Original Article
Bacterial etiology of acute otitis media in Spain in the post-pneumococcal conjugate vaccine era
Etiología bacteriana de la otitis media aguda en españa en la era de la vacuna neumocócica conjugada
Felix Pumarolaa,
, Ignacio Salamanca de la Cuevab, Alessandra Sistiaga-Hernandoc, Pilar García-Corbeirac, Fernando A. Moraga-Llopd, Sara Cardelúse, Cynthia McCoigc, Justo Ramón Gómez Martínezf, Rosa Rosell Ferrerg, Jesús Iniesta Turpinh, Raghavendra Devadigai
Corresponding author
a Hospital Vall d’Hebron, Unidad de ORL Pediátrica, Barcelona, Spain
b Instituto Hispalense de Pediatría, Unidad de Estudio e Investigación, Sevilla, Spain
c GSK Vaccines, Medical Department, Madrid, Spain
d Hospital Vall d’Hebron, Unidad de Enfermedades Infecciosas Pediátricas, Barcelona, Spain
e Hospital de San Juan de Dios, Esplugues de Llobregat, Barcelona, Spain
f Hospital Universitario Central de Asturias, Servicio de Otorrinolaringología, Oviedo, Spain
g Hospital Universitari Parc Taulí de Sabadell, Servicio de Otorrinolaringología, Sabadell, Barcelona, Spain
h Hospital Clínico Universitario Virgen de la Arrixaca, Servicio de Otorrinolaringología, El Palmar, Murcia, Spain
i GSK Pharmaceuticals Pvt. Ltd., Bangalore, India
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Ltd., Bangalore, India" "etiqueta" => "i" "identificador" => "aff0040" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Etiología bacteriana de la otitis media aguda en españa en la era de la vacuna neumocócica conjugada" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1243 "Ancho" => 1609 "Tamanyo" => 85422 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Antibacterial susceptibility of <span class="elsevierStyleItalic">Haemophilus influenzae</span>-positive episodes (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Globally, acute otitis media (AOM) is one of the most common childhood infections affecting over 75% of children younger than 3 years of age<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> and representing the most common condition for antibiotic prescription in young children.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> Approximately 709 million cases of AOM occur throughout the world each year, of which 51% occur in children younger than 5 years of age.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain, the annual incidence of AOM in children below 2 years of age is estimated at 392 per 1000 person-years, as compared with 263 per 1000 person-years in children aged between 3 and 5 years.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> Antibiotics are prescribed as first-line treatment in more than 90% of Spanish children presenting with symptoms of AOM (e.g. ear discharge), although an initial observation is recommended beforehand.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Following the introduction of the 7-valent pneumococcal conjugate vaccine (PCV) (PCV7; <span class="elsevierStyleItalic">Prevenar 7</span>, Pfizer/Wyeth, USA) onto the Spanish private market in 2001,<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> the vaccination coverage rate in children younger than 5 years had reached 50–60% by 2007.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> Other licensed PCV formulations have since been introduced in Spain, including the 10-valent PCV (PCV10; <span class="elsevierStyleItalic">Synflorix</span>™, GSK Vaccines, Belgium) in 2009 and 13-valent PCV (PCV13; <span class="elsevierStyleItalic">Prevenar 13</span>, Pfizer/Wyeth, USA) in 2010.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Before the introduction of PCV, <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> (Spn) and <span class="elsevierStyleItalic">Haemophilus influenzae</span> (Hi) were the most important etiological bacterial agents for AOM in Spanish children.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> However, the underlying microbiology of infectious diseases changes over time as a consequence of vaccination and antibiotic consumption<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> and several global studies have documented a decrease in the circulation of pneumococcal vaccine serotypes and an increase in non-vaccine serotypes and Hi serotypes since PCV7 implementation.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> This study was designed to assess the bacterial etiology of AOM in Spanish children younger than 3 years of age using both culture and polymerase chain reaction (PCR); it complements a previous study describing the bacterial etiology of recurrent AOM and AOM treatment failures in Spanish children during the post-PCV era.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and participants</span><p id="par0025" class="elsevierStylePara elsevierViewall">This prospective, epidemiological study was conducted at seven centres across Spain between February 2009 and May 2012 (GSK study identifier: 111425). Children aged ≥3 to 36 months with ear–nose–throat specialist-confirmed AOM, and who could provide a middle ear fluid sample (MEF), were enrolled in the study. MEF samples were collected by tympanocentesis; in case of otorrhea, the samples were collected via deep aspiration of MEF through needle insertion after ear canal cleaning.</p><p id="par0030" class="elsevierStylePara elsevierViewall">AOM was confirmed based on the acute and sudden onset of the disease within the previous 3 days: fever, irritability, intense erythema of the tympanum or earache; and presence of effusion in the middle ear. The presence of middle ear effusion was characterized by tympanum bulging, limited or no mobility in the tympanum (evaluated using pneumatic otoscopy), fluid behind the tympanum and/or otorrhea (defined as perforation occurring within 48<span class="elsevierStyleHsp" style=""></span>h before enrollment).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Children were excluded from participating in the study if they were hospitalized during the AOM episode (to exclude possible confusion with intrahospital infections) or in the event of otitis externa/otitis media with effusion: AOM for >72<span class="elsevierStyleHsp" style=""></span>h or otorrhea for >48<span class="elsevierStyleHsp" style=""></span>h before enrollment; or in situ transtympanic aerators. Children who received antibiotics for illnesses other than AOM during the 72-hour period before enrollment and were prescribed antibiotics before performing tympanocentesis were also excluded. Finally, patients with protocol-forbidden medical conditions were excluded.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The study adhered to the principles of Good Clinical Practice, including the 1964 Declaration of Helsinki and local Spanish rules and regulations. The study was approved by the Institutional Review Board of each participating center and parents/guardians provided written informed consent before enrollment.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Bacterial identification and antibacterial susceptibility testing</span><p id="par0045" class="elsevierStylePara elsevierViewall">MEF samples were collected by tympanocentesis performed under otoscopy through a reusable <span class="elsevierStyleItalic">CDT Aspirator</span> attached to a <span class="elsevierStyleItalic">CDT speculum</span>, or by sampling of spontaneous otorrhea. In cases of bilateral AOM, MEF samples were collected from both ears. Tympanocentesis was performed without anesthesia. Aspirated MEF samples were inoculated onto Amies transport medium<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> and kept at room temperature for 16<span class="elsevierStyleHsp" style=""></span>h (and up to a maximum of 48<span class="elsevierStyleHsp" style=""></span>h) before subsequent analysis at a GSK-designated laboratory. MEF samples were then inoculated onto chocolate (with bacitracin for otorrhea samples) and blood agar (with nalidixic acid). Bacterial identification was undertaken using standard bacteriological procedures.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> Serotyping for Spn was performed by Quellung's reaction and for Hi using monovalent anti-sera.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Culture-negative samples were further analyzed using real-time PCR assay for the presence of the pneumococcal pneumolysin (ply) gene,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> pneumococcal wzg gene,<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> and the omp2 gene for non-capsulated and capsulated Hi.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> Inhibited PCR reactions were all checked using a commercial exogenous internal positive control (Applied Biosystems, Foster City, CA, USA). A subsequent extraction for eliminating inhibitors was performed on inhibited samples using 20% (w/v) Chelex-100 resin (BioRad Laboratories, Hercules, CA, USA). The samples were further tested for antibacterial susceptibility. Minimal inhibitory concentrations were derived using <span class="elsevierStyleItalic">Etest</span> (bioMérieux, France) and interpreted with the criteria published by the Clinical and Laboratory Standards Institute in 2009.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analyses</span><p id="par0055" class="elsevierStylePara elsevierViewall">Analyses were performed on children meeting all the selection criteria, complying with protocol-defined procedures, and from whom laboratory results of the MEF sample were available. The proportion of AOM episodes caused by Spn, Hi and other bacterial pathogens and the percentages of Spn and Hi serotypes were calculated. Only the first AOM episode was included and any recurrent AOM cases were excluded from analyses. The antibacterial susceptibility of Spn and Hi was determined. History of previous PCV, Hi-type B and influenza vaccinations was recorded. All statistical analyses were performed using <span class="elsevierStyleItalic">SAS version 9.2</span> (SAS Institute Inc., Cary, NC, USA).</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Study participants and demographics</span><p id="par0060" class="elsevierStylePara elsevierViewall">Of 125 AOM episodes in 124 subjects, recorded during the study period, 117 episodes (tympanocentesis<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>91; otorrhea<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>26) (from 117 subjects) were analyzed. Only one subject had two AOM episodes, of which one episode was eliminated from the analyses. Therefore, a total of eight AOM episodes were excluded from the analyses: protocol violation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), having a protocol-forbidden medical condition (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4) and missing MEF/otorrhea sample (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3). The median age of children was 17 months (range: 3–35) and 60.7% were male. AOM episodes were most frequently observed in children aged 11–22 months (46.2%; 54/117) followed by 23–35 months (32.5%; 38/117) and 3–10 months (21.4%; 25/117). At least one dose of a pneumococcal vaccine and Hi-type B vaccine was received by 69.2% and 95.7% subjects, respectively. None of the subjects received influenza vaccine. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents information on age groups in the study, summary of vaccination history and antibiotic treatment.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Bacterial identification</span><p id="par0065" class="elsevierStylePara elsevierViewall">The microbiological results are reported in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. Bacterial culture tests were performed for 117 episodes. Growth for any bacterium was cultured from 66% (77/117) of episodes: 82% of which (63/77) were culture-positive for at least one bacterium under study (Spn, Hi, <span class="elsevierStyleItalic">Streptococcus pyogenes</span> [Spy] or <span class="elsevierStyleItalic">Moraxella catarrhalis</span> [Mcat]). The most frequent bacteria were Hi (42%; 32/77) and Spn (31%; 24/77). Spy was isolated in 10 samples and Mcat in 1 sample; co-infection was detected in 10 episodes, of which 4 co-infections involved bacterium under study: Spn and Hi (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3); Spy and Hi (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1). The remaining 40 episodes were culture-negative. However, PCR was performed for 42 episodes (40 culture-negative episodes<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>2 culture-positive episodes), of which 48% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>20) were found to be Hi-positive and 55% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>23) were Spn-positive.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Combined culture and PCR results indicated that 52 AOM episodes (44%) were Hi-positive and 46 (39%) were Spn-positive; 17 episodes (15%) were positive for both Hi and Spn.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The most common Spn serotypes amongst culture-positive episodes were 19F (17%; 4/24) and 19A (13%; 3/24) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In episodes from children who had been previously vaccinated, PCV7 vaccine serotypes (14 and 19F) were present in 19% (3/16) of episodes and PCV7/PCV13 vaccine serotype (6B) was present in 6% (1/16) of episodes (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). PCV7 vaccine serotype (19F) was present in 25% (2/8) episodes from unvaccinated children.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">All 32 Hi-positive episodes were non-typeable (NTHi): 69% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>22) in vaccinated (PCV vaccine) and 31% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) in unvaccinated (PCV vaccine) children.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Antibacterial susceptibility</span><p id="par0085" class="elsevierStylePara elsevierViewall">Of the 24 Spn-positive episodes, all (100%) were susceptible to cefotaxime, 22 (92%) to amoxicillin, 17 (71%) to erythromycin and 17 (74%) to cefpodoxime (since there was one missing Spn-positive episode susceptible to only cefpodoxime, 23 of 24 Spn-positive episodes were considered for the analyses). Ten episodes were susceptible and intermediately susceptible to penicillin G and four (17%) were resistant to penicillin (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Serotype 19A was most commonly resistant to penicillin G, amoxicillin, cefpodoxime, and erythromycin.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Of the 32 Hi-positive episodes, all (100%) were susceptible to both cefpodoxime and cefotaxime and 26 (81%) to amoxicillin/clavulanic acid. Six episodes (19%) were resistant to amoxicillin/clavulanic acid (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Multi-drug resistance was observed in 17% (4/24) Spn-positive episodes: one episode was resistant to penicillin G, cefpodoxime and erythromycin; and three episodes were resistant to penicillin G, amoxicillin, cefpodoxime and erythromycin. Multi-drug resistance was observed in six NTHi-positive episodes (19%).</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Microbiological results in relation to vaccination status</span><p id="par0100" class="elsevierStylePara elsevierViewall">Of the 81 children positive for at least one pathogenic bacteria by combined culture<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>PCR, 55 (68%) children had received the appropriate PCV doses according to their age: 61% (11/18) aged 3–10 months, 64% (21/33) aged 11–22 months and 77% (23/30) aged 23–35 months. The vaccines administered corresponded to PCV7 in 62 children (77%, where 44 children [71%] received ≥3 doses), PCV10 in nine (11%, where six children [67%] received ≥3 doses) and PCV13 in 17 children (21%, where two children [12%] received ≥3 doses). There was no statistically significant difference in terms of vaccination between Hi-positive (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.000) and Spn-positive children (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.9497).</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">This study identified and characterized the bacterial pathogens associated with AOM in Spanish children less than 3 years of age during the post-PCV era. We found a relatively high percentage (69%) of episodes culture-positive for at least one pathogenic bacterium by combined culture and PCR. Hi and Spn were the most common pathogens isolated from AOM episodes. This finding is in agreement with previous studies conducted in Mexico, Columbia, Venezuela, Germany and Spain that have implicated these pathogens as the main causative agents of AOM.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">17–21</span></a> Interestingly, similar proportions of Spn and Hi detected by culture and PCR highlight the relevance of PCR as an effective detection method. This is corroborated by a former study that identified Spn and Hi in culture-negative samples using PCR-based diagnosis.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Spn and NTHi are highly responsible for the vast number of AOM cases throughout the world, which has not changed significantly in the past fifty years before or after PCV introduction.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">17,23</span></a> Widespread vaccination with PCV could result in a lower role in AOM for Spn. This could in turn result in NTHi becoming a more important pathogen in the years to come.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">At least one dose of a Hi-type B vaccine was received by 112 children (95.7%). In our study, NTHi was responsible for all Hi-positive episodes, as has previously been observed in etiology studies where the majority or all Hi-positive episodes were non-typeable.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">17,18,20,24</span></a> Vaccination with Hi-type B could result in a lower incidence of Hi-type B as pathogen causing AOM, but has not been able to reduce the incidence of NTHi. The most common pneumococcal serotype was 19F followed by 19A in this study. An earlier study from Spain also found 19F as the predominant serotype followed by 23F which was not found in this study.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> The persistence of 19F is noteworthy and underscores the lack of vaccine efficacy against this serotype in Spain. Although serotype distribution varies geographically, studies in Spain and several other countries have emphasized the predominance of serotype 19A after PCV introduction.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">21,25–27</span></a> The presence of 19A in this study possibly indicates insufficient cross-protection against this serotype by PCVs. Although Spn and NTHi are the main causative pathogens of AOM, and with Spn being the less predominant pathogen, some papers have recently highlighted a shifting of pathogens, with Spn being less frequent than NTHi in young children, in concordance with our data.<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">23,28</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">As more than 80% of physicians prescribed an antibiotic as initial treatment for patients with AOM in Spain,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> high antibiotic resistance is expected.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> However, in this study we observed that the majority of Spn and Hi-positive episodes were susceptible to amoxicillin and amoxicillin/clavulanic acid, respectively. This finding supports the continued use of amoxicillin or amoxicillin/clavulanic as the first line of AOM treatment in Spain.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> Also, all Spn<span class="elsevierStyleItalic">-</span> and Hi-positive episodes were susceptible to cefotaxime. Our antibacterial susceptibility patterns are similar to previous findings in Spain<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> and may be helpful when considering antibiotic management in Spain.</p><p id="par0125" class="elsevierStylePara elsevierViewall">The AOM cases in this study may not be representative of all AOM cases in the Spanish population and the results should be considered as merely descriptive. Although tympanocentesis is an effective method for identifying bacterial pathogens from the middle ear, it is not routinely performed in Spain and contributed to our relatively small enrollment numbers and inability to draw strong conclusions. Furthermore, our study excluded recurrent AOM cases and included only the first AOM episode, which could be another limiting factor given that in Spain, it is difficult to perform tympanocentesis on the first AOM episode.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Our study shows that in this post-PCV era, NTHi and Spn were the leading bacterial etiological agents of AOM in young Spanish children, and shifting pathogens has been observed where NTHi has emerged as an important pathogen of AOM. Further studies are needed to evaluate the impact of pneumococcal vaccination on AOM disease burden, after higher vaccination coverage rate is reached.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Trademarks</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Prevenar 7 and Prevenar 13</span> are registered trademarks of Pfizer/Wyeth.</p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Synflorix</span>™ is a registered trademark of the GSK group of companies.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">This study (GSK study identifier: 111425) was sponsored by GlaxoSmithKline Biologicals SA. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and publishing of the manuscript.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Authorship</span><p id="par0150" class="elsevierStylePara elsevierViewall">All authors had full access to the data and were involved in revising the manuscript critically for important intellectual content, and gave final approval. The corresponding author had final responsibility to submit for publication. A confidentiality agreement was set between the authors and the sponsor.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">Sistiaga-Hernando A, García-Corbeira P, McCoig C and Devadiga R are employees of the GSK group of companies. Sistiaga-Hernando A, García-Corbeira P and McCoig C report ownership of stock options/restricted shares from the GSK group of companies. Pumarola F reports payments received from the GSK group of companies for congress registration fees. Gómez Martínez JR and Iniesta Turpin J report investigator fees received by their institution from the GSK group of companies during the conduct of the study. Salamanca de la Cueva I, Moraga-Llop FA, Cardelús S and Rosell Ferrer R report no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres746725" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec749893" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres746724" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec749894" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design and participants" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Bacterial identification and antibacterial susceptibility testing" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analyses" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Study participants and demographics" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Bacterial identification" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Antibacterial susceptibility" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Microbiological results in relation to vaccination status" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Trademarks" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Authorship" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-28" "fechaAceptado" => "2015-10-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec749893" "palabras" => array:4 [ 0 => "Acute otitis media" 1 => "Children" 2 => "Spain" 3 => "Pneumococcal conjugate vaccine" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec749894" "palabras" => array:4 [ 0 => "Otitis media aguda" 1 => "Niños" 2 => "España" 3 => "Vacuna neumocócica conjugada" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute otitis media (AOM) is common in children aged <3 years. A pneumococcal conjugate vaccine (PCV) (PCV7; <span class="elsevierStyleItalic">Prevenar</span>, Pfizer/Wyeth, USA) has been available in Spain since 2001, which has a coverage rate of 50–60% in children aged <5 years.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Children aged ≥3 to 36 months with AOM confirmed by an ear-nose-throat specialist were enrolled at seven centers in Spain (February 2009–May 2012) (GSK study identifier: 111425). Middle-ear-fluid samples were collected by tympanocentesis or spontaneous otorrhea and cultured for bacterial identification. Culture-negative samples were further analyzed using polymerase chain reaction (PCR).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of 125 confirmed AOM episodes in 124 children, 117 were analyzed (median age: 17 months (range: 3–35); eight AOM episodes were excluded from analyses. Overall, 69% (81/117) episodes were combined culture- and PCR-positive for ≥1 bacterial pathogen; 44% (52/117) and 39% (46/117) were positive for <span class="elsevierStyleItalic">Haemophilus influenzae</span> (Hi) and <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> (Spn), respectively. 77 of 117 episodes were cultured for ≥1 bacteria, of which 63 were culture-positive; most commonly Spn (24/77; 31%) and Hi (32/77; 42%). PCR on culture-negative episodes identified 48% Hi- and 55% Spn-positive episodes. The most common Spn serotype was 19F (4/24; 17%) followed by 19A (3/24; 13%); all Hi-positive episodes were non-typeable (NTHi). 81/117 AOM episodes (69%) occurred in children who had received ≥1 pneumococcal vaccine dose.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">NTHi and Spn were the main etiological agents for AOM in Spain. Impact of pneumococcal vaccination on AOM requires further evaluation in Spain, after higher vaccination coverage rate is reached.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La otitis media aguda (OMA) es común en niños menores de 3 años. En España hay disponible una vacuna neumocócica conjugada (VNC) (VNC7; <span class="elsevierStyleItalic">Prevenar</span>, Pfizer/Wyeth, EE. UU.) desde 2001, habiéndose alcanzado una cobertura vacunal del 50-60% en niños menores de 5 años.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se reclutó a niños de 3 a 36 meses con OMA confirmada por especialista en otorrinolaringología en 7 centros españoles (febrero 2009-mayo 2012) (Proyectoe GSK: 111425). Se obtuvieron muestras de exudado del oído medio mediante timpanocentesis o de otorrea espontánea, y se hizo cultivo para identificación bacteriana. En muestras con cultivos negativos se realizó análisis adicional mediante reacción en cadena de la polimerasa (PCR).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">De 125 episodios de OMA confirmados en 124 niños, se analizaron 117 (edad mediana: 17 meses [rango: 3–35]); 8 episodios de OMA fueron excluidos del análisis. En total, combinando resultados de cultivo y PCR, se identificaron uno o más patógenos bacterianos en el 69% (81/117) de los episodios; identificándose <span class="elsevierStyleItalic">Haemophilus influenzae</span> (Hi) en el 44% (52/117) y <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> (Spn) en el 39% (46/117). En 77 de los 117 episodios se hizo cultivo para uno o más patógenos, resultando positivo en 63, con mayor frecuencia para Spn (24/77; 31%) e Hi (32/77; 42%). La PCR en episodios con cultivos negativos detectó Hi en el 48% y Spn en el 55% de las muestras. El serotipo de Spn más común fue el 19F (4/24; 17%) seguido del 19A (3/24; 13%); todos los episodios en los que se identificó Hi correspondieron a Hi no tipificable (HiNT). Un total de 81/117 episodios de OMA (69%) se presentaron en niños que habían recibido una o más dosis de vacuna antineumocócica.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">HiNT y Spn resultaron ser los principales agentes etiológicos de la OMA en España. Para conocer el impacto de la vacunación antineumocócica en la OMA en España harán falta estudios adicionales cuando se haya alcanzado un nivel de cobertura mayor.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as: Pumarola F, Salamanca de la Cueva I, Sistiaga-Hernando A, García-Corbeira P, Moraga-Llop FA, Cardelús S, et al. Etiología bacteriana de la otitis media aguda en españa en la era de la vacuna neumocócica conjugada. An Pediatr (Barc). 2016;85:224–231.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Upon presentation orally at the National Congress of the Spanish Society of Otorhinolaryngology and Cervical-Facial Pathology (SEORL-PCF) held in Madrid (Spain) from 25 to 28 October 2013.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1601 "Ancho" => 1607 "Tamanyo" => 107416 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Serogroup and serotype distribution of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24). <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes with respective serotypes and serogroups. OTHER<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>serogroups 8, 15, 22, 35 (1 episode each) and 21 (2 episodes).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1499 "Ancho" => 2173 "Tamanyo" => 122378 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Antibacterial susceptibility of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1243 "Ancho" => 1609 "Tamanyo" => 85422 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Antibacterial susceptibility of <span class="elsevierStyleItalic">Haemophilus influenzae</span>-positive episodes (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32).</p>" ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>total number of subjects.</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span> (%)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number (percentage) of subjects in each group.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics \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">Categories \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"><span class="elsevierStyleItalic">n</span> (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Age groups (N</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">117)</span></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Age (months)</td><td class="td" title="table-entry " align="left" valign="top">03–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 (21.4) \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">11–22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54 (46.2) \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">23–35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 (32.5) \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">Summary of vaccination history (N</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">117)</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Child received at least one dose of a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81 (69.2) \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"><span class="elsevierStyleHsp" style=""></span>Pneumococcal vaccine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 (30.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Child received at least one dose of a <span class="elsevierStyleItalic">Haemophilus influenzae</span>-type B vaccine</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">112 (95.7) \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">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (2.6) \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">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (1.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Child received at least one dose of a Influenza vaccine</td><td class="td" title="table-entry " align="left" valign="top">Yes \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></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">116 (99.1) \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">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (0.9) \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">Antibiotic treatment (N</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">117)</span></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Antibiotics taken before the sample was obtained</td><td class="td" title="table-entry " align="left" valign="top">Yes \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></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">117 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Antibiotics taken within the past one month</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (6.0) \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">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">110 (94.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233409.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Characteristics of enrolled children.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number of episodes analyzed according to culture, PCR or both.</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span>′ (%)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>numbers (percentage) of episodes positive for each bacterium.</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">There were two AOM episodes that were tested by both culture and PCR.</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note</span>: Culture-negative episodes were not tested for <span class="elsevierStyleItalic">Streptococcus pyogenes</span> and <span class="elsevierStyleItalic">Moraxella catarrhalis</span> by PCR.</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">AOM, acute otitis media; PCR, polymerase chain reaction.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Culture (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>77) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">PCR (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>42) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Combined culture<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>PCR (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>117) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><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"><span class="elsevierStyleItalic">n</span>′ (%) \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"><span class="elsevierStyleItalic">n</span>′ (%) \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"><span class="elsevierStyleItalic">n</span>′ (%) \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">Positive for at least 1 pathogenic bacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63 (82) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29 (69) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81 (69) \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"><span class="elsevierStyleItalic">Streptococcus pneumoniae</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 (31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (55) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46 (39) \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"><span class="elsevierStyleItalic">Haemophilus influenzae</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (48) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (44) \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"><span class="elsevierStyleItalic">Streptococcus pyogenes</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (13) \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">– \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"><span class="elsevierStyleItalic">Moraxella catarrhalis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1) \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">– \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">Co-infection with <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Haemophilus influenzae</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (15) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233406.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Bacterial identification of AOM episodes by culture and PCR.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes vaccinated and unvaccinated with pneumococcal conjugate vaccine.</p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span> (%)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number (percentage) of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes in each category.</p>" "tablatextoimagen" => array:2 [ 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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">PCV name \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Serotypes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Vaccinated total (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><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="" 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"><span class="elsevierStyleItalic">n</span> (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">PCV7</td><td class="td" title="table-entry " align="left" valign="top">14<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</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 (6) \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">19A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (19) \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">19C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (6) \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">19F<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</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 (13) \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">Other (8, 15, 21, 35) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (25) \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">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (13) \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">PCV13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Other (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (6) \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">PCV7 and PCV13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6B<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</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 (6) \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">PCV10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Other A (10A) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233408.png" ] ] 1 => 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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Serotypes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Unvaccinated total (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><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"><span class="elsevierStyleItalic">n</span> (%) \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">18F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (13) \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">19F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (25) \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">23B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (25) \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">Other (22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (13) \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">Other B (15B) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (13) \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">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (13) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233407.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Serotypes 6B, 14 and 19F are all present in PCV7, PCV10 and PCV13.</p> <p class="elsevierStyleNotepara" id="npar0010">PCV, pneumococcal conjugate vaccine; PCV7, 7-valent PCV; PCV10, 10-valent PCV; PCV13, 13-valent PCV.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Serogroups and serotypes of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>-positive episodes (by culture) by name of pneumococcal conjugate vaccination status (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prospects for a vaccine against otitis media" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.W. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 11 | 6 | 17 |
| 2024 October | 74 | 46 | 120 |
| 2024 September | 68 | 32 | 100 |
| 2024 August | 76 | 60 | 136 |
| 2024 July | 54 | 27 | 81 |
| 2024 June | 95 | 36 | 131 |
| 2024 May | 71 | 45 | 116 |
| 2024 April | 80 | 37 | 117 |
| 2024 March | 68 | 23 | 91 |
| 2024 February | 57 | 24 | 81 |
| 2024 January | 55 | 22 | 77 |
| 2023 December | 45 | 27 | 72 |
| 2023 November | 43 | 25 | 68 |
| 2023 October | 44 | 37 | 81 |
| 2023 September | 40 | 29 | 69 |
| 2023 August | 38 | 23 | 61 |
| 2023 July | 49 | 25 | 74 |
| 2023 June | 45 | 30 | 75 |
| 2023 May | 55 | 26 | 81 |
| 2023 April | 65 | 19 | 84 |
| 2023 March | 114 | 27 | 141 |
| 2023 February | 55 | 15 | 70 |
| 2023 January | 44 | 20 | 64 |
| 2022 December | 69 | 34 | 103 |
| 2022 November | 71 | 32 | 103 |
| 2022 October | 70 | 52 | 122 |
| 2022 September | 39 | 30 | 69 |
| 2022 August | 44 | 39 | 83 |
| 2022 July | 44 | 45 | 89 |
| 2022 June | 36 | 41 | 77 |
| 2022 May | 43 | 24 | 67 |
| 2022 April | 43 | 46 | 89 |
| 2022 March | 63 | 55 | 118 |
| 2022 February | 35 | 29 | 64 |
| 2022 January | 46 | 33 | 79 |
| 2021 December | 63 | 42 | 105 |
| 2021 November | 69 | 53 | 122 |
| 2021 October | 105 | 90 | 195 |
| 2021 September | 61 | 47 | 108 |
| 2021 August | 53 | 57 | 110 |
| 2021 July | 42 | 50 | 92 |
| 2021 June | 42 | 44 | 86 |
| 2021 May | 56 | 38 | 94 |
| 2021 April | 120 | 57 | 177 |
| 2021 March | 66 | 43 | 109 |
| 2021 February | 59 | 18 | 77 |
| 2021 January | 43 | 39 | 82 |
| 2020 December | 49 | 29 | 78 |
| 2020 November | 29 | 19 | 48 |
| 2020 October | 24 | 27 | 51 |
| 2020 September | 24 | 22 | 46 |
| 2020 August | 25 | 8 | 33 |
| 2020 July | 26 | 20 | 46 |
| 2020 June | 31 | 18 | 49 |
| 2020 May | 38 | 22 | 60 |
| 2020 April | 37 | 17 | 54 |
| 2020 March | 46 | 15 | 61 |
| 2020 February | 77 | 10 | 87 |
| 2020 January | 53 | 9 | 62 |
| 2019 December | 74 | 27 | 101 |
| 2019 November | 35 | 8 | 43 |
| 2019 October | 22 | 7 | 29 |
| 2019 September | 35 | 11 | 46 |
| 2019 August | 91 | 21 | 112 |
| 2019 July | 31 | 13 | 44 |
| 2019 June | 31 | 26 | 57 |
| 2019 May | 63 | 16 | 79 |
| 2019 April | 41 | 26 | 67 |
| 2019 March | 30 | 14 | 44 |
| 2019 February | 47 | 22 | 69 |
| 2019 January | 41 | 20 | 61 |
| 2018 December | 38 | 33 | 71 |
| 2018 November | 124 | 42 | 166 |
| 2018 October | 265 | 18 | 283 |
| 2018 September | 175 | 7 | 182 |
| 2018 August | 3 | 0 | 3 |
| 2018 July | 2 | 0 | 2 |
| 2018 June | 3 | 0 | 3 |
| 2018 May | 5 | 0 | 5 |
| 2018 April | 19 | 0 | 19 |
| 2018 March | 29 | 0 | 29 |
| 2018 February | 19 | 0 | 19 |
| 2018 January | 22 | 0 | 22 |
| 2017 December | 21 | 0 | 21 |
| 2017 November | 26 | 0 | 26 |
| 2017 October | 26 | 0 | 26 |
| 2017 September | 27 | 0 | 27 |
| 2017 August | 16 | 0 | 16 |
| 2017 July | 19 | 1 | 20 |
| 2017 June | 22 | 11 | 33 |
| 2017 May | 33 | 12 | 45 |
| 2017 April | 17 | 10 | 27 |
| 2017 March | 17 | 16 | 33 |
| 2017 February | 18 | 10 | 28 |
| 2017 January | 9 | 21 | 30 |
| 2016 December | 30 | 24 | 54 |
| 2016 November | 68 | 61 | 129 |
| 2016 October | 18 | 35 | 53 |
| 2016 September | 7 | 15 | 22 |
| 2016 August | 13 | 7 | 20 |
| 2016 July | 3 | 3 | 6 |
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