Update of SEPAR Guideline “Diagnosis and Treatment of Drug-Resistant Tuberculosis”

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Adaptado de Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0220">1</a> y Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0325">22</a>. (Actualiza la figura 2 de la normativa de 2017<a class="elsevierStyleCrossRef" href="#bib0220">1</a>)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José A. Caminero, José-María García-García, Joan A. Caylà, Francisco J. García-Pérez, Juan J. Palacios, Juan Ruiz-Manzano" "autores" => array:6 [ 0 => array:2 [ "nombre" => "José A." "apellidos" => "Caminero" ] 1 => array:2 [ "nombre" => "José-María" "apellidos" => "García-García" ] 2 => array:2 [ "nombre" => "Joan A." "apellidos" => "Caylà" ] 3 => array:2 [ "nombre" => "Francisco J." "apellidos" => "García-Pérez" ] 4 => array:2 [ "nombre" => "Juan J." 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Around the lesion are the typical yellowish sulfur granules, highly characteristic of the genus Actinomyces. 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Caminero, José-María García-García, Joan A. Caylà, Francisco J. García-Pérez, Juan J. Palacios, Juan Ruiz-Manzano" "autores" => array:6 [ 0 => array:3 [ "nombre" => "José A." "apellidos" => "Caminero" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 1 => array:4 [ "nombre" => "José-María" "apellidos" => "García-García" "email" => array:1 [ 0 => "josemariagarcia@separ.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "Joan A." 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"apellidos" => "Palacios" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] 5 => array:3 [ "nombre" => "Juan" "apellidos" => "Ruiz-Manzano" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "h" "identificador" => "aff0040" ] ] ] ] "afiliaciones" => array:8 [ 0 => array:3 [ "entidad" => "Servicio de Neumología, Hospital General de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unión Internacional contra la Tuberculosis y Enfermedades Respiratorias (La Unión), París, France" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Programa Integrado de Investigación en Tuberculosis (PII TB) de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Neumología, Hospital Universitario San Agustín, Avilés, Asturias, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Fundación de la Unidad de Investigación en Tuberculosis (fuiTB) de Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Neumología, Hospital Universitario de La Princesa, Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Unidad de Referencia Regional de Micobacterias, Servicio de Microbiología, Hospital Universitario Central de Asturias, Oviedo, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Centro Médico Teknon, Barcelona, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización de la normativa SEPAR «Diagnóstico y tratamiento de la tuberculosis con resistencia a fármacos»" ] ] "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" => 1848 "Ancho" => 3167 "Tamanyo" => 541658 ] ] "descripcion" => array:1 [ "en" => "Characteristics of drugs with activity against M. tuberculosis. Adapted from Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0220">1</a> and Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0325">22</a> (Updates Figure 2 of the 2017guidelines<a class="elsevierStyleCrossRef" href="#bib0220">1</a>)." ] ] ] "textoCompleto" => "IntroductionIn 2017, the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) published guidelines on the diagnosis and treatment of drug-resistant tuberculosis (DR-TB).<a class="elsevierStyleCrossRef" href="#bib0220">1</a> Since important updated evidence on the management of these patients has appeared,<a class="elsevierStyleCrossRefs" href="#bib0225">2–4</a> prompting the publication of 2 new guidelines by the World Health Organization (WHO),<a class="elsevierStyleCrossRefs" href="#bib0240">5,6</a> and another by the American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC)/European Respiratory Society (ERS)/Infectious Diseases Society of America (IDSA),<a class="elsevierStyleCrossRef" href="#bib0250">7</a> in addition to recent WHO communications on TB diagnosis and treatment.<a class="elsevierStyleCrossRefs" href="#bib0255">8–10</a>In the light of this new knowledge, an update of the 2017 SEPAR guidelines is needed.Diagnosis of TuberculosisXpert® MTB/RIF UltraCepheid has developed a new generation Xpert® MTB/RIF Ultra technique with enhanced susceptibility using 2 amplification targets (IS6110 and IS1081) and a larger polymerase chain reaction chamber (50μl in Ultra, vs 25μl in the Xpert® MTB/RIF). The new Ultra system features a lower mycobacterial detection limit (16 colony-forming units per ml compared to 131 in the Xpert® MTB/RIF).<a class="elsevierStyleCrossRefs" href="#bib0270">11,12</a>It uses the same semi-quantitative categories as Xpert® MTB/RIF (high, medium, low and very low), but a new category called “detected trace” has been added, offering increased sensitivity (90% sensitivity in pulmonary TB compared to sputum culture).<a class="elsevierStyleCrossRef" href="#bib0255">8</a> In people living with human immunodeficiency virus (HIV), children, and patients being evaluated for extrapulmonary TB or suspected TB, “trace calls” should be considered as true positives.<a class="elsevierStyleCrossRef" href="#bib0270">11</a>The current WHO recommendation for the use of Xpert® MTB/RIF also applies to the Ultra technique: it should be used as the initial diagnostic test in all adults and children with signs and symptoms of TB and for the study of selected extrapulmonary samples (cerebrospinal fluid, lymph nodes and tissue samples), and samples from children (nasopharyngeal, gastric, and stool specimens<a class="elsevierStyleCrossRefs" href="#bib0255">8,11</a>).Possibility of Using Other Rapid Molecular Methods for the Diagnosis of Tuberculosis and Drug-resistant TuberculosisSince 2017, evidence has accumulated to recommend other molecular methods, either to replace Xpert® MTB/RIF (normal or Ultra version) or to supplement it, since this test only detects rpoB mutations. Some of the different available alternatives include: BD MAX® MDR-TB (Becton Dickinson)<a class="elsevierStyleCrossRef" href="#bib0280">13</a>; Abbott RealTime® MTB RIF/INH assay; FluoroType® MTBDR (Hain); Anyplex® MTB/NTM y Anyplex® MTB/MDR/XDR (Seegene); TrueNat® (Molbio Diagnostics).<a class="elsevierStyleCrossRef" href="#bib0285">14</a> These techniques all use real-time polymerase chain reaction amplification systems for specific targets, with varying degrees of automation. In addition to detecting Mycobacterium tuberculosis complex and rifampicin resistance (RR), some can be used (in 1 or 2 steps) to amplify the spectrum of isoniazid (H) resistance detection (BD MAX® MDR-TB, Abbott RealTime® MTB RIF/INH assay, FluoroType® MTBDR, Anyplex® MTB/MDR/XDR). Anyplex® MTB/NTM can simultaneously detect non-tuberculous mycobacteria, information that is highly useful in differential diagnosis when the diagnosis of M. tuberculosis disease is not confirmed by any of the techniques used. They can also be used to amplify resistance detected to fluoroquinolones (FQ) and aminoglycosides/polypeptides (Anyplex® MTB/MR/XDR), the latter being similar to the GenoType®MDRsl already mentioned in our 2017 recommendation.We will clearly have to remain alert to the development of new technologies in the immediate future, given the advances in the diagnosis of this disease.Finally, it should be noted that molecular tests can also help improve the final outcome of patients with TB (the use of Xpert® MTB/RIF as an initial test to replace sputum smears has led to improved cure rates, reduced mortality and fewer cases lost before start of treatment<a class="elsevierStyleCrossRef" href="#bib0255">8</a>).Discrepancies in Rifampicin Resistance Results by Different MethodsIn line with current evidence, it is agreed that a patient who shows TB with RR (RR-TB) using any properly performed method (either phenotypic or molecular) should be considered and treated as such, even if the results from other methods are conflicting.<a class="elsevierStyleCrossRef" href="#bib0290">15</a> Complete genome sequencing of M. tuberculosis helps resolve discrepancies and allows for the detection of mutations not identified by other methods.<a class="elsevierStyleCrossRefs" href="#bib0295">16,17</a> It is a test that will certainly become part of routine diagnosis as its use becomes widespread.Basis for Treatment of all Forms of Tuberculosis, Both Susceptible and Drug-ResistantNumber of Drugs Needed to Treat tuberculosisThe recommendation to use at least 4 previously unused drugs, or drugs with proven M. tuberculosis susceptibility, was made on the basis that there might be resistance to one of the 4 compounds (as in the case of H in the initial regimen) and because some of them might have reduced efficacy, such as the case of ethionamide (Eto)/prothionamide (Pto), cycloserine, or para-aminosalicylic acid in patients with RR-TB or multidrug-resistant (MDR)-TB (TB resistant to at least H+R).<a class="elsevierStyleCrossRefs" href="#bib0305">18,19</a> Susceptibility to H+R can now be determined at the beginning of treatment, and powerful drugs, such as FQ, linezolid (LZD), bedaquiline (BDQ) and clofazimine (Cfz), that have a very low probability of being resistant (a rapid molecular test can be performed in the case of FQ) and show good bactericidal and sterilizing activity,<a class="elsevierStyleCrossRefs" href="#bib0305">18–21</a> can be used in the initial regimen. Thus, a course of only 3 new drugs for 6–9 months may be sufficient to cure TB with a minimum risk of acquisition of resistance or subsequent relapses.<a class="elsevierStyleCrossRefs" href="#bib0305">18–20</a>If susceptibility results are not available for any of the key drugs for which reliable susceptibility tests are available (H, R, FQ), or if such tests do not exist (as in the case of BDQ), doubts regarding resistance may arise and recourse to some drugs of doubtful efficacy may be necessary. In such cases, the recommendation of at least 4 drugs to treat TB would remain in force.<a class="elsevierStyleCrossRefs" href="#bib0305">18,20,22</a> In the case of BDQ, some publications have warned of the emergence of resistance,<a class="elsevierStyleCrossRefs" href="#bib0330">23,24</a> but these cases remain exceptional and are limited to settings in which the drug has not been used properly. We must remain alert to these communications, but for the moment, this drug can be expected to be susceptible in Spain.Change in the Choice of So-called Essential and Accompanying DrugsAll the new drugs (FQ, Lzd, BDQ, Cfz) that are already fully incorporated into the treatment of RR-TB/MDR-TB can be considered essential (with good bactericidal and/or sterilizing capacity), so the use of accompanying medications would be unnecessary, except in situations of widespread resistance.<a class="elsevierStyleCrossRefs" href="#bib0310">19,20</a> At present, the recommendation should be to use at least 3 essential drugs, with at least 1–2 that show good bactericidal activity and 1–2 with good sterilizing activity. No accompanying drug should be included unless unavoidable<a class="elsevierStyleCrossRef" href="#bib0325">22</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Rational Classification of Drugs With Activity Against M. tuberculosisThis section has been substantially modified based on the results of the WHO meta-analysis, on changes in the classification subsequently recommended by the WHO and on updated data on the bactericidal and/or sterilizing activity of these drugs as set out in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<a class="elsevierStyleCrossRefs" href="#bib0230">3,6,21</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Treatment of Tuberculosis by Resistance PatternImportant changes have been made, especially in the case of RR-TB/MDR-TB and extensively drug-resistant TB (XDR-TB, meaning MDR-TB plus resistance to at least one FQ and to a second-line injectable drug [kanamycin, amikacin, capreomycin]) listed in <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Treatment of Tuberculosis With Susceptibility to Rifampicin and Proven or Unknown Susceptibility to IsoniazidThere are no changes with respect to the previous guidelines. In new cases of TB in which susceptibility to all drugs is presumed, or if the absence of mutations in the rpoB gene (molecular detection of resistance to R) has been confirmed by molecular testing, the ideal treatment regimen is 2 HRZE/4 HR. However, if the absence of gene mutations in rpoB, katG and inhA (molecular detection of resistance to H) is confirmed by molecular testing in the first days of treatment, 2 HRZ/4 HR would be sufficient<a class="elsevierStyleCrossRefs" href="#bib0285">14,18</a>(strong recommendation, high quality of evidence [⊕⊕⊕⊕]).To reduce the possibility of errors and the possible selection of resistance, these drugs should always be administered in fixed combination doses and with directly observed treatment in patients who have risk factors for poor therapeutic compliance.<a class="elsevierStyleCrossRef" href="#bib0220">1</a>Treatment of Tuberculosis Resistant to Isoniazid (Mono- or Polyresistance), But Susceptible to RifampicinThe 9 HRZE regimen recommended as a priority in the 2017 guidelines should still be prioritized<a class="elsevierStyleCrossRef" href="#bib0220">1</a>(conditional recommendation, low [⊕] to very low [] evidence quality). The use of high doses of H may be evaluated, especially if a rapid molecular test (GenoType®) that shows the absence of mutation in the katG gene is available. However, the other regimens recommended in our 2017 guidelines, consisting of 2 FQ-REZ/7 FQ-RE (E: ethambutol, Z: pyrazinamide), should be replaced by the WHO recommended regimen of 6 Lfx-REZ(H) (Lfx: levofloxacin),<a class="elsevierStyleCrossRefs" href="#bib0240">5,6</a> while taking into account our previous recommendations for the FQ-containing regimen, i.e., Lfx should only be included in the regimen if it is administered from the beginning with the other drugs. It should not be added if H resistance results will only be received after 3–4 weeks of treatment, due to the possible risk of inadvertent monotherapy. These recommendations, which led to the inclusion of LFx in this regimen, are based on a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0225">2</a> in which the vast majority of patients came from sites where the results of H resistance testing were determined very quickly, but this situation is unusual, even in our setting. It should also be noted that another meta-analysis<a class="elsevierStyleCrossRef" href="#bib0340">25</a> found that 9 RZE is equally effective in curing cases with resistance or susceptibility to H.Treatment of Tuberculosis Resistant to Rifampicin (Mono- or Polyresistance), But Susceptible to IsoniazidIt is still true to say that cases of isolated resistance to R are rare in clinical practice, and that since resistance to R determines prognosis in patients with MDR-TB, these patients should be managed as MDR-TB patients, and treated as such, adding H to the regimen, of course, because if its susceptibility is confirmed, it will be an important contribution to treatment<a class="elsevierStyleCrossRefs" href="#bib0220">1,6</a>(conditional recommendation, low [⊕] to very low [] quality of evidence).Treatment of Multidrug-Resistant Tuberculosis (MDR-TB)The significant amount of evidence accumulated in this section<a class="elsevierStyleCrossRefs" href="#bib0230">3,4,6,19,20</a> requires a significant change in the recommendations made in the 2017 guidelines.<a class="elsevierStyleCrossRef" href="#bib0220">1</a> Fortunately, this evidence is bringing about almost continuous changes in recent months. Thus, in March 2019, the WHO guidelines<a class="elsevierStyleCrossRef" href="#bib0245">6</a> prioritized long individualized oral regimens of 18–20 months’ duration. However, after studies with new drugs appeared, the WHO itself published a rapid communication in December 2019<a class="elsevierStyleCrossRef" href="#bib0260">9</a> recommending that priority be given to shorter oral regimens including BDQ, and in a new publication that appeared in January 2020,<a class="elsevierStyleCrossRef" href="#bib0265">10</a> based on accumulated evidence, it recommended prioritizing a shorter BDQ regimen.Therefore, based on the latest evidence in the treatment of RR-TB/MDR-TB, priority should be given to shorter oral regimens based on BDQ,<a class="elsevierStyleCrossRefs" href="#bib0260">9,10</a> and shorter (or longer) injectable regimens should no longer be used in RR-TB/MDR-TB As a result, the regimen that was recommended as a priority in our 2017 guidelines should no longer be used, especially as the cumulative evidence has shown that oral regimens are better and much less toxic.Based on this, one of the following regimens may be recommended in these patients:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">(A)Shorter oral regimens with BDQ</li></ul>In this section, one of the following 3 regimens could be considered. The advantages and disadvantages of these regimens will be analyzed.1. This first regimen offers 2 possibilities:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">(a)If the sputum smear is negative at month 4: 4 Bdq*-Lfx/moxifloxacin (Mfx)-Cfz-Eto/Pto-E-Z-hH/2 BDQ-Lfx/Mfx-Cfz-Z-E/3 Lfx/Mfx-Cfz-Z-E.</li><li class="elsevierStyleListItem" id="lsti0015">(b)If the sputum smear is positive at month 4: 6 BDQ*-Lfx/Mfx-Cfz-Eto/Pto-E-Z-hH/5 Lfx/Mfx-Cfz-Z-E.(conditional recommendation, low [⊕] to very low [] quality of evidence)</li></ul>*In both options, BDQ should be administered for 6 months, accompanied in the first option by intensive-phase drugs for the first 4 months and continuation-phase drugs for the next 2 months, completing treatment with 3 more months of continuation-phase drugs alone (9 months total). However, if the sputum smear remains positive at the end of month 4, all drugs in this intensive phase and BDQ will be administered for 6 months, followed by continuation-phase drugs for 5 months, for a total duration of treatment of 11 months (option b). If the sputum smear remains positive at the end of month 6, this regimen will be considered to have failed and a different regimen should be designed. hH means high-dose H.This treatment regimen has the advantage that it has the most supporting evidence, and is therefore recommended as a priority by the WHO in its latest publication in January 2020.<a class="elsevierStyleCrossRef" href="#bib0265">10</a> It is practically the same as the regimen we recommended in our 2017 guidelines,<a class="elsevierStyleCrossRef" href="#bib0220">1</a> and it is supported by a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0345">26</a> and a randomized clinical trial,<a class="elsevierStyleCrossRef" href="#bib0350">27</a> the only difference being the use of BDQ instead of amikacin. However, it has the drawback that it still uses 7 drugs in the intensive phase, including some with very little or doubtful efficacy,<a class="elsevierStyleCrossRef" href="#bib0230">3</a> such as Eto/Pto, E, Z and hH; some of which are as poorly tolerated as Eto/Pto.Because of the speed with which new evidence is accumulating on this topic, the WHO will probably soon amend its recommendations in favor of one of the other 2 options set out below.2. 6 BDQ-hLfx-LZD-Cfz/3 hLfx-LZD-Cfz (conditional recommendation, low [⊕] to very low [] quality of evidence)If the sputum smear remains positive at the end of month 6, this regimen will be considered to have failed and a different individualized regimen should be designed. (hLfx means high-dose Lfx). hLfx is preferred because it causes less QTc interval prolongation on electrocardiogram than Mfx,<a class="elsevierStyleCrossRef" href="#bib0355">28</a> taking into account that the regimen contains 2 other drugs that also prolong QTc (BDQ and Cfz).This regimen has the advantage that it uses the 4 drugs that are given priority in the WHO recommendations of 2019<a class="elsevierStyleCrossRef" href="#bib0245">6</a> and, since they all have sterilizing activity,<a class="elsevierStyleCrossRef" href="#bib0320">21</a> a total of 9 months of treatment would be sufficient. Moreover, since BDQ, Lzd, and Cfz have been used sparingly in the treatment of RR-TB/MDR-TB in Spain, drug susceptibility may be assumed to be highly probable.Ideally, a susceptibility test should be performed to rule out resistance to FQ before beginning this regimen, although it could also apply to patients with RR-TB/MDR-TB who have never received these drugs for TB treatment.3. 6–9 BDQ-hLfx-Lzd (conditional recommendation, low [⊕] to very low [] quality of evidence)According to the section on the number of drugs needed to treat TB, a 6-month regimen with high doses of LFx+Lzd+BDQ<a class="elsevierStyleCrossRefs" href="#bib0305">18,19</a> would meet all requirements to be considered an effective regimen. It consists of 3 new drugs, all of which have bactericidal and sterilizing capacity, although susceptibility must be confirmed for Lfx.<a class="elsevierStyleCrossRefs" href="#bib0305">18–21</a> In this regimen, LFx is preferred to MFX, because it is causes less QTc prolongation on electrocardiogram,<a class="elsevierStyleCrossRef" href="#bib0355">28</a> taking into account that the regimen already contains another drug with the same effect (BDQ). If the sputum smear is still positive at the end of month 2, the regimen should be prolonged until 9 months, provided that the sputum smear and culture are negative at the end of month 4 of treatment.<a class="elsevierStyleCrossRef" href="#bib0290">15</a>This regimen is very similar to the BPaL combination being successfully tested in the NIX-TB randomized clinical trials in patients with XDR-TB.<a class="elsevierStyleCrossRefs" href="#bib0360">29,30</a> The 6-month of Lzd+BDQ+pretomanid has been approved by the U.S. FDA.<a class="elsevierStyleCrossRef" href="#bib0370">31</a> Promising outcomes have been published recently<a class="elsevierStyleCrossRef" href="#bib0375">32</a> and it has already been included in the WHO recommendations.<a class="elsevierStyleCrossRef" href="#bib0260">9</a> Pretomanid is not marketed in Spain. The study<a class="elsevierStyleCrossRefs" href="#bib0365">30,32</a> has limitations that were mentioned in the recent WHO communication: it has a small number of patients (108) and adverse effects were observed (hematological, hepatic, optical and peripheral neuropathy), although a large proportion of these were related to the use of high doses of Lzd (1200mg/day), whereas 600mg/day may be sufficient. The shorter oral regimen proposed in these guidelines would only lead, in terms of NIX-TB to switching LFx for pretomanid because BPaL was indicated for patients with FQ resistance. Moreover, according to the available data, pretomanid is no better than Lfx in the treatment of TB.<a class="elsevierStyleCrossRef" href="#bib0380">33</a>The advantages of these 6–9-month oral regimens (Lfx+Lzd+BDQ in MDR-TB and Lzd+BDQ+pretomanid in XDR-TB) are that all drugs are administered orally, they use the best second-line drugs, they are not ototoxic, they do not need ion monitoring, and because the courses are much shorter, the potential risk of dropout is reduced. The drawbacks of these regimens are similar to the others, including the need to monitor the QTc interval (when they contain 2 drugs – LFx and BDQ – that prolong QTc) and to monitor the possible toxicity of Lzd, although this should be less than in the other regimens as the time of administration is shorter.A regimen such as the one discussed, which is shorter and administered orally, must be used in programmatic research conditions (patient monitoring, support, and proper inclusion, principles of good clinical practice, informed patient consent, active monitoring and treatment of drug side effects, treatment monitoring, evaluation of the final outcome, standardized data collection), which would constitute the minimum requirements for the management of these patients.<a class="elsevierStyleCrossRef" href="#bib0260">9</a>It is therefore very possible that patients will immediately be able to receive these novel treatments under the conditions described above.<a class="elsevierStyleCrossRef" href="#bib0260">9</a>One important limitation associated with BDQ is its high price and difficult accessibility. Given its essential role in the new treatment regimens, efforts must be made at the institutional level to facilitate its availability in Spain.<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020">(B)Longer oral regimen</li></ul>Although this regimen was recommended until a few months ago as a priority by WHO,<a class="elsevierStyleCrossRef" href="#bib0245">6</a> it should now be relegated to a second step,<a class="elsevierStyleCrossRefs" href="#bib0265">10,11</a> which would consist of a 6-month intensive phase with BDQ+Lfx/Mfx+Lzd+Cfz, plus a 12-month continuation phase with Lfx/Mfx+Lzd+Cfz (conditional recommendation, low [⊕] to very low [] evidence quality), thus meeting the criteria of the WHO recommendations of March 2019.<a class="elsevierStyleCrossRef" href="#bib0245">6</a> The regimen proposed by ATS/CDC/ERS/IDSA<a class="elsevierStyleCrossRef" href="#bib0250">7</a> follows the same order of priority and drug groups as that of WHO, although it differs in terms of higher drug numbers (5 in the intensive phase and 4 in the continuation phase) and a longer treatment time (15 to 21 months after culture conversion).<a class="elsevierStyleCrossRef" href="#bib0250">7</a>There is no doubt that this regimen will be very effective, because it uses the best drugs available in the treatment of RR-TB/MDR-TB.<a class="elsevierStyleCrossRefs" href="#bib0230">3,6</a> However, based on the above considerations, it may involve too many drugs (4) administered for too long, especially since they are all very potent with almost certain susceptibility and sterilizing capacity.<a class="elsevierStyleCrossRefs" href="#bib0310">19,20,34</a>The disparities between these international guidelines<a class="elsevierStyleCrossRefs" href="#bib0245">6,7</a> may emerge from the fact that the recommendations have a low or very low quality of evidence. Moreover, both guidelines are based on a meta-analysis performed by the WHO itself<a class="elsevierStyleCrossRef" href="#bib0230">3</a> to assess the value of each drug in the different RR-TB/MDR-TB regimens. This study concluded that Lzd, carbapenems, Lfx/Mfx, BDQ and Cfz were the most effective drugs, and the remaining drugs contributed little to the possible success of RR-TB/MDR-TB treatment; the latter included Eto/Pto, cycloserine, para-aminosalicylic acid, E, and Z. It also found that the inclusion of drugs such as kanamycin or capreomycin was associated with a worse therapeutic outcome. This meta-analysis<a class="elsevierStyleCrossRef" href="#bib0230">3</a> also concluded that the most effective regimen was a combination of 4–5 effective drugs and a minimum duration of 18 months. However, a recognized limitation of this study is that practically all the regimens analyzed contained quite a few drugs associated with very slight or no improvement in outcomes (ineffective, weak drugs),<a class="elsevierStyleCrossRef" href="#bib0230">3</a> and few had useful sterilizing activity.<a class="elsevierStyleCrossRef" href="#bib0310">19</a>Treatment of Patients With Extensively Drug-Resistant Tuberculosis (XDR-TB) or Even Broader Resistance PatternsWhile significant progress has also been made in this area, we continue to believe that these forms of TB are so difficult to manage (in clinical practice and in programmatic conditions) that they should be treated by highly skilled specialists and in units that can guarantee close supervision of the treatment and proper management of adverse reactions.Contact TracingThe news in this area is that enough evidence has been accumulated to be able to recommend, as an alternative to the periodic reviews that remain the most widely accepted recommendation, a preventive regimen with an FQ (Mfx or LFx)<a class="elsevierStyleCrossRef" href="#bib0390">35</a> in close contacts of RR-TB/MDR-TB cases in whom disease is ruled out, especially in children or immunosuppressed individuals. This treatment should be administered for a period of 6 months (conditional recommendation, very low [] quality of evidence).Treatment of Tuberculosis in People Living With Human Immunodeficiency VirusTreatment of drug-susceptible or drug-resistant TB in HIV-infected patients is the same as in non-infected patients. In patients with both infections who have not started treatment, starting TB treatment will be prioritized. If the patient has CD4 <50mm–3 at 2 weeks, good adherence, and no side effects have been confirmed, combination antiretroviral therapy (cART) will be started. In patients with higher CD4 counts, cART can begin after month 2, when the patient is already taking fewer TB drugs. Better survival has been observed with these regimens.<a class="elsevierStyleCrossRefs" href="#bib0395">36,37</a> In cases of tuberculous meningitis, cART should start after 8 weeks of TB treatment.<a class="elsevierStyleCrossRef" href="#bib0405">38</a>The interactions between rifamycins and some antiretrovirals should be taken into account; in these cases, rifabutin may be an alternative to rifampicin but that would rule out fixed drug doses, so a cART based on efavirenz would be advisable.<a class="elsevierStyleCrossRef" href="#bib0410">39</a>These patients should be managed by clinical experts in both infections, with monitoring for adherence to both treatments (using directly observed treatment if necessary; methadone maintenance programs help treatment in heroin users). Side effects and the possibility of immune reconstitution syndrome should be monitored, along with the usual follow-up.<a class="elsevierStyleCrossRef" href="#bib0410">39</a> TB-HIV co-infection is a very serious worldwide problem that will only be solved with firm political commitment.<a class="elsevierStyleCrossRef" href="#bib0415">40</a>Conclusions<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025">1.The systematic use of rapid molecular tests is recommended in the diagnosis of TB to increase the diagnostic sensitivity of the disease, to help early detection of drug resistance, and to achieve better therapeutic outcomes for patients.</li><li class="elsevierStyleListItem" id="lsti0030">2.Although resistance in TB complicates treatment and the chances of success, if basic management guidelines are followed, acceptable cure rates can be achieved in the vast majority of patients. These basic procedures, which summarize virtually the entire guidelines, are set out in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0035">3.Treatment plans for these patients, both initial and adjusted, should always be consulted with experts. To this end, health authorities<a class="elsevierStyleCrossRef" href="#bib0420">41</a> and/or scientific societies should promote the organization of expert groups at state level.</li><li class="elsevierStyleListItem" id="lsti0040">4.The top priorities will continue to be to offer adequate treatment to all patients with susceptible TB and to achieve good adherence in order to avoid the development of resistance.</li></ul>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1372269" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1260944" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1372268" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1260943" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Diagnosis of Tuberculosis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Xpert® MTB/RIF Ultra" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Possibility of Using Other Rapid Molecular Methods for the Diagnosis of Tuberculosis and Drug-resistant Tuberculosis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Discrepancies in Rifampicin Resistance Results by Different Methods" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Basis for Treatment of all Forms of Tuberculosis, Both Susceptible and Drug-Resistant" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Number of Drugs Needed to Treat tuberculosis" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Change in the Choice of So-called Essential and Accompanying Drugs" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Rational Classification of Drugs With Activity Against M. tuberculosis" ] 8 => array:3 [ "identificador" => "sec0050" "titulo" => "Treatment of Tuberculosis by Resistance Pattern" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment of Tuberculosis With Susceptibility to Rifampicin and Proven or Unknown Susceptibility to Isoniazid" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment of Tuberculosis Resistant to Isoniazid (Mono- or Polyresistance), But Susceptible to Rifampicin" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Treatment of Tuberculosis Resistant to Rifampicin (Mono- or Polyresistance), But Susceptible to Isoniazid" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Treatment of Multidrug-Resistant Tuberculosis (MDR-TB)" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Treatment of Patients With Extensively Drug-Resistant Tuberculosis (XDR-TB) or Even Broader Resistance Patterns" ] ] ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Contact Tracing" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Treatment of Tuberculosis in People Living With Human Immunodeficiency Virus" ] 11 => array:2 [ "identificador" => "sec0090" "titulo" => "Conclusions" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1260944" "palabras" => array:4 [ 0 => "Tuberculosis" 1 => "Diagnosis" 2 => "Treatment" 3 => "Resistant tuberculosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1260943" "palabras" => array:4 [ 0 => "Tuberculosis" 1 => "Diagnóstico" 2 => "Tratamiento" 3 => "Tuberculosis resistente" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "New evidence and knowledge about the clinical management of drug-resistant tuberculosis (TB) in the last 3 years, makes it necessary to update the recent guideline published by SEPAR in 2017, mainly in relation to new diagnostic methods, drug classification, and regimens of treatment recommended to treat patients with isoniazid-resistance TB, rifampicin resistance TB and multidrug-resistant TB. With respect to tuberculosis diagnosis, we recommend the use of rapid molecular assays that also help to detect mutations associated with resistance. In relation to the treatment of multidrug-resistant TB we prioritize effective all-oral shorter treatment regimens including bedaquiline, a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline and linezolid, instead of the previously recommended short-course treatment with aminoglycosides and other less effective and more toxic drugs. The design of these regimens (initial schedule and changes in the regimen if necessary) should be made in accordance with drug-resistant TB experts; the treatment should be the responsibility of personnel with experience in the treatment of TB and in TB units guaranteeing the follow-up of the treatment and the management of drugs adverse effects." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La evidencia acumulada en los 3 últimos años sobre el manejo clínico de la tuberculosis (TB) con resistencia a fármacos ha sido tan importante que hace necesario actualizar la normativa que SEPAR publicó en 2017, sobre todo en lo referente a nuevos métodos diagnósticos, a la clasificación racional de los fármacos con actividad frente a Mycobacterium tuberculosis y a los esquemas básicos a recomendar en los pacientes con TB con resistencia a isoniacida, con resistencia a rifampicina o con multifarmacorresistencia. En el diagnóstico de la enfermedad recomendamos la utilización de métodos moleculares rápidos que son útiles además para la detección precoz de mutaciones asociadas a resistencias a fármacos. Para el tratamiento de los enfermos con TB con multifarmacorresistencia se hace necesario dar prioridad a esquemas orales acortados que incluyan bedaquilina, una fluoroquinolona (levofloxacino o moxifloxacino) y linezolid en lugar de los esquemas cortos previamente recomendados con aminoglucósidos y otros muchos fármacos de menor eficacia y más tóxicos. La recomendación de la normativa es que el diseño de los tratamientos en estos pacientes, tanto el inicial como si se precisan cambios, sea consultado siempre con expertos en el manejo de TB con resistencia a fármacos y que se realicen por personal con experiencia en TB y en unidades que garanticen la supervisión de los tratamientos y el abordaje de sus reacciones adversas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Caminero JA, García-García J-M, Caylà JA, García-Pérez FJ, Palacios JJ, Ruiz-Manzano J. Actualización de la normativa SEPAR «Diagnóstico y tratamiento de la tuberculosis con resistencia a fármacos». Arch Bronconeumol. 2020;56:514–521." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1848 "Ancho" => 3167 "Tamanyo" => 541658 ] ] "descripcion" => array:1 [ "en" => "Characteristics of drugs with activity against M. tuberculosis. Adapted from Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0220">1</a> and Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0325">22</a> (Updates Figure 2 of the 2017guidelines<a class="elsevierStyleCrossRef" href="#bib0220">1</a>)." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group 1. First-line oral drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Essential: Rifampicin, isoniazid and pyrazinamide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Accompanying: Ethambutol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group 2. This corresponds to the current WHO group A.<a class="elsevierStyleCrossRef" href="#bib0245">6</a>Three groups of drugs are included here, to be prioritized in the following order: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a Levofloxacin or moxifloxacin. Ideally, resistance to these drugs should be ruled out using rapid molecular methods such as GenoType® or Anyplex® \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b Linezolid \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c Bedaquiline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group 3. This corresponds to the current WHO group B.<a class="elsevierStyleCrossRef" href="#bib0245">6</a>Two drugs are included here, one of which (clofazimin) has much greater evidence of action than the other (cycloserin). If one of the 2 is to be chosen, clofazimin will always be givenpriority<a class="elsevierStyleCrossRefs" href="#bib0230">3,6</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a Clofazimin. This should be the drug of choice if any of the drugs in group 2 cannot be used \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b Cycloserine. In some specific cases, some of the drugs in group 4 may be used prior to cycloserine on the basis of their better bactericidal and/or sterilizing action \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group 4. This corresponds to the current WHO group C,<a class="elsevierStyleCrossRef" href="#bib0245">6</a>but the sequence of inclusion in the regimens should be asfollows<a class="elsevierStyleCrossRef" href="#bib0315">20</a>: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a Meropenem, or imipenem/cilastatin. Both should be given at the same time as amoxicillin/clavulanate to facilitate their effectiveness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b Delamanid. Sometimes it may be preferable to use this drug before carbapenems because of the possibility of oral administration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c Amikacin<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>. This should only be used if these 3 conditions are met. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 Possible resistance has been ruled out by a rapid molecular test \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 Periodic audiometric checks can be done \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 There are no other drugs available among those previously listed in groups 2 and 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">d Ethionamide or prothionamide. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">e Pyrazinamide. Its use here applies to cases of rifampicin-resistant tuberculosis/multidrug-resistant tuberculosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">f Ethambutol. Its use here applies to cases of rifampicin-resistant tuberculosis/multidrug-resistant tuberculosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">g Para-aminosalicylic acid \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2356438.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Streptomycin may sometimes be evaluated for use in place of amikacin if there is resistance to amikacin and susceptibility to streptomycin, but the 3 conditions previously described in the table must also be fulfilled." ] ] ] "descripcion" => array:1 [ "en" => "Rational Classification and Sequential Use of Anti-tuberculosis Drugs in the Design of a Treatment Regimen for Both Drug-susceptible and Drug-resistant Tuberculosis. (This Table Updates Table 3 of the 2017 Guidelines<a class="elsevierStyleCrossRef" href="#bib0220">1</a>)." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "E: ethambutol; H: isoniazid; LFx: levofloxacin; R: rifampicin; TB: tuberculosis; Z: pyrazinamide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Initial TB cases with R susceptibility (known or unknown Hsusceptibility<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- 2 HRZE/4 HR, or 2 HRZ/4 HR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* 2 HRZ/4 HR in cases where susceptibility to H can be determined in the first 2 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. TB cases with resistance to H (mono- or polyresistance), but with susceptibility toR<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a>,<a class="elsevierStyleCrossRef" href="#tblfn0025">d</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- 9 HRZE, or 6 LFx-RZE (H) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. Cases with resistance to R (mono- or polyresistance), but with susceptibility to H, or if susceptibility to H is not known \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Same treatment as MDR-TB, which is discussed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>, adding H to the regimen, but not taking into account it among the 4 new drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2356437.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Do not switch to the continuation phase (4HR) until one of the following 2 circumstances occurs: sputum smear is already negative, or that susceptibility to H and R is determined." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "Treatment should be prolonged beyond 6 months in patients in whom sputum smear and/or culture conversion is delayed beyond 2 months.<a class="elsevierStyleCrossRefs" href="#bib0220">1,18</a> As a reference, these patients will receive prolonged treatment with H+R up to a minimum of 4 months after the cultures are negative." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "High doses of H are recommended if the 9HRZE regimen is selected." ] 3 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "d" "nota" => "6 Lfx-RZE) should only be included in the regimen if the entire regimen (including Lfx) is administered from the start. It should not be used if H resistance results will be received after 3–4 weeks of treatment, due to the possible risk of inadvertent monotherapy. In this case use 9HRZE." ] ] ] "descripcion" => array:1 [ "en" => "Recommended Basic Regimens for Patients With Susceptible Tuberculosis and Mono/Polyresistance.<a class="elsevierStyleCrossRefs" href="#bib0220">1,20,22</a> (This Table Updates Table 4 of the 2017 Guidelines)." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "BDQ: Bedaquiline; Cfz: clofazimine; E: ethambutol; Eto: ethionamide; FQ: fluoroquinolones; hH: high doses of H (15–20mg/kg weight); hLfx: high doses of LFx (1000mg/day); Lfx: levofloxacin; Lzd: linezolid; MDR-TB: multidrug-resistant tuberculosis; MFX: Moxifloxacin; Pto: protionamide; SLID: second-line injectable drugs; XDR-TB: extensively multidrug-resistant TB; Z: pyrazinamide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Cases with MDR-TB, but without resistance to second-line drugs. One of the following regimens could be used, listed in order of priority: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Shorter oral regimens with BDQ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Option a: If the sputum smear is negative at month 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 Bdq<a class="elsevierStyleCrossRef" href="#tblfn0030">a</a>-Lfx/Mfx-Cfz-Eto/Pto-E-Z-Hh/2 Bdq-Lfx/Mfx-Cfz-Z-E/3 Lfx/Mfx-Cfz-Z-E \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Option b: If the sputum smear is positive at month 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 Bdq<a class="elsevierStyleCrossRef" href="#tblfn0030">a</a>-Lfx/Mfx-Cfz-Eto/Pto-E-Z-Hh/5 Lfx/Mfx-Cfz-Z-E. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. 6<a class="elsevierStyleCrossRef" href="#tblfn0035">b</a> Bdq-hLfx-Lzd-Cfz/3 hLfx-Lzd-Cfz \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. 6–9 Bdq-hLfx-Lzd<a class="elsevierStyleCrossRef" href="#tblfn0040">c</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Longer oral regimen \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 Bdq-Lfx-Lzd-Cfz/12 Lfx-Lzd-Cfz \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. Cases with MDR-TB and additional resistance to FQ, SLID, both, or even broader patterns of XDR-TB resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a. Consult with experts and design a regimen that follows all the recommendations made in these guidelines, selecting a minimum of 3–4 new drugs, following the rational classification listed (groups 1 to 4) in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> of this document and trying to include the maximum number of bactericidal and sterilizing drugs. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b. For cases that only have XDR-TB and not resistance to BDQ or Lzd, the pretomanid regimen not yet marketed in Spain must be evaluated: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 BDQ-Lzd-pretomanid \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2356439.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "a" "nota" => "If sputum smear remains positive at the end of month 4, this intensive phase should be prolonged up to 6 months with all of the same drugs (option b). If still positive at 6 months, this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered." ] 1 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "b" "nota" => "If sputum smear remains positive at month 6, this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered." ] 2 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "c" "nota" => "If sputum smear remains positive at the end of month 2, prolong treatment for up to 9 months with all 3 drugs. If the sputum smear is still positive at the end of month 4, this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered." ] ] ] "descripcion" => array:1 [ "en" => "Recommended Basic Regimens for Patients With MDR-TB.<a class="elsevierStyleCrossRefs" href="#bib0245">6,9,10,19,20,22,30–32</a> (This Table Updates Table 5 of the 2017 Guidelines)." ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Am: amikacin; BDQ: bedaquiline; Cfz: clofazimine; Cs: cycloserine; DLM: delamanid; DST: drug susceptibility test; E: ethambutol; Eto: ethionamide; FQ: fluoroquinolones; H: isoniazid; HIV: human immunodeficiency virus; hLfx: high doses of Lfx (1000mg/day): Lfx: levofloxacin; Lzd: linezolid; MDR-TB: multidrug-resistant tuberculosis; PAS: para-aminosalicylic acid; Pto: protionamide; R: rifampicin; S: streptomycin; RR-TB: rifampicin-resistant tuberculosis; SLID: second-line injectable drugs; XDR-TB: extremely drug-resistant tuberculosis; Z: pyrazinamide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Steps \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Considerations \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Diagnosis \t\t\t\t\t\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">Take into account• Drug history: One month of monotherapy, or adding a single drug to a treatment regimen that is not effective, is an important indicator of possible resistance to that drug, or of possible reduced efficacy• Drug susceptibility tests (DST): Highly reliable for R, H, FQ and SLID. Less reliable for S, E, and Z. Very unreliable for Eto/Pto, CS and PAS. The method for Lzd, BDQ, Dlm, Cfz and carbapenems has yet to be standardized• Perform a rapid molecular test to detect RR-TB or MDR-TB in all cases where TB is presumed• In all cases with RR-TB or MDR-TB, perform a rapid molecular test to detect resistance to FQ and SLID.• Perform HIV test \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. Number of medications \t\t\t\t\t\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">• Consultation and advice from experts to design an effective regimen• At least 3–4 effective drugs: never used in the past or with susceptibility demonstrated by DST, taking into account DST reliability discussed in point 1 and possible cross-resistance• At least 1–2 drugs with good bactericidal capacity and at least 1–2 with good sterilizing capacity. Try to avoid drugs without bactericidal or sterilizing capacity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. Selection of medications \t\t\t\t\t\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">• Rational introduction according to <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>• Always give priority to the 3 drugs in group 2 (FQ, BDQ, Lzd), provided susceptibility has been confirmed (FQ) or presumed (BDQ, Lzd)• Use high-dose Lfx or moxifloxacin• In case of having to resort to group 3, always give priority to Cfz• In the case of having to resort to group 4, always introduce them in this order: carbapenems, Dlm, Am, Eto/Pto, Z, E and PAS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4. Treatment regimens<a class="elsevierStyleCrossRef" href="#tblfn0045">a</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">RR-TB/MDR-TB patients:• See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>, with recommendation of 3 shorter oral regimens with BDQ, option A (1a and b, 2,3*). *6–9 BDQ-hLfx-LZD will be used if there is a test that demonstrates susceptibility to FQ; and if BDQ and LZD have not been used previously for the treatment of TB in the patient• Also in this table see longer oral regimen (option B)XDR-TB patients: Evaluate 6 BDQ-Lzd-pretomanid• In all of them, the electrocardiographic QTc must be monitored<a class="elsevierStyleCrossRef" href="#tblfn0050">b</a>• Always with directly observed treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5. Surgery \t\t\t\t\t\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">Consider if these 3 conditions are met• 1. Less than 4 effective drugs; 2. Localized lesions; 3. Sufficient respiratory reserve after resection• Evaluate, particularly in XDR-TB and pre-XDR-TB due to FQ resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2356436.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "a" "nota" => "An expert should always be consulted when designing a treatment regimen for these patients." ] 1 => array:3 [ "identificador" => "tblfn0050" "etiqueta" => "b" "nota" => "Levofloxacin, moxifloxacin and clofazimin, like bedaquiline and delamanid, may cause QTc alterations on ECG. We recommend two papers<a class="elsevierStyleCrossRefs" href="#bib0425">42,43</a> on the effects of drugs used in the treatment of MDR and XDR tuberculosis on QTc on ECG." ] ] ] "descripcion" => array:1 [ "en" => "Summary of Good Practices in MDR-TB Management. This Table Updates Table 8 of the 2017 guidelines.<a class="elsevierStyleCrossRef" href="#bib0220">1</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0220" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and Treatment of Drug-Resistant Tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.A. Caminero" 1 => "J.A. Cayla" 2 => "J.M. García-García" 3 => "F.J. García-Pérez" 4 => "J.J. Palacios Gutiérrez" 5 => "J. Ruiz Manzano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arbres.2017.02.006" "Revista" => array:6 [ "tituloSerie" => "Arch Bronconeumol" "fecha" => "2017" "volumen" => "53" "paginaInicial" => "501" "paginaFinal" => "509" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28359606" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0225" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Fregonese" 1 => "S.D. Ahuja" 2 => "O.W. Akkerman" 3 => "D. Arakaki-Sanchez" 4 => "I. Avakaka" 5 => "P. Baghaei" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-2600(18)30078-X" "Revista" => array:6 [ "tituloSerie" => "Lancet Respir Med" "fecha" => "2018" "volumen" => "6" "paginaInicial" => "265" "paginaFinal" => "275" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29595509" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0230" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Collaborative Group for the Meta-analysis of Individual Patient Data in MDR-TB Treatment 2017 Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual data and meta-analysis" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "The Collaborative Group for the Meta-analysis of Individual Patient Data in MDR-TB Treatment 2017" "etal" => true "autores" => array:6 [ 0 => "N. Ahmad" 1 => "S.D. Ahuja" 2 => "O.W. Akkerman" 3 => "J.C. Alffenaar" 4 => "L.F. Anderson" 5 => "P. Baghaei" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(18)31644-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2018" "volumen" => "392" "paginaInicial" => "821" "paginaFinal" => "834" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30215381" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0235" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Schnippel" 1 => "N. Ndjeka" 2 => "G. Maartens" 3 => "G. Meintjes" 4 => "I. Master" 5 => "N. Ismail" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-2600(18)30235-2" "Revista" => array:6 [ "tituloSerie" => "Lancet Respir Med" "fecha" => "2018" "volumen" => "6" "paginaInicial" => "699" "paginaFinal" => "706" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30001994" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0240" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "World Health Organization. WHO treatment guidelines for isoniazid-resistant tuberculosis. Supplement to the WHO treatment guidelines for drug-resistant tuberculosis. World Health Organization Document 2018. Licence: CC BY-NC-SA 3.0 IGO. WHO/CDS/TB/2018.7: 1-31. Available from: <a target="_blank" href="https://www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/">https://www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/</a> [accessed 21.01.20]." ] ] ] 5 => array:3 [ "identificador" => "bib0245" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Available from: <a target="_blank" href="https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/">https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/</a> [accessed 21.01.20]." ] ] ] 6 => array:3 [ "identificador" => "bib0250" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Nahid" 1 => "S.R. Mase" 2 => "G.B. Migliori" 3 => "G. Sotgiu" 4 => "G.H. Bothamley" 5 => "J.L. Brozet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.201909-1874ST" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2019" "volumen" => "200" "paginaInicial" => "e93" "paginaFinal" => "e142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31729908" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0255" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular assays intended as initial tests for the diagnosis of pulmonary and extrapulmonary TB and rifampicin resistance in adults and children: Rapid communication. Policy update" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "World Health Organization" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2020" "editorial" => "World Health Organization" "editorialLocalizacion" => "Geneva" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0260" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Rapid communication: key changes to treatment of drug-resistant tuberculosis" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2019" "editorial" => "World Health Organization" "editorialLocalizacion" => "Geneva" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0265" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Frequently asked questions on the WHO rapid communication 2019: key changes to the treatment of drug-resistant TB Version: 1.1" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "World Health Organization" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:2 [ "fecha" => "2020" "editorial" => "World Health Organization" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0270" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Planning for country transition to Xpert MTB/RIF Ultra Cartridges" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Laboratory Initiative" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:2 [ "fecha" => "2017" "editorial" => "Global Laboratory Initiative" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0275" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Xpert MTB/RIF ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.E. Dorman" 1 => "S.G. Schumacvher" 2 => "D. Alland" 3 => "P. Nabeta" 4 => "D.T. Armstrong" 5 => "B. King" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(17)30691-6" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2018" "volumen" => "18" "paginaInicial" => "76" "paginaFinal" => "84" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29198911" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0280" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multicenter study of the accuracy of the BD MAX™ MDR-TB assay for detection of Mycobacterium tuberculosis complex and mutations associated with resistance to rifampin and isoniazid" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Shah" 1 => "S. Paradis" 2 => "J. Betz" 3 => "N. Beylis" 4 => "R. Bharadwaj" 5 => "T. Caceres" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/ciz932" "Revista" => array:2 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2019" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0285" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rapid, point-of-care diagnosis of tuberculosis with novel Truenat assay: cost-effectiveness analysis for India's public sector" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.J. Lee" 1 => "N. Kumarasamy" 2 => "G.N. Sivaramakrishnan" 3 => "K.H. Mayer" 4 => "S. Tripathy" 5 => "A.D. Paltiel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0218890" "Revista" => array:5 [ "tituloSerie" => "PLOS ONE" "fecha" => "2019" "volumen" => "14" "paginaInicial" => "e0218890" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31265470" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0290" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Miotto" 1 => "B. Tessema" 2 => "E. Tagliani" 3 => "L. Chindelevitch" 4 => "A.M. Starks" 5 => "C. Emerson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.01354-2017" "Revista" => array:5 [ "tituloSerie" => "Eur Respir J" "fecha" => "2017" "volumen" => "50" "paginaInicial" => "1701354" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29284687" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0295" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prediction of susceptibility to first-line tuberculosis drugs by DNA sequencing" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "CRyPTIC Consortium and the 100,000 Genomes Project" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1800474" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2018" "volumen" => "379" "paginaInicial" => "1403" "paginaFinal" => "1415" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30280646" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0300" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The future of TB resistance diagnosis: the essentials on whole genome sequencing and rapid testing methods" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Moreno-Molina" 1 => "I. Comas" 2 => "V. Furió" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arbres.2019.01.002" "Revista" => array:6 [ "tituloSerie" => "Arch Bronconeumol" "fecha" => "2019" "volumen" => "55" "paginaInicial" => "421" "paginaFinal" => "426" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30795867" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0305" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "W. Fox" 1 => "G.A. Ellard" 2 => "D.A. Mitchison" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Int J Tuberc Lung Dis" "fecha" => "1999" "volumen" => "3" "numero" => "Suppl. 2" "paginaInicial" => "S231" "paginaFinal" => "S279" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10529902" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0310" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multidrug-resistant tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.A. Caminero" 1 => "A.L. García-Basteiro" 2 => "A. Rendon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(19)30696-8" "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "2019" "volumen" => "394" "paginaInicial" => "298" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31354137" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0315" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The future of drug-resistant tuberculosis treatment: learning from the past and the 2019 World Health Organization consolidated guidelines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.A. Caminero" 1 => "A.L. García-Basteiro" 2 => "A. Rendon" 3 => "A. Piubello" 4 => "E. Pontali" 5 => "G.B. Migliori" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.01272-2019" "Revista" => array:5 [ "tituloSerie" => "Eur Respir J" "fecha" => "2019" "volumen" => "54" "paginaInicial" => "1901272" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31601719" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0320" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Classification of anti-TB drugs: a new potential proposal based on the most recent evidence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.A. Caminero" 1 => "A. Scardigli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.00432-2015" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2015" "volumen" => "46" "paginaInicial" => "887" "paginaFinal" => "893" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26424519" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0325" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of drug-susceptible and drug-resistant tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.A. Caminero" 1 => "A. Scardigli" 2 => "van der Werf" 3 => "M. Tadolini" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "editores" => "G.B.Migliori, G.Bothamley, R.Duarte" "titulo" => "Tuberculosis (ERS Monograph)" "paginaInicial" => "152" "paginaFinal" => "178" "serieFecha" => "2018" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0330" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acquired resistance to bedaquiline and delamanid in therapy for tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.V. Bloemberg" 1 => "P.M. Keller" 2 => "D. Stucki" 3 => "A. Trauner" 4 => "S. Borrell" 5 => "T. Latshang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMc1505196" "Revista" => array:5 [ "tituloSerie" => "N Eng J Med" "fecha" => "2015" "volumen" => "373" "paginaInicial" => "1986" "paginaFinal" => "1988" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0335" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bedaquiline microheteroresistance after cessation of tuberculosis treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. De Vos" 1 => "S.D. Ley" 2 => "K.B. Wiggins" 3 => "B. Derendinger" 4 => "A. Dippenaar" 5 => "M. Grobbelaar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMc1815121" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2019" "volumen" => "380" "paginaInicial" => "2178" "paginaFinal" => "2180" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31141643" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0340" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Gegia" 1 => "N. Winzster" 2 => "A. Benedetti" 3 => "D. van Soolingen" 4 => "D. Menzies" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(16)30407-8" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2017" "volumen" => "17" "paginaInicial" => "223" "paginaFinal" => "234" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27865891" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0345" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effectiveness and safety of standardised shorter regimens for multidrug-resistant tuberculosis: individual patient data and aggregate data meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Ahmad Khan" 1 => "M.A.H. Salim" 2 => "P. du Cros" 3 => "E.C. Casas" 4 => "A. Khamraev" 5 => "W. Sikhondze" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.00061-2017" "Revista" => array:5 [ "tituloSerie" => "Eur Respir J" "fecha" => "2017" "volumen" => "50" "paginaInicial" => "1700061" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28751411" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0350" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A trial of a shorter regimen for rifampin-resistant tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.J. Nunn" 1 => "P.P.J. Philipps" 2 => "S.K. Meredith" 3 => "C.Y. Chi" 4 => "F. Conradie" 5 => "D. Dalai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1811867" "Revista" => array:2 [ "tituloSerie" => "N Eng J Med" "fecha" => "2019" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0355" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Taubel" 1 => "A. Naseem" 2 => "T. Harada" 3 => "D. Wang" 4 => "R. Arezina" 5 => "U. Lorch" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2125.2009.03595.x" "Revista" => array:6 [ "tituloSerie" => "Br J Clin Pharmacol" "fecha" => "2010" "volumen" => "69" "paginaInicial" => "391" "paginaFinal" => "400" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20406223" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0360" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "and the writing group members of the Global TB Network Clinical Trials Committee" "etal" => false "autores" => array:3 [ 0 => "E. Pontali" 1 => "M.C. Raviglione" 2 => "G.B. Migliori" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/16000617.0035-2019" "Revista" => array:5 [ "tituloSerie" => "Eur Respir Rev" "fecha" => "2019" "volumen" => "28" "paginaInicial" => "190035" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31142549" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0365" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FDA Advisory Committee votes favorably on the question of the ffectiveness and safety of pretomanid in combination with bedaquiline and linezolid for treatment of highly drug-resistant forms of tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T.B. Alliance" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2019" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0370" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "TB Alliance. FDA approves new treatment for highly drug-resistant forms of tuberculosis. Available from: <a target="_blank" href="https://www.tballiance.org/news/fda-approves-new-treatment-highly-drug-resistant-forms-tuberculosis">https://www.tballiance.org/news/fda-approves-new-treatment-highly-drug-resistant-forms-tuberculosis</a> [accessed 24.01.20]." ] ] ] 31 => array:3 [ "identificador" => "bib0375" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of highly drug-resistant pulmonary tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Conradie" 1 => "A.H. Diacon" 2 => "N. Ngubane" 3 => "P. Howel" 4 => "D. Everitt" 5 => "A.M. Crook" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1901814" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2020" "volumen" => "382" "paginaInicial" => "893" "paginaFinal" => "902" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32130813" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0380" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New drugs for the treatment of tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.H. Ignatius" 1 => "K.E. Dooley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ccm.2019.08.001" "Revista" => array:6 [ "tituloSerie" => "Clin Chest Med" "fecha" => "2019" "volumen" => "40" "paginaInicial" => "811" "paginaFinal" => "827" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31731986" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0385" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multidrug-resistant tuberculosis. Authors’ reply" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Menzies" 1 => "A. Benedetti" 2 => "G.B. Migliori" 3 => "P. Nahid" 4 => "B. Seaworth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(19)30692-0" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2019" "volumen" => "394" "paginaInicial" => "299" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31354139" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0390" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Management of drug-resistant tuberculosis in children: a field guide" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "edicion" => "Fourth edition" "fecha" => "2018" "editorial" => "The Sentinel Project for Pediatric Drug-Resistant Tuberculosis" "editorialLocalizacion" => "Boston, USA" ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0395" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Timing of initiation of antiretroviral drugs during tuberculosis therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.S. Abdool Karim" 1 => "K. Naidoo" 2 => "A. Grobler" 3 => "N. Padayatchi" 4 => "C. Baxter" 5 => "A. Gray" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0905848" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2010" "volumen" => "362" "paginaInicial" => "697" "paginaFinal" => "706" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20181971" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0400" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "CAMELIA (ANRS 1295–CIPRA KH001) Study Team" "etal" => true "autores" => array:6 [ 0 => "F.X. Blanc" 1 => "T. Sok" 2 => "D. Laureillard" 3 => "L. Borand" 4 => "C. Rekacewicz" 5 => "E. Nerrienet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1013911" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2011" "volumen" => "365" "paginaInicial" => "1471" "paginaFinal" => "1481" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22010913" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0405" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Treatment of LTBI and TB for persons with HIV. CDC" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2016" ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0410" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Panel de Expertos del Grupo de estudio de Sida (Gesida-SEIMC). Recomendaciones de Gesida sobre el tratamiento de la tuberculosis en adultos infectados por el virus de la inmunodeficiencia humana (actualización mayo de 2018). Available from: <a target="_blank" href="http://gesida-seimc.org/wp-content/uploads/2018/06/gesida_TB_en_VIH_Version_FINAL_5_de_junio_2018.pdf">http://gesida-seimc.org/wp-content/uploads/2018/06/gesida_TB_en_VIH_Version_FINAL_5_de_junio_2018.pdf</a> [accessed 13.01.20]." ] ] ] 39 => array:3 [ "identificador" => "bib0415" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tuberculosis-HIV co-infection: progress and challenges after two decades of global antiretroviral treatment roll-out" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Letang" 1 => "J. Ellis" 2 => "K. Naidoo" 3 => "E.C. Casas" 4 => "P. Sánchez" 5 => "R. Hassan-Moosa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arbres.2019.11.015" "Revista" => array:2 [ "tituloSerie" => "Arch Bronconeumol" "fecha" => "2019" ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0420" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Plan para la Prevención y Control de la TB en España" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2019" "editorial" => "Ministerio de Sanidad, Consumo y Bienestar Social" "editorialLocalizacion" => "Madrid" ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0425" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "QTc prolongation and treatment of multidrug-resistant tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E. Harausz" 1 => "H. Cox" 2 => "M. Rich" 3 => "C.D. Mitnick" 4 => "P. Zimetbaum" 5 => "J. Furin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5588/ijtld.14.0335" "Revista" => array:6 [ "tituloSerie" => "Int J Tuberc Lung Dis" "fecha" => "2015" "volumen" => "19" "paginaInicial" => "385" "paginaFinal" => "391" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25859992" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0430" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H.Y. Yoon" 1 => "K.W. Jo" 2 => "G.B. Nam" 3 => "T. Shim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5588/ijtld.17.0174" "Revista" => array:6 [ "tituloSerie" => "Int J Tuberc Lung Dis" "fecha" => "2017" "volumen" => "21" "paginaInicial" => "996" "paginaFinal" => "1001" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28826448" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005600000008/v2_202008090657/S1579212920301580/v2_202008090657/en/main.assets" "Apartado" => array:4 [ "identificador" => "54644" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "SEPAR's voice" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005600000008/v2_202008090657/S1579212920301580/v2_202008090657/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212920301580?idApp=UINPBA00003Z"]

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Recommendations of SEPAR

Update of SEPAR Guideline “Diagnosis and Treatment of Drug-Resistant Tuberculosis”

Actualización de la normativa SEPAR «Diagnóstico y tratamiento de la tuberculosis con resistencia a fármacos»

José A. Camineroa,b,c, José-María García-Garcíac,d,

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josemariagarcia@separ.es

Corresponding author.

, Joan A. Caylàc,e, Francisco J. García-Pérezc,f, Juan J. Palaciosc,g, Juan Ruiz-Manzanoc,h

a Servicio de Neumología, Hospital General de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain

b Unión Internacional contra la Tuberculosis y Enfermedades Respiratorias (La Unión), París, France

c Programa Integrado de Investigación en Tuberculosis (PII TB) de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Barcelona, Spain

d Unidad de Gestión Clínica de Neumología, Hospital Universitario San Agustín, Avilés, Asturias, Spain

e Fundación de la Unidad de Investigación en Tuberculosis (fuiTB) de Barcelona, Spain

f Servicio de Neumología, Hospital Universitario de La Princesa, Madrid, Spain

g Unidad de Referencia Regional de Micobacterias, Servicio de Microbiología, Hospital Universitario Central de Asturias, Oviedo, Spain

h Centro Médico Teknon, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In 2017&#44; the Spanish Society of Pulmonology and Thoracic Surgery &#40;SEPAR&#41; published guidelines on the diagnosis and treatment of drug-resistant tuberculosis &#40;DR-TB&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> Since important updated evidence on the management of these patients has appeared&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">2&#8211;4</span></a> prompting the publication of 2 new guidelines by the World Health Organization &#40;WHO&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">5&#44;6</span></a> and another by the American Thoracic Society &#40;ATS&#41;&#47;Centers for Disease Control and Prevention &#40;CDC&#41;&#47;European Respiratory Society &#40;ERS&#41;&#47;Infectious Diseases Society of America &#40;IDSA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">7</span></a> in addition to recent WHO communications on TB diagnosis and treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">8&#8211;10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the light of this new knowledge&#44; an update of the 2017 SEPAR guidelines is needed&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of Tuberculosis</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Xpert&#174; MTB&#47;RIF Ultra</span><p id="par0015" class="elsevierStylePara elsevierViewall">Cepheid has developed a new generation Xpert&#174; MTB&#47;RIF Ultra technique with enhanced susceptibility using 2 amplification targets &#40;IS6110 and IS1081&#41; and a larger polymerase chain reaction chamber &#40;50<span class="elsevierStyleHsp" style=""></span>&#956;l in Ultra&#44; vs 25<span class="elsevierStyleHsp" style=""></span>&#956;l in the Xpert&#174; MTB&#47;RIF&#41;&#46; The new Ultra system features a lower mycobacterial detection limit &#40;16 colony-forming units per ml compared to 131 in the Xpert&#174; MTB&#47;RIF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">It uses the same semi-quantitative categories as Xpert&#174; MTB&#47;RIF &#40;high&#44; medium&#44; low and very low&#41;&#44; but a new category called &#8220;detected trace&#8221; has been added&#44; offering increased sensitivity &#40;90&#37; sensitivity in pulmonary TB compared to sputum culture&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">8</span></a> In people living with human immunodeficiency virus &#40;HIV&#41;&#44; children&#44; and patients being evaluated for extrapulmonary TB or suspected TB&#44; &#8220;trace calls&#8221; should be considered as true positives&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The current WHO recommendation for the use of Xpert&#174; MTB&#47;RIF also applies to the Ultra technique&#58; it should be used as the initial diagnostic test in all adults and children with signs and symptoms of TB and for the study of selected extrapulmonary samples &#40;cerebrospinal fluid&#44; lymph nodes and tissue samples&#41;&#44; and samples from children &#40;nasopharyngeal&#44; gastric&#44; and stool specimens<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">8&#44;11</span></a>&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Possibility of Using Other Rapid Molecular Methods for the Diagnosis of Tuberculosis and Drug-resistant Tuberculosis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Since 2017&#44; evidence has accumulated to recommend other molecular methods&#44; either to replace Xpert&#174; MTB&#47;RIF &#40;normal or Ultra version&#41; or to supplement it&#44; since this test only detects <span class="elsevierStyleItalic">rpoB</span> mutations&#46; Some of the different available alternatives include&#58; BD MAX&#174; MDR-TB &#40;Becton Dickinson&#41;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a>&#59; Abbott RealTime&#174; MTB RIF&#47;INH assay&#59; FluoroType&#174; MTBDR &#40;Hain&#41;&#59; Anyplex&#174; MTB&#47;NTM y Anyplex&#174; MTB&#47;MDR&#47;XDR &#40;Seegene&#41;&#59; TrueNat&#174; &#40;Molbio Diagnostics&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">14</span></a> These techniques all use real-time polymerase chain reaction amplification systems for specific targets&#44; with varying degrees of automation&#46; In addition to detecting <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> complex and rifampicin resistance &#40;RR&#41;&#44; some can be used &#40;in 1 or 2 steps&#41; to amplify the spectrum of isoniazid &#40;H&#41; resistance detection &#40;BD MAX&#174; MDR-TB&#44; Abbott RealTime&#174; MTB RIF&#47;INH assay&#44; FluoroType&#174; MTBDR&#44; Anyplex&#174; MTB&#47;MDR&#47;XDR&#41;&#46; Anyplex&#174; MTB&#47;NTM can simultaneously detect non-tuberculous mycobacteria&#44; information that is highly useful in differential diagnosis when the diagnosis of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> disease is not confirmed by any of the techniques used&#46; They can also be used to amplify resistance detected to fluoroquinolones &#40;FQ&#41; and aminoglycosides&#47;polypeptides &#40;Anyplex&#174; MTB&#47;MR&#47;XDR&#41;&#44; the latter being similar to the GenoType&#174;MDR<span class="elsevierStyleItalic">sl</span> already mentioned in our 2017 recommendation&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We will clearly have to remain alert to the development of new technologies in the immediate future&#44; given the advances in the diagnosis of this disease&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that molecular tests can also help improve the final outcome of patients with TB &#40;the use of Xpert&#174; MTB&#47;RIF as an initial test to replace sputum smears has led to improved cure rates&#44; reduced mortality and fewer cases lost before start of treatment<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">8</span></a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discrepancies in Rifampicin Resistance Results by Different Methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">In line with current evidence&#44; it is agreed that a patient who shows TB with RR &#40;RR-TB&#41; using any properly performed method &#40;either phenotypic or molecular&#41; should be considered and treated as such&#44; even if the results from other methods are conflicting&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a> Complete genome sequencing of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> helps resolve discrepancies and allows for the detection of mutations not identified by other methods&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">16&#44;17</span></a> It is a test that will certainly become part of routine diagnosis as its use becomes widespread&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Basis for Treatment of all Forms of Tuberculosis&#44; Both Susceptible and Drug-Resistant</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Number of Drugs Needed to Treat tuberculosis</span><p id="par0050" class="elsevierStylePara elsevierViewall">The recommendation to use at least 4 previously unused drugs&#44; or drugs with proven <span class="elsevierStyleItalic">M&#46; tuberculosis</span> susceptibility&#44; was made on the basis that there might be resistance to one of the 4 compounds &#40;as in the case of H in the initial regimen&#41; and because some of them might have reduced efficacy&#44; such as the case of ethionamide &#40;Eto&#41;&#47;prothionamide &#40;Pto&#41;&#44; cycloserine&#44; or para-aminosalicylic acid in patients with RR-TB or multidrug-resistant &#40;MDR&#41;-TB &#40;TB resistant to at least H&#43;R&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#44;19</span></a> Susceptibility to H&#43;R can now be determined at the beginning of treatment&#44; and powerful drugs&#44; such as FQ&#44; linezolid &#40;LZD&#41;&#44; bedaquiline &#40;BDQ&#41; and clofazimine &#40;Cfz&#41;&#44; that have a very low probability of being resistant &#40;a rapid molecular test can be performed in the case of FQ&#41; and show good bactericidal and sterilizing activity&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#8211;21</span></a> can be used in the initial regimen&#46; Thus&#44; a course of only 3 new drugs for 6&#8211;9 months may be sufficient to cure TB with a minimum risk of acquisition of resistance or subsequent relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#8211;20</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">If susceptibility results are not available for any of the key drugs for which reliable susceptibility tests are available &#40;H&#44; R&#44; FQ&#41;&#44; or if such tests do not exist &#40;as in the case of BDQ&#41;&#44; doubts regarding resistance may arise and recourse to some drugs of doubtful efficacy may be necessary&#46; In such cases&#44; the recommendation of at least 4 drugs to treat TB would remain in force&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#44;20&#44;22</span></a> In the case of BDQ&#44; some publications have warned of the emergence of resistance&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">23&#44;24</span></a> but these cases remain exceptional and are limited to settings in which the drug has not been used properly&#46; We must remain alert to these communications&#44; but for the moment&#44; this drug can be expected to be susceptible in Spain&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Change in the Choice of So-called Essential and Accompanying Drugs</span><p id="par0060" class="elsevierStylePara elsevierViewall">All the new drugs &#40;FQ&#44; Lzd&#44; BDQ&#44; Cfz&#41; that are already fully incorporated into the treatment of RR-TB&#47;MDR-TB can be considered essential &#40;with good bactericidal and&#47;or sterilizing capacity&#41;&#44; so the use of accompanying medications would be unnecessary&#44; except in situations of widespread resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">19&#44;20</span></a> At present&#44; the recommendation should be to use at least 3 essential drugs&#44; with at least 1&#8211;2 that show good bactericidal activity and 1&#8211;2 with good sterilizing activity&#46; No accompanying drug should be included unless unavoidable<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rational Classification of Drugs With Activity Against <span class="elsevierStyleItalic">M&#46; tuberculosis</span></span><p id="par0065" class="elsevierStylePara elsevierViewall">This section has been substantially modified based on the results of the WHO meta-analysis&#44; on changes in the classification subsequently recommended by the WHO and on updated data on the bactericidal and&#47;or sterilizing activity of these drugs as set out in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#44;6&#44;21</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of Tuberculosis by Resistance Pattern</span><p id="par0070" class="elsevierStylePara elsevierViewall">Important changes have been made&#44; especially in the case of RR-TB&#47;MDR-TB and extensively drug-resistant TB &#40;XDR-TB&#44; meaning MDR-TB plus resistance to at least one FQ and to a second-line injectable drug &#91;kanamycin&#44; amikacin&#44; capreomycin&#93;&#41; listed in <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment of Tuberculosis With Susceptibility to Rifampicin and Proven or Unknown Susceptibility to Isoniazid</span><p id="par0075" class="elsevierStylePara elsevierViewall">There are no changes with respect to the previous guidelines&#46; In new cases of TB in which susceptibility to all drugs is presumed&#44; or if the absence of mutations in the <span class="elsevierStyleItalic">rpoB</span> gene &#40;molecular detection of resistance to R&#41; has been confirmed by molecular testing&#44; the ideal treatment regimen is 2 HRZE&#47;4 HR&#46; However&#44; if the absence of gene mutations in <span class="elsevierStyleItalic">rpoB</span>&#44; <span class="elsevierStyleItalic">katG</span> and <span class="elsevierStyleItalic">inhA</span> &#40;molecular detection of resistance to H&#41; is confirmed by molecular testing in the first days of treatment&#44; 2 HRZ&#47;4 HR would be sufficient<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">14&#44;18</span></a><span class="elsevierStyleItalic">&#40;strong recommendation&#44; high quality of evidence</span> &#91;<span class="elsevierStyleItalic">&#8853;&#8853;&#8853;&#8853;</span>&#93;&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">To reduce the possibility of errors and the possible selection of resistance&#44; these drugs should always be administered in fixed combination doses and with directly observed treatment in patients who have risk factors for poor therapeutic compliance&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of Tuberculosis Resistant to Isoniazid &#40;Mono- or Polyresistance&#41;&#44; But Susceptible to Rifampicin</span><p id="par0085" class="elsevierStylePara elsevierViewall">The 9 HRZE regimen recommended as a priority in the 2017 guidelines should still be prioritized<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low</span> &#91;&#8853;&#93; <span class="elsevierStyleItalic">to very low &#91;&#93; evidence quality&#41;</span>&#46; The use of high doses of H may be evaluated&#44; especially if a rapid molecular test &#40;GenoType&#174;&#41; that shows the absence of mutation in the <span class="elsevierStyleItalic">katG</span> gene is available&#46; However&#44; the other regimens recommended in our 2017 guidelines&#44; consisting of 2 FQ-REZ&#47;7 FQ-RE &#40;E&#58; ethambutol&#44; Z&#58; pyrazinamide&#41;&#44; should be replaced by the WHO recommended regimen of 6 Lfx-REZ&#40;H&#41; &#40;Lfx&#58; levofloxacin&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">5&#44;6</span></a> while taking into account our previous recommendations for the FQ-containing regimen&#44; i&#46;e&#46;&#44; Lfx should only be included in the regimen if it is administered from the beginning with the other drugs&#46; It should not be added if H resistance results will only be received after 3&#8211;4 weeks of treatment&#44; due to the possible risk of inadvertent monotherapy&#46; These recommendations&#44; which led to the inclusion of LFx in this regimen&#44; are based on a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">2</span></a> in which the vast majority of patients came from sites where the results of H resistance testing were determined very quickly&#44; but this situation is unusual&#44; even in our setting&#46; It should also be noted that another meta-analysis<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">25</span></a> found that 9 RZE is equally effective in curing cases with resistance or susceptibility to H&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of Tuberculosis Resistant to Rifampicin &#40;Mono- or Polyresistance&#41;&#44; But Susceptible to Isoniazid</span><p id="par0090" class="elsevierStylePara elsevierViewall">It is still true to say that cases of isolated resistance to R are rare in clinical practice&#44; and that since resistance to R determines prognosis in patients with MDR-TB&#44; these patients should be managed as MDR-TB patients&#44; and treated as such&#44; adding H to the regimen&#44; of course&#44; because if its susceptibility is confirmed&#44; it will be an important contribution to treatment<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">1&#44;6</span></a><span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low &#91;&#8853;&#93;</span> to <span class="elsevierStyleItalic">very low &#91;&#93; quality of evidence&#41;</span>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Treatment of Multidrug-Resistant Tuberculosis &#40;MDR-TB&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall">The significant amount of evidence accumulated in this section<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#44;4&#44;6&#44;19&#44;20</span></a> requires a significant change in the recommendations made in the 2017 guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> Fortunately&#44; this evidence is bringing about almost continuous changes in recent months&#46; Thus&#44; in March 2019&#44; the WHO guidelines<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> prioritized long individualized oral regimens of 18&#8211;20 months&#8217; duration&#46; However&#44; after studies with new drugs appeared&#44; the WHO itself published a rapid communication in December 2019<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">9</span></a> recommending that priority be given to shorter oral regimens including BDQ&#44; and in a new publication that appeared in January 2020&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">10</span></a> based on accumulated evidence&#44; it recommended prioritizing a shorter BDQ regimen&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Therefore&#44; based on the latest evidence in the treatment of RR-TB&#47;MDR-TB&#44; priority should be given to shorter oral regimens based on BDQ&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">9&#44;10</span></a> and shorter &#40;or longer&#41; injectable regimens should no longer be used in RR-TB&#47;MDR-TB As a result&#44; the regimen that was recommended as a priority in our 2017 guidelines should no longer be used&#44; especially as the cumulative evidence has shown that oral regimens are better and much less toxic&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Based on this&#44; one of the following regimens may be recommended in these patients&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;A&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Shorter oral regimens with BDQ</span></p></li></ul></p><p id="par0115" class="elsevierStylePara elsevierViewall">In this section&#44; one of the following 3 regimens could be considered&#46; The advantages and disadvantages of these regimens will be analyzed&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">1&#46;</span> This first regimen offers 2 possibilities&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;a&#41;</span><p id="par0125" class="elsevierStylePara elsevierViewall">If the sputum smear is negative at month 4&#58; 4 Bdq&#42;-Lfx&#47;moxifloxacin &#40;Mfx&#41;-Cfz-Eto&#47;Pto-E-Z-hH&#47;2 BDQ-Lfx&#47;Mfx-Cfz-Z-E&#47;3 Lfx&#47;Mfx-Cfz-Z-E&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;b&#41;</span><p id="par0130" class="elsevierStylePara elsevierViewall">If the sputum smear is positive at month 4&#58; 6 BDQ&#42;-Lfx&#47;Mfx-Cfz-Eto&#47;Pto-E-Z-hH&#47;5 Lfx&#47;Mfx-Cfz-Z-E&#46;<span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low &#91;&#8853;&#93; to very low &#91;&#93; quality of evidence&#41;</span></p></li></ul></p><p id="par0135" class="elsevierStylePara elsevierViewall">&#42;In both options&#44; BDQ should be administered for 6 months&#44; accompanied in the first option by intensive-phase drugs for the first 4 months and continuation-phase drugs for the next 2 months&#44; completing treatment with 3 more months of continuation-phase drugs alone &#40;9 months total&#41;&#46; However&#44; if the sputum smear remains positive at the end of month 4&#44; all drugs in this intensive phase and BDQ will be administered for 6 months&#44; followed by continuation-phase drugs for 5 months&#44; for a total duration of treatment of 11 months &#40;option b&#41;&#46; If the sputum smear remains positive at the end of month 6&#44; this regimen will be considered to have failed and a different regimen should be designed&#46; hH means high-dose H&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">This treatment regimen has the advantage that it has the most supporting evidence&#44; and is therefore recommended as a priority by the WHO in its latest publication in January 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">10</span></a> It is practically the same as the regimen we recommended in our 2017 guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> and it is supported by a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">26</span></a> and a randomized clinical trial&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">27</span></a> the only difference being the use of BDQ instead of amikacin&#46; However&#44; it has the drawback that it still uses 7 drugs in the intensive phase&#44; including some with very little or doubtful efficacy&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> such as Eto&#47;Pto&#44; E&#44; Z and hH&#59; some of which are as poorly tolerated as Eto&#47;Pto&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Because of the speed with which new evidence is accumulating on this topic&#44; the WHO will probably soon amend its recommendations in favor of one of the other 2 options set out below&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">2&#46;</span> 6 BDQ-hLfx-LZD-Cfz&#47;3 hLfx-LZD-Cfz <span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low &#91;&#8853;&#93; to very low &#91;&#93; quality of evidence&#41;</span></p><p id="par0155" class="elsevierStylePara elsevierViewall">If the sputum smear remains positive at the end of month 6&#44; this regimen will be considered to have failed and a different individualized regimen should be designed&#46; &#40;hLfx means high-dose Lfx&#41;&#46; hLfx is preferred because it causes less QTc interval prolongation on electrocardiogram than Mfx&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a> taking into account that the regimen contains 2 other drugs that also prolong QTc &#40;BDQ and Cfz&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">This regimen has the advantage that it uses the 4 drugs that are given priority in the WHO recommendations of 2019<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> and&#44; since they all have sterilizing activity&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">21</span></a> a total of 9 months of treatment would be sufficient&#46; Moreover&#44; since BDQ&#44; Lzd&#44; and Cfz have been used sparingly in the treatment of RR-TB&#47;MDR-TB in Spain&#44; drug susceptibility may be assumed to be highly probable&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Ideally&#44; a susceptibility test should be performed to rule out resistance to FQ before beginning this regimen&#44; although it could also apply to patients with RR-TB&#47;MDR-TB who have never received these drugs for TB treatment&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">3&#46;</span> 6&#8211;9 BDQ-hLfx-Lzd <span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low &#91;&#8853;&#93; to very low &#91;&#93; quality of evidence&#41;</span></p><p id="par0175" class="elsevierStylePara elsevierViewall">According to the section on the number of drugs needed to treat TB&#44; a 6-month regimen with high doses of LFx&#43;Lzd&#43;BDQ<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#44;19</span></a> would meet all requirements to be considered an effective regimen&#46; It consists of 3 new drugs&#44; all of which have bactericidal and sterilizing capacity&#44; although susceptibility must be confirmed for Lfx&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#8211;21</span></a> In this regimen&#44; LFx is preferred to MFX&#44; because it is causes less QTc prolongation on electrocardiogram&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a> taking into account that the regimen already contains another drug with the same effect &#40;BDQ&#41;&#46; If the sputum smear is still positive at the end of month 2&#44; the regimen should be prolonged until 9 months&#44; provided that the sputum smear and culture are negative at the end of month 4 of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">This regimen is very similar to the BPaL combination being successfully tested in the NIX-TB randomized clinical trials in patients with XDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">29&#44;30</span></a> The 6-month of Lzd&#43;BDQ&#43;pretomanid has been approved by the U&#46;S&#46; FDA&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">31</span></a> Promising outcomes have been published recently<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">32</span></a> and it has already been included in the WHO recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">9</span></a> Pretomanid is not marketed in Spain&#46; The study<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">30&#44;32</span></a> has limitations that were mentioned in the recent WHO communication&#58; it has a small number of patients &#40;108&#41; and adverse effects were observed &#40;hematological&#44; hepatic&#44; optical and peripheral neuropathy&#41;&#44; although a large proportion of these were related to the use of high doses of Lzd &#40;1200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; whereas 600<span class="elsevierStyleHsp" style=""></span>mg&#47;day may be sufficient&#46; The shorter oral regimen proposed in these guidelines would only lead&#44; in terms of NIX-TB to switching LFx for pretomanid because BPaL was indicated for patients with FQ resistance&#46; Moreover&#44; according to the available data&#44; pretomanid is no better than Lfx in the treatment of TB&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">33</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The advantages of these 6&#8211;9-month oral regimens &#40;Lfx&#43;Lzd&#43;BDQ in MDR-TB and Lzd&#43;BDQ&#43;pretomanid in XDR-TB&#41; are that all drugs are administered orally&#44; they use the best second-line drugs&#44; they are not ototoxic&#44; they do not need ion monitoring&#44; and because the courses are much shorter&#44; the potential risk of dropout is reduced&#46; The drawbacks of these regimens are similar to the others&#44; including the need to monitor the QTc interval &#40;when they contain 2 drugs &#8211; LFx and BDQ &#8211; that prolong QTc&#41; and to monitor the possible toxicity of Lzd&#44; although this should be less than in the other regimens as the time of administration is shorter&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">A regimen such as the one discussed&#44; which is shorter and administered orally&#44; must be used in programmatic research conditions &#40;patient monitoring&#44; support&#44; and proper inclusion&#44; principles of good clinical practice&#44; informed patient consent&#44; active monitoring and treatment of drug side effects&#44; treatment monitoring&#44; evaluation of the final outcome&#44; standardized data collection&#41;&#44; which would constitute the minimum requirements for the management of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">9</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">It is therefore very possible that patients will immediately be able to receive these novel treatments under the conditions described above&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">9</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">One important limitation associated with BDQ is its high price and difficult accessibility&#46; Given its essential role in the new treatment regimens&#44; efforts must be made at the institutional level to facilitate its availability in Spain&#46;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;B&#41;</span><p id="par0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Longer oral regimen</span></p></li></ul></p><p id="par0210" class="elsevierStylePara elsevierViewall">Although this regimen was recommended until a few months ago as a priority by WHO&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> it should now be relegated to a second step&#44;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">10&#44;11</span></a> which would consist of a 6-month intensive phase with BDQ&#43;Lfx&#47;Mfx&#43;Lzd&#43;Cfz&#44; plus a 12-month continuation phase with Lfx&#47;Mfx&#43;Lzd&#43;Cfz <span class="elsevierStyleItalic">&#40;conditional recommendation&#44; low &#91;&#8853;&#93; to very low &#91;&#93; evidence quality&#41;</span>&#44; thus meeting the criteria of the WHO recommendations of March 2019&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> The regimen proposed by ATS&#47;CDC&#47;ERS&#47;IDSA<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">7</span></a> follows the same order of priority and drug groups as that of WHO&#44; although it differs in terms of higher drug numbers &#40;5 in the intensive phase and 4 in the continuation phase&#41; and a longer treatment time &#40;15 to 21 months after culture conversion&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">7</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">There is no doubt that this regimen will be very effective&#44; because it uses the best drugs available in the treatment of RR-TB&#47;MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#44;6</span></a> However&#44; based on the above considerations&#44; it may involve too many drugs &#40;4&#41; administered for too long&#44; especially since they are all very potent with almost certain susceptibility and sterilizing capacity&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">19&#44;20&#44;34</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The disparities between these international guidelines<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">6&#44;7</span></a> may emerge from the fact that the recommendations have a low or very low quality of evidence&#46; Moreover&#44; both guidelines are based on a meta-analysis performed by the WHO itself<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> to assess the value of each drug in the different RR-TB&#47;MDR-TB regimens&#46; This study concluded that Lzd&#44; carbapenems&#44; Lfx&#47;Mfx&#44; BDQ and Cfz were the most effective drugs&#44; and the remaining drugs contributed little to the possible success of RR-TB&#47;MDR-TB treatment&#59; the latter included Eto&#47;Pto&#44; cycloserine&#44; para-aminosalicylic acid&#44; E&#44; and Z&#46; It also found that the inclusion of drugs such as kanamycin or capreomycin was associated with a worse therapeutic outcome&#46; This meta-analysis<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> also concluded that the most effective regimen was a combination of 4&#8211;5 effective drugs and a minimum duration of 18 months&#46; However&#44; a recognized limitation of this study is that practically all the regimens analyzed contained quite a few drugs associated with very slight or no improvement in outcomes &#40;ineffective&#44; weak drugs&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> and few had useful sterilizing activity&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment of Patients With Extensively Drug-Resistant Tuberculosis &#40;XDR-TB&#41; or Even Broader Resistance Patterns</span><p id="par0225" class="elsevierStylePara elsevierViewall">While significant progress has also been made in this area&#44; we continue to believe that these forms of TB are so difficult to manage &#40;in clinical practice and in programmatic conditions&#41; that they should be treated by highly skilled specialists and in units that can guarantee close supervision of the treatment and proper management of adverse reactions&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Contact Tracing</span><p id="par0230" class="elsevierStylePara elsevierViewall">The news in this area is that enough evidence has been accumulated to be able to recommend&#44; as an alternative to the periodic reviews that remain the most widely accepted recommendation&#44; a preventive regimen with an FQ &#40;Mfx or LFx&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">35</span></a> in close contacts of RR-TB&#47;MDR-TB cases in whom disease is ruled out&#44; especially in children or immunosuppressed individuals&#46; This treatment should be administered for a period of 6 months <span class="elsevierStyleItalic">&#40;conditional recommendation&#44; very low &#91;&#93; quality of evidence&#41;&#46;</span></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Treatment of Tuberculosis in People Living With Human Immunodeficiency Virus</span><p id="par0235" class="elsevierStylePara elsevierViewall">Treatment of drug-susceptible or drug-resistant TB in HIV-infected patients is the same as in non-infected patients&#46; In patients with both infections who have not started treatment&#44; starting TB treatment will be prioritized&#46; If the patient has CD4 &#60;50<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">&#8211;3</span> at 2 weeks&#44; good adherence&#44; and no side effects have been confirmed&#44; combination antiretroviral therapy &#40;cART&#41; will be started&#46; In patients with higher CD4 counts&#44; cART can begin after month 2&#44; when the patient is already taking fewer TB drugs&#46; Better survival has been observed with these regimens&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">36&#44;37</span></a> In cases of tuberculous meningitis&#44; cART should start after 8 weeks of TB treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">The interactions between rifamycins and some antiretrovirals should be taken into account&#59; in these cases&#44; rifabutin may be an alternative to rifampicin but that would rule out fixed drug doses&#44; so a cART based on efavirenz would be advisable&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">These patients should be managed by clinical experts in both infections&#44; with monitoring for adherence to both treatments &#40;using directly observed treatment if necessary&#59; methadone maintenance programs help treatment in heroin users&#41;&#46; Side effects and the possibility of immune reconstitution syndrome should be monitored&#44; along with the usual follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a> TB-HIV co-infection is a very serious worldwide problem that will only be solved with firm political commitment&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions</span><p id="par0250" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1&#46;</span><p id="par0255" class="elsevierStylePara elsevierViewall">The systematic use of rapid molecular tests is recommended in the diagnosis of TB to increase the diagnostic sensitivity of the disease&#44; to help early detection of drug resistance&#44; and to achieve better therapeutic outcomes for patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2&#46;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Although resistance in TB complicates treatment and the chances of success&#44; if basic management guidelines are followed&#44; acceptable cure rates can be achieved in the vast majority of patients&#46; These basic procedures&#44; which summarize virtually the entire guidelines&#44; are set out in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3&#46;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Treatment plans for these patients&#44; both initial and adjusted&#44; should always be consulted with experts&#46; To this end&#44; health authorities<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">41</span></a> and&#47;or scientific societies should promote the organization of expert groups at state level&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">4&#46;</span><p id="par0270" class="elsevierStylePara elsevierViewall">The top priorities will continue to be to offer adequate treatment to all patients with susceptible TB and to achieve good adherence in order to avoid the development of resistance&#46;</p></li></ul></p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">New evidence and knowledge about the clinical management of drug-resistant tuberculosis &#40;TB&#41; in the last 3 years&#44; makes it necessary to update the recent guideline published by SEPAR in 2017&#44; mainly in relation to new diagnostic methods&#44; drug classification&#44; and regimens of treatment recommended to treat patients with isoniazid-resistance TB&#44; rifampicin resistance TB and multidrug-resistant TB&#46; With respect to tuberculosis diagnosis&#44; we recommend the use of rapid molecular assays that also help to detect mutations associated with resistance&#46; In relation to the treatment of multidrug-resistant TB we prioritize effective all-oral shorter treatment regimens including bedaquiline&#44; a fluoroquinolone &#40;levofloxacin or moxifloxacin&#41;&#44; bedaquiline and linezolid&#44; instead of the previously recommended short-course treatment with aminoglycosides and other less effective and more toxic drugs&#46; The design of these regimens &#40;initial schedule and changes in the regimen if necessary&#41; should be made in accordance with drug-resistant TB experts&#59; the treatment should be the&#160;responsibility of personnel with experience in the treatment of TB and in TB units guaranteeing the follow-up of the treatment and the management of drugs adverse effects&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La evidencia acumulada en los 3 &#250;ltimos a&#241;os sobre el manejo cl&#237;nico de la tuberculosis &#40;TB&#41; con resistencia a f&#225;rmacos ha sido tan importante que hace necesario actualizar la normativa que SEPAR public&#243; en 2017&#44; sobre todo en lo referente a nuevos m&#233;todos diagn&#243;sticos&#44; a la clasificaci&#243;n racional de los f&#225;rmacos con actividad frente a <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> y a los esquemas b&#225;sicos a recomendar en los pacientes con TB con resistencia a isoniacida&#44; con resistencia a rifampicina o con multifarmacorresistencia&#46; En el diagn&#243;stico de la enfermedad recomendamos la utilizaci&#243;n de m&#233;todos moleculares r&#225;pidos que son &#250;tiles adem&#225;s para la detecci&#243;n precoz de mutaciones asociadas a resistencias a f&#225;rmacos&#46; Para el tratamiento de los enfermos con TB con multifarmacorresistencia se hace necesario dar prioridad a esquemas orales acortados que incluyan bedaquilina&#44; una fluoroquinolona &#40;levofloxacino o moxifloxacino&#41; y linezolid en lugar de los esquemas cortos previamente recomendados con aminogluc&#243;sidos y otros muchos f&#225;rmacos de menor eficacia y m&#225;s t&#243;xicos&#46; La recomendaci&#243;n de la normativa es que el dise&#241;o de los tratamientos en estos pacientes&#44; tanto el inicial como si se precisan cambios&#44; sea consultado siempre con expertos en el manejo de TB con resistencia a f&#225;rmacos y que se realicen por personal con experiencia en TB y en unidades que garanticen la supervisi&#243;n de los tratamientos y el abordaje de sus reacciones adversas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Please cite this article as&#58; Caminero JA&#44; Garc&#237;a-Garc&#237;a J-M&#44; Cayl&#224; JA&#44; Garc&#237;a-P&#233;rez FJ&#44; Palacios JJ&#44; Ruiz-Manzano J&#46; Actualizaci&#243;n de la normativa SEPAR &#171;Diagn&#243;stico y tratamiento de la tuberculosis con resistencia a f&#225;rmacos&#187;&#46; Arch Bronconeumol&#46; 2020&#59;56&#58;514&#8211;521&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Characteristics of drugs with activity against <span class="elsevierStyleItalic">M&#46; tuberculosis&#46;</span> Adapted from Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> and Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">22</span></a> &#40;<span class="elsevierStyleItalic">Updates Figure 2 of the 2017</span><span class="elsevierStyleItalic">guidelines</span><a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a>&#41;&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Group 1&#46; First-line oral drugs</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Group 2&#46; This corresponds to the current WHO group A&#46;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleItalic">Three groups of drugs are included here&#44; to be prioritized in the following order&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>a Levofloxacin or moxifloxacin&#46; Ideally&#44; resistance to these drugs should be ruled out using rapid molecular methods such as GenoType&#174; or Anyplex&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>b Linezolid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>c Bedaquiline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Group 3&#46; This corresponds to the current WHO group B&#46;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleItalic">Two drugs are included here&#44; one of which &#40;clofazimin&#41; has much greater evidence of action than the other &#40;cycloserin&#41;&#46; If one of the 2 is to be chosen&#44; clofazimin will always be given</span><span class="elsevierStyleItalic">priority</span><a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#44;6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>a Clofazimin&#46; This should be the drug of choice if any of the drugs in group 2 cannot be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>b Cycloserine&#46; In some specific cases&#44; some of the drugs in group 4 may be used prior to cycloserine on the basis of their better bactericidal and&#47;or sterilizing action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Group 4&#46; This corresponds to the current WHO group C</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleItalic">but the sequence of inclusion in the regimens should be as</span><span class="elsevierStyleItalic">follows</span><a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">20</span></a>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>a Meropenem&#44; or imipenem&#47;cilastatin&#46; Both should be given at the same time as amoxicillin&#47;clavulanate to facilitate their effectiveness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>b Delamanid&#46; Sometimes it may be preferable to use this drug before carbapenems because of the possibility of oral administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>c Amikacin<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#46; This should only be used if these 3 conditions are met&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1 Possible resistance has been ruled out by a rapid molecular test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2 Periodic audiometric checks can be done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3 There are no other drugs available among those previously listed in groups 2 and 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>d Ethionamide or prothionamide&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>e Pyrazinamide&#46; Its use here applies to cases of rifampicin-resistant tuberculosis&#47;multidrug-resistant tuberculosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>f Ethambutol&#46; Its use here applies to cases of rifampicin-resistant tuberculosis&#47;multidrug-resistant tuberculosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>g Para-aminosalicylic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2356438.png"
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          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Streptomycin may sometimes be evaluated for use in place of amikacin if there is resistance to amikacin and susceptibility to streptomycin&#44; but the 3 conditions previously described in the table must also be fulfilled&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Rational Classification and Sequential Use of Anti-tuberculosis Drugs in the Design of a Treatment Regimen for Both Drug-susceptible and Drug-resistant Tuberculosis&#46; &#40;This Table Updates Table 3 of the 2017 Guidelines<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a>&#41;&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">E&#58; ethambutol&#59; H&#58; isoniazid&#59; LFx&#58; levofloxacin&#59; R&#58; rifampicin&#59; TB&#58; tuberculosis&#59; Z&#58; pyrazinamide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">1&#46; Initial TB cases with R susceptibility &#40;known or unknown H</span><span class="elsevierStyleBold">susceptibility</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>- 2 HRZE&#47;4 HR&#44; or 2 HRZ&#47;4 HR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#42; 2 HRZ&#47;4 HR in cases where susceptibility to H can be determined in the first 2 weeks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">2&#46; TB cases with resistance to H &#40;mono- or polyresistance&#41;&#44; but with susceptibility to</span><span class="elsevierStyleBold">R</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>- 9 HRZE&#44; or 6 LFx-RZE &#40;H&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">3&#46; Cases with resistance to R &#40;mono- or polyresistance&#41;&#44; but with susceptibility to H</span>&#44; or if susceptibility to H is not known&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>- Same treatment as MDR-TB&#44; which is discussed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#44; adding H to the regimen&#44; but not taking into account it among the 4 new drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2356437.png"
              ]
            ]
          ]
          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Do not switch to the continuation phase &#40;4HR&#41; until one of the following 2 circumstances occurs&#58; sputum smear is already negative&#44; or that susceptibility to H and R is determined&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Treatment should be prolonged beyond 6 months in patients in whom sputum smear and&#47;or culture conversion is delayed beyond 2 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">1&#44;18</span></a> As a reference&#44; these patients will receive prolonged treatment with H&#43;R up to a minimum of 4 months after the cultures are negative&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">High doses of H are recommended if the 9HRZE regimen is selected&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">6 Lfx-RZE&#41; should only be included in the regimen if the entire regimen &#40;including Lfx&#41; is administered from the start&#46; It should not be used if H resistance results will be received after 3&#8211;4 weeks of treatment&#44; due to the possible risk of inadvertent monotherapy&#46; In this case use 9HRZE&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With Susceptible Tuberculosis and Mono&#47;Polyresistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">1&#44;20&#44;22</span></a> &#40;This Table Updates Table 4 of the 2017 Guidelines&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">BDQ&#58; Bedaquiline&#59; Cfz&#58; clofazimine&#59; E&#58; ethambutol&#59; Eto&#58; ethionamide&#59; FQ&#58; fluoroquinolones&#59; hH&#58; high doses of H &#40;15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg weight&#41;&#59; hLfx&#58; high doses of LFx &#40;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#59; Lfx&#58; levofloxacin&#59; Lzd&#58; linezolid&#59; MDR-TB&#58; multidrug-resistant tuberculosis&#59; MFX&#58; Moxifloxacin&#59; Pto&#58; protionamide&#59; SLID&#58; second-line injectable drugs&#59; XDR-TB&#58; extensively multidrug-resistant TB&#59; Z&#58; pyrazinamide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">1&#46; Cases with MDR-TB&#44; but without resistance to second-line drugs&#46;</span> One of the following regimens could be used&#44; listed in order of priority&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">A&#46; Shorter oral regimens with BDQ</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1&#46; Option a&#58; If the sputum smear is negative at month 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>4 Bdq<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a>-Lfx&#47;Mfx-Cfz-Eto&#47;Pto-E-Z-Hh&#47;2 Bdq-Lfx&#47;Mfx-Cfz-Z-E&#47;3 Lfx&#47;Mfx-Cfz-Z-E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Option b&#58; If the sputum smear is positive at month 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>6 Bdq<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a>-Lfx&#47;Mfx-Cfz-Eto&#47;Pto-E-Z-Hh&#47;5 Lfx&#47;Mfx-Cfz-Z-E&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2&#46; 6<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a> Bdq-hLfx-Lzd-Cfz&#47;3 hLfx-Lzd-Cfz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3&#46; 6&#8211;9 Bdq-hLfx-Lzd<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">B&#46; Longer oral regimen</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>6 Bdq-Lfx-Lzd-Cfz&#47;12 Lfx-Lzd-Cfz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">2&#46; Cases with MDR-TB and additional resistance to FQ&#44; SLID&#44; both&#44; or even broader patterns of XDR-TB resistance</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>a&#46; Consult with experts and design a regimen that follows all the recommendations made in these guidelines&#44; selecting a minimum of 3&#8211;4 new drugs&#44; following the rational classification listed &#40;groups 1 to 4&#41; in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> of this document and trying to include the maximum number of bactericidal and sterilizing drugs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>b&#46; For cases that only have XDR-TB and not resistance to BDQ or Lzd&#44; the pretomanid regimen not yet marketed in Spain must be evaluated&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>6 BDQ-Lzd-pretomanid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2356439.png"
              ]
            ]
          ]
          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">If sputum smear remains positive at the end of month 4&#44; this intensive phase should be prolonged up to 6 months with all of the same drugs &#40;option b&#41;&#46; If still positive at 6 months&#44; this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">If sputum smear remains positive at month 6&#44; this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">If sputum smear remains positive at the end of month 2&#44; prolong treatment for up to 9 months with all 3 drugs&#46; If the sputum smear is still positive at the end of month 4&#44; this should be taken as an indicator that the regimen is failing and an alternative regimen should be considered&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">6&#44;9&#44;10&#44;19&#44;20&#44;22&#44;30&#8211;32</span></a> &#40;This Table Updates Table 5 of the 2017 Guidelines&#41;&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Am&#58; amikacin&#59; BDQ&#58; bedaquiline&#59; Cfz&#58; clofazimine&#59; Cs&#58; cycloserine&#59; DLM&#58; delamanid&#59; DST&#58; drug susceptibility test&#59; E&#58; ethambutol&#59; Eto&#58; ethionamide&#59; FQ&#58; fluoroquinolones&#59; H&#58; isoniazid&#59; HIV&#58; human immunodeficiency virus&#59; hLfx&#58; high doses of Lfx &#40;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#58; Lfx&#58; levofloxacin&#59; Lzd&#58; linezolid&#59; MDR-TB&#58; multidrug-resistant tuberculosis&#59; PAS&#58; para-aminosalicylic acid&#59; Pto&#58; protionamide&#59; R&#58; rifampicin&#59; S&#58; streptomycin&#59; RR-TB&#58; rifampicin-resistant tuberculosis&#59; SLID&#58; second-line injectable drugs&#59; XDR-TB&#58; extremely drug-resistant tuberculosis&#59; Z&#58; pyrazinamide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Steps&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; Diagnosis&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">Take into account&#8226; Drug history&#58; One month of monotherapy&#44; or adding a single drug to a treatment regimen that is not effective&#44; is an important indicator of possible resistance to that drug&#44; or of possible reduced efficacy&#8226; Drug susceptibility tests &#40;DST&#41;&#58; Highly reliable for R&#44; H&#44; FQ and SLID&#46; Less reliable for S&#44; E&#44; and Z&#46; Very unreliable for Eto&#47;Pto&#44; CS and PAS&#46; The method for Lzd&#44; BDQ&#44; Dlm&#44; Cfz and carbapenems has yet to be standardized&#8226; Perform a rapid molecular test to detect RR-TB or MDR-TB in all cases where TB is presumed&#8226; In all cases with RR-TB or MDR-TB&#44; perform a rapid molecular test to detect resistance to FQ and SLID&#46;&#8226; Perform HIV test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; Number of medications&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">&#8226; Consultation and advice from experts to design an effective regimen&#8226; At least 3&#8211;4 effective drugs&#58; never used in the past or with susceptibility demonstrated by DST&#44; taking into account <span class="elsevierStyleUnderline">DST reliability</span> discussed in point 1 and possible cross-resistance&#8226; At least 1&#8211;2 drugs with good bactericidal capacity and at least 1&#8211;2 with good sterilizing capacity&#46; Try to avoid drugs without bactericidal or sterilizing capacity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; Selection of medications&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">&#8226; Rational introduction according to <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#8226; Always give priority to the 3 drugs in group 2 &#40;FQ&#44; BDQ&#44; Lzd&#41;&#44; provided susceptibility has been confirmed &#40;FQ&#41; or presumed &#40;BDQ&#44; Lzd&#41;&#8226; Use high-dose Lfx or moxifloxacin&#8226; In case of having to resort to group 3&#44; always give priority to Cfz&#8226; In the case of having to resort to group 4&#44; always introduce them in this order&#58; carbapenems&#44; Dlm&#44; Am&#44; Eto&#47;Pto&#44; Z&#44; E and PAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46; Treatment regimens<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">a</span></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"><span class="elsevierStyleBold">RR-TB&#47;MDR-TB patients&#58;</span>&#8226; See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#44; with recommendation of 3 <span class="elsevierStyleUnderline">shorter</span> oral regimens with BDQ&#44; option A &#40;1a and b&#44; 2&#44;3&#42;&#41;&#46; &#42;6&#8211;9 BDQ-hLfx-LZD will be used if there is a test that demonstrates susceptibility to FQ&#59; and if BDQ and LZD have not been used previously for the treatment of TB in the patient&#8226; Also in this table see <span class="elsevierStyleUnderline">longer</span> oral regimen &#40;option B&#41;<span class="elsevierStyleBold">XDR-TB patients&#58;</span> Evaluate 6 BDQ-Lzd-pretomanid&#8226; In all of them&#44; the electrocardiographic QTc must be monitored<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">b</span></a>&#8226; Always with directly observed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46; Surgery&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">Consider if these 3 conditions are met&#8226; 1&#46; Less than 4 effective drugs&#59; 2&#46; Localized lesions&#59; 3&#46; Sufficient respiratory reserve after resection&#8226; Evaluate&#44; particularly in XDR-TB and pre-XDR-TB due to FQ resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2356436.png"
              ]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">An expert should always be consulted when designing a treatment regimen for these patients&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Levofloxacin&#44; moxifloxacin and clofazimin&#44; like bedaquiline and delamanid&#44; may cause QTc alterations on ECG&#46; We recommend two papers<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">42&#44;43</span></a> on the effects of drugs used in the treatment of MDR and XDR tuberculosis on QTc on ECG&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Summary of Good Practices in MDR-TB Management&#46; This Table Updates Table 8 of the 2017 guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a></p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:43 [
            0 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and Treatment of Drug-Resistant Tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Caminero"
                            1 => "J&#46;A&#46; Cayla"
                            2 => "J&#46;M&#46; Garc&#237;a-Garc&#237;a"
                            3 => "F&#46;J&#46; Garc&#237;a-P&#233;rez"
                            4 => "J&#46;J&#46; Palacios Guti&#233;rrez"
                            5 => "J&#46; Ruiz Manzano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2017.02.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2017"
                        "volumen" => "53"
                        "paginaInicial" => "501"
                        "paginaFinal" => "509"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28359606"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of different treatments for isoniazid-resistant tuberculosis&#58; an individual patient data meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Fregonese"
                            1 => "S&#46;D&#46; Ahuja"
                            2 => "O&#46;W&#46; Akkerman"
                            3 => "D&#46; Arakaki-Sanchez"
                            4 => "I&#46; Avakaka"
                            5 => "P&#46; Baghaei"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(18)30078-X"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Respir Med"
                        "fecha" => "2018"
                        "volumen" => "6"
                        "paginaInicial" => "265"
                        "paginaFinal" => "275"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29595509"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Collaborative Group for the Meta-analysis of Individual Patient Data in MDR-TB Treatment 2017 Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis&#58; an individual data and meta-analysis"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "The Collaborative Group for the Meta-analysis of Individual Patient Data in MDR-TB Treatment 2017"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Ahmad"
                            1 => "S&#46;D&#46; Ahuja"
                            2 => "O&#46;W&#46; Akkerman"
                            3 => "J&#46;C&#46; Alffenaar"
                            4 => "L&#46;F&#46; Anderson"
                            5 => "P&#46; Baghaei"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(18)31644-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2018"
                        "volumen" => "392"
                        "paginaInicial" => "821"
                        "paginaFinal" => "834"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30215381"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis&#58; a retrospective cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Schnippel"
                            1 => "N&#46; Ndjeka"
                            2 => "G&#46; Maartens"
                            3 => "G&#46; Meintjes"
                            4 => "I&#46; Master"
                            5 => "N&#46; Ismail"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(18)30235-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Respir Med"
                        "fecha" => "2018"
                        "volumen" => "6"
                        "paginaInicial" => "699"
                        "paginaFinal" => "706"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30001994"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "World Health Organization&#46; WHO treatment guidelines for isoniazid-resistant tuberculosis&#46; Supplement to the WHO treatment guidelines for drug-resistant tuberculosis&#46; World Health Organization Document 2018&#46; Licence&#58; CC BY-NC-SA 3&#46;0 IGO&#46; WHO&#47;CDS&#47;TB&#47;2018&#46;7&#58; 1-31&#46; Available from&#58; <a target="_blank" href="https://www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/">https&#58;&#47;&#47;www&#46;who&#46;int&#47;tb&#47;publications&#47;2018&#47;WHO&#95;guidelines&#95;isoniazid&#95;resistant&#95;TB&#47;en&#47;</a> &#91;accessed 21&#46;01&#46;20&#93;&#46;"
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "WHO consolidated guidelines on drug-resistant tuberculosis treatment&#46; Geneva&#58; World Health Organization&#59; 2019&#46; Licence&#58; CC BY-NC-SA 3&#46;0 IGO&#46; Available from&#58; <a target="_blank" href="https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/">https&#58;&#47;&#47;www&#46;who&#46;int&#47;tb&#47;publications&#47;2019&#47;consolidated-guidelines-drug-resistant-TB-treatment&#47;en&#47;</a> &#91;accessed 21&#46;01&#46;20&#93;&#46;"
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of drug-resistant tuberculosis&#46; An official ATS&#47;CDC&#47;ERS&#47;IDSA clinical practice guideline"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Nahid"
                            1 => "S&#46;R&#46; Mase"
                            2 => "G&#46;B&#46; Migliori"
                            3 => "G&#46; Sotgiu"
                            4 => "G&#46;H&#46; Bothamley"
                            5 => "J&#46;L&#46; Brozet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.201909-1874ST"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2019"
                        "volumen" => "200"
                        "paginaInicial" => "e93"
                        "paginaFinal" => "e142"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31729908"
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                      "titulo" => "Planning for country transition to Xpert MTB&#47;RIF Ultra Cartridges"
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                            4 => "A&#46;M&#46; Starks"
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                        "paginaInicial" => "1403"
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                          0 => array:2 [
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                            "web" => "Medline"
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                        "paginaInicial" => "S231"
                        "paginaFinal" => "S279"
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                            "web" => "Medline"
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                        "paginaInicial" => "1986"
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                      "titulo" => "Levofloxacin can be used effectively as a positive control in thorough QT&#47;QTc studies in healthy volunteers"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Taubel"
                            1 => "A&#46; Naseem"
                            2 => "T&#46; Harada"
                            3 => "D&#46; Wang"
                            4 => "R&#46; Arezina"
                            5 => "U&#46; Lorch"
                          ]
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                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2125.2009.03595.x"
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                        "fecha" => "2010"
                        "volumen" => "69"
                        "paginaInicial" => "391"
                        "paginaFinal" => "400"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20406223"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
              ]
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              "etiqueta" => "29"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regimens to treat multidrug-resistant tuberculosis&#58; past&#44; present and future perspectives"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "and the writing group members of the Global TB Network Clinical Trials Committee"
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46; Pontali"
                            1 => "M&#46;C&#46; Raviglione"
                            2 => "G&#46;B&#46; Migliori"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/16000617.0035-2019"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir Rev"
                        "fecha" => "2019"
                        "volumen" => "28"
                        "paginaInicial" => "190035"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31142549"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "FDA Advisory Committee votes favorably on the question of the ffectiveness and safety of pretomanid in combination with bedaquiline and linezolid for treatment of highly drug-resistant forms of tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46;B&#46; Alliance"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2019"
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                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "TB Alliance&#46; FDA approves new treatment for highly drug-resistant forms of tuberculosis&#46; Available from&#58; <a target="_blank" href="https://www.tballiance.org/news/fda-approves-new-treatment-highly-drug-resistant-forms-tuberculosis">https&#58;&#47;&#47;www&#46;tballiance&#46;org&#47;news&#47;fda-approves-new-treatment-highly-drug-resistant-forms-tuberculosis</a> &#91;accessed 24&#46;01&#46;20&#93;&#46;"
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              ]
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              "identificador" => "bib0375"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of highly drug-resistant pulmonary tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Conradie"
                            1 => "A&#46;H&#46; Diacon"
                            2 => "N&#46; Ngubane"
                            3 => "P&#46; Howel"
                            4 => "D&#46; Everitt"
                            5 => "A&#46;M&#46; Crook"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1901814"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2020"
                        "volumen" => "382"
                        "paginaInicial" => "893"
                        "paginaFinal" => "902"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32130813"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New drugs for the treatment of tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46;H&#46; Ignatius"
                            1 => "K&#46;E&#46; Dooley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ccm.2019.08.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chest Med"
                        "fecha" => "2019"
                        "volumen" => "40"
                        "paginaInicial" => "811"
                        "paginaFinal" => "827"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31731986"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multidrug-resistant tuberculosis&#46; Authors&#8217; reply"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46; Menzies"
                            1 => "A&#46; Benedetti"
                            2 => "G&#46;B&#46; Migliori"
                            3 => "P&#46; Nahid"
                            4 => "B&#46; Seaworth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(19)30692-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2019"
                        "volumen" => "394"
                        "paginaInicial" => "299"
                        "paginaFinal" => "300"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31354139"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "Management of drug-resistant tuberculosis in children&#58; a field guide"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:4 [
                        "edicion" => "Fourth edition"
                        "fecha" => "2018"
                        "editorial" => "The Sentinel Project for Pediatric Drug-Resistant Tuberculosis"
                        "editorialLocalizacion" => "Boston&#44; USA"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Timing of initiation of antiretroviral drugs during tuberculosis therapy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;S&#46; Abdool Karim"
                            1 => "K&#46; Naidoo"
                            2 => "A&#46; Grobler"
                            3 => "N&#46; Padayatchi"
                            4 => "C&#46; Baxter"
                            5 => "A&#46; Gray"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0905848"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2010"
                        "volumen" => "362"
                        "paginaInicial" => "697"
                        "paginaFinal" => "706"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20181971"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "CAMELIA &#40;ANRS 1295&#8211;CIPRA KH001&#41; Study Team"
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                            0 => "F&#46;X&#46; Blanc"
                            1 => "T&#46; Sok"
                            2 => "D&#46; Laureillard"
                            3 => "L&#46; Borand"
                            4 => "C&#46; Rekacewicz"
                            5 => "E&#46; Nerrienet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1013911"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "1471"
                        "paginaFinal" => "1481"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22010913"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0405"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "Treatment of LTBI and TB for persons with HIV&#46; CDC"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2016"
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                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Panel de Expertos del Grupo de estudio de Sida &#40;Gesida-SEIMC&#41;&#46; Recomendaciones de Gesida sobre el tratamiento de la tuberculosis en adultos infectados por el virus de la inmunodeficiencia humana &#40;actualizaci&#243;n mayo de 2018&#41;&#46; Available from&#58; <a target="_blank" href="http://gesida-seimc.org/wp-content/uploads/2018/06/gesida_TB_en_VIH_Version_FINAL_5_de_junio_2018.pdf">http&#58;&#47;&#47;gesida-seimc&#46;org&#47;wp-content&#47;uploads&#47;2018&#47;06&#47;gesida&#95;TB&#95;en&#95;VIH&#95;Version&#95;FINAL&#95;5&#95;de&#95;junio&#95;2018&#46;pdf</a> &#91;accessed 13&#46;01&#46;20&#93;&#46;"
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              ]
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              "identificador" => "bib0415"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tuberculosis-HIV co-infection&#58; progress and challenges after two decades of global antiretroviral treatment roll-out"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Letang"
                            1 => "J&#46; Ellis"
                            2 => "K&#46; Naidoo"
                            3 => "E&#46;C&#46; Casas"
                            4 => "P&#46; S&#225;nchez"
                            5 => "R&#46; Hassan-Moosa"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2019.11.015"
                      "Revista" => array:2 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2019"
                      ]
                    ]
                  ]
                ]
              ]
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            40 => array:3 [
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              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:1 [
                      "titulo" => "Plan para la Prevenci&#243;n y Control de la TB en Espa&#241;a"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "2019"
                        "editorial" => "Ministerio de Sanidad&#44; Consumo y Bienestar Social"
                        "editorialLocalizacion" => "Madrid"
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                    ]
                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "QTc prolongation and treatment of multidrug-resistant tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46; Harausz"
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                            2 => "M&#46; Rich"
                            3 => "C&#46;D&#46; Mitnick"
                            4 => "P&#46; Zimetbaum"
                            5 => "J&#46; Furin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5588/ijtld.14.0335"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Tuberc Lung Dis"
                        "fecha" => "2015"
                        "volumen" => "19"
                        "paginaInicial" => "385"
                        "paginaFinal" => "391"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25859992"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "H&#46;Y&#46; Yoon"
                            1 => "K&#46;W&#46; Jo"
                            2 => "G&#46;B&#46; Nam"
                            3 => "T&#46; Shim"
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                        "tituloSerie" => "Int J Tuberc Lung Dis"
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                        "paginaFinal" => "1001"
                        "link" => array:1 [
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2020.03.014

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Year/Month	Html	Pdf	Total

2024 November	10	4	14
2024 October	89	49	138
2024 September	83	43	126
2024 August	107	58	165
2024 July	73	33	106
2024 June	87	66	153
2024 May	148	42	190
2024 April	61	43	104
2024 March	56	28	84
2024 February	49	26	75
2024 January	1	0	1
2023 November	1	0	1
2023 October	5	0	5
2023 September	2	0	2
2023 August	7	2	9
2023 April	2	0	2
2023 March	13	7	20
2023 February	81	50	131
2023 January	63	47	110
2022 December	82	41	123
2022 November	84	30	114
2022 October	71	36	107
2022 September	66	28	94
2022 August	42	40	82
2022 July	67	57	124
2022 June	48	42	90
2022 May	49	38	87
2022 April	45	29	74
2022 March	50	51	101
2022 February	33	23	56
2022 January	3	2	5
2021 June	13	0	13
2021 April	1	2	3
2020 November	1	0	1
2020 October	1	0	1
2020 August	1	0	1
2020 July	4	2	6
2020 June	2	2	4

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