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In addition, their activity and susceptibility against the microorganisms involved, their penetration and diffusion at the infection site, and the patients' clinical conditions must also be taken into account. PK/PD indices help to optimise clinical and microbiological efficacy, minimise selective pressure for resistance development, and are crucial for selecting an appropriate dosing regimen.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">Determining the plasma concentration of a drug provides an understanding of the exposure achieved with the administered dose and allows dosing adjustments according to the estimated PK/PD indices. This is called therapeutic drug monitoring (TDM), and is based on the premise that there is a quantitative and predictable relationship between blood drug concentrations and therapeutic or toxic response.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Optimising dosing according to PK/PD parameters is particularly important in the paediatric population.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Many physiological changes that occur during the first years of life cause large intra- and inter-individual variability in exposure after administration of a given dose (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–5</span></a> Exposure may also be affected by diseases or clinical situations that can modify the PK profile of drugs, mainly by increasing or decreasing plasma clearance (CL) or volume of distribution (Vd). Other factors include drug interactions, abnormal renal or hepatic function, or certain interventions such as extra-renal CL techniques, extracorporeal membrane oxygenation (ECMO), or therapeutic hypothermia.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0020" class="elsevierStylePara elsevierViewall">Therefore, paediatric patients are a group in which antimicrobial TDM may play a key role, especially when there are comorbidities and/or they are receiving therapies that affect drug PK. However, it is important to be aware of the current evidence regarding the need for monitoring individual antibiotics or antifungals. The criteria that justify the TDM of a given drug include the following aspects: a narrow therapeutic margin, significant inter- and intra-individual PK variability, and, ideally, a proven relationship between plasma concentrations and toxicity and/or efficacy.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">When a drug meets these criteria and TDM is recommended, it is essential to know the therapeutic index, the monitoring guidelines (type and timing of sample collection), as well as the specific recommendations on adjusting dosage based on the sampling data. Interpreting, comparing, and standardising the methods used in routine healthcare practice for TDM is challenging due to significant variations in the level of experience in TDM, availability of different TDM techniques, and the methods employed in different hospitals. Furthermore, there is a lack of evidence on the benefits and clinical implications of TDM for some antibiotics and antifungals in the paediatric population.</p><p id="p0030" class="elsevierStylePara elsevierViewall">The aim of this consensus document is to provide evidence-based recommendations for the most commonly monitored antibiotics and antifungals in paediatrics, in order to establish a consistent working methodology. A working group was created and members were appointed by the participating scientific societies: the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Paediatric Infectious Diseases (SEIP). A literature search was performed in PubMed for articles published during the last 15 years (2007–2022), without language restrictions, using the following MeSH terms: (“antibacterial agents” or “antifungal agents”) and (“drug monitoring” or “pharmacokinetics” or “pharmacodynamics”) and (“children” or “paediatrics” or “neonates”). The search was extended to antimicrobials and classes of antimicrobials of interest. In addition, a manual search of the references from the articles identified in the initial search was conducted, resulting in the inclusion of additional articles. The working group discussed the findings and reached consensus on formulating the recommendations.</p><p id="p0035" class="elsevierStylePara elsevierViewall">Initial dosing guidelines are not addressed in this document, as they are defined in another consensus document (<a href="https://www.seipweb.es/dosisantibioticos/">https://www.seipweb.es/dosisantibioticos/</a>).</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Recommendations</span><p id="p0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents the recommendations on TDM rationales and indications, while <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> provides interpretations and dosing adjustments. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> also shows the PK/PD characteristics of each drug group to provide context for these recommendations. It should be noted that recommendations for dosing adjustments should always be tailored to the clinical context, specific patient characteristics, micro-organism, and type of infection, and should be used as an additional tool to support clinical decision-making.</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><elsevierMultimedia ident="t0015"></elsevierMultimedia></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">General considerations on TDM and estimation of PK/PD parameters</span><p id="p0045" class="elsevierStylePara elsevierViewall">The following section provides some general considerations on the recommended methodology for TDM and estimation of PK/PD parameters in routine clinical practice.</p><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Blood sample collection for TDM</span><p id="p0050" class="elsevierStylePara elsevierViewall">Ideally, the blood sample for determination of plasma concentrations should not be obtained via the same vascular catheter used to administer the drug. The preferred collection method is venipuncture. If this is not possible, alternative methods include discarding a small volume of the collected blood before sampling, or ensuring that as many hours as possible have elapsed between the end of the infusion and blood collection.</p><p id="p0055" class="elsevierStylePara elsevierViewall">A number of methods are currently under study that will facilitate sampling and/or minimise draw volume using different matrices and less invasive techniques (e.g. dried blood on paper, saliva).</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Pharmacodynamic parameters (MIC)</span><p id="p0060" class="elsevierStylePara elsevierViewall">Ideally, PK/PD indices should be estimated using the established MIC value of the microorganism causing the infection. However, this value may not be available or the pathogen may be unknown and empirical treatment may be needed. In these cases, consider using ECOFF or EUCAST, or defer TDM until microbiological culture results are available. Another option is to use the most frequent MIC value for that strain, taking local epidemiology into account.</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Dosing adjustments based on the results of TDM</span><p id="p0065" class="elsevierStylePara elsevierViewall">Regarding the estimation of individual PK parameters for each paediatric patient and dosing recommendations based on TDM results, it is recommended, whenever possible, to use a population PK model within a Bayesian prediction program that has been specifically validated for paediatric and/or neonatal populations. Subsequently, plasma concentrations should be rechecked whenever dose adjustments are made, especially for drugs with nonlinear kinetics.</p></span></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Antibiotics</span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Aminoglycosides</span><p id="p0070" class="elsevierStylePara elsevierViewall">Aminoglycosides are hydrophilic drugs with high polarity. Thus, they have poor capacity to cross biological membranes (blood–brain barrier, bronchial secretions, vitreous humour). Their antibacterial activity is compromised in acidic media, presence of cations, hyperosmolar environments, and the presence of pus or mucus. Elimination is via the renal route.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Neonates show great intra- and inter-individual variability associated with changes in aminoglycoside Vd and renal Cl. These parameters are influenced by body weight (direct relationship with Vd), gestational age at delivery (maturational state of the elimination organs), and post-natal age (renal Cl increases more rapidly after birth). Weight-adjusted Vd will be higher in preterm infants because they have a higher proportion of body water in their tissues.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">Aminoglycosides exhibit concentration-dependent bactericidal activity with moderate/prolonged post-antibiotic effect. Increased efficacy of aminoglycosides is associated with (C<span class="elsevierStyleInf">max</span>)/MIC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8–10, while toxicity is associated with C<span class="elsevierStyleInf">min.</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> To minimise blood draws in the paediatric and neonatal population, a single draw at 8–12 h is usually made to allow estimation of the C<span class="elsevierStyleInf">min</span> and C<span class="elsevierStyleInf">max</span> using population kinetic models. Recently, AUC<span class="elsevierStyleInf">0–24h</span>/MIC has been suggested as an ratio index for dosing adjustment, especially in complicated infections.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Glycopeptides</span><p id="p0085" class="elsevierStylePara elsevierViewall">Glycopeptides are water-soluble antibiotics with low oral bioavailability (BA) and therefore require intravenous administration. Vancomycin is well distributed in most body fluids and tissues. It has low/moderate plasma protein binding (PPB) (25%–50%) and moderate to variable penetration into bone (5%–67%) and the central nervous system (CNS) (20%, increased in case of meningitis). In contrast, teicoplanin has a higher PPB (90%) and highly variable tissue concentrations.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Elimination of glycopeptides is mainly renal. The presence of comorbidities and concomitant medications may influence the tissue distribution, elimination, and toxicity of vancomycin.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> As with aminoglycosides, neonates exhibit significant variability in plasma vancomycin concentrations. Several major factors may cause nephrotoxicity and reduced renal function, including body weight and height, post-menstrual and post-natal age, and intrinsic neonatal factors such as immaturity, or certain drug treatments.</p><p id="p0090" class="elsevierStylePara elsevierViewall">The bactericidal activity of glycopeptides is time- and concentration-dependent.</p><p id="p0095" class="elsevierStylePara elsevierViewall">The PK/PD parameter associated with increased efficiency is the AUC<span class="elsevierStyleInf">0–24h</span>/MIC ratio. The established value for methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> is 400–600 mg·h/L, but it is less well defined for other species. Although vancomycin has traditionally been considered time-dependent and C<span class="elsevierStyleInf">min</span> has been the main PK/PD parameter, the new American guidelines recommend the use of AUC<span class="elsevierStyleInf">0–24h</span>/MIC for monitoring to avoid possible overexposure and associated nephrotoxicity.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> CoNS infections in neonates are noteworthy, as there is a low risk of therapeutic failure of vancomycin, and a lower AUC<span class="elsevierStyleInf">0–24h</span>/MIC value (between 240 and 480) may be appropriate.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0100" class="elsevierStylePara elsevierViewall">Regarding teicoplanin, although the target of AUC<span class="elsevierStyleInf">0–24h</span>/MIC in adults is well defined (750–900), it is currently recommended to monitor C<span class="elsevierStyleInf">min</span> in both adults and paediatric patients.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Linezolid</span><p id="p0105" class="elsevierStylePara elsevierViewall">Linezolid is a lipophilic antibiotic with 100% oral BA independent of food intake and good tissue distribution (90% to CNS, 20% to bone). PPB is low (30%) and 60% of the metabolism is hepatic through non-enzymatic oxidation rather than via cytochrome p-450, leading to the production of practically inactive metabolites. Renal excretion is 80% (30% unchanged and 50% as inactive metabolites). Population studies have identified body weight and aspartate aminotransferase (AST) values as the covariates with the greatest impact on linezolid Cl. Higher AST values have been associated with higher AUC<span class="elsevierStyleInf">0–24h</span>, and higher body weight with higher CL.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0110" class="elsevierStylePara elsevierViewall">Linezolid has bacteriostatic activity against staphylococci and enterococci, and bactericidal activity against streptococci and pneumococci. These activities are time- and concentration-dependent. The PK/PD parameters predictive of efficacy of linezolid are an AUC<span class="elsevierStyleInf">0–24h</span>/MIC between 80 and 120 or the percentage of time between 2 consecutive doses during which the drug concentration is above the MIC (fT<span class="elsevierStyleInf">>MIC</span>), which should be between 80% and 100%. However, in routine clinical practice, it is usually considered as time-dependent and C<span class="elsevierStyleInf">min</span> is used.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">In cases of infections caused by microorganisms with a MIC ><span class="elsevierStyleHsp" style=""></span>1 mg/L, this target cannot be reached with the standard dose (10 mg/kg/8 h) and a larger one should be administered.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Beta-lactams</span><p id="p0120" class="elsevierStylePara elsevierViewall">Beta-lactam antibiotics are primarily hydrophilic. PPB varies significantly between drugs (20%–30% for piperacillin-tazobactam, 16%–19% for cefepime, 10%–15% for ceftazidime, and 2% for meropenem), while renal excretion is the primary route of elimination. Their hydrophilic nature means that Vd is affected by systemic inflammatory response syndrome, fluid therapy, or the use of vasopressors. This effect more pronounced in critical patients and particularly in septic, neutropenic, and/or burn patients.</p><p id="p0125" class="elsevierStylePara elsevierViewall">Beta-lactam bactericidal activity shows time-dependent PDs. The most important PK/PD parameter for efficacy is fT<span class="elsevierStyleInf">>MIC</span>. Currently, there is disagreement on the optimal value of the steady-state free concentration of the drug, ranging from 1 to 4–6 times above the MIC at 100% fT<span class="elsevierStyleInf">>MIC</span>. Several studies have shown a higher probability of achieving target PK/PD with extended or continuous infusion of piperacillin-tazobactam, ceftazidime, and meropenem in cancer patients with febrile neutropenia, infections caused by microorganisms classified as “susceptible, increased exposure” by EUCAST, or in critical patients.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="p0130" class="elsevierStylePara elsevierViewall">Currently, there is limited evidence on the impact of beta-lactam TDM on clinical outcomes in the paediatric population. For this reason, monitoring is mainly recommended for certain antibiotics, targeted therapy for difficult-to-treat infections, certain clinical situations (e.g. septic shock), patients with devices that alter PK parameters (e.g. ECMO, renal replacement therapy), and/or suspected beta-lactam toxicity (especially in the case of carbapenemics).<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Antifungals</span><p id="p0135" class="elsevierStylePara elsevierViewall">There are varying levels of recommendation and evidence regarding the need for TDM for different families of antifungals. This consensus document focuses on the triazoles because they have the strongest evidence of the clinical benefit of TDM and because they are widely used in immunocompromised paediatric patients. Notably, isavuconazole has been included even though it is currently not approved for paediatric use. Approval is expected soon and its use in clinical practice is increasing.</p><p id="p0140" class="elsevierStylePara elsevierViewall">Finally, monitoring of all patients on flucytosine, although its use is currently rare, is recommended to ensure efficacy and because of its high toxicity.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Triazoles</span><p id="p0145" class="elsevierStylePara elsevierViewall">Triazoles (and azoles in general) are lipophilic drugs, with varying degrees of lipophilicity depending on their structure. For example, itraconazole has a very lipophilic tail compared to other azoles. Their oral BA is generally good (><span class="elsevierStyleHsp" style=""></span>50%). Food intake can alter BA: it is increased by the use of itraconazole capsules and posaconazole oral suspension (especially with high-fat foods), and decreased by voriconazole and itraconazole (oral suspension).<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Unlike fluconazole and isavuconazole, food intake does not affect posaconazole absorption when administered as a gastro-resistant tablet. Triazoles are widely distributed in the body with good penetration into most tissues. Elimination of fluconazole is mainly renal (80%), whereas for others such as itraconazole, voriconazole, posaconazole, and isavuconazole, elimination occurs via hepatic metabolism. Several factors may influence elimination, including age, concomitant medication, and genetic polymorphisms of cytochrome P450, particularly the CYP2C19 isoenzyme for voriconazole.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Due to its long plasma elimination half-life (t<span class="elsevierStyleInf">1/2</span>), loading doses are needed to reduce the time required to reach steady state. Some of these drugs have nonlinear PK due to potential saturation of hepatic metabolism. As a result, small increases in dose can significantly increase plasma concentrations and t<span class="elsevierStyleInf">1/2</span>. Most relevant interactions of azoles are due to their ability to inhibit cytochrome P450 enzymes. They all inhibit CYP3A4 isoenzyme. Isavuconazole also inhibits CYP3A5 and voriconazole inhibits CYP2C9. A number of them also have an inducing effect.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="p0150" class="elsevierStylePara elsevierViewall">Azoles have concentration- and time-dependent fungistatic activity against <span class="elsevierStyleItalic">Candida</span> spp. and time-dependent fungicidal activity against <span class="elsevierStyleItalic">Aspergillus</span> spp. C<span class="elsevierStyleInf">min</span> is the main TDM PK/PD parameter. The optimal value of C<span class="elsevierStyleInf">min</span> depends on the type of azole and its prophylactic or therapeutic indication.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="p0155" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a> show the indications, procedures, interpretation, and use of TDM for posaconazole, itraconazole, voriconazole, and isavuconazole. Although TDM is not typically recommended for fluconazole, monitoring may be needed in specific patients with renal impairment, and/or on renal replacement therapy, with severe burns, and with infections in hard-to-access sites.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p></span></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Conclusions</span><p id="p0160" class="elsevierStylePara elsevierViewall">Optimised PK/PD parameters are fundamental tools in the selection, use, and dosing of antibiotics and antifungals in paediatrics. TDM of these drugs can be very useful in clinical decision-making to maximise the clinical efficacy of antimicrobial therapy, minimise the likelihood of adverse effects, and prevent the emergence of resistance. The evidence supporting TDM in paediatrics varies between different families of antibiotics and antifungals. It is well established for aminoglycosides, vancomycin and voriconazole, and it is recommended in all paediatric patients. However, the evidence is much weaker for others, such as beta-lactams, linezolid, and isavuconazole, where TDM is recommended only in selected patients, pending further clinical evidence in the paediatric population to justify TDM on a routine basis.</p><p id="p0165" class="elsevierStylePara elsevierViewall">The availability and type of analytical techniques used in TDM, as well as their implementation or interpretation, may vary widely between hospitals, making it difficult to standardise this clinical practice. To ensure consistent practice, a working methodology and evidence-based recommendations for dosing adjustments should be established. In addition, the implementation of clinical PK units within antimicrobial therapy optimization programs is essential. This consensus document aims to provide standardised protocols for the implementation of antibiotic and antifungal TDM in paediatrics, taking into account the variability of the paediatric population and the PK characteristics of each drug. Finally, although TDM is a very useful tool for optimising antimicrobial therapy in this population, any recommendation for dose adjustment must be made by consensus in multidisciplinary teams, while taking into account the microorganism involved, the individual characteristics of each patient, and their particular clinical situation.</p></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Ethical responsibilities</span><p id="p0170" class="elsevierStylePara elsevierViewall">The authors accept the responsibilities defined by the International Committee of Medical Journal Editors (available at <a href="http://www.icmje.org/">http://www.icmje.org/</a> and in Hospital Pharmacy).</p></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Funding</span><p id="p0175" class="elsevierStylePara elsevierViewall">None of the authors have received funding for this work.</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">CRediT authorship contribution statement</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Sonia Luque:</span> Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Investigation, Formal analysis, Conceptualization. <span class="elsevierStyleBold">Natalia Mendoza-Palomar:</span> Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. <span class="elsevierStyleBold">David Aguilera-Alonso:</span> Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis. <span class="elsevierStyleBold">Beatriz Garrido:</span> Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis. <span class="elsevierStyleBold">Marta Miarons:</span> Writing – review & editing, Visualization, Supervision, Investigation, Formal analysis. <span class="elsevierStyleBold">Ana Isabel Piqueras:</span> Writing – review & editing, Validation, Methodology, Investigation, Formal analysis. <span class="elsevierStyleBold">Enrique Tévar:</span> Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis. <span class="elsevierStyleBold">Eneritz Velasco-Arnaiz:</span> Writing – review & editing, Visualization, Validation, Investigation, Formal analysis. <span class="elsevierStyleBold">Aurora Fernàndez-Polo:</span> Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2243235" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1876279" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2243234" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1876280" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "Recommendations" ] 6 => array:3 [ "identificador" => "s0015" "titulo" => "General considerations on TDM and estimation of PK/PD parameters" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0020" "titulo" => "Blood sample collection for TDM" ] 1 => array:2 [ "identificador" => "s0025" "titulo" => "Pharmacodynamic parameters (MIC)" ] 2 => array:2 [ "identificador" => "s0030" "titulo" => "Dosing adjustments based on the results of TDM" ] ] ] 7 => array:3 [ "identificador" => "s0035" "titulo" => "Antibiotics" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "s0040" "titulo" => "Aminoglycosides" ] 1 => array:2 [ "identificador" => "s0045" "titulo" => "Glycopeptides" ] 2 => array:2 [ "identificador" => "s0050" "titulo" => "Linezolid" ] 3 => array:2 [ "identificador" => "s0055" "titulo" => "Beta-lactams" ] 4 => array:2 [ "identificador" => "s0060" "titulo" => "Antifungals" ] 5 => array:2 [ "identificador" => "s0065" "titulo" => "Triazoles" ] ] ] 8 => array:2 [ "identificador" => "s0070" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "s0075" "titulo" => "Ethical responsibilities" ] 10 => array:2 [ "identificador" => "s0080" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "s0085" "titulo" => "CRediT authorship contribution statement" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-11-13" "fechaAceptado" => "2023-11-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1876279" "palabras" => array:8 [ 0 => "Therapeutic drug monitoring" 1 => "Pharmacokinetics" 2 => "Pharmacodynamics" 3 => "Antibiotics" 4 => "Antifungals" 5 => "Paediatric" 6 => "Newborn" 7 => "Special populations" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1876280" "palabras" => array:8 [ 0 => "Monitorización terapéutica" 1 => "Farmacocinética" 2 => "Farmacodinamia" 3 => "Antibióticos" 4 => "Antifúngicos" 5 => "Pediatría" 6 => "Neonatos" 7 => "Poblaciones especiales" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host.</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals—usually used off-label in paediatrics—to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.</p><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0055" class="elsevierStyleSimplePara elsevierViewall">La monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico, basada en parámetros farmacocinéticos y farmacodinámicos (PK/PD), es una estrategia cada vez más utilizada para la optimización del tratamiento de infecciones con el fin de mejorar la eficacia, reducir la aparición de toxicidades y prevenir la selección de resistencias antimicrobianas, especialmente en poblaciones vulnerables como neonatos, pacientes críticos o inmunodeprimidos.</p><p id="sp0060" class="elsevierStyleSimplePara elsevierViewall">En la población neonatal y pediátrica, las infecciones representan un porcentaje elevado de los ingresos hospitalarios, siendo los antimicrobianos los fármacos más utilizados en este grupo poblacional. Sin embargo, establecer los regímenes posológicos óptimos en esta población es complejo debido a la menor evidencia respecto a la eficacia y seguridad de algunos antimicrobianos, especialmente en los de reciente comercialización que son utilizados habitualmente fuera de ficha técnica y al limitado número de estudios PK/PD disponibles en pediatría. Es bien conocido que el paciente pediátrico se caracteriza por presentar una serie de variaciones de los parámetros farmacocinéticos (como el aclaramiento o el volumen de distribución) debido a los propios cambios madurativos que pueden modificar la exposición a los antimicrobianos y comprometer el éxito del tratamiento. A su vez, es un grupo poblacional más susceptible a presentar potenciales efectos adversos a los fármacos, hecho que conlleva la necesidad de una monitorización más estricta.</p><p id="sp0065" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este documento de consenso, elaborado entre la Sociedad Española de Farmacia Hospitalaria (SEFH) y Sociedad Española de Infectología Pediátrica (SEIP), es describir la evidencia disponible sobre las indicaciones de la monitorización terapéutica de antibióticos y antifúngicos en pacientes neonatales y pediátricos, y proporcionar recomendaciones prácticas para su monitorización y ajuste de dosis, con el fin de optimizar el tratamiento, maximizando su eficacia y seguridad.</p></span>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This article is published simultaneously in Farmacia Hospitalaria: <span class="elsevierStyleInterRef" id="intr9005" href="doi:10.1016/j.farma.2024.02.013">https://doi.org/10.1016/j.farma.2024.02.013</span>, with the consent of the authors and editors.</p>" ] 1 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="np0040">Both authors contributed equally to this work.</p>" "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:3 [ "apendice" => "<p id="p0190" class="elsevierStylePara elsevierViewall">The above-mentioned authors have written the article on behalf of the following groups:</p> <p id="p0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEFH Working Group on Pharmaceutical Care in Infectious Diseases:</span></p> <p id="p0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Leonor Periañez Parraga (Hospital Universitari Son Espases, Mallorca)</p> <p id="p0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Deputy Coordinator/Secretary:</span> Sònia Luque Pardos (Hospital del Mar, Barcelona)</p> <p id="p0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Advisory spokespersons:</span></p> <p id="p0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">M. Victoria</span> Gil Navarro (Hospital Universitario Virgen del Rocío, Sevilla)</p> <p id="p0220" class="elsevierStylePara elsevierViewall">José María Gutiérrez Urbón (Hospital Juan Canalejo, La Coruña)</p> <p id="p0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinating Committee:</span></p> <p id="p0230" class="elsevierStylePara elsevierViewall">Carmen Rodríguez González (Hospital General Universitario Gregorio Marañón, Madrid)</p> <p id="p0235" class="elsevierStylePara elsevierViewall">Beatriz Mejuto Perez del Molino (Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela)</p> <p id="p0240" class="elsevierStylePara elsevierViewall">Eva Campelo Sanchez (Hospital Álvaro Cunqueiro, Eoxi Vigo)</p> <p id="p0245" class="elsevierStylePara elsevierViewall">Francisco Moreno Ramos (Hospital Universitario La Paz)</p> <p id="p0250" class="elsevierStylePara elsevierViewall">Maria Eugenia Martínez Núñez (Hospital Universitario de Getafe, Madrid)</p> <p id="p0255" class="elsevierStylePara elsevierViewall">María Eugenia Rodríguez Mateos (Hospital Puerta del Mar, Cádiz)</p> <p id="p0260" class="elsevierStylePara elsevierViewall">María Núñez Núñez (Hospital Universitario Clínico San Cecilio, Granada)</p> <p id="p0265" class="elsevierStylePara elsevierViewall">Svetlana Sadyrbaeva Dolgova (Hospital Universitario Virgen de las Nieves, Granada)</p> <p id="p0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEFH Spokesperson:</span> Aurora Fernàndez Polo (Hospital Universitari Vall d'Hebron, Barcelona)</p> <p id="p0275" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Resident:</span> Alba Pau Parra (Hospital Universitari Vall d'Hebron, Barcelona)</p> <p id="p0280" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEFH Pharmacokinetics and Pharmacogenetics Working Group (PKGen):</span></p> <p id="p0285" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Enrique Tévar Alfonso (Hospital Universitario Nuestra Señora de la Candelaria, S/C de Tenerife)</p> <p id="p0290" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Vice-coordinator:</span> Begoña Porta Oltra (Hospital Universitario Doctor Peset, Valencia)</p> <p id="p0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0300" class="elsevierStylePara elsevierViewall">Azucena Aldaz Pastor (Clínica Universitaria, Navarra)</p> <p id="p0305" class="elsevierStylePara elsevierViewall">M. Dolores Aumente Rubio (Hospital Reina Sofía, Córdoba)</p> <p id="p0310" class="elsevierStylePara elsevierViewall">M. Dolores Bellés Medall (Hospital General Universitario, Castellón)</p> <p id="p0315" class="elsevierStylePara elsevierViewall">Remedios Marqués Miñana (Hospital La Fe, Valencia)</p> <p id="p0320" class="elsevierStylePara elsevierViewall">Patricio Mas Serrano (Hospital General Universitario, Alicante)</p> <p id="p0325" class="elsevierStylePara elsevierViewall">Jose Germán Sánchez Hernández (Complejo Asistencial Universitario, Salamanca)</p> <p id="p0330" class="elsevierStylePara elsevierViewall">Javier Milara Paya (Hospital General, Valencia)</p> <p id="p0335" class="elsevierStylePara elsevierViewall">Dolors Soy Muner (Hospital Clinic, Barcelona)</p> <p id="p0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEFH Paediatric Pharmacy Working Group:</span></p> <p id="p0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span><span class="elsevierStyleItalic">M. Teresa</span> Pozas del Río (Hospital Infantil Universitario Niño Jesús, Madrid)</p> <p id="p0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Secretary:</span> Belén Rodríguez Marrodán (Hospital Universitario Puerta de Hierro, Madrid)</p> <p id="p0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0360" class="elsevierStylePara elsevierViewall">Concha Álvarez del Vayo (Hospital Universitario Virgen del Rocío, Sevilla)</p> <p id="p0365" class="elsevierStylePara elsevierViewall">María Teresa Bosch Peligero (Hospital Germans Trias i Pujol, Barcelona)</p> <p id="p0370" class="elsevierStylePara elsevierViewall">Maria José Cabañas Poy (Hospital Universitario Vall d'Hebron, Barcelona)</p> <p id="p0375" class="elsevierStylePara elsevierViewall">Raquel Escrig (Hospital Universitario y Politécnico La Fe, Valencia)</p> <p id="p0380" class="elsevierStylePara elsevierViewall">Cecilia M Fernández-Llamazares (Hospital General Universitario Gregorio Marañón, Madrid)</p> <p id="p0385" class="elsevierStylePara elsevierViewall">Carmen Gallego Fernández (Hospital Materno Infantil HUR, Málaga)</p> <p id="p0390" class="elsevierStylePara elsevierViewall">Ana García Robles (Hospital Universitario y Politécnico La Fe, Valencia)</p> <p id="p0395" class="elsevierStylePara elsevierViewall">Yolanda Hernández Gago (Complejo Hospitalario Universitario Insular, Gran Canaria)</p> <p id="p0400" class="elsevierStylePara elsevierViewall">Cristina Martínez Roca (Complejo Hospitalario Universitario de A Coruña, A Coruña)</p> <p id="p0405" class="elsevierStylePara elsevierViewall">Miquel Villaronga Flaqué (Hospital Sant Joan de Déu, Barcelona)</p> <p id="p0410" class="elsevierStylePara elsevierViewall">Marta Miarons Font (Consorci Hospitalari de Vic, Barcelona)</p> <p id="p0415" class="elsevierStylePara elsevierViewall">Beatriz Garrido Corro (Hospital Virgen de la Arrixaca, Murcia)</p> <p id="p0420" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEIP Bacterial Infections Working Group:</span></p> <p id="p0425" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Leticia Martínez Campos (Hospital Universitario Torrecárdenas, Almería)</p> <p id="p0430" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Secretary:</span> Jesús Saavedra Lozano (Hospital Gregorio Marañón, Madrid)</p> <p id="p0435" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0440" class="elsevierStylePara elsevierViewall">David Aguilera Alonso (Hospital Gregorio Marañón, Madrid)</p> <p id="p0445" class="elsevierStylePara elsevierViewall">Cristina Calvo Rey (Hospital la Paz, Madrid)</p> <p id="p0450" class="elsevierStylePara elsevierViewall">Jaime Carrasco Colom (Hospital Universitario Son Espases, Mallorca)</p> <p id="p0455" class="elsevierStylePara elsevierViewall">Elena Colino Gil (Hospital de las Palmas, Gran Canaria)</p> <p id="p0460" class="elsevierStylePara elsevierViewall">David López Martín (Hospital Costa del Sol, Marbella)</p> <p id="p0465" class="elsevierStylePara elsevierViewall">Ana Isabel Menasalvas Ruiz (Hospital Virgen de la Arrixaca, Murcia)</p> <p id="p0470" class="elsevierStylePara elsevierViewall">Esmeralda Núñez Cuadros (Hospital Carlos Haya, Málaga)</p> <p id="p0475" class="elsevierStylePara elsevierViewall">Carlos Rodrigo Gonzalo de Liria (Hospital Vall d'Hebrón, Barcelona)</p> <p id="p0480" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEIP Invasive Fungal Infection Working Group:</span></p> <p id="p0485" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Peter Olbrich (Hospital Virgen del Rocío, Sevilla)</p> <p id="p0490" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Secretary:</span> Begoña Carazo Gallego (Hospital Carlos Haya, Málaga)</p> <p id="p0495" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0500" class="elsevierStylePara elsevierViewall">Laura Ferreras Antolín (St. George's Hospital, London)</p> <p id="p0505" class="elsevierStylePara elsevierViewall">Carlos Daniel Grasa Lozano (Hospital La Paz, Madrid)</p> <p id="p0510" class="elsevierStylePara elsevierViewall">Natalia Mendoza Palomar (Hospital Vall d'Hebron, Barcelona)</p> <p id="p0515" class="elsevierStylePara elsevierViewall">Marisa Navarro Gómez (Hospital Gregorio Marañón, Madrid)</p> <p id="p0520" class="elsevierStylePara elsevierViewall">Olaf Neth (Hospital Virgen del Rocío, Sevilla)</p> <p id="p0525" class="elsevierStylePara elsevierViewall">José Tomás Ramos Amador (Hospital Clínico San Carlos, Madrid)</p> <p id="p0530" class="elsevierStylePara elsevierViewall">Elena Rincón López (Hospital Gregorio Marañon, Madrid)</p> <p id="p0535" class="elsevierStylePara elsevierViewall">Sílvia Simó Nebot (Hospital Sant Joan de Déu, Barcelona)</p> <p id="p0540" class="elsevierStylePara elsevierViewall">Pere Soler Palacín (Hospital Vall d'Hebrón, Barcelona)</p> <p id="p0545" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEIP Antimicrobial Optimisation Programmes Working Group (PROA):</span></p> <p id="p0550" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Fernando Baquero Artigao (JD SEIP, Hospital La Paz, Madrid)</p> <p id="p0555" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Secretary:</span> Leticia Martínez Campos (JD SEIP- GT IA SEIP, H. Torrecárdenas, Almería)</p> <p id="p0560" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0565" class="elsevierStylePara elsevierViewall">Carlos Rodrigo Gonzalo de Liria (GT-IB SEIP, Hospital Germans Trias i Pujol, Barcelona)</p> <p id="p0570" class="elsevierStylePara elsevierViewall">José Tomás Ramos Amador (GT-IF-SEIP, Hospital Clínico San Carlos, Madrid)</p> <p id="p0575" class="elsevierStylePara elsevierViewall">Cristian Launes Montaña (GT-IR-SEIP, Hospital Sant Joan de Deu, Barcelona)</p> <p id="p0580" class="elsevierStylePara elsevierViewall">Maria Carmen Suarez Arrabal (GT IyF-SEIP, C.S. Sardinero, Santander)</p> <p id="p0585" class="elsevierStylePara elsevierViewall">Luis Escosa García (GT IRAS, Hospital La Paz, Madrid)</p> <p id="p0590" class="elsevierStylePara elsevierViewall">Susana Melendo Pérez (Hospital Vall d'Hebron, Barcelona)</p> <p id="p0595" class="elsevierStylePara elsevierViewall">David Aguilera Alonso (Hospital Gregorio Marañón, Madrid)</p> <p id="p0600" class="elsevierStylePara elsevierViewall">Walter Goycoechea Valdivia (Hospital Virgen del Rocío, Sevilla)</p> <p id="p0605" class="elsevierStylePara elsevierViewall">Eneritz Velasco Arnaiz (Hospital Sant Joan de Déu, Barcelona)</p> <p id="p0610" class="elsevierStylePara elsevierViewall">Cristina Epalza Ibarrondo (Hospital 12 de Octubre, Madrid)</p> <p id="p0615" class="elsevierStylePara elsevierViewall">Marta García Ascaso (Hospital Niño Jesús, Madrid)</p> <p id="p0620" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SEIP Healthcare-Related Infections Working Group</span>:</p> <p id="p0625" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Coordinator:</span> Luis Escosa (Hospital la Paz, Madrid)</p> <p id="p0630" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Team members:</span></p> <p id="p0635" class="elsevierStylePara elsevierViewall">Walter Alfredo Goycochea Valdivia (Hospital Virgen del Rocío, Sevilla)</p> <p id="p0640" class="elsevierStylePara elsevierViewall">Ana Isabel Menasalvas Ruiz (Hospital Virgen de la Arrixaca, Murcia)</p> <p id="p0645" class="elsevierStylePara elsevierViewall">Olaf Neth (Hospital Virgen del Rocío, Sevilla)</p> <p id="p0650" class="elsevierStylePara elsevierViewall">Anabel Piqueras (Hospital la Fe, Valencia)</p> <p id="p0655" class="elsevierStylePara elsevierViewall">María del Mar Santos Sebastián (Hospital Gregorio Marañón, Madrid)</p> <p id="p0660" class="elsevierStylePara elsevierViewall">Eneritz Velasco (Hospital Sant Joan de Deu, Barcelona)</p> <p id="p0665" class="elsevierStylePara elsevierViewall">David Aguilera Alonso (Hospital Gregorio Marañón, Madrid)</p> <p id="p0670" class="elsevierStylePara elsevierViewall">Laura Martín (Hospital Regional de Málaga)</p> <p id="p0675" class="elsevierStylePara elsevierViewall">Daniel Blázquez Gamero (Hospital 12 de Octubre, Madrid)</p>" "titulo" => "Appendix A" "identificador" => "s0090" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "tbl0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Adapted from Le et al.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">TBW, total body water; AUC<span class="elsevierStyleInf">0–24h</span>, area under the plasma concentration curve over 24 h; C<span class="elsevierStyleInf">max</span>, maximum concentration; ECW, extracellular water; GFR, glomerular filtration rate; T<span class="elsevierStyleInf">max</span>, time to reach C<span class="elsevierStyleInf">max</span>; t<span class="elsevierStyleInf">1/2</span>, elimination half-life; PPB, plasma protein binding; Vd, volume of distribution; ↑, increase compared to adulthood; ↓, decrease compared to adulthood.</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Affected pharmacokinetic process \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Altered physiological factor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Physiological change compared to adulthood \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pharmacokinetic change \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Affected age \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absorption</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastric intraluminal pH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ C<span class="elsevierStyleInf">max</span> of weak acids<span class="elsevierStyleHsp" style=""></span>↑ C<span class="elsevierStyleInf">max</span> of weak bases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastric emptying time \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erratic and long \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ T<span class="elsevierStyleInf">max</span> of fat-soluble drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NeonatesInfants up to 6–8 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intestinal transit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ T<span class="elsevierStyleInf">max</span> of fat-soluble drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biliary and pancreatic function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased, poor secretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ C<span class="elsevierStyleInf">max</span> and AUC<span class="elsevierStyleInf">0–24h</span> of lipid soluble drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Distribution</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Body composition</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ Body water: TBW and ECW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ Vd hydrophilic drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates and infants \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Body fat and muscle mass:↓ neonates ↑ infants \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ Vd lipophilic drugs (neonates)↑ Vd lipophilic drugs (infants) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates and infants \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma protein binding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ Protein and ↓ binding capacity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ Free fraction, ↑ Vd of drugs with high PPB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates and infants \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metabolism</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Liver enzyme activity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ Activity of drug metabolising enzymes CYPP450, CYP2E1, CYP2D6, CYP2C9, and CYP2C19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ t<span class="elsevierStyleInf">1/2</span> of drug substrates of these isoenzymes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ t<span class="elsevierStyleInf">1/2</span> of drugs with hepatic clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clearance</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GFR</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ GFR in neonates \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ t<span class="elsevierStyleInf">1/2</span> of drugs with renal clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ GFR in children \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ t<span class="elsevierStyleInf">1/2</span> of drugs with renal excretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Children \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal tubular secretion and reabsorption \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ tubular secretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ t<span class="elsevierStyleInf">1/2</span> of drugs with renal clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonates \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3655203.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Age-related physiological changes that affect antibiotic and antifungal pharmacokinetics in paediatric patients.</p>" ] ] 1 => array:8 [ "identificador" => "t0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "tbl0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">AUC<span class="elsevierStyleInf">0–24h</span>, area under the plasma concentration curve over 24 h; renal Cl, renal clearance; MIC, minimum inhibitory concentration; C<span class="elsevierStyleInf">max</span>, maximum or peak concentration; C<span class="elsevierStyleInf">min</span>, minimum or trough concentration (to be drawn just before administration of the next dose); ECMO, extracorporeal membrane oxygenation; <span class="elsevierStyleItalic">f</span>, free fraction of drug; TDM, therapeutic drug monitoring; PPB, plasma protein binding; Vd, volume of distribution.</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Family \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rationale \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indications \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Antibiotics</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aminoglycosides<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–9</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High inter-individual variability in PK as a function of age, maturational development, and gestational age at birthOptimisation of efficacy and prevention of toxicity associated with C<span class="elsevierStyleInf">max</span> and C<span class="elsevierStyleInf">min</span>, respectivelyNarrow therapeutic marginAdverse effects may be severe (e.g. nephrotoxicity and/or ototoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All paediatric or neonatal patients in the following situations: Treatment duration ><span class="elsevierStyleHsp" style=""></span>48–72 hPatent ductus arteriosus (neonates)Neonatal asphyxiaPatients with renal CL abnormalities (onco-haematological, cystic fibrosis, acute or chronic renal failure, major burns, etc)Critical condition or in shockSevere infection, hard-to-access sites, or uncontrolled infection<a class="elsevierStyleCrossRef" href="#tf0005"><span class="elsevierStyleSup">a</span></a>ECMO or renal replacement therapyUnfavourable clinical course of infectionConcomitant use of other nephrotoxic and/or ototoxic drugsSuspected toxicity to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glycopeptides<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–14</span></a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Vancomycin</span>High inter-individual variability in PK as a function of age, maturational development, and gestational age at birthOptimisation of efficacy and prevention of toxicity, both associated with C<span class="elsevierStyleInf">min</span> and AUC<span class="elsevierStyleInf">0–24h</span>Prevention of bacterial resistance selectionAdverse effects may be severe (e.g. nephrotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All paediatric patients, mainly in the following situations:Treatment duration ><span class="elsevierStyleHsp" style=""></span>3–5 dHigh doses (≥<span class="elsevierStyleHsp" style=""></span>60 mg/kg/d) or continuous infusionNeonatesPatients with renal CL abnormalities (onco-haematological, cystic fibrosis, acute or chronic renal failure, major burns, etc)Critical condition or in shockPatients with abnormal nutritional status (obese or underweight)Severe infection, hard-to-access sites, or uncontrolled infection<a class="elsevierStyleCrossRef" href="#tf0005"><span class="elsevierStyleSup">a</span></a>ECMO or renal replacement therapyUnfavourable clinical course of infectionConcomitant use of other nephrotoxic drugsSuspected toxicity to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Teicoplanin (less evidence for TDM than vancomycin)</span>High inter-individual variability in PK as a function of age, maturational development, and gestational age at birthOptimisation of efficacy and prevention of toxicity, both associated with C<span class="elsevierStyleInf">min</span>Risk of suboptimal plasma concentrationsAdverse effects may be severe (e.g. nephrotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recommended in the following clinical situations:Treatment duration ><span class="elsevierStyleHsp" style=""></span>3–5 dUse of high doses (><span class="elsevierStyleHsp" style=""></span>12 mg/kg/d maintenance dose)NeonatesRenal Cl abnormalities (onco-haematological, burns, acute or chronic renal failure, etc)Patients with abnormal nutritional status (obese or underweight) and/or severe hypoalbuminaemiaSevere infection, hard-to-access sites, or uncontrolled infection<a class="elsevierStyleCrossRef" href="#tf0005"><span class="elsevierStyleSup">a</span></a>ECMO or renal replacement therapyUnfavourable clinical course of infectionConcomitant use of nephrotoxic drugsSuspected toxicity to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Linezolid<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High inter-individual variability in PK as a function of age, maturational development, and gestational age at birthEfficacy and toxicity associated with C<span class="elsevierStyleInf">min</span> and AUC<span class="elsevierStyleInf">0–24h</span>Risk of suboptimal concentrations due to increased renal Cl (in infections caused by microorganisms with MIC ><span class="elsevierStyleHsp" style=""></span>1 mg/L)Adverse effects may be severe (e.g. haematological toxicity, neurotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recommended for paediatric patients in the following situations:Prolonged treatment (><span class="elsevierStyleHsp" style=""></span>14 d)Renal Cl abnormalities (onco-haematological, burns, acute or chronic renal failure, etc)Liver failureCritical condition or in shockPatients with abnormal nutritional status (obese or underweight)Severe infection, hard-to-access sites, or uncontrolled infection<a class="elsevierStyleCrossRef" href="#tf0005"><span class="elsevierStyleSup">a</span></a>Infection caused by a microorganism with MIC ><span class="elsevierStyleHsp" style=""></span>1 mg/LECMO or renal replacement therapyUnfavourable clinical course of infectionSuspected toxicity to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Beta-lactams<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High inter-individual variability in PK as a function of age, maturational development, and gestational age at birthEfficacy linked to the percentage of time between doses in which free drug concentrations are above the MIC of the causative pathogen (<span class="elsevierStyleItalic">f</span> % T<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>MIC)Risk of suboptimal concentrations due to increased renal ClToxicity related to elevated plasma concentrations (evidence for some beta-lactams)Adverse effects that may be severe (e.g. neurotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recommended for paediatric patients in the following situations:Renal Cl disorders (onco-haematological, burns, acute or chronic renal failure, etc)Severe burnsCritical condition or in shockPatients with severe hypoalbuminaemia (for beta-lactams with high PPB).Severe infection, hard-to-access sites, or uncontrolled infection<a class="elsevierStyleCrossRef" href="#tf0005"><span class="elsevierStyleSup">a</span></a>Infections caused by microorganisms with reduced susceptibility to the antibiotic (high MIC)ECMO or renal replacement therapyUnfavourable clinical course of infectionSuspected toxicity to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Antifungals</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Triazoles<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19–21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High intra- and inter-individual variability in PKs as a function of age and maturational developmentEfficacy and toxicity associated with plasma concentrations (less evidence for isavuconazole)Multiple drug–drug interactions with concomitant medication that may alter plasma concentrationsAdverse effects that may be severe (e.g. neurologic, ocular or hepatic toxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Voriconazole and posaconazole (oral suspension):All paediatric patientsItraconazole, all paediatric patients, especially if they have:Gastrointestinal abnormalities (if administered orally)Risk of drug interactionsSuspected breakthrough invasive fungal infectionUnfavourable clinical course of infectionSuspected toxicity to treatmentPosaconazole (tablets or vial):Gastrointestinal abnormalities (if administered orally)Risk of drug interactionsSuspected toxicity to treatmentIsavuconazole: TDM is recommended in all paediatric patients until more data are available, especially in critical patients with suspected toxicity or unfavourable clinical course \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3655202.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tf0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="np0005">Complicated infections or difficult-to-access site: Those with high inoculum and uncontrolled source of infection (pneumonia, non-surgical peritonitis, endocarditis) or those in which antibiotic penetration is limited by the characteristics of the site of infection (osteoarticular, ocular, cardiac, pulmonary, or central nervous system).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Rationale and indications for antibiotic and antifungal TDM in paediatric patients.</p>" ] ] 2 => array:8 [ "identificador" => "t0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "tbl0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">AUC<span class="elsevierStyleInf">0–24h</span>, area under curve for plasma concentration over 24 h; MIC, minimum inhibitory concentration; C<span class="elsevierStyleInf">max</span>, maximum or peak concentration; C<span class="elsevierStyleInf">min</span>, minimum or trough concentration (measure just before administration of the next dose); C<span class="elsevierStyleInf">ss</span>, average steady-state concentration; C<span class="elsevierStyleInf">8–12h</span>, plasma concentration 8–12 h after start of intravenous infusion; f, free fraction; CF, cystic fibrosis; IFI, invasive fungal infection; IV, intravenous route; PK, pharmacokinetic; PK/PD, pharmacokinetic-pharmacodynamic; GFR, glomerular filtration rate; CoNS, coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span>.</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Time of determination \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">First and subsequent determinations \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Target PK/PD index \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Potentially toxic plasma exposure \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recommended dosing adjustment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Antibiotics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Aminoglycosides</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Amikacin (extended interval administration)</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">8–12h</span>: 8–12 h after start of infusion (to estimate C<span class="elsevierStyleInf">min</span> and C<span class="elsevierStyleInf">max</span> using a population PK model) ±<span class="elsevierStyleHsp" style=""></span>C<span class="elsevierStyleInf">max</span> (30 min after end of 30 min IV infusion) (only in patients with increased Vd such as critical, septic, or burn patients)If minimising the number of samples is required, collect a single sample at 8–12 hIn patients with increased GFR (critical with correct renal function, CF, or oncohaematoma), measuring at 8 h is recommended to avoid undetectable levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination after administering the first doseMeasure weekly or sooner if dosing has been previously adjusted or toxicity is suspected \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">max</span>/MIC: 8–10 mg/LC<span class="elsevierStyleInf">max</span>: 24–35 mg/LA higher C<span class="elsevierStyleInf">max</span> (up to 60–80 mg/L) may be needed in complicated infections or in hard-to access sites<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a> caused by microorganisms with high MICs, or in septic patients C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4 mg/L to prevent toxicity (ideally undetectable) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> > 4 mg/L (nephrotoxicity)C<span class="elsevierStyleInf">min</span> > 10 mg/L (ototoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model included in a Bayesian prediction programIf unavailable, estimates could be made based on nomograms adapted from the adult population (Hartford or Urban-Craig)<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>Consider reducing the dosing interval if C<span class="elsevierStyleInf">min</span> remains below MIC for more than 12 h between consecutive doses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Gentamicin/Tobramycin (extended interval administration)</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">8–12h</span>: 8–12 h after start of infusion (to estimate C<span class="elsevierStyleInf">min</span> and C<span class="elsevierStyleInf">max</span> using a population PK model) ±<span class="elsevierStyleHsp" style=""></span>C<span class="elsevierStyleInf">max</span> (30 min after end of 30 min IV infusion) (only in patients with increased Vd such as critical, septic, or burn patients)If minimising the number of samples is required, collect a single sample at 8–12 hMeasurement at 8 h is recommended to avoid undetectable levels in patients with increased GFR (critical patients with correct renal function, CF, or oncohaematoma) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination after administering the first doseMeasure weekly or sooner if dosing has been previously adjusted or toxicity is suspected \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">max</span>/MIC: 8–10 mg/LA higher C<span class="elsevierStyleInf">max</span> (up to 15–20 mg/L) may be needed in complicated or hard-to-reach infections<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a> caused by microorganisms with high MICs, or in septic patients C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1 mg/L to prevent nephrotoxicity (ideally undetectable) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> > 2 mg/L (nephrotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model included in a Bayesian prediction programIf unavailable, estimates could be made based on nomograms adapted from the adult population (Hartford or Urban-Craig)<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>Consider reducing the dosing interval if C<span class="elsevierStyleInf">min</span> remains below MIC for more than 12 h between consecutive doses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Glycopeptides</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Vancomycin (intermittent infusion)</span><a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>C<span class="elsevierStyleInf">max</span> (1–2 h after end of 1 h intravenous infusion)<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> to estimate AUC<span class="elsevierStyleInf">0–24h</span> (C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>C<span class="elsevierStyleInf">max</span> if unable to estimate AUC<span class="elsevierStyleInf">0–24h</span> via PK modelling program, or in patients with suspected Vd alteration, such as critical, septic, or burn patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 24–48 h after starting treatmentMeasure at 3–5 d or sooner in the case of changes in renal function or suspected toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span>/MIC: 400–600<a class="elsevierStyleCrossRef" href="#tf0015"><span class="elsevierStyleSup">b</span></a> (preferably in the lower range)For neonates with late sepsis due to CoNS, an AUC<span class="elsevierStyleInf">0–24h</span>/MIC of 240–480 is sufficientIn case AUC<span class="elsevierStyleInf">0–24h</span> cannot be estimated, it is recommended to use C<span class="elsevierStyleInf">min</span>C<span class="elsevierStyleInf">min</span>: 10–15 mg/LIn hard-to-access infections<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a>, C<span class="elsevierStyleInf">min</span> up to 15–20 mg/LFor neonates with late sepsis due to CoNS, a reduced C<span class="elsevierStyleInf">min</span> of 5–10 mg/L is acceptable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span>/MIC ><span class="elsevierStyleHsp" style=""></span>600-800<a class="elsevierStyleCrossRef" href="#tf0015"><span class="elsevierStyleSup">b</span></a>C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>20 mg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span> estimations and dosing adjustments should be made using a population PK model within a Bayesian prediction programIf AUC<span class="elsevierStyleInf">0–24h</span> cannot be estimated, the following options are recommended:If C<span class="elsevierStyleInf">min</span> is sub-therapeutic: increase the dose by 20% (in uncomplicated infections) or 20%–25% (in complicated infections).If C<span class="elsevierStyleInf">min</span> is supratherapeutic: reduce the dose by 15%–20% or prolong the dosing interval Depending on type of infection and/or presence of toxicity, consider skipping the next dose, repeat monitoring at 6–8 h until therapeutic concentration is reached, and restart with adjusted dosesIn patients who fail to achieve target PK/PD despite administration of maximum doses, consider continuous infusion of vancomycin<a class="elsevierStyleCrossRef" href="#tf0020"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Vancomycin (continuous infusion)</span><a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">ss</span>: measure at any time after steady-state equilibrium is reached and draw from the arm contralateral to the infusion pump \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 24–48 h after starting treatmentMeasure at 3–5 d or sooner in the case of changes in renal function or suspected toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span>/MIC: 400–600<a class="elsevierStyleCrossRef" href="#tf0015"><span class="elsevierStyleSup">b</span></a> (preferably in the lower range)Equivalent to the following C<span class="elsevierStyleInf">ss</span> values:Neonates and infants up to 90 d:C<span class="elsevierStyleInf">ss</span>: 15–25 mg/LPatients aged ><span class="elsevierStyleHsp" style=""></span>90 d: C<span class="elsevierStyleInf">ss</span>: 20–25 mg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span>/MIC ><span class="elsevierStyleHsp" style=""></span>600–800<a class="elsevierStyleCrossRef" href="#tf0015"><span class="elsevierStyleSup">b</span></a>C<span class="elsevierStyleInf">ss</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>25 mg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AUC<span class="elsevierStyleInf">0–24h</span> estimations and dosing adjustments should be made using a population PK model within a Bayesian prediction programIf AUC<span class="elsevierStyleInf">0–24h</span> cannot be estimated, the new dose can be calculated assuming linear PK with the following formula, provided there are no significant changes in clinical status or renal function: new dose (mg/d)=target C<span class="elsevierStyleInf">ss</span>/measured C<span class="elsevierStyleInf">ss</span> · previous dose (mg/d) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Teicoplanin</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 3–5 d after starting treatment (with loading dose)Measure weekly or sooner if dosing has been previously adjusted, there are changes in renal function, or suspected toxicity<a class="elsevierStyleCrossRef" href="#tf0025"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span>: 10–20 mg/LC<span class="elsevierStyleInf">min</span>: 20–40 mg/L in complicated or difficult-to-reach infections<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>40 mg/L (thrombocytopenia)C<span class="elsevierStyleInf">min</span> ≥ 60 mg/L (nephrotoxicity) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model within a Bayesian prediction program.If unavailable, there are no specific recommendations. Adjust the dosage according to clinical criteria assuming a linear PK or consider discontinuation in the presence of toxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Oxazolidinones</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Linezolid,</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span>AUC<span class="elsevierStyleInf">0–24h</span> (uncommon in routine clinical practice) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 48 h after starting treatmentMeasure weekly or sooner if dosing has been previously adjusted or toxicity is suspected \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span>: 2–7 mg/L (definitions of the upper limit vary from 7 to 10 mg/L)AUC<span class="elsevierStyleInf">0–24h</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>80–100 mg·h/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>7–10 mg/L (haematological toxicity data in adults)AUC<span class="elsevierStyleInf">0–24h</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>300–400 mg·h/L (in adults) (can be estimated from C<span class="elsevierStyleInf">min</span> using a population PK program) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model within a Bayesian prediction programIf unavailable, adjust the dosage according to clinical criteria assuming a linear PK or consider discontinuation in the presence of toxicity In adults, it is recommended to adjust dosing by modifying the dosing interval while maintaining the same dose \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Beta-lactams</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cefepime</span><a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermittent or extended infusion:Continuous infusion C<span class="elsevierStyleInf">min</span>:C<span class="elsevierStyleInf">ss</span> (measure any time after steady-state equilibrium is reached and draw from the arm contralateral to the infusion pump)Piperacillin C<span class="elsevierStyleInf">min</span> > 128 mg/L<a class="elsevierStyleCrossRef" href="#tf0035"><span class="elsevierStyleSup">f</span></a>C<span class="elsevierStyleInf">min</span> > 44.5 mg/L<a class="elsevierStyleCrossRef" href="#tf0035"><span class="elsevierStyleSup">f</span></a></td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 24–48 h after starting treatmentMeasure weekly or sooner if dosing has been previously adjusted, there is an unfavourable clinical course, changes in renal function, or suspected toxicity</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">fT<span class="elsevierStyleInf">>MIC</span> (beta-lactam free concentration (f C<span class="elsevierStyleInf">min</span>/f C<span class="elsevierStyleInf">ss</span>)>MIC of the infecting organism during 100% of the inter-dose interval<a class="elsevierStyleCrossRef" href="#tf0030"><span class="elsevierStyleSup">e</span></a>In critical or septic patients, or those with complicated or hard-to-reach infections, it is recommended to achieve a f C<span class="elsevierStyleInf">min</span>/f C<span class="elsevierStyleInf">ss</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>4–5 times MIC of the infecting organism during 100% of the inter-dose interval<a class="elsevierStyleCrossRef" href="#tf0030"><span class="elsevierStyleSup">e</span></a> (fT ><span class="elsevierStyleHsp" style=""></span>4–5 · MIC)An fC<span class="elsevierStyleInf">min</span> or fC<span class="elsevierStyleInf">ss</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>8–10 times MIC of the infecting organism for 100% of the inter-dose interval has been suggested as an upper limit for adult patients<a class="elsevierStyleCrossRef" href="#tf0030"><span class="elsevierStyleSup">e</span></a> (fT ><span class="elsevierStyleHsp" style=""></span>8–10 · MIC)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>20–22 mg/L<a class="elsevierStyleCrossRef" href="#tf0035"><span class="elsevierStyleSup">f</span></a>C<span class="elsevierStyleInf">ss</span> > 35 mg/L<a class="elsevierStyleCrossRef" href="#tf0035"><span class="elsevierStyleSup">f</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model within a Bayesian prediction program.If unavailable, a linear PK can be assumed and dosing can be adjusted proportionally to achieve the target C<span class="elsevierStyleInf">min</span> or C<span class="elsevierStyleInf">ss</span> according to clinical criteria or consider discontinuing treatment in the case of toxicityIn adults, dose adjustments of 25%–50% or modifications in the dosing interval have both been suggested</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Ceftazidime</span><a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> > 64–100 mg/L<a class="elsevierStyleCrossRef" href="#tf0035"><span class="elsevierStyleSup">f</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Piperacillin-tazobactam</span><a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Meropenem</span><a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Antifungals</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Triazoles</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Itraconazole</span><a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 5–7 d after starting treatmentCheck weekly or sooner in the case of previous dosage adjustment, unfavourable clinical course, or introduction or withdrawal of concomitant drugs that may interact with the antifungal, and/or suspected toxicity</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prophylaxis:C<span class="elsevierStyleInf">min</span> > 0.5 mg/LTreatment:C<span class="elsevierStyleInf">min</span>: 1–2 mg/L (sum values of itraconazole and hydroxy-itraconazole) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>17 mg/L (sum values of itraconazole and hydroxy-itraconazole) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model within a Bayesian prediction program (available for oncohematology and cystic fibrosis patients) If unavailable, adjust the dosage according to clinical criteria or consider discontinuation in the presence of toxicity</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Posaconazole</span><a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prophylaxis:C<span class="elsevierStyleInf">min</span>: 0.7–2.5 mg/LTreatment:C<span class="elsevierStyleInf">min</span>: 1–2.5 mg/L (if refractory IFI ><span class="elsevierStyleHsp" style=""></span>1.3 mg/L)Consider a higher C<span class="elsevierStyleInf">min</span> in fungal infections with high MICs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> > 3.75 mg/L \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Voriconazole</span><a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19–21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First measurement 3–4 d after starting treatmentCheck weekly or sooner in the case of previous dosage adjustment, unfavourable clinical course, or introduction or withdrawal of concomitant drugs that may interact with the antifungal, and/or suspected toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span>: 1–5 mg/L (both treatment and prophylaxis)C<span class="elsevierStyleInf">min</span> value should reach the upper range in the case of complicated or difficult-to-access infections<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>6 mg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dosing adjustments should be made using a population PK model within a Bayesian prediction program.If unavailable, the following recommendations can be followed:If C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1 mg/L: 50% increase in daily dose. In the case of dose increase on 2 or more consecutive occasions without achieving the desired C<span class="elsevierStyleInf">min</span>: 50% increase of the daily dose, and adjust the frequency of administration from every 12 h to every 8 hIf C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>5 mg/L: reduce the dose according to clinical criteria or consider discontinuation in the presence of toxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Isavuconazole</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C<span class="elsevierStyleInf">min</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First determination 4–6 d after starting treatmentCheck weekly or sooner in the case of previous dosage adjustment, unfavourable clinical course, or introduction or withdrawal of concomitant drugs that may interact with the antifungal, and/or suspected toxicityIn treatments ><span class="elsevierStyleHsp" style=""></span>21 d, consider spacing controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prophylaxis and treatment:C<span class="elsevierStyleInf">min</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2.5–5.0 mg/LConsider higher C<span class="elsevierStyleInf">min</span> (between 5 and 10 mg/L) in hard-to-reach infections<a class="elsevierStyleCrossRef" href="#tf0010"><span class="elsevierStyleSup">a</span></a> or those caused by fungi with high MICs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There are no specific recommendations for dosing adjustments in paediatrics, so it is recommended to adjust dosing according to clinical criteria or to consider discontinuation in the presence of toxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3655201.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tf0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="np0010">Complicated or hard-to-reach infections: Cases with high inoculum and uncontrolled source of infection (pneumonia, non-surgical peritonitis, endocarditis) or cases in which antibiotic penetration is limited by the characteristics of the infection site (osteoarticular, ocular, cardiac, pulmonary, or central nervous system).</p>" ] 1 => array:3 [ "identificador" => "tf0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="np0015">Vancomycin: If the MIC of the causative pathogen is unknown, a value of 1 mg/L is assumed by default. If a population model is used for the estimation of AUC<span class="elsevierStyleInf">0–24h</span>, a sample can be drawn at any time as no C<span class="elsevierStyleInf">max</span> measurement is required.</p>" ] 2 => array:3 [ "identificador" => "tf0020" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="np0020">Vancomycin: When considering the continuous infusion of vancomycin, near-exclusive venous access should be ensured, as its physicochemical incompatibilities with other drugs may prevent co-infusion through the same lumen.</p>" ] 3 => array:3 [ "identificador" => "tf0025" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="np0025">Teicoplanin: Critical patients with hypoalbuminaemia, onco-haematoma, or unstable renal function should be monitored every 2–3 d.</p>" ] 4 => array:3 [ "identificador" => "tf0030" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="np0030">Beta-lactams: If MICs are unknown (due to empirical treatment or while pending results), the epidemiological cut-off value (ECOFF) or the sensitivity cut-off value (EUCAST) can be used, or TDM can be deferred until the results of microbiological cultures are available. Another option is to use the most frequent MIC value for that strain, taking local epidemiology into account.</p>" ] 5 => array:3 [ "identificador" => "tf0035" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="np0035">Beta-lactams: Potentially toxic plasma concentrations are not well defined and studies in the adult population have reported widely varying concentrations.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Recommendations for antibiotic and antifungal therapeutic drug monitoring in paediatric patients: determination, interpretation, and dosing adjustment.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:47 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.H. Abdul-Aziz" 1 => "J.W.C. Alffenaar" 2 => "M. Bassetti" 3 => "H. Bracht" 4 => "G. Dimopoulos" 5 => "D. Marriott" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Intensive Care Med" "fecha" => "2020" "volumen" => "46" "paginaInicial" => "1127" "paginaFinal" => "1153" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Editorial: therapeutic drug monitoring (TDM): a useful tool for pediatric pharmacology applied to routine clinical practice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Simeoli" 1 => "T.P.C. Dorlo" 2 => "L.M. Hanff" 3 => "A.D.R. Huitema" 4 => "E. Dreesen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/FPHAR.2022.931843" "Revista" => array:3 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2022" "paginaInicial" => "13" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimizing antibiotic drug therapy in pediatrics: current state and future needs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Le" 1 => "J.S. Bradley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jcph.1128" "Revista" => array:7 [ "tituloSerie" => "J Clin Pharmacol" "fecha" => "2018" "volumen" => "58" "numero" => "Suppl 10" "paginaInicial" => "S108" "paginaFinal" => "S122" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30248202" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetic considerations in pediatric pharmacotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S.Y. Lim" 1 => "R.S. Pettit" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ajhp/zxz161" "Revista" => array:6 [ "tituloSerie" => "Am J Health Syst Pharm" "fecha" => "2019" "volumen" => "76" "paginaInicial" => "1472" "paginaFinal" => "1480" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31532503" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paediatric pharmacokinetics: key considerations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.K. Batchelor"