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seasonal variation and study population&#46; In 2014&#44; the overall incidence rate per 100&#44;000 inhabitants was 4&#46;8 for Europe and 5&#46;4 for Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent decades&#44; the number of cases of IPD has progressively declined due to the administration of the pneumococcal vaccination in the pediatric immunization schedule&#46; This vaccination has helped reduced the main reservoir of pneumococcus&#58; the airways of children younger than 2 years&#46; By decreasing the reservoir&#44; the vaccine not only decreases the active infection in vaccinated children but also the risk of infection for the unvaccinated population&#44; both pediatric and adult&#44; which is defined as &#8220;herd immunity&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7&#44;8</span></a> In the United States&#44; 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which increased the incidence of IPD in the pediatric population from 2&#46;1 in 2012 to 5&#46;4&#47;100&#44;000 inhabitants in 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The vaccine also has a significant effect on controlling the resistance to antibiotics&#44; because numerous serotypes associated with multiresistance are included in the employed vaccines&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7&#44;12</span></a> However&#44; the associated risk is the emergence of other serotypes&#44; a phenomenon known as serotype replacement&#44; which replaces the previous serotypes&#46; Infections caused by nonvaccine strains increased overall&#44; especially in the population older than 65 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13&#8211;15</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Prognostic factors of mortality</span><p id="par0035" class="elsevierStylePara elsevierViewall">Pneumococcal infection causes approximately 1&#46;6 million deaths per year worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a> It is estimated that 10&#8211;15&#37; 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mortality is increased if there are certain associated diseases&#44; such as immunosuppression secondary to drugs&#44; HIV infection&#44; tumors&#44; heart disease&#44; cerebrovascular disease&#44; chronic liver disease&#44; nicotine addiction and alcoholism&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">5&#44;18&#44;24&#44;25</span></a> Other factors such as the functional state&#44; institutionalization and a high number of comorbidities confer a poorer prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">24</span></a> Moreover&#44; greater clinical severity results in higher mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">20&#44;26&#44;27</span></a> The main factors associated with early mortality are respiratory failure &#40;need for mechanical ventilation&#41;&#44; cardiovascular failure &#40;septic shock&#41; and a low level of consciousness&#44; which seem to be related to an excessive inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antibiotic resistance &#8211; impact on treatment</span><p id="par0050" class="elsevierStylePara elsevierViewall">Penicillin has classically been the first-choice antibiotic for treating pneumococcal infection&#46; In the 1970s&#44; the first strains resistant to beta-lactams and to other antibiotic groups were reported in South Africa&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">29</span></a> In the following years&#44; there was a marked increase in resistance rates&#44; which have decreased significantly since 2008 after the change in the penicillin sensitivity cutoffs by the Clinical and Laboratory Standards Institute&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">30</span></a> This change was performed after confirming that penicillin treatment of respiratory infections caused by strains with reduced penicillin sensitivity was not associated with increased treatment failure&#46; Considering that beta-lactams reach high concentrations in lung tissue&#44; conventional dosages for these drugs are adequate for treating infections by strains with low-level resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">31</span></a> In Europe&#44; the current rates of resistance to penicillin and cephalosporin are estimated at 11&#37; and 6&#37;&#44; respectively&#44; which are somewhat higher than those in the United States &#40;4&#37; and 2&#46;4&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The clinical significance of reduced sensitivity to beta-lactams is a controversial subject&#46; A meta-analysis published in 2006 observed that penicillin resistance was associated with increased mortality in patients hospitalized with pneumococcal pneumonia&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">32</span></a> However&#44; mortality seemed to be related to an increased comorbidity of the patients&#46; Other studies have shown that the clinical importance of resistance depends on the antimicrobial used for treating the pneumococcal infection&#46; Thus&#44; the study by Yu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a> observed that in vitro treatment of pneumococcal bacteremia with inactive drugs was not associated with increased mortality at 14 days when ceftriaxone&#44; cefotaxime or penicillin were used but was associated with increased mortality when cefuroxime was used&#44; which was attributed to the different pharmacodynamics of this antibiotic&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a> Other studies have confirmed that the progression does not worsen in patients treated with adequate dosages of beta-lactams&#44; provided these have high activity against the pneumococcus&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">25&#44;33&#44;34</span></a> Except for meningeal infections&#44; in which antimicrobial dissemination to the cerebrospinal fluid is essential&#44; the intermediate resistance to beta-lactams does not influence mortality&#44; provided appropriate dosages are used&#46; However&#44; high-grade resistance can result in therapeutic failure&#44; especially in meningitis&#46; Penicillin resistance has not been related to more severe clinical forms or to a higher incidence of suppurative complications&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">For macrolides&#44; the resistance rates are quite high&#44; ranging from 20&#37; to 30&#37; in Spain&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">6&#44;11</span></a> Macrolide resistance can be low-grade &#40;using an efflux pump that eliminates the drug&#44; encoded by the <span class="elsevierStyleItalic">mef</span> gene&#41; or high-grade &#40;produced by a change in the bacteria&#39;s conformation&#44; through an RNA methylase&#44; encoded by the <span class="elsevierStyleItalic">erm</span> gene&#41;&#46; The latter mechanism is predominant in Europe&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a> Macrolide resistance is not associated with more severe clinical conditions or a higher rate of suppurative infections&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a> although therapeutic failures have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">36&#44;37</span></a> The clinical guidelines recommend avoiding monotherapy with macrolides in populations with high resistance rates due to the associated high risk of failure&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">With regard to quinolones&#44; the resistance rates remain low &#40;2&#8211;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">38</span></a> Since they are not used in children&#44; the selective pressure on the main reservoir of pneumococcus is lower&#46; Therapeutic failures have been reported in quinolone-resistant bacterial infections&#44; as has the development of resistances during therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">39</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> lists the resistance rates of the main antimicrobials&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Combined resistance to several antibiotics is a growing problem&#46; In a study in the Community of Madrid&#44; 91&#46;7&#37; of the pneumococci with reduced penicillin-sensitivity were erythromycin resistant&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> Multiresistance&#44; defined by resistance to 3 families of antimicrobials&#44; is a growing worldwide problem&#44; with rates reaching 59&#46;3&#37; in a recent study in Asia&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">40</span></a> Although cases of extremely resistant pneumococci have been reported&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">41</span></a> there is practically no resistance to antibiotics such as vancomycin&#44; linezolid and tigecycline&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;6</span></a> The clinical impact of the resistance of pneumococcus is still a limited problem due to the availability of alternative drugs for most clinical conditions&#46; Nevertheless&#44; it is essential to maintain strict epidemiological surveillance that identifies at-risk populations<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">35&#44;42</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; and optimizes the therapeutic strategies&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Treatment of invasive pneumococcal disease</span><p id="par0075" class="elsevierStylePara elsevierViewall">The benefit of empiric combination therapy &#40;CT&#41; using a beta-lactam with macrolides or quinolones for treating IPD is controversial&#46; The rationale for CT is based not only on providing a more potent treatment against resistant pneumococci but also coverage against other microorganisms in mixed respiratory infections&#44; caused by pneumococcus and atypical bacteria&#46; Most studies that compared the efficacy of CT versus monotherapy were observational and were performed on patients with bacteremia secondary to pneumonia&#44; where the impact of resistance is lower than in other infections such as meningitis and endocarditis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17&#44;43&#8211;52</span></a> There appears to be more evidence in favor of CT&#44; especially in severe clinical forms &#40;with septic shock or groups III&#8211;V of the Fine scale&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">43&#44;44</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">There is also no evidence on the best CT regimen&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> However&#44; CT that includes a macrolide has shown a clinical benefit most consistently&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17&#44;44&#44;46&#44;47&#44;52</span></a> This finding is explained by several factors&#58; a broader spectrum of activity &#40;in mixed infections caused by atypical bacteria&#41;&#44; dual or synergistic antibacterial effects and a potential anti-inflammatory or immunomodulatory effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">47&#44;53&#44;54</span></a> Macrolides reduce the formation of proinflammatory cytokines&#44; an essential aspect in severe clinical forms in which an excessive inflammatory response secondary to the infection has been reported&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Studies that have analyzed CT with quinolones have not observed superiority versus the macrolide in reducing mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> Nevertheless&#44; quinolones can be an alternative to macrolides due to the former&#39;s excellent bioavailability&#44; oral formulation and deep coverage against atypical bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">55</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Although there are no specific IPD guidelines&#44; clinical guidelines have been published on therapies for pneumonia and meningitis&#44; as well as recommendations based on expert opinion&#46; As a general rule&#44; the recommended CT for severe pneumococcal pneumonia is a third-generation cephalosporin &#40;cefotaxime or ceftriaxone&#41; and a macrolide &#40;azithromycin or clarithromycin&#41; or&#44; alternatively&#44; a quinolone &#40;levofloxacin or moxifloxacin&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">56&#44;57</span></a> For meningitis&#44; the therapy should include a third-generation cephalosporin combined with vancomycin&#46; Moxifloxacin is an alternative therapy for patients with allergies to beta-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">New antibiotics</span><p id="par0095" class="elsevierStylePara elsevierViewall">Although antibiotic resistance is not currently a severe problem&#44; the World Health Organization has classified penicillin-resistant pneumococci &#40;PRP&#41; among the bacteria that require the introduction of new antibiotics&#44; with a medium priority level&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">59</span></a> In recent years&#44; antibiotics have been developed with activity against Gram-positive bacteria&#44; directed mainly against <span class="elsevierStyleItalic">Staphylococcus aureus</span> and enterococci&#46; These antibiotics have advantages over the current therapeutic arsenal for pneumococcal infection&#46; Ceftaroline and ceftobiprole are 2 new cephalosporins that stand out due to their broad spectrum against Gram-positive bacteria and are active against methicillin-resistant <span class="elsevierStyleItalic">S&#46; aureus</span> &#40;MRSA&#41; and PRP&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Ceftaroline is indicated for treating community-acquired pneumonia &#40;CAP&#41; and skin and soft tissue infections&#44; although it has been used for infectious endocarditis&#44; osteomyelitis and meningitis&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">60</span></a> Ceftaroline&#39;s greater affinity for certain penicillin-binding proteins &#40;PBPs&#41; enables it to overcome the main resistance mechanism of pneumococcus against beta-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">61</span></a> Ceftaroline&#39;s intrinsic activity is up to 8-fold greater than that of other cephalosporins&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">62</span></a> The efficacy of ceftaroline in treating CAP &#40;groups III&#8211;IV of the Fine scale&#41; has been assessed in the FOCUS clinical trials&#44; with a superior clinical response to that of ceftriaxone &#40;85&#46;5&#37; vs&#46; 68&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> In the patient subgroup with pneumococcal bacteremia&#44; the efficacy of ceftaroline was superior to that of ceftriaxone &#40;78&#46;9&#37; vs&#46; 66&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> These trials used a lower dosage of ceftriaxone &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41; than that typically recommended &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41;&#46; New clinical trials comparing ceftaroline with ceftriaxone at full dosages are therefore needed to establish its actual clinical efficacy&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Ceftobiprole is active against MRSA and PRP&#44; with an activity similar to that of cefepime&#44; ceftazidime and piperacillin-tazobactam against Gram-negative bacteria&#46; Ceftobiprole&#39;s considerable affinity for PBP-2 makes it a potentially effective antibiotic against PRP and ceftriaxone-resistant bacteria&#46; Two clinical trials have evaluated the efficacy of ceftobiprole in CAP and nosocomial pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">64&#44;65</span></a> Both trials observed that ceftobiprole was not inferior to the comparator &#40;ceftriaxone and linezolid in CAP&#59; and ceftazidime and linezolid in nosocomial pneumonia&#41;&#46; However&#44; the efficacy of ceftobiprole was inferior in the patient subgroup with ventilator-associated pneumonia &#40;38&#46;5&#37; vs&#46; 56&#46;7&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">65</span></a> which seems to be due to a change in the drug&#39;s volume of distribution in this patient subgroup&#46; Therefore&#44; ceftobiprole is indicated for treating CAP and nosocomial pneumonia not associated with mechanical ventilation&#44; although the drug is still not marketed in Spain&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Tedizolid is an oxazolidinone active against MRSA&#44; PRP and enterococcus and has shown high efficacy and safety compared with linezolid in skin and soft tissue infections&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">66</span></a> Although there are no specific studies on pneumococcal infection&#44; tedizolid has an activity up to 4-fold greater than that of linezolid against pneumococcus&#44; including strains resistant to linezolid and penicillin&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">67</span></a> Good pulmonary dissemination has been observed in murine models of pneumococcal infection&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">68</span></a> Clinical trials are currently underway for this indication&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Dalbavancin&#44; oritavancin and telavancin are lipoglycopeptides with activity superior to that of vancomycin against Gram-positive bacteria &#40;MRSA&#44; pneumococcus&#44; enterococcus&#44; coagulase-negative staphylococcus&#41;&#46; Dalbavancin and oritavancin have been studied only in skin and soft tissue infections&#46; Telavancin has been used in ventilator-associated pneumonia&#44; with good preliminary results in MRSA infections&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">69</span></a> Although there are no specific clinical trials with these drugs in IPD&#44; their excellent in vitro activity against pneumococcus indicates that they could be a possible alternative to current treatments&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Vaccines</span><p id="par0120" class="elsevierStylePara elsevierViewall">There are currently 2 types of vaccines against pneumococcus&#46; The advantages of the pneumococcal polysaccharide vaccine &#40;PPSV23&#41; are its larger number of serotypes &#40;around 82&#37; of the strains that produce infection in the population&#41;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> and its easier and more inexpensive production&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">70</span></a> The vaccine was included in the vaccine schedule in Spain starting in 2003 for patients older than 2 years and for those older than 60 years with risk factors &#40;chronic disease&#44; asplenia&#44; renal failure&#44; cirrhosis&#44; diabetes&#44; alcoholism&#44; cerebrospinal fluid fistula&#44; cochlear implants&#44; HIV infection&#44; immunosuppressive therapy and chemotherapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> However&#44; the vaccine does have a number of limitations&#58; &#40;1&#41; The T-cell-independent immune response varies with patient age and comorbidity and is therefore not effective in children<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">72</span></a>&#59; &#40;2&#41; the vaccine does not produce an immunological memory or anamnestic response and does not achieve immune reinforcement with revaccination<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">73</span></a>&#59; and &#40;3&#41; the vaccine presents the phenomenon of immune tolerance or reduced response to revaccination &#40;repeated doses of the vaccine produce a weaker response against most serotypes&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">74</span></a> and its effectiveness reaches only 50&#8211;80&#37;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">75</span></a> and decreases over time&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">76</span></a> Although PPSV23 has been recommended for adults for more than 15 years&#44; the coverage of the at-risk population is very low in our setting&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The pneumococcal conjugate vaccine &#40;PCV&#41; is formed by the binding of the polysaccharide to an antigenic protein&#44; which creates a T-cell-dependent response and confers immunological memory with effective protection in children and immunosuppressed patients&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">70</span></a> After its approval in 2000 for use in the United States in children younger than 2 years&#44; PCV was introduced to Europe in 2001&#46; Initially&#44; PCV7 was employed&#44; which included the 7 most prevalent serotypes in the 1990s&#46; In 2009&#44; PCV10 was introduced&#44; which was substituted in 2010 by the present PCV13 with 13 serotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> In 2011&#44; the American and European pharmaceutical regulatory agencies approved PCV13 for individuals older than 50 years&#44; after the vaccine&#39;s clinical efficacy and safety had been demonstrated&#46; The main advantages of PCV13 are its greater immunogenic response than PPSV23 and its longer duration and memory after the second vaccine dose&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">77&#44;78</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Based on these data&#44; the indications for the pneumococcal vaccination for adults have been reviewed&#44; establishing a sequential strategy in 2 stages&#46; In this manner&#44; the immunogenic advantages of PCV13 are exploited&#44; without losing the broad serotype coverage of PPSV23&#46; The current recommendation is to administer an initial dose of PCV13&#44; followed by a dose of PPSV23&#46; The subsequent administration of PPSV23 could generate an increased response for the common serotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">79</span></a> The current indications from the Spanish scientific societies &#40;2017&#41;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> are listed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0135" class="elsevierStylePara elsevierViewall">IPD is a prevalent disease associated with significant mortality&#46; In recent years&#44; studies have been performed to identify the at-risk population and improve the treatment&#46; Although the scientific evidence is still limited&#44; the current clinical guidelines recommend CT of a beta-lactam and a macrolide for the empiric therapy of pneumococcal pneumonia&#46; Although the antibiotic resistance of pneumococci is a growing problem&#44; there are generally effective therapeutic regimens&#46; In recent years&#44; drugs have been developed that are active against Gram-positive bacteria&#44; whose place in the therapeutic strategy for infections by resistant pneumococci is still uncertain&#46; Conjugate vaccines have provided a considerable benefit in preventing pneumococcal infections&#44; not only in vaccinated individuals but also in the general population&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Prognostic factors of mortality"
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          "titulo" => "Antibiotic resistance &#8211; impact on treatment"
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            0 => "<span class="elsevierStyleItalic">Streptococcus pneumoniae</span>"
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            2 => "Resistance"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Invasive pneumococcal disease is a severe infection that mainly affects patients with associated comorbidity&#46; The pediatric conjugate vaccination has resulted in a change in the adult vaccination strategy&#46; The antibiotic resistance of pneumococcus is not currently a severe problem&#46; Nevertheless&#44; the World Health Organisation has included pneumococcus among the bacteria whose treatment requires the introduction of new drugs&#44; such as ceftaroline and ceftobiprole&#46; Although the scientific evidence is still limited&#44; the combination of beta-lactams and macrolides is recommended as empiric therapy for bacteraemic pneumococcal pneumonia&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad neumoc&#243;cica invasiva es una infecci&#243;n grave que afecta principalmente a pacientes con comorbilidad asociada&#46; El beneficio de la vacuna conjugada infantil ha condicionado un cambio de la estrategia de vacunaci&#243;n en el adulto&#46; La resistencia a antibi&#243;ticos no supone un problema grave en la actualidad&#44; a pesar de lo cual la Organizaci&#243;n Mundial de la Salud ha incluido al neumococo entre las bacterias cuyo tratamiento requiere la introducci&#243;n de nuevos f&#225;rmacos&#44; como ceftarolina y ceftobiprol&#46; Aunque la evidencia cient&#237;fica es todav&#237;a limitada&#44; se recomienda la asociaci&#243;n de betalact&#225;micos y macr&#243;lidos como terapia emp&#237;rica de la neumon&#237;a neumoc&#243;cica bacteri&#233;mica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as&#58; Dom&#237;nguez-Alegr&#237;a AR&#44; Pintado V&#44; Barbolla I&#46; Tratamiento y prevenci&#243;n de la enfermedad neumoc&#243;cica invasiva&#46; Rev Clin Esp&#46; 2018&#59;218&#58;244&#8211;252&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibiotic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Europe<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">United States<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Spain<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">6&#44;38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Penicillin&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#46;9<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cefotaxime&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macrolide&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&#46;4<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinolones&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The isolates in this study come from respiratory samples &#40;37&#46;8&#37;&#41; and blood cultures &#40;62&#46;2&#37;&#41;&#46; The isolates referenced in the other studies come from samples of sterile sites&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Cutoffs used according to EUCAST 2014&#46;</p>"
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              "identificador" => "tblfn0015"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Cutoff used according to the Clinical and Laboratory Standards Institute&#44; 2008&#46;</p>"
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          ]
        ]
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Resistance of pneumococcus to the main antimicrobials&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Use of antibiotics in the previous 3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospitalization in the previous 3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pneumonia in the previous year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nosocomial acquisition<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Institutionalization or stay at a day center&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#60;5 years or &#8805;65 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic obstructive pulmonary disease<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Risk factors for infection by antibiotic-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#46;</p>"
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        "tabla" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author and year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects on mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mufson and Stanek&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">17</span></a> 1999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal bacteremia &#40;mostly with a pulmonary focus&#41;<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>392 &#40;children and adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Benefit of the combinations with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Waterer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">43</span></a> 2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>225 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Benefit in severe pneumonia &#40;Fine IV&#8211;V&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mart&#237;nez et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">44</span></a> 2003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>409 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Greater benefit in severe pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Baddour et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> 2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal bacteremia of any origin<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>844 &#40;older than 15 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; No combination superior to any other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weiss and Tillotson&#44;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">52</span></a> 2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metersky et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2209 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide but not with quinolone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sligl et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">47</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Community-acquired pneumonia in critical patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Harbarth et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">48</span></a> 2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>107 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dwyer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">49</span></a> 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>340 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">50</span></a> 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal pneumonia &#40;with or without bacteremia&#41;<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>638&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&#46; Nonsignificant benefit of quinolone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chokshi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">51</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>189 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="middle">One dose of PCV13 &#40;if they have previously been treated with PPSV23&#44; wait at least 1 year before administering&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Immunodepressed</span><br><span class="elsevierStyleHsp" style=""></span>Hematologic or solid tumor<br><span class="elsevierStyleHsp" style=""></span>Chronic kidney disease &#40;stage IV&#8211;V&#41;<br><span class="elsevierStyleHsp" style=""></span>Transplantation<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a><br><span class="elsevierStyleHsp" style=""></span>Immunosuppressive therapy or chemotherapy<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">e</span></a><br><span class="elsevierStyleHsp" style=""></span>HIV infection<br><span class="elsevierStyleHsp" style=""></span>Inflammatory bowel disease<br><span class="elsevierStyleHsp" style=""></span>Autoimmune disease<br><span class="elsevierStyleHsp" style=""></span>Cerebrospinal fluid fistula<br><span class="elsevierStyleHsp" style=""></span>Cochlear implant<br><span class="elsevierStyleHsp" style=""></span>Anatomical or functional asplenia</td><td class="td" title="table-entry  " align="left" valign="top">No previous vaccination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Previous vaccination with PPSV23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One dose of PCV13&#44; followed by one dose of PPSV23<br>Minimum interval of 8 weeks &#40;optimal period greater than 1 year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">One dose of PCV13 &#40;after at least 1 year of vaccination with PPSV23&#41;&#46; Revaccinate with PPSV23 if 5 or more years have past since the initial dose&#44; up to a maximum of 2 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Serotypes included in each vaccine&#58;</span><br><span class="elsevierStyleHsp" style=""></span>PCV13&#58; 4&#44; 6B&#44; 9V&#44; 14&#44; 18C&#44; 19F and 23F&#44; 1&#44; 5&#44; 7F&#44; 3&#44; 6A&#44; 19A<br><span class="elsevierStyleHsp" style=""></span>PPSV23&#58; 1&#44; 2&#44; 3&#44; 4&#44; 5&#44; 6B&#44; 7F&#44; 8&#44; 9N&#44; 9V&#44; 10A&#44; 11A&#44; 12F&#44; 14&#44; 15B&#44; 17F&#44; 18C&#44; 19A&#44; 19F&#44; 20&#44; 22F&#44; 23F and 33F</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Chronic obstructive pulmonary disease&#44; severe asthma and interstitial lung disease&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a></p>"
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              "identificador" => "tblfn0030"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Ischemic heart disease&#44; valvular heart disease&#44; heart failure&#44; congenital heart disease and stroke&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Active smoker with packets-year index &#40;PYI&#41; &#62;15&#59; ex-smoker of &#60;10 years with PYI &#62;20&#59; active smoker with respiratory disease regardless of PYI&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Patients undergoing treatment with methotrexate&#44; rituximab&#44; abatacept and tocilizumab might require 2 doses or might have to wait 1&#8211;3 months after completing the treatment&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Indications for pneumococcal vaccination in adults&#46;</p>"
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Review
Treatment and prevention of invasive pneumococcal disease
Tratamiento y prevención de la enfermedad neumocócica invasiva
A.R. Domínguez-Alegríaa,
Corresponding author
alegria.rda@gmail.com

Corresponding author.
, V. Pintadob, I. Barbollaa
a Servicio de Medicina Interna, Hospital Ramón y Cajal, Madrid, Spain
b Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
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pneumococcal infection has high morbidity and mortality&#44; especially in patients with certain chronic diseases &#40;heart failure&#44; hepatic cirrhosis&#44; chronic pulmonary disease and diabetes&#41; or risk factors &#40;extreme age&#44; immunosuppression&#44; alcoholism and nicotine addiction&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">According to data from the US Centers for Disease Control&#44; the overall incidence of IPD in the US in 2015 was estimated at 9&#46;2 cases per 100&#44;000 inhabitants&#44; predominantly in children younger than 1 year and adults older than 65 years&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a> These data vary depending on factors such as geographical area&#44; seasonal variation and study population&#46; In 2014&#44; the overall incidence rate per 100&#44;000 inhabitants was 4&#46;8 for Europe and 5&#46;4 for Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent decades&#44; the number of cases of IPD has progressively declined due to the administration of the pneumococcal vaccination in the pediatric immunization schedule&#46; This vaccination has helped reduced the main reservoir of pneumococcus&#58; the airways of children younger than 2 years&#46; By decreasing the reservoir&#44; the vaccine not only decreases the active infection in vaccinated children but also the risk of infection for the unvaccinated population&#44; both pediatric and adult&#44; which is defined as &#8220;herd immunity&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7&#44;8</span></a> In the United States&#44; in particular&#44; it has been estimated that&#44; after the introduction of the conjugate vaccine&#44; there was a 40&#37; reduction in the overall incidence of IPD &#40;73&#37; in children younger than 5 years and 57&#37; in adults older than 65 years&#41;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">8</span></a> and a reduction in nasopharyngeal colonization in more than 50&#37; of unvaccinated individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In Spain&#44; the vaccine also showed a benefit in reducing the incidence of IPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7&#44;10&#44;11</span></a> However&#44; the vaccine&#39;s inclusion in the pediatric immunization calendar differs among autonomous communities&#46; In the Community of Madrid&#44; for example&#44; the vaccine was withdrawn from the calendar in July 2012&#44; which increased the incidence of IPD in the pediatric population from 2&#46;1 in 2012 to 5&#46;4&#47;100&#44;000 inhabitants in 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The vaccine also has a significant effect on controlling the resistance to antibiotics&#44; because numerous serotypes associated with multiresistance are included in the employed vaccines&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7&#44;12</span></a> However&#44; the associated risk is the emergence of other serotypes&#44; a phenomenon known as serotype replacement&#44; which replaces the previous serotypes&#46; Infections caused by nonvaccine strains increased overall&#44; especially in the population older than 65 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13&#8211;15</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Prognostic factors of mortality</span><p id="par0035" class="elsevierStylePara elsevierViewall">Pneumococcal infection causes approximately 1&#46;6 million deaths per year worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a> It is estimated that 10&#8211;15&#37; of adults with IPD die as a result of the infection&#44;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;6&#44;16</span></a> a figure that can reach 20&#8211;30&#37; for the elderly and patients with comorbidities&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">15&#44;17</span></a> Approximately half of the deaths occur in the first 5 days of the infection&#44; despite appropriate&#44; early and effective treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">18</span></a> The elements that influence the development and mortality of the disease depend on the bacteria&#44; host and treatment&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The bacteria-dependent factors include its virulence&#44; invasive capacity and antibiotic resistance mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19&#44;20</span></a> Various studies have demonstrated an association between mortality and the pneumococcal serotype&#44; although the exact mechanism that causes this association has not been clarified&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19&#8211;21</span></a> A Danish cohort<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">21</span></a> that included 18&#44;858 patients observed a 3-fold greater risk associated with certain serotypes &#40;including some emerging replacement serotypes such as 3 and 19F&#41; compared with other less virulent ones such as serotype 1&#46; The capsule&#44; which determines the bacterial serotype&#44; appears to be a determinant both in the invasive capacity and in the virulence&#46; A study using a murine model of meningitis<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">22</span></a> observed an increased release of cytokines and greater tissue destruction associated with a typically colonizer serotype &#40;6B&#41;&#44; compared with a typically invasive serotype &#40;7F&#41;&#46; The difference appears to be due to the greater thickness of the bacterial capsule characteristic of serotype 6B&#44; which leads to an increased inflammatory response and more aggressive infection&#46; Additionally&#44; some colonizing serotypes cause IPD mainly in patients with comorbidity and can therefore behave as opportunistic microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">20</span></a> The bacterial load is also associated with a poorer prognosis&#46; Cill&#243;niz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">23</span></a> observed that the positivity of blood cultures in less than 9&#46;2<span class="elsevierStyleHsp" style=""></span>h was associated with more severe clinical forms&#44; longer hospitalization and increased mortality&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient&#39;s age not only increases the risk of bacteremia but is also a predictor of mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19&#44;20</span></a> It has been observed that every decade of age increases the mortality risk 1&#46;5-fold&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">19</span></a> Furthermore&#44; mortality is increased if there are certain associated diseases&#44; such as immunosuppression secondary to drugs&#44; HIV infection&#44; tumors&#44; heart disease&#44; cerebrovascular disease&#44; chronic liver disease&#44; nicotine addiction and alcoholism&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">5&#44;18&#44;24&#44;25</span></a> Other factors such as the functional state&#44; institutionalization and a high number of comorbidities confer a poorer prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">24</span></a> Moreover&#44; greater clinical severity results in higher mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">20&#44;26&#44;27</span></a> The main factors associated with early mortality are respiratory failure &#40;need for mechanical ventilation&#41;&#44; cardiovascular failure &#40;septic shock&#41; and a low level of consciousness&#44; which seem to be related to an excessive inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antibiotic resistance &#8211; impact on treatment</span><p id="par0050" class="elsevierStylePara elsevierViewall">Penicillin has classically been the first-choice antibiotic for treating pneumococcal infection&#46; In the 1970s&#44; the first strains resistant to beta-lactams and to other antibiotic groups were reported in South Africa&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">29</span></a> In the following years&#44; there was a marked increase in resistance rates&#44; which have decreased significantly since 2008 after the change in the penicillin sensitivity cutoffs by the Clinical and Laboratory Standards Institute&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">30</span></a> This change was performed after confirming that penicillin treatment of respiratory infections caused by strains with reduced penicillin sensitivity was not associated with increased treatment failure&#46; Considering that beta-lactams reach high concentrations in lung tissue&#44; conventional dosages for these drugs are adequate for treating infections by strains with low-level resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">31</span></a> In Europe&#44; the current rates of resistance to penicillin and cephalosporin are estimated at 11&#37; and 6&#37;&#44; respectively&#44; which are somewhat higher than those in the United States &#40;4&#37; and 2&#46;4&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The clinical significance of reduced sensitivity to beta-lactams is a controversial subject&#46; A meta-analysis published in 2006 observed that penicillin resistance was associated with increased mortality in patients hospitalized with pneumococcal pneumonia&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">32</span></a> However&#44; mortality seemed to be related to an increased comorbidity of the patients&#46; Other studies have shown that the clinical importance of resistance depends on the antimicrobial used for treating the pneumococcal infection&#46; Thus&#44; the study by Yu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a> observed that in vitro treatment of pneumococcal bacteremia with inactive drugs was not associated with increased mortality at 14 days when ceftriaxone&#44; cefotaxime or penicillin were used but was associated with increased mortality when cefuroxime was used&#44; which was attributed to the different pharmacodynamics of this antibiotic&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a> Other studies have confirmed that the progression does not worsen in patients treated with adequate dosages of beta-lactams&#44; provided these have high activity against the pneumococcus&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">25&#44;33&#44;34</span></a> Except for meningeal infections&#44; in which antimicrobial dissemination to the cerebrospinal fluid is essential&#44; the intermediate resistance to beta-lactams does not influence mortality&#44; provided appropriate dosages are used&#46; However&#44; high-grade resistance can result in therapeutic failure&#44; especially in meningitis&#46; Penicillin resistance has not been related to more severe clinical forms or to a higher incidence of suppurative complications&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">For macrolides&#44; the resistance rates are quite high&#44; ranging from 20&#37; to 30&#37; in Spain&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">6&#44;11</span></a> Macrolide resistance can be low-grade &#40;using an efflux pump that eliminates the drug&#44; encoded by the <span class="elsevierStyleItalic">mef</span> gene&#41; or high-grade &#40;produced by a change in the bacteria&#39;s conformation&#44; through an RNA methylase&#44; encoded by the <span class="elsevierStyleItalic">erm</span> gene&#41;&#46; The latter mechanism is predominant in Europe&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a> Macrolide resistance is not associated with more severe clinical conditions or a higher rate of suppurative infections&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a> although therapeutic failures have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">36&#44;37</span></a> The clinical guidelines recommend avoiding monotherapy with macrolides in populations with high resistance rates due to the associated high risk of failure&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">With regard to quinolones&#44; the resistance rates remain low &#40;2&#8211;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">38</span></a> Since they are not used in children&#44; the selective pressure on the main reservoir of pneumococcus is lower&#46; Therapeutic failures have been reported in quinolone-resistant bacterial infections&#44; as has the development of resistances during therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">39</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> lists the resistance rates of the main antimicrobials&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Combined resistance to several antibiotics is a growing problem&#46; In a study in the Community of Madrid&#44; 91&#46;7&#37; of the pneumococci with reduced penicillin-sensitivity were erythromycin resistant&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> Multiresistance&#44; defined by resistance to 3 families of antimicrobials&#44; is a growing worldwide problem&#44; with rates reaching 59&#46;3&#37; in a recent study in Asia&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">40</span></a> Although cases of extremely resistant pneumococci have been reported&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">41</span></a> there is practically no resistance to antibiotics such as vancomycin&#44; linezolid and tigecycline&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;6</span></a> The clinical impact of the resistance of pneumococcus is still a limited problem due to the availability of alternative drugs for most clinical conditions&#46; Nevertheless&#44; it is essential to maintain strict epidemiological surveillance that identifies at-risk populations<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">35&#44;42</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; and optimizes the therapeutic strategies&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Treatment of invasive pneumococcal disease</span><p id="par0075" class="elsevierStylePara elsevierViewall">The benefit of empiric combination therapy &#40;CT&#41; using a beta-lactam with macrolides or quinolones for treating IPD is controversial&#46; The rationale for CT is based not only on providing a more potent treatment against resistant pneumococci but also coverage against other microorganisms in mixed respiratory infections&#44; caused by pneumococcus and atypical bacteria&#46; Most studies that compared the efficacy of CT versus monotherapy were observational and were performed on patients with bacteremia secondary to pneumonia&#44; where the impact of resistance is lower than in other infections such as meningitis and endocarditis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17&#44;43&#8211;52</span></a> There appears to be more evidence in favor of CT&#44; especially in severe clinical forms &#40;with septic shock or groups III&#8211;V of the Fine scale&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">43&#44;44</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">There is also no evidence on the best CT regimen&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> However&#44; CT that includes a macrolide has shown a clinical benefit most consistently&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17&#44;44&#44;46&#44;47&#44;52</span></a> This finding is explained by several factors&#58; a broader spectrum of activity &#40;in mixed infections caused by atypical bacteria&#41;&#44; dual or synergistic antibacterial effects and a potential anti-inflammatory or immunomodulatory effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">47&#44;53&#44;54</span></a> Macrolides reduce the formation of proinflammatory cytokines&#44; an essential aspect in severe clinical forms in which an excessive inflammatory response secondary to the infection has been reported&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Studies that have analyzed CT with quinolones have not observed superiority versus the macrolide in reducing mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> Nevertheless&#44; quinolones can be an alternative to macrolides due to the former&#39;s excellent bioavailability&#44; oral formulation and deep coverage against atypical bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">55</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Although there are no specific IPD guidelines&#44; clinical guidelines have been published on therapies for pneumonia and meningitis&#44; as well as recommendations based on expert opinion&#46; As a general rule&#44; the recommended CT for severe pneumococcal pneumonia is a third-generation cephalosporin &#40;cefotaxime or ceftriaxone&#41; and a macrolide &#40;azithromycin or clarithromycin&#41; or&#44; alternatively&#44; a quinolone &#40;levofloxacin or moxifloxacin&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">56&#44;57</span></a> For meningitis&#44; the therapy should include a third-generation cephalosporin combined with vancomycin&#46; Moxifloxacin is an alternative therapy for patients with allergies to beta-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">New antibiotics</span><p id="par0095" class="elsevierStylePara elsevierViewall">Although antibiotic resistance is not currently a severe problem&#44; the World Health Organization has classified penicillin-resistant pneumococci &#40;PRP&#41; among the bacteria that require the introduction of new antibiotics&#44; with a medium priority level&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">59</span></a> In recent years&#44; antibiotics have been developed with activity against Gram-positive bacteria&#44; directed mainly against <span class="elsevierStyleItalic">Staphylococcus aureus</span> and enterococci&#46; These antibiotics have advantages over the current therapeutic arsenal for pneumococcal infection&#46; Ceftaroline and ceftobiprole are 2 new cephalosporins that stand out due to their broad spectrum against Gram-positive bacteria and are active against methicillin-resistant <span class="elsevierStyleItalic">S&#46; aureus</span> &#40;MRSA&#41; and PRP&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Ceftaroline is indicated for treating community-acquired pneumonia &#40;CAP&#41; and skin and soft tissue infections&#44; although it has been used for infectious endocarditis&#44; osteomyelitis and meningitis&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">60</span></a> Ceftaroline&#39;s greater affinity for certain penicillin-binding proteins &#40;PBPs&#41; enables it to overcome the main resistance mechanism of pneumococcus against beta-lactams&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">61</span></a> Ceftaroline&#39;s intrinsic activity is up to 8-fold greater than that of other cephalosporins&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">62</span></a> The efficacy of ceftaroline in treating CAP &#40;groups III&#8211;IV of the Fine scale&#41; has been assessed in the FOCUS clinical trials&#44; with a superior clinical response to that of ceftriaxone &#40;85&#46;5&#37; vs&#46; 68&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> In the patient subgroup with pneumococcal bacteremia&#44; the efficacy of ceftaroline was superior to that of ceftriaxone &#40;78&#46;9&#37; vs&#46; 66&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> These trials used a lower dosage of ceftriaxone &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41; than that typically recommended &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41;&#46; New clinical trials comparing ceftaroline with ceftriaxone at full dosages are therefore needed to establish its actual clinical efficacy&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Ceftobiprole is active against MRSA and PRP&#44; with an activity similar to that of cefepime&#44; ceftazidime and piperacillin-tazobactam against Gram-negative bacteria&#46; Ceftobiprole&#39;s considerable affinity for PBP-2 makes it a potentially effective antibiotic against PRP and ceftriaxone-resistant bacteria&#46; Two clinical trials have evaluated the efficacy of ceftobiprole in CAP and nosocomial pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">64&#44;65</span></a> Both trials observed that ceftobiprole was not inferior to the comparator &#40;ceftriaxone and linezolid in CAP&#59; and ceftazidime and linezolid in nosocomial pneumonia&#41;&#46; However&#44; the efficacy of ceftobiprole was inferior in the patient subgroup with ventilator-associated pneumonia &#40;38&#46;5&#37; vs&#46; 56&#46;7&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">65</span></a> which seems to be due to a change in the drug&#39;s volume of distribution in this patient subgroup&#46; Therefore&#44; ceftobiprole is indicated for treating CAP and nosocomial pneumonia not associated with mechanical ventilation&#44; although the drug is still not marketed in Spain&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Tedizolid is an oxazolidinone active against MRSA&#44; PRP and enterococcus and has shown high efficacy and safety compared with linezolid in skin and soft tissue infections&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">66</span></a> Although there are no specific studies on pneumococcal infection&#44; tedizolid has an activity up to 4-fold greater than that of linezolid against pneumococcus&#44; including strains resistant to linezolid and penicillin&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">67</span></a> Good pulmonary dissemination has been observed in murine models of pneumococcal infection&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">68</span></a> Clinical trials are currently underway for this indication&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Dalbavancin&#44; oritavancin and telavancin are lipoglycopeptides with activity superior to that of vancomycin against Gram-positive bacteria &#40;MRSA&#44; pneumococcus&#44; enterococcus&#44; coagulase-negative staphylococcus&#41;&#46; Dalbavancin and oritavancin have been studied only in skin and soft tissue infections&#46; Telavancin has been used in ventilator-associated pneumonia&#44; with good preliminary results in MRSA infections&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">69</span></a> Although there are no specific clinical trials with these drugs in IPD&#44; their excellent in vitro activity against pneumococcus indicates that they could be a possible alternative to current treatments&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Vaccines</span><p id="par0120" class="elsevierStylePara elsevierViewall">There are currently 2 types of vaccines against pneumococcus&#46; The advantages of the pneumococcal polysaccharide vaccine &#40;PPSV23&#41; are its larger number of serotypes &#40;around 82&#37; of the strains that produce infection in the population&#41;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> and its easier and more inexpensive production&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">70</span></a> The vaccine was included in the vaccine schedule in Spain starting in 2003 for patients older than 2 years and for those older than 60 years with risk factors &#40;chronic disease&#44; asplenia&#44; renal failure&#44; cirrhosis&#44; diabetes&#44; alcoholism&#44; cerebrospinal fluid fistula&#44; cochlear implants&#44; HIV infection&#44; immunosuppressive therapy and chemotherapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> However&#44; the vaccine does have a number of limitations&#58; &#40;1&#41; The T-cell-independent immune response varies with patient age and comorbidity and is therefore not effective in children<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">72</span></a>&#59; &#40;2&#41; the vaccine does not produce an immunological memory or anamnestic response and does not achieve immune reinforcement with revaccination<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">73</span></a>&#59; and &#40;3&#41; the vaccine presents the phenomenon of immune tolerance or reduced response to revaccination &#40;repeated doses of the vaccine produce a weaker response against most serotypes&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">74</span></a> and its effectiveness reaches only 50&#8211;80&#37;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">75</span></a> and decreases over time&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">76</span></a> Although PPSV23 has been recommended for adults for more than 15 years&#44; the coverage of the at-risk population is very low in our setting&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The pneumococcal conjugate vaccine &#40;PCV&#41; is formed by the binding of the polysaccharide to an antigenic protein&#44; which creates a T-cell-dependent response and confers immunological memory with effective protection in children and immunosuppressed patients&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">70</span></a> After its approval in 2000 for use in the United States in children younger than 2 years&#44; PCV was introduced to Europe in 2001&#46; Initially&#44; PCV7 was employed&#44; which included the 7 most prevalent serotypes in the 1990s&#46; In 2009&#44; PCV10 was introduced&#44; which was substituted in 2010 by the present PCV13 with 13 serotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> In 2011&#44; the American and European pharmaceutical regulatory agencies approved PCV13 for individuals older than 50 years&#44; after the vaccine&#39;s clinical efficacy and safety had been demonstrated&#46; The main advantages of PCV13 are its greater immunogenic response than PPSV23 and its longer duration and memory after the second vaccine dose&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">77&#44;78</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Based on these data&#44; the indications for the pneumococcal vaccination for adults have been reviewed&#44; establishing a sequential strategy in 2 stages&#46; In this manner&#44; the immunogenic advantages of PCV13 are exploited&#44; without losing the broad serotype coverage of PPSV23&#46; The current recommendation is to administer an initial dose of PCV13&#44; followed by a dose of PPSV23&#46; The subsequent administration of PPSV23 could generate an increased response for the common serotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">79</span></a> The current indications from the Spanish scientific societies &#40;2017&#41;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> are listed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0135" class="elsevierStylePara elsevierViewall">IPD is a prevalent disease associated with significant mortality&#46; In recent years&#44; studies have been performed to identify the at-risk population and improve the treatment&#46; Although the scientific evidence is still limited&#44; the current clinical guidelines recommend CT of a beta-lactam and a macrolide for the empiric therapy of pneumococcal pneumonia&#46; Although the antibiotic resistance of pneumococci is a growing problem&#44; there are generally effective therapeutic regimens&#46; In recent years&#44; drugs have been developed that are active against Gram-positive bacteria&#44; whose place in the therapeutic strategy for infections by resistant pneumococci is still uncertain&#46; Conjugate vaccines have provided a considerable benefit in preventing pneumococcal infections&#44; not only in vaccinated individuals but also in the general population&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1032087"
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        1 => array:2 [
          "identificador" => "xpalclavsec989120"
          "titulo" => "Keywords"
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          "titulo" => "Epidemiology"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Prognostic factors of mortality"
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          "identificador" => "sec0015"
          "titulo" => "Antibiotic resistance &#8211; impact on treatment"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Treatment of invasive pneumococcal disease"
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          "identificador" => "sec0025"
          "titulo" => "New antibiotics"
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          "identificador" => "sec0030"
          "titulo" => "Vaccines"
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    "fechaRecibido" => "2017-10-09"
    "fechaAceptado" => "2018-01-04"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Invasive pneumococcal disease is a severe infection that mainly affects patients with associated comorbidity&#46; The pediatric conjugate vaccination has resulted in a change in the adult vaccination strategy&#46; The antibiotic resistance of pneumococcus is not currently a severe problem&#46; Nevertheless&#44; the World Health Organisation has included pneumococcus among the bacteria whose treatment requires the introduction of new drugs&#44; such as ceftaroline and ceftobiprole&#46; Although the scientific evidence is still limited&#44; the combination of beta-lactams and macrolides is recommended as empiric therapy for bacteraemic pneumococcal pneumonia&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad neumoc&#243;cica invasiva es una infecci&#243;n grave que afecta principalmente a pacientes con comorbilidad asociada&#46; El beneficio de la vacuna conjugada infantil ha condicionado un cambio de la estrategia de vacunaci&#243;n en el adulto&#46; La resistencia a antibi&#243;ticos no supone un problema grave en la actualidad&#44; a pesar de lo cual la Organizaci&#243;n Mundial de la Salud ha incluido al neumococo entre las bacterias cuyo tratamiento requiere la introducci&#243;n de nuevos f&#225;rmacos&#44; como ceftarolina y ceftobiprol&#46; Aunque la evidencia cient&#237;fica es todav&#237;a limitada&#44; se recomienda la asociaci&#243;n de betalact&#225;micos y macr&#243;lidos como terapia emp&#237;rica de la neumon&#237;a neumoc&#243;cica bacteri&#233;mica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as&#58; Dom&#237;nguez-Alegr&#237;a AR&#44; Pintado V&#44; Barbolla I&#46; Tratamiento y prevenci&#243;n de la enfermedad neumoc&#243;cica invasiva&#46; Rev Clin Esp&#46; 2018&#59;218&#58;244&#8211;252&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibiotic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Europe<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">United States<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Spain<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">6&#44;38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Penicillin&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#46;9<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cefotaxime&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macrolide&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&#46;4<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinolones&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The isolates in this study come from respiratory samples &#40;37&#46;8&#37;&#41; and blood cultures &#40;62&#46;2&#37;&#41;&#46; The isolates referenced in the other studies come from samples of sterile sites&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Resistance of pneumococcus to the main antimicrobials&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Use of antibiotics in the previous 3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospitalization in the previous 3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pneumonia in the previous year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nosocomial acquisition<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Institutionalization or stay at a day center&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#60;5 years or &#8805;65 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic obstructive pulmonary disease<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Risk factors for infection by antibiotic-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#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" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author and year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects on mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mufson and Stanek&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">17</span></a> 1999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal bacteremia &#40;mostly with a pulmonary focus&#41;<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>392 &#40;children and adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Benefit of the combinations with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Waterer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">43</span></a> 2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>225 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Benefit in severe pneumonia &#40;Fine IV&#8211;V&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mart&#237;nez et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">44</span></a> 2003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>409 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; Greater benefit in severe pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Baddour et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> 2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal bacteremia of any origin<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>844 &#40;older than 15 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction&#46; No combination superior to any other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weiss and Tillotson&#44;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">52</span></a> 2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metersky et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2209 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide but not with quinolone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sligl et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">47</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Community-acquired pneumonia in critical patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the group with the combined treatment with macrolide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Harbarth et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">48</span></a> 2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>107 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dwyer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">49</span></a> 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>340 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">50</span></a> 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumococcal pneumonia &#40;with or without bacteremia&#41;<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>638&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&#46; Nonsignificant benefit of quinolone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chokshi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">51</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational retrospective<br>Multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteremic pneumococcal pneumonia<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>189 &#40;adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No difference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Influence of combined antibiotic therapy on mortality in pneumococcal infections&#46;</p>"
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        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at4"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Vaccination schedule</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Immunocompetent</span><br><span class="elsevierStyleHsp" style=""></span>Chronic respiratory disease<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a><br><span class="elsevierStyleHsp" style=""></span>Chronic liver disease<br><span class="elsevierStyleHsp" style=""></span>Cardiovascular disease<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a><br><span class="elsevierStyleHsp" style=""></span>Diabetes<br><span class="elsevierStyleHsp" style=""></span>Smoking<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">c</span></a><br><span class="elsevierStyleHsp" style=""></span>Alcoholism<br><span class="elsevierStyleHsp" style=""></span>Previous IPD<br><span class="elsevierStyleHsp" style=""></span>&#8805;65 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="middle">One dose of PCV13 &#40;if they have previously been treated with PPSV23&#44; wait at least 1 year before administering&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Immunodepressed</span><br><span class="elsevierStyleHsp" style=""></span>Hematologic or solid tumor<br><span class="elsevierStyleHsp" style=""></span>Chronic kidney disease &#40;stage IV&#8211;V&#41;<br><span class="elsevierStyleHsp" style=""></span>Transplantation<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a><br><span class="elsevierStyleHsp" style=""></span>Immunosuppressive therapy or chemotherapy<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">e</span></a><br><span class="elsevierStyleHsp" style=""></span>HIV infection<br><span class="elsevierStyleHsp" style=""></span>Inflammatory bowel disease<br><span class="elsevierStyleHsp" style=""></span>Autoimmune disease<br><span class="elsevierStyleHsp" style=""></span>Cerebrospinal fluid fistula<br><span class="elsevierStyleHsp" style=""></span>Cochlear implant<br><span class="elsevierStyleHsp" style=""></span>Anatomical or functional asplenia</td><td class="td" title="table-entry  " align="left" valign="top">No previous vaccination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Previous vaccination with PPSV23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One dose of PCV13&#44; followed by one dose of PPSV23<br>Minimum interval of 8 weeks &#40;optimal period greater than 1 year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">One dose of PCV13 &#40;after at least 1 year of vaccination with PPSV23&#41;&#46; Revaccinate with PPSV23 if 5 or more years have past since the initial dose&#44; up to a maximum of 2 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Serotypes included in each vaccine&#58;</span><br><span class="elsevierStyleHsp" style=""></span>PCV13&#58; 4&#44; 6B&#44; 9V&#44; 14&#44; 18C&#44; 19F and 23F&#44; 1&#44; 5&#44; 7F&#44; 3&#44; 6A&#44; 19A<br><span class="elsevierStyleHsp" style=""></span>PPSV23&#58; 1&#44; 2&#44; 3&#44; 4&#44; 5&#44; 6B&#44; 7F&#44; 8&#44; 9N&#44; 9V&#44; 10A&#44; 11A&#44; 12F&#44; 14&#44; 15B&#44; 17F&#44; 18C&#44; 19A&#44; 19F&#44; 20&#44; 22F&#44; 23F and 33F</td></tr></tbody></table>
                  """
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          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Chronic obstructive pulmonary disease&#44; severe asthma and interstitial lung disease&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a></p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Ischemic heart disease&#44; valvular heart disease&#44; heart failure&#44; congenital heart disease and stroke&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Active smoker with packets-year index &#40;PYI&#41; &#62;15&#59; ex-smoker of &#60;10 years with PYI &#62;20&#59; active smoker with respiratory disease regardless of PYI&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Patients with hematopoietic cell transplants should be administered 4 doses of PCV13 &#40;starting 3&#8211;6 months after the transplantation&#44; first 3 doses at 1-month intervals and the fourth at 6 months after the third dose&#41;&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Patients undergoing treatment with methotrexate&#44; rituximab&#44; abatacept and tocilizumab might require 2 doses or might have to wait 1&#8211;3 months after completing the treatment&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Indications for pneumococcal vaccination in adults&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:79 [
            0 => array:3 [
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                    0 => array:2 [
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                  "host" => array:1 [
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                      "titulo" => "Epidemiology of invasive pneumococcal infections&#58; manifestations&#44; incidence and case fatality rate correlated to age&#44; gender and risk factors"
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                        0 => array:2 [
                          "etal" => true
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                            2 => "R&#46; Andersson"
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            2 => array:3 [
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              "etiqueta" => "3"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Caracter&#237;sticas cl&#237;nicas y microbiol&#243;gicas de las manifestaciones inusuales de la enfermedad invasiva neumoc&#243;cica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "A&#46; Sousa"
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                            2 => "A&#46; Nodar"
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            3 => array:3 [
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                          "etal" => false
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                  "host" => array:1 [
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                      "Revista" => array:6 [
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            4 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "5"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Which individuals are at increased risk of pneumococcal disease and why&#63; Impact of COPD&#44; asthma&#44; smoking&#44; diabetes&#44; and&#47;or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Torres"
                            1 => "F&#46; Blasi"
                            2 => "N&#46; Dartois"
                            3 => "M&#46; Akova"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thoraxjnl-2015-206780"
                      "Revista" => array:6 [
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                        "fecha" => "2015"
                        "volumen" => "70"
                        "paginaInicial" => "984"
                        "paginaFinal" => "989"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26219979"
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            5 => array:3 [
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              "etiqueta" => "6"
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                      "titulo" => "Invasive pneumococcal disease &#8211; annual epidemiological report 2016 &#91;2014 data&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
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Original language: English
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