Molecular epidemiology of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae in Seville | Enfermedades Infecciosas y Microbiología Clínica

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"documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Enferm Infecc Microbiol Clin. 2012;30:175-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 7417 "formatos" => array:3 [ "EPUB" => 9 "HTML" => 6593 "PDF" => 815 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original" "titulo" => "Cuadros clínicos asociados a bacteriemia causada por las nuevas especies incluidas en el antiguo grupo Streptococcus bovis" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "179" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Diseases associated with bloodstream infections caused by the new species included in the old Streptococcus bovis group" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Luis Gómez-Garcés, Yolanda Gil, Almudena Burillo, Isabel Wilhelmi, Maria Palomo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "José Luis" "apellidos" => "Gómez-Garcés" ] 1 => array:2 [ "nombre" => "Yolanda" "apellidos" => "Gil" ] 2 => array:2 [ "nombre" => "Almudena" "apellidos" => "Burillo" ] 3 => array:2 [ "nombre" => "Isabel" "apellidos" => "Wilhelmi" ] 4 => array:2 [ "nombre" => "Maria" "apellidos" => "Palomo" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X1100317X?idApp=UINPBA00004N" "url" => "/0213005X/0000003000000004/v1_201305090333/S0213005X1100317X/v1_201305090333/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Molecular epidemiology of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae in Seville" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "180" "paginaFinal" => "183" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Patricia Iraurgui, María José Torres, Javier Aznar" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Patricia" "apellidos" => "Iraurgui" "email" => array:2 [ 0 => "pat_ira@hotmail.com" 1 => "patriciairaurgui@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "María José" "apellidos" => "Torres" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Javier" "apellidos" => "Aznar" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Microbiology Department, University of Seville, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Microbiology Service, University Hospital Virgen del Rocío, Seville, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Epidemiología molecular de la resistencia a fluorquinolonas en aislamientos clínicos invasivos de Streptococcus pneumoniae en Sevilla" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 882 "Ancho" => 1576 "Tamanyo" => 75228 ] ] "descripcion" => array:1 [ "en" => "PFGE of S. pneumoniae isolates." ] ] ] "textoCompleto" => "IntroductionStreptococcus pneumoniae is the main cause of community-acquired pneumonia and an important agent of meningitis and bacteraemia. Due to the emergence of drug-resistant pneumococcal isolates and the clinical failures reported with older fluoroquinolones (FQs), newer fluoroquinolones have been recommended for the treatment of pneumococcal infections.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>The 2001 Spanish surveillance study<a class="elsevierStyleCrossRef" href="#bib0010">2</a> found a 7% prevalence of ciprofloxacin resistance among S. pneumoniae isolates. A recent nationwide study, SAUCE, observed a decreasing trend in the FQ resistance rates in Spain, with ciprofloxacin and levofloxacin (LVX) resistance rates of 2.2% and 0.5%, respectively, in 2006–2007.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The mechanisms of resistance to FQs include DNA gyrase and topoisomerase IV mutations and active efflux of agents from the cell.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> When the mutation affects only one of both targets, we have a first-step mutant. Second-step mutants result from mutations in DNA gyrase and topoisomerase IV.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Decreased susceptibility to FQs is primarily due to amino acid substitutions in the ParC subunit of topoisomerase IV or in the GyrA subunit of DNA gyrase and less in ParE and GyrB.<a class="elsevierStyleCrossRefs" href="#bib0035">7–9</a> The active efflux is also cause of low-level or first-step resistance. This mechanism mostly affects hydrophilic quinolones like norfloxacin (NFX) and ciprofloxacin.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>In order to detect low-level-resistant pneumococci and prevent in vivo selection of resistant mutants or therapeutic failures, the French Microbiology Society suggests a screening method with NFX.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The aim of this study was to establish surveillance and conduct molecular characterization, of fluoroquinolone-resistant S. pneumoniae in order to monitor the increase of fluoroquinolone resistance in Seville. NFX-resistant S. pneumoniae isolates were characterized by QRDR substitutions, reserpine-sensitive efflux, serotype and pulsed-field gel electrophoresis (PFGE) patterns.Materials and methodsS. pneumoniae isolatesWe recovered 274 invasive isolates (49%) from the 560 obtained from 2002 to 2008 in Seville. These included 114 paediatric isolates (96 previously typed by serological determination of capsular type) and 160 adult isolates, representing a subset of all invasive isolates. All isolates were recovered from sterile fluids: blood (232 isolates), cerebrospinal fluid (30 isolates), pleural fluid (10 isolates), and synovial fluid (2 isolates). The samples were cultured on Columbia Blood agar in 5% CO2 at 37°C, and the α-haemolytic colonies were tested for optochin susceptibility and bile solubility to differentiate S. pneumoniae from other α-haemolytic streptococci. Pneumococcal isolates were stored at −70°C in skimmed milk.SerotypingIsolates were serotyped using the published multiplex PCR protocol with 7 sequential reactions.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Each of the seven reactions included four serotype-specific primer pairs and a conserved region of the cps operon as internal positive control. We modified the order of the primers proposed to improve the efficiency of the original scheme for surveying our geographic area.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The multiplex assay was supplemented by sequencing and a PCR assay to differentiate between serotypes 6A, 6B and 6C.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>PFGEGenetic similarity of the isolates was tested by PFGE. S. pneumoniae DNA was embedded in agarose blocks and digested with SmaI restriction enzyme. PFGE was performed in 1.2% agarose gel for 21h at 11°C in 0.5× TBE, at 6V/cm, with pulse times of 1–30s and an angle of 60°. The gel was stained with 1mg/mL of ethidium bromide for 30min.PFGE profiles were analysed optically and using Bionumerics software. We have defined a “clone” as isolates that differed by not more than 3 bands, or 90%.Antimicrobial susceptibilitiesSusceptibility to NFX and LVX was determined by E-test diffusion and 5μg disc diffusion (only NFX) on Müller-Hinton Blood (bioMerieux) with 0.5 McFarland standard densities.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> When the inhibition zone around a disk of NFX was <10mm or the MIC was >16μg/ml, we considered it a low-level fluoroquinolone resistant pneumococcus.<a class="elsevierStyleCrossRefs" href="#bib0040">8,10</a> When the NFX MIC was >16μg/ml and the LVX MIC was ≥8mg/mL we considered it a high-level fluoroquinolone resistant pneumococcus.<a class="elsevierStyleCrossRefs" href="#bib0050">10,14</a>Sequencing and identification of mutationsWe identified the mutated genes through PCR and reverse hybridization with specific probes for ParC and GyrA sequence (CAP-Resistenz, GenID® GmbH, Straßberg) in all the strains with an NFX MIC>16μg/ml. The GyrA, GyrB, ParC, and ParE genes from S. pneumoniae were also amplified by PCR and sequenced to detect QRDR mutations as described.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Active effluxAll strains with NFX MICs>16mg/ml were grown with and without reserpine (10μg/ml) in Müller-Hinton medium containing 5% sheep blood with doubling dilutions of NFX. Strains with a fourfold or greater reduction in NFX MIC in the presence of reserpine<a class="elsevierStyleCrossRef" href="#bib0080">16</a> were considered positive for reserpine-sensitive efflux.ResultsFourteen isolates (5.1%) showed an inhibition zone of >9mm around a disk containing 5μg of NFX and a MIC>16μg/ml to NFX by the E-test diffusion method (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Ten (6.3%) strains were isolated from adult patients and four (3.5%) more from infants. Eight of 10 adult isolates were susceptible to LVX and the remaining two had a MIC>32μg/ml, and the four infant isolates with NFX MIC>16μg/ml were all susceptible to LVX. These 4 infant isolates presented low non-susceptible MICs to NFX (24μg/ml).Two out of 274 isolates (0.7%) were resistant to LVX, both of them with a MIC>32μg/ml. Those isolates susceptible to LVX, but resistant to NFX could be low-level-resistant mutants and the two resistant isolates to both FQs could be high-level-resistant mutants.A probe hybridization test was performed on the 14 NFX resistant isolates, and mutations in ParC were detected in 6 of 12 low-level-resistant mutants. The remaining 6 isolates hybridized with wild sequences of both genes. One of the two possible high-level-resistant mutants showed mutations in ParC and GyrA sequences, while the other one only in ParC sequence.All strains with mutations in the ParC by the probe hybridization test were confirmed by sequencing, and the most common genotype observed was S79F (ParC) substitution. Additionally, sequencing detected one more resistant strain with the S79Y mutation. Seven of the 12 low-level-resistant isolates (58.3%) had mutations in ParC. Only in one of the two high-level-resistant isolates were mutations detected in ParC and GyrA genes. The other LVX resistant isolates showed a mutation in ParC. All substitutions observed in the resistant isolates are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. No mutation was found in the ParE and GyrB genes.Overall, 10 (71.4%) isolates were positive for reserpine-inhibited efflux. All the five isolates without QRDR substitutions though NFX-resistant were positive for reserpine-inhibited efflux. The isolate with high-level resistance that only showed ParC mutation was also positive for reserpine-inhibited efflux.The 14 NFX-resistant S. pneumoniae isolates studied belonged to 9 different serotypes, 19A (4 isolates), 8 (2), 6A (1), 14 (1), 18 (1), 38 (1), 3 (1), 9V (1) and 7F (1) and one isolate could not be amplified.PFGE revealed significant heterogeneity among the NFX-resistant isolates, and most of them were genetically unrelated (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Nine different profiles were found, and 3 of these contained two isolates each. Two of the strains with the same genotype were serotype 19A, and were isolated from the same patient. The isolates were obtained in two different episodes and hospital admissions, separated by 4 months. The patient was a 28-year-old man with Job syndrome, characterized by recurrent skin abscesses, atopic dermatitis, pneumonia and high serum levels of IgE. The patient was first hospitalized diagnosed with a community-acquired pneumonia (CAP). Sputum and blood samples were taken and LVX empirical treatment was started. S. pneumoniae susceptible to penicillin (E-test MIC of 0.016μg/ml) and LVX (E-test MIC of 2μg/ml) was grown in both samples. Two months later, the patient was hospitalized again with a new diagnosis of CAP. Isolates were not obtained, but he was again treated with LVX. Four months after the first hospitalization, he returned to the hospital with a S. pneumoniae bacteraemia. The S. pneumoniae isolated from blood cultures was susceptible to penicillin (E-test MIC of 0.006μg/ml), but resistant to LVX (E-test MIC of >32μg/ml). The first isolate carried a mutation in the QRDR of ParC (S79F) and the second one had an additional GyrA mutation (S81F).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiscussionAlthough antimicrobial resistance rates in S. pneumoniae continue being a worldwide problem, the prevalence of FQ-resistant strains remains low (1–7%).<a class="elsevierStyleCrossRefs" href="#bib0085">17–19</a> A 1998–2002 United States surveillance study found a higher prevalence of LVX resistance among lower respiratory tract isolates compared to blood isolates.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>In the 1998 Active Bacterial Core Surveillance program, the Centers for Disease Control and Prevention reported a LVX resistance rate of 0.2% among 3475 invasive isolates.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> In our study, a higher LVX resistance rate (0.7%) was found among invasive isolates. Although the resistance level is low, surveillance is necessary, especially to prevent cases of in vivo resistance development as reported. We performed the screening test proposed by CA-SFM to detect low-level-resistant isolates, as failing to detect them may lead to treatment failure.<a class="elsevierStyleCrossRefs" href="#bib0110">22–24</a> In Spain, a fatal LVX treatment failure was reported in a patient with a pneumococcal pneumonia who developed in vivo resistance,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> and in this work, we described a new case that developed in vivo resistance.Ten (6.3%) adult isolates and 4 (3.5%) infant isolates showed a MIC>16μg/ml to NFX by the E-test diffusion method, but only 2 (1.3%) adult isolates, and none of the infant isolates were LVX-resistant. Moreover, 4 infant isolates presented low non-susceptible MICs to NFX (24μg/ml) and the only resistance mechanism detected was the active efflux, suggesting that these infant strains had probably not been exposed to FQ.We have found mutations in the Ser-79 of ParC and Ser-81 of GyrA. ParC substitutions at Ser-79 were to either Phe or Tyr, but the S79F substitution was more prevalent. We detected mutations exclusively in ParC sequence in 8 isolates (57.1%), and 7 of them were susceptible to LVX (first-step resistance). There was one isolate that only had ParC mutation and was resistant to LVX. We found other polymorphisms not related to fluoroquinolone resistance in this isolate, ParC (K137N) and ParE (I460V). It was also positive to reserpine effect. This resistance pattern is unusual, because the isolate is high-level-resistant in a first-step mutation. The clinical impact of this pattern is very important, and the isolate should be studied more thoroughly. The 5 isolates with low-level resistance without mutations in the QRDR genes were positive to reserpine effect. As expected, the isolate with ParC and GyrA mutations (Ser-81) was not susceptible to NFX and LVX (high-level resistance).Although penicillin- or macrolide-resistant isolates have spread clonally, the clonal relationship of fluoroquinolone-resistant isolates remains unclear.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In the present study we did not find any clonal and serotype relationship, probably due to the low number of resistant strains. However, clonal diversity in LVX-resistant isolates has been reported in other large surveillance studies.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Among the 3 pairs of isolates with the same PFGE profile, a different serotype was observed in one case, another pair had one non-typeable isolate, and the third pair was the strain that developed resistance in vivo.When we performed the assay to estimate the efflux, the MICs obtained for NFX by microdilution without reserpine varied in one or two dilutions, but remained in the same category, except in two infant isolates. These two isolates had an MIC of 24μg/ml by E-test and 16μg/ml by microdilution. Mutations in the QRDR genes were not detected. According to CA-SFM recommendations, by E-test, these could be low-level fluoroquinolone-resistant pneumococci.Active efflux mechanism was found in 10 of 14 NFX-resistant isolates, being associated with other resistance mechanisms in 5 isolates. The other 5 isolates that only presented the efflux mechanism showed lower MICs to NFX (24μg/ml) and the isolates that presented a ParC mutation showed higher MICs to NFX regardless of having the efflux mechanism or not.The screening method that we have used, using only NFX and LVX E-test, is the simplest alternative according to Varon et al. This option does not discriminate between increased efflux and altered topoisomerase IV, but detects the most frequent low-level-resistant mutants.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres151018" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Method" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec138968" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres151019" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec138969" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "S. pneumoniae isolates" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Serotyping" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "PFGE" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Antimicrobial susceptibilities" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Sequencing and identification of mutations" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Active efflux" ] ] ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-03-29" "fechaAceptado" => "2011-10-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec138968" "palabras" => array:5 [ 0 => "S. pneumoniae" 1 => "Resistance" 2 => "Fluoroquinolone" 3 => "Mutation" 4 => "Sequencing" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec138969" "palabras" => array:5 [ 0 => "S. pneumoniae" 1 => "Resistencia" 2 => "Fluorquinolona" 3 => "Mutación" 4 => "Secuenciación" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionDue to the emergence of drug-resistant pneumococcal isolates, new fluoroquinolones have been recommended for the treatment of pneumococcal infections. The purpose of this study was to establish surveillance, and to conduct molecular characterization, of fluoroquinolone-resistant Streptococcus pneumoniae in Seville. MethodNorfloxacin-resistant S. pneumoniae isolates were characterized by quinolone resistance-determining region (QRDR) substitutions, reserpine-sensitive efflux, serotype and by pulsed-field gel electrophoresis (PFGE) patterns. ResultsFourteen isolates (5.1%) showed an MIC>16μg/ml to norfloxacin. Eight of 10 adult isolates were susceptible to levofloxacin. The 4 infant isolates with norfloxacin MIC>16μg/ml were susceptible to levofloxacin. Seven of these 12 low-level-resistant isolates had mutations in ParC, while mutations both in ParC and GyrA genes were only detected in one of the two high-level-resistant isolates. All the isolates without QRDR substitutions that remained norfloxacin-resistant were positive for reserpine-inhibited efflux. The serotyping and PFGE revealed significant heterogeneity. We obtained 9 different profiles, 3 of which had two isolates each. Two of the isolates with the same pulsotype were from the same patient. The first isolate showed a mutation in the QRDR of ParC, and the second one had an additional GyrA mutation. ConclusionIn our study a levofloxacin resistance rate of 0.7% was found among invasive isolates. Although resistance level is low, surveillance is necessary, especially to prevent cases of in vivo resistance development as reported." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "IntroducciónEn los últimos años se ha detectado un aumento de resistencias a fluorquinolonas entre las cepas de Streptococcus pneumoniae. El objetivo de este estudio es realizar la caracterización molecular y vigilancia de la resistencia a fluorquinolonas en aislamientos de Streptococcus pneumoniae en Sevilla. MétodosLa caracterización de las cepas resistentes a norfloxacina se realizó mediante el estudio de las mutaciones en los genes QRDR, estudio de bombas de reflujo con reserpina, serotipado y patrones de electroforesis en campo pulsante (ECP). ResultadosCatorce (5,1%) aislamientos mostraron una CMI a norfloxacino >16μg/ml. De los 10 aislamientos de adultos, 8 fueron sensibles a levofloxacina. Los 4 aislamientos pediátricos resistentes a norfloxacina fueron sensibles a levofloxacina. Siete de los 12 aislamientos con bajo nivel de resistencia mostraron una mutación en parC, mientras que sólo en una de las dos cepas con resistencia de alto nivel encontramos mutaciones en los genes ParC y GyrA. Los aislamientos que no mostraron tener mutaciones, pero eran resistentes a la norfloxacina, fueron positivos para la reserpina. El serotipado y los patrones de ECP revelaron una considerable heterogeneidad. Obtuvimos 9 perfiles diferentes, 3 de los cuales contenían 2 aislamientos cada uno. Dos de los aislamientos con el mismo pulsotipo resultaron ser del mismo paciente. El primer aislamiento mostró una mutación en el parC y el segundo, una mutación adicional en el gyrA. ConclusionesAunque la tasa de resistencia a levofloxacina obtenida fue baja (0,7%), es necesaria una vigilancia para prevenir el desarrollo de resistencias in vivo como la que detectamos." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 882 "Ancho" => 1576 "Tamanyo" => 75228 ] ] "descripcion" => array:1 [ "en" => "PFGE of S. pneumoniae isolates." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "N.T.: non-typeable." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PFGE type \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Serotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">CMI NFX (μg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">CMI LVX (μg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mutations in ParC by commercial assay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mutations in GyrA by commercial assay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mutations in ParC by sequencing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mutations in GyrA by sequencing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Reserpine effect \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S81F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79Y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79Y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N.T. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">128 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S79F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab245102.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Molecular characteristics of NFX-resistant S. pneumoniae isolates." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:27 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.A. Mandell" 1 => "R.G. Wunderink" 2 => "A. Anzueto" 3 => "J.G. Bartlett" 4 => "G.D. Campbell" 5 => "N.C. Dean" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1086/511159" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2007" "volumen" => "44" "paginaInicial" => "S27" "paginaFinal" => "S72" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17278083" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998–1999) multicenter surveillance study in Spain" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Pérez-Trallero" 1 => "C. Fernandez-Mazarrasa" 2 => "C. García-Rey" 3 => "E. Bouza" 4 => "L. Aguilar" 5 => "J. García-de-Lomas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/AAC.45.12.3334-3340.2001" "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "2001" "volumen" => "45" "paginaInicial" => "3334" "paginaFinal" => "3340" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11709305" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial resistance among respiratory pathogens in Spain: latest data and changes over 11 years (1996–1997 to 2006–2007)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Pérez-Trallero" 1 => "J.E. Martín-Herrero" 2 => "A. Mazón" 3 => "C. García-Delafuente" 4 => "P. Robles" 5 => "V. 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Molecular epidemiology of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae in Seville

Epidemiología molecular de la resistencia a fluorquinolonas en aislamientos clínicos invasivos de Streptococcus pneumoniae en Sevilla

Patricia Iraurguia,

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pat_ira@hotmail.com
patriciairaurgui@gmail.com

Corresponding author.

, María José Torresa, Javier Aznara,b

a Microbiology Department, University of Seville, Spain

b Microbiology Service, University Hospital Virgen del Rocío, Seville, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Streptococcus pneumoniae</span> is the main cause of community-acquired pneumonia and an important agent of meningitis and bacteraemia&#46; Due to the emergence of drug-resistant pneumococcal isolates and the clinical failures reported with older fluoroquinolones &#40;FQs&#41;&#44; newer fluoroquinolones have been recommended for the treatment of pneumococcal infections&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The 2001 Spanish surveillance study<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> found a 7&#37; prevalence of ciprofloxacin resistance among <span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates&#46; A recent nationwide study&#44; SAUCE&#44; observed a decreasing trend in the FQ resistance rates in Spain&#44; with ciprofloxacin and levofloxacin &#40;LVX&#41; resistance rates of 2&#46;2&#37; and 0&#46;5&#37;&#44; respectively&#44; in 2006&#8211;2007&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The mechanisms of resistance to FQs include DNA gyrase and topoisomerase IV mutations and active efflux of agents from the cell&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> When the mutation affects only one of both targets&#44; we have a first-step mutant&#46; Second-step mutants result from mutations in DNA gyrase and topoisomerase IV&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Decreased susceptibility to FQs is primarily due to amino acid substitutions in the ParC subunit of topoisomerase IV or in the GyrA subunit of DNA gyrase and less in ParE and GyrB&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a> The active efflux is also cause of low-level or first-step resistance&#46; This mechanism mostly affects hydrophilic quinolones like norfloxacin &#40;NFX&#41; and ciprofloxacin&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In order to detect low-level-resistant pneumococci and prevent <span class="elsevierStyleItalic">in vivo</span> selection of resistant mutants or therapeutic failures&#44; the French Microbiology Society suggests a screening method with NFX&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study was to establish surveillance and conduct molecular characterization&#44; of fluoroquinolone-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span> in order to monitor the increase of fluoroquinolone resistance in Seville&#46; NFX-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates were characterized by QRDR substitutions&#44; reserpine-sensitive efflux&#44; serotype and pulsed-field gel electrophoresis &#40;PFGE&#41; patterns&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle"><span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates</span><p id="par0030" class="elsevierStylePara elsevierViewall">We recovered 274 invasive isolates &#40;49&#37;&#41; from the 560 obtained from 2002 to 2008 in Seville&#46; These included 114 paediatric isolates &#40;96 previously typed by serological determination of capsular type&#41; and 160 adult isolates&#44; representing a subset of all invasive isolates&#46; All isolates were recovered from sterile fluids&#58; blood &#40;232 isolates&#41;&#44; cerebrospinal fluid &#40;30 isolates&#41;&#44; pleural fluid &#40;10 isolates&#41;&#44; and synovial fluid &#40;2 isolates&#41;&#46; The samples were cultured on Columbia Blood agar in 5&#37; CO<span class="elsevierStyleInf">2</span> at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; and the &#945;-haemolytic colonies were tested for optochin susceptibility and bile solubility to differentiate <span class="elsevierStyleItalic">S&#46; pneumoniae</span> from other &#945;-haemolytic streptococci&#46; Pneumococcal isolates were stored at &#8722;70<span class="elsevierStyleHsp" style=""></span>&#176;C in skimmed milk&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Serotyping</span><p id="par0035" class="elsevierStylePara elsevierViewall">Isolates were serotyped using the published multiplex PCR protocol with 7 sequential reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Each of the seven reactions included four serotype-specific primer pairs and a conserved region of the <span class="elsevierStyleItalic">cps</span> operon as internal positive control&#46; We modified the order of the primers proposed to improve the efficiency of the original scheme for surveying our geographic area&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The multiplex assay was supplemented by sequencing and a PCR assay to differentiate between serotypes 6A&#44; 6B and 6C&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">PFGE</span><p id="par0040" class="elsevierStylePara elsevierViewall">Genetic similarity of the isolates was tested by PFGE&#46; <span class="elsevierStyleItalic">S&#46; pneumoniae</span> DNA was embedded in agarose blocks and digested with <span class="elsevierStyleItalic">Sma</span>I restriction enzyme&#46; PFGE was performed in 1&#46;2&#37; agarose gel for 21<span class="elsevierStyleHsp" style=""></span>h at 11<span class="elsevierStyleHsp" style=""></span>&#176;C in 0&#46;5&#215; TBE&#44; at 6<span class="elsevierStyleHsp" style=""></span>V&#47;cm&#44; with pulse times of 1&#8211;30<span class="elsevierStyleHsp" style=""></span>s and an angle of 60&#176;&#46; The gel was stained with 1<span class="elsevierStyleHsp" style=""></span>mg&#47;mL of ethidium bromide for 30<span class="elsevierStyleHsp" style=""></span>min&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">PFGE profiles were analysed optically and using Bionumerics software&#46; We have defined a &#8220;clone&#8221; as isolates that differed by not more than 3 bands&#44; or 90&#37;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Antimicrobial susceptibilities</span><p id="par0050" class="elsevierStylePara elsevierViewall">Susceptibility to NFX and LVX was determined by <span class="elsevierStyleItalic">E</span>-test diffusion and 5<span class="elsevierStyleHsp" style=""></span>&#956;g disc diffusion &#40;only NFX&#41; on M&#252;ller-Hinton Blood &#40;bioMerieux&#41; with 0&#46;5 McFarland standard densities&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> When the inhibition zone around a disk of NFX was &#60;10<span class="elsevierStyleHsp" style=""></span>mm or the MIC was &#62;16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; we considered it a low-level fluoroquinolone resistant pneumococcus&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10</span></a> When the NFX MIC was &#62;16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml and the LVX MIC was &#8805;8<span class="elsevierStyleHsp" style=""></span>mg&#47;mL we considered it a high-level fluoroquinolone resistant pneumococcus&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;14</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Sequencing and identification of mutations</span><p id="par0055" class="elsevierStylePara elsevierViewall">We identified the mutated genes through PCR and reverse hybridization with specific probes for ParC and GyrA sequence &#40;CAP-Resistenz&#44; GenID<span class="elsevierStyleSup">&#174;</span> GmbH&#44; Stra&#223;berg&#41; in all the strains with an NFX MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; The GyrA&#44; GyrB&#44; ParC&#44; and ParE genes from <span class="elsevierStyleItalic">S&#46; pneumoniae</span> were also amplified by PCR and sequenced to detect QRDR mutations as described&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Active efflux</span><p id="par0060" class="elsevierStylePara elsevierViewall">All strains with NFX MICs<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>mg&#47;ml were grown with and without reserpine &#40;10<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; in M&#252;ller-Hinton medium containing 5&#37; sheep blood with doubling dilutions of NFX&#46; Strains with a fourfold or greater reduction in NFX MIC in the presence of reserpine<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> were considered positive for reserpine-sensitive efflux&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">Fourteen isolates &#40;5&#46;1&#37;&#41; showed an inhibition zone of &#62;9<span class="elsevierStyleHsp" style=""></span>mm around a disk containing 5<span class="elsevierStyleHsp" style=""></span>&#956;g of NFX and a MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml to NFX by the <span class="elsevierStyleItalic">E</span>-test diffusion method &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Ten &#40;6&#46;3&#37;&#41; strains were isolated from adult patients and four &#40;3&#46;5&#37;&#41; more from infants&#46; Eight of 10 adult isolates were susceptible to LVX and the remaining two had a MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; and the four infant isolates with NFX MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml were all susceptible to LVX&#46; These 4 infant isolates presented low non-susceptible MICs to NFX &#40;24<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Two out of 274 isolates &#40;0&#46;7&#37;&#41; were resistant to LVX&#44; both of them with a MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; Those isolates susceptible to LVX&#44; but resistant to NFX could be low-level-resistant mutants and the two resistant isolates to both FQs could be high-level-resistant mutants&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A probe hybridization test was performed on the 14 NFX resistant isolates&#44; and mutations in ParC were detected in 6 of 12 low-level-resistant mutants&#46; The remaining 6 isolates hybridized with wild sequences of both genes&#46; One of the two possible high-level-resistant mutants showed mutations in ParC and GyrA sequences&#44; while the other one only in ParC sequence&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">All strains with mutations in the ParC by the probe hybridization test were confirmed by sequencing&#44; and the most common genotype observed was S79F &#40;ParC&#41; substitution&#46; Additionally&#44; sequencing detected one more resistant strain with the S79Y mutation&#46; Seven of the 12 low-level-resistant isolates &#40;58&#46;3&#37;&#41; had mutations in ParC&#46; Only in one of the two high-level-resistant isolates were mutations detected in ParC and GyrA genes&#46; The other LVX resistant isolates showed a mutation in ParC&#46; All substitutions observed in the resistant isolates are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; No mutation was found in the ParE and GyrB genes&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Overall&#44; 10 &#40;71&#46;4&#37;&#41; isolates were positive for reserpine-inhibited efflux&#46; All the five isolates without QRDR substitutions though NFX-resistant were positive for reserpine-inhibited efflux&#46; The isolate with high-level resistance that only showed ParC mutation was also positive for reserpine-inhibited efflux&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The 14 NFX-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates studied belonged to 9 different serotypes&#44; 19A &#40;4 isolates&#41;&#44; 8 &#40;2&#41;&#44; 6A &#40;1&#41;&#44; 14 &#40;1&#41;&#44; 18 &#40;1&#41;&#44; 38 &#40;1&#41;&#44; 3 &#40;1&#41;&#44; 9V &#40;1&#41; and 7F &#40;1&#41; and one isolate could not be amplified&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">PFGE revealed significant heterogeneity among the NFX-resistant isolates&#44; and most of them were genetically unrelated &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Nine different profiles were found&#44; and 3 of these contained two isolates each&#46; Two of the strains with the same genotype were serotype 19A&#44; and were isolated from the same patient&#46; The isolates were obtained in two different episodes and hospital admissions&#44; separated by 4 months&#46; The patient was a 28-year-old man with Job syndrome&#44; characterized by recurrent skin abscesses&#44; atopic dermatitis&#44; pneumonia and high serum levels of IgE&#46; The patient was first hospitalized diagnosed with a community-acquired pneumonia &#40;CAP&#41;&#46; Sputum and blood samples were taken and LVX empirical treatment was started&#46; <span class="elsevierStyleItalic">S&#46; pneumoniae</span> susceptible to penicillin &#40;<span class="elsevierStyleItalic">E</span>-test MIC of 0&#46;016<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; and LVX &#40;<span class="elsevierStyleItalic">E</span>-test MIC of 2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; was grown in both samples&#46; Two months later&#44; the patient was hospitalized again with a new diagnosis of CAP&#46; Isolates were not obtained&#44; but he was again treated with LVX&#46; Four months after the first hospitalization&#44; he returned to the hospital with a <span class="elsevierStyleItalic">S&#46; pneumoniae</span> bacteraemia&#46; The <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">pneumoniae</span> isolated from blood cultures was susceptible to penicillin &#40;<span class="elsevierStyleItalic">E</span>-test MIC of 0&#46;006<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41;&#44; but resistant to LVX &#40;<span class="elsevierStyleItalic">E</span>-test MIC of &#62;32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41;&#46; The first isolate carried a mutation in the QRDR of ParC &#40;S79F&#41; and the second one had an additional GyrA mutation &#40;S81F&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">Although antimicrobial resistance rates in <span class="elsevierStyleItalic">S&#46; pneumoniae</span> continue being a worldwide problem&#44; the prevalence of FQ-resistant strains remains low &#40;1&#8211;7&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a> A 1998&#8211;2002 United States surveillance study found a higher prevalence of LVX resistance among lower respiratory tract isolates compared to blood isolates&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In the 1998 Active Bacterial Core Surveillance program&#44; the Centers for Disease Control and Prevention reported a LVX resistance rate of 0&#46;2&#37; among 3475 invasive isolates&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In our study&#44; a higher LVX resistance rate &#40;0&#46;7&#37;&#41; was found among invasive isolates&#46; Although the resistance level is low&#44; surveillance is necessary&#44; especially to prevent cases of <span class="elsevierStyleItalic">in vivo</span> resistance development as reported&#46; We performed the screening test proposed by CA-SFM to detect low-level-resistant isolates&#44; as failing to detect them may lead to treatment failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a> In Spain&#44; a fatal LVX treatment failure was reported in a patient with a pneumococcal pneumonia who developed <span class="elsevierStyleItalic">in vivo</span> resistance&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and in this work&#44; we described a new case that developed <span class="elsevierStyleItalic">in vivo</span> resistance&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Ten &#40;6&#46;3&#37;&#41; adult isolates and 4 &#40;3&#46;5&#37;&#41; infant isolates showed a MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml to NFX by the <span class="elsevierStyleItalic">E</span>-test diffusion method&#44; but only 2 &#40;1&#46;3&#37;&#41; adult isolates&#44; and none of the infant isolates were LVX-resistant&#46; Moreover&#44; 4 infant isolates presented low non-susceptible MICs to NFX &#40;24<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; and the only resistance mechanism detected was the active efflux&#44; suggesting that these infant strains had probably not been exposed to FQ&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">We have found mutations in the Ser-79 of ParC and Ser-81 of GyrA&#46; ParC substitutions at Ser-79 were to either Phe or Tyr&#44; but the S79F substitution was more prevalent&#46; We detected mutations exclusively in ParC sequence in 8 isolates &#40;57&#46;1&#37;&#41;&#44; and 7 of them were susceptible to LVX &#40;first-step resistance&#41;&#46; There was one isolate that only had ParC mutation and was resistant to LVX&#46; We found other polymorphisms not related to fluoroquinolone resistance in this isolate&#44; ParC &#40;K137N&#41; and ParE &#40;I460V&#41;&#46; It was also positive to reserpine effect&#46; This resistance pattern is unusual&#44; because the isolate is high-level-resistant in a first-step mutation&#46; The clinical impact of this pattern is very important&#44; and the isolate should be studied more thoroughly&#46; The 5 isolates with low-level resistance without mutations in the QRDR genes were positive to reserpine effect&#46; As expected&#44; the isolate with ParC and GyrA mutations &#40;Ser-81&#41; was not susceptible to NFX and LVX &#40;high-level resistance&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Although penicillin- or macrolide-resistant isolates have spread clonally&#44; the clonal relationship of fluoroquinolone-resistant isolates remains unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In the present study we did not find any clonal and serotype relationship&#44; probably due to the low number of resistant strains&#46; However&#44; clonal diversity in LVX-resistant isolates has been reported in other large surveillance studies&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Among the 3 pairs of isolates with the same PFGE profile&#44; a different serotype was observed in one case&#44; another pair had one non-typeable isolate&#44; and the third pair was the strain that developed resistance <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">When we performed the assay to estimate the efflux&#44; the MICs obtained for NFX by microdilution without reserpine varied in one or two dilutions&#44; but remained in the same category&#44; except in two infant isolates&#46; These two isolates had an MIC of 24<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml by <span class="elsevierStyleItalic">E</span>-test and 16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml by microdilution&#46; Mutations in the QRDR genes were not detected&#46; According to CA-SFM recommendations&#44; by <span class="elsevierStyleItalic">E</span>-test&#44; these could be low-level fluoroquinolone-resistant pneumococci&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Active efflux mechanism was found in 10 of 14 NFX-resistant isolates&#44; being associated with other resistance mechanisms in 5 isolates&#46; The other 5 isolates that only presented the efflux mechanism showed lower MICs to NFX &#40;24<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; and the isolates that presented a ParC mutation showed higher MICs to NFX regardless of having the efflux mechanism or not&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The screening method that we have used&#44; using only NFX and LVX <span class="elsevierStyleItalic">E</span>-test&#44; is the simplest alternative according to Varon et al&#46; This option does not discriminate between increased efflux and altered topoisomerase IV&#44; but detects the most frequent low-level-resistant mutants&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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            0 => "Resumen"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "S&#46; pneumoniae isolates"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Serotyping"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "PFGE"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Antimicrobial susceptibilities"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Sequencing and identification of mutations"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Active efflux"
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        6 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Results"
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          "identificador" => "sec0050"
          "titulo" => "Discussion"
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        8 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2011-03-29"
    "fechaAceptado" => "2011-10-02"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec138968"
          "palabras" => array:5 [
            0 => "<span class="elsevierStyleItalic">S&#46; pneumoniae</span>"
            1 => "Resistance"
            2 => "Fluoroquinolone"
            3 => "Mutation"
            4 => "Sequencing"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec138969"
          "palabras" => array:5 [
            0 => "<span class="elsevierStyleItalic">S&#46; pneumoniae</span>"
            1 => "Resistencia"
            2 => "Fluorquinolona"
            3 => "Mutaci&#243;n"
            4 => "Secuenciaci&#243;n"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Due to the emergence of drug-resistant pneumococcal isolates&#44; new fluoroquinolones have been recommended for the treatment of pneumococcal infections&#46; The purpose of this study was to establish surveillance&#44; and to conduct molecular characterization&#44; of fluoroquinolone-resistant <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> in Seville&#46;</p> <span class="elsevierStyleSectionTitle">Method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Norfloxacin-resistant <span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates were characterized by quinolone resistance-determining region &#40;QRDR&#41; substitutions&#44; reserpine-sensitive efflux&#44; serotype and by pulsed-field gel electrophoresis &#40;PFGE&#41; patterns&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Fourteen isolates &#40;5&#46;1&#37;&#41; showed an MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml to norfloxacin&#46; Eight of 10 adult isolates were susceptible to levofloxacin&#46; The 4 infant isolates with norfloxacin MIC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml were susceptible to levofloxacin&#46; Seven of these 12 low-level-resistant isolates had mutations in ParC&#44; while mutations both in ParC and GyrA genes were only detected in one of the two high-level-resistant isolates&#46; All the isolates without QRDR substitutions that remained norfloxacin-resistant were positive for reserpine-inhibited efflux&#46; The serotyping and PFGE revealed significant heterogeneity&#46; We obtained 9 different profiles&#44; 3 of which had two isolates each&#46; Two of the isolates with the same pulsotype were from the same patient&#46; The first isolate showed a mutation in the QRDR of ParC&#44; and the second one had an additional GyrA mutation&#46;</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In our study a levofloxacin resistance rate of 0&#46;7&#37; was found among invasive isolates&#46; Although resistance level is low&#44; surveillance is necessary&#44; especially to prevent cases of <span class="elsevierStyleItalic">in vivo</span> resistance development as reported&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En los &#250;ltimos a&#241;os se ha detectado un aumento de resistencias a fluorquinolonas entre las cepas de <span class="elsevierStyleItalic">Streptococcus pneumoniae&#46;</span> El objetivo de este estudio es realizar la caracterizaci&#243;n molecular y vigilancia de la resistencia a fluorquinolonas en aislamientos de <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> en Sevilla&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La caracterizaci&#243;n de las cepas resistentes a norfloxacina se realiz&#243; mediante el estudio de las mutaciones en los genes QRDR&#44; estudio de bombas de reflujo con reserpina&#44; serotipado y patrones de electroforesis en campo pulsante &#40;ECP&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Catorce &#40;5&#44;1&#37;&#41; aislamientos mostraron una CMI a norfloxacino &#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; De los 10 aislamientos de adultos&#44; 8 fueron sensibles a levofloxacina&#46; Los 4 aislamientos pedi&#225;tricos resistentes a norfloxacina fueron sensibles a levofloxacina&#46; Siete de los 12 aislamientos con bajo nivel de resistencia mostraron una mutaci&#243;n en parC&#44; mientras que s&#243;lo en una de las dos cepas con resistencia de alto nivel encontramos mutaciones en los genes ParC y GyrA&#46; Los aislamientos que no mostraron tener mutaciones&#44; pero eran resistentes a la norfloxacina&#44; fueron positivos para la reserpina&#46; El serotipado y los patrones de ECP revelaron una considerable heterogeneidad&#46; Obtuvimos 9 perfiles diferentes&#44; 3 de los cuales conten&#237;an 2 aislamientos cada uno&#46; Dos de los aislamientos con el mismo pulsotipo resultaron ser del mismo paciente&#46; El primer aislamiento mostr&#243; una mutaci&#243;n en el parC y el segundo&#44; una mutaci&#243;n adicional en el gyrA&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Aunque la tasa de resistencia a levofloxacina obtenida fue baja &#40;0&#44;7&#37;&#41;&#44; es necesaria una vigilancia para prevenir el desarrollo de resistencias <span class="elsevierStyleItalic">in vivo</span> como la que detectamos&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PFGE of <span class="elsevierStyleItalic">S&#46; pneumoniae</span> isolates&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">N&#46;T&#46;&#58; non-typeable&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PFGE type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Serotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">CMI NFX &#40;&#956;g&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">CMI LVX &#40;&#956;g&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations in ParC by commercial assay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations in GyrA by commercial assay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations in ParC by sequencing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations in GyrA by sequencing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Reserpine effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S81F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S79F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;T&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">128&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">WT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab245102.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Molecular characteristics of NFX-resistant <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">pneumoniae</span> isolates&#46;</p>"
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        0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Infectious Diseases Society of America&#47;American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;A&#46; Mandell"
                            1 => "R&#46;G&#46; Wunderink"
                            2 => "A&#46; Anzueto"
                            3 => "J&#46;G&#46; Bartlett"
                            4 => "G&#46;D&#46; Campbell"
                            5 => "N&#46;C&#46; Dean"
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                    0 => array:2 [
                      "doi" => "10.1086/511159"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2007"
                        "volumen" => "44"
                        "paginaInicial" => "S27"
                        "paginaFinal" => "S72"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17278083"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antimicrobial susceptibilities of 1&#44;684 <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and 2&#44;039 <span class="elsevierStyleItalic">Streptococcus pyogenes</span> isolates and their ecological relationships&#58; results of a 1-year &#40;1998&#8211;1999&#41; multicenter surveillance study in Spain"
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                            0 => "E&#46; P&#233;rez-Trallero"
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                            2 => "C&#46; Garc&#237;a-Rey"
                            3 => "E&#46; Bouza"
                            4 => "L&#46; Aguilar"
                            5 => "J&#46; Garc&#237;a-de-Lomas"
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                      "doi" => "10.1128/AAC.45.12.3334-3340.2001"
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                        "tituloSerie" => "Antimicrob Agents Chemother"
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                        "volumen" => "45"
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                        "paginaFinal" => "3340"
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                    0 => array:2 [
                      "titulo" => "Antimicrobial resistance among respiratory pathogens in Spain&#58; latest data and changes over 11 years &#40;1996&#8211;1997 to 2006&#8211;2007&#41;"
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                        0 => array:2 [
                          "etal" => true
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                            1 => "J&#46;E&#46; Mart&#237;n-Herrero"
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                            3 => "C&#46; Garc&#237;a-Delafuente"
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                        "tituloSerie" => "Clin Infect Dis"
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                      "titulo" => "Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46;P&#46; Brenwald"
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                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
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                        "paginaInicial" => "2032"
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                        0 => array:2 [
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                            1 => "V&#46; Zeller"
                            2 => "M&#46;-D&#46; Kitzis"
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                            4 => "L&#46; Gutmann"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9124836"
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                0 => array:2 [
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                      "titulo" => "Prevalence of single mutations in topoisomerase type II genes among levofloxacin-susceptible clinical strains of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> isolated in the United States in 1992 to 1996 and 1999 to 2000"
                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "T&#46;A&#46; Davies"
                            1 => "A&#46; Evangelista"
                            2 => "S&#46; Pfleger"
                            3 => "K&#46; Bush"
                            4 => "D&#46;F&#46; Sahm"
                            5 => "R&#46; Goldschmidt"
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                        "tituloSerie" => "Antimicrob Agents Chemother"
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]

Article information

ISSN: 0213005X
Original language: English

DOI:10.1016/j.eimc.2011.10.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	13	4	17
2024 September	32	5	37
2024 August	20	6	26
2024 July	16	2	18
2024 June	18	5	23
2024 May	12	5	17
2024 April	24	7	31
2024 March	21	8	29
2024 February	10	2	12
2024 January	16	1	17
2023 December	11	6	17
2023 November	31	6	37
2023 October	29	3	32
2023 September	21	5	26
2023 August	12	0	12
2023 July	15	4	19
2023 June	14	3	17
2023 May	12	3	15
2023 April	12	0	12
2023 March	30	3	33
2023 February	16	4	20
2023 January	12	3	15
2022 December	23	9	32
2022 November	32	15	47
2022 October	17	11	28
2022 September	14	12	26
2022 August	15	12	27
2022 July	13	6	19
2022 June	16	11	27
2022 May	23	12	35
2022 April	46	15	61
2022 March	26	13	39
2022 February	27	3	30
2022 January	23	10	33
2021 December	29	13	42
2021 November	22	6	28
2021 October	43	14	57
2021 September	33	6	39
2021 August	17	9	26
2021 July	25	12	37
2021 June	20	9	29
2021 May	21	10	31
2021 April	31	19	50
2021 March	25	16	41
2021 February	15	6	21
2021 January	16	7	23
2020 December	13	9	22
2020 November	10	11	21
2020 October	8	5	13
2020 September	24	7	31
2020 August	16	4	20
2020 July	22	7	29
2020 June	11	15	26
2020 May	22	19	41
2020 April	9	13	22
2020 March	21	13	34
2020 February	17	19	36
2020 January	22	11	33
2019 December	34	18	52
2019 November	9	14	23
2019 October	16	11	27
2019 September	16	4	20
2019 August	12	6	18
2019 July	8	12	20
2019 June	19	28	47
2019 May	84	36	120
2019 April	36	28	64
2019 March	6	12	18
2019 February	11	9	20
2019 January	13	7	20
2018 December	10	15	25
2018 November	19	5	24
2018 October	15	9	24
2018 September	21	5	26
2018 August	13	6	19
2018 July	8	1	9
2018 June	4	2	6
2018 May	9	4	13
2018 April	5	4	9
2018 March	2	0	2
2018 February	9	0	9
2018 January	10	0	10
2017 December	10	2	12
2017 November	16	0	16
2017 October	18	1	19
2017 September	10	8	18
2017 August	25	3	28
2017 July	15	6	21
2017 June	13	7	20
2017 May	17	21	38
2017 April	19	7	26
2017 March	29	12	41
2017 February	14	3	17
2017 January	6	1	7
2016 December	14	3	17
2016 November	19	1	20
2016 October	60	14	74
2016 September	34	2	36
2016 August	15	3	18
2016 July	28	3	31
2016 June	33	13	46
2016 May	21	8	29
2016 April	17	13	30
2016 March	17	16	33
2016 February	17	19	36
2016 January	28	12	40
2015 December	26	12	38
2015 November	19	10	29
2015 October	31	14	45
2015 September	21	12	33
2015 August	18	5	23
2015 July	19	3	22
2015 June	8	2	10
2015 May	16	5	21
2015 April	15	14	29
2015 March	28	10	38
2015 February	24	2	26
2015 January	23	3	26
2014 December	41	5	46
2014 November	19	1	20
2014 October	26	5	31
2014 September	22	1	23
2014 August	29	1	30
2014 July	36	3	39
2014 June	21	0	21
2014 May	24	1	25
2014 April	37	1	38
2014 March	44	16	60
2014 February	50	6	56
2014 January	52	3	55
2013 December	49	4	53
2013 November	46	10	56
2013 October	56	8	64
2013 September	50	10	60
2013 August	94	10	104
2013 July	71	8	79
2013 June	17	4	21
2013 May	24	5	29
2013 April	22	12	34
2013 March	17	4	21
2013 February	7	6	13
2013 January	3	1	4
2012 December	4	1	5
2012 November	0	2	2
2012 October	0	1	1
2012 September	2	1	3
2012 March	956	0	956

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