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Domínguez-Alegría, V. Pintado, I. Barbolla" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A.R." "apellidos" => "Domínguez-Alegría" "email" => array:1 [ 0 => "alegria.rda@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "V." "apellidos" => "Pintado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "I." "apellidos" => "Barbolla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Ramón y Cajal, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento y prevención de la enfermedad neumocócica invasiva" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Invasive pneumococcal disease (IPD) is defined as an infectious process in which the microorganism is isolated in a sterile territory (e.g., blood, cerebrospinal fluid, pleural fluid). Pneumonia is the most common clinical form (68–80%), followed by primary bacteremia and meningitis.<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1,2</span></a> Other less common clinical conditions include osteomyelitis, peritonitis and endocarditis. These less common forms usually appear in patients with associated comorbidity and are caused by strains not included in the vaccine components, which have greater resistance.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Currently, pneumococcal infection has high morbidity and mortality, especially in patients with certain chronic diseases (heart failure, hepatic cirrhosis, chronic pulmonary disease and diabetes) or risk factors (extreme age, immunosuppression, alcoholism and nicotine addiction).<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2,4,5</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, the overall incidence of IPD in the US in 2015 was estimated at 9.2 cases per 100,000 inhabitants, predominantly in children younger than 1 year and adults older than 65 years.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a> These data vary depending on factors such as geographical area, seasonal variation and study population. In 2014, the overall incidence rate per 100,000 inhabitants was 4.8 for Europe and 5.4 for Spain.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent decades, the number of cases of IPD has progressively declined due to the administration of the pneumococcal vaccination in the pediatric immunization schedule. This vaccination has helped reduced the main reservoir of pneumococcus: the airways of children younger than 2 years. By decreasing the reservoir, the vaccine not only decreases the active infection in vaccinated children but also the risk of infection for the unvaccinated population, both pediatric and adult, which is defined as “herd immunity”.<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7,8</span></a> In the United States, in particular, it has been estimated that, after the introduction of the conjugate vaccine, there was a 40% reduction in the overall incidence of IPD (73% in children younger than 5 years and 57% in adults older than 65 years)<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">8</span></a> and a reduction in nasopharyngeal colonization in more than 50% of unvaccinated individuals.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In Spain, the vaccine also showed a benefit in reducing the incidence of IPD.<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7,10,11</span></a> However, the vaccine's inclusion in the pediatric immunization calendar differs among autonomous communities. In the Community of Madrid, for example, the vaccine was withdrawn from the calendar in July 2012, which increased the incidence of IPD in the pediatric population from 2.1 in 2012 to 5.4/100,000 inhabitants in 2014.<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, because numerous serotypes associated with multiresistance are included in the employed vaccines.<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">7,12</span></a> However, the associated risk is the emergence of other serotypes, a phenomenon known as serotype replacement, which replaces the previous serotypes. Infections caused by nonvaccine strains increased overall, especially in the population older than 65 years.<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13–15</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 1.6 million deaths per year worldwide.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">6</span></a> It is estimated that 10–15% of adults with IPD die as a result of the infection,<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2,6,16</span></a> a figure that can reach 20–30% for the elderly and patients with comorbidities.<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">15,17</span></a> Approximately half of the deaths occur in the first 5 days of the infection, despite appropriate, early and effective treatment.<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, host and treatment.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The bacteria-dependent factors include its virulence, invasive capacity and antibiotic resistance mechanisms.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19,20</span></a> Various studies have demonstrated an association between mortality and the pneumococcal serotype, although the exact mechanism that causes this association has not been clarified.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19–21</span></a> A Danish cohort<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">21</span></a> that included 18,858 patients observed a 3-fold greater risk associated with certain serotypes (including some emerging replacement serotypes such as 3 and 19F) compared with other less virulent ones such as serotype 1. The capsule, which determines the bacterial serotype, appears to be a determinant both in the invasive capacity and in the virulence. 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 (6B), compared with a typically invasive serotype (7F). The difference appears to be due to the greater thickness of the bacterial capsule characteristic of serotype 6B, which leads to an increased inflammatory response and more aggressive infection. Additionally, some colonizing serotypes cause IPD mainly in patients with comorbidity and can therefore behave as opportunistic microorganisms.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">20</span></a> The bacterial load is also associated with a poorer prognosis. Cillóniz et al.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">23</span></a> observed that the positivity of blood cultures in less than 9.2<span class="elsevierStyleHsp" style=""></span>h was associated with more severe clinical forms, longer hospitalization and increased mortality.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient's age not only increases the risk of bacteremia but is also a predictor of mortality.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">19,20</span></a> It has been observed that every decade of age increases the mortality risk 1.5-fold.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">19</span></a> Furthermore, mortality is increased if there are certain associated diseases, such as immunosuppression secondary to drugs, HIV infection, tumors, heart disease, cerebrovascular disease, chronic liver disease, nicotine addiction and alcoholism.<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">5,18,24,25</span></a> Other factors such as the functional state, institutionalization and a high number of comorbidities confer a poorer prognosis.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">24</span></a> Moreover, greater clinical severity results in higher mortality.<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">20,26,27</span></a> The main factors associated with early mortality are respiratory failure (need for mechanical ventilation), cardiovascular failure (septic shock) and a low level of consciousness, which seem to be related to an excessive inflammatory response.<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 – impact on treatment</span><p id="par0050" class="elsevierStylePara elsevierViewall">Penicillin has classically been the first-choice antibiotic for treating pneumococcal infection. In the 1970s, the first strains resistant to beta-lactams and to other antibiotic groups were reported in South Africa.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">29</span></a> In the following years, there was a marked increase in resistance rates, which have decreased significantly since 2008 after the change in the penicillin sensitivity cutoffs by the Clinical and Laboratory Standards Institute.<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. Considering that beta-lactams reach high concentrations in lung tissue, conventional dosages for these drugs are adequate for treating infections by strains with low-level resistance.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">31</span></a> In Europe, the current rates of resistance to penicillin and cephalosporin are estimated at 11% and 6%, respectively, which are somewhat higher than those in the United States (4% and 2.4%).<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1,6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The clinical significance of reduced sensitivity to beta-lactams is a controversial subject. A meta-analysis published in 2006 observed that penicillin resistance was associated with increased mortality in patients hospitalized with pneumococcal pneumonia.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">32</span></a> However, mortality seemed to be related to an increased comorbidity of the patients. Other studies have shown that the clinical importance of resistance depends on the antimicrobial used for treating the pneumococcal infection. Thus, the study by Yu et al.<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, cefotaxime or penicillin were used but was associated with increased mortality when cefuroxime was used, which was attributed to the different pharmacodynamics of this antibiotic.<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, provided these have high activity against the pneumococcus.<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">25,33,34</span></a> Except for meningeal infections, in which antimicrobial dissemination to the cerebrospinal fluid is essential, the intermediate resistance to beta-lactams does not influence mortality, provided appropriate dosages are used. However, high-grade resistance can result in therapeutic failure, especially in meningitis. Penicillin resistance has not been related to more severe clinical forms or to a higher incidence of suppurative complications.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">For macrolides, the resistance rates are quite high, ranging from 20% to 30% in Spain.<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">6,11</span></a> Macrolide resistance can be low-grade (using an efflux pump that eliminates the drug, encoded by the <span class="elsevierStyleItalic">mef</span> gene) or high-grade (produced by a change in the bacteria's conformation, through an RNA methylase, encoded by the <span class="elsevierStyleItalic">erm</span> gene). The latter mechanism is predominant in Europe.<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,<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a> although therapeutic failures have been reported.<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">36,37</span></a> The clinical guidelines recommend avoiding monotherapy with macrolides in populations with high resistance rates due to the associated high risk of failure.</p><p id="par0065" class="elsevierStylePara elsevierViewall">With regard to quinolones, the resistance rates remain low (2–3%).<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">38</span></a> Since they are not used in children, the selective pressure on the main reservoir of pneumococcus is lower. Therapeutic failures have been reported in quinolone-resistant bacterial infections, as has the development of resistances during therapy.<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.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Combined resistance to several antibiotics is a growing problem. In a study in the Community of Madrid, 91.7% of the pneumococci with reduced penicillin-sensitivity were erythromycin resistant.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> Multiresistance, defined by resistance to 3 families of antimicrobials, is a growing worldwide problem, with rates reaching 59.3% in a recent study in Asia.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">40</span></a> Although cases of extremely resistant pneumococci have been reported,<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">41</span></a> there is practically no resistance to antibiotics such as vancomycin, linezolid and tigecycline.<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1,6</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. Nevertheless, it is essential to maintain strict epidemiological surveillance that identifies at-risk populations<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">35,42</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) and optimizes the therapeutic strategies.</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 (CT) using a beta-lactam with macrolides or quinolones for treating IPD is controversial. 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, caused by pneumococcus and atypical bacteria. Most studies that compared the efficacy of CT versus monotherapy were observational and were performed on patients with bacteremia secondary to pneumonia, where the impact of resistance is lower than in other infections such as meningitis and endocarditis (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17,43–52</span></a> There appears to be more evidence in favor of CT, especially in severe clinical forms (with septic shock or groups III–V of the Fine scale).<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">43,44</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">There is also no evidence on the best CT regimen.<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> However, CT that includes a macrolide has shown a clinical benefit most consistently.<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">17,44,46,47,52</span></a> This finding is explained by several factors: a broader spectrum of activity (in mixed infections caused by atypical bacteria), dual or synergistic antibacterial effects and a potential anti-inflammatory or immunomodulatory effect.<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">47,53,54</span></a> Macrolides reduce the formation of proinflammatory cytokines, an essential aspect in severe clinical forms in which an excessive inflammatory response secondary to the infection has been reported.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Studies that have analyzed CT with quinolones have not observed superiority versus the macrolide in reducing mortality.<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> Nevertheless, quinolones can be an alternative to macrolides due to the former's excellent bioavailability, oral formulation and deep coverage against atypical bacteria.<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, clinical guidelines have been published on therapies for pneumonia and meningitis, as well as recommendations based on expert opinion. As a general rule, the recommended CT for severe pneumococcal pneumonia is a third-generation cephalosporin (cefotaxime or ceftriaxone) and a macrolide (azithromycin or clarithromycin) or, alternatively, a quinolone (levofloxacin or moxifloxacin).<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">56,57</span></a> For meningitis, the therapy should include a third-generation cephalosporin combined with vancomycin. Moxifloxacin is an alternative therapy for patients with allergies to beta-lactams.<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, the World Health Organization has classified penicillin-resistant pneumococci (PRP) among the bacteria that require the introduction of new antibiotics, with a medium priority level.<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">59</span></a> In recent years, antibiotics have been developed with activity against Gram-positive bacteria, directed mainly against <span class="elsevierStyleItalic">Staphylococcus aureus</span> and enterococci. These antibiotics have advantages over the current therapeutic arsenal for pneumococcal infection. 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. aureus</span> (MRSA) and PRP.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Ceftaroline is indicated for treating community-acquired pneumonia (CAP) and skin and soft tissue infections, although it has been used for infectious endocarditis, osteomyelitis and meningitis.<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">60</span></a> Ceftaroline's greater affinity for certain penicillin-binding proteins (PBPs) enables it to overcome the main resistance mechanism of pneumococcus against beta-lactams.<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">61</span></a> Ceftaroline's intrinsic activity is up to 8-fold greater than that of other cephalosporins.<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">62</span></a> The efficacy of ceftaroline in treating CAP (groups III–IV of the Fine scale) has been assessed in the FOCUS clinical trials, with a superior clinical response to that of ceftriaxone (85.5% vs. 68.6%).<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> In the patient subgroup with pneumococcal bacteremia, the efficacy of ceftaroline was superior to that of ceftriaxone (78.9% vs. 66.7%).<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a> These trials used a lower dosage of ceftriaxone (1<span class="elsevierStyleHsp" style=""></span>g/day) than that typically recommended (2<span class="elsevierStyleHsp" style=""></span>g/day). New clinical trials comparing ceftaroline with ceftriaxone at full dosages are therefore needed to establish its actual clinical efficacy.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Ceftobiprole is active against MRSA and PRP, with an activity similar to that of cefepime, ceftazidime and piperacillin-tazobactam against Gram-negative bacteria. Ceftobiprole's considerable affinity for PBP-2 makes it a potentially effective antibiotic against PRP and ceftriaxone-resistant bacteria. Two clinical trials have evaluated the efficacy of ceftobiprole in CAP and nosocomial pneumonia.<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">64,65</span></a> Both trials observed that ceftobiprole was not inferior to the comparator (ceftriaxone and linezolid in CAP; and ceftazidime and linezolid in nosocomial pneumonia). However, the efficacy of ceftobiprole was inferior in the patient subgroup with ventilator-associated pneumonia (38.5% vs. 56.7%),<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">65</span></a> which seems to be due to a change in the drug's volume of distribution in this patient subgroup. Therefore, ceftobiprole is indicated for treating CAP and nosocomial pneumonia not associated with mechanical ventilation, although the drug is still not marketed in Spain.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Tedizolid is an oxazolidinone active against MRSA, PRP and enterococcus and has shown high efficacy and safety compared with linezolid in skin and soft tissue infections.<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">66</span></a> Although there are no specific studies on pneumococcal infection, tedizolid has an activity up to 4-fold greater than that of linezolid against pneumococcus, including strains resistant to linezolid and penicillin.<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">67</span></a> Good pulmonary dissemination has been observed in murine models of pneumococcal infection.<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">68</span></a> Clinical trials are currently underway for this indication.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Dalbavancin, oritavancin and telavancin are lipoglycopeptides with activity superior to that of vancomycin against Gram-positive bacteria (MRSA, pneumococcus, enterococcus, coagulase-negative staphylococcus). Dalbavancin and oritavancin have been studied only in skin and soft tissue infections. Telavancin has been used in ventilator-associated pneumonia, with good preliminary results in MRSA infections.<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">69</span></a> Although there are no specific clinical trials with these drugs in IPD, their excellent in vitro activity against pneumococcus indicates that they could be a possible alternative to current treatments.</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. The advantages of the pneumococcal polysaccharide vaccine (PPSV23) are its larger number of serotypes (around 82% of the strains that produce infection in the population)<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> and its easier and more inexpensive production.<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 (chronic disease, asplenia, renal failure, cirrhosis, diabetes, alcoholism, cerebrospinal fluid fistula, cochlear implants, HIV infection, immunosuppressive therapy and chemotherapy).<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> However, the vaccine does have a number of limitations: (1) 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>; (2) 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>; and (3) the vaccine presents the phenomenon of immune tolerance or reduced response to revaccination (repeated doses of the vaccine produce a weaker response against most serotypes),<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">74</span></a> and its effectiveness reaches only 50–80%<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">75</span></a> and decreases over time.<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">76</span></a> Although PPSV23 has been recommended for adults for more than 15 years, the coverage of the at-risk population is very low in our setting.<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The pneumococcal conjugate vaccine (PCV) is formed by the binding of the polysaccharide to an antigenic protein, which creates a T-cell-dependent response and confers immunological memory with effective protection in children and immunosuppressed patients.<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, PCV was introduced to Europe in 2001. Initially, PCV7 was employed, which included the 7 most prevalent serotypes in the 1990s. In 2009, PCV10 was introduced, which was substituted in 2010 by the present PCV13 with 13 serotypes.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> In 2011, the American and European pharmaceutical regulatory agencies approved PCV13 for individuals older than 50 years, after the vaccine's clinical efficacy and safety had been demonstrated. The main advantages of PCV13 are its greater immunogenic response than PPSV23 and its longer duration and memory after the second vaccine dose.<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">77,78</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Based on these data, the indications for the pneumococcal vaccination for adults have been reviewed, establishing a sequential strategy in 2 stages. In this manner, the immunogenic advantages of PCV13 are exploited, without losing the broad serotype coverage of PPSV23. The current recommendation is to administer an initial dose of PCV13, followed by a dose of PPSV23. The subsequent administration of PPSV23 could generate an increased response for the common serotypes.<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">79</span></a> The current indications from the Spanish scientific societies (2017)<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> are listed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.</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. In recent years, studies have been performed to identify the at-risk population and improve the treatment. Although the scientific evidence is still limited, the current clinical guidelines recommend CT of a beta-lactam and a macrolide for the empiric therapy of pneumococcal pneumonia. Although the antibiotic resistance of pneumococci is a growing problem, there are generally effective therapeutic regimens. In recent years, drugs have been developed that are active against Gram-positive bacteria, whose place in the therapeutic strategy for infections by resistant pneumococci is still uncertain. Conjugate vaccines have provided a considerable benefit in preventing pneumococcal infections, not only in vaccinated individuals but also in the general population.</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1032087" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec989120" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1032088" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec989119" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Epidemiology" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Prognostic factors of mortality" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Antibiotic resistance – impact on treatment" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Treatment of invasive pneumococcal disease" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "New antibiotics" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Vaccines" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusion" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-10-09" "fechaAceptado" => "2018-01-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec989120" "palabras" => array:5 [ 0 => "<span class="elsevierStyleItalic">Streptococcus pneumoniae</span>" 1 => "Invasive pneumococcal disease" 2 => "Resistance" 3 => "Combined therapy" 4 => "Vaccine" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec989119" "palabras" => array:5 [ 0 => "<span class="elsevierStyleItalic">Streptococcus pneumoniae</span>" 1 => "Enfermedad neumocócica invasiva" 2 => "Resistencia" 3 => "Terapia combinada" 4 => "Vacuna" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "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. The pediatric conjugate vaccination has resulted in a change in the adult vaccination strategy. The antibiotic resistance of pneumococcus is not currently a severe problem. Nevertheless, the World Health Organisation has included pneumococcus among the bacteria whose treatment requires the introduction of new drugs, such as ceftaroline and ceftobiprole. Although the scientific evidence is still limited, the combination of beta-lactams and macrolides is recommended as empiric therapy for bacteraemic pneumococcal pneumonia.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad neumocócica invasiva es una infección grave que afecta principalmente a pacientes con comorbilidad asociada. El beneficio de la vacuna conjugada infantil ha condicionado un cambio de la estrategia de vacunación en el adulto. La resistencia a antibióticos no supone un problema grave en la actualidad, a pesar de lo cual la Organización Mundial de la Salud ha incluido al neumococo entre las bacterias cuyo tratamiento requiere la introducción de nuevos fármacos, como ceftarolina y ceftobiprol. Aunque la evidencia científica es todavía limitada, se recomienda la asociación de betalactámicos y macrólidos como terapia empírica de la neumonía neumocócica bacteriémica.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as: Domínguez-Alegría AR, Pintado V, Barbolla I. Tratamiento y prevención de la enfermedad neumocócica invasiva. Rev Clin Esp. 2018;218:244–252.</p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibiotic \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> \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> \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">6,38</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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, % \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27.9<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \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, % \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \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, % \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30.4<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \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> \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, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1757296.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The isolates in this study come from respiratory samples (37.8%) and blood cultures (62.2%). The isolates referenced in the other studies come from samples of sterile sites.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Cutoffs used according to EUCAST 2014.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Cutoff used according to the Clinical and Laboratory Standards Institute, 2008.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Resistance of pneumococcus to the main antimicrobials.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><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 \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 \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 \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> \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 \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 <5 years or ≥65 years \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> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1757295.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Risk factor especially for quinolone resistance.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Risk factors for infection by antibiotic-resistant <span class="elsevierStyleItalic">S. pneumoniae</span>.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author and year \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 \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 \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"> \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 \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,<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">17</span></a> 1999 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pneumococcal bacteremia (mostly with a pulmonary focus)<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>392 (children and adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction. Benefit of the combinations with macrolide \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.,<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">43</span></a> 2001 \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 \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>=<span class="elsevierStyleHsp" style=""></span>225 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction. Benefit in severe pneumonia (Fine IV–V) \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">Martínez et al.,<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">44</span></a> 2003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational retrospective \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>=<span class="elsevierStyleHsp" style=""></span>409 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction. Greater benefit in severe pneumonia \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.,<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> 2004 \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 \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>=<span class="elsevierStyleHsp" style=""></span>844 (older than 15 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction. No combination superior to any other \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,<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">52</span></a> 2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational retrospective \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>=<span class="elsevierStyleHsp" style=""></span>95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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 \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.,<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> 2007 \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 \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>=<span class="elsevierStyleHsp" style=""></span>2209 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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 \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.,<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">47</span></a> 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Meta-analysis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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 \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.,<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">48</span></a> 2005 \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 \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>=<span class="elsevierStyleHsp" style=""></span>107 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No difference \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.,<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">49</span></a> 2006 \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 \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>=<span class="elsevierStyleHsp" style=""></span>340 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No difference \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.,<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">50</span></a> 2006 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pneumococcal pneumonia (with or without bacteremia)<br><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>638 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No difference. Nonsignificant benefit of quinolone \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.,<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">51</span></a> 2007 \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 \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>=<span class="elsevierStyleHsp" style=""></span>189 (adults) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No difference \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1757293.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Influence of combined antibiotic therapy on mortality in pneumococcal infections.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk groups \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>≥65 years \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 (if they have previously been treated with PPSV23, wait at least 1 year before administering)</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 (stage IV–V)<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 \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 \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, followed by one dose of PPSV23<br>Minimum interval of 8 weeks (optimal period greater than 1 year) \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 (after at least 1 year of vaccination with PPSV23). Revaccinate with PPSV23 if 5 or more years have past since the initial dose, up to a maximum of 2 doses \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:</span><br><span class="elsevierStyleHsp" style=""></span>PCV13: 4, 6B, 9V, 14, 18C, 19F and 23F, 1, 5, 7F, 3, 6A, 19A<br><span class="elsevierStyleHsp" style=""></span>PPSV23: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1757294.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Chronic obstructive pulmonary disease, severe asthma and interstitial lung disease.<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, valvular heart disease, heart failure, congenital heart disease and stroke.</p>" ] 2 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Active smoker with packets-year index (PYI) >15; ex-smoker of <10 years with PYI >20; active smoker with respiratory disease regardless of PYI.</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 (starting 3–6 months after the transplantation, first 3 doses at 1-month intervals and the fourth at 6 months after the third dose).</p>" ] 4 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Patients undergoing treatment with methotrexate, rituximab, abatacept and tocilizumab might require 2 doses or might have to wait 1–3 months after completing the treatment.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Indications for pneumococcal vaccination in adults.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:79 [ 0 => array:3 [ "identificador" => "bib0400" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="https://www.cdc.gov/abcs/reports-findings/survreports/spneu15.html">https://www.cdc.gov/abcs/reports-findings/survreports/spneu15.html</a> [accessed 08.08.17]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Active Bacterial Core Surveillance (ABCs) report: Emerging Infections Program Network. <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>, 2015" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Centers for Disease Control and Prevention" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:2 [ "fecha" => "2016" "editorial" => "CDC" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0405" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. 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