Update on the diagnosis and treatment of pulmonary tuberculosis

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"apellidos" => "Caminero Luna" "email" => array:1 [ 0 => "jcamlun@gobiernodecanaris.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neumología, Hospital General de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Gran Canaria, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Tuberculosis Multi-Drogo-Resistente (MDR-TB) de La Unión Internacional contra la Tuberculosis y Enfermedades Respiratorias, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en el diagnóstico y tratamiento de la tuberculosis pulmonar" ] ] "textoCompleto" => "IntroductionEven well into the 21st century, tuberculosis (TB) is still the most important infectious disease in humans.<a class="elsevierStyleCrossRef" href="#bib0330">1</a> The dismal figures for the number of people who are currently infected (2.3billion), sick (9million new cases per year) or who have died (1.5million per year)<a class="elsevierStyleCrossRef" href="#bib0335">2</a> from this old endemic disease make it important to reflect on the failures in controlling a disease that has been curable for the last 50 years and preventable for the last several decades.<a class="elsevierStyleCrossRefs" href="#bib0330">1,3</a> TB is relatively simple and inexpensive to diagnose; it can be cured in most cases with well-tolerated and low-cost treatments.<a class="elsevierStyleCrossRef" href="#bib0340">3</a> Furthermore, it is estimated that of the 9 million people who become ill every year, approximately half a million are carriers of isoniazid and rifampicin-resistant TB (multidrug-resistant TB [MDR-TB]).<a class="elsevierStyleCrossRef" href="#bib0335">2</a> These patients are very difficult to cure, because these are the two most efficient drugs against the disease. It is evident that new resources for diagnosis and treatment are required if we are to control this epidemic, as well as MDR-TB. These resources have become available within the last decade and are discussed in this article, along with the current status of the infection.Diagnosis of tuberculosisIn the aggression inflicted by Mycobacterium tuberculosis (M. tuberculosis), several scenarios are possible, depending on the virulence of the bacillus and the immune system response. Thus, an infection might not occur (due to effective alveolar macrophages), the infected patient might not become ill (latent infection) or the patient might end up developing TB.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>Even though the highest priority should be to diagnose sick patients with TB (those who might die from the disease and can transmit it), due to the process by which M. tuberculosis aggression is produced, we will discuss the diagnosis of the infection first and then the diagnosis of the disease.Diagnosing the tuberculosis infectionJust 10–15 years ago, only one tool was available for diagnosing TB infection: the so-called tuberculin (TST), PPD or Mantoux Test. However, due to the drawbacks of the TST and its lack of availability throughout large parts of the world, other methods began to be adopted that were based on interferon-gamma release (interferon-γ release assays [IGRA]) against exposure to specific M. tuberculosis antigens.<a class="elsevierStyleCrossRefs" href="#bib0345">4,5</a>The TST reveals the body's hypersensitivity to the presence of tuberculosis bacillus proteins, a hypersensitivity that is acquired in most cases after an M. tuberculosis infection. The hypersensitivity might, however, be caused by a Bacillus Calmette-Guérin (BCG) vaccine or an infection by environmental bacteria. Tuberculin gives rise to an inflammatory reaction in infected individuals (even if they have never been sick), with significant cellular infiltration of the dermis, which produces visible and palpable induration in the area and can be accompanied by edema, erythema and in rare occasions vesiculation, necrosis and regional lymphadenitis. Positivity appears within 2 and 12 weeks after infection. There is therefore a window within that time that might require repeating the test. The results are expressed in millimeters of induration, and a diameter ≥5mm is considered positive.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a> The TST should be limited to children, patients with immunodeficiency and suspected TB, for the diagnosis of infection in patients with immunodepression, people who live with patients infected with TB and health personnel to detect recent converters. The application of the TST for diagnosis in adults presenting respiratory symptoms lacks a sound basis.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>Two types of IGRA tests are currently being performed. The first and most widely used test measures (by means of ELISA) the amount of interferon-gamma released in the patient's blood when exposed to specific M. tuberculosis antigens. If the serum belongs to a patient previously infected with M. tuberculosis, memory T-cells respond to this antigenic stimulus and release interferon-gamma. However, if the patient has not been previously infected, the serum will not react or release interferon-gamma, and the test result will be negative. The only marketed test for this is called Quantiferon TB Gold and employs the antigens Esat 6, CFP10 and TB 7.7. This test enables the differentiation of individuals infected with M. tuberculosis from those sensitized by the BCG vaccine (which lost these antigens during the manufacturing process) or by most environmental mycobacteria. A result above 0.35 is considered positive, and a result below 0.35 is deemed negative. The second method, which is less commonly used and has not yet been marketed, uses an ELISPOT test (a variant of ELISA) to detect monocytes responding to this antigen stimulus.<a class="elsevierStyleCrossRef" href="#bib0355">6</a> Although this technique might be slightly more sensitive, it is more complex and less reproducible and is therefore not as widely used.<a class="elsevierStyleCrossRef" href="#bib0360">7</a>The major advantages of IGRAs are their better reproducibility and ease of interpretation, as well as their lack of interference with the BCG vaccine. However, it is not clear whether IGRAs are superior to the TST in the results. There is a 10–20% discrepancy between the results of the IGRAs and TST.<a class="elsevierStyleCrossRef" href="#bib0365">8</a> Therefore, for patients for whom there is significant interest in ruling out TB infection, one of these tests (TST or IGRA) should be performed first, and if negative, the other should be applied. If the results of either these tests are positive, the diagnosis of tuberculosis infection may be accepted.Diagnosing the tuberculosis diseaseThe TB diagnosis is still based on clinical suspicion, radiography and microbiological tests, although the latter of these have undergone major developments in recent years, mainly with the emergence of rapid molecular methods.Clinical manifestationsOne of the main problems with TB is the scarce specificity in its signs and symptoms, which are similar to many respiratory diseases, even some mild ones. The onset is insidious in most cases.<a class="elsevierStyleCrossRef" href="#bib0345">4</a> Symptoms can be localized or general (low fever, night sweats, dyspnea, fatigue, loss of appetite and weight loss). Local symptoms will depend on the affected organ. The most frequent location (80% in immunocompetent individuals) is pulmonary, and the most common symptoms are extended cough and/or expectoration, although the clinical condition can be accompanied also by dyspnea, chest pain and hemoptysis.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a> In all patients reporting cough and/or expectoration lasting over 10–15 days, pulmonary TB should be ruled out by means of a chest X-ray and microbiology tests.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>Chest X-rayAn X-ray revealing infiltrates and/or cavitations predominantly in the upper lobes and apical segment of the lower lobes is suggestive of pulmonary TB; however, any pulmonary segment or lobe can be affected. X-rays can appear normal only in some primary TB forms, frequently in people infected with HIV and who present serious immunodepression.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>Although a very sensitive method, simple radiography is not always specific, and there is no pathognomonic radiological sign for TB. Therefore, even in the presence of lesions highly suggestive of TB in an X-ray and within a favorable clinical and epidemiological context, the diagnosis of the disease should never be admitted based solely on radiological data, even if they are of great assistance.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a> Given its sensitivity, however, chest radiography is still a good method for ruling out TB. Therefore, if an immunocompetent patient has a normal X-ray, it is virtually certain that they will not have pulmonary TB.Other imaging methods do not contribute much to diagnosing TB, especially in its pulmonary presentation. Only a chest CT scan can provide valuable information on the mediastinum and small lesions, which go unnoticed in chest X-rays. For its part, an MRI can provide information in cases of extrapulmonary TB, particularly osteoarticular TB.Microbiological diagnosisThe only accurate TB diagnosis consists of isolating M. tuberculosis in a sample taken from the patient, either by way of culture or by a molecular method. Therefore, all efforts should be made to obtain valid samples to be analyzed by bacilloscopy, culture and molecular methods. Thus, the microbiological diagnosis of TB comprises four successive stages:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1)Bacilloscopy. Viewing a sputum smear under a microscope remains the initial test for suspected cases of TB due to its quickness, low cost, simplicity and clear relation with the patient's contagiousness. However, it is a tedious test with moderate sensitivity. A negative bacilloscopy does not therefore rule out TB.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a> The sensitivity of bacilloscopy varies: 70–90% in TB with cavitated lesions; 50–70% in patients showing only infiltrates in lung X-rays; and less than 50% in patients with pulmonary nodules or in the various forms of extrapulmonary TB (<10% in tuberculous serositis). On the other hand, specificity ranges from 96% to 99%.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>However, acid-alcohol resistance detected by bacilloscopy is a property common to all species of Mycobacterium (not only M. tuberculosis). The definitive diagnosis should therefore be confirmed by a culture or molecular methods. Bacilloscopy is also unable to differentiate live from dead bacillus.</li><li class="elsevierStyleListItem" id="lsti0010">2)M. tuberculosis detection by molecular methods. The contributions made by the GeneXpert test in the last five years are particularly relevant. It is a simple and reproducible method consisting of a real-time polymerase chain reaction; within approximately 2h, the results can be positive for up to 70% of TBs with negative bacilloscopy and positive cultures.<a class="elsevierStyleCrossRefs" href="#bib0370">9–11</a> This outcome is achieved by detecting the presence of M. tuberculosis DNA in the sample, and at the same time it identifies DNA changes that can produce resistance to rifampicin. Thus, in less than 2h, it provides an accurate diagnosis both for TB and for resistance to rifampicin, a drug essential for treating TB. Overall sensitivity is nearly 90%, reaching 98% for patients with positive bacilloscopy and approximately 70% for those with negative bacilloscopy. Given that GeneXpert is much more sensitive than bacilloscopy, the technique is chosen for patients with more paubacillary TBs, such as those infected with HIV. Overall specificity is 99%, compared with the culture gold standard. Moreover, overall sensitivity for detecting rifampicin resistance is 95%, with 98% specificity. These data indicate that if a patient has a GeneXpert positive for rifampicin resistance, they must be treated as having MDR-TB, because resistance to this drug is associated with isoniazid resistance in over 95% of cases.<a class="elsevierStyleCrossRefs" href="#bib0375">10,12</a>GeneXpert is an automated process and does not require a laboratory infrastructure. The World Health Organization recently recommended GeneXpert as an initial diagnosis test (before bacilloscopy) for patients with HIV suspected to have TB or when rifampicin resistance or MDR-TB are suspected.<a class="elsevierStyleCrossRefs" href="#bib0375">10,11</a> This test has also proven to be effective for diagnosing TB in children<a class="elsevierStyleCrossRefs" href="#bib0375">10,13,14</a> and in extrapulmonary forms.<a class="elsevierStyleCrossRefs" href="#bib0375">10,15</a> Within the next 2–3 years, GeneXpert will likely replace the centennial bacilloscopy as the initial diagnostic test for all patients suspected of having TB. This prediction is a realistic forecast, considering that the equipment only needs an electric power source and can even be installed outside the laboratory facilities.<a class="elsevierStyleCrossRef" href="#bib0405">16</a></li><li class="elsevierStyleListItem" id="lsti0015">3)Culture of M. tuberculosis. Culture is still the gold standard for diagnosing TB, not only because it is the most sensitive bacteriological method available (can be positive with only 10 bacilli per cubic centimeters in the sample), but also because M. tuberculosis identification methods can be used with this test to fully confirm the disease. The major drawback of cultures is the delay in obtaining results (2–4 weeks in liquid media and 4–8 weeks in solid media),<a class="elsevierStyleCrossRef" href="#bib0385">12</a> due to the slow growth of the bacillus. This turnaround time is unacceptable for making therapeutic decisions. Moreover, a negative culture does not rule out the disease because the presentation might be paubacillary, such as extrapulmonary TBs or some incipient pulmonary presentations.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4</a>In cultures revealing mycobacterial growth, the particular species should be identified, either by biochemical methods, which are tedious and take several weeks, or preferably by molecular tests, which have been adopted in recent years due to their speed and simplicity.</li><li class="elsevierStyleListItem" id="lsti0020">4)Antibiogram. When possible, in vitro studies of anti-TB drug sensitivity (antibiograms) should be performed for all cases. Alternatively, this potential resistance should be detected by molecular methods. Ideally, rifampicin and isoniazid resistance studies should be performed, provided there is a sample available. If the result is positive for resistance to rifampicin (the drug that most determines the prognosis of TB), fluoroquinolone (FQ) resistance studies should also be conducted, namely for levofloxacin and moxifloxacin, as well as the second-line injectable drugs (amikacin or capreomycin) planned for use as treatment. The credibility of the conventional sensitivity tests for these drugs is very good and can therefore provide guidance for the therapeutic plan. In contrast, it is not advisable to test other drugs, because the results from available tests are unreliable.<a class="elsevierStyleCrossRefs" href="#bib0385">12,17</a></li></ul>Susceptibility tests can be either phenotypic or genotypic. The former have the disadvantage that M. tuberculosis needs to grow in the culture media, which can take several weeks. However, molecular testing can provide results within 24–48h, detecting by means of genetic amplification the genetic mutations of the bacillus that cause resistance to anti-TB drugs. These methods include GeneXpert, which can detect rifampicin resistance within 2h, and GenoType, also known as line probe assay (LPA), which can detect rifampicin and isoniazid resistance within 48h.<a class="elsevierStyleCrossRefs" href="#bib0415">18,19</a> Both methods can be performed directly on the sample and do not require waiting for culture growth. GenoType/LPA results are also promising for detecting resistance to FQ and second-line injectable antibiotics (kanamycin, amikacin and capreomycin).<a class="elsevierStyleCrossRef" href="#bib0425">20</a> This GenoType/LPA is also able to differentiate between M. tuberculosis and over 30 different mycobacteria. Given that GenoType/LPA is a conventional polymerase chain reaction, its drawback is that it requires a biomolecular laboratory with 3 separate spaces. It also requires a higher bacillus load in order to be performed. Ideally, GenoType/LPA is applied in samples with positive bacilloscopy.Possibilities for diagnosis in TBIn certain circumstances and despite performing all the tests mentioned above, it might not be possible to achieve a bacteriological confirmation of TB. In these cases, the judgment for endorsing a therapeutic approach should be based on the patient's collection of clinical, radiological and laboratory data. Thus, in order to accept a case as TB, at least one of the following criteria should be met:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">1.Positive bacilloscopy and/or culture of the studied sample.</li><li class="elsevierStyleListItem" id="lsti0030">2.M. tuberculosis detected by a molecular method.</li><li class="elsevierStyleListItem" id="lsti0035">3.A biopsy showing granulomas and caseous necrosis.</li><li class="elsevierStyleListItem" id="lsti0040">4.Compatible clinical condition and radiology results of patients for whom previous studies have resulted negative and for whom other possible diagnoses have been ruled out. Under this assumption, the patient should be prescribed anti-TB treatment.</li></ul>Treatment of tuberculosisInitial treatment of tuberculosisDuring the 2 decades from the discovery of streptomycin in 1943 to the discovery of rifampicin in 1963, practically all the drugs with activity against M. tuberculosis known so far were discovered. In addition, numerous randomized clinical trials were performed that served as the basis for treating TB, both drug-sensitive and drug-resistant.<a class="elsevierStyleCrossRefs" href="#bib0385">12,21,22</a> The bacteriological basis to be met by any treatment are (i) the combination of drugs to prevent the selection of resistances and (ii) application of extended treatment that ensures not only the cure but also the prevention of a possible relapse.<a class="elsevierStyleCrossRefs" href="#bib0385">12,21,22</a>In order to ensure the maximum possibility for cure without relapse, every treatment should combine at least 4 not previously used drugs. At least 2 of the drugs should be “essential”, one with good bactericidal activity (ability to eliminate bacilli in active replication, which are the ones causing the symptoms and the possible death of the patient) and another with good sterilizing capacity (able to eliminate bacilli in latent phases, i.e., producers of relapses). Given that these are the drugs that will cure the patient, their use should ideally be maintained throughout the treatment. The other two drugs are known as “accompanying” drugs, which means they are not included in the treatment regime to eliminate bacilli in a particular way, but rather are intended to protect the “essential” drugs. In theory, these “accompanying” drugs may be suspended once bacteriological conversion is achieved, which means there is a highly reduced bacillary population.<a class="elsevierStyleCrossRefs" href="#bib0385">12,22</a>It is worth highlighting that if a given “essential” drug cannot be used due to resistance or toxicity, it should be replaced by another with similar action (bactericidal or sterilizing).<a class="elsevierStyleCrossRefs" href="#bib0385">12,22</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the bactericidal, sterilizing and resistance-prevention capacity of the various drugs, as well as their toxicity.<a class="elsevierStyleCrossRef" href="#bib0435">22</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>To aid in the selection of the 4 drugs for TB treatment, they have been classified into 5 groups (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0385">12,22–25</a> Group 1 has higher activity, followed by the other groups in decreasing order of efficacy and tolerance. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the recommended dosage for all drugs with action against M. tuberculosis.<a class="elsevierStyleCrossRefs" href="#bib0385">12,24</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Thus, an initial TB presumed to be sensitive to all drugs should receive all 4 drugs from Group 1, i.e., isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). The first two drugs (H and R) should be administered over the course of the 6 months of treatment, and the other two (Z and E) drugs should be administered for the first 2 months or until the bacilloscopy results are negative. In favorable situations with no resistance to H+R and provided the susceptibility test results are available within 3 weeks, it might be possible to not use ethambutol and to administer only H+R+Z from the beginning.<a class="elsevierStyleCrossRefs" href="#bib0435">22,26</a> If the susceptibility test shows sensitivity to H+R by the end of the second month, Z+E may be suspended and treatment continued with H+R until 6 months of treatment have been completed. The drugs should be taken in the morning and on an empty stomach. Noncompliance with the treatment (or worse, irregular compliance) compromises the curing process and is the most common way by which microbiological resistance is induced.<a class="elsevierStyleCrossRefs" href="#bib0340">3,12</a> This regime is equally applicable to children, pregnant or breastfeeding women, patients with HIV or extrapulmonary TB; however, patients with HIV infection and those with certain forms of extrapulmonary TB (meningeal, disseminated) may have their treatment extended to 9–12 months.<a class="elsevierStyleCrossRefs" href="#bib0435">22,27</a>This 6-month regime, even if well tolerated and highly effective, still has a long duration and therefore requires strict supervision in many cases. The goal of TB treatment is to be able to shorten it as much as possible without losing efficacy. New FQs (moxifloxacin and gatifloxacin) or some rifampicins (rifapentine) can contribute to reducing treatment to 4 months. However, various clinical trials have recently published their results<a class="elsevierStyleCrossRefs" href="#bib0465">28–31</a> and concluded that the 4-month regimen is inferior to the 6-month regimen, particularly in relation to the relapse rate.Treatment of drug-resistant TBDrug-resistant TB, especially with rifampicin resistance, has become the main challenge in the attempt to eliminate this worldwide millennial plague. Rifampicin is by far the most active drug against M. tuberculosis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0385">12,22</a> For this reason, TB cases in which it is not possible to use this drug either due to resistance or intolerance are more difficult to cure, requiring more extensive treatments (at least 18 months), and their prognosis is the poorest. Rifampicin resistance is probably sufficient for defining a TB as MDR, which can easily be detected by rapid molecular methods.<a class="elsevierStyleCrossRefs" href="#bib0375">10,19,32,33</a> Including isoniazid in the definition of MDR-TB (resistance at least to H+R) has little influence on the final therapeutic regimen, its duration and prognosis.<a class="elsevierStyleCrossRef" href="#bib0385">12</a>The other drugs with action against M. tuberculosis include the new FQs<a class="elsevierStyleCrossRefs" href="#bib0385">12,22</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) included in Group 2 (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). They clearly outline the prognosis of extensively drug-resistant TB (XDR-TB),<a class="elsevierStyleCrossRefs" href="#bib0495">34,35</a> defined as those MDR-TB cases in which there is also additional resistance to some FQ and to at least one of the 3 available second-line injectable drugs (kanamycin, amikacin and capreomycin).Both MDR-TB and XDR-TB pose a number of challenges. First, we are facing a new epidemic about which practically nothing was known until recent years and for which there is little quality evidence regarding the most appropriate treatment.<a class="elsevierStyleCrossRefs" href="#bib0385">12,36</a> Second, after several decades, TB is once again being referred to as a potentially incurable disease.<a class="elsevierStyleCrossRef" href="#bib0510">37</a>The increased occurrence of MDR-TB evidenced in the last 10 years has led to the development of recommendations for diagnosing and treating these complex cases.<a class="elsevierStyleCrossRefs" href="#bib0385">12,22–25,38</a> As when treating other TBs, at least 4 new drugs should be combined (or at least drugs with a high probability of susceptibility), following the rational classification set forth in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> for their selection. Treatment should be extended for at least 21–24 months.<a class="elsevierStyleCrossRefs" href="#bib0385">12,22–25,38</a> This duration makes strict supervision necessary as well as a deep understanding of the adverse reactions presented by most patients.<a class="elsevierStyleCrossRef" href="#bib0385">12</a> The experience in Bangladesh, with a therapeutic success rate close to 90% and a regimen of only 9 months,<a class="elsevierStyleCrossRefs" href="#bib0520">39–41</a> has become a great hope for the future, mostly for patients with MDR-TB who have not been treated with second-line drugs in the past and who have a fair probability of sensitivity to FQs.In designing a treatment regime for patients with MDR-TB, the indications set out in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> should be followed. According to these indications and by seeking 4 new drugs from the classification set forth in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, patients with MDR-TB should be administered an FQ (high doses of levofloxacin or moxifloxacin), a second-line injectable drug (capreomycin or amikacin, in the case of Spain) and 2 other accompanying drugs, preferably prothionamide and cycloserine. The FQ and the injectable drug should be part of the therapeutic plan. The injectable drug should be administered at least until cultures are negative. Pyrazinamide should always be administered, but it is not included in the 4 new drugs, because it has often been used in the past and there is a high chance that transmission occurred from another patient with resistance to the drug. Ethambutol may be considered for patients who have never been treated with it, but it should not be considered as one of the 4 active drugs.<a class="elsevierStyleCrossRefs" href="#bib0385">12,17,23,26</a><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>It is important to highlight how in Group 5, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, a number of drugs have been included that have classically had little efficacy or little evidence of efficacy. However, over the last 5 years, evidence has shown that a number of these drugs (linezolid, bedaquiline, delamanid) have good efficacy, probably better than the ones included in Group 4 and even the second-line injectable drugs in Group 3.<a class="elsevierStyleCrossRef" href="#bib0535">42</a>Linezolid may be considered an “essential” drug, with both bactericidal and sterilizing capacities.<a class="elsevierStyleCrossRefs" href="#bib0540">43,44</a> Two small randomized clinical trials<a class="elsevierStyleCrossRefs" href="#bib0550">45,46</a> and various meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0560">47–49</a> have proven its effectiveness for treating MDR-TB, especially XDR-TB. However, there are two downsides: its high price and its toxicity profile when administered for more than 6–8 weeks, consisting of hematological disorders and polyneuropathies.<a class="elsevierStyleCrossRef" href="#bib0575">50</a> Price is a matter of the market; a number of publications have demonstrated good efficacy with linezolid at 1 USD per 600-mg tablet.<a class="elsevierStyleCrossRef" href="#bib0580">51</a> Toxicity is linked to dosage,<a class="elsevierStyleCrossRef" href="#bib0585">52</a> but the toxicity can be relatively easy to control.<a class="elsevierStyleCrossRef" href="#bib0550">45</a>Bedaquiline is the only drug approved by the Food and Drug Administration in 50 years for TB treatment (previously the only one was rifampicin), and it could also be considered an “essential” drug due to its good bactericidal and sterilizing action.<a class="elsevierStyleCrossRefs" href="#bib0590">53–55</a> Two clinical trials<a class="elsevierStyleCrossRefs" href="#bib0605">56,57</a> have demonstrated its efficacy in treating MDR-TB, especially XDR-TB, and it is already being used in several countries.<a class="elsevierStyleCrossRef" href="#bib0615">58</a> Similarly, delamanid, a drug approved by the European Medicine Agency, is a metronidazole derivative that also has good bactericidal and sterilizing activity.<a class="elsevierStyleCrossRefs" href="#bib0620">59,60</a> Two other randomized clinical trials<a class="elsevierStyleCrossRefs" href="#bib0630">61,62</a> have described its usefulness in treating MDR-TB, especially XDR-TB. In summary, linezolid, bedaquiline and delamanid are destined to play an important role in the treatment of MDR-TB.<a class="elsevierStyleCrossRef" href="#bib0535">42</a>Treatment of the tuberculosis infection (chemoprophylaxis)Anti-TB chemoprophylaxis is the specific chemotherapy employed to prevent the development of the disease in a healthy infected patients who are at risk of TB. The benefit of this chemotherapy has been shown to persist up to 20 years in immunocompetent patients, although it is assumed to last a lifetime. This situation changes radically in patients with HIV and extensive immunodepression, where the duration of preventive treatment and the probability of needing to repeat it are subjects of debate. Chemoprophylaxis is usually performed with one morning dose of isoniazid on an empty stomach every day for 9 months, using the same dosage for treating the disease. A number of 3-month H+R regimes have also been described with similar efficacy.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4,63</a> A simpler chemoprophylaxis is currently being validated and consists of 1 weekly dose of isoniazid and rifapentine (a rifampicin with longer half-life) for 3 months. This means that there would only be 12 doses of the treatment, which would have similar efficacy to 9 months of isoniazid.<a class="elsevierStyleCrossRefs" href="#bib0645">64,65</a>There are differences in the indications for prophylaxis from one country to another; the United States has broader indications while Europe has more limited indications. There are only 4 groups for which the indication for prophylaxis is universal: patients with a double infection by M. tuberculosis and HIV; recently infected patients, especially children; patients with radiological lesions suggestive of residual TB not treated in the past; and patients infected by M. Tuberculosis who will undergo biological treatments or who are predicted to develop extensive immunodepression. For the remaining groups, the indication is debatable and will ultimately be at the discretion of each physician.<a class="elsevierStyleCrossRefs" href="#bib0340">3,4,63</a>Conflicts of interestThe author declares that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres611124" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec625113" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres611123" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec625112" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Diagnosis of tuberculosis" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosing the tuberculosis infection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosing the tuberculosis disease" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Clinical manifestations" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Chest X-ray" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Microbiological diagnosis" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Possibilities for diagnosis in TB" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Treatment of tuberculosis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Initial treatment of tuberculosis" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment of drug-resistant TB" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment of the tuberculosis infection (chemoprophylaxis)" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-26" "fechaAceptado" => "2015-09-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec625113" "palabras" => array:4 [ 0 => "Pulmonary tuberculosis" 1 => "GeneXpert" 2 => "Multi-drug-resistant tuberculosis" 3 => "Chemoprophylaxis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec625112" "palabras" => array:4 [ 0 => "Tuberculosis pulmonar" 1 => "GeneXpert" 2 => "Tuberculosis multirresistente" 3 => "Quimioprofilaxis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Tuberculosis (TB) remains the most important human infectious disease. Currently, the TB diagnosis is still based on the clinical presentation, radiographic findings and microbiological results; all of which have sensitivity or specificity issues. For that reason, the immediate future involves rapid molecular microbiological techniques, in particular GeneXpert (which is more sensitive than bacilloscopy and is able to detect rifampicin resistance) and GenoType. The current six-month treatment for TB has remained unchanged for decades. Attempts to shorten this treatment have failed. In recent years, new drugs have been reported that could contribute to TB treatment in the near future, and are already being used in multi-drug-resistance TB." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La tuberculosis (TB) sigue siendo la enfermedad infecciosa humana más importante que existe. El diagnóstico actual de la TB sigue basándose en la presentación clínica, los hallazgos radiográficos y los resultados microbiológicos; todos ellos con problemas de sensibilidad o especificidad. Es por ello que el futuro más inmediato pasa por las técnicas microbiológicas rápidas moleculares, sobre todo el GeneXpert (más sensible que la baciloscopia y con capacidad de detectar resistencia a la rifampicina) y el GenoType. El tratamiento actual de la TB sigue siendo el mismo de 6 meses utilizado desde hace décadas. Los intentos por acortar este tratamiento están fracasando en la actualidad. En los últimos años se han descrito nuevos fármacos que podrían contribuir al tratamiento de la TB en un futuro cercano, y que ya se utilizan en la TB con multifarmacorresistencias." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Caminero Luna JA. Actualización en el diagnóstico y tratamiento de la tuberculosis pulmonar. Rev Clin Esp. 2016;216:76-84." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0385">12</a> and Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0390">13</a>" "tabla" => array:2 [ "leyenda" => "Abbreviations: Mfx/Lfx, moxifloxacin/levofloxacin; PAS, para-amino salicylic acid." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "fx1.jpeg" "imagenAlto" => 1638 "imagenAncho" => 3238 "imagenTamanyo" => 328869 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Activity and Toxicity of Active Drugs against M. tuberculosis." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Group 1: First-generation orally administered drugs<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Essential drugs: isoniazid, rifampicin, pyrazinamide \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">- Accompanying drug: ethambutol \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">Group 2: Fluoroquinolones<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- High doses of levofloxacin or moxifloxacin→all essential \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">Group 3: Injectables<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Streptomycin, kanamycin, amikacin, capreomycin→all essential \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">Group 4:Other less effective second-line drugs<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Ethionamide/prothionamide, cycloserine, PAS→all accompanying drugs \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">Group 5:Other drugs with less clinical experience<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Essential drugs: linezolid, bedaquiline, delamanid \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">- Accompanying drugs: clofazimine, amoxicillin/clavulanic acid, meropenem o imipenem \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001146.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "All possible drugs should be used." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Only one of these drugs should be used, because they have the same gene target. Consider it an active drug in MDR-TB cases, but add it without considering it an active drug in XDR-TB cases." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Streptomycin should be avoided due to its high rate of resistance associated with isoniazid." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "All possible drugs should be used if necessary. eEthionamide and prothionamide are practically the same drug. Abbreviation: PAS, para-amino salicylic acid." ] ] ] "descripcion" => array:1 [ "en" => "Rational classification and sequential use of anti-TB drugs." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviations: ECG, electrocardiogram; IM, intramuscular; IV, intravenous; Max, maximum; QTc, corrected QT interval." "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 \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 \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 \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/kg. Max. 600mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatitis, hypersensitivity reactions \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV, IM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/kg. Max. 300mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatitis, peripheral neuropathy \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25–30mg/kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatitis, hyperuricemia \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg/kg. 15mg/kg in continuation phase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Optic neuritis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IM, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15mg/kg. Max 1g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotoxicity, cranial nerve VIII disorders \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/prothionamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">750–1000mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gastroenteritis, hepatitis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">750–1000mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Personality disorders, depression \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IM, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15mg/kg. Max. 0.75–1g/24–48h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ototoxicity, nephrotoxicity \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IM, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15mg/kg. Max. 0.75–1g/24–48h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ototoxicity, nephrotoxicity \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IM, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15mg/kg. Max. 0.75–1g/24–48h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ototoxicity, nephrotoxicity \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15mg/kg.→750mg–1g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tenosynovitis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tenosynovitis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–15g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gastroenteritis, hepatitis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100–200mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Eosinophilic gastroenteritis/pigmentation \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">600mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pancytopenia, gastrointestinal alterations, polyneuritis \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g/8–12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hematological disorders \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400mg/day for 15 days, then 200mg 3 times a week until a maximum of 6 months have been completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gastric intolerance, pancreatitis, hepatitis, QTc disorders on ECG \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mg/12h, up to 6 months maximum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anemia, nausea, QTc disorders on ECG \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001145.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs with activity against M. tuberculosis. Recommended dosage and most frequent adverse effects." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Scardigli et al.<a class="elsevierStyleCrossRef" href="#bib0410">17</a> and Caminero et al.<a class="elsevierStyleCrossRef" href="#bib0535">42</a>" "tabla" => array:2 [ "leyenda" => "Abbreviations: E, ethambutol; FQ: fluoroquinolones; H, isoniazid; DST: drug sensitivity tests; XDR-TB, extensively drug-resistance tuberculosis; HIV, human immunodeficiency virus; Z, pyrazinamide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Steps \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 \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. Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Consider…• Drug history: one month of monotherapy, or adding a single drug to a treatment regime that is not effective; these are major indications of possible resistance to this drug.• DST: more reliable for H and R; fairly reliable for second-generation injectable drugs and FQs; less reliable for E and Z; unreliable for drugs in Groups 4 and 5 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)→not recommended.• Perform an HIV test. If positive, start antiretroviral therapy. \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. Number of drugs \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 drugs: never used in the past or with susceptibility proven by DST, taking into account DST reliability previously commented and cross-resistances.At least 2 essential drugs (one with high bactericide capacity and another with sterilizing capacity) and 2 accompanying drugs to protect the essential drugs. \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. Selection of drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">• Rational introduction as per <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>• Use first generation drugs if still effective, generally not to be included among the “4 effective drugs”• High doses of levofloxacin or moxifloxacin• One second generation injectable• Use drugs in Group 4 up to achieving 4 effective drugs• If required, use drugs from Group 5 to reinforce the scheme or when the 4 effective drugs number is not achieved. The sequence for introduction should be: linezolid, bedaquiline, clofazimine, carbapenem/clavulanic acid. High doses of H to be considered \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. Treatment duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">• Intensive phase: at least until bacilloscopy and culture result negative. Even longer duration in case of not having 3 effective drugs in the continuation phase or in case of suspected FQ resistance.• Continuation phase: at least up to completing 20 months of treatment in total. \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. Surgery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To be considered only if the following conditions are met:• 1) <4 effective drugs; 2) localized lesions; and 3) sufficient respiratory reserve after resection• To be considered mainly in MDR-TB and pre-XDR-TB due to FQ resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001144.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Basic recommendations for diagnosing and treating TB-MFR." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:65 [ 0 => array:3 [ "identificador" => "bib0330" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Controversial topics in tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.A. 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Update on the diagnosis and treatment of pulmonary tuberculosis

Actualización en el diagnóstico y tratamiento de la tuberculosis pulmonar

J.A. Caminero Lunaa,b

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

b Unidad de Tuberculosis Multi-Drogo-Resistente (MDR-TB) de La Unión Internacional contra la Tuberculosis y Enfermedades Respiratorias, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Even well into the 21st century&#44; tuberculosis &#40;TB&#41; is still the most important infectious disease in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> The dismal figures for the number of people who are currently infected &#40;2&#46;3<span class="elsevierStyleHsp" style=""></span>billion&#41;&#44; sick &#40;9<span class="elsevierStyleHsp" style=""></span>million new cases per year&#41; or who have died &#40;1&#46;5<span class="elsevierStyleHsp" style=""></span>million per year&#41;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> from this old endemic disease make it important to reflect on the failures in controlling a disease that has been curable for the last 50 years and preventable for the last several decades&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;3</span></a> TB is relatively simple and inexpensive to diagnose&#59; it can be cured in most cases with well-tolerated and low-cost treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">3</span></a> Furthermore&#44; it is estimated that of the 9 million people who become ill every year&#44; approximately half a million are carriers of isoniazid and rifampicin-resistant TB &#40;multidrug-resistant TB &#91;MDR-TB&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> These patients are very difficult to cure&#44; because these are the two most efficient drugs against the disease&#46; It is evident that new resources for diagnosis and treatment are required if we are to control this epidemic&#44; as well as MDR-TB&#46; These resources have become available within the last decade and are discussed in this article&#44; along with the current status of the infection&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of tuberculosis</span><p id="par0010" class="elsevierStylePara elsevierViewall">In the aggression inflicted by <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> &#40;<span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#41;&#44; several scenarios are possible&#44; depending on the virulence of the bacillus and the immune system response&#46; Thus&#44; an infection might not occur &#40;due to effective alveolar macrophages&#41;&#44; the infected patient might not become ill &#40;latent infection&#41; or the patient might end up developing TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Even though the highest priority should be to diagnose sick patients with TB &#40;those who might die from the disease and can transmit it&#41;&#44; due to the process by which <span class="elsevierStyleItalic">M&#46; tuberculosis</span> aggression is produced&#44; we will discuss the diagnosis of the infection first and then the diagnosis of the disease&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosing the tuberculosis infection</span><p id="par0020" class="elsevierStylePara elsevierViewall">Just 10&#8211;15 years ago&#44; only one tool was available for diagnosing TB infection&#58; the so-called tuberculin &#40;TST&#41;&#44; PPD or Mantoux Test&#46; However&#44; due to the drawbacks of the TST and its lack of availability throughout large parts of the world&#44; other methods began to be adopted that were based on interferon-gamma release &#40;interferon-&#947; release assays &#91;IGRA&#93;&#41; against exposure to specific <span class="elsevierStyleItalic">M&#46; tuberculosis</span> antigens&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The TST reveals the body&#39;s hypersensitivity to the presence of tuberculosis bacillus proteins&#44; a hypersensitivity that is acquired in most cases after an <span class="elsevierStyleItalic">M&#46; tuberculosis</span> infection&#46; The hypersensitivity might&#44; however&#44; be caused by a Bacillus Calmette-Gu&#233;rin &#40;BCG&#41; vaccine or an infection by environmental bacteria&#46; Tuberculin gives rise to an inflammatory reaction in infected individuals &#40;even if they have never been sick&#41;&#44; with significant cellular infiltration of the dermis&#44; which produces visible and palpable induration in the area and can be accompanied by edema&#44; erythema and in rare occasions vesiculation&#44; necrosis and regional lymphadenitis&#46; Positivity appears within 2 and 12 weeks after infection&#46; There is therefore a window within that time that might require repeating the test&#46; The results are expressed in millimeters of induration&#44; and a diameter &#8805;5<span class="elsevierStyleHsp" style=""></span>mm is considered positive&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a> The TST should be limited to children&#44; patients with immunodeficiency and suspected TB&#44; for the diagnosis of infection in patients with immunodepression&#44; people who live with patients infected with TB and health personnel to detect recent converters&#46; The application of the TST for diagnosis in adults presenting respiratory symptoms lacks a sound basis&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Two types of IGRA tests are currently being performed&#46; The first and most widely used test measures &#40;by means of ELISA&#41; the amount of interferon-gamma released in the patient&#39;s blood when exposed to specific <span class="elsevierStyleItalic">M&#46; tuberculosis</span> antigens&#46; If the serum belongs to a patient previously infected with <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; memory T-cells respond to this antigenic stimulus and release interferon-gamma&#46; However&#44; if the patient has not been previously infected&#44; the serum will not react or release interferon-gamma&#44; and the test result will be negative&#46; The only marketed test for this is called Quantiferon TB Gold and employs the antigens Esat 6&#44; CFP10 and TB 7&#46;7&#46; This test enables the differentiation of individuals infected with <span class="elsevierStyleItalic">M&#46; tuberculosis</span> from those sensitized by the BCG vaccine &#40;which lost these antigens during the manufacturing process&#41; or by most environmental mycobacteria&#46; A result above 0&#46;35 is considered positive&#44; and a result below 0&#46;35 is deemed negative&#46; The second method&#44; which is less commonly used and has not yet been marketed&#44; uses an ELISPOT test &#40;a variant of ELISA&#41; to detect monocytes responding to this antigen stimulus&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">6</span></a> Although this technique might be slightly more sensitive&#44; it is more complex and less reproducible and is therefore not as widely used&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The major advantages of IGRAs are their better reproducibility and ease of interpretation&#44; as well as their lack of interference with the BCG vaccine&#46; However&#44; it is not clear whether IGRAs are superior to the TST in the results&#46; There is a 10&#8211;20&#37; discrepancy between the results of the IGRAs and TST&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">8</span></a> Therefore&#44; for patients for whom there is significant interest in ruling out TB infection&#44; one of these tests &#40;TST or IGRA&#41; should be performed first&#44; and if negative&#44; the other should be applied&#46; If the results of either these tests are positive&#44; the diagnosis of tuberculosis infection may be accepted&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosing the tuberculosis disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">The TB diagnosis is still based on clinical suspicion&#44; radiography and microbiological tests&#44; although the latter of these have undergone major developments in recent years&#44; mainly with the emergence of rapid molecular methods&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical manifestations</span><p id="par0045" class="elsevierStylePara elsevierViewall">One of the main problems with TB is the scarce specificity in its signs and symptoms&#44; which are similar to many respiratory diseases&#44; even some mild ones&#46; The onset is insidious in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">4</span></a> Symptoms can be localized or general &#40;low fever&#44; night sweats&#44; dyspnea&#44; fatigue&#44; loss of appetite and weight loss&#41;&#46; Local symptoms will depend on the affected organ&#46; The most frequent location &#40;80&#37; in immunocompetent individuals&#41; is pulmonary&#44; and the most common symptoms are extended cough and&#47;or expectoration&#44; although the clinical condition can be accompanied also by dyspnea&#44; chest pain and hemoptysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a> In all patients reporting cough and&#47;or expectoration lasting over 10&#8211;15 days&#44; pulmonary TB should be ruled out by means of a chest X-ray and microbiology tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chest X-ray</span><p id="par0050" class="elsevierStylePara elsevierViewall">An X-ray revealing infiltrates and&#47;or cavitations predominantly in the upper lobes and apical segment of the lower lobes is suggestive of pulmonary TB&#59; however&#44; any pulmonary segment or lobe can be affected&#46; X-rays can appear normal only in some primary TB forms&#44; frequently in people infected with HIV and who present serious immunodepression&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Although a very sensitive method&#44; simple radiography is not always specific&#44; and there is no pathognomonic radiological sign for TB&#46; Therefore&#44; even in the presence of lesions highly suggestive of TB in an X-ray and within a favorable clinical and epidemiological context&#44; the diagnosis of the disease should never be admitted based solely on radiological data&#44; even if they are of great assistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a> Given its sensitivity&#44; however&#44; chest radiography is still a good method for ruling out TB&#46; Therefore&#44; if an immunocompetent patient has a normal X-ray&#44; it is virtually certain that they will not have pulmonary TB&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Other imaging methods do not contribute much to diagnosing TB&#44; especially in its pulmonary presentation&#46; Only a chest CT scan can provide valuable information on the mediastinum and small lesions&#44; which go unnoticed in chest X-rays&#46; For its part&#44; an MRI can provide information in cases of extrapulmonary TB&#44; particularly osteoarticular TB&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Microbiological diagnosis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The only accurate TB diagnosis consists of isolating <span class="elsevierStyleItalic">M&#46; tuberculosis</span> in a sample taken from the patient&#44; either by way of culture or by a molecular method&#46; Therefore&#44; all efforts should be made to obtain valid samples to be analyzed by bacilloscopy&#44; culture and molecular methods&#46; Thus&#44; the microbiological diagnosis of TB comprises four successive stages&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Bacilloscopy</span>&#46; Viewing a sputum smear under a microscope remains the initial test for suspected cases of TB due to its quickness&#44; low cost&#44; simplicity and clear relation with the patient&#39;s contagiousness&#46; However&#44; it is a tedious test with moderate sensitivity&#46; A negative bacilloscopy does not therefore rule out TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a> The sensitivity of bacilloscopy varies&#58; 70&#8211;90&#37; in TB with cavitated lesions&#59; 50&#8211;70&#37; in patients showing only infiltrates in lung X-rays&#59; and less than 50&#37; in patients with pulmonary nodules or in the various forms of extrapulmonary TB &#40;&#60;10&#37; in tuberculous serositis&#41;&#46; On the other hand&#44; specificity ranges from 96&#37; to 99&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">However&#44; acid-alcohol resistance detected by bacilloscopy is a property common to all species of <span class="elsevierStyleItalic">Mycobacterium</span> &#40;not only <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#41;&#46; The definitive diagnosis should therefore be confirmed by a culture or molecular methods&#46; Bacilloscopy is also unable to differentiate live from dead bacillus&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">M&#46; tuberculosis</span> detection by molecular methods&#46; The contributions made by the GeneXpert test in the last five years are particularly relevant&#46; It is a simple and reproducible method consisting of a real-time polymerase chain reaction&#59; within approximately 2<span class="elsevierStyleHsp" style=""></span>h&#44; the results can be positive for up to 70&#37; of TBs with negative bacilloscopy and positive cultures&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">9&#8211;11</span></a> This outcome is achieved by detecting the presence of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> DNA in the sample&#44; and at the same time it identifies DNA changes that can produce resistance to rifampicin&#46; Thus&#44; in less than 2<span class="elsevierStyleHsp" style=""></span>h&#44; it provides an accurate diagnosis both for TB and for resistance to rifampicin&#44; a drug essential for treating TB&#46; Overall sensitivity is nearly 90&#37;&#44; reaching 98&#37; for patients with positive bacilloscopy and approximately 70&#37; for those with negative bacilloscopy&#46; Given that GeneXpert is much more sensitive than bacilloscopy&#44; the technique is chosen for patients with more paubacillary TBs&#44; such as those infected with HIV&#46; Overall specificity is 99&#37;&#44; compared with the culture gold standard&#46; Moreover&#44; overall sensitivity for detecting rifampicin resistance is 95&#37;&#44; with 98&#37; specificity&#46; These data indicate that if a patient has a GeneXpert positive for rifampicin resistance&#44; they must be treated as having MDR-TB&#44; because resistance to this drug is associated with isoniazid resistance in over 95&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;12</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">GeneXpert is an automated process and does not require a laboratory infrastructure&#46; The World Health Organization recently recommended GeneXpert as an initial diagnosis test &#40;before bacilloscopy&#41; for patients with HIV suspected to have TB or when rifampicin resistance or MDR-TB are suspected&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;11</span></a> This test has also proven to be effective for diagnosing TB in children<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;13&#44;14</span></a> and in extrapulmonary forms&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;15</span></a> Within the next 2&#8211;3 years&#44; GeneXpert will likely replace the centennial bacilloscopy as the initial diagnostic test for all patients suspected of having TB&#46; This prediction is a realistic forecast&#44; considering that the equipment only needs an electric power source and can even be installed outside the laboratory facilities&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">16</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#41;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Culture of <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; Culture is still the gold standard for diagnosing TB&#44; not only because it is the most sensitive bacteriological method available &#40;can be positive with only 10 bacilli per cubic centimeters in the sample&#41;&#44; but also because <span class="elsevierStyleItalic">M&#46; tuberculosis</span> identification methods can be used with this test to fully confirm the disease&#46; The major drawback of cultures is the delay in obtaining results &#40;2&#8211;4 weeks in liquid media and 4&#8211;8 weeks in solid media&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> due to the slow growth of the bacillus&#46; This turnaround time is unacceptable for making therapeutic decisions&#46; Moreover&#44; a negative culture does not rule out the disease because the presentation might be paubacillary&#44; such as extrapulmonary TBs or some incipient pulmonary presentations&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In cultures revealing mycobacterial growth&#44; the particular species should be identified&#44; either by biochemical methods&#44; which are tedious and take several weeks&#44; or preferably by molecular tests&#44; which have been adopted in recent years due to their speed and simplicity&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#41;</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Antibiogram</span>&#46; When possible&#44; <span class="elsevierStyleItalic">in vitro</span> studies of anti-TB drug sensitivity &#40;antibiograms&#41; should be performed for all cases&#46; Alternatively&#44; this potential resistance should be detected by molecular methods&#46; Ideally&#44; rifampicin and isoniazid resistance studies should be performed&#44; provided there is a sample available&#46; If the result is positive for resistance to rifampicin &#40;the drug that most determines the prognosis of TB&#41;&#44; fluoroquinolone &#40;FQ&#41; resistance studies should also be conducted&#44; namely for levofloxacin and moxifloxacin&#44; as well as the second-line injectable drugs &#40;amikacin or capreomycin&#41; planned for use as treatment&#46; The credibility of the conventional sensitivity tests for these drugs is very good and can therefore provide guidance for the therapeutic plan&#46; In contrast&#44; it is not advisable to test other drugs&#44; because the results from available tests are unreliable&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;17</span></a></p></li></ul></p><p id="par0105" class="elsevierStylePara elsevierViewall">Susceptibility tests can be either phenotypic or genotypic&#46; The former have the disadvantage that <span class="elsevierStyleItalic">M&#46; tuberculosis</span> needs to grow in the culture media&#44; which can take several weeks&#46; However&#44; molecular testing can provide results within 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#44; detecting by means of genetic amplification the genetic mutations of the bacillus that cause resistance to anti-TB drugs&#46; These methods include GeneXpert&#44; which can detect rifampicin resistance within 2<span class="elsevierStyleHsp" style=""></span>h&#44; and GenoType&#44; also known as line probe assay &#40;LPA&#41;&#44; which can detect rifampicin and isoniazid resistance within 48<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">18&#44;19</span></a> Both methods can be performed directly on the sample and do not require waiting for culture growth&#46; GenoType&#47;LPA results are also promising for detecting resistance to FQ and second-line injectable antibiotics &#40;kanamycin&#44; amikacin and capreomycin&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> This GenoType&#47;LPA is also able to differentiate between <span class="elsevierStyleItalic">M&#46; tuberculosis</span> and over 30 different mycobacteria&#46; Given that GenoType&#47;LPA is a conventional polymerase chain reaction&#44; its drawback is that it requires a biomolecular laboratory with 3 separate spaces&#46; It also requires a higher bacillus load in order to be performed&#46; Ideally&#44; GenoType&#47;LPA is applied in samples with positive bacilloscopy&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Possibilities for diagnosis in TB</span><p id="par0110" class="elsevierStylePara elsevierViewall">In certain circumstances and despite performing all the tests mentioned above&#44; it might not be possible to achieve a bacteriological confirmation of TB&#46; In these cases&#44; the judgment for endorsing a therapeutic approach should be based on the patient&#39;s collection of clinical&#44; radiological and laboratory data&#46; Thus&#44; in order to accept a case as TB&#44; at least one of the following criteria should be met&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1&#46;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Positive bacilloscopy and&#47;or culture of the studied sample&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2&#46;</span><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">M&#46; tuberculosis</span> detected by a molecular method&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3&#46;</span><p id="par0125" class="elsevierStylePara elsevierViewall">A biopsy showing granulomas and caseous necrosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">4&#46;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Compatible clinical condition and radiology results of patients for whom previous studies have resulted negative and for whom other possible diagnoses have been ruled out&#46; Under this assumption&#44; the patient should be prescribed anti-TB treatment&#46;</p></li></ul></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment of tuberculosis</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Initial treatment of tuberculosis</span><p id="par0135" class="elsevierStylePara elsevierViewall">During the 2 decades from the discovery of streptomycin in 1943 to the discovery of rifampicin in 1963&#44; practically all the drugs with activity against <span class="elsevierStyleItalic">M&#46; tuberculosis</span> known so far were discovered&#46; In addition&#44; numerous randomized clinical trials were performed that served as the basis for treating TB&#44; both drug-sensitive and drug-resistant&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;21&#44;22</span></a> The bacteriological basis to be met by any treatment are &#40;i&#41; the combination of drugs to prevent the selection of resistances and &#40;ii&#41; application of extended treatment that ensures not only the cure but also the prevention of a possible relapse&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;21&#44;22</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In order to ensure the maximum possibility for cure without relapse&#44; every treatment should combine at least 4 not previously used drugs&#46; At least 2 of the drugs should be &#8220;essential&#8221;&#44; one with good bactericidal activity &#40;ability to eliminate bacilli in active replication&#44; which are the ones causing the symptoms and the possible death of the patient&#41; and another with good sterilizing capacity &#40;able to eliminate bacilli in latent phases&#44; i&#46;e&#46;&#44; producers of relapses&#41;&#46; Given that these are the drugs that will cure the patient&#44; their use should ideally be maintained throughout the treatment&#46; The other two drugs are known as &#8220;accompanying&#8221; drugs&#44; which means they are not included in the treatment regime to eliminate bacilli in a particular way&#44; but rather are intended to protect the &#8220;essential&#8221; drugs&#46; In theory&#44; these &#8220;accompanying&#8221; drugs may be suspended once bacteriological conversion is achieved&#44; which means there is a highly reduced bacillary population&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">It is worth highlighting that if a given &#8220;essential&#8221; drug cannot be used due to resistance or toxicity&#44; it should be replaced by another with similar action &#40;bactericidal or sterilizing&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the bactericidal&#44; sterilizing and resistance-prevention capacity of the various drugs&#44; as well as their toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">To aid in the selection of the 4 drugs for TB treatment&#44; they have been classified into 5 groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22&#8211;25</span></a> Group 1 has higher activity&#44; followed by the other groups in decreasing order of efficacy and tolerance&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the recommended dosage for all drugs with action against <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;24</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Thus&#44; an initial TB presumed to be sensitive to all drugs should receive all 4 drugs from Group 1&#44; i&#46;e&#46;&#44; isoniazid &#40;H&#41;&#44; rifampicin &#40;R&#41;&#44; pyrazinamide &#40;Z&#41; and ethambutol &#40;E&#41;&#46; The first two drugs &#40;H and R&#41; should be administered over the course of the 6 months of treatment&#44; and the other two &#40;Z and E&#41; drugs should be administered for the first 2 months or until the bacilloscopy results are negative&#46; In favorable situations with no resistance to H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R and provided the susceptibility test results are available within 3 weeks&#44; it might be possible to not use ethambutol and to administer only H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Z from the beginning&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">22&#44;26</span></a> If the susceptibility test shows sensitivity to H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R by the end of the second month&#44; Z<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>E may be suspended and treatment continued with H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R until 6 months of treatment have been completed&#46; The drugs should be taken in the morning and on an empty stomach&#46; Noncompliance with the treatment &#40;or worse&#44; irregular compliance&#41; compromises the curing process and is the most common way by which microbiological resistance is induced&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;12</span></a> This regime is equally applicable to children&#44; pregnant or breastfeeding women&#44; patients with HIV or extrapulmonary TB&#59; however&#44; patients with HIV infection and those with certain forms of extrapulmonary TB &#40;meningeal&#44; disseminated&#41; may have their treatment extended to 9&#8211;12 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">22&#44;27</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">This 6-month regime&#44; even if well tolerated and highly effective&#44; still has a long duration and therefore requires strict supervision in many cases&#46; The goal of TB treatment is to be able to shorten it as much as possible without losing efficacy&#46; New FQs &#40;moxifloxacin and gatifloxacin&#41; or some rifampicins &#40;rifapentine&#41; can contribute to reducing treatment to 4 months&#46; However&#44; various clinical trials have recently published their results<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">28&#8211;31</span></a> and concluded that the 4-month regimen is inferior to the 6-month regimen&#44; particularly in relation to the relapse rate&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment of drug-resistant TB</span><p id="par0165" class="elsevierStylePara elsevierViewall">Drug-resistant TB&#44; especially with rifampicin resistance&#44; has become the main challenge in the attempt to eliminate this worldwide millennial plague&#46; Rifampicin is by far the most active drug against <span class="elsevierStyleItalic">M&#46; tuberculosis</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22</span></a> For this reason&#44; TB cases in which it is not possible to use this drug either due to resistance or intolerance are more difficult to cure&#44; requiring more extensive treatments &#40;at least 18 months&#41;&#44; and their prognosis is the poorest&#46; Rifampicin resistance is probably sufficient for defining a TB as MDR&#44; which can easily be detected by rapid molecular methods&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;19&#44;32&#44;33</span></a> Including isoniazid in the definition of MDR-TB &#40;resistance at least to H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R&#41; has little influence on the final therapeutic regimen&#44; its duration and prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The other drugs with action against <span class="elsevierStyleItalic">M&#46; tuberculosis</span> include the new FQs<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; included in Group 2 &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; They clearly outline the prognosis of extensively drug-resistant TB &#40;XDR-TB&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">34&#44;35</span></a> defined as those MDR-TB cases in which there is also additional resistance to some FQ and to at least one of the 3 available second-line injectable drugs &#40;kanamycin&#44; amikacin and capreomycin&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Both MDR-TB and XDR-TB pose a number of challenges&#46; First&#44; we are facing a new epidemic about which practically nothing was known until recent years and for which there is little quality evidence regarding the most appropriate treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;36</span></a> Second&#44; after several decades&#44; TB is once again being referred to as a potentially incurable disease&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">37</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The increased occurrence of MDR-TB evidenced in the last 10 years has led to the development of recommendations for diagnosing and treating these complex cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22&#8211;25&#44;38</span></a> As when treating other TBs&#44; at least 4 new drugs should be combined &#40;or at least drugs with a high probability of susceptibility&#41;&#44; following the rational classification set forth in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> for their selection&#46; Treatment should be extended for at least 21&#8211;24 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;22&#8211;25&#44;38</span></a> This duration makes strict supervision necessary as well as a deep understanding of the adverse reactions presented by most patients&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> The experience in Bangladesh&#44; with a therapeutic success rate close to 90&#37; and a regimen of only 9 months&#44;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">39&#8211;41</span></a> has become a great hope for the future&#44; mostly for patients with MDR-TB who have not been treated with second-line drugs in the past and who have a fair probability of sensitivity to FQs&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">In designing a treatment regime for patients with MDR-TB&#44; the indications set out in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> should be followed&#46; According to these indications and by seeking 4 new drugs from the classification set forth in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; patients with MDR-TB should be administered an FQ &#40;high doses of levofloxacin or moxifloxacin&#41;&#44; a second-line injectable drug &#40;capreomycin or amikacin&#44; in the case of Spain&#41; and 2 other accompanying drugs&#44; preferably prothionamide and cycloserine&#46; The FQ and the injectable drug should be part of the therapeutic plan&#46; The injectable drug should be administered at least until cultures are negative&#46; Pyrazinamide should always be administered&#44; but it is not included in the 4 new drugs&#44; because it has often been used in the past and there is a high chance that transmission occurred from another patient with resistance to the drug&#46; Ethambutol may be considered for patients who have never been treated with it&#44; but it should not be considered as one of the 4 active drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">12&#44;17&#44;23&#44;26</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">It is important to highlight how in Group 5&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; a number of drugs have been included that have classically had little efficacy or little evidence of efficacy&#46; However&#44; over the last 5 years&#44; evidence has shown that a number of these drugs &#40;linezolid&#44; bedaquiline&#44; delamanid&#41; have good efficacy&#44; probably better than the ones included in Group 4 and even the second-line injectable drugs in Group 3&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Linezolid may be considered an &#8220;essential&#8221; drug&#44; with both bactericidal and sterilizing capacities&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">43&#44;44</span></a> Two small randomized clinical trials<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">45&#44;46</span></a> and various meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">47&#8211;49</span></a> have proven its effectiveness for treating MDR-TB&#44; especially XDR-TB&#46; However&#44; there are two downsides&#58; its high price and its toxicity profile when administered for more than 6&#8211;8 weeks&#44; consisting of hematological disorders and polyneuropathies&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a> Price is a matter of the market&#59; a number of publications have demonstrated good efficacy with linezolid at 1 USD per 600-mg tablet&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">51</span></a> Toxicity is linked to dosage&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">52</span></a> but the toxicity can be relatively easy to control&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">45</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Bedaquiline is the only drug approved by the Food and Drug Administration in 50 years for TB treatment &#40;previously the only one was rifampicin&#41;&#44; and it could also be considered an &#8220;essential&#8221; drug due to its good bactericidal and sterilizing action&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">53&#8211;55</span></a> Two clinical trials<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">56&#44;57</span></a> have demonstrated its efficacy in treating MDR-TB&#44; especially XDR-TB&#44; and it is already being used in several countries&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">58</span></a> Similarly&#44; delamanid&#44; a drug approved by the European Medicine Agency&#44; is a metronidazole derivative that also has good bactericidal and sterilizing activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">59&#44;60</span></a> Two other randomized clinical trials<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">61&#44;62</span></a> have described its usefulness in treating MDR-TB&#44; especially XDR-TB&#46; In summary&#44; linezolid&#44; bedaquiline and delamanid are destined to play an important role in the treatment of MDR-TB&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of the tuberculosis infection &#40;chemoprophylaxis&#41;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Anti-TB chemoprophylaxis is the specific chemotherapy employed to prevent the development of the disease in a healthy infected patients who are at risk of TB&#46; The benefit of this chemotherapy has been shown to persist up to 20 years in immunocompetent patients&#44; although it is assumed to last a lifetime&#46; This situation changes radically in patients with HIV and extensive immunodepression&#44; where the duration of preventive treatment and the probability of needing to repeat it are subjects of debate&#46; Chemoprophylaxis is usually performed with one morning dose of isoniazid on an empty stomach every day for 9 months&#44; using the same dosage for treating the disease&#46; A number of 3-month H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>R regimes have also been described with similar efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4&#44;63</span></a> A simpler chemoprophylaxis is currently being validated and consists of 1 weekly dose of isoniazid and rifapentine &#40;a rifampicin with longer half-life&#41; for 3 months&#46; This means that there would only be 12 doses of the treatment&#44; which would have similar efficacy to 9 months of isoniazid&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">64&#44;65</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">There are differences in the indications for prophylaxis from one country to another&#59; the United States has broader indications while Europe has more limited indications&#46; There are only 4 groups for which the indication for prophylaxis is universal&#58; patients with a double infection by <span class="elsevierStyleItalic">M&#46; tuberculosis</span> and HIV&#59; recently infected patients&#44; especially children&#59; patients with radiological lesions suggestive of residual TB not treated in the past&#59; and patients infected by <span class="elsevierStyleItalic">M&#46; Tuberculosis</span> who will undergo biological treatments or who are predicted to develop extensive immunodepression&#46; For the remaining groups&#44; the indication is debatable and will ultimately be at the discretion of each physician&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">3&#44;4&#44;63</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The author declares that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres611124"
          "titulo" => "Abstract"
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        1 => array:2 [
          "identificador" => "xpalclavsec625113"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Diagnosis of tuberculosis"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Diagnosing the tuberculosis infection"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Diagnosing the tuberculosis disease"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Clinical manifestations"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Chest X-ray"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Microbiological diagnosis"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Possibilities for diagnosis in TB"
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          "titulo" => "Treatment of tuberculosis"
          "secciones" => array:3 [
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              "identificador" => "sec0050"
              "titulo" => "Initial treatment of tuberculosis"
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            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Treatment of drug-resistant TB"
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            2 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Treatment of the tuberculosis infection &#40;chemoprophylaxis&#41;"
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          ]
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          "identificador" => "sec0065"
          "titulo" => "Conflicts of interest"
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    "fechaRecibido" => "2015-07-26"
    "fechaAceptado" => "2015-09-11"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec625113"
          "palabras" => array:4 [
            0 => "Pulmonary tuberculosis"
            1 => "GeneXpert"
            2 => "Multi-drug-resistant tuberculosis"
            3 => "Chemoprophylaxis"
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      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Tuberculosis pulmonar"
            1 => "GeneXpert"
            2 => "Tuberculosis multirresistente"
            3 => "Quimioprofilaxis"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Tuberculosis &#40;TB&#41; remains the most important human infectious disease&#46; Currently&#44; the TB diagnosis is still based on the clinical presentation&#44; radiographic findings and microbiological results&#59; all of which have sensitivity or specificity issues&#46; For that reason&#44; the immediate future involves rapid molecular microbiological techniques&#44; in particular GeneXpert &#40;which is more sensitive than bacilloscopy and is able to detect rifampicin resistance&#41; and GenoType&#46; The current six-month treatment for TB has remained unchanged for decades&#46; Attempts to shorten this treatment have failed&#46; In recent years&#44; new drugs have been reported that could contribute to TB treatment in the near future&#44; and are already being used in multi-drug-resistance TB&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La tuberculosis &#40;TB&#41; sigue siendo la enfermedad infecciosa humana m&#225;s importante que existe&#46; El diagn&#243;stico actual de la TB sigue bas&#225;ndose en la presentaci&#243;n cl&#237;nica&#44; los hallazgos radiogr&#225;ficos y los resultados microbiol&#243;gicos&#59; todos ellos con problemas de sensibilidad o especificidad&#46; Es por ello que el futuro m&#225;s inmediato pasa por las t&#233;cnicas microbiol&#243;gicas r&#225;pidas moleculares&#44; sobre todo el GeneXpert &#40;m&#225;s sensible que la baciloscopia y con capacidad de detectar resistencia a la rifampicina&#41; y el GenoType&#46; El tratamiento actual de la TB sigue siendo el mismo de 6 meses utilizado desde hace d&#233;cadas&#46; Los intentos por acortar este tratamiento est&#225;n fracasando en la actualidad&#46; En los &#250;ltimos a&#241;os se han descrito nuevos f&#225;rmacos que podr&#237;an contribuir al tratamiento de la TB en un futuro cercano&#44; y que ya se utilizan en la TB con multifarmacorresistencias&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Caminero Luna JA&#46; Actualizaci&#243;n en el diagn&#243;stico y tratamiento de la tuberculosis pulmonar&#46; Rev Clin Esp&#46; 2016&#59;216&#58;76-84&#46;</p>"
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> and Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">13</span></a>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; Mfx&#47;Lfx&#44; moxifloxacin&#47;levofloxacin&#59; PAS&#44; para-amino salicylic acid&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Activity and Toxicity of Active Drugs against <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#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">Group 1&#58; First-generation orally administered drugs</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>- Essential 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>- Accompanying 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="elsevierStyleItalic">Group 2&#58; 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 doses of levofloxacin or moxifloxacin<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>all essential&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">Group 3&#58; Injectables</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><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>- Streptomycin&#44; kanamycin&#44; amikacin&#44; capreomycin<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>all essential&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">Group 4&#58;Other less effective second-line 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>- Ethionamide&#47;prothionamide&#44; cycloserine&#44; PAS<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>all accompanying 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"><span class="elsevierStyleItalic">Group 5&#58;Other drugs with less clinical experience</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>- Essential 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>- Accompanying drugs&#58; clofazimine&#44; amoxicillin&#47;clavulanic acid&#44; meropenem o imipenem&nbsp;\t\t\t\t\t\t\n
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              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">All possible drugs should be used&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Only one of these drugs should be used&#44; because they have the same gene target&#46; Consider it an active drug in MDR-TB cases&#44; but add it without considering it an active drug in XDR-TB cases&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Streptomycin should be avoided due to its high rate of resistance associated with isoniazid&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">All possible drugs should be used if necessary&#46;</p> <p class="elsevierStyleNotepara" id="npar0025"><span class="elsevierStyleSup">e</span>Ethionamide and prothionamide are practically the same drug&#46;</p> <p class="elsevierStyleNotepara" id="npar0030"><span class="elsevierStyleItalic">Abbreviation</span>&#58; PAS&#44; para-amino salicylic acid&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Rational classification and sequential use of anti-TB drugs&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; ECG&#44; electrocardiogram&#59; IM&#44; intramuscular&#59; IV&#44; intravenous&#59; Max&#44; maximum&#59; QTc&#44; corrected QT interval&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="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; IV&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; IV&#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&#46; Max&#46; 300<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; peripheral neuropathy&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&#44; 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&#46; 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; IV&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 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; cranial nerve VIII 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">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&#44; 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 disorders&#44; 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; IV&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; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24&#8211;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&#44; 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; IV&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; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24&#8211;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&#44; 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; IV&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; 0&#46;75&#8211;1<span class="elsevierStyleHsp" style=""></span>g&#47;24&#8211;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&#44; 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&#46;<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>750<span class="elsevierStyleHsp" style=""></span>mg&#8211;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">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<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&#44; 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">Eosinophilic gastroenteritis&#47;pigmentation&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; IV&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&#44; gastrointestinal alterations&#44; 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">IV&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&#8211;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&#44; then 200<span class="elsevierStyleHsp" style=""></span>mg 3 times a week until a maximum of 6 months have been completed&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; QTc disorders 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&#44; up to 6 months maximum&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; QTc disorders on ECG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Drugs with activity against <span class="elsevierStyleItalic">M&#46; tuberculosis&#46;</span> Recommended dosage and most frequent adverse effects&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Scardigli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a> and Caminero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a>"
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; E&#44; ethambutol&#59; FQ&#58; fluoroquinolones&#59; H&#44; isoniazid&#59; DST&#58; drug sensitivity tests&#59; XDR-TB&#44; extensively drug-resistance tuberculosis&#59; HIV&#44; human immunodeficiency virus&#59; Z&#44; pyrazinamide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="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">Consider&#8230;&#8226; Drug history&#58; one month of monotherapy&#44; or adding a single drug to a treatment regime that is not effective&#59; these are major indications of possible resistance to this drug&#46;&#8226; DST&#58; more reliable for H and R&#59; fairly reliable for second-generation injectable drugs and FQs&#59; less reliable for E and Z&#59; unreliable for drugs in Groups 4 and 5 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>not recommended&#46;&#8226; Perform an HIV test&#46; If positive&#44; start antiretroviral therapy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="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 drugs&#58; never used in the past or with susceptibility proven by DST&#44; taking into account DST reliability previously commented and cross-resistances&#46;At least 2 essential drugs &#40;one with high bactericide capacity and another with sterilizing capacity&#41; and 2 accompanying drugs to protect the essential drugs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="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">&#8226; Rational introduction as per <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#8226; Use first generation drugs if still effective&#44; generally not to be included among the &#8220;4 effective drugs&#8221;&#8226; High doses of levofloxacin or moxifloxacin&#8226; One second generation injectable&#8226; Use drugs in Group 4 up to achieving 4 effective drugs&#8226; If required&#44; use drugs from Group 5 to reinforce the scheme or when the 4 effective drugs number is not achieved&#46; The sequence for introduction should be&#58; linezolid&#44; bedaquiline&#44; clofazimine&#44; carbapenem&#47;clavulanic acid&#46; High doses of H to be considered&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">&#8226; Intensive phase&#58; at least until bacilloscopy and culture result negative&#46; Even longer duration in case of not having 3 effective drugs in the continuation phase or in case of suspected FQ resistance&#46;&#8226; Continuation phase&#58; at least up to completing 20 months of treatment in total&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="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">To be considered only if the following conditions are met&#58;&#8226; 1&#41; &#60;4 effective drugs&#59; 2&#41; localized lesions&#59; and 3&#41; sufficient respiratory reserve after resection&#8226; To be considered mainly in MDR-TB and pre-XDR-TB due to FQ resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Basic recommendations for diagnosing and treating TB-MFR&#46;</p>"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2015.11.001

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