fluid shifts seen in ICU patients. However, as both antibiotics have significant protein binding (i.e. 80–90%) and are subject to hepatic as well as renal clearance, altered PK may arise in the setting of hypoalbuminemia as well as ARC. Notably, these effects are yet to be extensively investigated and so dosing regimen adjustments of lincosamides in critical care patients are largely theoretical and currently based on expert opinion.Concentration-dependent antibioticsEfficacy best correlates with peak antibiotic concentration (Cmax) to MIC ratio (Cmax/MIC) for antibiotics with a concentration dependent PK/PD index. Aminoglycosides and metronidazole belong in this category and there are important implications when dosing these agents in the setting of increased Vd such as is seen in severe sepsis, burns and trauma.For example, conventional dosing of aminoglycosides used in patients with septic shock have been shown consistently to have difficulty in attaining specified targets.<a class="elsevierStyleCrossRefs" href="#bib0640">36–38</a> As they are hydrophilic in nature, the pharmacokinetics of aminoglycosides such as amikacin, gentamicin and tobramycin are heavily influenced by factors such as a positive fluid balance and ARC.<a class="elsevierStyleCrossRefs" href="#bib0655">39,40</a>All of the above point to a need for a better understanding of how TDM can optimize aminoglycoside therapy in the ICU. Practically, sampling half an hour post administration of the aminoglycoside will help approximate the Cmax, with the corresponding MIC determined either via a known or suspected pathogen isolate or clinical breakpoint based on epidemiological data. Subsequent sampling anywhere between 6 and 14hours post-dose to a trough concentration will be a useful indicator for aminoglycoside clearance when the data is then analyzed using Bayesian dosing software. One upside with the aminoglycosides from a dosing point of view is that these molecules do not have a high albumin affinity, and so TDM strategies do not necessarily need to take into account potential effects of hypoalbuminemia on unbound concentrations.Concentration-dependent with time-dependence antibioticsThe area under the concentration-time curve during a 24-hour time period (AUC0–24) to the MIC ratio (AUC0–24/MIC) is a valuable PK/PD index to describe the efficacy of antimicrobials, including glycopeptides, oxazolidinones, fluoroquinolones, polymixins, daptomycin, azithromycin and tigecycline.For vancomycin, a PD target of AUC0–24/MIC of 400 has been advocated to achieve clinical effectiveness with vancomycin in the treatment of Staphylococcus aureus pneumonia and bacteremia,<a class="elsevierStyleCrossRefs" href="#bib0665">41,42</a> In the absence of clinical data, this ratio is a suitable PD target for other Gram-positive pathogens such as Enterococcus spp. and coagulase-negative Staphylococcus spp. However, with MICs creep for organisms such as methicillin resistant Staphylococcus aureus (MRSA),<a class="elsevierStyleCrossRef" href="#bib0675">43</a> targets of AUC0–24/MIC of 400 are increasingly difficult to attain in the setting of severe sepsis.To illustrate, for an isolate with an MIC of 2mg/L, the clinical breakpoint based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) data,<a class="elsevierStyleCrossRef" href="#bib0680">44</a> an AUC0–24 of 800mg/L/h (a trough concentration of more than 20–25mg/L) would be required, increasing risks of toxicity.<a class="elsevierStyleCrossRef" href="#bib0520">12</a> As simulated models have suggested a daily dose of 3–4g of vancomycin are needed to achieve 90% probability of attaining the above PD for an isolate with an MIC 1mg/L in ICU patients (not including patients with augmented renal clearance that would require even higher doses),<a class="elsevierStyleCrossRef" href="#bib0685">45</a> this would again mean proportionally higher doses and more risk of toxicity when treating isolates with higher vancomycin MICs. Use of continuous vancomycin infusions have been proposed as a means to achieve target concentrations faster,<a class="elsevierStyleCrossRef" href="#bib0690">46</a> as well as ensuring consistency in serum concentrations.<a class="elsevierStyleCrossRef" href="#bib0695">47</a> However, there is only retrospective outcome data on the advantages of continuous versus intermittent vancomycin dosing.<a class="elsevierStyleCrossRef" href="#bib0700">48</a>Fluoroquinolones, such as ciprofloxacin, display predominantly concentration-dependent killing with time-dependent microbiologic eradication. As ciprofloxacin is lipophilic and concentrates in tissues, changes in fluid redistribution associated with sepsis do not have a marked impact when compared to more hydrophilic antibiotics.<a class="elsevierStyleCrossRef" href="#bib0705">49</a> However, an initial ciprofloxacin dose of 400mg intravenously (IV) has been shown to be inadequate in attaining desired AUC0–24/MIC ratios of ≥125 or Cmax/MIC ratios of >10 in the critical care setting.<a class="elsevierStyleCrossRef" href="#bib0710">50</a> Additionally, a dosing regimen of 400mg 12-hourly IV reached optimal killing concentrations for pathogens with MICs < 0.25mg/L, a relatively low threshold for isolates in the ICU.<a class="elsevierStyleCrossRef" href="#bib0715">51</a> Subsequently, the use of 600mg 12-hourly IV has been recommended as the optimal dosing strategy for ciprofloxacin in ICU patients not in renal failure, however, there is yet to be any trial data to validate this altered dosing regimen.Similar to the fluoroquinolones, daptomycin exhibits a largely concentration-dependent effect together with some time-dependent killing. Daptomycin, however, is a much more hydrophilic molecule with higher protein binding (up to 93%), and as such, in vivo drug distribution may be greatly influenced by changes in Vd and hypoalbuminemia. An approved dose of 6mg/kg 24-hourly for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia has shown to provide lower daptomycin exposure in the critically ill, with doses of between 8 and 10mg/kg 24-hourly having a higher probability of attaining target AUC0–24/MIC ratios.<a class="elsevierStyleCrossRef" href="#bib0720">52</a> Of significance, regular monitoring of creatinine phosphokinase, as a marker for rhabdomyolysis, needs to be considered when utilizing higher daptomycin doses, as a rise in trough drug concentration (Cmin) have been associated with this form of toxicity.<a class="elsevierStyleCrossRef" href="#bib0725">53</a>As the first oxazolidinone antibiotic, linezolid is effective in the treatment of Gram-positive infections, and has excellent distribution into tissues such as the lungs.<a class="elsevierStyleCrossRef" href="#bib0730">54</a> Both AUC0–24/MIC and fT>MIC have been used to define the activity of linezolid, with optimal PK/PD indices in plasma reported as 80–120 (AUC0–24/MIC) and 2–10mg/L (Cmin) based on pathogen MICs of ≤2mg/L.<a class="elsevierStyleCrossRef" href="#bib0735">55</a> However, although previous data has shown that standard doses of 600mg 12-hourly achieve target plasma concentrations in the general population,<a class="elsevierStyleCrossRef" href="#bib0740">56</a> there have been several reports of subtherapeutic concentrations and treatment failure with high inter- and intra-patient variability among the critically ill.<a class="elsevierStyleCrossRefs" href="#bib0745">57–60</a>The use of a 300mg loading dose in combination with a 900mg continuous infusion on day 1 of treatment, followed by a continuous infusion of 1200mg 24-hourly thereafter has been shown to be more likely attain AUC0–24/MIC ratio of >80 compared with standard intermittent doses in a small group of critically ill patients.<a class="elsevierStyleCrossRef" href="#bib0745">57</a> Although this may be a reasonable alternative in critically ill patients with normal renal function, larger trial data with infection-related outcomes and accounting for concomitant antibiotic therapy are required to validate these preliminary findings.Importantly, doses higher than 1200mg per day of linezolid may be required in some instances. A well-defined linear relationship between Cmin and AUC0–24 means that there is potential to utilize Cmin as a useful PK/PD index for TDM in the future,<a class="elsevierStyleCrossRefs" href="#bib0760">60,61</a> especially in the context of higher doses. A recent study from Lopez-García et al. evaluated the preliminary safety of doses 600mg 8-hourly as part of a TDM program and found that where the Cmin remained below 6mg/L, no hematological toxicity was observed.<a class="elsevierStyleCrossRef" href="#bib0770">62</a> In some of the patients in this analysis, the increased dose resulted in a higher Cmin and hematological toxicity was observed which highlights the importance of accurate dose adaptation.The emergence of multi-drug resistant Gram-negative pathogens and a lack of novel antibiotics has meant that older drug classes, such as the polymyxins, have re-emerged as important treatment options. Colistin, or polymixin E, is becoming a more widely prescribed antibiotic in the ICU. Dose optimization of colistin remains complex, in part due to substantial inter-patient variability in the in vivo conversion of colistin methanesulfonate ([CMS], the prodrug) to colistin.<a class="elsevierStyleCrossRef" href="#bib0775">63</a> The bacterial killing profile of colistin best correlates with AUC0–24/MIC, however, optimal PK/PD targets in critically ill patients are yet to be fully confirmed.<a class="elsevierStyleCrossRefs" href="#bib0780">64,65</a>One problem that has specific relevance in the critical care setting is the delay in exposure to effective therapy. Conversion of intravenously administered CMS to colistin may take several hours to achieve plasma concentrations deemed high enough to be effective. Added to this, the extent of conversion has been found to be low in the setting of normal renal function, due primarily to increased tubular secretion of CMS prior to conversion. As such, caution has been advised when using colistin as monotherapy, and the use of combination therapy, such as with carbapenems, is advocated.<a class="elsevierStyleCrossRef" href="#bib0790">66</a> When used in conjunction with other antibiotics, use of loading doses factoring in target MICs and body weight, and maintenance doses calculated based on renal clearance is generally recommended for critically ill patients.<a class="elsevierStyleCrossRefs" href="#bib0775">63,67</a>Antibiotic dosing in multi-organ dysfunction syndrome (MODS)Termed MODS when two or more organ systems are involved, worsening organ function caused by severe infection is associated with grave outcomes and treatment failure.<a class="elsevierStyleCrossRef" href="#bib0800">68</a> After the initial phase of severe sepsis and septic shock, ongoing sepsis-induced hypoperfusion to vital organs and tissues as a result of cardiovascular dysfunction can have a profound effect on the PK profile of both hydrophilic and lipophilic antibiotics.<a class="elsevierStyleCrossRef" href="#bib0805">69</a> Additionally, as these patients are often sicker and in urgent need of anti-infective therapy, there is a balance between appropriate and excessive exposure to these drugs. It is important to remember that this balance is not necessarily easy to attain in the setting of fluctuating hemodynamics and organ function, and that there will always be a degree of uncertainty when adjusting dosing regimens in MODS.Hepatic impairmentAntibiotics that are lipophilic and/or highly albumin-bound may undergo extensive liver metabolism, resulting in metabolites that are more easily eliminated. Severe hepatic dysfunction or hepatic failure may compromise this metabolism in a number of ways including a compromise in hepatic blood flow, reduced hepatocyte function and decreased biliary excretion.<a class="elsevierStyleCrossRef" href="#bib0810">70</a> There is a risk in the presence of very severe dysfunction that accumulation of these antibiotics has the potential to result in toxicity.One example of an antibiotic that requires dosage adjustment in hepatic dysfunction is tigecycline, which is both lipophilic and highly protein bound (71–89%). Predominantly eliminated in feces via bile acid conjugates,<a class="elsevierStyleCrossRef" href="#bib0815">71</a> tigecycline elimination has been shown to be reduced in hepatic failure, with a 43% increase in elimination half life in patients with severe hepatic impairment.<a class="elsevierStyleCrossRef" href="#bib0805">69</a> Thus, the manufacturer recommends halving the usual maintenance dose in severe liver disease, whilst maintaining the usual loading dose.<a class="elsevierStyleCrossRef" href="#bib0820">72</a>Renal impairmentRenal dysfunction has dosing implications for parent compounds of hydrophilic antibiotics as well as renally cleared metabolites of some moderately lipophilic antibiotics. Renal function needs to be continually and judiciously monitored so that prompt dosage adjustments for these drugs can be made so as to minimize toxicity risk. It is important to note that the PK/PD index of the antibiotic contributes significantly to how adjustments in doses and dosing regimens are made.For time dependent antibiotics cleared via the kidneys, such as the β-lactams, a dosage reduction rather than decreasing dosing frequency is likely to be the optimal choice in reducing drug accumulation but ensuring the fT>MIC is maintained. Conversely, concentration dependence antibiotics will require extending the dosing frequency rather than reducing the dose; therefore maximizing bacterial killing by preserving the Cmax/MIC. For concentration-dependent with time-dependence antibiotics, dosage adjustments in renal failure are usually derived based on which component of the PK/PD index predominates. For example, as the fluoroquinolones have predominant concentration-dependence with time dependence, adjusting in renal failure may entail prolonging the dosing interval rather than altering the dose.Antibiotic dosing in continuous renal replacement therapy (CRRT)Persistent renal failure and the accumulation of metabolic waste products such as urea often warrant the need for intervention among critically ill patients. Therefore, the use of renal replacement therapy is common practice in the ICU, with CRRT, intermittent, and hybrid forms of therapy utilized. Use of CRRT involves modalities such as continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD) and continuous venovenous hemodiafiltration (CVVHDF), with no best method currently established in the literature. Consequently, there is widespread heterogeneity in how CRRT is employed in the critical care setting, with variability in doses of CRRT employed, blood and dialysate flow rate, types of filters and dialysis membranes used and surface area.<a class="elsevierStyleCrossRefs" href="#bib0825">73,74</a> Added to this are the practical issues associated with reduced delivery of CRRT such as interruptions due to filter clotting and patient time away for diagnostic and procedural purposes.Although each of these types of CRRT are efficient in removing hydrophilic antibiotics, the variation in practice means that unfortunately there is no ‘one size fits all’ in dosing recommendations for these drugs in CRRT. This may be even more appreciable when considering that the residual endogenous clearance of patients has been reported as a more useful covariate in predicting systemic antibiotic clearance than treatment with CRRT.<a class="elsevierStyleCrossRef" href="#bib0835">75</a> Nevertheless, a brief review of antibiotic dosing studies in CRRT may help decipher some useful recommendations for dose optimization in this challenging cohort.For example, although standardizing glycopeptide dosing across different types of CRRT is complex and problematic,<a class="elsevierStyleCrossRef" href="#bib0840">76</a> some data report up to 50% of total glycopeptide clearance is achieved via CVVH.<a class="elsevierStyleCrossRefs" href="#bib0845">77,78</a> Based on these findings in CVVH, some investigators recommend adopting a vancomycin maintenance dose of 500–750mg 12-hourly to achieve target steady-state Cmin of 15–20mg/L.<a class="elsevierStyleCrossRef" href="#bib0850">78</a> Others have proposed use of a 35mg/kg loading dose, most likely higher than necessary, followed by use of a 14mg/kg continuous infusion to expedite attainment of adequate Cmin values in the setting of both CVVH and CVVHDF.<a class="elsevierStyleCrossRef" href="#bib0855">79</a> Teicoplanin clearance in CRRT may be even more variable due to hypoalbuminemic states likely leading to increased drug elimination. Use of higher doses or dose supplementation may be advisable in this setting,<a class="elsevierStyleCrossRef" href="#bib0845">77</a> with TDM being the mainstay in guiding therapy as inter-individual variability cannot be completely controlled.<a class="elsevierStyleCrossRefs" href="#bib0860">80,81</a>Aminoglycoside exposure in the setting of CRRT has also been described.<a class="elsevierStyleCrossRefs" href="#bib0870">82,83</a> So as to attain optimal PK/PD targets in the critically ill, investigators have shown that doses of these antibiotics should remain consistent with those used in patients not on CRRT. However, data show that drug concentrations at 24hours (i.e. Cmin) remain above the threshold for renal toxicity risk,<a class="elsevierStyleCrossRef" href="#bib0875">83</a> and so extending the dosing frequency beyond this period, to perhaps 36-hourly, should be considered together with use of TDM to determine adequate clearance.β-Lactam dosing in CRRT remains difficult, with considerable variability in dosing required to achieve PK/PD targets and a high dependency on the type of CRRT employed.<a class="elsevierStyleCrossRefs" href="#bib0830">74,81</a> Having said this, there is now more data to support the strategy of using dosing regimens which increase the exposure of these antibiotics, when compared to other renal replacement therapies such as intermittent haemodialysis.<a class="elsevierStyleCrossRef" href="#bib0880">84</a> Indeed, some investigators recommend using similar doses of β-lactams to those used in the absence of renal failure during the first 48hours of CRRT.<a class="elsevierStyleCrossRef" href="#bib0885">85</a>A recent randomized controlled trial of intermittent bolus versus continuous infusion (CI) meropenem in CVVH illustrated some interesting points.<a class="elsevierStyleCrossRef" href="#bib0890">86</a> Firstly and most importantly, the dosing regimen of meropenem used in both groups correlated with the total daily dosage recommended to be used in patients with ‘normal’ renal function. Secondly, PK/PD targets were more rapidly attained and sustained in the CI group. Finally, results indicated that if more resistant pathogens were being targeted then CI had a higher likelihood to result in more consistent achievement of PK/PD targets, indicating a selected application for meropenem CI in CRRT.Antibiotic dosing in extracorporeal membrane oxygenation (ECMO)ECMO is an important intervention in patients with severe cardiorespiratory failure and can take on two forms: (1) venovenous (VV) ECMO which oxygenates blood from the large central veins and returns it to the venous system for distribution via the heart, thereby supporting lung function, (2) venoarterial (VA) ECMO which oxygenates blood drawn from the right atrium and returns it to the arterial system via the distal descending aorta, hence providing both respiratory and cardiac support. Both these forms require the movement of blood through an extracorporeal circuit consisting of polyvinyl chloride (PVC) tubing, an oxygenator and a heat exchanger.<a class="elsevierStyleCrossRef" href="#bib0895">87</a> From a PK point of view, however, there is potential for drug degradation and/or adsorption of drugs to the extracorporeal circuit.<a class="elsevierStyleCrossRefs" href="#bib0900">88,89</a>Recent ex vivo experimental studies have shown significantly lower drug recovery at 24hours in the ECMO circuit compared to controls for meropenem and highly protein bound antibiotics such as ceftriaxone.<a class="elsevierStyleCrossRefs" href="#bib0905">89,90</a> As ECMO circuits represent an additional PK compartment through the use of priming solutions and the ongoing need for blood products and maintenance fluid, the Vd, particularly for hydrophilic antibiotics, may be increased.<a class="elsevierStyleCrossRef" href="#bib0895">87</a>Interestingly, it is not only the PK profile of hydrophilic drugs that have the potential to be altered. Lipophilic drugs, such as voriconazole, have also been shown to sequester in the ECMO circuit, necessitating higher doses to maintain therapeutic concentrations.<a class="elsevierStyleCrossRef" href="#bib0915">91</a> This is mainly thought to be due to adsorption to ECMO membranes and tubing,<a class="elsevierStyleCrossRef" href="#bib0895">87</a> however, data from ex vivo models suggest that this cannot be extrapolated for lipophilic drugs in general. In the same study that illustrated significant losses of ceftriaxone to the ECMO circuit, Shekar and colleagues did not find the same degree of losses for ciprofloxacin and linezolid, antibiotics considered to be more lipophilic than the β-lactams.<a class="elsevierStyleCrossRef" href="#bib0910">90</a>It is clear from these preliminary findings that much work remains to be done in quantifying the degree of altered antibiotic exposure during ECMO so that therapy can be optimized in this setting. Considering patients on ECMO may also require other treatments that impact on antibiotic exposure, such as RRT, the use of TDM and individualizing dosing regimens appears to be a useful intervention until more robust dosing data become available.ConclusionIn summary, optimization of antibiotic therapy in the critically ill is a complex endeavor that needs to take into account various factors including different treatment modalities that can influence the success of therapy. Central to any dosing strategy, however, is knowledge of the PK/PD of the antibiotic in question. As early and appropriate antibiotic therapy is vital to ensuring beneficial outcomes in severe sepsis and septic shock, understanding initial pathophysiology and its impact on antibiotic PK is crucial to ensuring optimal use of these live saving drugs. Further, there should be an appreciation of the dynamic nature of pathophysiological effects on PK and how manifestations such as MODS can occur, requiring prompt review and appropriate alteration of therapy. Finally, interventions such as CRRT and ECMO have the ability to effect antibiotic concentrations. Given this complexity of dosing in critically ill patients, we believe that where possible, TDM should be utilized to ensure patients achieve therapeutic antibiotic concentrations.Conflict of interestThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres817770" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec814894" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres817771" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec814895" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Severe sepsis and septic shock" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Initial pathophysiology and its impact on antibiotic pharmacokinetics (Fig. 1)" ] ] ] 6 => array:2 [ "identificador" => "sec0020" "titulo" => "Time-dependent antibiotics" ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Concentration-dependent antibiotics" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Concentration-dependent with time-dependence antibiotics" ] 9 => array:3 [ "identificador" => "sec0035" "titulo" => "Antibiotic dosing in multi-organ dysfunction syndrome (MODS)" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Hepatic impairment" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Renal impairment" ] ] ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Antibiotic dosing in continuous renal replacement therapy (CRRT)" ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Antibiotic dosing in extracorporeal membrane oxygenation (ECMO)" ] 12 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusion" ] 13 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-10" "fechaAceptado" => "2015-07-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec814894" "palabras" => array:5 [ 0 => "Antibiotics" 1 => "Dose optimization" 2 => "Critically ill" 3 => "Severe sepsis" 4 => "Septic shock" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec814895" "palabras" => array:5 [ 0 => "Antibióticos" 1 => "Optimización de la dosis" 2 => "Críticamente enfermo" 3 => "Sepsis grave" 4 => "Choque séptico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections – including severe sepsis, septic shock and ventilator-associated pneumonia – but also of the pathogen–drug exposure relationship (i.e. pharmacokinetic/pharmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients; however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El uso sensato de los antibióticos existentes resulta fundamental para mantener su actividad contra las infecciones. En la era de la resistencia a múltiples fármacos, esto resulta especialmente importante en áreas clínicas caracterizadas por un uso elevado de antibióticos, como por ejemplo las UCI. La optimización de la dosis de antibióticos en pacientes críticamente enfermos requiere sólidos conocimientos no solo sobre las alteraciones fisiológicas asociadas a las infecciones graves (incluida la sepsis grave, el choque séptico y la neumonía asociada a la ventilación) sino también sobre la relación entre patógenos y la exposición a fármacos (esto es, el índice farmacocinético/farmacodinámico). Es importante considerar el hecho de que los cambios extremos en la función orgánica, como los observados en pacientes hiperdinámicos o en aquellos con síndrome de disfunción multiorgánica, pueden tener un efecto sobre la exposición a los fármacos, por lo que se requiere una vigilancia constante al revisar los regímenes posológicos de los antibióticos en los pacientes críticamente enfermos. La terapia de reemplazo renal continuo y la oxigenación por membrana extracorporal siguen constituyendo intervenciones importantes en este tipo de pacientes; no obstante, ambos tratamientos pueden tener un profundo impacto sobre la exposición a los antibióticos. Sugerimos poner un especial énfasis sobre el uso de la monitorización farmacoterapéutica y sobre la individualización de la dosis al optimizar el tratamiento en estos entornos terapéuticos." ] ] "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" => 1532 "Ancho" => 2257 "Tamanyo" => 181514 ] ] "descripcion" => array:1 [ "en" => "Initial pathophysiology of severe sepsis/septic shock and its impact on antibiotic pharmacokinetics." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "fT>MIC – time that the unbound or ‘free’ concentration of the drug exceeds the minimum inhibitory concentration (MIC).Cmax/MIC – maximum antibiotic concentration (Cmax) to MIC ratio.AUC0–24/MIC – area under the concentration-time curve during a 24-hour time period (AUC0–24) to the MIC ratio." "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" style="border-bottom: 2px solid black">Class \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">PK/PD index \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">Hydrophilic or lipophilic \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">Volume of distribution \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">Metabolism and/or excretion \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">Common antibiotics within the class with high protein binding affinity (i.e. >70%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aminoglycosides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cmax/MIC AUC0–24/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hydrophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nil \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">β-Lactam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">fT>MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hydrophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cefazolin (75–85%), Ceftriaxone (85–95%), Dicloxacillin (97%), Ertapenem (85–95%), Flucloxacillin (95%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fluoroquinolones \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AUC0–24/MIC Cmax/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Both hepatic metabolism and renal clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nil \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glycopeptides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AUC0–24/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hydrophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Teicoplanin (90–95%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glycylcyclines (e.g. Tigecycline) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AUC0–24/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly biliary/gut (59%) with some renal clearance (33%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tigecycline (71–89%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lincosamides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">fT>MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Both hepatic metabolism and renal clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clindamycin (90%), Lincomycin (80–90%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipopeptides (e.g. Daptomycin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cmax/MIC AUC0–24/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hydrophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Daptomycin (90–93%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macrolides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">fT>MIC (Clarithromycin, erythromycin) AUC0–24/MIC (Azithromycin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Primarily hepatic metabolism with some renal and non-renal clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Erythromycin (73–81%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oxazolidinones (e.g. Linezolid) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AUC0–24/MIC fT>MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Amphiphilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly renal with some gut clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nil \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polymixins (e.g. Colistin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AUC0–24/MIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hydrophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nil \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1374566.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of PK/PD index and properties of antibiotic classes. (Data for volume of distribution, metabolism and/or excretion, and protein binding<a class="elsevierStyleCrossRefs" href="#bib0590">26,92</a>)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:92 [ 0 => array:3 [ "identificador" => "bib0465" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nosocomial pneumonia and mortality among patients in intensive care units" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.Y. Fagon" 1 => "J. Chastre" 2 => "A. Vuagnat" 3 => "J.L. Trouillet" 4 => "A. Novara" 5 => "C. Gibert" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1996" "volumen" => "275" "paginaInicial" => "866" "paginaFinal" => "869" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8596225" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0470" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial therapy in critically ill patients altered disposition and pharmacokinetic variability" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F. Pea" 1 => "P. Viale" 2 => "M. Furlanut" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200544100-00002" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2005" "volumen" => "44" "paginaInicial" => "1009" "paginaFinal" => "1034" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16176116" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0475" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Hanberger" 1 => "M. Antonelli" 2 => "M. Holmbom" 3 => "J. Lipman" 4 => "P. Pickkers" 5 => "M. Leone" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-2334-14-513" "Revista" => array:5 [ "tituloSerie" => "BMC Infect Dis" "fecha" => "2014" "volumen" => "14" "paginaInicial" => "513" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0480" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0b013e3181eb3ccd" "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2010" "volumen" => "38" "paginaInicial" => "1773" "paginaFinal" => "1785" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0485" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The ACCP-SCCM consensus conference on sepsis and organ failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "1992" "volumen" => "101" "paginaInicial" => "1481" "paginaFinal" => "1483" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0490" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Critical care and the global burden of critical illness in adults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(10)60446-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2010" "volumen" => "376" "paginaInicial" => "1339" "paginaFinal" => "1346" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0495" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe sepsis and septic shock" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1208623" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2013" "volumen" => "369" "paginaInicial" => "840" "paginaFinal" => "851" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0500" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2001" "volumen" => "29" "paginaInicial" => "1303" "paginaFinal" => "1310" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0505" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nationwide trends of severe sepsis in the 21st century (2000–2007)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.11-0352" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2011" "volumen" => "140" "paginaInicial" => "1223" "paginaFinal" => "1231" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0510" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunotherapy of sepsis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(01)00093-7" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2001" "volumen" => "1" "paginaInicial" => "165" "paginaFinal" => "174" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0515" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ccc.2010.09.006" "Revista" => array:6 [ "tituloSerie" => "Crit Care Clin" "fecha" => "2011" "volumen" => "27" "paginaInicial" => "19" "paginaFinal" => "34" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0520" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(14)70036-2" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2014" "volumen" => "14" "paginaInicial" => "498" "paginaFinal" => "509" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0525" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2005" "volumen" => "21" "paginaInicial" => "50" "paginaFinal" => "55" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0530" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vital organ blood flow during hyperdynamic sepsis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2003" "volumen" => "124" "paginaInicial" => "1053" "paginaFinal" => "1059" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0535" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Implications of augmented renal clearance in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrneph.2011.92" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Nephrol" "fecha" => "2011" "volumen" => "7" "paginaInicial" => "539" "paginaFinal" => "543" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0540" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Augmented renal clearance in septic patients and implications for vancomycin optimisation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2011.12.011" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2012" "volumen" => "39" "paginaInicial" => "420" "paginaFinal" => "423" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0545" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/cc12544" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2013" "volumen" => "17" "paginaInicial" => "R35" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0550" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jcrc.2013.03.003" "Revista" => array:6 [ "tituloSerie" => "J Crit Care" "fecha" => "2013" "volumen" => "28" "paginaInicial" => "695" "paginaFinal" => "700" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0555" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pitfalls of using estimations of glomerular filtration rate in an intensive care population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1445-5994.2009.02160.x" "Revista" => array:6 [ "tituloSerie" => "Intern Med J" "fecha" => "2011" "volumen" => "41" "paginaInicial" => "537" "paginaFinal" => "543" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0560" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single-center study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00134-007-0745-5" "Revista" => array:6 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2007" "volumen" => "33" "paginaInicial" => "1900" "paginaFinal" => "1906" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0565" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glomerular hyperfiltration and albuminuria in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anaesth Intensive Care" "fecha" => "2008" "volumen" => "36" "paginaInicial" => "674" "paginaFinal" => "680" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0570" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.11-1671" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2012" "volumen" => "142" "paginaInicial" => "30" "paginaFinal" => "39" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0575" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypoalbuminemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Intern Emerg Med" "fecha" => "2012" "numero" => "Suppl. 7" "paginaInicial" => "193" "paginaFinal" => "199" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0580" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human serum albumin: from bench to bedside" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.mam.2011.12.002" "Revista" => array:6 [ "tituloSerie" => "Mol Aspects Med" "fecha" => "2012" "volumen" => "33" "paginaInicial" => "209" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0585" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the Saline versus Albumin Fluid Evaluation (SAFE) study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bmj.38985.398704.7C" "Revista" => array:5 [ "tituloSerie" => "BMJ" "fecha" => "2006" "volumen" => "333" "paginaInicial" => "1044" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0590" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/11539220-000000000-00000" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2011" "volumen" => "50" "paginaInicial" => "99" "paginaFinal" => "110" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0595" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacodynamics of cefepime in patients with Gram-negative infections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2002" "volumen" => "50" "paginaInicial" => "425" "paginaFinal" => "428" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0600" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.49.12.4920-4927.2005" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2005" "volumen" => "49" "paginaInicial" => "4920" "paginaFinal" => "4927" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0605" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.00294-06" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2007" "volumen" => "51" "paginaInicial" => "1725" "paginaFinal" => "1730" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0610" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A systematic review of the clinical benefits of continuous administration of beta-lactam antibiotics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0b013e3181a0054d" "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2009" "volumen" => "37" "paginaInicial" => "2071" "paginaFinal" => "2078" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0615" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/cc11405" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2012" "volumen" => "16" "paginaInicial" => "R113" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0620" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/cis856" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2013" "volumen" => "56" "paginaInicial" => "236" "paginaFinal" => "244" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0625" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Even high-dose extended infusions may not yield desired concentrations of β-lactams: the value of therapeutic drug monitoring" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Infect Dis" "fecha" => "2015" "paginaInicial" => "1" "paginaFinal" => "4" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0630" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous beta-lactam infusion in critically ill patients: the clinical evidence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/2110-5820-2-37" "Revista" => array:5 [ "tituloSerie" => "Ann Intensive Care" "fecha" => "2012" "volumen" => "2" "paginaInicial" => "37" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0635" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jac/dkt523" "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2014" "volumen" => "69" "paginaInicial" => "1416" "paginaFinal" => "1423" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0640" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Experience with a once-daily dosing program of aminoglycosides in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00134-002-1313-7" "Revista" => array:6 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2002" "volumen" => "28" "paginaInicial" => "936" "paginaFinal" => "942" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0645" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimizing use of aminoglycosides in the critically ill" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2007-996406" "Revista" => array:6 [ "tituloSerie" => "Semin Respir Crit Care Med" "fecha" => "2007" "volumen" => "28" "paginaInicial" => "596" "paginaFinal" => "603" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0650" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Suboptimal aminoglycoside dosing in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/FTD.0b013e31818b6b2f" "Revista" => array:6 [ "tituloSerie" => "Ther Drug Monit" "fecha" => "2008" "volumen" => "30" "paginaInicial" => "674" "paginaFinal" => "681" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0655" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Augmented renal clearance: implications for antibacterial dosing in the critically ill" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/11318140-000000000-00000" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2010" "volumen" => "49" "paginaInicial" => "1" "paginaFinal" => "16" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0660" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predictors of insufficient amikacin peak concentration in critically ill patients receiving a 25mg/kg total body weight regimen" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00134-014-3276-x" "Revista" => array:6 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2014" "volumen" => "40" "paginaInicial" => "998" "paginaFinal" => "1005" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0665" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2004" "volumen" => "43" "paginaInicial" => "925" "paginaFinal" => "942" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0670" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/cir124" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2011" "volumen" => "52" "paginaInicial" => "975" "paginaFinal" => "981" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0675" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates (“the MIC Creep”): implications for therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3410/M4-4" "Revista" => array:5 [ "tituloSerie" => "F1000 Med Rep" "fecha" => "2012" "volumen" => "4" "paginaInicial" => "4" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0680" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 50. 2015. Available at: <a href="http://www.eucast.org/">http://www.eucast.org</a>." ] ] ] 44 => array:3 [ "identificador" => "bib0685" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetic/pharmacodynamic analysis of vancomycin in ICU patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00134-006-0470-5" "Revista" => array:6 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2007" "volumen" => "33" "paginaInicial" => "279" "paginaFinal" => "285" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0690" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2001" "volumen" => "45" "paginaInicial" => "2460" "paginaFinal" => "2467" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0695" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum vancomycin levels resulting from continuous or intermittent infusion in critically ill burn patients with or without continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/BCR.0b013e31825042fa" "Revista" => array:6 [ "tituloSerie" => "J Burn Care Res" "fecha" => "2012" "volumen" => "33" "paginaInicial" => "e254" "paginaFinal" => "e262" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0700" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pneumonia caused by oxacillin-resistant Staphylococcus aureus treated with glycopeptides" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2005" "volumen" => "33" "paginaInicial" => "1983" "paginaFinal" => "1987" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0705" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2005.04.005" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2005" "volumen" => "26" "paginaInicial" => "50" "paginaFinal" => "55" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0710" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400mg" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2478/v10039-012-0028-4" "Revista" => array:6 [ "tituloSerie" => "Adv Med Sci" "fecha" => "2012" "volumen" => "57" "paginaInicial" => "217" "paginaFinal" => "223" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0715" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jcrc.2007.11.011" "Revista" => array:6 [ "tituloSerie" => "J Crit Care" "fecha" => "2008" "volumen" => "23" "paginaInicial" => "422" "paginaFinal" => "430" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0720" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/cit582" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2013" "volumen" => "57" "paginaInicial" => "1568" "paginaFinal" => "1576" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0725" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1086/652767" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2010" "volumen" => "50" "paginaInicial" => "1568" "paginaFinal" => "1574" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0730" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Linezolid pharmacokinetics and pharmacodynamics in clinical treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jac/dkr072" "Revista" => array:7 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2011" "volumen" => "66" "numero" => "Suppl. 4" "paginaInicial" => "iv7" "paginaFinal" => "iv15" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0735" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200342150-00007" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2003" "volumen" => "42" "paginaInicial" => "1411" "paginaFinal" => "1423" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0740" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200342130-00004" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2003" "volumen" => "42" "paginaInicial" => "1129" "paginaFinal" => "1140" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0745" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2007.09.009" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "122" "paginaFinal" => "129" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0750" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of linezolid in septic patients with and without extended dialysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00228-009-0766-9" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Pharmacol" "fecha" => "2010" "volumen" => "66" "paginaInicial" => "291" "paginaFinal" => "298" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0755" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk factors for a low linezolid trough plasma concentration in acute infections" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.01694-12" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2013" "volumen" => "57" "paginaInicial" => "1913" "paginaFinal" => "1917" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0760" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/cc13984" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2014" "volumen" => "18" "paginaInicial" => "R148" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0765" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.00177-10" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2010" "volumen" => "54" "paginaInicial" => "4605" "paginaFinal" => "4610" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0770" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "[Epub ahead of print]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics and preliminary safety of high dose linezolid for the treatment of Gram-positive bacterial infections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jinf.2015.06.007" "Revista" => array:2 [ "tituloSerie" => "J Infect" "fecha" => "2015" ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0775" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.01733-10" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2011" "volumen" => "55" "paginaInicial" => "3284" "paginaFinal" => "3294" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0780" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dosing of colistin – back to basic PK/PD" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.coph.2011.07.004" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pharmacol" "fecha" => "2011" "volumen" => "11" "paginaInicial" => "464" "paginaFinal" => "469" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0785" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/2110-5820-1-30" "Revista" => array:5 [ "tituloSerie" => "Ann Intensive Care" "fecha" => "2011" "volumen" => "1" "paginaInicial" => "30" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0790" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Colistin in the 21st century" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/QCO.0b013e328332e672" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Infect Dis" "fecha" => "2009" "volumen" => "22" "paginaInicial" => "535" "paginaFinal" => "543" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0795" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.01361-08" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2009" "volumen" => "53" "paginaInicial" => "3430" "paginaFinal" => "3436" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0800" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Crit Care Clin" "fecha" => "2000" "volumen" => "16" "paginaInicial" => "179" "paginaFinal" => "192" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0805" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antibiotic dosing in multiple organ dysfunction syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.10-2371" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2011" "volumen" => "139" "paginaInicial" => "1210" "paginaFinal" => "1220" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0810" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics and dosage adjustment in patients with renal dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00228-009-0678-8" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Pharmacol" "fecha" => "2009" "volumen" => "65" "paginaInicial" => "757" "paginaFinal" => "773" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0815" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tigecycline pharmacokinetic/pharmacodynamic update" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2008" "volumen" => "62" "numero" => "Suppl. 1" "paginaInicial" => "11" "paginaFinal" => "16" ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0820" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Pfizer Pharmaceuticals. Tygacil (tigecycline) for injection: product information." ] ] ] 72 => array:3 [ "identificador" => "bib0825" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Principles of antibacterial dosing in continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0b013e3181aab3d0" "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2009" "volumen" => "37" "paginaInicial" => "2268" "paginaFinal" => "2282" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0830" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MCC.0b013e32835685ad" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Crit Care" "fecha" => "2012" "volumen" => "18" "paginaInicial" => "460" "paginaFinal" => "471" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0835" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200847030-00003" "Revista" => array:7 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2008" "volumen" => "47" "paginaInicial" => "173" "paginaFinal" => "180" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S147444220300485X" "estado" => "S300" "issn" => "14744422" ] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0840" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2013.01.018" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2013" "volumen" => "41" "paginaInicial" => "564" "paginaFinal" => "568" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0845" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Clin Pharmacol Ther" "fecha" => "2010" "volumen" => "48" "paginaInicial" => "243" "paginaFinal" => "249" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0850" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2011.04.010" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2011" "volumen" => "38" "paginaInicial" => "152" "paginaFinal" => "156" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0855" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new regimen for continuous infusion of vancomycin during continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jac/dkt261" "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2013" "volumen" => "68" "paginaInicial" => "2859" "paginaFinal" => "2865" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0860" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2125.2004.02143.x" "Revista" => array:6 [ "tituloSerie" => "Br J Clin Pharmacol" "fecha" => "2004" "volumen" => "58" "paginaInicial" => "259" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0865" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0b013e318241e553" "Revista" => array:7 [ "tituloSerie" => "Crit Care Med" "fecha" => "2012" "volumen" => "40" "paginaInicial" => "1523" "paginaFinal" => "1528" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S1474442213701248" "estado" => "S300" "issn" => "14744422" ] ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0870" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.00374-11" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2011" "volumen" => "55" "paginaInicial" => "4639" "paginaFinal" => "4642" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0875" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2011.01.026" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2011" "volumen" => "37" "paginaInicial" => "531" "paginaFinal" => "535" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0880" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200746120-00003" "Revista" => array:7 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "997" "paginaFinal" => "1038" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022510X10004090" "estado" => "S300" "issn" => "0022510X" ] ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0885" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/cc10257" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2011" "volumen" => "15" "paginaInicial" => "R137" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0890" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijantimicag.2014.09.009" "Revista" => array:6 [ "tituloSerie" => "Int J Antimicrob Agents" "fecha" => "2015" "volumen" => "45" "paginaInicial" => "41" "paginaFinal" => "45" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0895" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "e9-18" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jcrc.2012.02.013" "Revista" => array:5 [ "tituloSerie" => "J Crit Care." "fecha" => "2012" "volumen" => "27" "paginaInicial" => "741" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0900" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00134-007-0606-2" "Revista" => array:6 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2007" "volumen" => "33" "paginaInicial" => "1018" "paginaFinal" => "1024" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0905" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/cc11679" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2012" "volumen" => "16" "paginaInicial" => "R194" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0910" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Protein bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s13054-015-0891-z" "Revista" => array:5 [ "tituloSerie" => "Crit Care" "fecha" => "2015" "volumen" => "19" "paginaInicial" => "164" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0915" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jac/dkp026" "Revista" => array:6 [ "tituloSerie" => "J Antimicrob Chemother" "fecha" => "2009" "volumen" => "63" "paginaInicial" => "767" "paginaFinal" => "770" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib0920" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "DRUGDEX System [database on the Internet]. Ann Arbor (MI): Truven Health Analytics; 2013. Available at: <a href="http://www.micromedexsolutions.com/">www.micromedexsolutions.com</a>. Subscription required to view." ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000727/v2_201703210124/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/21735727/0000003900000009/v2_201703210124/S2173572715000727/v2_201703210124/en/main.pdf?idApp=WMIE&text.app=https://medintensiva.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000727?idApp=WMIE"]

Statistics

Special article

Antibiotic dose optimization in critically ill patients

Optimización de la dosis de antibióticos en pacientes críticamente enfermos

M.O. Cottaa,b,c,d,

Corresponding author

meninocotta@gmail.com

Corresponding author.

, J.A. Robertsa,b,d, J. Lipmana,b

a Burns Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia

b Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

c Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia

d School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia

Read

18684

Times
was read the article

8463

Total PDF

10221

Total HTML

Share statistics

 array:23 [
  "pii" => "S2173572715000727"
  "issn" => "21735727"
  "doi" => "10.1016/j.medine.2015.07.001"
  "estado" => "S300"
  "fechaPublicacion" => "2015-12-01"
  "aid" => "827"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and SEMICYUC"
  "copyrightAnyo" => "2015"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "fla"
  "cita" => "Med Intensiva. 2015;39:563-72"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 5850
    "formatos" => array:3 [
      "EPUB" => 189
      "HTML" => 3477
      "PDF" => 2184
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S2173572715000648"
    "issn" => "21735727"
    "doi" => "10.1016/j.medine.2015.06.001"
    "estado" => "S300"
    "fechaPublicacion" => "2015-12-01"
    "aid" => "824"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and SEMICYUC"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "sco"
    "cita" => "Med Intensiva. 2015;39:573-4"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 2399
      "formatos" => array:3 [
        "EPUB" => 188
        "HTML" => 1474
        "PDF" => 737
      ]
    ]
    "en" => array:10 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Point of view</span>"
      "titulo" => "Does early versus late tracheotomy afford benefits in ventilated patients&#63;"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "573"
          "paginaFinal" => "574"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "&#191;Aporta beneficios la traqueotom&#237;a precoz frente a la tard&#237;a en el enfermo ventilado&#63;"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J&#46;M&#46; A&#241;&#243;n"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "J&#46;M&#46;"
              "apellidos" => "A&#241;&#243;n"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0210569115001667"
        "doi" => "10.1016/j.medin.2015.06.007"
        "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/S0210569115001667?idApp=WMIE"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000648?idApp=WMIE"
    "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000648/v2_201703210124/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S2173572715000703"
    "issn" => "21735727"
    "doi" => "10.1016/j.medine.2015.05.005"
    "estado" => "S300"
    "fechaPublicacion" => "2015-12-01"
    "aid" => "807"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and SEMICYUC"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Med Intensiva. 2015;39:552-62"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 4202
      "formatos" => array:3 [
        "EPUB" => 173
        "HTML" => 3025
        "PDF" => 1004
      ]
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>"
      "titulo" => "Forum for debate&#58; Safety of allogeneic blood transfusion alternatives in the surgical&#47;critically ill patient"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "552"
          "paginaFinal" => "562"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Foro de debate&#58; seguridad de las alternativas a la transfusi&#243;n alog&#233;nica en el paciente quir&#250;rgico y&#47;o cr&#237;tico"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "M&#46; Mu&#241;oz G&#243;mez, E&#46; Bisbe Vives, M&#46; Basora Macaya, J&#46;A&#46; Garc&#237;a Erce, A&#46; G&#243;mez Luque, S&#46;R&#46; Leal-Noval, M&#46;J&#46; Colomina, J&#46; Comin Colet, E&#46; Contreras Barbeta, J&#46; Cuenca Espi&#233;rrez, A&#46; Garcia de Lorenzo y Mateos, F&#46; Gomoll&#243;n Garc&#237;a, M&#46; Izuel Ram&#237;, M&#46;V&#46; Moral Garc&#237;a, J&#46;B&#46; Montoro Ronsano, J&#46;A&#46; P&#225;ramo Fern&#225;ndez, A&#46; Pereira Saavedra, M&#46; Quintana Diaz, &#193;&#46; Remacha Sevilla, R&#46; Salinas Argente, C&#46; S&#225;nchez P&#233;rez, G&#46; Tirado Angl&#233;s, P&#46; Torrabadella de Reinoso"
          "autores" => array:23 [
            0 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Mu&#241;oz G&#243;mez"
            ]
            1 => array:2 [
              "nombre" => "E&#46;"
              "apellidos" => "Bisbe Vives"
            ]
            2 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Basora Macaya"
            ]
            3 => array:2 [
              "nombre" => "J&#46;A&#46;"
              "apellidos" => "Garc&#237;a Erce"
            ]
            4 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "G&#243;mez Luque"
            ]
            5 => array:2 [
              "nombre" => "S&#46;R&#46;"
              "apellidos" => "Leal-Noval"
            ]
            6 => array:2 [
              "nombre" => "M&#46;J&#46;"
              "apellidos" => "Colomina"
            ]
            7 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "Comin Colet"
            ]
            8 => array:2 [
              "nombre" => "E&#46;"
              "apellidos" => "Contreras Barbeta"
            ]
            9 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "Cuenca Espi&#233;rrez"
            ]
            10 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "Garcia de Lorenzo y Mateos"
            ]
            11 => array:2 [
              "nombre" => "F&#46;"
              "apellidos" => "Gomoll&#243;n Garc&#237;a"
            ]
            12 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Izuel Ram&#237;"
            ]
            13 => array:2 [
              "nombre" => "M&#46;V&#46;"
              "apellidos" => "Moral Garc&#237;a"
            ]
            14 => array:2 [
              "nombre" => "J&#46;B&#46;"
              "apellidos" => "Montoro Ronsano"
            ]
            15 => array:2 [
              "nombre" => "J&#46;A&#46;"
              "apellidos" => "P&#225;ramo Fern&#225;ndez"
            ]
            16 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "Pereira Saavedra"
            ]
            17 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Quintana Diaz"
            ]
            18 => array:2 [
              "nombre" => "&#193;&#46;"
              "apellidos" => "Remacha Sevilla"
            ]
            19 => array:2 [
              "nombre" => "R&#46;"
              "apellidos" => "Salinas Argente"
            ]
            20 => array:2 [
              "nombre" => "C&#46;"
              "apellidos" => "S&#225;nchez P&#233;rez"
            ]
            21 => array:2 [
              "nombre" => "G&#46;"
              "apellidos" => "Tirado Angl&#233;s"
            ]
            22 => array:2 [
              "nombre" => "P&#46;"
              "apellidos" => "Torrabadella de Reinoso"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0210569115001175"
        "doi" => "10.1016/j.medin.2015.05.006"
        "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/S0210569115001175?idApp=WMIE"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000703?idApp=WMIE"
    "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000703/v2_201703210124/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>"
    "titulo" => "Antibiotic dose optimization in critically ill patients"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "563"
        "paginaFinal" => "572"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "M&#46;O&#46; Cotta, J&#46;A&#46; Roberts, J&#46; Lipman"
        "autores" => array:3 [
          0 => array:4 [
            "nombre" => "M&#46;O&#46;"
            "apellidos" => "Cotta"
            "email" => array:1 [
              0 => "meninocotta&#64;gmail&#46;com"
            ]
            "referencia" => array:5 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
              3 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
              4 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "J&#46;A&#46;"
            "apellidos" => "Roberts"
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "J&#46;"
            "apellidos" => "Lipman"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Burns Trauma and Critical Care Research Centre&#44; University of Queensland&#44; Brisbane&#44; Queensland&#44; Australia"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Royal Brisbane and Women&#39;s Hospital&#44; Brisbane&#44; Queensland&#44; Australia"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Department of Medicine&#44; Royal Melbourne Hospital&#44; University of Melbourne&#44; Parkville&#44; Victoria&#44; Australia"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "School of Pharmacy&#44; University of Queensland&#44; Brisbane&#44; Queensland&#44; Australia"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Optimizaci&#243;n de la dosis de antibi&#243;ticos en pacientes cr&#237;ticamente enfermos"
      ]
    ]
    "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" => 1532
            "Ancho" => 2257
            "Tamanyo" => 181514
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Initial pathophysiology of severe sepsis&#47;septic shock and its impact on antibiotic pharmacokinetics&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Given an era of accelerating bacterial resistance and dwindling antimicrobial resources&#44; optimization of existing antibiotic therapy is an increasingly important consideration for clinicians worldwide&#46; There is perhaps added significance among intensive care unit &#40;ICU&#41; patients&#44; as these patients are at high risk of infection-related mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">1</span></a> They are also more prone to acute and often marked changes in pathophysiology and are subject to invasive intervention&#44; both of which have the potential to significantly alter drug exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Antibiotics are one of the most commonly prescribed drug classes in the ICU and they have the ability to dramatically improve patient outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">3&#44;4</span></a> Therefore&#44; it stands to reason that maximizing the likelihood of eradicating infection whilst lowering the risk of unwanted effects should be the end goal for all prescribed antibiotic therapy&#46; This is perhaps why determining the relationship between exposure of antibiotics in vivo &#40;i&#46;e&#46; pharmacokinetics&#44; PK&#41; and what clinical response it elicits &#40;pharmacodynamics&#44; PD&#41; has gained much prominence in critical care literature&#46; The purpose of this review is to discuss variations in PK that commonly occur among the critically ill&#44; through both existing pathophysiology as well as associated interventions&#44; and to offer insights on how antibiotic therapy can be tailored accordingly so as to optimize desired PD effects&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Severe sepsis and septic shock</span><p id="par0015" class="elsevierStylePara elsevierViewall">Sepsis is a common occurrence within the ICU and is defined as a systemic inflammatory response to infection&#44; which can be complicated by organ dysfunction &#40;&#8216;severe sepsis&#8217;&#41; or persistent hypotension refractory to fluid resuscitation &#40;&#8216;septic shock&#8217;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">5</span></a> Although the incidence of sepsis worldwide is currently unknown&#44; extrapolations from United States data conservatively estimate an occurrence of 19 million cases annually&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">6&#44;7</span></a> Added to this high burden are reports indicating a severe sepsis mortality rate of nearly 30&#37; in developed countries&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">8&#44;9</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Initial pathophysiology and its impact on antibiotic pharmacokinetics &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;</span><p id="par0020" class="elsevierStylePara elsevierViewall">One of the first clinical observations during severe sepsis and septic shock is significant fluid shift from the intravascular compartment &#40;i&#46;e&#46; blood vessels&#41; into interstitial space due to endothelial damage and increased capillary leak&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">10</span></a> The resultant hypotension is often fulminant&#44; requiring urgent and aggressive delivery of intravenous resuscitation fluid&#44; which in turn can further increase interstitial volume&#46; Depending on the physiochemical properties of the antibiotic&#44; these large amounts of extravascular fluid may have a significant impact on drug distribution and hence dosing strategies&#46; For example&#44; initial doses of hydrophilic antibiotics &#40;i&#46;e&#46; that concentrate more in blood and interstitial fluid of tissues&#41; will need to take into account these increased volumes&#46; In this case&#44; due to the greater volume of distribution &#40;<span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span>&#41; noted for these drugs&#44; use of loading doses should be considered to ensure early achievement of therapeutic concentrations&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">11&#44;12</span></a> Lipophilic antibiotics &#40;i&#46;e&#46; that concentrate intra-cellularly and in adipose tissue&#41;&#44; on the other hand&#44; are not greatly influenced by changes in fluid volume and may not require alterations in initial dosing&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">A main element of the systemic inflammatory response during sepsis is that initial vasodilation is associated with a hyperdynamic cardiovascular state&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">14</span></a> Increased cardiac output is further driven by use of resuscitation fluid and vasopressors&#44; resulting in increased blood flow to major organs including the kidneys&#46; Although the exact mechanism has not been fully elucidated&#44; the end result may be that of increased renal blood blow and glomerular filtration leading to enhanced renal drug elimination&#44; termed &#8216;augmented renal clearance&#8217; &#40;ARC&#41;&#46; ARC has previously been defined as a creatinine clearance &#8805; 130<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">15</span></a> There are now numerous reports of the prevalence of ARC in septic as well as other groups of critically ill patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Mathematical formulae to estimate glomerular filtration rate have all been derived from outside of the ICU and so have limited applicability in determining this increased renal clearance&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">19</span></a> Additionally&#44; serum creatinine concentrations are not sensitive enough to identify patients with ARC and so a measured urine creatinine clearance collection over a specified period remains the preferred method for clinical use&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">17</span></a> Recent data suggests that a 2-hour creatinine clearance may be a suitable substitute for longer collection times&#44; such as the standard 24-hour creatinine clearance&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">20</span></a> though the importance of accuracy of sample collection is required with shorter collection times&#46; Although generally not applicable for determining initial antibiotic dosing regimens&#44; it may be an important consideration in some patients&#44; particularly younger males&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">21</span></a> with severe sepsis and septic shock&#44; as important data is accumulating that ARC is associated with subtherapeutic exposure to renally cleared antibiotics such as the &#946;-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">22</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Another common phenomenon soon after the initial phase of severe sepsis and septic shock is the pronounced reduction in serum albumin concentrations &#40;hypoalbuminemia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">23</span></a> Albumin constitutes nearly two-thirds of all human serum proteins and is the primary protein responsible for drug-protein binding&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">24</span></a> Previously defined as a serum albumin concentration less than 25<span class="elsevierStyleHsp" style=""></span>g&#47;L&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">25</span></a> hypoalbuminemia has a direct impact on the PK of antibiotics&#44; particularly on those antibiotics that are highly protein bound&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">26</span></a> Firstly&#44; it increases the unbound or &#8216;free&#8217; fraction of drug&#46; This is important given that it is only the unbound drug that can exert a pharmacodynamic effect&#46; As hypoalbuminemic states can increase the amount of drug that distributes into tissues&#44; this is likely to have a direct effect on the <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span> of an antibiotic&#46; Finally&#44; as only the unbound drug in the intravascular compartment is available for metabolism and elimination&#44; low serum albumin concentrations may mean that there is higher proportion of unbound drug available for clearance leading to low concentrations toward the end of the dosing interval&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Now that the main considerations for altered drug pharmacokinetics during the initial phase of severe sepsis and septic shock have been described&#44; the next step is to apply this knowledge when formulating dosing strategies for antibiotics based on their pathogen-exposure relationship&#44; also known as the pharmacokinetic&#47;pharmacodynamic &#40;PK&#47;PD&#41; index &#40;see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> for summary of PK&#47;PD index of antibiotic classes&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Time-dependent antibiotics</span><p id="par0045" class="elsevierStylePara elsevierViewall">Antibiotics that belong to this category exhibit maximum bactericidal activity when unbound concentrations of the drug exceed the minimum inhibitory concentration &#40;MIC&#41; of the bacterial pathogen &#40;<span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span>&#41;&#46; The main classes of antibiotics in this group include &#946;-lactams &#40;penicillins&#44; cephalosporins&#44; carbapenems&#44; monobactams&#41; and lincosamides &#40;clindamycin and lincomycin&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">From these&#44; the broad-spectrum &#946;-lactams are perhaps the most important group in the critical care setting&#46; Particularly for Gram-negative infections&#44; the maximal effect of bacterial killing and suppression of resistance emergence for &#946;-lactams has previously been shown to be when the unbound trough drug concentration to MIC ratio is four to six&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">27&#8211;29</span></a> Increasing MICs among bacterial isolates from hospital ICUs has meant that aggressive dosing of &#946;-lactams is a fundamental consideration in the setting of severe sepsis and septic shock&#46; Added to this&#44; the hydrophilicity of these agents means that they are not only prone to the effects of an increased <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span>&#44; but also increased clearance in those patients exhibiting ARC&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">It is for these reasons that use of continuous or extended infusions with front-loading doses&#44; as opposed to traditional intermittent bolus doses&#44; have gained prominence when administering &#946;-lactams in the ICU&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">30</span></a> Although some studies have shown favorable results in terms of continuous infusions attaining higher plasma &#946;-lactam concentrations and increased rates of clinical cure when compared to intermittent bolus administration&#44;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">31&#44;32</span></a> a large randomized controlled trial is still required to confirm differences&#44; if any&#44; in patient outcomes&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Another important consideration in the optimization of &#946;-lactam therapy in the ICU is the use of therapeutic drug monitoring &#40;TDM&#41;&#46; Measuring trough concentrations of the free fraction of &#946;-lactams in plasma is a useful tool in ensuring that PK&#47;PD targets for efficacy are being met&#46; Use of TDM may be particularly important when faced with the conundrum of treating multi-resistant pathogens with high MICs to &#946;-lactams in the setting of patients with potentially increased renal clearance&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">33</span></a> A trough <span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span> ratio of one is generally recommended when administering intermittent bolus or extended infusions&#44; whilst for continuous infusions&#44; a steady-state <span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span> ratio of between four to six is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">34</span></a> There is&#44; however&#44; scope for more robust studies that better define optimal &#946;-lactam PK&#47;PD targets&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">35</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Lincosamides represent the other main antibiotic class demonstrating primarily a time-dependent PK&#47;PD index&#46; Being more lipophilic than the &#946;-lactams&#44; the <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span> of lincosamides such as lincomycin and clindamycin are less likely to be affected by fluid shifts seen in ICU patients&#46; However&#44; as both antibiotics have significant protein binding &#40;i&#46;e&#46; 80&#8211;90&#37;&#41; and are subject to hepatic as well as renal clearance&#44; altered PK may arise in the setting of hypoalbuminemia as well as ARC&#46; Notably&#44; these effects are yet to be extensively investigated and so dosing regimen adjustments of lincosamides in critical care patients are largely theoretical and currently based on expert opinion&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Concentration-dependent antibiotics</span><p id="par0070" class="elsevierStylePara elsevierViewall">Efficacy best correlates with peak antibiotic concentration &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#41; to MIC ratio &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC&#41; for antibiotics with a concentration dependent PK&#47;PD index&#46; Aminoglycosides and metronidazole belong in this category and there are important implications when dosing these agents in the setting of increased <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span> such as is seen in severe sepsis&#44; burns and trauma&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">For example&#44; conventional dosing of aminoglycosides used in patients with septic shock have been shown consistently to have difficulty in attaining specified targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">36&#8211;38</span></a> As they are hydrophilic in nature&#44; the pharmacokinetics of aminoglycosides such as amikacin&#44; gentamicin and tobramycin are heavily influenced by factors such as a positive fluid balance and ARC&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">39&#44;40</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">All of the above point to a need for a better understanding of how TDM can optimize aminoglycoside therapy in the ICU&#46; Practically&#44; sampling half an hour post administration of the aminoglycoside will help approximate the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#44; with the corresponding MIC determined either via a known or suspected pathogen isolate or clinical breakpoint based on epidemiological data&#46; Subsequent sampling anywhere between 6 and 14<span class="elsevierStyleHsp" style=""></span>hours post-dose to a trough concentration will be a useful indicator for aminoglycoside clearance when the data is then analyzed using Bayesian dosing software&#46; One upside with the aminoglycosides from a dosing point of view is that these molecules do not have a high albumin affinity&#44; and so TDM strategies do not necessarily need to take into account potential effects of hypoalbuminemia on unbound concentrations&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Concentration-dependent with time-dependence antibiotics</span><p id="par0085" class="elsevierStylePara elsevierViewall">The area under the concentration-time curve during a 24-hour time period &#40;AUC<span class="elsevierStyleInf">0&#8211;24</span>&#41; to the MIC ratio &#40;AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&#41; is a valuable PK&#47;PD index to describe the efficacy of antimicrobials&#44; including glycopeptides&#44; oxazolidinones&#44; fluoroquinolones&#44; polymixins&#44; daptomycin&#44; azithromycin and tigecycline&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">For vancomycin&#44; a PD target of AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC of 400 has been advocated to achieve clinical effectiveness with vancomycin in the treatment of <span class="elsevierStyleItalic">Staphylococcus aureus</span> pneumonia and bacteremia&#44;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">41&#44;42</span></a> In the absence of clinical data&#44; this ratio is a suitable PD target for other Gram-positive pathogens such as <span class="elsevierStyleItalic">Enterococcus</span> spp&#46; and coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span> spp&#46; However&#44; with MICs creep for organisms such as methicillin resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> &#40;MRSA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">43</span></a> targets of AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC of 400 are increasingly difficult to attain in the setting of severe sepsis&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">To illustrate&#44; for an isolate with an MIC of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; the clinical breakpoint based on the European Committee on Antimicrobial Susceptibility Testing &#40;EUCAST&#41; data&#44;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">44</span></a> an AUC<span class="elsevierStyleInf">0&#8211;24</span> of 800<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#47;h &#40;a trough concentration of more than 20&#8211;25<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41; would be required&#44; increasing risks of toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">12</span></a> As simulated models have suggested a daily dose of 3&#8211;4<span class="elsevierStyleHsp" style=""></span>g of vancomycin are needed to achieve 90&#37; probability of attaining the above PD for an isolate with an MIC 1<span class="elsevierStyleHsp" style=""></span>mg&#47;L in ICU patients &#40;not including patients with augmented renal clearance that would require even higher doses&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">45</span></a> this would again mean proportionally higher doses and more risk of toxicity when treating isolates with higher vancomycin MICs&#46; Use of continuous vancomycin infusions have been proposed as a means to achieve target concentrations faster&#44;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">46</span></a> as well as ensuring consistency in serum concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">47</span></a> However&#44; there is only retrospective outcome data on the advantages of continuous versus intermittent vancomycin dosing&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">48</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Fluoroquinolones&#44; such as ciprofloxacin&#44; display predominantly concentration-dependent killing with time-dependent microbiologic eradication&#46; As ciprofloxacin is lipophilic and concentrates in tissues&#44; changes in fluid redistribution associated with sepsis do not have a marked impact when compared to more hydrophilic antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">49</span></a> However&#44; an initial ciprofloxacin dose of 400<span class="elsevierStyleHsp" style=""></span>mg intravenously &#40;IV&#41; has been shown to be inadequate in attaining desired AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC ratios of &#8805;125 or <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC ratios of &#62;10 in the critical care setting&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">50</span></a> Additionally&#44; a dosing regimen of 400<span class="elsevierStyleHsp" style=""></span>mg 12-hourly IV reached optimal killing concentrations for pathogens with MICs &#60; 0&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; a relatively low threshold for isolates in the ICU&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">51</span></a> Subsequently&#44; the use of 600<span class="elsevierStyleHsp" style=""></span>mg 12-hourly IV has been recommended as the optimal dosing strategy for ciprofloxacin in ICU patients not in renal failure&#44; however&#44; there is yet to be any trial data to validate this altered dosing regimen&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Similar to the fluoroquinolones&#44; daptomycin exhibits a largely concentration-dependent effect together with some time-dependent killing&#46; Daptomycin&#44; however&#44; is a much more hydrophilic molecule with higher protein binding &#40;up to 93&#37;&#41;&#44; and as such&#44; in vivo drug distribution may be greatly influenced by changes in V<span class="elsevierStyleInf">d</span> and hypoalbuminemia&#46; An approved dose of 6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg 24-hourly for the treatment of methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> bacteraemia has shown to provide lower daptomycin exposure in the critically ill&#44; with doses of between 8 and 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg 24-hourly having a higher probability of attaining target AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC ratios&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">52</span></a> Of significance&#44; regular monitoring of creatinine phosphokinase&#44; as a marker for rhabdomyolysis&#44; needs to be considered when utilizing higher daptomycin doses&#44; as a rise in trough drug concentration &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#41; have been associated with this form of toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">53</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">As the first oxazolidinone antibiotic&#44; linezolid is effective in the treatment of Gram-positive infections&#44; and has excellent distribution into tissues such as the lungs&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">54</span></a> Both AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC and <span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span> have been used to define the activity of linezolid&#44; with optimal PK&#47;PD indices in plasma reported as 80&#8211;120 &#40;AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&#41; and 2&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#41; based on pathogen MICs of &#8804;2<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">55</span></a> However&#44; although previous data has shown that standard doses of 600<span class="elsevierStyleHsp" style=""></span>mg 12-hourly achieve target plasma concentrations in the general population&#44;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">56</span></a> there have been several reports of subtherapeutic concentrations and treatment failure with high inter- and intra-patient variability among the critically ill&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">57&#8211;60</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The use of a 300<span class="elsevierStyleHsp" style=""></span>mg loading dose in combination with a 900<span class="elsevierStyleHsp" style=""></span>mg continuous infusion on day 1 of treatment&#44; followed by a continuous infusion of 1200<span class="elsevierStyleHsp" style=""></span>mg 24-hourly thereafter has been shown to be more likely attain AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC ratio of &#62;80 compared with standard intermittent doses in a small group of critically ill patients&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">57</span></a> Although this may be a reasonable alternative in critically ill patients with normal renal function&#44; larger trial data with infection-related outcomes and accounting for concomitant antibiotic therapy are required to validate these preliminary findings&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Importantly&#44; doses higher than 1200<span class="elsevierStyleHsp" style=""></span>mg per day of linezolid may be required in some instances&#46; A well-defined linear relationship between <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> and AUC<span class="elsevierStyleInf">0&#8211;24</span> means that there is potential to utilize <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> as a useful PK&#47;PD index for TDM in the future&#44;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">60&#44;61</span></a> especially in the context of higher doses&#46; A recent study from Lopez-Garc&#237;a et al&#46; evaluated the preliminary safety of doses 600<span class="elsevierStyleHsp" style=""></span>mg 8-hourly as part of a TDM program and found that where the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> remained below 6<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; no hematological toxicity was observed&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">62</span></a> In some of the patients in this analysis&#44; the increased dose resulted in a higher <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> and hematological toxicity was observed which highlights the importance of accurate dose adaptation&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The emergence of multi-drug resistant Gram-negative pathogens and a lack of novel antibiotics has meant that older drug classes&#44; such as the polymyxins&#44; have re-emerged as important treatment options&#46; Colistin&#44; or polymixin E&#44; is becoming a more widely prescribed antibiotic in the ICU&#46; Dose optimization of colistin remains complex&#44; in part due to substantial inter-patient variability in the in vivo conversion of colistin methanesulfonate &#40;&#91;CMS&#93;&#44; the prodrug&#41; to colistin&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">63</span></a> The bacterial killing profile of colistin best correlates with AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&#44; however&#44; optimal PK&#47;PD targets in critically ill patients are yet to be fully confirmed&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">64&#44;65</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">One problem that has specific relevance in the critical care setting is the delay in exposure to effective therapy&#46; Conversion of intravenously administered CMS to colistin may take several hours to achieve plasma concentrations deemed high enough to be effective&#46; Added to this&#44; the extent of conversion has been found to be low in the setting of normal renal function&#44; due primarily to increased tubular secretion of CMS prior to conversion&#46; As such&#44; caution has been advised when using colistin as monotherapy&#44; and the use of combination therapy&#44; such as with carbapenems&#44; is advocated&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">66</span></a> When used in conjunction with other antibiotics&#44; use of loading doses factoring in target MICs and body weight&#44; and maintenance doses calculated based on renal clearance is generally recommended for critically ill patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">63&#44;67</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Antibiotic dosing in multi-organ dysfunction syndrome &#40;MODS&#41;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Termed MODS when two or more organ systems are involved&#44; worsening organ function caused by severe infection is associated with grave outcomes and treatment failure&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">68</span></a> After the initial phase of severe sepsis and septic shock&#44; ongoing sepsis-induced hypoperfusion to vital organs and tissues as a result of cardiovascular dysfunction can have a profound effect on the PK profile of both hydrophilic and lipophilic antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">69</span></a> Additionally&#44; as these patients are often sicker and in urgent need of anti-infective therapy&#44; there is a balance between appropriate and excessive exposure to these drugs&#46; It is important to remember that this balance is not necessarily easy to attain in the setting of fluctuating hemodynamics and organ function&#44; and that there will always be a degree of uncertainty when adjusting dosing regimens in MODS&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hepatic impairment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Antibiotics that are lipophilic and&#47;or highly albumin-bound may undergo extensive liver metabolism&#44; resulting in metabolites that are more easily eliminated&#46; Severe hepatic dysfunction or hepatic failure may compromise this metabolism in a number of ways including a compromise in hepatic blood flow&#44; reduced hepatocyte function and decreased biliary excretion&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">70</span></a> There is a risk in the presence of very severe dysfunction that accumulation of these antibiotics has the potential to result in toxicity&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">One example of an antibiotic that requires dosage adjustment in hepatic dysfunction is tigecycline&#44; which is both lipophilic and highly protein bound &#40;71&#8211;89&#37;&#41;&#46; Predominantly eliminated in feces via bile acid conjugates&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">71</span></a> tigecycline elimination has been shown to be reduced in hepatic failure&#44; with a 43&#37; increase in elimination half life in patients with severe hepatic impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">69</span></a> Thus&#44; the manufacturer recommends halving the usual maintenance dose in severe liver disease&#44; whilst maintaining the usual loading dose&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">72</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Renal impairment</span><p id="par0150" class="elsevierStylePara elsevierViewall">Renal dysfunction has dosing implications for parent compounds of hydrophilic antibiotics as well as renally cleared metabolites of some moderately lipophilic antibiotics&#46; Renal function needs to be continually and judiciously monitored so that prompt dosage adjustments for these drugs can be made so as to minimize toxicity risk&#46; It is important to note that the PK&#47;PD index of the antibiotic contributes significantly to how adjustments in doses and dosing regimens are made&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">For time dependent antibiotics cleared via the kidneys&#44; such as the &#946;-lactams&#44; a dosage reduction rather than decreasing dosing frequency is likely to be the optimal choice in reducing drug accumulation but ensuring the <span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span> is maintained&#46; Conversely&#44; concentration dependence antibiotics will require extending the dosing frequency rather than reducing the dose&#59; therefore maximizing bacterial killing by preserving the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC&#46; For concentration-dependent with time-dependence antibiotics&#44; dosage adjustments in renal failure are usually derived based on which component of the PK&#47;PD index predominates&#46; For example&#44; as the fluoroquinolones have predominant concentration-dependence with time dependence&#44; adjusting in renal failure may entail prolonging the dosing interval rather than altering the dose&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Antibiotic dosing in continuous renal replacement therapy &#40;CRRT&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Persistent renal failure and the accumulation of metabolic waste products such as urea often warrant the need for intervention among critically ill patients&#46; Therefore&#44; the use of renal replacement therapy is common practice in the ICU&#44; with CRRT&#44; intermittent&#44; and hybrid forms of therapy utilized&#46; Use of CRRT involves modalities such as continuous venovenous hemofiltration &#40;CVVH&#41;&#44; continuous venovenous hemodialysis &#40;CVVHD&#41; and continuous venovenous hemodiafiltration &#40;CVVHDF&#41;&#44; with no best method currently established in the literature&#46; Consequently&#44; there is widespread heterogeneity in how CRRT is employed in the critical care setting&#44; with variability in doses of CRRT employed&#44; blood and dialysate flow rate&#44; types of filters and dialysis membranes used and surface area&#46;<a class="elsevierStyleCrossRefs" href="#bib0825"><span class="elsevierStyleSup">73&#44;74</span></a> Added to this are the practical issues associated with reduced delivery of CRRT such as interruptions due to filter clotting and patient time away for diagnostic and procedural purposes&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Although each of these types of CRRT are efficient in removing hydrophilic antibiotics&#44; the variation in practice means that unfortunately there is no &#8216;one size fits all&#8217; in dosing recommendations for these drugs in CRRT&#46; This may be even more appreciable when considering that the residual endogenous clearance of patients has been reported as a more useful covariate in predicting systemic antibiotic clearance than treatment with CRRT&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">75</span></a> Nevertheless&#44; a brief review of antibiotic dosing studies in CRRT may help decipher some useful recommendations for dose optimization in this challenging cohort&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">For example&#44; although standardizing glycopeptide dosing across different types of CRRT is complex and problematic&#44;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">76</span></a> some data report up to 50&#37; of total glycopeptide clearance is achieved via CVVH&#46;<a class="elsevierStyleCrossRefs" href="#bib0845"><span class="elsevierStyleSup">77&#44;78</span></a> Based on these findings in CVVH&#44; some investigators recommend adopting a vancomycin maintenance dose of 500&#8211;750<span class="elsevierStyleHsp" style=""></span>mg 12-hourly to achieve target steady-state <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> of 15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">78</span></a> Others have proposed use of a 35<span class="elsevierStyleHsp" style=""></span>mg&#47;kg loading dose&#44; most likely higher than necessary&#44; followed by use of a 14<span class="elsevierStyleHsp" style=""></span>mg&#47;kg continuous infusion to expedite attainment of adequate <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> values in the setting of both CVVH and CVVHDF&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">79</span></a> Teicoplanin clearance in CRRT may be even more variable due to hypoalbuminemic states likely leading to increased drug elimination&#46; Use of higher doses or dose supplementation may be advisable in this setting&#44;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">77</span></a> with TDM being the mainstay in guiding therapy as inter-individual variability cannot be completely controlled&#46;<a class="elsevierStyleCrossRefs" href="#bib0860"><span class="elsevierStyleSup">80&#44;81</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Aminoglycoside exposure in the setting of CRRT has also been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">82&#44;83</span></a> So as to attain optimal PK&#47;PD targets in the critically ill&#44; investigators have shown that doses of these antibiotics should remain consistent with those used in patients not on CRRT&#46; However&#44; data show that drug concentrations at 24<span class="elsevierStyleHsp" style=""></span>hours &#40;i&#46;e&#46; <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#41; remain above the threshold for renal toxicity risk&#44;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">83</span></a> and so extending the dosing frequency beyond this period&#44; to perhaps 36-hourly&#44; should be considered together with use of TDM to determine adequate clearance&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">&#946;-Lactam dosing in CRRT remains difficult&#44; with considerable variability in dosing required to achieve PK&#47;PD targets and a high dependency on the type of CRRT employed&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">74&#44;81</span></a> Having said this&#44; there is now more data to support the strategy of using dosing regimens which increase the exposure of these antibiotics&#44; when compared to other renal replacement therapies such as intermittent haemodialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">84</span></a> Indeed&#44; some investigators recommend using similar doses of &#946;-lactams to those used in the absence of renal failure during the first 48<span class="elsevierStyleHsp" style=""></span>hours of CRRT&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">85</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">A recent randomized controlled trial of intermittent bolus versus continuous infusion &#40;CI&#41; meropenem in CVVH illustrated some interesting points&#46;<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">86</span></a> Firstly and most importantly&#44; the dosing regimen of meropenem used in both groups correlated with the total daily dosage recommended to be used in patients with &#8216;normal&#8217; renal function&#46; Secondly&#44; PK&#47;PD targets were more rapidly attained and sustained in the CI group&#46; Finally&#44; results indicated that if more resistant pathogens were being targeted then CI had a higher likelihood to result in more consistent achievement of PK&#47;PD targets&#44; indicating a selected application for meropenem CI in CRRT&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Antibiotic dosing in extracorporeal membrane oxygenation &#40;ECMO&#41;</span><p id="par0190" class="elsevierStylePara elsevierViewall">ECMO is an important intervention in patients with severe cardiorespiratory failure and can take on two forms&#58; &#40;1&#41; venovenous &#40;VV&#41; ECMO which oxygenates blood from the large central veins and returns it to the venous system for distribution via the heart&#44; thereby supporting lung function&#44; &#40;2&#41; venoarterial &#40;VA&#41; ECMO which oxygenates blood drawn from the right atrium and returns it to the arterial system via the distal descending aorta&#44; hence providing both respiratory and cardiac support&#46; Both these forms require the movement of blood through an extracorporeal circuit consisting of polyvinyl chloride &#40;PVC&#41; tubing&#44; an oxygenator and a heat exchanger&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">87</span></a> From a PK point of view&#44; however&#44; there is potential for drug degradation and&#47;or adsorption of drugs to the extracorporeal circuit&#46;<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">88&#44;89</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Recent ex vivo experimental studies have shown significantly lower drug recovery at 24<span class="elsevierStyleHsp" style=""></span>hours in the ECMO circuit compared to controls for meropenem and highly protein bound antibiotics such as ceftriaxone&#46;<a class="elsevierStyleCrossRefs" href="#bib0905"><span class="elsevierStyleSup">89&#44;90</span></a> As ECMO circuits represent an additional PK compartment through the use of priming solutions and the ongoing need for blood products and maintenance fluid&#44; the <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">d</span></span>&#44; particularly for hydrophilic antibiotics&#44; may be increased&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">87</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Interestingly&#44; it is not only the PK profile of hydrophilic drugs that have the potential to be altered&#46; Lipophilic drugs&#44; such as voriconazole&#44; have also been shown to sequester in the ECMO circuit&#44; necessitating higher doses to maintain therapeutic concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">91</span></a> This is mainly thought to be due to adsorption to ECMO membranes and tubing&#44;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">87</span></a> however&#44; data from ex vivo models suggest that this cannot be extrapolated for lipophilic drugs in general&#46; In the same study that illustrated significant losses of ceftriaxone to the ECMO circuit&#44; Shekar and colleagues did not find the same degree of losses for ciprofloxacin and linezolid&#44; antibiotics considered to be more lipophilic than the &#946;-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">90</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">It is clear from these preliminary findings that much work remains to be done in quantifying the degree of altered antibiotic exposure during ECMO so that therapy can be optimized in this setting&#46; Considering patients on ECMO may also require other treatments that impact on antibiotic exposure&#44; such as RRT&#44; the use of TDM and individualizing dosing regimens appears to be a useful intervention until more robust dosing data become available&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conclusion</span><p id="par0210" class="elsevierStylePara elsevierViewall">In summary&#44; optimization of antibiotic therapy in the critically ill is a complex endeavor that needs to take into account various factors including different treatment modalities that can influence the success of therapy&#46; Central to any dosing strategy&#44; however&#44; is knowledge of the PK&#47;PD of the antibiotic in question&#46; As early and appropriate antibiotic therapy is vital to ensuring beneficial outcomes in severe sepsis and septic shock&#44; understanding initial pathophysiology and its impact on antibiotic PK is crucial to ensuring optimal use of these live saving drugs&#46; Further&#44; there should be an appreciation of the dynamic nature of pathophysiological effects on PK and how manifestations such as MODS can occur&#44; requiring prompt review and appropriate alteration of therapy&#46; Finally&#44; interventions such as CRRT and ECMO have the ability to effect antibiotic concentrations&#46; Given this complexity of dosing in critically ill patients&#44; we believe that where possible&#44; TDM should be utilized to ensure patients achieve therapeutic antibiotic concentrations&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:15 [
        0 => array:3 [
          "identificador" => "xres817770"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec814894"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres817771"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec814895"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Severe sepsis and septic shock"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Initial pathophysiology and its impact on antibiotic pharmacokinetics &#40;Fig&#46; 1&#41;"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Time-dependent antibiotics"
        ]
        7 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Concentration-dependent antibiotics"
        ]
        8 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Concentration-dependent with time-dependence antibiotics"
        ]
        9 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Antibiotic dosing in multi-organ dysfunction syndrome &#40;MODS&#41;"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Hepatic impairment"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Renal impairment"
            ]
          ]
        ]
        10 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Antibiotic dosing in continuous renal replacement therapy &#40;CRRT&#41;"
        ]
        11 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Antibiotic dosing in extracorporeal membrane oxygenation &#40;ECMO&#41;"
        ]
        12 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Conclusion"
        ]
        13 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conflict of interest"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-06-10"
    "fechaAceptado" => "2015-07-21"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec814894"
          "palabras" => array:5 [
            0 => "Antibiotics"
            1 => "Dose optimization"
            2 => "Critically ill"
            3 => "Severe sepsis"
            4 => "Septic shock"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec814895"
          "palabras" => array:5 [
            0 => "Antibi&#243;ticos"
            1 => "Optimizaci&#243;n de la dosis"
            2 => "Cr&#237;ticamente enfermo"
            3 => "Sepsis grave"
            4 => "Choque s&#233;ptico"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The judicious use of existing antibiotics is essential for preserving their activity against infections&#46; In the era of multi-drug resistance&#44; this is of particular importance in clinical areas characterized by high antibiotic use&#44; such as the ICU&#46; Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections &#8211; including severe sepsis&#44; septic shock and ventilator-associated pneumonia &#8211; but also of the pathogen&#8211;drug exposure relationship &#40;i&#46;e&#46; pharmacokinetic&#47;pharmacodynamic index&#41;&#46; An important consideration is the fact that extreme shifts in organ function&#44; such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome&#44; can have an impact upon drug exposure&#44; and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill&#46; The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients&#59; however&#44; both of these treatments can have a profound effect on antibiotic exposure&#46; We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El uso sensato de los antibi&#243;ticos existentes resulta fundamental para mantener su actividad contra las infecciones&#46; En la era de la resistencia a m&#250;ltiples f&#225;rmacos&#44; esto resulta especialmente importante en &#225;reas cl&#237;nicas caracterizadas por un uso elevado de antibi&#243;ticos&#44; como por ejemplo las UCI&#46; La optimizaci&#243;n de la dosis de antibi&#243;ticos en pacientes cr&#237;ticamente enfermos requiere s&#243;lidos conocimientos no solo sobre las alteraciones fisiol&#243;gicas asociadas a las infecciones graves &#40;incluida la sepsis grave&#44; el choque s&#233;ptico y la neumon&#237;a asociada a la ventilaci&#243;n&#41; sino tambi&#233;n sobre la relaci&#243;n entre pat&#243;genos y la exposici&#243;n a f&#225;rmacos &#40;esto es&#44; el &#237;ndice farmacocin&#233;tico&#47;farmacodin&#225;mico&#41;&#46; Es importante considerar el hecho de que los cambios extremos en la funci&#243;n org&#225;nica&#44; como los observados en pacientes hiperdin&#225;micos o en aquellos con s&#237;ndrome de disfunci&#243;n multiorg&#225;nica&#44; pueden tener un efecto sobre la exposici&#243;n a los f&#225;rmacos&#44; por lo que se requiere una vigilancia constante al revisar los reg&#237;menes posol&#243;gicos de los antibi&#243;ticos en los pacientes cr&#237;ticamente enfermos&#46; La terapia de reemplazo renal continuo y la oxigenaci&#243;n por membrana extracorporal siguen constituyendo intervenciones importantes en este tipo de pacientes&#59; no obstante&#44; ambos tratamientos pueden tener un profundo impacto sobre la exposici&#243;n a los antibi&#243;ticos&#46; Sugerimos poner un especial &#233;nfasis sobre el uso de la monitorizaci&#243;n farmacoterap&#233;utica y sobre la individualizaci&#243;n de la dosis al optimizar el tratamiento en estos entornos terap&#233;uticos&#46;</p></span>"
      ]
    ]
    "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" => 1532
            "Ancho" => 2257
            "Tamanyo" => 181514
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Initial pathophysiology of severe sepsis&#47;septic shock and its impact on antibiotic pharmacokinetics&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span> &#8211; time that the unbound or &#8216;free&#8217; concentration of the drug exceeds the minimum inhibitory concentration &#40;MIC&#41;&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC &#8211; maximum antibiotic concentration &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#41; to MIC ratio&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC &#8211; area under the concentration-time curve during a 24-hour time period &#40;AUC<span class="elsevierStyleInf">0&#8211;24</span>&#41; to the MIC ratio&#46;</p>"
          "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" style="border-bottom: 2px solid black">Class&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">PK&#47;PD index&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">Hydrophilic or lipophilic&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">Volume of distribution&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">Metabolism and&#47;or excretion&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">Common antibiotics within the class with high protein binding affinity &#40;i&#46;e&#46; &#62;70&#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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aminoglycosides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC<br>AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hydrophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#946;-Lactam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hydrophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cefazolin &#40;75&#8211;85&#37;&#41;&#44; Ceftriaxone &#40;85&#8211;95&#37;&#41;&#44; Dicloxacillin &#40;97&#37;&#41;&#44; Ertapenem &#40;85&#8211;95&#37;&#41;&#44; Flucloxacillin &#40;95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fluoroquinolones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC<br><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lipophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Both hepatic metabolism and renal clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glycopeptides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hydrophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Teicoplanin &#40;90&#8211;95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glycylcyclines<br>&#40;e&#46;g&#46; Tigecycline&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lipophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly biliary&#47;gut &#40;59&#37;&#41; with some renal clearance &#40;33&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tigecycline &#40;71&#8211;89&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lincosamides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lipophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Both hepatic metabolism and renal clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clindamycin &#40;90&#37;&#41;&#44; Lincomycin &#40;80&#8211;90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipopeptides &#40;e&#46;g&#46; Daptomycin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#47;MIC<br>AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hydrophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daptomycin &#40;90&#8211;93&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macrolides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span><br>&#40;Clarithromycin&#44; erythromycin&#41;<br>AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC<br>&#40;Azithromycin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lipophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Primarily hepatic metabolism with some renal and non-renal clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Erythromycin &#40;73&#8211;81&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oxazolidinones<br>&#40;e&#46;g&#46; Linezolid&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC<br><span class="elsevierStyleItalic">f</span>T<span class="elsevierStyleInf">&#62;MIC</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Amphiphilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly renal with some gut clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polymixins<br>&#40;e&#46;g&#46; Colistin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AUC<span class="elsevierStyleInf">0&#8211;24</span>&#47;MIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hydrophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1374566.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Summary of PK&#47;PD index and properties of antibiotic classes&#46; &#40;Data for volume of distribution&#44; metabolism and&#47;or excretion&#44; and protein binding<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">26&#44;92</span></a>&#41;&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:92 [
            0 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nosocomial pneumonia and mortality among patients in intensive care units"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;Y&#46; Fagon"
                            1 => "J&#46; Chastre"
                            2 => "A&#46; Vuagnat"
                            3 => "J&#46;L&#46; Trouillet"
                            4 => "A&#46; Novara"
                            5 => "C&#46; Gibert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1996"
                        "volumen" => "275"
                        "paginaInicial" => "866"
                        "paginaFinal" => "869"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8596225"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antimicrobial therapy in critically ill patients altered disposition and pharmacokinetic variability"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "F&#46; Pea"
                            1 => "P&#46; Viale"
                            2 => "M&#46; Furlanut"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003088-200544100-00002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2005"
                        "volumen" => "44"
                        "paginaInicial" => "1009"
                        "paginaFinal" => "1034"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16176116"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Infections&#44; antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Hanberger"
                            1 => "M&#46; Antonelli"
                            2 => "M&#46; Holmbom"
                            3 => "J&#46; Lipman"
                            4 => "P&#46; Pickkers"
                            5 => "M&#46; Leone"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2334-14-513"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Infect Dis"
                        "fecha" => "2014"
                        "volumen" => "14"
                        "paginaInicial" => "513"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0480"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock&#58; a propensity-matched analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e3181eb3ccd"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2010"
                        "volumen" => "38"
                        "paginaInicial" => "1773"
                        "paginaFinal" => "1785"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0485"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The ACCP-SCCM consensus conference on sepsis and organ failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "1992"
                        "volumen" => "101"
                        "paginaInicial" => "1481"
                        "paginaFinal" => "1483"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0490"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Critical care and the global burden of critical illness in adults"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(10)60446-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2010"
                        "volumen" => "376"
                        "paginaInicial" => "1339"
                        "paginaFinal" => "1346"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0495"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe sepsis and septic shock"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1208623"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2013"
                        "volumen" => "369"
                        "paginaInicial" => "840"
                        "paginaFinal" => "851"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0500"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology of severe sepsis in the United States&#58; analysis of incidence&#44; outcome&#44; and associated costs of care"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2001"
                        "volumen" => "29"
                        "paginaInicial" => "1303"
                        "paginaFinal" => "1310"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0505"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nationwide trends of severe sepsis in the 21st century &#40;2000&#8211;2007&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.11-0352"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2011"
                        "volumen" => "140"
                        "paginaInicial" => "1223"
                        "paginaFinal" => "1231"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunotherapy of sepsis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1473-3099(01)00093-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2001"
                        "volumen" => "1"
                        "paginaInicial" => "165"
                        "paginaFinal" => "174"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0515"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ccc.2010.09.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Clin"
                        "fecha" => "2011"
                        "volumen" => "27"
                        "paginaInicial" => "19"
                        "paginaFinal" => "34"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Individualised antibiotic dosing for patients who are critically ill&#58; challenges and potential solutions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1473-3099(14)70036-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2014"
                        "volumen" => "14"
                        "paginaInicial" => "498"
                        "paginaFinal" => "509"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2005"
                        "volumen" => "21"
                        "paginaInicial" => "50"
                        "paginaFinal" => "55"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vital organ blood flow during hyperdynamic sepsis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2003"
                        "volumen" => "124"
                        "paginaInicial" => "1053"
                        "paginaFinal" => "1059"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Implications of augmented renal clearance in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrneph.2011.92"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Nephrol"
                        "fecha" => "2011"
                        "volumen" => "7"
                        "paginaInicial" => "539"
                        "paginaFinal" => "543"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Augmented renal clearance in septic patients and implications for vancomycin optimisation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2011.12.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2012"
                        "volumen" => "39"
                        "paginaInicial" => "420"
                        "paginaFinal" => "423"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations&#58; identifying at-risk patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/cc12544"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2013"
                        "volumen" => "17"
                        "paginaInicial" => "R35"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jcrc.2013.03.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Crit Care"
                        "fecha" => "2013"
                        "volumen" => "28"
                        "paginaInicial" => "695"
                        "paginaFinal" => "700"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pitfalls of using estimations of glomerular filtration rate in an intensive care population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1445-5994.2009.02160.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intern Med J"
                        "fecha" => "2011"
                        "volumen" => "41"
                        "paginaInicial" => "537"
                        "paginaFinal" => "543"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients&#58; a single-center study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-007-0745-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intensive Care Med"
                        "fecha" => "2007"
                        "volumen" => "33"
                        "paginaInicial" => "1900"
                        "paginaFinal" => "1906"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glomerular hyperfiltration and albuminuria in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anaesth Intensive Care"
                        "fecha" => "2008"
                        "volumen" => "36"
                        "paginaInicial" => "674"
                        "paginaFinal" => "680"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subtherapeutic initial &#946;-lactam concentrations in select critically ill patients&#58; association between augmented renal clearance and low trough drug concentrations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.11-1671"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2012"
                        "volumen" => "142"
                        "paginaInicial" => "30"
                        "paginaFinal" => "39"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypoalbuminemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Intern Emerg Med"
                        "fecha" => "2012"
                        "numero" => "Suppl&#46; 7"
                        "paginaInicial" => "193"
                        "paginaFinal" => "199"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human serum albumin&#58; from bench to bedside"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.mam.2011.12.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Aspects Med"
                        "fecha" => "2012"
                        "volumen" => "33"
                        "paginaInicial" => "209"
                        "paginaFinal" => "290"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units&#58; analysis of data from the Saline versus Albumin Fluid Evaluation &#40;SAFE&#41; study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bmj.38985.398704.7C"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2006"
                        "volumen" => "333"
                        "paginaInicial" => "1044"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/11539220-000000000-00000"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2011"
                        "volumen" => "50"
                        "paginaInicial" => "99"
                        "paginaFinal" => "110"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacodynamics of cefepime in patients with Gram-negative infections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2002"
                        "volumen" => "50"
                        "paginaInicial" => "425"
                        "paginaFinal" => "428"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimization of meropenem minimum concentration&#47;MIC ratio to suppress in vitro resistance of <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.49.12.4920-4927.2005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2005"
                        "volumen" => "49"
                        "paginaInicial" => "4920"
                        "paginaFinal" => "4927"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.00294-06"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2007"
                        "volumen" => "51"
                        "paginaInicial" => "1725"
                        "paginaFinal" => "1730"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A systematic review of the clinical benefits of continuous administration of beta-lactam antibiotics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e3181a0054d"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2009"
                        "volumen" => "37"
                        "paginaInicial" => "2071"
                        "paginaFinal" => "2078"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients&#58; a randomized open-label controlled trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/cc11405"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2012"
                        "volumen" => "16"
                        "paginaInicial" => "R113"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Continuous infusion of beta-lactam antibiotics in severe sepsis&#58; a multicenter double-blind&#44; randomized controlled trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/cis856"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2013"
                        "volumen" => "56"
                        "paginaInicial" => "236"
                        "paginaFinal" => "244"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Even high-dose extended infusions may not yield desired concentrations of &#946;-lactams&#58; the value of therapeutic drug monitoring"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Infect Dis"
                        "fecha" => "2015"
                        "paginaInicial" => "1"
                        "paginaFinal" => "4"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Continuous beta-lactam infusion in critically ill patients&#58; the clinical evidence"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/2110-5820-2-37"
                      "Revista" => array:5 [
                        "tituloSerie" => "Ann Intensive Care"
                        "fecha" => "2012"
                        "volumen" => "2"
                        "paginaInicial" => "37"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An international&#44; multicentre survey of &#946;-lactam antibiotic therapeutic drug monitoring practice in intensive care units"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jac/dkt523"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2014"
                        "volumen" => "69"
                        "paginaInicial" => "1416"
                        "paginaFinal" => "1423"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Experience with a once-daily dosing program of aminoglycosides in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-002-1313-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intensive Care Med"
                        "fecha" => "2002"
                        "volumen" => "28"
                        "paginaInicial" => "936"
                        "paginaFinal" => "942"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0645"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimizing use of aminoglycosides in the critically ill"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-2007-996406"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Respir Crit Care Med"
                        "fecha" => "2007"
                        "volumen" => "28"
                        "paginaInicial" => "596"
                        "paginaFinal" => "603"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0650"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Suboptimal aminoglycoside dosing in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/FTD.0b013e31818b6b2f"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ther Drug Monit"
                        "fecha" => "2008"
                        "volumen" => "30"
                        "paginaInicial" => "674"
                        "paginaFinal" => "681"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0655"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Augmented renal clearance&#58; implications for antibacterial dosing in the critically ill"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/11318140-000000000-00000"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2010"
                        "volumen" => "49"
                        "paginaInicial" => "1"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0660"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predictors of insufficient amikacin peak concentration in critically ill patients receiving a 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg total body weight regimen"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-014-3276-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intensive Care Med"
                        "fecha" => "2014"
                        "volumen" => "40"
                        "paginaInicial" => "998"
                        "paginaFinal" => "1005"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0665"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2004"
                        "volumen" => "43"
                        "paginaInicial" => "925"
                        "paginaFinal" => "942"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0670"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia&#58; support for consensus guidelines suggested targets"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/cir124"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2011"
                        "volumen" => "52"
                        "paginaInicial" => "975"
                        "paginaFinal" => "981"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0675"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates &#40;&#8220;the MIC Creep&#8221;&#41;&#58; implications for therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3410/M4-4"
                      "Revista" => array:5 [
                        "tituloSerie" => "F1000 Med Rep"
                        "fecha" => "2012"
                        "volumen" => "4"
                        "paginaInicial" => "4"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0680"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "The European Committee on Antimicrobial Susceptibility Testing&#46; Breakpoint tables for interpretation of MICs and zone diameters&#46; Version 50&#46; 2015&#46; Available at&#58; <a href="http://www.eucast.org/">http&#58;&#47;&#47;www&#46;eucast&#46;org</a>&#46;"
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0685"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetic&#47;pharmacodynamic analysis of vancomycin in ICU patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-006-0470-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intensive Care Med"
                        "fecha" => "2007"
                        "volumen" => "33"
                        "paginaInicial" => "279"
                        "paginaFinal" => "285"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0690"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections&#58; prospective multicenter randomized study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2001"
                        "volumen" => "45"
                        "paginaInicial" => "2460"
                        "paginaFinal" => "2467"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0695"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum vancomycin levels resulting from continuous or intermittent infusion in critically ill burn patients with or without continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/BCR.0b013e31825042fa"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Burn Care Res"
                        "fecha" => "2012"
                        "volumen" => "33"
                        "paginaInicial" => "e254"
                        "paginaFinal" => "e262"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0700"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pneumonia caused by oxacillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> treated with glycopeptides"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2005"
                        "volumen" => "33"
                        "paginaInicial" => "1983"
                        "paginaFinal" => "1987"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0705"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2005.04.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2005"
                        "volumen" => "26"
                        "paginaInicial" => "50"
                        "paginaFinal" => "55"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0710"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400<span class="elsevierStyleHsp" style=""></span>mg"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2478/v10039-012-0028-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Adv Med Sci"
                        "fecha" => "2012"
                        "volumen" => "57"
                        "paginaInicial" => "217"
                        "paginaFinal" => "223"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0715"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ciprofloxacin pharmacokinetics in critically ill patients&#58; a prospective cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jcrc.2007.11.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Crit Care"
                        "fecha" => "2008"
                        "volumen" => "23"
                        "paginaInicial" => "422"
                        "paginaFinal" => "430"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0720"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> bacteremia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/cit582"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2013"
                        "volumen" => "57"
                        "paginaInicial" => "1568"
                        "paginaFinal" => "1576"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0725"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Daptomycin exposure and the probability of elevations in the creatine phosphokinase level&#58; data from a randomized trial of patients with bacteremia and endocarditis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/652767"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2010"
                        "volumen" => "50"
                        "paginaInicial" => "1568"
                        "paginaFinal" => "1574"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0730"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Linezolid pharmacokinetics and pharmacodynamics in clinical treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jac/dkr072"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2011"
                        "volumen" => "66"
                        "numero" => "Suppl&#46; 4"
                        "paginaInicial" => "iv7"
                        "paginaFinal" => "iv15"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0735"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003088-200342150-00007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2003"
                        "volumen" => "42"
                        "paginaInicial" => "1411"
                        "paginaFinal" => "1423"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0740"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical pharmacokinetics of linezolid&#44; a novel oxazolidinone antibacterial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003088-200342130-00004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2003"
                        "volumen" => "42"
                        "paginaInicial" => "1129"
                        "paginaFinal" => "1140"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0745"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Linezolid pharmacokinetic&#47;pharmacodynamic profile in critically ill septic patients&#58; intermittent versus continuous infusion"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2007.09.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2008"
                        "volumen" => "31"
                        "paginaInicial" => "122"
                        "paginaFinal" => "129"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0750"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of linezolid in septic patients with and without extended dialysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00228-009-0766-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Pharmacol"
                        "fecha" => "2010"
                        "volumen" => "66"
                        "paginaInicial" => "291"
                        "paginaFinal" => "298"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0755"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk factors for a low linezolid trough plasma concentration in acute infections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.01694-12"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2013"
                        "volumen" => "57"
                        "paginaInicial" => "1913"
                        "paginaFinal" => "1917"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0760"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Variability of linezolid concentrations after standard dosing in critically ill patients&#58; a prospective observational study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/cc13984"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2014"
                        "volumen" => "18"
                        "paginaInicial" => "R148"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0765"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Therapeutic drug monitoring of linezolid&#58; a retrospective monocentric analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.00177-10"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2010"
                        "volumen" => "54"
                        "paginaInicial" => "4605"
                        "paginaFinal" => "4610"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0770"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "&#91;Epub ahead of print&#93;"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics and preliminary safety of high dose linezolid for the treatment of Gram-positive bacterial infections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jinf.2015.06.007"
                      "Revista" => array:2 [
                        "tituloSerie" => "J Infect"
                        "fecha" => "2015"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0775"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.01733-10"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2011"
                        "volumen" => "55"
                        "paginaInicial" => "3284"
                        "paginaFinal" => "3294"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0780"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dosing of colistin &#8211; back to basic PK&#47;PD"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.coph.2011.07.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Pharmacol"
                        "fecha" => "2011"
                        "volumen" => "11"
                        "paginaInicial" => "464"
                        "paginaFinal" => "469"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0785"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Colistin&#58; recent data on pharmacodynamics properties and clinical efficacy in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/2110-5820-1-30"
                      "Revista" => array:5 [
                        "tituloSerie" => "Ann Intensive Care"
                        "fecha" => "2011"
                        "volumen" => "1"
                        "paginaInicial" => "30"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0790"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Colistin in the 21st century"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/QCO.0b013e328332e672"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Infect Dis"
                        "fecha" => "2009"
                        "volumen" => "22"
                        "paginaInicial" => "535"
                        "paginaFinal" => "543"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0795"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.01361-08"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2009"
                        "volumen" => "53"
                        "paginaInicial" => "3430"
                        "paginaFinal" => "3436"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0800"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe sepsis and septic shock&#46; Definitions&#44; epidemiology&#44; and clinical manifestations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Clin"
                        "fecha" => "2000"
                        "volumen" => "16"
                        "paginaInicial" => "179"
                        "paginaFinal" => "192"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0805"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antibiotic dosing in multiple organ dysfunction syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.10-2371"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2011"
                        "volumen" => "139"
                        "paginaInicial" => "1210"
                        "paginaFinal" => "1220"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0810"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics and dosage adjustment in patients with renal dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00228-009-0678-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Pharmacol"
                        "fecha" => "2009"
                        "volumen" => "65"
                        "paginaInicial" => "757"
                        "paginaFinal" => "773"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0815"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tigecycline pharmacokinetic&#47;pharmacodynamic update"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2008"
                        "volumen" => "62"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "11"
                        "paginaFinal" => "16"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0820"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Pfizer Pharmaceuticals&#46; Tygacil &#40;tigecycline&#41; for injection&#58; product information&#46;"
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0825"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Principles of antibacterial dosing in continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e3181aab3d0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2009"
                        "volumen" => "37"
                        "paginaInicial" => "2268"
                        "paginaFinal" => "2282"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0830"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improving antibiotic dosing in special situations in the ICU&#58; burns&#44; renal replacement therapy and extracorporeal membrane oxygenation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MCC.0b013e32835685ad"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Crit Care"
                        "fecha" => "2012"
                        "volumen" => "18"
                        "paginaInicial" => "460"
                        "paginaFinal" => "471"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0835"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003088-200847030-00003"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2008"
                        "volumen" => "47"
                        "paginaInicial" => "173"
                        "paginaFinal" => "180"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S147444220300485X"
                          "estado" => "S300"
                          "issn" => "14744422"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0840"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2013.01.018"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2013"
                        "volumen" => "41"
                        "paginaInicial" => "564"
                        "paginaFinal" => "568"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib0845"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Clin Pharmacol Ther"
                        "fecha" => "2010"
                        "volumen" => "48"
                        "paginaInicial" => "243"
                        "paginaFinal" => "249"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib0850"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2011.04.010"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2011"
                        "volumen" => "38"
                        "paginaInicial" => "152"
                        "paginaFinal" => "156"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib0855"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A new regimen for continuous infusion of vancomycin during continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jac/dkt261"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2013"
                        "volumen" => "68"
                        "paginaInicial" => "2859"
                        "paginaFinal" => "2865"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib0860"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2125.2004.02143.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Clin Pharmacol"
                        "fecha" => "2004"
                        "volumen" => "58"
                        "paginaInicial" => "259"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib0865"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e318241e553"
                      "Revista" => array:7 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2012"
                        "volumen" => "40"
                        "paginaInicial" => "1523"
                        "paginaFinal" => "1528"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1474442213701248"
                          "estado" => "S300"
                          "issn" => "14744422"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib0870"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/AAC.00374-11"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2011"
                        "volumen" => "55"
                        "paginaInicial" => "4639"
                        "paginaFinal" => "4642"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib0875"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2011.01.026"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2011"
                        "volumen" => "37"
                        "paginaInicial" => "531"
                        "paginaFinal" => "535"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib0880"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003088-200746120-00003"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2007"
                        "volumen" => "46"
                        "paginaInicial" => "997"
                        "paginaFinal" => "1038"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022510X10004090"
                          "estado" => "S300"
                          "issn" => "0022510X"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib0885"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recommended &#946;-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/cc10257"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2011"
                        "volumen" => "15"
                        "paginaInicial" => "R137"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib0890"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration&#58; a randomised controlled trial of continuous infusion versus intermittent bolus administration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijantimicag.2014.09.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Antimicrob Agents"
                        "fecha" => "2015"
                        "volumen" => "45"
                        "paginaInicial" => "41"
                        "paginaFinal" => "45"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib0895"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "e9-18"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jcrc.2012.02.013"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Crit Care&#46;"
                        "fecha" => "2012"
                        "volumen" => "27"
                        "paginaInicial" => "741"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib0900"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Potential drug sequestration during extracorporeal membrane oxygenation&#58; results from an ex vivo experiment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-007-0606-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intensive Care Med"
                        "fecha" => "2007"
                        "volumen" => "33"
                        "paginaInicial" => "1018"
                        "paginaFinal" => "1024"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            88 => array:3 [
              "identificador" => "bib0905"
              "etiqueta" => "89"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/cc11679"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2012"
                        "volumen" => "16"
                        "paginaInicial" => "R194"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            89 => array:3 [
              "identificador" => "bib0910"
              "etiqueta" => "90"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Protein bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit&#58; results from an ex vivo study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13054-015-0891-z"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2015"
                        "volumen" => "19"
                        "paginaInicial" => "164"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            90 => array:3 [
              "identificador" => "bib0915"
              "etiqueta" => "91"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jac/dkp026"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Antimicrob Chemother"
                        "fecha" => "2009"
                        "volumen" => "63"
                        "paginaInicial" => "767"
                        "paginaFinal" => "770"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            91 => array:3 [
              "identificador" => "bib0920"
              "etiqueta" => "92"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "DRUGDEX System &#91;database on the Internet&#93;&#46; Ann Arbor &#40;MI&#41;&#58; Truven Health Analytics&#59; 2013&#46; Available at&#58; <a href="http://www.micromedexsolutions.com/">www&#46;micromedexsolutions&#46;com</a>&#46; Subscription required to view&#46;"
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/21735727/0000003900000009/v2_201703210124/S2173572715000727/v2_201703210124/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/21735727/0000003900000009/v2_201703210124/S2173572715000727/v2_201703210124/en/main.pdf?idApp=WMIE&text.app=https://medintensiva.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572715000727?idApp=WMIE"
]

Article information

ISSN: 21735727
Original language: English

DOI:10.1016/j.medine.2015.07.001

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	11	19
2024 October	49	71	120
2024 September	53	49	102
2024 August	78	67	145
2024 July	83	71	154
2024 June	90	80	170
2024 May	63	52	115
2024 April	94	63	157
2024 March	84	61	145
2024 February	107	87	194
2024 January	53	81	134
2023 December	66	104	170
2023 November	81	116	197
2023 October	93	96	189
2023 September	62	123	185
2023 August	58	78	136
2023 July	87	121	208
2023 June	82	90	172
2023 May	120	107	227
2023 April	119	72	191
2023 March	177	100	277
2023 February	134	118	252
2023 January	117	88	205
2022 December	127	90	217
2022 November	96	114	210
2022 October	153	145	298
2022 September	102	115	217
2022 August	90	114	204
2022 July	85	140	225
2022 June	54	110	164
2022 May	59	123	182
2022 April	55	94	149
2022 March	111	129	240
2022 February	103	94	197
2022 January	161	104	265
2021 December	138	108	246
2021 November	155	125	280
2021 October	231	180	411
2021 September	116	93	209
2021 August	87	140	227
2021 July	82	184	266
2021 June	64	124	188
2021 May	83	168	251
2021 April	368	274	642
2021 March	240	214	454
2021 February	221	127	348
2021 January	158	110	268
2020 December	111	135	246
2020 November	161	132	293
2020 October	198	117	315
2020 September	187	117	304
2020 August	121	101	222
2020 July	97	101	198
2020 June	185	84	269
2020 May	175	90	265
2020 April	178	126	304
2020 March	136	93	229
2020 February	292	167	459
2020 January	146	117	263
2019 December	149	148	297
2019 November	139	190	329
2019 October	345	210	555
2019 September	190	179	369
2019 August	143	92	235
2019 July	132	95	227
2019 June	113	86	199
2019 May	214	137	351
2019 April	175	175	350
2019 March	130	75	205
2019 February	114	67	181
2019 January	99	60	159
2018 December	130	69	199
2018 November	209	128	337
2018 October	80	37	117
2018 September	45	5	50
2018 August	20	7	27
2018 July	21	6	27
2018 June	32	10	42
2018 May	12	3	15
2018 April	56	9	65
2018 March	21	6	27
2018 February	22	5	27
2018 January	29	7	36
2017 December	22	9	31
2017 November	27	6	33
2017 October	35	9	44
2017 September	28	7	35
2017 August	18	9	27
2017 July	24	11	35
2017 June	33	7	40
2017 May	33	10	43
2017 April	32	9	41
2017 March	18	3	21
2017 February	29	7	36
2017 January	24	6	30
2016 December	26	8	34
2016 November	38	5	43
2016 October	43	14	57
2016 September	35	12	47
2016 August	31	6	37
2016 July	21	14	35

Show all

Indexed in:

Follow us:

Subscribe:

Statistics

Indexed in:

Follow us:

Subscribe:

Statistics

Subscribe to our newsletter