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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Template for collecting patient anti-TB drug history&#46; Adapted from Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction and Rationale for the Guidelines</span><p id="par0005" class="elsevierStylePara elsevierViewall">After decades during which tuberculosis &#40;TB&#41; became an almost universally curable disease&#44; the emergence of strains of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> &#40;<span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#41; resistant to the most active drugs available has once again made TB a major threat and a challenge to global public health&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> It is&#44; however&#44; important to remember that if access to appropriate diagnosis and treatment are guaranteed&#44; the chances of curing all patients with TB are very high&#44; even among carriers of highly resistant strains&#46; Protocolized clinical management is essential if the treatment of these patients is to be successful&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">2&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The current global status of multidrug-resistant TB &#40;MDR-TB&#41; &#8211; TB resistant to at least isoniazid &#40;H&#41; and rifampicin &#40;R&#41; &#8211; is worrying&#44; and the overall response to this situation has been unsatisfactory&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">1&#44;10</span></a> An estimated 3&#46;9&#37; of new TB cases worldwide are thought to be MDR-TB&#44; and this rate rises to 21&#37; in previously treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> Of the estimated 10&#46;6 million cases of TB occurring in 2015 &#40;1&#46;8 million deaths&#41;&#44; about 580<span class="elsevierStyleHsp" style=""></span>000 cases may have been rifampicin-resistant &#40;RR-TB&#41; or MDR-TB&#44; leading to around 250<span class="elsevierStyleHsp" style=""></span>000 deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> Worldwide&#44; however&#44; less than 150<span class="elsevierStyleHsp" style=""></span>000 cases &#40;26&#37; of the estimated total&#41; were reported&#44; with a cure rate of 52&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> In other words&#44; only about 10&#37; of the estimated MDR-TB patients worldwide were cured&#44; a rate that is totally ineffective for controlling the epidemic&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although the prevalence of MDR-TB in Spain remains difficult to pinpoint due to underreporting of TB and failure to perform systematic resistance testing&#44; the situation seems more favorable&#58; 0&#46;1&#37; cases of TB in Spanish natives and 2&#46;2&#37; in immigrants were primary MDR-TB&#44; of which 3&#46;4&#37; and 10&#46;2&#37;&#44; respectively&#44; showed primary resistance to H&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">11&#44;12</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of Drug-Resistant Tuberculosis</span><p id="par0020" class="elsevierStylePara elsevierViewall">TB diagnosis is still based on clinical suspicion&#44; radiology&#44; and microbiological testing&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">13</span></a> The clinical and radiological features of drug-resistant tuberculosis &#40;DR-TB&#41; are indistinguishable from those of drug-susceptible TB&#44; so diagnosis of DR-TB must always be based on microbiological and&#47;or molecular evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Drug Susceptibility Studies</span><p id="par0025" class="elsevierStylePara elsevierViewall">Spanish guidelines currently recommend cultures and susceptibility studies&#44; including at least isoniazid &#40;H&#41; and rifampicin &#40;R&#41;&#44; in all patients with TB&#44; irrespective of whether the patient is treatment-na&#239;ve or presents a risk factor for DR-TB &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;6&#44;16&#44;17</span></a> &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">If resistance to R is shown&#44; the susceptibility study should be extended to include the fluoroquinolone &#40;FQ&#41; and the second-line injectable drug &#40;SLID&#41; that will be used in the rescue treatment offered to the patient<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> &#40;levofloxacin &#91;Lfx&#93;&#47;moxifloxacin &#91;Mfx&#93; and amikacin &#91;Am&#93;&#47;capreomycin &#91;Cm&#93; in Spain&#41; &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111161"></elsevierMultimedia>&#93;&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The results of conventional susceptibility testing to all these drugs are very reliable&#44; so this information can be used to guide the recommended treatment regimen&#46; In contrast&#44; the clinical credibility of susceptibility testing to other drugs such as ethambutol &#40;E&#41;&#44; pyrazinamide &#40;Z&#41;&#44; ethionamide&#47;prothionamide &#40;Eth&#47;Pth&#41;&#44; cycloserine &#40;Cs&#41;&#44; para-aminosalicylic acid &#40;PAS&#41;&#44; or clofazimine &#40;Cfz&#41; is significantly lower&#44; and these results can often confound rather than assist decisions regarding the possible treatment regimen needed by the patient&#46; For this reason&#44; routine testing is not recommended&#44; and if these tests are performed&#44; the results must be viewed with caution<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6&#44;18</span></a> &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111162"></elsevierMultimedia>&#93; to very low &#91;<elsevierMultimedia ident="201708291348111163"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Phenotypic and Genotypic Drug Susceptibility Testing</span><p id="par0040" class="elsevierStylePara elsevierViewall">Susceptibility tests can be performed using phenotypic or genotypic methods&#46; Phenotypic testing must be performed on mycobacteria in active growth phase in the culture media&#44; so results will be unavailable for at least 2&#8211;3 weeks if liquid media are used&#44; and up to 4&#8211;8 weeks in the case of solid media&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> This delay may be excessive if a decision is to be made regarding the ideal treatment of the patient&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In contrast&#44; molecular tests&#44; which use genetic amplification techniques to detect mutations in genes coding for resistance to anti-TB drugs&#44; provide results within 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#46; For this reason&#44; such tests&#44; when available&#44; should be performed in all patients diagnosed with TB &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Specific Molecular Techniques&#58; Xpert MTB&#47;RIF &#40;Cepheid&#41; and GenotypeMDR<span class="elsevierStyleItalic">plus</span> &#40;Hain&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">One of the most important of these molecular techniques is the Xpert MTB&#47;RIF &#40;Cepheid&#41; that can detect resistance to R within 2<span class="elsevierStyleHsp" style=""></span>h with a sensitivity of 95&#37; and a specificity of 98&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">14&#44;17</span></a> This technique is much more sensitive than sputum smears &#40;positive in up to 70&#37;&#8211;90&#37; of cases with negative smear test and positive culture&#41;&#44; and represents an important advance in early detection&#46; The GenotypeMDR<span class="elsevierStyleItalic">plus</span> &#40;Hain&#41; or line probe assay can also simultaneously detect mutations in genes that encode resistance to isoniazid &#40;<span class="elsevierStyleItalic">kat</span>G and <span class="elsevierStyleItalic">inh</span>A&#41; and rifampicin &#40;<span class="elsevierStyleItalic">rpo</span>B&#41; within a period of 6&#8211;24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Both molecular techniques can be carried out in direct samples&#44; without the need to wait for the isolate to grow in culture&#46; The clinical significance of the <span class="elsevierStyleItalic">inh</span> A gene mutation and&#47;or the <span class="elsevierStyleItalic">kat</span>G gene and the recommendation to use H despite proven resistance are described in detail in the online version of this guideline&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">21&#8211;28</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Version 2 of the GenotypeMDR<span class="elsevierStyleItalic">sl</span> &#40;Hain&#41; line probe assay can be used to detect resistance to FQ &#40;<span class="elsevierStyleItalic">gyr</span>A and <span class="elsevierStyleItalic">gyr</span>B mutations&#41; and to SLID &#40;genetic mutations in <span class="elsevierStyleItalic">rrs</span> and the <span class="elsevierStyleItalic">eis</span> promoter region&#41;&#46; The specificity of this method for both FQs and SLID is higher than 98&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">29&#8211;31</span></a> so this information should be taken into consideration in the design of the treatment schedule<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">32&#44;33</span></a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111164"></elsevierMultimedia>&#93;&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical History of Previously Administered Drugs</span><p id="par0065" class="elsevierStylePara elsevierViewall">It is of utmost importance to consult the clinical records of patients previously treated for TB to determine their drug history&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> When the wrong drug has been administered for more than 1 month&#44; the possibility of resistance and reduced efficacy must be suspected&#44; even if the susceptibility testing suggests the opposite&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;34</span></a> There are simple drug history templates that can help with this task&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> It is also necessary to determine if the patient&#39;s index case had DR-TB&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis of Drug-Resistant Tuberculosis&#58; Conclusions</span><p id="par0070" class="elsevierStylePara elsevierViewall">This guideline recommends that&#58; &#40;1&#41; all patients with diagnosis of TB undergo H and R susceptibility testing&#44; using a rapid test molecular if available&#59; &#40;2&#41; if resistance to R and&#47;or H is demonstrated&#44; susceptibility tests to the FQ and SLID proposed for the subsequent treatment schedule should be performed&#44; using GenotypeMDR<span class="elsevierStyleItalic">sl</span> &#40;Hain&#41; v2 if possible&#59; &#40;3&#41; standard phenotypic tests must also be performed&#59; while these take longer and support the treatment decision to a lesser degree&#44; they can resolve any discrepancies between the methods&#59; and &#40;4&#41; a clinical drug history is essential for designing future treatment regimens&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Principles for the Treatment of Both Drug-Susceptible and Drug-Resistant Forms of Tuberculosis</span><p id="par0075" class="elsevierStylePara elsevierViewall">All TB treatment must meet 2 basic bacteriological requirements&#58; drugs must be combined to prevent the selection of resistance and the treatment must be administered for long enough to ensure cure and avoid relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;35&#44;36</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">To ensure cure of TB without relapse as far as possible&#44; it is recommended that all treatment regimens involve a combination of at least 4 previously unused drugs or drugs to which the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> has shown susceptibility&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;15&#44;36</span></a> Of these&#44; 2 must be core drugs&#44; capable of eliminating the majority of the bacilli and curing the patient&#46; At least 1 of these core drugs must have good bactericidal activity &#40;ability to eliminate rapidly multiplying bacilli located in cavitated lesions that cause symptoms and transmission&#41;&#44; and at least 1 must have good sterilizing activity &#40;ability to eliminate those bacilli in semilatent phases that are responsible for relapses&#41;&#46; The other 2 drugs are what we call companion compounds&#44; and their mission is to protect the core drugs from selection of resistance<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;36</span></a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111165"></elsevierMultimedia>&#93;&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">To assist in the selection of the drugs needed to make up a TB regimen&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the bactericidal and sterilizing capacity of the different drugs&#44; their ability to prevent the selection of resistance&#44; and their toxicity profile&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2a and 2b</a> list in detail the doses of the different drugs with activity against <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; the route of administration&#44; and the most common adverse effects&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></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="par0095" class="elsevierStylePara elsevierViewall">To assist in the selection of the 4 drugs that must be included in any treatment of initial phase TB&#44; these compounds should be classified into 5 different groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a>&#41;&#44; starting with Group 1&#44; the group with the greatest activity&#44; and continuing with the others in decreasing order of effectiveness and tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;8&#44;37&#44;38</span></a> Prescribing physicians should work their way down through these groups until at least 4 new drugs or drugs very likely to be susceptible have been combined&#44; ensuring the inclusion of at least 1 bactericidal drug and 1 sterilizing drug&#46; Guidelines for starting each of the drugs included in these groups are shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111166"></elsevierMultimedia>&#93;&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Group 1 consists of &#8220;first-line oral drugs&#8221;&#44; so called because these are used in the first instance in practically all patients with drug-susceptible TB&#46; This group comprises the most effective&#44; the best tolerated&#44; and the least expensive products&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">37&#44;38</span></a> Drugs classified as core because of their bactericidal &#40;H and R&#41; or sterilizing &#40;R and Z&#41; activity must be distinguished from companion drugs &#40;E&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;36</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Group 2 consists of the FQs &#40;high-dose Lfx or Mfx&#41;&#44; which are also core drugs with bactericidal and sterilizing activity and low toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37&#44;38</span></a> Moreover&#44; if these products can be used&#44; they clearly affect prognosis in the treatment of MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;39&#44;40</span></a> Although no specific studies have been performed&#44; evidence suggests the presence of considerable cross-resistance between these 2 FQs&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Group 3 consists of second-line injectable drugs&#46; These are also core drugs&#44; due to their bactericidal activity&#44; but with little or no sterilizing ability and they are far more toxic than the FQs&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37&#44;38</span></a> This cumulative toxicity and the need for administration by injection greatly limit their use&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Group 4 is composed of 6 different drugs that might be administered in combination because they attack <span class="elsevierStyleItalic">M&#46; tuberculosis via</span> different targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;6&#44;37&#44;38</span></a> This is a mixed group consisting of drugs that could be considered core due to their activity&#44; although the accumulated evidence is still scant &#40;linezolid&#44; bedaquiline and delamanid&#41;&#44; and others that have stronger supporting evidence but moderate or low activity &#40;ethionamide&#47;prothionamide and cycloserine&#47;terizidone&#41; and would behave as companion drugs&#44; and a third&#44; clofazimine&#44; which seems to have good sterilizing activity&#46; The selection of one or the other will depend on their availability and possible adverse effects&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Linezolid can be considered a core drug&#44; with bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> Several publications<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;41&#8211;43</span></a> have confirmed its role in the treatment of MDR-TB and extensively drug resistant TB &#40;XDR-TB&#41;&#46; Linezolid has 2 drawbacks&#44; namely its cost and its toxicity profile when administered for more than 6&#8211;8 weeks&#44; with frequent hematological alterations and polyneuropathies&#46; Toxicity problems are highly dose-dependent<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> and relatively easy to manage&#44; given the low dose recommended for MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;41</span></a> while the price has fallen since the generic molecule became available in 2016&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Bedaquiline can also be considered core due to its bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;44</span></a> Two clinical trials have demonstrated its efficacy in the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">45&#44;46</span></a> particularly in XDR-TB &#40;MDR-TB resistant to at least 1 FQ and 1 SLID &#91;kanamycin&#44; amikacin&#44; capreomycin&#93;&#41;&#44; and it is used in many countries&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Finally&#44; delamanid and pretomanid are metronidazole derivatives with bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;47&#8211;51</span></a> Two randomized clinical trials have demonstrated the usefulness of delamanid in the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">48&#44;49</span></a> particularly in XDR-TB&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Linezolid&#44; bedaquiline&#44; and delamanid are all likely to play a significant role in the treatment of MDR-TB in the very near future&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> and may also be of use in the treatment of susceptible TB&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Aside from the foregoing drugs&#44; the most effective compounds are the thioamides &#40;ethionamide&#47;prothionamide&#41;&#46; These may be mildly bactericidal&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> but show potential cross-resistance with H &#40;<span class="elsevierStyleItalic">inh</span>A gene mutation&#44; detectable by GenotypeMDRplus&#41; and a poor gastric tolerance profile&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> The next most active is clofazimine&#44; an important component of short treatments of MDR-TB due to its possible sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">8&#44;26&#44;52</span></a> The last is cycloserine &#40;similar to terizidone in terms of action&#41;&#44; which has good oral tolerance&#44; but limited activity and potentially serious psychiatric adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;53</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A hypothetical Group 5 would include the carbapenems &#40;imipenem or meropenem&#41; combined with clavulanic acid &#40;as this does not exist separately&#44; it must be administered with amoxicillin&#41;&#44; which are probably quite active despite the scant supporting evidence<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;54</span></a>&#59; PAS&#44; which is very ineffective&#44; with poor gastric tolerance<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37</span></a>&#59; and thioacetazone&#44; which is very weak&#44; potentially toxic in patients with human immunodeficiency virus &#40;HIV&#41;&#44; and very difficult to obtain&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of Tuberculosis According to Resistance Patterns</span><p id="par0150" class="elsevierStylePara elsevierViewall">TB&#44; according to possible resistance patterns&#44; difficulty of treatment and the different prognoses involved&#44; can be classified into 5 large groups in ascending order of complexity<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Primary Tuberculosis Susceptible to All Anti-TB Drugs</span><p id="par0155" class="elsevierStylePara elsevierViewall">The ideal treatment regimen for new TB cases in which susceptibility to all drugs is assumed would be 2HRZE&#47;4HR&#44; taking into consideration the factors listed in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a><a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;13&#44;15&#44;36&#44;56</span></a> &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46; To reduce the possibility of errors and selection of resistances&#44; these drugs should be administered in fixed dose combinations &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2a and 2b</a>&#41; with directly observed therapy in patients with risk factors for poor treatment compliance&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of Tuberculosis Resistant to Isoniazid &#40;Single or Multiple Resistances&#41; but Susceptible to Rifampicin</span><p id="par0160" class="elsevierStylePara elsevierViewall">This is a relatively common situation&#46; In these cases&#44; the recommendation is to use 9 HRZE &#40;in this case&#44; high doses of H may be considered&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">23</span></a> and to perform a susceptibility study with the remaining first-line drugs &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111167"></elsevierMultimedia>&#93; to very low &#40;<elsevierMultimedia ident="201708291348111168"></elsevierMultimedia>&#41; quality of evidence&#41;&#46; A regimen containing 2FQ-REZ&#47;7CF-RE could also be considered &#40;with an FQ susceptibility study&#41;&#44; but FQ &#40;Lfx&#47;Mfx&#41; should only be included if it is administered from the beginning of treatment along with the other drugs&#46; It should not be added if results of resistance testing to H are received after 3&#8211;4 weeks of treatment&#44; due to possible risk of de facto monotherapy&#46; See options in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">4&#44;6&#44;15</span></a> A third possibility&#44; in line with current SEPAR recommendations is 2RZE&#47;10RE&#44; with has been used successfully in standard treatments when H had to be discontinued due to intolerance&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of Tuberculosis Resistant to Rifampicin &#40;Single or Multiple Resistances&#41;&#44; but Susceptible to Isoniazid</span><p id="par0165" class="elsevierStylePara elsevierViewall">As cases of isolated resistance to R are very rare in clinical practice&#44; and since R is the compound that determines prognosis in patients with MDR-TB&#44; these patients should be approached as MDR-TB cases&#44; and treated as such&#44; with the addition of H to the schedule&#44; of course&#44; because if susceptibility is confirmed&#44; this will contribute significantly to the treatment<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6</span></a> &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111169"></elsevierMultimedia>&#93; to very low &#91;<elsevierMultimedia ident="2017082913481111610"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Treatment of Multi-Drug Resistant Tuberculosis Susceptible to Fluoroquinolones and Second-Line Injectable Drugs</span><p id="par0170" class="elsevierStylePara elsevierViewall">Following the rationale of this guideline&#44; the ideal regimen for these patients would include an FQ &#40;Mfx&#44; or high-dose Lfx&#41;&#44; a second-line injectable drug &#40;at least until cultures become negative&#41;&#44; and 2 drugs selected from Group 4 of this guideline&#46; Z should also be included in this regimen if susceptible&#44; due to its possible activity&#44; taking into account that the susceptibility test is not reliable &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111611"></elsevierMultimedia>&#93; quality of evidence&#41;&#46; The options listed in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a> should be considered&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">The total duration of this combination of 4 new drugs plus Z is much more controversial&#46; The conventionally recommended regimens of more than 21 months<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;8&#44;9</span></a> have not achieved success rates greater than 55&#37;&#8211;70&#37;&#44; particularly due to high drop-out rates&#44;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">40&#44;57&#44;58</span></a> which are clearly associated with the extensive length of treatment&#44; and also with poor tolerance and toxicity&#46; For this reason&#44; this guideline recommends that priority be given to the 9- to 12-month schedule recently recommended by the WHO<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a> for all patients with R-resistant TB&#44; or with MDR-TB who have not previously received FQ or SLID&#44; or who show susceptibility <span class="elsevierStyleItalic">in vitro</span> to these 2 classes of antibiotics &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111612"></elsevierMultimedia>&#93; quality of evidence&#41;&#46; This regimen consists of an initial phase of 4 months &#40;or until sputum smears become negative&#41; with kanamycin &#40;Am or Cm in Spain&#41;&#44; high-dose moxifloxacin&#44; clofazimine&#44; ethionamide&#47;prothionamide&#44; pyrazinamide&#44; ethambutol&#44; and high-dose H&#46; The continuation phase will be of 5 months of high-dose moxifloxacin&#44; clofazimine&#44; ethambutol&#44; and pyrazinamide&#46; Patients must be closely monitored for possible adverse effects&#44; primarily possible prolongation of the QTc interval on electrocardiogram&#44; due in particular to the high moxifloxacin doses recommended in this regimen&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment of Patients With Multi-Drug Resistant Tuberculosis and Added Resistance to Fluoroquinolones&#44; Second-Line Injectable Drugs&#44; or Both&#44; or Even Broader Patterns of Resistance</span><p id="par0180" class="elsevierStylePara elsevierViewall">The clinical and operational management of these forms of TB are already pose considerable difficulties&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6</span></a> They must be treated by experts in the disease&#44; in units that can guarantee close follow-up of treatment and appropriate management of adverse reactions&#46; Possible regimens that can be administered to the vast majority of these patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Role of Surgery</span><p id="par0185" class="elsevierStylePara elsevierViewall">Surgery can also contribute to the success of the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;8&#44;59</span></a> although it can only be considered in the few patients that meet the following 3 conditions<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#58; &#40;1&#41; reasonably localized resectable lesion&#59; &#40;2&#41; sufficient respiratory reserve for the patient to tolerate surgery and the postoperative period&#59; and &#40;3&#41; lack of medications available to design a curative regimen for the patient&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> If the last premise is met&#44; surgery may be considered in patients with FQ-resistant MDR-TB or an even broader resistance pattern &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111613"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Monitoring During Treatment and Evaluation of Results</span><p id="par0190" class="elsevierStylePara elsevierViewall">Patients should be monitored at least once a month during the intensive treatment phase&#44; and then every 1 or 2 months during the continuation phase&#46; Aspects that should be evaluated in each of these controls are listed in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 6</a>&#44; and criteria for evaluating treatment outcomes are described in detail in <a class="elsevierStyleCrossRef" href="#tbl0040">Table 7</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">60</span></a></p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><elsevierMultimedia ident="tbl0040"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Management of Contacts</span><p id="par0195" class="elsevierStylePara elsevierViewall">Available evidence suggests that if a contact of a case with MDR-TB develops TB&#44; they should receive the same treatment as the index case while pending susceptibility test results&#44; with possible subsequent adjustment after the test results are received&#46; If the secondary case is not confirmed microbiologically&#44; as can happen in children&#44; in paucibacillary TB&#44; or in extrapulmonary TB&#44; the regimen of the index case must continue&#46; Systematic treatment of the tubercular infection in contacts of MDR-TB patients is not recommended&#44; unless they have another risk factor for MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;6&#44;61</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">Although TB resistances complicate treatment and the chances of success&#44; following basic rules of management will ensure acceptable cure rates in the vast majority of patients&#46; The basic principles and a summary of most of these guidelines can be found in <a class="elsevierStyleCrossRef" href="#tbl0045">Table 8</a>&#46;In all cases&#44; an expert should be consulted when designing a treatment scheme for these patients&#46; For this purpose&#44; the foundation of national expert groups sponsored by the health authorities and&#47;or the scientific societies is recommended&#46;The first priority is still to offer patients with susceptible TB the appropriate treatment&#44; in order to avoid the appearance of resistance&#46;</p><elsevierMultimedia ident="tbl0045"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of Interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction and Rationale for the Guidelines"
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          "titulo" => "Diagnosis of Drug-Resistant Tuberculosis"
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              "titulo" => "Specific Molecular Techniques&#58; Xpert MTB&#47;RIF &#40;Cepheid&#41; and GenotypeMDRplus &#40;Hain&#41;"
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              "identificador" => "sec0030"
              "titulo" => "Clinical History of Previously Administered Drugs"
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          "titulo" => "Principles for the Treatment of Both Drug-Susceptible and Drug-Resistant Forms of Tuberculosis"
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          "titulo" => "Rational Classification of Drugs With Activity Against M&#46; tuberculosis"
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          "titulo" => "Treatment of Tuberculosis According to Resistance Patterns"
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              "titulo" => "Treatment of Multi-Drug Resistant Tuberculosis Susceptible to Fluoroquinolones and Second-Line Injectable Drugs"
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              "titulo" => "Treatment of Patients With Multi-Drug Resistant Tuberculosis and Added Resistance to Fluoroquinolones&#44; Second-Line Injectable Drugs&#44; or Both&#44; or Even Broader Patterns of Resistance"
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            1 => "Tuberculosis con resistencia a f&#225;rmacos"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In the last 2 decades&#44; drug-resistant tuberculosis has become a threat and a challenge to worldwide public health&#46; The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies&#46; Nevertheless&#44; it is important to remember that with the appropriatesystematic clinical management&#44; most of these patients can be cured&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients&#44; from those infected by strains that are sensitive to all drugs&#44; to those who are extensively drug-resistant&#46; Specific recommendations are given forall cases&#46; The current and future role of new molecular methods for detecting resistance&#44; shorter multi-drug-resistant tuberculosis regimens&#44; and new drugs with activity against <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> are also addressed&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">En las &#250;ltimas 2 d&#233;cadas la tuberculosis con resistencia a f&#225;rmacos se ha convertido en una amenaza y un reto para la salud p&#250;blica mundial&#46; El diagn&#243;stico y el tratamiento de estas formas de tuberculosis es mucho m&#225;s complejo&#44; y el pron&#243;stico empeora claramente a medida que se incrementa el patr&#243;n de las resistencias&#46; Sin embargo&#44; es necesario destacar c&#243;mo con el manejo cl&#237;nico y program&#225;tico adecuado de estos enfermos se puede conseguir la curaci&#243;n de una mayor&#237;a de ellos&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">En esta normativa se razonan las bases del diagn&#243;stico y tratamiento de todos los pacientes afectos de tuberculosis&#44; desde aquellos que tienen formas de la enfermedad con sensibilidad a todos los f&#225;rmacos hasta aquellos que son portadores de los patrones m&#225;s extensos de resistencia&#46; Asimismo&#44; se dan recomendaciones espec&#237;ficas para cada uno de estos supuestos&#46; Tambi&#233;n se aborda el papel que ya est&#225;n teniendo y pueden tener en un futuro inmediato los nuevos m&#233;todos moleculares de detecci&#243;n de resistencias&#44; los esquemas acortados de tratamiento de la tuberculosis multi-farmacorresistente &#40;TB-MDR&#41; y los nuevos f&#225;rmacos con actividad frente a <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0125">Please cite this article as&#58; Caminero JA&#44; Cayla JA&#44; Garc&#237;a-Garc&#237;a J-M&#44; Garc&#237;a-P&#233;rez FJ&#44; Palacios JJ&#44; Ruiz-Manzano J&#46; Diagn&#243;stico y tratamiento de la tuberculosis con resistencia a f&#225;rmacos&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;501&#8211;509&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Template for collecting patient anti-TB drug history&#46; Adapted from Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p>"
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          "en" => "<p id="spar0030" 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="#bib0485"><span class="elsevierStyleSup">36</span></a></p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Prevention of resistance&#44; bactericidal activity and sterilizing activity are listed in descending order &#40;high&#44; moderate&#44; and low activity&#41;&#44; while toxicity &#40;right-hand arrow&#41; is listed in ascending order &#40;low&#44; moderate&#44; high&#41;&#44; so that the best available drugs combining all these features appear in the top row&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">High risk factors</span>&nbsp;\t\t\t\t\t\t\n
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Most Common Adverse Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; Max&#46; 600<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#44; hypersensitivity reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&#44; IM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at normal doses &#40;max&#46; 300<span class="elsevierStyleHsp" style=""></span>mg&#41;<br>15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at high doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#46; Peripheral neuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pyrazinamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#46; Hyperuricemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethambutol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg in continuation phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Optic neuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Streptomycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; Max&#46; 1<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotoxicity&#44; 8th cranial nerve involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethionamide&#47;prothionamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">750&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastroenteritis&#47;hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cycloserine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">750&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Personality changes&#47;depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Capreomycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;day or&#47;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kanamycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h or&#47;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Amikacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h or 48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Levofloxacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>750<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleSup">&#8722;1</span><span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tenosynovitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Moxifloxacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tenosynovitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;15<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastroenteritis&#47;hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clofazimine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&#8211;200<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pigmentation&#47;eosinophilic enteritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linezolid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pancytopenia&#47;gastrointestinal disorders&#47;polyneuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;8<span class="elsevierStyleHsp" style=""></span>h or 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hematological disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bedaquiline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400<span class="elsevierStyleHsp" style=""></span>mg&#47;day for 15 days and then 200<span class="elsevierStyleHsp" style=""></span>mg&#47;3 times a week for a maximum of 6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastric intolerance&#44; pancreatitis&#44; hepatitis&#44; altered QTc on ECG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delamanid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for a maximum of 6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anemia&#44; nausea&#44; altered QTc on ECG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Drugs With Anti-<span class="elsevierStyleItalic">M&#46; tuberculosis</span> Activity&#46; Recommended Doses and Most Common Adverse Effects &#40;a&#44; Recommended Doses for Each of the Drugs Used Individually&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">3</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">4</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; Lange et al&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">61</span></a></p>"
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            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" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin &#40;H&#43;R&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rifinah 300</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 150</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 300</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;50<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 50<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin&#43;pyrazinamide &#40;H&#43;R&#43;Z&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rifater</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 50</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 120</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; Z 300</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>In children under the age of 10 years&#44; adjust according to dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 20&#8211;30<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;40<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 40&#8211;49<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 50&#8211;64<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 65<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin&#43;pyrazinamide&#43;ethambutol &#40;H&#43;R&#43;Z&#43;E&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rimstar</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 75</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 150</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; Z 400</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; E 275</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;39<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 40&#8211;54<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 55&#8211;70<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 70<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501028.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Drugs With Anti-<span class="elsevierStyleItalic">M&#46; tuberculosis</span> Activity&#46; Recommended Doses and Most Common Adverse Effects &#40;b&#44; Recommended Doses for Combinations of the Most Common Drugs Available in Spain&#41;&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">4</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">37</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">First-line drugs for oral administration</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Core drugs&#58; isoniazid&#44; rifampicin&#44; pyrazinamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Companion drug&#58; ethambutol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Fluoroquinolones</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>High-dose levofloxacin or moxifloxacin&#44; all are core&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Second-line injectable drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Streptomycin<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&#44; kanamycin&#44; amikacin&#44; capreomycin&#44; all are core&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Mixed group of core drugs with little evidence and less effective companion drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>core drugs&#58; linezolid&#44; bedaquiline&#44; delamanid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>companion drugs&#58; clofazimine&#44; prothionamide&#47;ethionamide&#44; cycloserine&#47;terizidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Other drugs with less clinical experience&#44; or less effective and more toxic</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Carbapenems &#40;meropenem&#47;imipenem&#41;&#43;amoxicillin&#47;clavulanic acid&#44; PAS&#44; thioacetazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1501023.png"
              ]
            ]
          ]
          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Use all possible drugs&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Use only 1&#44; because the genetic target is the same&#46; Consider it as active drug in MDR-TB cases&#46; In XDR-TB cases&#44; add a fluoroquinolone and&#47;or an injectable if <span class="elsevierStyleItalic">in vitro</span> susceptibility to any of these drugs is maintained&#44; and always try to ensure it is different from the previously used compound&#46; In XDR-TB&#44; these products should not be included among the 4 active agents of the regimen&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Avoid streptomycin due to its high rate of resistance associated with isoniazid&#44; but it may be considered if it is seen to be susceptible on resistance testing&#44; and if it has not been previously used in the patient&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Use all possible drugs as required to achieve a total of 4 new products&#46; Ethionamide and prothionamide are interchangeable because they have the same mechanism of action and the same side effects&#46; The same applies to cycloserine and terizidone&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Only use in extreme cases&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Rational Classification and Sequential Use of Anti-TB Drugs When Designing a Treatment Regimen for Drug-Susceptible or Drug Resistant TB&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; Caminero&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial TB cases susceptible to all drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2HRZE&#47;4&#40;HR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">TB cases resistant to H &#40;single or multiple resistances&#41;&#44; but susceptible to R</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">d</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>9HRZE&#44; or 2FQ-REZ&#47;7FQ-RE or 2RZE&#47;10RE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Cases resistant to R &#40;single or multiple resistances&#41; but susceptible to H&#44; or if susceptibility to H is unknown</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Same treatment as MDR-TB&#44; which is shown in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#44; adding H to the regimen&#44; but without counting it as one of the 4 new drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501021.png"
              ]
            ]
          ]
          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">There is no consensus with regard to the duration of this treatment in HIV-infected patients&#44; and some groups and scientific societies recommend continuing treatment for 9 months&#44; with the aim of reducing the relapse rate&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Do not switch to the continuation phase &#40;4 HR&#41; until 1 of the following 2 circumstances occurs&#58; sputum smear is negative&#44; or susceptibility to H and R is confirmed&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Prolong treatment beyond 6 months in patients in whom sputum smears and&#47;or cultures take longer than 2 months to become negative&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> As a reference&#44; these patients will continue treatment with H&#43;R for at least 4 months after cultures become negative&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">If the 9 HRZE regimen is selected&#44; high doses of H will be given&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0050">FQ &#40;Lfx&#47;Mfx&#41; should only be included in the regimen if it is administered with the rest of the drugs from the beginning&#46; It should not be added if results of resistance testing to H are received after 3&#8211;4 weeks of treatment&#44; due to the possible risk of de facto monotherapy&#46; In this case&#44; use 9 HRZE&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With Susceptible TB and Single or Multiple Resistances&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">CP&#58; continuation phase&#46; Until completion of 21 months of treatment&#59; IP&#58; intensive phase&#46; Until cultures become negative&#44; or up to 6 months in case of extensive lesions&#46; Continue for at least 4 months if the patient is not expectorating and no follow-up sputum tests can be performed&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a>&#59; Caminero&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">MDR-TB cases&#44; but without resistance to second-line drugs</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Short regimen&#58; 4<a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">a</span></a> &#40;Cm&#47;Am&#43;Mfx<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">b</span></a>&#43;Pth&#47;Eth&#43;Cfz&#43;E&#43;Z&#43;H<a class="elsevierStyleCrossRef" href="#tblfn0065"><span class="elsevierStyleSup">c</span></a>&#41;&#47;5 &#40;Mfx<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">b</span></a>&#43;Cfz&#43;E&#43;Z&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Standard regimen&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intensive phase &#40;Cm<a class="elsevierStyleCrossRef" href="#tblfn0070"><span class="elsevierStyleSup">d</span></a>&#43;Mfx&#47;Lfx&#43;Z&#43;2 Group 4 drugs<a class="elsevierStyleCrossRef" href="#tblfn0075"><span class="elsevierStyleSup">e</span></a>&#41;&#47;continuation phase &#40;Mfx&#47;Lfx&#43;Z&#43;2 Group 4 drugs<a class="elsevierStyleCrossRef" href="#tblfn0075"><span class="elsevierStyleSup">e</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">MDR-TB cases with additional resistance to the FQ&#44; SLID&#44; both&#44; or even broader XDR-TB resistance patterns</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Consult experts and design a regimen that follows all the recommendations made in this guideline&#44; looking for a minimum of 4 new drugs&#44; following the rational classification provided &#40;Groups 1 to 5&#41;&#44; with the aim of including the maximum number of bactericidal and sterilizing drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0055"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">At least 4 months or until sputum smear testing becomes negative&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0060"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0060">High doses of Mfx &#40;800<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0065"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0065">High doses of H &#40;15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg body weight&#41;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0070"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0070">The injectable drug may be given 3 times per week &#40;with an interval of 48<span class="elsevierStyleHsp" style=""></span>h between doses&#41; when sputum smears become negative&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0075"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0075">Two Group 4 drugs will be chosen on the basis of availability and potential adverse effects&#46;</p>"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With MDR-TB&#46;</p>"
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            "identificador" => "at7"
            "detalle" => "Table "
            "rol" => "short"
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            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#43;M12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Medical visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sputum smear &#40;&#215;2&#8211;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Culture &#40;&#215;2&#8211;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical laboratory tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">EKG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ENT audiometry&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chest radiograph&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ophthalmological examination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Psychiatric evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            0 => array:3 [
              "identificador" => "tblfn0080"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0080">Optional in case of good clinical progress and negative sputum smear and culture at the end of the fourth month&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0085"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0085">Only if the patient is receiving high-dose moxifloxacin&#44; delamanid and&#47;or bedaquiline&#46; If normal doses of moxifloxacin are given&#44; a EKG every 2&#8211;3 months is sufficient&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0090"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0090">Only if the patient is treated with an injectable drug&#44; either aminoglycoside or capreomycin&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0095"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0095">Only if the patient is receiving ethambutol and&#47;or linezolid&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0100"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0100">Only if the patient is receiving cycloserine or terizidone&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Follow-Up Required During TB Treatment&#46;</p>"
        ]
      ]
      9 => array:8 [
        "identificador" => "tbl0040"
        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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            "identificador" => "at8"
            "detalle" => "Table "
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; World Health Organization&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">60</span></a></p>"
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            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Definition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Treatment outcomes in TB patients without rifampicin resistance and without MDR</span>-<span class="elsevierStyleItalic">TB</span><a class="elsevierStyleCrossRef" href="#tblfn0105"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cured&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patient with bacteriologically confirmed TB at the start of treatment and negative sputum smear or culture in the last month of treatment and on at least 1 previous 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Completed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who completed treatment without evidence of failure&#44; but without evidence of negative sputum smear or culture in the last month of treatment and on at least 1 previous test&#44; either because the tests were not performed&#44; or because the results are not available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Treatment failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patient with TB with positive sputum smear or culture in month 5 or later during 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who dies for any reason before starting or during the course of 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lost-to-follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who did not start treatment or suspended treatment for 30 consecutive days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Not evaluated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient without assigned treatment outcome&#46; Includes cases transferred to another treatment unit&#44; and cases in whom treatment outcome is unknown&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Outcomes of TB patients with rifampicin-resistant disease&#44; or MDR&#47;XDR-TB treated with second-line drugs</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cured&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment completed as recommended by national guidelines without evidence of failure and 3 or more consecutive negative cultures at least 30 days apart&#44; after the intensive phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Completed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment completed as recommended by the national policy without evidence of failure&#44; but without evidence of 3 or more consecutive negative cultures at least 30 days apart&#44; after the intensive phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Failed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment was discontinued or a permanent change of regimen or at least 2 anti-TB drugs were required due to&#58;<br>Failure to convert<a class="elsevierStyleCrossRef" href="#tblfn0110"><span class="elsevierStyleSup">b</span></a> at the end of the intensive phase&#44; or<br>Bacteriological reversion<a class="elsevierStyleCrossRef" href="#tblfn0115"><span class="elsevierStyleSup">c</span></a> in the continuation phase after conversion to a negative status&#44; or<br>Evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs&#44; or<br>Adverse drug reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who dies for any reason before starting or during the course of 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lost-to-follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who did not start treatment or suspended treatment for 30 consecutive days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Not evaluated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient without assigned treatment outcome&#46; Includes cases transferred to another treatment unit&#44; and cases in whom treatment outcome is unknown&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0105"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0105">Successful treatment&#58; the sum of cures plus completed treatment&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0110"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0110">Conversion&#58; 2 negative cultures obtained at least 30 days apart&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0115"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0115">Reversion&#58; 2 positive cultures performed at least 30 days apart after initial conversion &#40;continuation phase&#41;&#46;</p> <p class="elsevierStyleNotepara" id="npar0120">Successful treatment&#58; the sum of cures plus completed treatment&#46;</p>"
            ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Criteria for Evaluating Treatment Outcomes in TB Patients&#44; Following WHO Recommendations&#46;</p>"
        ]
      ]
      10 => array:8 [
        "identificador" => "tbl0045"
        "etiqueta" => "Table 8"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at9"
            "detalle" => "Table "
            "rol" => "short"
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          "leyenda" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">In all cases&#44; an expert should be consulted when designing a treatment scheme for these patients&#46;</p><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Adapted from&#58; Caminero and Scardigli&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Steps&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#46; Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Take in account&#58;</span><br>Drug history&#58; 1 month of monotherapy&#44; or the addition of a single drug to an ineffective treatment regimen is an important indicator of possible resistance to that drug&#44; or possibly lower efficacy&#46;<br>Drug susceptibility testing &#40;DST&#41;&#58; very reliable for R and H&#59; quite reliable for second-line injectable drugs and FQ&#59; less reliable for S&#44; E&#44; and Z&#59; unreliable for Eth&#47;Pth&#44; Cs&#44; and PAS&#46; The exact method and credibility remain to be determined for Lzd&#44; Bdq Cfz&#44; Dlm&#44; and carbapenems<br>HIV testing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46; Number of drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At least 4 effective medications&#58; never used in the past or with susceptibility demonstrated on DST&#44; taking into account DST reliability mentioned in point 1 and possible cross-resistance<br>At least 2 core drugs &#40;at least 1 with high bactericidal activity and at least 1 other with sterilizing capacity&#41; and 2 companion drugs to protect the core drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&#46; Selection of drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rational introduction according to <a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a><br>For MDR-TB&#44; try to use first-line drugs if they are still effective&#46; However&#44; in this case&#44; do not count them among the &#8220;4 effective drugs&#8221;<br>High-dose levofloxacin or moxifloxacin<br>A second-line injectable drug or S&#44; if it is still susceptible and has not been used previously<br>Use Group 4 drugs until 4 effective drugs have been included<br>Consider high-dose H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#46; Treatment duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Short regimen&#58; 9 months&#46; Intensive phase of at least 4 months or until sputum smear testing becomes negative&#46; Continuation phase&#58; 5 months<br>Standard regimen&#58; 21 months&#46; Intensive phase&#58; at least until sputum smear and culture become negative&#59; always for at least 6 months&#46; Even longer if there are less than 3 effective drugs in the continuation phase&#44; or resistance to FQ is suspected&#46; Continuation phase&#58; at least until 21 months of treatment in total and 12 months with negative cultures<br>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="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&#46; Surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Consider only if the following 3 conditions are met&#58;</span><br>&#40;1&#41; less than 4 effective drugs&#59; &#40;2&#41; localized lesions&#59; and &#40;3&#41; sufficient respiratory reserve after resection<br>In XDR and pre-XDR-TB especially&#44; assess for resistance to FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&#46; Ideal regimen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Standard</span>&#58; if only standard regimens have been administered in the past&#44; both for first- and second-line treatment&#46;<br><span class="elsevierStyleItalic">Individualized</span>&#58; if second-line drugs other than standard treatments have been used&#44; or in contacts of MDR patients who have used them&#46; In the latter case&#44; treat with the regimen that was effective in the index case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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SEPAR's voice
Diagnosis and Treatment of Drug-Resistant Tuberculosis
Diagnóstico y tratamiento de la tuberculosis con resistencia a fármacos
José A. Camineroa,b,c,
Corresponding author
jcamlun@gobiernodecanarias.org

Corresponding author.
, Joan A. Caylac,d, José-María García-Garcíac,e, Francisco J. García-Pérezc,f, Juan J. Palaciosc,g, Juan Ruiz-Manzanoc,h,i
a Servicio de Neumología, Hospital General de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
b Unidad de Tuberculosis con Multi-Drogo Resistencia, 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 Servicio de Epidemiología, Agència de Salut Pública de Barcelona, CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
e Unidad de Gestión Clínica de Neumología, Hospital Universitario San Agustín, Avilés, Asturias, 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 Servicio de Neumología, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain
i Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Template for collecting patient anti-TB drug history&#46; Adapted from Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction and Rationale for the Guidelines</span><p id="par0005" class="elsevierStylePara elsevierViewall">After decades during which tuberculosis &#40;TB&#41; became an almost universally curable disease&#44; the emergence of strains of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> &#40;<span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#41; resistant to the most active drugs available has once again made TB a major threat and a challenge to global public health&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> It is&#44; however&#44; important to remember that if access to appropriate diagnosis and treatment are guaranteed&#44; the chances of curing all patients with TB are very high&#44; even among carriers of highly resistant strains&#46; Protocolized clinical management is essential if the treatment of these patients is to be successful&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">2&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The current global status of multidrug-resistant TB &#40;MDR-TB&#41; &#8211; TB resistant to at least isoniazid &#40;H&#41; and rifampicin &#40;R&#41; &#8211; is worrying&#44; and the overall response to this situation has been unsatisfactory&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">1&#44;10</span></a> An estimated 3&#46;9&#37; of new TB cases worldwide are thought to be MDR-TB&#44; and this rate rises to 21&#37; in previously treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> Of the estimated 10&#46;6 million cases of TB occurring in 2015 &#40;1&#46;8 million deaths&#41;&#44; about 580<span class="elsevierStyleHsp" style=""></span>000 cases may have been rifampicin-resistant &#40;RR-TB&#41; or MDR-TB&#44; leading to around 250<span class="elsevierStyleHsp" style=""></span>000 deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> Worldwide&#44; however&#44; less than 150<span class="elsevierStyleHsp" style=""></span>000 cases &#40;26&#37; of the estimated total&#41; were reported&#44; with a cure rate of 52&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">1</span></a> In other words&#44; only about 10&#37; of the estimated MDR-TB patients worldwide were cured&#44; a rate that is totally ineffective for controlling the epidemic&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although the prevalence of MDR-TB in Spain remains difficult to pinpoint due to underreporting of TB and failure to perform systematic resistance testing&#44; the situation seems more favorable&#58; 0&#46;1&#37; cases of TB in Spanish natives and 2&#46;2&#37; in immigrants were primary MDR-TB&#44; of which 3&#46;4&#37; and 10&#46;2&#37;&#44; respectively&#44; showed primary resistance to H&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">11&#44;12</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of Drug-Resistant Tuberculosis</span><p id="par0020" class="elsevierStylePara elsevierViewall">TB diagnosis is still based on clinical suspicion&#44; radiology&#44; and microbiological testing&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">13</span></a> The clinical and radiological features of drug-resistant tuberculosis &#40;DR-TB&#41; are indistinguishable from those of drug-susceptible TB&#44; so diagnosis of DR-TB must always be based on microbiological and&#47;or molecular evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Drug Susceptibility Studies</span><p id="par0025" class="elsevierStylePara elsevierViewall">Spanish guidelines currently recommend cultures and susceptibility studies&#44; including at least isoniazid &#40;H&#41; and rifampicin &#40;R&#41;&#44; in all patients with TB&#44; irrespective of whether the patient is treatment-na&#239;ve or presents a risk factor for DR-TB &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;6&#44;16&#44;17</span></a> &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">If resistance to R is shown&#44; the susceptibility study should be extended to include the fluoroquinolone &#40;FQ&#41; and the second-line injectable drug &#40;SLID&#41; that will be used in the rescue treatment offered to the patient<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> &#40;levofloxacin &#91;Lfx&#93;&#47;moxifloxacin &#91;Mfx&#93; and amikacin &#91;Am&#93;&#47;capreomycin &#91;Cm&#93; in Spain&#41; &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111161"></elsevierMultimedia>&#93;&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The results of conventional susceptibility testing to all these drugs are very reliable&#44; so this information can be used to guide the recommended treatment regimen&#46; In contrast&#44; the clinical credibility of susceptibility testing to other drugs such as ethambutol &#40;E&#41;&#44; pyrazinamide &#40;Z&#41;&#44; ethionamide&#47;prothionamide &#40;Eth&#47;Pth&#41;&#44; cycloserine &#40;Cs&#41;&#44; para-aminosalicylic acid &#40;PAS&#41;&#44; or clofazimine &#40;Cfz&#41; is significantly lower&#44; and these results can often confound rather than assist decisions regarding the possible treatment regimen needed by the patient&#46; For this reason&#44; routine testing is not recommended&#44; and if these tests are performed&#44; the results must be viewed with caution<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6&#44;18</span></a> &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111162"></elsevierMultimedia>&#93; to very low &#91;<elsevierMultimedia ident="201708291348111163"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Phenotypic and Genotypic Drug Susceptibility Testing</span><p id="par0040" class="elsevierStylePara elsevierViewall">Susceptibility tests can be performed using phenotypic or genotypic methods&#46; Phenotypic testing must be performed on mycobacteria in active growth phase in the culture media&#44; so results will be unavailable for at least 2&#8211;3 weeks if liquid media are used&#44; and up to 4&#8211;8 weeks in the case of solid media&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> This delay may be excessive if a decision is to be made regarding the ideal treatment of the patient&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In contrast&#44; molecular tests&#44; which use genetic amplification techniques to detect mutations in genes coding for resistance to anti-TB drugs&#44; provide results within 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#46; For this reason&#44; such tests&#44; when available&#44; should be performed in all patients diagnosed with TB &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Specific Molecular Techniques&#58; Xpert MTB&#47;RIF &#40;Cepheid&#41; and GenotypeMDR<span class="elsevierStyleItalic">plus</span> &#40;Hain&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">One of the most important of these molecular techniques is the Xpert MTB&#47;RIF &#40;Cepheid&#41; that can detect resistance to R within 2<span class="elsevierStyleHsp" style=""></span>h with a sensitivity of 95&#37; and a specificity of 98&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">14&#44;17</span></a> This technique is much more sensitive than sputum smears &#40;positive in up to 70&#37;&#8211;90&#37; of cases with negative smear test and positive culture&#41;&#44; and represents an important advance in early detection&#46; The GenotypeMDR<span class="elsevierStyleItalic">plus</span> &#40;Hain&#41; or line probe assay can also simultaneously detect mutations in genes that encode resistance to isoniazid &#40;<span class="elsevierStyleItalic">kat</span>G and <span class="elsevierStyleItalic">inh</span>A&#41; and rifampicin &#40;<span class="elsevierStyleItalic">rpo</span>B&#41; within a period of 6&#8211;24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Both molecular techniques can be carried out in direct samples&#44; without the need to wait for the isolate to grow in culture&#46; The clinical significance of the <span class="elsevierStyleItalic">inh</span> A gene mutation and&#47;or the <span class="elsevierStyleItalic">kat</span>G gene and the recommendation to use H despite proven resistance are described in detail in the online version of this guideline&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">21&#8211;28</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Version 2 of the GenotypeMDR<span class="elsevierStyleItalic">sl</span> &#40;Hain&#41; line probe assay can be used to detect resistance to FQ &#40;<span class="elsevierStyleItalic">gyr</span>A and <span class="elsevierStyleItalic">gyr</span>B mutations&#41; and to SLID &#40;genetic mutations in <span class="elsevierStyleItalic">rrs</span> and the <span class="elsevierStyleItalic">eis</span> promoter region&#41;&#46; The specificity of this method for both FQs and SLID is higher than 98&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">29&#8211;31</span></a> so this information should be taken into consideration in the design of the treatment schedule<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">32&#44;33</span></a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111164"></elsevierMultimedia>&#93;&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical History of Previously Administered Drugs</span><p id="par0065" class="elsevierStylePara elsevierViewall">It is of utmost importance to consult the clinical records of patients previously treated for TB to determine their drug history&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> When the wrong drug has been administered for more than 1 month&#44; the possibility of resistance and reduced efficacy must be suspected&#44; even if the susceptibility testing suggests the opposite&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;34</span></a> There are simple drug history templates that can help with this task&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> It is also necessary to determine if the patient&#39;s index case had DR-TB&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis of Drug-Resistant Tuberculosis&#58; Conclusions</span><p id="par0070" class="elsevierStylePara elsevierViewall">This guideline recommends that&#58; &#40;1&#41; all patients with diagnosis of TB undergo H and R susceptibility testing&#44; using a rapid test molecular if available&#59; &#40;2&#41; if resistance to R and&#47;or H is demonstrated&#44; susceptibility tests to the FQ and SLID proposed for the subsequent treatment schedule should be performed&#44; using GenotypeMDR<span class="elsevierStyleItalic">sl</span> &#40;Hain&#41; v2 if possible&#59; &#40;3&#41; standard phenotypic tests must also be performed&#59; while these take longer and support the treatment decision to a lesser degree&#44; they can resolve any discrepancies between the methods&#59; and &#40;4&#41; a clinical drug history is essential for designing future treatment regimens&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Principles for the Treatment of Both Drug-Susceptible and Drug-Resistant Forms of Tuberculosis</span><p id="par0075" class="elsevierStylePara elsevierViewall">All TB treatment must meet 2 basic bacteriological requirements&#58; drugs must be combined to prevent the selection of resistance and the treatment must be administered for long enough to ensure cure and avoid relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;35&#44;36</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">To ensure cure of TB without relapse as far as possible&#44; it is recommended that all treatment regimens involve a combination of at least 4 previously unused drugs or drugs to which the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> has shown susceptibility&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;15&#44;36</span></a> Of these&#44; 2 must be core drugs&#44; capable of eliminating the majority of the bacilli and curing the patient&#46; At least 1 of these core drugs must have good bactericidal activity &#40;ability to eliminate rapidly multiplying bacilli located in cavitated lesions that cause symptoms and transmission&#41;&#44; and at least 1 must have good sterilizing activity &#40;ability to eliminate those bacilli in semilatent phases that are responsible for relapses&#41;&#46; The other 2 drugs are what we call companion compounds&#44; and their mission is to protect the core drugs from selection of resistance<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;36</span></a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111165"></elsevierMultimedia>&#93;&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">To assist in the selection of the drugs needed to make up a TB regimen&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the bactericidal and sterilizing capacity of the different drugs&#44; their ability to prevent the selection of resistance&#44; and their toxicity profile&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2a and 2b</a> list in detail the doses of the different drugs with activity against <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; the route of administration&#44; and the most common adverse effects&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></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="par0095" class="elsevierStylePara elsevierViewall">To assist in the selection of the 4 drugs that must be included in any treatment of initial phase TB&#44; these compounds should be classified into 5 different groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a>&#41;&#44; starting with Group 1&#44; the group with the greatest activity&#44; and continuing with the others in decreasing order of effectiveness and tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;8&#44;37&#44;38</span></a> Prescribing physicians should work their way down through these groups until at least 4 new drugs or drugs very likely to be susceptible have been combined&#44; ensuring the inclusion of at least 1 bactericidal drug and 1 sterilizing drug&#46; Guidelines for starting each of the drugs included in these groups are shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a> &#40;conditional recommendation&#44; moderate quality of evidence &#91;&#8853;&#8853;<elsevierMultimedia ident="201708291348111166"></elsevierMultimedia>&#93;&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Group 1 consists of &#8220;first-line oral drugs&#8221;&#44; so called because these are used in the first instance in practically all patients with drug-susceptible TB&#46; This group comprises the most effective&#44; the best tolerated&#44; and the least expensive products&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">37&#44;38</span></a> Drugs classified as core because of their bactericidal &#40;H and R&#41; or sterilizing &#40;R and Z&#41; activity must be distinguished from companion drugs &#40;E&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;36</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Group 2 consists of the FQs &#40;high-dose Lfx or Mfx&#41;&#44; which are also core drugs with bactericidal and sterilizing activity and low toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37&#44;38</span></a> Moreover&#44; if these products can be used&#44; they clearly affect prognosis in the treatment of MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;39&#44;40</span></a> Although no specific studies have been performed&#44; evidence suggests the presence of considerable cross-resistance between these 2 FQs&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Group 3 consists of second-line injectable drugs&#46; These are also core drugs&#44; due to their bactericidal activity&#44; but with little or no sterilizing ability and they are far more toxic than the FQs&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37&#44;38</span></a> This cumulative toxicity and the need for administration by injection greatly limit their use&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Group 4 is composed of 6 different drugs that might be administered in combination because they attack <span class="elsevierStyleItalic">M&#46; tuberculosis via</span> different targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;6&#44;37&#44;38</span></a> This is a mixed group consisting of drugs that could be considered core due to their activity&#44; although the accumulated evidence is still scant &#40;linezolid&#44; bedaquiline and delamanid&#41;&#44; and others that have stronger supporting evidence but moderate or low activity &#40;ethionamide&#47;prothionamide and cycloserine&#47;terizidone&#41; and would behave as companion drugs&#44; and a third&#44; clofazimine&#44; which seems to have good sterilizing activity&#46; The selection of one or the other will depend on their availability and possible adverse effects&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Linezolid can be considered a core drug&#44; with bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> Several publications<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;41&#8211;43</span></a> have confirmed its role in the treatment of MDR-TB and extensively drug resistant TB &#40;XDR-TB&#41;&#46; Linezolid has 2 drawbacks&#44; namely its cost and its toxicity profile when administered for more than 6&#8211;8 weeks&#44; with frequent hematological alterations and polyneuropathies&#46; Toxicity problems are highly dose-dependent<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> and relatively easy to manage&#44; given the low dose recommended for MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;41</span></a> while the price has fallen since the generic molecule became available in 2016&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Bedaquiline can also be considered core due to its bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;44</span></a> Two clinical trials have demonstrated its efficacy in the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">45&#44;46</span></a> particularly in XDR-TB &#40;MDR-TB resistant to at least 1 FQ and 1 SLID &#91;kanamycin&#44; amikacin&#44; capreomycin&#93;&#41;&#44; and it is used in many countries&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Finally&#44; delamanid and pretomanid are metronidazole derivatives with bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">38&#44;47&#8211;51</span></a> Two randomized clinical trials have demonstrated the usefulness of delamanid in the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">48&#44;49</span></a> particularly in XDR-TB&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Linezolid&#44; bedaquiline&#44; and delamanid are all likely to play a significant role in the treatment of MDR-TB in the very near future&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a> and may also be of use in the treatment of susceptible TB&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Aside from the foregoing drugs&#44; the most effective compounds are the thioamides &#40;ethionamide&#47;prothionamide&#41;&#46; These may be mildly bactericidal&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> but show potential cross-resistance with H &#40;<span class="elsevierStyleItalic">inh</span>A gene mutation&#44; detectable by GenotypeMDRplus&#41; and a poor gastric tolerance profile&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> The next most active is clofazimine&#44; an important component of short treatments of MDR-TB due to its possible sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">8&#44;26&#44;52</span></a> The last is cycloserine &#40;similar to terizidone in terms of action&#41;&#44; which has good oral tolerance&#44; but limited activity and potentially serious psychiatric adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;53</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A hypothetical Group 5 would include the carbapenems &#40;imipenem or meropenem&#41; combined with clavulanic acid &#40;as this does not exist separately&#44; it must be administered with amoxicillin&#41;&#44; which are probably quite active despite the scant supporting evidence<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;54</span></a>&#59; PAS&#44; which is very ineffective&#44; with poor gastric tolerance<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;37</span></a>&#59; and thioacetazone&#44; which is very weak&#44; potentially toxic in patients with human immunodeficiency virus &#40;HIV&#41;&#44; and very difficult to obtain&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of Tuberculosis According to Resistance Patterns</span><p id="par0150" class="elsevierStylePara elsevierViewall">TB&#44; according to possible resistance patterns&#44; difficulty of treatment and the different prognoses involved&#44; can be classified into 5 large groups in ascending order of complexity<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Primary Tuberculosis Susceptible to All Anti-TB Drugs</span><p id="par0155" class="elsevierStylePara elsevierViewall">The ideal treatment regimen for new TB cases in which susceptibility to all drugs is assumed would be 2HRZE&#47;4HR&#44; taking into consideration the factors listed in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a><a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;13&#44;15&#44;36&#44;56</span></a> &#40;strong recommendation&#44; high quality of evidence &#91;&#8853;&#8853;&#8853;&#8853;&#93;&#41;&#46; To reduce the possibility of errors and selection of resistances&#44; these drugs should be administered in fixed dose combinations &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2a and 2b</a>&#41; with directly observed therapy in patients with risk factors for poor treatment compliance&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of Tuberculosis Resistant to Isoniazid &#40;Single or Multiple Resistances&#41; but Susceptible to Rifampicin</span><p id="par0160" class="elsevierStylePara elsevierViewall">This is a relatively common situation&#46; In these cases&#44; the recommendation is to use 9 HRZE &#40;in this case&#44; high doses of H may be considered&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">23</span></a> and to perform a susceptibility study with the remaining first-line drugs &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111167"></elsevierMultimedia>&#93; to very low &#40;<elsevierMultimedia ident="201708291348111168"></elsevierMultimedia>&#41; quality of evidence&#41;&#46; A regimen containing 2FQ-REZ&#47;7CF-RE could also be considered &#40;with an FQ susceptibility study&#41;&#44; but FQ &#40;Lfx&#47;Mfx&#41; should only be included if it is administered from the beginning of treatment along with the other drugs&#46; It should not be added if results of resistance testing to H are received after 3&#8211;4 weeks of treatment&#44; due to possible risk of de facto monotherapy&#46; See options in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">4&#44;6&#44;15</span></a> A third possibility&#44; in line with current SEPAR recommendations is 2RZE&#47;10RE&#44; with has been used successfully in standard treatments when H had to be discontinued due to intolerance&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of Tuberculosis Resistant to Rifampicin &#40;Single or Multiple Resistances&#41;&#44; but Susceptible to Isoniazid</span><p id="par0165" class="elsevierStylePara elsevierViewall">As cases of isolated resistance to R are very rare in clinical practice&#44; and since R is the compound that determines prognosis in patients with MDR-TB&#44; these patients should be approached as MDR-TB cases&#44; and treated as such&#44; with the addition of H to the schedule&#44; of course&#44; because if susceptibility is confirmed&#44; this will contribute significantly to the treatment<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6</span></a> &#40;conditional recommendation&#44; low &#91;&#8853;<elsevierMultimedia ident="201708291348111169"></elsevierMultimedia>&#93; to very low &#91;<elsevierMultimedia ident="2017082913481111610"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Treatment of Multi-Drug Resistant Tuberculosis Susceptible to Fluoroquinolones and Second-Line Injectable Drugs</span><p id="par0170" class="elsevierStylePara elsevierViewall">Following the rationale of this guideline&#44; the ideal regimen for these patients would include an FQ &#40;Mfx&#44; or high-dose Lfx&#41;&#44; a second-line injectable drug &#40;at least until cultures become negative&#41;&#44; and 2 drugs selected from Group 4 of this guideline&#46; Z should also be included in this regimen if susceptible&#44; due to its possible activity&#44; taking into account that the susceptibility test is not reliable &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111611"></elsevierMultimedia>&#93; quality of evidence&#41;&#46; The options listed in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a> should be considered&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">The total duration of this combination of 4 new drugs plus Z is much more controversial&#46; The conventionally recommended regimens of more than 21 months<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;8&#44;9</span></a> have not achieved success rates greater than 55&#37;&#8211;70&#37;&#44; particularly due to high drop-out rates&#44;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">40&#44;57&#44;58</span></a> which are clearly associated with the extensive length of treatment&#44; and also with poor tolerance and toxicity&#46; For this reason&#44; this guideline recommends that priority be given to the 9- to 12-month schedule recently recommended by the WHO<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a> for all patients with R-resistant TB&#44; or with MDR-TB who have not previously received FQ or SLID&#44; or who show susceptibility <span class="elsevierStyleItalic">in vitro</span> to these 2 classes of antibiotics &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111612"></elsevierMultimedia>&#93; quality of evidence&#41;&#46; This regimen consists of an initial phase of 4 months &#40;or until sputum smears become negative&#41; with kanamycin &#40;Am or Cm in Spain&#41;&#44; high-dose moxifloxacin&#44; clofazimine&#44; ethionamide&#47;prothionamide&#44; pyrazinamide&#44; ethambutol&#44; and high-dose H&#46; The continuation phase will be of 5 months of high-dose moxifloxacin&#44; clofazimine&#44; ethambutol&#44; and pyrazinamide&#46; Patients must be closely monitored for possible adverse effects&#44; primarily possible prolongation of the QTc interval on electrocardiogram&#44; due in particular to the high moxifloxacin doses recommended in this regimen&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment of Patients With Multi-Drug Resistant Tuberculosis and Added Resistance to Fluoroquinolones&#44; Second-Line Injectable Drugs&#44; or Both&#44; or Even Broader Patterns of Resistance</span><p id="par0180" class="elsevierStylePara elsevierViewall">The clinical and operational management of these forms of TB are already pose considerable difficulties&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">5&#44;6</span></a> They must be treated by experts in the disease&#44; in units that can guarantee close follow-up of treatment and appropriate management of adverse reactions&#46; Possible regimens that can be administered to the vast majority of these patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Role of Surgery</span><p id="par0185" class="elsevierStylePara elsevierViewall">Surgery can also contribute to the success of the treatment of MDR-TB&#44;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">6&#44;8&#44;59</span></a> although it can only be considered in the few patients that meet the following 3 conditions<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#58; &#40;1&#41; reasonably localized resectable lesion&#59; &#40;2&#41; sufficient respiratory reserve for the patient to tolerate surgery and the postoperative period&#59; and &#40;3&#41; lack of medications available to design a curative regimen for the patient&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> If the last premise is met&#44; surgery may be considered in patients with FQ-resistant MDR-TB or an even broader resistance pattern &#40;conditional recommendation&#44; very low &#91;<elsevierMultimedia ident="2017082913481111613"></elsevierMultimedia>&#93; quality of evidence&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Monitoring During Treatment and Evaluation of Results</span><p id="par0190" class="elsevierStylePara elsevierViewall">Patients should be monitored at least once a month during the intensive treatment phase&#44; and then every 1 or 2 months during the continuation phase&#46; Aspects that should be evaluated in each of these controls are listed in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 6</a>&#44; and criteria for evaluating treatment outcomes are described in detail in <a class="elsevierStyleCrossRef" href="#tbl0040">Table 7</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">60</span></a></p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><elsevierMultimedia ident="tbl0040"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Management of Contacts</span><p id="par0195" class="elsevierStylePara elsevierViewall">Available evidence suggests that if a contact of a case with MDR-TB develops TB&#44; they should receive the same treatment as the index case while pending susceptibility test results&#44; with possible subsequent adjustment after the test results are received&#46; If the secondary case is not confirmed microbiologically&#44; as can happen in children&#44; in paucibacillary TB&#44; or in extrapulmonary TB&#44; the regimen of the index case must continue&#46; Systematic treatment of the tubercular infection in contacts of MDR-TB patients is not recommended&#44; unless they have another risk factor for MDR-TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;4&#44;6&#44;61</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">Although TB resistances complicate treatment and the chances of success&#44; following basic rules of management will ensure acceptable cure rates in the vast majority of patients&#46; The basic principles and a summary of most of these guidelines can be found in <a class="elsevierStyleCrossRef" href="#tbl0045">Table 8</a>&#46;In all cases&#44; an expert should be consulted when designing a treatment scheme for these patients&#46; For this purpose&#44; the foundation of national expert groups sponsored by the health authorities and&#47;or the scientific societies is recommended&#46;The first priority is still to offer patients with susceptible TB the appropriate treatment&#44; in order to avoid the appearance of resistance&#46;</p><elsevierMultimedia ident="tbl0045"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of Interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Specific Molecular Techniques&#58; Xpert MTB&#47;RIF &#40;Cepheid&#41; and GenotypeMDRplus &#40;Hain&#41;"
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              "titulo" => "Clinical History of Previously Administered Drugs"
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          "titulo" => "Principles for the Treatment of Both Drug-Susceptible and Drug-Resistant Forms of Tuberculosis"
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          "titulo" => "Rational Classification of Drugs With Activity Against M&#46; tuberculosis"
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              "titulo" => "Treatment of Tuberculosis Resistant to Rifampicin &#40;Single or Multiple Resistances&#41;&#44; but Susceptible to Isoniazid"
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              "titulo" => "Treatment of Multi-Drug Resistant Tuberculosis Susceptible to Fluoroquinolones and Second-Line Injectable Drugs"
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              "titulo" => "Treatment of Patients With Multi-Drug Resistant Tuberculosis and Added Resistance to Fluoroquinolones&#44; Second-Line Injectable Drugs&#44; or Both&#44; or Even Broader Patterns of Resistance"
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            2 => "Extremely drug-resistant tuberculosis"
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            0 => "Tuberculosis"
            1 => "Tuberculosis con resistencia a f&#225;rmacos"
            2 => "Tuberculosis multi-drogorresistente"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In the last 2 decades&#44; drug-resistant tuberculosis has become a threat and a challenge to worldwide public health&#46; The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies&#46; Nevertheless&#44; it is important to remember that with the appropriatesystematic clinical management&#44; most of these patients can be cured&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients&#44; from those infected by strains that are sensitive to all drugs&#44; to those who are extensively drug-resistant&#46; Specific recommendations are given forall cases&#46; The current and future role of new molecular methods for detecting resistance&#44; shorter multi-drug-resistant tuberculosis regimens&#44; and new drugs with activity against <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> are also addressed&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">En las &#250;ltimas 2 d&#233;cadas la tuberculosis con resistencia a f&#225;rmacos se ha convertido en una amenaza y un reto para la salud p&#250;blica mundial&#46; El diagn&#243;stico y el tratamiento de estas formas de tuberculosis es mucho m&#225;s complejo&#44; y el pron&#243;stico empeora claramente a medida que se incrementa el patr&#243;n de las resistencias&#46; Sin embargo&#44; es necesario destacar c&#243;mo con el manejo cl&#237;nico y program&#225;tico adecuado de estos enfermos se puede conseguir la curaci&#243;n de una mayor&#237;a de ellos&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">En esta normativa se razonan las bases del diagn&#243;stico y tratamiento de todos los pacientes afectos de tuberculosis&#44; desde aquellos que tienen formas de la enfermedad con sensibilidad a todos los f&#225;rmacos hasta aquellos que son portadores de los patrones m&#225;s extensos de resistencia&#46; Asimismo&#44; se dan recomendaciones espec&#237;ficas para cada uno de estos supuestos&#46; Tambi&#233;n se aborda el papel que ya est&#225;n teniendo y pueden tener en un futuro inmediato los nuevos m&#233;todos moleculares de detecci&#243;n de resistencias&#44; los esquemas acortados de tratamiento de la tuberculosis multi-farmacorresistente &#40;TB-MDR&#41; y los nuevos f&#225;rmacos con actividad frente a <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0125">Please cite this article as&#58; Caminero JA&#44; Cayla JA&#44; Garc&#237;a-Garc&#237;a J-M&#44; Garc&#237;a-P&#233;rez FJ&#44; Palacios JJ&#44; Ruiz-Manzano J&#46; Diagn&#243;stico y tratamiento de la tuberculosis con resistencia a f&#225;rmacos&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;501&#8211;509&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Template for collecting patient anti-TB drug history&#46; Adapted from Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a></p>"
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          "en" => "<p id="spar0030" 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="#bib0485"><span class="elsevierStyleSup">36</span></a></p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Prevention of resistance&#44; bactericidal activity and sterilizing activity are listed in descending order &#40;high&#44; moderate&#44; and low activity&#41;&#44; while toxicity &#40;right-hand arrow&#41; is listed in ascending order &#40;low&#44; moderate&#44; high&#41;&#44; so that the best available drugs combining all these features appear in the top row&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">High risk factors</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients previously treated for TB&#44; particularly those who failed previous treatment regimens&#44; but also relapsers and drop-outs resuming 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cohabitant or close contact of an MDR-TB patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Moderate risk factors</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients with positive sputum smear at the end of the second month of initial treatment &#40;HRZE&#41; and in whom initial drug susceptibility is unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients from countries with high rates of initial MDR-TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients who live in closed institutions&#44; such as prisons or hostels where there have been cases of MDR-TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Healthcare personnel&#44; particularly those who treat MDR-TB cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients with comorbidities that may lead to situations of malabsorption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HIV infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1501027.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Risk Factors for Drug-Resistant Tuberculosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">3&#44;6&#44;16</span></a></p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2a"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table 2"
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Most Common Adverse Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; Max&#46; 600<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#44; hypersensitivity reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&#44; IM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at normal doses &#40;max&#46; 300<span class="elsevierStyleHsp" style=""></span>mg&#41;<br>15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at high doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#46; Peripheral neuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pyrazinamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatitis&#46; Hyperuricemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethambutol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg in continuation phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Optic neuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Streptomycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; Max&#46; 1<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotoxicity&#44; 8th cranial nerve involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethionamide&#47;prothionamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">750&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastroenteritis&#47;hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cycloserine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">750&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Personality changes&#47;depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Capreomycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;day or&#47;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kanamycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h or&#47;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Amikacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Max&#46; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h or 48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ototoxicity&#47;nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Levofloxacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>750<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleSup">&#8722;1</span><span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tenosynovitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Moxifloxacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tenosynovitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;15<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastroenteritis&#47;hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clofazimine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&#8211;200<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pigmentation&#47;eosinophilic enteritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linezolid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#44; <span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pancytopenia&#47;gastrointestinal disorders&#47;polyneuritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;8<span class="elsevierStyleHsp" style=""></span>h or 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hematological disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bedaquiline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400<span class="elsevierStyleHsp" style=""></span>mg&#47;day for 15 days and then 200<span class="elsevierStyleHsp" style=""></span>mg&#47;3 times a week for a maximum of 6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gastric intolerance&#44; pancreatitis&#44; hepatitis&#44; altered QTc on ECG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delamanid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for a maximum of 6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anemia&#44; nausea&#44; altered QTc on ECG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501022.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Drugs With Anti-<span class="elsevierStyleItalic">M&#46; tuberculosis</span> Activity&#46; Recommended Doses and Most Common Adverse Effects &#40;a&#44; Recommended Doses for Each of the Drugs Used Individually&#41;&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 2b"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table 2"
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">3</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">4</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; Lange et al&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">61</span></a></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" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin &#40;H&#43;R&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rifinah 300</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 150</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 300</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;50<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 50<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin&#43;pyrazinamide &#40;H&#43;R&#43;Z&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rifater</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 50</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 120</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; Z 300</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>In children under the age of 10 years&#44; adjust according to dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 20&#8211;30<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;40<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 40&#8211;49<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 50&#8211;64<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 65<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Combination isoniazid&#43;rifampicin&#43;pyrazinamide&#43;ethambutol &#40;H&#43;R&#43;Z&#43;E&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rimstar</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#174;</span></span><span class="elsevierStyleItalic">&#40;H 75</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; R 150</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; Z 400</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#44; E 275</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 30&#8211;39<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 40&#8211;54<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients weighing 55&#8211;70<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Patients 70<span class="elsevierStyleHsp" style=""></span>kg or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>tab&#46;&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501028.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Drugs With Anti-<span class="elsevierStyleItalic">M&#46; tuberculosis</span> Activity&#46; Recommended Doses and Most Common Adverse Effects &#40;b&#44; Recommended Doses for Combinations of the Most Common Drugs Available in Spain&#41;&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">4</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">37</span></a>&#59; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">First-line drugs for oral administration</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Core drugs&#58; isoniazid&#44; rifampicin&#44; pyrazinamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Companion drug&#58; ethambutol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Fluoroquinolones</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>High-dose levofloxacin or moxifloxacin&#44; all are core&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Second-line injectable drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Streptomycin<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&#44; kanamycin&#44; amikacin&#44; capreomycin&#44; all are core&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Mixed group of core drugs with little evidence and less effective companion drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>core drugs&#58; linezolid&#44; bedaquiline&#44; delamanid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>companion drugs&#58; clofazimine&#44; prothionamide&#47;ethionamide&#44; cycloserine&#47;terizidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Other drugs with less clinical experience&#44; or less effective and more toxic</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Carbapenems &#40;meropenem&#47;imipenem&#41;&#43;amoxicillin&#47;clavulanic acid&#44; PAS&#44; thioacetazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501023.png"
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          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Use all possible drugs&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Use only 1&#44; because the genetic target is the same&#46; Consider it as active drug in MDR-TB cases&#46; In XDR-TB cases&#44; add a fluoroquinolone and&#47;or an injectable if <span class="elsevierStyleItalic">in vitro</span> susceptibility to any of these drugs is maintained&#44; and always try to ensure it is different from the previously used compound&#46; In XDR-TB&#44; these products should not be included among the 4 active agents of the regimen&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Avoid streptomycin due to its high rate of resistance associated with isoniazid&#44; but it may be considered if it is seen to be susceptible on resistance testing&#44; and if it has not been previously used in the patient&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Use all possible drugs as required to achieve a total of 4 new products&#46; Ethionamide and prothionamide are interchangeable because they have the same mechanism of action and the same side effects&#46; The same applies to cycloserine and terizidone&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Only use in extreme cases&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Rational Classification and Sequential Use of Anti-TB Drugs When Designing a Treatment Regimen for Drug-Susceptible or Drug Resistant TB&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; Caminero&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial TB cases susceptible to all drugs</span><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2HRZE&#47;4&#40;HR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">TB cases resistant to H &#40;single or multiple resistances&#41;&#44; but susceptible to R</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">d</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>9HRZE&#44; or 2FQ-REZ&#47;7FQ-RE or 2RZE&#47;10RE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Cases resistant to R &#40;single or multiple resistances&#41; but susceptible to H&#44; or if susceptibility to H is unknown</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Same treatment as MDR-TB&#44; which is shown in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#44; adding H to the regimen&#44; but without counting it as one of the 4 new drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1501021.png"
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          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">There is no consensus with regard to the duration of this treatment in HIV-infected patients&#44; and some groups and scientific societies recommend continuing treatment for 9 months&#44; with the aim of reducing the relapse rate&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Do not switch to the continuation phase &#40;4 HR&#41; until 1 of the following 2 circumstances occurs&#58; sputum smear is negative&#44; or susceptibility to H and R is confirmed&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Prolong treatment beyond 6 months in patients in whom sputum smears and&#47;or cultures take longer than 2 months to become negative&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a> As a reference&#44; these patients will continue treatment with H&#43;R for at least 4 months after cultures become negative&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">If the 9 HRZE regimen is selected&#44; high doses of H will be given&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0050">FQ &#40;Lfx&#47;Mfx&#41; should only be included in the regimen if it is administered with the rest of the drugs from the beginning&#46; It should not be added if results of resistance testing to H are received after 3&#8211;4 weeks of treatment&#44; due to the possible risk of de facto monotherapy&#46; In this case&#44; use 9 HRZE&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With Susceptible TB and Single or Multiple Resistances&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">CP&#58; continuation phase&#46; Until completion of 21 months of treatment&#59; IP&#58; intensive phase&#46; Until cultures become negative&#44; or up to 6 months in case of extensive lesions&#46; Continue for at least 4 months if the patient is not expectorating and no follow-up sputum tests can be performed&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">6</span></a>&#59; World Health Organization<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">8</span></a>&#59; Caminero&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">55</span></a></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">MDR-TB cases&#44; but without resistance to second-line drugs</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Short regimen&#58; 4<a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">a</span></a> &#40;Cm&#47;Am&#43;Mfx<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">b</span></a>&#43;Pth&#47;Eth&#43;Cfz&#43;E&#43;Z&#43;H<a class="elsevierStyleCrossRef" href="#tblfn0065"><span class="elsevierStyleSup">c</span></a>&#41;&#47;5 &#40;Mfx<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">b</span></a>&#43;Cfz&#43;E&#43;Z&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Standard regimen&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intensive phase &#40;Cm<a class="elsevierStyleCrossRef" href="#tblfn0070"><span class="elsevierStyleSup">d</span></a>&#43;Mfx&#47;Lfx&#43;Z&#43;2 Group 4 drugs<a class="elsevierStyleCrossRef" href="#tblfn0075"><span class="elsevierStyleSup">e</span></a>&#41;&#47;continuation phase &#40;Mfx&#47;Lfx&#43;Z&#43;2 Group 4 drugs<a class="elsevierStyleCrossRef" href="#tblfn0075"><span class="elsevierStyleSup">e</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">MDR-TB cases with additional resistance to the FQ&#44; SLID&#44; both&#44; or even broader XDR-TB resistance patterns</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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Consult experts and design a regimen that follows all the recommendations made in this guideline&#44; looking for a minimum of 4 new drugs&#44; following the rational classification provided &#40;Groups 1 to 5&#41;&#44; with the aim of including the maximum number of bactericidal and sterilizing drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1501026.png"
              ]
            ]
          ]
          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0055"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">At least 4 months or until sputum smear testing becomes negative&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0060"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0060">High doses of Mfx &#40;800<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0065"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0065">High doses of H &#40;15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg body weight&#41;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0070"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0070">The injectable drug may be given 3 times per week &#40;with an interval of 48<span class="elsevierStyleHsp" style=""></span>h between doses&#41; when sputum smears become negative&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0075"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0075">Two Group 4 drugs will be chosen on the basis of availability and potential adverse effects&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Recommended Basic Regimens for Patients With MDR-TB&#46;</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at7"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">M11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#43;M12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Medical visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sputum smear &#40;&#215;2&#8211;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Culture &#40;&#215;2&#8211;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0080"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical laboratory tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">EKG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0085"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ENT audiometry&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0090"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chest radiograph&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ophthalmological examination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0095"><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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Psychiatric evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X<a class="elsevierStyleCrossRef" href="#tblfn0100"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0080">Optional in case of good clinical progress and negative sputum smear and culture at the end of the fourth month&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0085"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0085">Only if the patient is receiving high-dose moxifloxacin&#44; delamanid and&#47;or bedaquiline&#46; If normal doses of moxifloxacin are given&#44; a EKG every 2&#8211;3 months is sufficient&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0090"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0090">Only if the patient is treated with an injectable drug&#44; either aminoglycoside or capreomycin&#46;</p>"
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              "identificador" => "tblfn0095"
              "etiqueta" => "d"
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            ]
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              "identificador" => "tblfn0100"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0100">Only if the patient is receiving cycloserine or terizidone&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Follow-Up Required During TB Treatment&#46;</p>"
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        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at8"
            "detalle" => "Table "
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; World Health Organization&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">60</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Definition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Treatment outcomes in TB patients without rifampicin resistance and without MDR</span>-<span class="elsevierStyleItalic">TB</span><a class="elsevierStyleCrossRef" href="#tblfn0105"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cured&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patient with bacteriologically confirmed TB at the start of treatment and negative sputum smear or culture in the last month of treatment and on at least 1 previous 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Completed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who completed treatment without evidence of failure&#44; but without evidence of negative sputum smear or culture in the last month of treatment and on at least 1 previous test&#44; either because the tests were not performed&#44; or because the results are not available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Treatment failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patient with TB with positive sputum smear or culture in month 5 or later during 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who dies for any reason before starting or during the course of 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lost-to-follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who did not start treatment or suspended treatment for 30 consecutive days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Not evaluated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient without assigned treatment outcome&#46; Includes cases transferred to another treatment unit&#44; and cases in whom treatment outcome is unknown&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Outcomes of TB patients with rifampicin-resistant disease&#44; or MDR&#47;XDR-TB treated with second-line drugs</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cured&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment completed as recommended by national guidelines without evidence of failure and 3 or more consecutive negative cultures at least 30 days apart&#44; after the intensive phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Completed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment completed as recommended by the national policy without evidence of failure&#44; but without evidence of 3 or more consecutive negative cultures at least 30 days apart&#44; after the intensive phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Failed treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment was discontinued or a permanent change of regimen or at least 2 anti-TB drugs were required due to&#58;<br>Failure to convert<a class="elsevierStyleCrossRef" href="#tblfn0110"><span class="elsevierStyleSup">b</span></a> at the end of the intensive phase&#44; or<br>Bacteriological reversion<a class="elsevierStyleCrossRef" href="#tblfn0115"><span class="elsevierStyleSup">c</span></a> in the continuation phase after conversion to a negative status&#44; or<br>Evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs&#44; or<br>Adverse drug reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who dies for any reason before starting or during the course of 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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lost-to-follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient who did not start treatment or suspended treatment for 30 consecutive days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Not evaluated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TB patient without assigned treatment outcome&#46; Includes cases transferred to another treatment unit&#44; and cases in whom treatment outcome is unknown&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0105"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0105">Successful treatment&#58; the sum of cures plus completed treatment&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0110"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0110">Conversion&#58; 2 negative cultures obtained at least 30 days apart&#46;</p>"
            ]
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              "identificador" => "tblfn0115"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0115">Reversion&#58; 2 positive cultures performed at least 30 days apart after initial conversion &#40;continuation phase&#41;&#46;</p> <p class="elsevierStyleNotepara" id="npar0120">Successful treatment&#58; the sum of cures plus completed treatment&#46;</p>"
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          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Criteria for Evaluating Treatment Outcomes in TB Patients&#44; Following WHO Recommendations&#46;</p>"
        ]
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          "leyenda" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">In all cases&#44; an expert should be consulted when designing a treatment scheme for these patients&#46;</p><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Adapted from&#58; Caminero and Scardigli&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">38</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Steps&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#46; Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Take in account&#58;</span><br>Drug history&#58; 1 month of monotherapy&#44; or the addition of a single drug to an ineffective treatment regimen is an important indicator of possible resistance to that drug&#44; or possibly lower efficacy&#46;<br>Drug susceptibility testing &#40;DST&#41;&#58; very reliable for R and H&#59; quite reliable for second-line injectable drugs and FQ&#59; less reliable for S&#44; E&#44; and Z&#59; unreliable for Eth&#47;Pth&#44; Cs&#44; and PAS&#46; The exact method and credibility remain to be determined for Lzd&#44; Bdq Cfz&#44; Dlm&#44; and carbapenems<br>HIV testing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46; Number of drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At least 4 effective medications&#58; never used in the past or with susceptibility demonstrated on DST&#44; taking into account DST reliability mentioned in point 1 and possible cross-resistance<br>At least 2 core drugs &#40;at least 1 with high bactericidal activity and at least 1 other with sterilizing capacity&#41; and 2 companion drugs to protect the core drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&#46; Selection of drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rational introduction according to <a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a><br>For MDR-TB&#44; try to use first-line drugs if they are still effective&#46; However&#44; in this case&#44; do not count them among the &#8220;4 effective drugs&#8221;<br>High-dose levofloxacin or moxifloxacin<br>A second-line injectable drug or S&#44; if it is still susceptible and has not been used previously<br>Use Group 4 drugs until 4 effective drugs have been included<br>Consider high-dose H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#46; Treatment duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Short regimen&#58; 9 months&#46; Intensive phase of at least 4 months or until sputum smear testing becomes negative&#46; Continuation phase&#58; 5 months<br>Standard regimen&#58; 21 months&#46; Intensive phase&#58; at least until sputum smear and culture become negative&#59; always for at least 6 months&#46; Even longer if there are less than 3 effective drugs in the continuation phase&#44; or resistance to FQ is suspected&#46; Continuation phase&#58; at least until 21 months of treatment in total and 12 months with negative cultures<br>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="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&#46; Surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Consider only if the following 3 conditions are met&#58;</span><br>&#40;1&#41; less than 4 effective drugs&#59; &#40;2&#41; localized lesions&#59; and &#40;3&#41; sufficient respiratory reserve after resection<br>In XDR and pre-XDR-TB especially&#44; assess for resistance to FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&#46; Ideal regimen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Standard</span>&#58; if only standard regimens have been administered in the past&#44; both for first- and second-line treatment&#46;<br><span class="elsevierStyleItalic">Individualized</span>&#58; if second-line drugs other than standard treatments have been used&#44; or in contacts of MDR patients who have used them&#46; In the latter case&#44; treat with the regimen that was effective in the index case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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ISSN: 15792129
Original language: English
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