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Original article
Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study
Sensibilidad de Pseudomonas aeruginosa y análisis PK/PD de su actividad antimicrobiana: estudio de vigilancia de 18 años
Ana Valeroa, Arantxa Islab, Alicia Rodríguez-Gascónb, Andrés Canutc,
Corresponding author
, María Ángeles Solinísb,
Corresponding author
marian.solinis@ehu.eus

Corresponding author.
a Pharmacy Service, Fundació Sant Hospital, Passeig Joan Brudieu 8, 25700 La Seu d,Urgell, Spain
b Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
c Microbiology Service, Hospital Universitario de Álava (HUA), Instituto de Investigación Sanitaria de Álava (BIOARABA), Servicio Vasco de Salud-Osakidetza, C/Francisco Leandro de Viana s/n, 01009 Vitoria-Gasteiz, Spain
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<span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; <span class="elsevierStyleItalic">Klebsiella pneumoniae</span>&#44; <span class="elsevierStyleItalic">Acinetobacter baumannii</span>&#44; <span class="elsevierStyleItalic">P&#46; aeruginosa</span> and <span class="elsevierStyleItalic">Enterobacter</span> species&#46; These bacteria are increasingly prevalent in our hospitals and increasingly resistant to many of the antimicrobial agents&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> which is a serious health problem that needs to be addressed urgently&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Alert to antimicrobial resistance crisis&#44; the May 2015 World Health Assembly adopted a global action plan on this issue&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> The main goal of this plan is to ensure&#44; for as long as possible&#44; continuity of successful treatment and prevention of infectious diseases with effective and safe medicines that are quality-assured&#44; used in a responsible way&#44; and accessible to all who need them&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The therapeutic approaches against <span class="elsevierStyleItalic">P&#46; aeruginosa</span> infections are particularly challenging due to its intrinsically resistance to the majority of antimicrobial agents&#44; and its ability to become resistant in the course of the antibiotic treatment&#44; which greatly complicates the selection of appropriate treatment&#44; and subsequently&#44; increases the morbidity and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> In this sense&#44; the inadequate empirical therapy&#44; suboptimal dosing and delays in the initiation of appropriate treatment are associated with high mortality rates and contribute to an increased length of hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Surveillance has been recognized as a fundamental component in the control of organisms with resistance to antimicrobial agents&#46; Surveillance of antimicrobial susceptibility enables the assessment of the burden of disease&#44; determination of risk factors&#44; and identification of temporal trends in occurrence and resistance patterns of infectious diseases&#46; Such information may be used to establish empirical antimicrobial therapy recommendations&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> although it would imply that clinicians should be familiarized with the local epidemiologic surveillance programs to choose wisely the most appropriate empirical therapy against pseudomonal infections&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Another useful tool to guide antipseudomonal therapy is the pharmacokinetic&#47;pharmacodynamic &#40;PK&#47;PD&#41; analysis with Monte Carlo simulation&#44; which provides a reasonable prediction of the probability of success for a treatment&#44; incorporating the variability of the pharmacokinetic parameters and the bacterial population MIC distribution &#40;local MIC distributions&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;8</span></a> In a recent surveillance study carried out with <span class="elsevierStyleItalic">P&#46; aeruginosa</span> isolates from an intensive care unit &#40;ICU&#41;&#44; we concluded that both&#44; susceptibility rates and the success probability associated to the activity of the antimicrobial agent are complementary tools&#44; and they have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Therefore&#44; considering the alarming increase of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> resistance against several antimicrobials and the consequent loss of treatment options that this fact entails&#44; the aim of the present study was to evaluate the adequacy of the antimicrobial therapy against <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; in admitted patients in a tertiary Spanish Hospital&#44; excluding those at Intensive Care Units &#40;ICU&#41;&#46; With this goal in mind&#44; firstly&#44; the changes in the susceptibility of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> strains to the antimicrobials in an 18 years period &#40;2000&#8211;2017&#41; were analyzed&#46; Moreover&#44; the therapy success probability over the 18 years was also evaluated by applying a PK&#47;PD modeling approach as a microbiological surveillance tool&#44; by using PK&#47;PD indexes as surrogate markers of efficacy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Microbiological data acquisition and calculation of susceptibility</span><p id="par0035" class="elsevierStylePara elsevierViewall">The susceptibility of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> against amikacin&#44; cefepime&#44; ceftazidime&#44; ciprofloxacin&#44; gentamicin&#44; levofloxacin&#44; imipenem&#44; meropenem&#44; piperacillin&#47;tazobactam and tobramycin was studied&#46; MIC distributions corresponding to clinical isolates collected from the admitted patients at the University Hospital of Araba &#40;HUA&#41;&#44; for every antimicrobial agent were extracted from the hospital database&#46; Data were collected from 2000 to 2017&#44; excluding those from ICUs&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The percentage of susceptible strains was estimated considering the CLSI breakpoints<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and following the methodology recommended by the CLSI guideline&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> that is&#44; considering only the first isolate per patient&#44; per analysis period&#44; irrespective of body site&#44; antimicrobial susceptibility profile&#44; or other phenotypical characteristics and including only species for which there are 30 or more isolates&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The susceptibility data of clinical isolates was analyzed with the WHONET software&#44; version 5&#46;6&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pharmacokinetic data</span><p id="par0050" class="elsevierStylePara elsevierViewall">Pharmacokinetic parameters were obtained from published studies&#46; Prospective studies performed in patients with infections providing the PK parameters and variability were selected&#46; Data from patients in critically ill units were excluded&#46; The PK parameters of all antimicrobials used are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PK&#47;PD analysis and Monte Carlo simulation</span><p id="par0055" class="elsevierStylePara elsevierViewall">A 10&#44;000 subject Monte Carlo simulation was conducted&#44; with the Oracle&#174; Crystal Ball software&#44; for each antimicrobial and dosing regimen using the PK data from published models &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The magnitude of value of the PK&#47;PD indexes used as surrogate markers of efficacy for each antimicrobial are also shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The best PK&#47;PD index correlated with the efficacy for all betalactams used is the duration of time that active antimicrobial concentrations exceed the MICs&#44; this time-dependent index is expressed as the percentage of the dosing interval and only the fraction of drug not bound to proteins is considered &#40;&#37;&#402;T&#62;MIC&#41;&#46; Aminoglycosides and fluoroquinolones present concentration-time dependent bactericide action&#44; and therefore&#44; the PK&#47;PD indexes used have been Cmax&#47;MIC and AUC&#47;MIC&#44; respectively&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The probability that a specific value of a PK&#47;PD index associated with the efficacy of the antimicrobial treatment is achieved at a specific population of microorganisms is known as the cumulative fraction of response &#40;CFR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> It allowed us to calculate the probability of success for a treatment without knowledge of the susceptibility of the specific isolate responsible for the infection&#44; but taking into account the bacterial population MIC distribution&#46; A CFR &#8805;80&#37; but &#60;90&#37; was associated with moderate probabilities of success&#44; whereas a CFR &#8805;90&#37; was considered as optimal against that bacterial population&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The percentage of susceptible strains and the probability that PK&#47;PD indices reach the target over time&#44; were calculated over a 18 years period&#46; The annual rates were compared by linear regression for trends&#46; All statistical analyses were performed with IBM&#174; SPSS&#174;&#44; Statistics for Windows&#44; Version 24 &#40;IBM&#41;&#46; According to Friedrich et al&#46;&#44; <a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> an appropriate degree of fit was considered with a coefficient of determination &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span>&#41; of at least 0&#46;5 &#40;corresponding to a correlation coefficient of &#8805;0&#46;7&#41;&#46; A <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05 was considered statistically significant&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> features the antimicrobial year-by-year susceptibility to amikacin&#44; cefepime&#44; ceftazidime&#44; ciprofloxacin&#44; gentamicin&#44; imipenem&#44; levofloxacin&#44; meropenem&#44; piperacillin&#47;tazobactam and tobramycin of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> isolates from the hospitalized patients&#46; As it is shown&#44; the last year evaluated &#40;2017&#41; <span class="elsevierStyleItalic">P&#46; aeruginosa</span> displayed a susceptibility to amikacin&#44; penicillins and cephalosporins equal or higher than 85&#37;&#59; for tobramycin and meropenem&#44; it was 76&#37; and 75&#37;&#44; respectively&#46; Susceptibility to the other antimicrobials was under 70&#37;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The trend analyses of antimicrobial susceptibility of <span class="elsevierStyleItalic">P&#46; aeruginosa</span> over time are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; The susceptibility rates to amikacin and betalactams were stable during the evaluated period&#46; In contrast&#44; the susceptibility to quinolones&#44; gentamicin and tobramycin decreased significantly over time&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 2</a> provide an overview of the probability of PK&#47;PD target attainment according to MIC distributions &#40;CFR values&#41; for the antimicrobials studied at the selected dosing regimens&#46; In summary&#44; in 2017&#44; the last year evaluated &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; only meropenem 1<span class="elsevierStyleHsp" style=""></span>g every 6<span class="elsevierStyleHsp" style=""></span>h &#40;q6h&#41; administered as extended infusion was able to attain CFR &#62;90&#37; &#40;92&#37;&#41;&#46; CFRs between 80&#8211;90&#37; were attained with ceftazidime 2<span class="elsevierStyleHsp" style=""></span>g q8h &#40;88&#37;&#41;&#44; piperacillin&#47;tazobactam 4&#46;5<span class="elsevierStyleHsp" style=""></span>g q6h &#40;83&#37;&#41;&#44; meropenem 1<span class="elsevierStyleHsp" style=""></span>g q8h &#40;86&#37;&#41;&#44; and imipenem 1<span class="elsevierStyleHsp" style=""></span>g q6h &#40;82&#37;&#41;&#46; The CFRs for the other treatments evaluated were always lower than 80&#37;&#46; Fluoroquinolones and aminoglycosides &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; achieved the lowest CFR values &#40;&#60;35&#37;&#41;&#46; Supplementary Table 1 shows the CFR values obtained annually of each antimicrobial evaluated&#46; CFR values for amikacin have not been included because when antibiograms were carried out&#44; amikacin concentrations tested ranged from 4<span class="elsevierStyleHsp" style=""></span>mg&#47;L to 32<span class="elsevierStyleHsp" style=""></span>mg&#47;L and&#44; therefore&#44; MICs lower than 4<span class="elsevierStyleHsp" style=""></span>mg&#47;L were not available and the CFR could not be adequately calculated&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> presents the linear regression studies for CFR values&#46; A statistically significant trend over time was observed for fluoroquinolones and imipenem&#46; In the case of levofloxacin and ciprofloxacin&#44; a significant decrease was observed in CFR values from 40&#8211;59&#37; in 2000 to 0&#8211;29&#37; in 2017&#44; depending on the dose but the activity was low from the start of the evaluated period&#46; Imipenem showed a decrease in antimicrobial activity in all dosing regimens except for 500<span class="elsevierStyleHsp" style=""></span>mg q12h&#44; for which CFR values were always under 70&#37;&#59; for 1<span class="elsevierStyleHsp" style=""></span>g q6h antimicrobial activity decreased from 95&#37; to 82&#37;&#44; maintaining moderate activity&#46; For other regimens&#44; CFR values decreased from high probabilities to target attainment &#40;&#62;90&#37;&#41; to low probabilities &#40;CFR&#60;70&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Two microbiological surveillance tools have been used to evaluate the antimicrobial therapy against <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#58; &#40;i&#41; the analysis of susceptibility changes of the antimicrobials over time&#44; and &#40;ii&#41; the analysis of the activity of the empirical antipseudomonal treatments by using a PK&#47;PD modeling approach&#46; After the evaluation over 18 years of the adequacy of the therapy&#44; differences in the expected efficacy of the antimicrobials&#44; in terms of susceptibilities or CFRs&#44; were observed depending on the tool used&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">P&#46; aeruginosa</span> is intrinsically resistant to several antimicrobial agents&#46; Recently&#44; Mensa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> have published the estimated prevalence of this bacteria in Spanish hospitals&#44; and overall&#44; resistance rates are over 20&#8211;30&#37; for most antipseudomonal antimicrobials&#44; except for amikacin&#44; colistin and the recently introduced ceftolozane-tazobactam with values over 5&#37;&#46; In our study&#44; in 2017 only amikacin and the betalactams ceftazidime&#44; cefepime and piperacillin&#47;tazobactam&#44; showed susceptibilities higher than 85&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Over the 18 years evaluated&#44; a decrease in the susceptibility was observed only for gentamicin&#44; tobramycin&#44; and fluoroquinolones &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#59; but this reduction showed a poor relationship between both variables &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#41; susceptibility and time&#44; despite statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Different national action plans on antimicrobial resistance&#44; which have been implemented in the HUA hospital to control the emergence of resistances&#44; have probably influenced substantially the obtained results&#44; that is&#44; the susceptibility rates and their evolution over the time&#46; Bacteremia Zero<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> project &#40;2009&#41; and &#8220;Zero-VAP&#8221; bundle<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> &#40;2011&#41;&#44; consisting of the implantation of measures to prevent central venous catheter-related bacteremia and a bundle of ventilator-associated pneumonia &#40;VAP&#41; prevention measures&#44; respectively&#46; Although these programs have been implemented in the ICU&#44; they can have an important role in the prevention of the intra-hospital dissemination of resistances&#46; Programs for optimizing the use of antibiotics in hospitals &#40;called PROA&#41;&#44; implemented in the HUA hospital since 2015&#44; are promoted by the Ministry of Health&#44; Social Services and Equality of Spain as a Strategic and Action Plan to Reduce the Risk of Selection and Dissemination of Resistance to Antibiotics 2014&#8211;2018&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> The main objectives<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> of these programs are &#40;i&#41; to improve the clinical results of patients with infections&#44; &#40;ii&#41; to minimize the adverse effects associated with the use of antimicrobials &#40;including the appearance and dissemination of the resistance&#41;&#44; and &#40;iii&#41; to ensure the use of cost-effective treatments&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">PK&#47;PD analysis is outlined as a needed strategy to wisely optimize dosing regimens of the antimicrobial agents in order to conserve their therapeutic value&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> moreover&#44; its incorporation to clinical routine would contribute to reach the main objectives of the surveillance programs&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In this study&#44; Monte Carlo simulation&#44; pharmacokinetic modeling and institution-specific MIC determination have been used to evaluate antimicrobial dosing regimen for the empirical treatment of <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#46; It is important to remark that the expected probability of success estimated by applying Monte Carlo simulation for the evaluated antimicrobials do not match their susceptibilities&#46; Meropenem &#40;susceptibility of 75&#37;&#41; administered as 1<span class="elsevierStyleHsp" style=""></span>g q6 or 8<span class="elsevierStyleHsp" style=""></span>h was able to attain high and moderate probabilities of success &#40;92&#37; and 86&#37;&#44; respectively&#41;&#46; Ceftazidime and piperacillin&#47;tazobactam &#40;susceptibilities of 91 and 88&#37;&#44; respectively&#41;&#44; administered at the highest dose&#44; showed only moderate probabilities to attain the PK&#47;PD target&#44; and cefepime&#44; despite its high susceptibility &#40;85&#37;&#41; provided CFRs under 70&#37; for all dosage regimens evaluated&#46; On the contrary and surprisingly&#44; imipenem at highest dose was able to achieve moderate probability of success &#40;CFR 82&#37;&#41; with only a 67&#37; of susceptible isolates&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In the case of cefepime there is a controversy on its susceptibility breakpoint that could explain the observed differences&#46; According to the CLSI criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> the cefepime MIC breakpoint was &#8804;8<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46; However&#44; Bhat et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> based on pharmacodynamic and clinical grounds&#44; have suggested to lower the breakpoints for cefepime in countries where the cefepime dosage of 1 to 2<span class="elsevierStyleHsp" style=""></span>g every 12<span class="elsevierStyleHsp" style=""></span>h is the licensed therapy for serious infections&#44; so that organisms with a cefepime MIC of 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml should be no longer regarded as susceptible to the antibiotic&#46; More recently&#44; Sue et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> also demonstrated worse outcomes related to high cefepime MICs for <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; despite being &#8220;susceptible&#8221; in the currently range&#44; and proposed that the current CLSI criteria for cefepime susceptibility did not predict clinical outcomes appropriately and that the breakpoint of 8<span class="elsevierStyleHsp" style=""></span>mg&#47;L is too high&#46; In our study&#44; if we calculate the susceptibility rate of <span class="elsevierStyleItalic">P&#46; aureginosa</span> against cefepime considering 8<span class="elsevierStyleHsp" style=""></span>mg&#47;L as resistant&#44; the susceptibility rate decreases &#40;for instance&#44; in 2017 from 85&#37; to 53&#37;&#41;&#44; and in this case&#44; CFR values would match better their susceptibilities&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The concentration-dependent antimicrobials&#44; fluoroquinolones&#44; gentamicin and tobramycin&#44; showed CFRs under 35&#37;&#44; although susceptibilities ranged from 67 to 76&#37;&#46; Unfortunately&#44; it has not been possible to calculate CFR values for amikacin&#44; because of MIC concentrations tested in the hospital only ranged from 4<span class="elsevierStyleHsp" style=""></span>mg&#47;L to 32<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;susceptibility breakpoint MIC &#8804;16<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46; This concentration range is adequate to categorize the strains as susceptible or resistant&#44; but it is not useful to estimate the CFR properly&#44; whose value depends on the knowledge of the MIC values corresponding to a wide distribution&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Estimation of CFR is also useful to determine not only which antimicrobial&#44; but also the dose regimen with the best likelihood of success&#46; An increase of the antimicrobial doses not always implies relevant changes in CFR values&#44; for example&#44; increases in ciprofloxacin dose did not significantly improve the probability of target attainment &#40;400<span class="elsevierStyleHsp" style=""></span>mg q12h and 400<span class="elsevierStyleHsp" style=""></span>mg q8h&#44; CFR 3&#8211;28&#37; respectively&#41;&#59; on the contrary&#44; for piperacillin&#47;tazobactam CFR ranged between 49&#37; &#40;4&#46;5<span class="elsevierStyleHsp" style=""></span>g q6h8&#41; to 83&#37; &#40;4&#46;5<span class="elsevierStyleHsp" style=""></span>g q6h&#41;&#46; Moreover&#44; considering the time-dependent activity of all betalactams&#44; the efficacy probably would improve by administering them through extended or continuous infusion&#44; as shown with meropenem&#44; although stability should be considered&#44; as in the case of imipenem&#44; with poor stability at room temperature&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Fluoroquinolones&#44; and also imipenem&#44; showed a statistically significant decreasing trend in the values of CFR over the 18 years evaluated&#44; however&#44; only in the case of ciprofloxacin and levofloxacin the coefficient of determination <span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span> was higher than 0&#46;5&#44; indicating good correlation&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In order to evaluate properly the results obtained in this theoretical PK&#47;PD analysis&#44; some limitations must be considered&#46; &#40;i&#41; PK information from the patients from whom <span class="elsevierStyleItalic">P&#46; aeruginosa</span> was isolated was not available&#46; Therefore&#44; it was extracted from prospective studies carried out in patients with infections&#44; excluding patients in ICUs and the PK&#47;PD analysis was carried out by using the mean PK parameters and their variability&#59; &#40;ii&#41; PK&#47;PD analysis is conditioned by the place of infection since the CFR would vary according to location&#44; preferably in the case of antibiotics with wide urinary excretion&#59; &#40;iii&#41; colistin has not been evaluated because it is hardly used in the patients admitted at the HUA&#44; with the exception of ICU patients &#40;not included in the study&#41;&#46; Additionally&#44; colistin&#39;s MIC distribution has not been tested until recent years&#44; and this antimicrobial does not have a widely accepted PK&#47;PD index&#59; &#40;iv&#41; extended infusion of beta-lactams has not been evaluated&#44; except for meropenem&#59; &#40;v&#41; in this study&#44; only the CLSI breakpoints have been considered&#46; EUCAST<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> &#40;European Committee on Antimicrobial Susceptibility Testing&#41; and CLSI<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> susceptibility breakpoints agree on six of the 10 antimicrobials studied&#44; and the breakpoints of amikacin&#44; imipenem&#44; ciprofloxacin and levofloxacin differ only in one dilution&#46; In 2017&#44; amikacin presented a susceptibility value of 22 percentage points lower by using EUCAST criterion instead CLSI&#59; the difference for the other three affected antimicrobials was less than 10 percentage points&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In brief&#44; empirical antipseudomonal therapy would vary considerably if&#44; in addition to susceptibility data&#44; PK&#47;PD analysis is considered&#46; Based only on susceptibility&#44; amikacin&#44; ceftazidime&#44; piperacillin&#47;tazobactam but also cefepime would be the best therapeutic options&#46; PK&#47;PD analyses was able to identify changes in antimicrobial activity not detected by simply assessing MIC indices&#44; meropenem provided high probabilities to achieve the PK&#47;PD target&#44; followed by ceftazidime&#44; piperacillin&#47;tazobactam and imipenem&#44; with moderate probabilities&#44; all of them administered at the highest doses&#46; In conclusion&#44; PK&#47;PD approach has allowed to preserve the therapeutic value of antimicrobials with low susceptible values&#44; such as carbapenems&#44; and the selection of the most efficacy antimicrobials among those with high rates of sensible isolates&#46; Both microbiological surveillance tools&#44; analysis of susceptibility and PK&#47;PD modeling&#44; should be considering together in the clinical routine to determine the most appropriate antimicrobial drug and its dose regimen&#44; contributing in this way to decrease the risk of treatment failure and resistances development&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Patients&#8217; data protection</span><p id="par0145" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">Nothing to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">We analysed the changes in the susceptibility of <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> to antimicrobials over an 18-year period &#40;2000-2017&#41; in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital &#40;excluding the intensive care unit&#41;&#46; In addition&#44; the antimicrobial activity was evaluated using pharmacokinetic&#47;pharmacodynamic &#40;PK&#47;PD&#41; criteria as a microbiological surveillance tool&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints&#46; Monte Carlo simulations were conducted to calculate the cumulative fraction of response &#40;CFR&#41;&#46; Linear regression analysis was applied to determine the trends in susceptibility and in the CFR&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">In 2017&#44; susceptibility rates were&#58; amikacin&#44; penicillins and cephalosporins &#8805;85&#37;&#44; tobramycin 76&#37;&#44; meropenem 75&#37; and gentamicin&#44; imipenem and fluoroquinolones &#60;70&#37;&#46; PK&#47;PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs&#59; meropenem administered in extended infusion attained a CFR &#62;90&#37;&#44; ceftazidime&#44; piperacillin&#47;tazobactam and imipenem provided CFRs between 80-90&#37;&#44; all of them administered at the highest doses&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Analysis of susceptibility and PK&#47;PD modelling&#44; should be considered together to select the most appropriate antimicrobial drug and dosage regimen&#46; Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered&#46; In this study&#44; the PK&#47;PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates&#44; such as carbapenems&#44; and the selection of the most effective antimicrobials among those with high rates of susceptibility&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Para evaluar la terapia antimicrobiana frente a <span class="elsevierStyleItalic">Pseudomonas aeruginosa &#40;P&#46; aeruginosa&#41;</span> en pacientes ingresados en un hospital terciario espa&#241;ol &#40;excluida Unidad de Cuidados Intensivos&#41;&#44; se analizaron los cambios en la sensibilidad a los antimicrobianos durante 18 a&#241;os &#40;2000-2017&#41;&#46; Tambi&#233;n se evalu&#243; la actividad antimicrobiana utilizando criterios farmacocin&#233;ticos&#47;farmacodin&#225;micos &#40;PK&#47;PD&#41; como herramienta de vigilancia microbiol&#243;gica&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La sensibilidad se estudi&#243; utilizando los puntos de corte del CLSI&#46; Se realizaron simulaciones de Monte Carlo para calcular la fracci&#243;n de respuesta acumulada &#40;CFR&#41;&#46; Se llev&#243; a cabo un an&#225;lisis de tendencia de sensibilidad y CFR mediante regresi&#243;n lineal&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En 2017&#44; la sensibilidad a amikacina&#44; penicilinas y cefalosporinas fue &#8805; 85&#37;&#59; tobramicina 76&#37;&#44; meropenem 75&#37; y para gentamicina&#44; imipenem y fluoroquinolonas &#60;<span class="elsevierStyleHsp" style=""></span>70&#37;&#46; El an&#225;lisis PK&#47;PD fue capaz de identificar cambios en la actividad antimicrobiana no detectados mediante la evaluaci&#243;n &#250;nicamente de las concentraciones m&#237;nimas inhibitorias&#59; meropenem administrado en forma de infusi&#243;n extendida alcanz&#243; una CFR<span class="elsevierStyleHsp" style=""></span>&#62; 90&#37;&#44; ceftazidima&#44; piperacilina&#47;tazobactam e imipenem proporcionaron CFR entre 80 y 90&#37;&#44; todos ellos administrados a las dosis m&#225;s altas&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La evaluaci&#243;n de la sensibilidad y el an&#225;lisis PK&#47;PD deben considerarse conjuntamente para seleccionar el tratamiento antimicrobiano m&#225;s apropiado&#58; f&#225;rmaco y r&#233;gimen de dosificaci&#243;n&#46; La terapia emp&#237;rica frente a <span class="elsevierStyleItalic">P&#46; aeruginosa</span> variar&#237;a considerablemente si se consideraran ambas herramientas de vigilancia microbiol&#243;gica&#46; En este estudio&#44; el an&#225;lisis PK&#47;PD ha permitido preservar el valor terap&#233;utico de antimicrobianos con bajos valores de sensibilidad&#44; como los carbapenems&#44; y la selecci&#243;n de los antimicrobianos de mayor eficacia&#44; entre aquellos que presentaban altos valores de sensibilidad&#46;</p></span>"
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            "titulo" => "Introducci&#243;n"
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            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
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        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0165" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0060"
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    "multimedia" => array:7 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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            "Alto" => 3632
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            "Tamanyo" => 612645
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Cumulative fraction of response &#40;CFR&#41; for standard dosage regimens of penicillins&#44; cephalosporins and carbapenems&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Cumulative fraction of response &#40;CFR&#41; for standard dosage regimens of aminoglycosides and fluoroquinolones&#46;</p>"
        ]
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      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">S&#58; Susceptible&#59; R&#58; Resistant&#59; &#37;&#402;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MIC&#58; Percentage of time that the antimicrobial free serum concentration remained above the MIC&#59; AUC&#58; Area under the concentration-time curve&#59; Cmax&#58; Maximum drug plasma concentration&#59; MIC&#58; Minimum Inhibitory Concentration&#59; Vd&#58; Volume of distribution&#44; Cl&#58; clearance&#59; AUC&#58; Area Under the Curve&#44; fu&#58; unbound drug fraction&#46;</p>"
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                  <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-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Antimicrobial agent&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC interpretive criteria &#40;mg&#47;L&#41;</th><th class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Dosing regimen&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Infusion time&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">PK&#47;PD target&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\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="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">S&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">R&nbsp;\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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#40;h&#41;&nbsp;\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">&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Vd &#40;L&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cl&#40;L&#47;h&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AUC&#40;mg h&#47;L&#41;&nbsp;\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="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">fu&nbsp;\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_rowhead " align="left" valign="\n
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                  \t\t\t\t">Amikacin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8804;16&nbsp;\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="char" valign="\n
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                  \t\t\t\t">&#8805;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\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="char" valign="\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cmax&#47;MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\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="char" valign="\n
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                  \t\t\t\t">15&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3&nbsp;\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">&nbsp;\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">&nbsp;\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_rowhead " align="left" valign="\n
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                  \t\t\t\t">Cefepime&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8804;8&nbsp;\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="char" valign="\n
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                  \t\t\t\t">&#8805;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#8211;2<span class="elsevierStyleHsp" style=""></span>g q&#47;8&#8211;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\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="char" valign="\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#37;&#402;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&nbsp;\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="char" valign="\n
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                  \t\t\t\t">0&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;25 &#40;L&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;3&nbsp;\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">&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ceftazidime&nbsp;\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="char" valign="\n
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                  \t\t\t\t">&#8804;8&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#37;&#402;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#46;98<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ciprofloxacin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">400<span class="elsevierStyleHsp" style=""></span>mg q&#47;8&#8211;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">AUC&#47;MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">20&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Gentamicin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5&#8211;7<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Cmax&#47;MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Imipenem&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g q&#47;6&#8211;8<span class="elsevierStyleHsp" style=""></span>h500<span class="elsevierStyleHsp" style=""></span>mg q&#47;6-12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;75&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">10&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;38&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Levofloxacin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">500<span class="elsevierStyleHsp" style=""></span>mg q&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">AUC&#47;MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">54&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Meropenem&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g q&#47;6&#8211;8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#37;&#402;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">20&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;92&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Piperacillin&#47;tazobactam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#8804;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8805;128&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#47;0&#46;5 q&#47;6-8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#37;&#402;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;5&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;22<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;12&nbsp;\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">&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tobramycin&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Cmax&#47;MIC<span class="elsevierStyleHsp" style=""></span>&#62;10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">20&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;91&nbsp;\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
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CLSI susceptibility breakpoints for <span class="elsevierStyleItalic">P&#46; aeruginosa</span> of the studied antimicrobials&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> dosing regimens evaluated&#44; pharmacokinetic&#47;pharmacodynamic &#40;PK&#47;PD&#41; targets&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;11&#8211;13</span></a> and pharmacokinetic parameters &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;14&#8211;18</span></a></p>"
        ]
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      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
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            "rol" => "short"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">In bold&#58; susceptibility &#8805;90&#37;&#59; Underlined&#58; susceptibility &#8805;80&#37; and &#60;90&#37;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antimicrobial agent&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2000&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2001&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2002&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2003&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2004&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2005&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2006&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2007&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2008&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2009&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2010&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2011&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2012&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2013&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2014&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2015&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2016&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2017&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amikacin&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cefepime&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">82</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">85</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">83</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">85</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">85</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleUnderline">84</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">91</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">91</span>&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">90</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  """
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Decreasing&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Cefepime 2<span class="elsevierStyleHsp" style=""></span>g q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cefepime 2<span class="elsevierStyleHsp" style=""></span>g q12h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#8722;0&#46;33&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ceftazidime 2<span class="elsevierStyleHsp" style=""></span>g q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;36&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ceftazidime 2<span class="elsevierStyleHsp" style=""></span>g q12h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\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_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ciprofloxacin 400<span class="elsevierStyleHsp" style=""></span>mg q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;90&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreasing&nbsp;\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_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ciprofloxacin 400<span class="elsevierStyleHsp" style=""></span>mg q12h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreasing&nbsp;\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
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                  \t\t\t\t">Gentamicin 7<span class="elsevierStyleHsp" style=""></span>mg&#47;kg q24h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gentamicin 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg q24h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;42&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;2&#46;43&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;16&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;1&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Imipenem 1<span class="elsevierStyleHsp" style=""></span>g q6h&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;52&nbsp;\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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;27&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Decreasing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Imipenem 1<span class="elsevierStyleHsp" style=""></span>g q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Decreasing&nbsp;\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
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                  \t\t\t\t">Imipenem 500<span class="elsevierStyleHsp" style=""></span>mg q6h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Decreasing&nbsp;\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_rowhead " align="left" valign="\n
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                  \t\t\t\t">Imipenem 500<span class="elsevierStyleHsp" style=""></span>mg q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Imipenem 500<span class="elsevierStyleHsp" style=""></span>mg q12h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Levofloxacin 500<span class="elsevierStyleHsp" style=""></span>mg q24h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Decreasing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Meropenem 1<span class="elsevierStyleHsp" style=""></span>g q6h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Meropenem 1<span class="elsevierStyleHsp" style=""></span>g q8h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Piperacillin&#47;tazobactam 4&#46;5<span class="elsevierStyleHsp" style=""></span>g q6h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#46;58&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;04&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8211;&nbsp;\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_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos