Methods for determining the antimicrobial susceptibility of mycobacteria | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

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Detección de mecanismos de resistencia" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:9 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: modified from Behr et al.,<a class="elsevierStyleCrossRef" href="#bib0295">9</a> Scorpio and Zhang<a class="elsevierStyleCrossRef" href="#bib0300">10</a> and Gonzalo-Asensio et al.<a class="elsevierStyleCrossRef" href="#bib0305">11</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2441 "Ancho" => 3566 "Tamanyo" => 384188 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Evolutionary tree of the Mycobacterium tuberculosis complex." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jesús Viñuelas-Bayón, María Asunción Vitoria, Sofía Samper" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Jesús" "apellidos" => "Viñuelas-Bayón" ] 1 => array:2 [ "nombre" => "María Asunción" "apellidos" => "Vitoria" ] 2 => array:2 [ "nombre" => "Sofía" "apellidos" => "Samper" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213005X17300678" "doi" => "10.1016/j.eimc.2017.01.015" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213005X17300678?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529993X17302150?idApp=UINPBA00004N" "url" => "/2529993X/0000003500000008/v2_201711110108/S2529993X17302150/v2_201711110108/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Methods for determining the antimicrobial susceptibility of mycobacteria" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "527" "paginaFinal" => "533" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Fernando Alcaide, Jaime Esteban, Julià González-Martin, Juan-José Palacios" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Fernando" "apellidos" => "Alcaide" "email" => array:1 [ 0 => "falcaide@bellvitgehospital.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Jaime" "apellidos" => "Esteban" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Julià" "apellidos" => "González-Martin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Juan-José" "apellidos" => "Palacios" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Microbiología, Hospital Universitari de Bellvitge, Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, GEIM (SEIMC), Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Microbiología Clínica, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid (UAM), GEIM (SEIMC), Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servei de Microbiologia-CDB, Hospital Clínic-ISGLOBAL, Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, GEIM (SEIMC), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Referencia Regional de Micobacterias, Servicio de Microbiología, Hospital Universitario Central de Asturias, GEIM (SEIMC), Oviedo, Asturias, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Métodos de determinación de sensibilidad a los antimicrobianos en micobacterias" ] ] "textoCompleto" => "IntroductionCurrently, more than 170 species of mycobacteria have been reported, and many of them are a major cause of morbidity and mortality in humans. Notable among them is tuberculosis (TB), caused by the Mycobacterium tuberculosis<a class="elsevierStyleCrossRef" href="#bib0140">1</a> complex. According to the WHO, around 9.6 million people became ill from TB in 2014 and 1.5 million died from it, with it being the primary cause of death by an infectious agent.<a class="elsevierStyleCrossRef" href="#bib0140">1</a> Also, in recent years, strains resistant to multiple drugs have appeared and are spreading. Thus, it is estimated that 480,000 people developed multidrug-resistant TB (MDR-TB; resistance to at least isoniazid and rifampicin) worldwide in 2014, of which 9% would have extended resistance (XDR-TB) to at least one of the second-line injectable drugs (capreomycin, kanamycin, or amikacin) and to a fluoroquinolone. Therefore, the rapid detection of resistance to antituberculosis drugs is fundamental to achieve adequate treatment and prevent the onset and spread of MDR-TB. Furthermore, nontuberculous mycobacteria (NTM) or environmental mycobacteria have become increasingly prevalent, with many of them being pathogenic (mycobacteriosis) and requiring a specific treatment that, in many cases, should be oriented by in vitro antimicrobial susceptibility testing.<a class="elsevierStyleCrossRefs" href="#bib0145">2–4</a>AntimicrobialsAlthough the therapeutic arsenal for mycobacterial infections is very limited, some new drugs are currently available, although not all have the same activity or are used to treat the same types of infection or different species (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0160">5</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Drugs used against the M. tuberculosis complexDrugs called “first line” treatments include those administered as the first choice and are isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and, for historical reasons, also streptomycin (S).<a class="elsevierStyleCrossRefs" href="#bib0160">5–7</a> The first four are those recommended by the WHO for a 6-month regimen (2HREZ+4HR). In cases of resistance, allergy, intolerance, hepatic toxicity or interaction with one or more of these drugs, second-line drugs should be used, including rifamycins (rifabutin, rifapentine), quinolones (ofloxacin, levofloxacin, moxifloxacin), aminoglycosides (amikacin, tobramycin), capreomycin, cycloserine, linezolid, isoniazid analogues (ethionamide, prothionamide), clofazimine, PAS or thiacetazone.<a class="elsevierStyleCrossRefs" href="#bib0160">5–7</a> In cases of MDR-TB or XDR-TB, recently developed drugs may also be used, such as bedaquiline and/or delamanid.<a class="elsevierStyleCrossRef" href="#bib0175">8</a>Drugs used against nontuberculous mycobacteriaThe treatment of NTM, with the exception of leprosy, is less standardised than that of TB, with wide variations between species.<a class="elsevierStyleCrossRefs" href="#bib0145">2,9</a> For most slow-growing species, the mainstays of treatment are clarithromycin, ethambutol and amikacin, complemented with other drugs such as quinolones, rifamycins, linezolid, and probably, with a lesser degree of efficacy, cephalosporins, carbapenems and tetracyclines. Mycobacterium kansasii and Mycobacterium xenopi infections are treated similarly to TB, except for pyrazinamide, since it does not have activity against NTM.<a class="elsevierStyleCrossRefs" href="#bib0145">2,9</a> Rapidly growing species are resistant to classic antituberculosis drugs and also have clarithromycin as the mainstay of treatment, with the exception of Mycobacterium fortuitum, which is resistant, as well as 80–85% of Mycobacterium abscessus isolates.<a class="elsevierStyleCrossRefs" href="#bib0145">2,9</a>Drug susceptibility testing in M. tuberculosis complexThe history of susceptibility testing for the M. tuberculosis complex arose parallel to the development of specific pharmacological treatment for TB, which began with the discovery of streptomycin in 1944. From the beginning, it was observed that monotherapy achieved an initial clinical improvement followed by a relapse of the disease. This phenomenon, known as ‘fall and rise’, was due to the selection of resistant bacteria. In 2000, the WHO defined resistance in various categories from an epidemiological point of view: (a) Resistance in new cases: strains isolated in patients who have never received antituberculosis treatment for more than one month. (b) Resistance in treated cases: strains isolated in patients who have previously received antituberculosis treatment for more than one month. (c) Multidrug resistance (MDR-TB): joint resistance to at least isoniazid and rifampicin. (d) Poly-resistance: resistance to more than one drug not including isoniazid and rifampicin at the same time. (e) Combined resistance: sum of all resistance types in a specific area. This indicates the resistant strain load in a community. In 2006, the category of Extended resistance (XDR-TB) was added, which was mentioned in the introduction.The definitive confirmation of M. tuberculosis complex drug resistance must always be conducted using microbiological methods. In studies in the 1960s by Canetti et al.,<a class="elsevierStyleCrossRef" href="#bib0185">10</a> the frequency of spontaneous mutations associated with each drug was established. In the case of isoniazid, ethambutol and streptomycin, a resistant mutant appeared in one out of 10−5–10−7 bacteria, for rifampicin in one out of 10−7–10−9 and for pyrazinamide in one out of 10−2–10−4. The theoretical frequency of mutants resistant to more than one drug would be the exponential sum of the individual mutants resistant to each drug. The bacterial populations present in the lesions were also estimated. Thus, small infiltrates had populations of 103–105 bacteria, and cavities could reach 107–109 bacteria which makes it very improbable that simultaneous mutations to more than one drug would occur spontaneously. TB is deemed resistant when 1% or more of the bacterial population is resistant to a certain drug.<a class="elsevierStyleCrossRef" href="#bib0185">10</a>The critical concentrations of the different drugs were established by international consensus and represent the lowest concentrations that inhibit the growth of “wild strains” (susceptible strains) of the M. tuberculosis complex that have never been exposed to said drugs, while not inhibiting the strains from patients that do not respond to treatment, considered resistant. They were initially postulated for the Löwenstein–Jensen medium, and later equivalencies were established for Middlebrook 7H10 and 7H11 agar media, as well as for automated liquid media culture systems.In vitro susceptibility testing in M. tuberculosis complex must be performed on the first isolate obtained from a new patient, in cases of suspected therapeutic failure and before the disease relapses.<a class="elsevierStyleCrossRefs" href="#bib0170">7,11–13</a> Also, when the TB simultaneously affects more than one organ, the tests must be done individually for each location, without assuming that the results will always coincide. All first-line drugs should be included (isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin), since they provide information about the therapeutic scheme currently recommended for most patients.<a class="elsevierStyleCrossRefs" href="#bib0170">7,11–14</a> Traditional second-line drugs (amikacin, capreomycin, clofazimine, cycloserine, ethionamide, kanamycin and PAS) and new ones, such as fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), linezolid, and, in certain cases, rifabutin, must be evaluated whenever: (a) a strain is resistant to isoniazid, rifampicin, ethambutol or pyrazinamide; (b) when mutations in genes that encode resistance to isoniazid and/or rifampicin are detected using molecular techniques; and (c) when clinical-epidemiological information is available that recommends doing so.<a class="elsevierStyleCrossRefs" href="#bib0200">13–15</a>Solid culture media-based methodsThe absolute concentrations method, described by Meissner, is based on the comparison of the number of colonies in the presence of the drug to the number of colonies in the culture medium without the drug. The results are affected by the size of the inoculum and by the precision in the definition of the critical concentration of each drug. The resistance ratio method, described by Mitchison, compares the minimum inhibitory concentration (MIC) of a specific strain to that of a reference strain. The results depend on the adequate standardisation of the drugs and the inoculum, although the critical concentrations do not need to be defined. The multiple proportion method, described by Canetti et al.<a class="elsevierStyleCrossRef" href="#bib0185">10</a> in 1963, shows the proportion of resistant bacilli present in a culture. Micro-organism resistance is considered clinically significant when the resistant bacterial population exceeds 1%. This is the most precise method and the one that produces fewest false results, which is why it is the most widely used worldwide.<a class="elsevierStyleCrossRefs" href="#bib0170">7,11,13,16</a> The epsilometer (E-test) method is based on a gradient of antimicrobial diffusion combining the principles of disc diffusion and agar dilution in the study of in vitro susceptibility. It is a quantitative technique to determine the MIC of antimicrobials.<a class="elsevierStyleCrossRef" href="#bib0220">17</a>Liquid culture media-based methodsThere are currently two nonradiometric systems for susceptibility testing: BACTEC™ MGIT™ 960 (Becton-Dickinson Diagnostics, Sparks, MD, USA) and VersaTREK® (Thermo Scientific, Westlake, OH, USA).<a class="elsevierStyleCrossRefs" href="#bib0170">7,11,13,18</a> Both use supplemented Middlebrook 7H9 medium, and the growth is shown via detection of the consumption/production of certain gases. The initial and secondary critical concentrations that are analysed come predetermined by the manufacturer for first-line drugs. Although the detection of MDR-TB does not usually pose any problems, there are some inter-laboratory discrepancies with streptomycin, ethambutol and pyrazinamide. In the case of pyrazinamide, since it is active in acidic media (pH 5.5), the pH of the culture medium must match these conditions, despite the fact that approximately 10% of M. tuberculosis isolates do not grow well at this pH. On the other hand, it is also possible to analyse critical concentrations of other second-line drugs if the assessed substance is available.Alternative susceptibility methodsIn mycobacteriophage-based techniques, when adding the phages to a culture in the presence of an antibiotic, the phages will only infect the viable mycobacteria, which are the resistant ones. These have been applied in isoniazid and rifampicin susceptibility tests, but they present problems with susceptibility, specificity and a high rate of contamination. Flow cytometry, using cell permeable nucleic acid stains, shows viable mycobacteria (the control mycobacteria and the drug-resistant ones) with higher levels of fluorescence compared to the non-viable ones (drug-susceptible). One of the drawbacks is the high cost of the equipment. Broth microdilution (Mycotb Sensititre® Thermo Scientific) allows for the MIC of multiple drugs to be determined. The greatest difficulty lies in reading and interpreting the results, since the growth of these bacteria is not homogeneous. The nitrate reductase test is based on the capacity of the M. tuberculosis complex to reduce nitrates to nitrites. Tubes of Löwenstein–Jensen medium incorporating KNO3, with and without drugs, are used for this purpose. Microscopic-observation drug-susceptibility (MODS) is based on the early detection of the cord factor exhibited by the M. tuberculosis complex, with the help of an inverted microscope. Resazurin microtiter assay (REMA) is an indirect method based on the detection of colour changes in the culture medium due to oxidation (blue) and reduction (pink) of resazurin.The WHO considers that nitrite reductase, MODS and REMA are simple, cheap techniques that can be used for rapid screening for resistance to isoniazid and rifampicin in countries with limited resources.<a class="elsevierStyleCrossRefs" href="#bib0190">11,13,19</a> Susceptibility and specificity data exceed 95%.Antimicrobial susceptibility testing in nontuberculous mycobacteriaAlthough more than 160 species of NTM have been reported, susceptibility testing is only recommended in clinically-significant isolates for which a correlation has been shown between in vitro and in vivo results.<a class="elsevierStyleCrossRefs" href="#bib0145">2,13</a> Thus, the Clinical and Laboratory Standards Institute (CLSI) establishes recommendations only for the group comprising Mycobacterium avium complex, M. kansasii, Mycobacterium marinum and non-pigmented rapidly growing mycobacteria.<a class="elsevierStyleCrossRef" href="#bib0170">7</a>Susceptibility testing in slow-growing nontuberculous mycobacteriaIn general, the methodology of choice that CLSI recommends is microdilution in cation-adjusted Mueller Hinton (CAMH) broth, supplemented with OADC or ADC. However, in some cases there are alternatives to this methodology.Recommendations for M. avium complexThe treatment of M. avium complex (MAC) is based on the use of clarithromycin as an essential or primary drug, and ethambutol and rifampicin (or rifabutin) as adjunct therapies, although there are data showing that other antibiotics (amikacin, linezolid and moxifloxacin) could be useful in some cases. Given that a clinical correlation has only been demonstrated with in vitro tests for macrolides, the CLSI recommends that only these drugs be tested.<a class="elsevierStyleCrossRef" href="#bib0170">7</a> However, when resistance to clarithromycin is present, it is reasonable to test other drugs (moxifloxacin, linezolid and aminoglycosides). Clarithromycin's activity is very sensitive to the culture medium and its pH, therefore the MICs used generally as cut-off points correspond to a CAMH medium at a slightly basic pH of 7.3–7.4. Another method that can be used is macrodilution using the BACTEC™, MGIT™ 960 and VersaTREK® systems.<a class="elsevierStyleCrossRefs" href="#bib0145">2,13</a> There is currently a commercial microdilution technique in microtitration plates (Slomyco, Sensititre®, Thermo Scientific), that allows for simple, reproducible in vitro susceptibility testing with a standard incubation of 7 days. Although it includes 13 antimicrobials with multiple concentrations, it is important to maintain the previously stated interpretation criteria (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Recommendations for M. kansasiiStandard treatments for infections caused by this mycobacteria include rifampicin (or rifabutin), isoniazid, and a third drug (ethambutol or streptomycin) for 18 months (at least 12 months of negative cultures). In cases of possible resistance, susceptibility should be conducted in vitro for these and other potentially-active antimicrobials (clarithromycin, moxifloxacin or levofloxacin, amikacin, linezolid and rifabutin).<a class="elsevierStyleCrossRefs" href="#bib0145">2,7,13</a> One aspect to highlight is that M. kansasii naturally presents a somewhat decreased susceptibility to isoniazid in comparison with M. tuberculosis, although it has clinical activity.The recommended method is microdilution, although the proportion method in Middlebrook 7H10 agar and automated nonradiometric systems have been used. As mentioned previously in MAC, there is currently a commercial microdilution technique that, although it includes multiple antimicrobials with diverse concentrations, it is important to follow the current interpretation criteria (CLSI).Recommendations for M. marinumAntimicrobial susceptibility testing is currently only recommended for this species when there is a clinical and microbiological failure, using the broth microdilution method at 28–30°C for 7 days.<a class="elsevierStyleCrossRefs" href="#bib0145">2,7,13</a>Other slow-growing nontuberculous mycobacteriaGenerally, it is recommended to perform in vitro susceptibility testing using broth microdilution with the same drugs and the same concentrations as for M. kansasii for all species with good growth (non-deficient) and in those in which therapeutic failure and persistent positive cultures are detected.Susceptibility testing in rapid-growing nontuberculous mycobacteriaTreatment for these micro-organisms is usually conducted with drugs against which the remaining species are resistant or, at least, have a lesser susceptibility. Due to all of this, in vitro susceptibility tests have certain differentiating features from the rest of the mycobacteria. The recommended technique is broth microdilution with an incubation of 3–4 days at 30°C (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0145">2,3,7,13</a> Other methods present interpretation problems and should not be used. We must keep in mind the possible presence of inducible erm methylases. Therefore, reincubating the plates for up to 14 days and assessing the increase of the macrolides’ MIC is recommended to detect this phenomenon. There is currently a commercial microdilution technique designed specifically for rapid-growing mycobacteria and aerobic actinomycetes (Rapmyco, Sensititre®, Thermo Scientific).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Mycobacteria resistance mechanismsAntibacterial resistance is mainly due to chromosomal mutations in genes that encode their target or the activating enzymes. They can be spontaneous or drug-induced after exposure to monotherapy.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3,20,21</a>IsoniazidResistance is associated above all with mutations in 2 genes (68–90%): (a) the katG gene, that is responsible for activating the drug; the most common mutation affects codon 315 and is related to high-level resistance (60–70% of resistance), and (b) the inhA gene, which intervenes in the synthesis of the bacterial wall. Mutations (8–20%) cause low-level and cross-resistance with ethionamide.<a class="elsevierStyleCrossRefs" href="#bib0200">13,20,21</a> NTM, except for M. kansasii and M. xenopi are resistant due to incapacity of activation of the drug.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3,13</a>Rifampicin and other rifamycinsResistance to the M. tuberculosis complex is related to mutations in the rpoB gene (>95%), involved in protein synthesis. Codons 526 and 531 are the most affected and confer high-level and cross-resistance with other rifamycins.<a class="elsevierStyleCrossRefs" href="#bib0200">13,20,21</a> Mutations in some codons will maintain susceptibility to rifabutin. Similar mutations in NTM have been described.Aminoglycosides and capreomycinResistance is based on ribosomal mutations involved in protein synthesis. Resistance to streptomycin is associated with mutations (50–60%) in the rpsL and rrs genes (codons 530–912), while resistance to amikacin, kanamycin, and capreomycin is associated with mutations in the rrs gene (codons 1400–1500).<a class="elsevierStyleCrossRefs" href="#bib0200">13,20,21</a> There is partial cross-resistance between them, with isolated resistance to streptomycin that may be susceptible to the others. The tlyA gene has been linked to resistance to capreomycin and the eis gene has been linked to resistance to kanamycin.EthambutolResistance is related to mutations in the embB gene, which is involved in bacterial wall synthesis. The majority (60–80%) have been described in codons 306 and 406.<a class="elsevierStyleCrossRefs" href="#bib0200">13,20,21</a> Some species of NTM have natural resistance.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3</a>PyrazinamideResistance is associated with mutations throughout the pncA gene (72–97%) that regulates drug activation. Mycobacterium bovis and its BGC variant, as well as NTM, have natural resistance.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3,13,20,21</a>FluoroquinolonesThe most frequent mechanism is mutations in the gyrA gene (85%) and the gyrB gene (10%). There is cross-resistance between fluoroquinolones, but not full resistance, depending on the affected codons.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3,13,20,21</a>Macrolides and ketolidesResistance is linked to mutations in the 23S ribosomal gene and, above all, to inducible methylases regulated by the erm gene. These are observed in species such as M. fortuitum and M. abscessus subsp. abscessus and subsp. bolletii.<a class="elsevierStyleCrossRef" href="#bib0145">2</a>Beta-lactamsResistance is associated with a decrease in the permeability and affinity of the PBPs and, mainly, to beta-lactamases.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3</a>Tetracyclines and glycylglycinesResistance to tetracyclines is due to ribosomal protection proteins or efflux pumps.<a class="elsevierStyleCrossRefs" href="#bib0145">2,3</a> To date, resistance to tigecycline has not been demonstrated.OxazolidinonesThe resistance of mycobacteria to linezolid is associated with mutations in the rRNA 23S gene.<a class="elsevierStyleCrossRefs" href="#bib0200">13,20</a>Co-trimoxazoleThe resistance mechanism is not clear in mycobacteria.Bedaquiline and delamanidThe resistance to bedaquiline has been associated with a mutation in the mmpR gene and the resistance to delamanid has been associated with the fbiA and fgd1 genes.<a class="elsevierStyleCrossRef" href="#bib0245">22</a>Molecular detection of resistancesThe reference method for determining resistance to antituberculosis drugs is the conventional phenotypic susceptibility test, although the results tend to take several weeks.<a class="elsevierStyleCrossRefs" href="#bib0170">7,11,13</a> Molecular detection of resistance, based on showing chromosomal mutations, offers quick and useful results.<a class="elsevierStyleCrossRefs" href="#bib0240">21,23</a> Commercial techniques are those which are most widely used due to their greater standardisation (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The most used are Xpert® MTB/RIF Assay (Cepheid, Sunnyvale, CA, USA) and GenoType® MTBDRplus (Hain Lifescience, Nehren, Germany), both approved by the WHO for the rapid diagnosis of MDR-TB. Xpert® MTB/RIF allows for diagnosis of the M. tuberculosis complex and the detection of mutations resistant to rifampicin in <2h, with minimal manipulation, limited to inserting the sample into a cartridge where the entire amplification and detection process is performed. The system uses five fluorescent probes covering the natural sequence of the 81pb region of the rpoB gene where more than 95% of resistances to rifampicin occur. For the diagnosis of pulmonary and extrapulmonary TB, susceptibility is 95–98% in samples with positive microscopy and 67–69% with negative microscopy, taking the culture as reference.<a class="elsevierStyleCrossRef" href="#bib0255">24</a> The specificity is 99%. In synthesis, Xpert MTB/RIF® provides 23% more positive cases than microscopy. Its greatest drawbacks are that it only detects resistance to rifampicin and its financial cost, although for countries with limited resources, the cost is 6–7 times lower (less than €10).<a class="elsevierStyleCrossRef" href="#bib0255">24</a> The GenoType® MTBDRplus is based on amplification and reverse hybridisation on nitrocellulose strips that contain immobilised probes corresponding to natural sequences and sequences of the most frequent mutations in the rpoB (rifampicin) and katG and inhA (isoniazid) genes. Currently, it can be used based on cultures or clinical samples, even with negative bacilloscopy. Various meta-analyses establish a global susceptibility of 98% for resistance to rifampicin and 84.3% for isoniazid, with 98–99.5% specificity. Samples with negative microscopy can have 5–12% invalid results due to low susceptibility. Results that are not interpretable due to the simultaneous absence of natural and mutated bands in the same locus, due to mutations not contained in the kit have been reported. Another possibility is a discrepant result with the sensitive genotype and resistant phenotype, due to mechanisms other than those detected by the commercial product. The resistant genotype and sensitive phenotype option would be caused by the coexistence of mixed or heteroresistant populations or low-level resistances, that have been described in 4–13% of cases.<a class="elsevierStyleCrossRef" href="#bib0260">25</a> At least 50% of patients with MDR-TB are resistant to other drugs. Tests have also been marketed to detect mutations of resistance to second-line drugs. The most well-known product is GenoType® MTBDRsl (Hain Lifescience). Two versions exist: v1.0 and v2.0. The first is directed at mutations of resistance to capreomycin and the aminoglycosides amikacin and kanamycin in the rrs gene (codons 1401 and 1484), as well as to fluoroquinolones in the gyrA gene (codons 90, 91 and 94), and to ethambutol in the embB gene (codon 306). A recent analysis observed good susceptibility to fluoroquinolones (83–85%), but lower susceptibility to aminoglycosides (77%), attributable to kanamycin (69.9%).<a class="elsevierStyleCrossRef" href="#bib0265">26</a> Version v2.0 seeks to improve yield including the gyrB gene for fluoroquinolones and the eis gene for kanamycin, suppressing the ethambutol of the kit. It has recently been evaluated with a susceptibility of 96% to kanamycin. However, a decrease in specificity for injectables (91%) has also been observed, due to the detection of mutations of still unknown significance in the eis gene in some susceptible strains.<a class="elsevierStyleCrossRef" href="#bib0270">27</a> Aside from the above, the following products are also being distributed to a certain extent: INNO-Lipa® RifTB (INNO Genetics, Gent, Belgium/Fujirebio, Tokyo, Japan), Anyplex II™ MTB/MDR/XDR (Seegene, Seoul, Korea) and the TB Resistance® Assay (AID; Autoimmun Diagnostika, Strassberg, Germany).<a class="elsevierStyleCrossRefs" href="#bib0225">18,21,23</a> Although not discounting phenotypic susceptibility tests, the main use of molecular resistance detection methods, in our environment, is to quickly confirm or rule out, and to a greater or lesser extent, based on the drugs, resistance in cases of high suspicion. Recently, a method has been marketed (GenoType® NTM-DR, Hain Lifescience) that, in addition to identifying some NTM species, allows detection of the erm gene in M. abscessus, and of the mutations in the rrs (aminoglycosides) and/or rrl (macrolides) genes.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Conflicts of interestThe authors have declared that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres938433" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec912118" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres938432" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec912117" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Antimicrobials" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Drugs used against the M. tuberculosis complex" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Drugs used against nontuberculous mycobacteria" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Drug susceptibility testing in M. tuberculosis complex" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Solid culture media-based methods" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Liquid culture media-based methods" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Alternative susceptibility methods" ] ] ] 7 => array:3 [ "identificador" => "sec0045" "titulo" => "Antimicrobial susceptibility testing in nontuberculous mycobacteria" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0050" "titulo" => "Susceptibility testing in slow-growing nontuberculous mycobacteria" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Recommendations for M. avium complex" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Recommendations for M. kansasii" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Recommendations for M. marinum" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Other slow-growing nontuberculous mycobacteria" ] ] ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Susceptibility testing in rapid-growing nontuberculous mycobacteria" ] ] ] 8 => array:3 [ "identificador" => "sec0080" "titulo" => "Mycobacteria resistance mechanisms" "secciones" => array:12 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Isoniazid" ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Rifampicin and other rifamycins" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Aminoglycosides and capreomycin" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Ethambutol" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Pyrazinamide" ] 5 => array:2 [ "identificador" => "sec0110" "titulo" => "Fluoroquinolones" ] 6 => array:2 [ "identificador" => "sec0115" "titulo" => "Macrolides and ketolides" ] 7 => array:2 [ "identificador" => "sec0120" "titulo" => "Beta-lactams" ] 8 => array:2 [ "identificador" => "sec0125" "titulo" => "Tetracyclines and glycylglycines" ] 9 => array:2 [ "identificador" => "sec0130" "titulo" => "Oxazolidinones" ] 10 => array:2 [ "identificador" => "sec0135" "titulo" => "Co-trimoxazole" ] 11 => array:2 [ "identificador" => "sec0140" "titulo" => "Bedaquiline and delamanid" ] ] ] 9 => array:2 [ "identificador" => "sec0145" "titulo" => "Molecular detection of resistances" ] 10 => array:2 [ "identificador" => "sec0150" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-06" "fechaAceptado" => "2016-04-07" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec912118" "palabras" => array:3 [ 0 => "Mycobacteria" 1 => "Susceptibility testing" 2 => "Resistance mechanisms" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec912117" "palabras" => array:3 [ 0 => "Micobacterias" 1 => "Prueba de sensibilidad" 2 => "Mecanismos de resistencia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Mycobacteria are a large group of microorganisms, multiple species of which are major causes of morbidity and mortality, such as tuberculosis and leprosy. At present, the emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis complex are one of the most serious health problems worldwide. Furthermore, in contrast to M. tuberculosis and Mycobacterium leprae, non-tuberculous mycobacteria (NTM) are more frequently isolated and, in many cases, treatment is based on drug susceptibility testing. This article is a review of the different methods to determine the in vitro drug susceptibility of M. tuberculosis complex and the most relevant NTM isolates. The molecular techniques currently used for rapid detection of resistance of clinical specimens are also analysed." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las micobacterias son un amplio grupo de microorganismos en el que múltiples especies son causa de una importante morbimortalidad, como la tuberculosis y la lepra. La aparición y diseminación de cepas del complejo Mycobacterium tuberculosis resistentes a diversos fármacos constituye en la actualidad uno de los problemas sanitarios de mayor gravedad a nivel mundial. Por otro lado, las micobacterias diferentes de M. tuberculosis y Mycobacterium leprae, denominadas micobacterias no tuberculosas (MNT), son aislamientos cada vez más frecuentes, requiriendo en muchos casos un tratamiento que precisa una orientación sobre la sensibilidad de estos microorganismos a los antimicrobianos. En el presente artículo se revisan los métodos para determinar la sensibilidad in vitro a los antimicobacterianos de los aislamientos del complejo M. tuberculosis y las MNT más relevantes. Además, también se realiza un análisis de las técnicas moleculares de detección rápida de la resistencia a partir de las muestras clínicas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Alcaide F, Esteban J, González-Martin J, Palacios J-J. Métodos de determinación de sensibilidad a los antimicrobianos en micobacterias. Enferm Infecc Microbiol Clin. 2017;35:527–533." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "MAC, M. avium complex; MDR, multidrug-resistant tuberculosis; MK, M. kansasii; NTM, nontuberculous mycobacteria; MTC, M. tuberculosis complex; MX, M. xenopi." "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">Mechanism of action \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">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">Action spectrum \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">Population–action \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Inhibition of the wall synthesis</td><td class="td" title="table-entry " align="left" valign="top">Isoniazid (isonicotinic acid hydrazide) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC, MK, MX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericide (active growth), bacteriostatic (latent) \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 and thiacetazone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC, variable in NTM (MK and M. marinum) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatics \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">MTC, various slow-growing NTM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \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">MTC, with the exception of M. bovis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericide (active and latent growth) \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">MTC (use restricted to MDR), variable in NTM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \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">Use restricted to MDR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Inhibition of protein synthesis</td><td class="td" title="table-entry " align="left" valign="top">Rifamycins (rifampicin, rifabutin, rifapentine) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC, MK, MX, 50% in MAC, variable in the rest of species \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericides in active and latent growth \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">Aminoglycosides (streptomycin, amikacin, tobramycin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC and most NTM (especially amikacin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericides \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">MTC (use in MDR). Variable for NTM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericide \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">MTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericide in active growth \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">Macrolides (clarithromycin, azithromycin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very effective in MAC. Active in NTM, except for M. fortuitum and M. abscessus. Of little use in MTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatics \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">Tetracyclines and tigecycline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Variable in NTM. Tigecycline more effective \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Inhibits folic acid synthesis</td><td class="td" title="table-entry " align="left" valign="top">Dapsone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M. leprae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PAS (para-aminosalicylic acid) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC (use in MDR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Co-trimoxazole \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Variable in NTM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \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">Inhibits DNA synthesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fluoroquinolones (ofloxacin, levofloxacin, moxifloxacin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTC, NTM (MAC group 50%, rest variable) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericides in active growth \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">Interferes in Fe metabolism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " 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">MTC, variable in NTM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bactericide \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">Inhibits ATP synthase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " 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">Use restricted to MDR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bacteriostatic \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1586947.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Mechanism and action spectrum of antimycobacterials." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antimicrobial \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC (μg/ml)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Susceptible \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">Intermediate \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">Resistant \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">Amikacin<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Clarithromycin</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Microdilution (pH 7.3–7.4)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥32 \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">Radiometric (pH 7.3–7.4)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8–16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥32 \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">Radiometric (pH 6.8)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></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="char" valign="top">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linezolid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥32 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1586948.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "The MIC for amikacin is not defined. Due to assimilation into other species, it may be considered resistant >32μg/ml." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Cation-adjusted Mueller Hinton (CAMH) medium, supplemented with OADC or ADC." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "12B radiometric medium. Some authors consider the same MICs for the BACTEC MGIT 960 and VersaTREK media." ] ] ] "descripcion" => array:1 [ "en" => "Interpretation criteria for susceptibility testing of the M. avium complex via broth microdilution." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antimicrobial \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC (μg/ml)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Susceptible \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">Intermediate \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">Resistant \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">Amikacin<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥64 \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">Cefoxitin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32–64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥128 \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">Ciprofloxacin/levofloxacin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Moxifloxacin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clarithromycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥8 \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">Doxycycline/minocycline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2–8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥16 \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">Imipenem \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Co-trimoxazole<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤2/38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥4/76 \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">Tobramycin<a class="elsevierStyleCrossRef" href="#tblfn0030">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≤4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥16 \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="char" valign="top">≤8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">≥32 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1586949.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "If the isolate is a strain of M. abscessus and the MIC is ≥64μg/ml, it must be repeated to confirm." ] 1 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "b" "nota" => "MIC defined by an 80% inhibition in growth control." ] 2 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "c" "nota" => "Only report in M. chelonae." ] ] ] "descripcion" => array:1 [ "en" => "Interpretation criteria for susceptibility testing of rapid-growing mycobacteria via broth microdilution." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AG, aminoglycosides; BD, bedaquiline; E, ethambutol; FQ, fluoroquinolones; H, isoniazid; LPA, line probe assay; N/A, not available; PCR, polymerase chain reaction; PZ, pyrazinamide; R, rifampicin; RT-PCR, real-time PCR.Modified from Tuberculosis Diagnostics Technology and Market Landscape, UNITAID WHO 2015." "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">Test \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">Brand \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">Method \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">Detection \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">Year \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">TB Resistance INH/RIF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \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">TB Resistance FLQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \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">TB Resistance AMG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \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">BioFilmChip MDR TB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autogenomics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, microarray \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2011 \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">Drug Resistance Detection Kit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CapitalBio Co \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, microarray \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MDR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \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">Xpert MTB/RIF assay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cepheid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \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">NTM/MDR TB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NIPRO Co \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NIPRO Co \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">PZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NIPRO Co \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PZ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">FLQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NIPRO Co \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">Anyplex II MTB/MDR/XDR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Seegene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R, FQ, AG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">Anyplex MTB/MDR/XDR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Seegene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">VereMTB Detection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Veredus Labs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, microarray \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">MeltPro RIF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zeesan Biotech \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \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">MeltPro INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zeesan Biotech \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \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">MeltPro FLQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zeesan Biotech \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \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">MeltPro AMG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zeesan Biotech \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \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">Genedrive Mycobact iD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Epistem \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RT-PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \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">INNO-LiPA Rif.TB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INNO Genetics/Fujirebio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/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">GenoType MTBDRplus v2.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hain Lifescience \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">GenoType MTBDRsl v1.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hain Lifescience \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AG, FQ, E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \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">GenoType MTBDRsl v2.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hain Lifescience \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, LPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AG, FQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \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">iC2.0-MYC assay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">iCubate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, microarray \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R, E, FQ, AG, BD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \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">HYDRA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Insilixa Inc. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR, microarray \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">H, R, PZ, E, FQ, AG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2015 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1586946.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Marketed methods for the detection of resistant mutations to antituberculosis drugs." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:27 [ 0 => array:3 [ "identificador" => "bib0140" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: www.who.int/tb/publications/global_report/en/ [accessed 10.05.16]" "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "World Health Organization Global Tuberculosis Report 2015. WHO/HTM/TB/2015.22" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2015" "editorial" => "WHO Press" "editorialLocalizacion" => "Geneva" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0145" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B.A. Brown-Elliott" 1 => "K.A. Nash" 2 => "R.J. 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Methods for determining the antimicrobial susceptibility of mycobacteria

Métodos de determinación de sensibilidad a los antimicrobianos en micobacterias

Fernando Alcaidea,

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falcaide@bellvitgehospital.cat

Corresponding author.

, Jaime Estebanb, Julià González-Martinc, Juan-José Palaciosd

a Servicio de Microbiología, Hospital Universitari de Bellvitge, Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, GEIM (SEIMC), Hospitalet de Llobregat, Barcelona, Spain

b Departamento de Microbiología Clínica, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid (UAM), GEIM (SEIMC), Madrid, Spain

c Servei de Microbiologia-CDB, Hospital Clínic-ISGLOBAL, Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, GEIM (SEIMC), Barcelona, Spain

d Unidad de Referencia Regional de Micobacterias, Servicio de Microbiología, Hospital Universitario Central de Asturias, GEIM (SEIMC), Oviedo, Asturias, Spain

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In cases of resistance&#44; allergy&#44; intolerance&#44; hepatic toxicity or interaction with one or more of these drugs&#44; second-line drugs should be used&#44; including rifamycins &#40;rifabutin&#44; rifapentine&#41;&#44; quinolones &#40;ofloxacin&#44; levofloxacin&#44; moxifloxacin&#41;&#44; aminoglycosides &#40;amikacin&#44; tobramycin&#41;&#44; capreomycin&#44; cycloserine&#44; linezolid&#44; isoniazid analogues &#40;ethionamide&#44; prothionamide&#41;&#44; clofazimine&#44; PAS or thiacetazone&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5&#8211;7</span></a> In cases of MDR-TB or XDR-TB&#44; recently developed drugs may also be used&#44; such as bedaquiline and&#47;or delamanid&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Drugs used against nontuberculous mycobacteria</span><p id="par0025" class="elsevierStylePara elsevierViewall">The treatment of NTM&#44; 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with the exception of <span class="elsevierStyleItalic">Mycobacterium fortuitum</span>&#44; which is resistant&#44; as well as 80&#8211;85&#37; of <span class="elsevierStyleItalic">Mycobacterium abscessus</span> isolates&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;9</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Drug susceptibility testing in <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex</span><p id="par0030" class="elsevierStylePara elsevierViewall">The history of susceptibility testing for the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex arose parallel to the development of specific pharmacological treatment for TB&#44; which began with the discovery of streptomycin in 1944&#46; From the beginning&#44; it was observed that monotherapy achieved an initial clinical improvement followed by a relapse of the disease&#46; This phenomenon&#44; known as &#8216;fall and rise&#8217;&#44; was due to the selection of resistant bacteria&#46; In 2000&#44; the WHO defined resistance in various categories from an epidemiological point of view&#58; &#40;a&#41; <span class="elsevierStyleItalic">Resistance in new cases</span>&#58; strains isolated in patients who have never received antituberculosis treatment for more than one month&#46; &#40;b&#41; <span class="elsevierStyleItalic">Resistance in treated cases</span>&#58; strains isolated in patients who have previously received antituberculosis treatment for more than one month&#46; &#40;c&#41; <span class="elsevierStyleItalic">Multidrug resistance</span> &#40;MDR-TB&#41;&#58; joint resistance to at least isoniazid and rifampicin&#46; &#40;d&#41; <span class="elsevierStyleItalic">Poly-resistance</span>&#58; resistance to more than one drug not including isoniazid and rifampicin at the same time&#46; &#40;e&#41; <span class="elsevierStyleItalic">Combined resistance</span>&#58; sum of all resistance types in a specific area&#46; This indicates the resistant strain load in a community&#46; In 2006&#44; the category of <span class="elsevierStyleItalic">Extended resistance</span> &#40;XDR-TB&#41; was added&#44; which was mentioned in the introduction&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The definitive confirmation of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex drug resistance must always be conducted using microbiological methods&#46; In studies in the 1960s by Canetti et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> the frequency of spontaneous mutations associated with each drug was established&#46; In the case of isoniazid&#44; ethambutol and streptomycin&#44; a resistant mutant appeared in one out of 10<span class="elsevierStyleSup">&#8722;5</span>&#8211;10<span class="elsevierStyleSup">&#8722;7</span> bacteria&#44; for rifampicin in one out of 10<span class="elsevierStyleSup">&#8722;7</span>&#8211;10<span class="elsevierStyleSup">&#8722;9</span> and for pyrazinamide in one out of 10<span class="elsevierStyleSup">&#8722;2</span>&#8211;10<span class="elsevierStyleSup">&#8722;4</span>&#46; The theoretical frequency of mutants resistant to more than one drug would be the exponential sum of the individual mutants resistant to each drug&#46; The bacterial populations present in the lesions were also estimated&#46; Thus&#44; small infiltrates had populations of 10<span class="elsevierStyleSup">3</span>&#8211;10<span class="elsevierStyleSup">5</span> bacteria&#44; and cavities could reach 10<span class="elsevierStyleSup">7</span>&#8211;10<span class="elsevierStyleSup">9</span> bacteria which makes it very improbable that simultaneous mutations to more than one drug would occur spontaneously&#46; TB is deemed resistant when 1&#37; or more of the bacterial population is resistant to a certain drug&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">critical concentrations</span> of the different drugs were established by international consensus and represent the lowest concentrations that inhibit the growth of &#8220;wild strains&#8221; &#40;susceptible strains&#41; of the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex that have never been exposed to said drugs&#44; while not inhibiting the strains from patients that do not respond to treatment&#44; considered resistant&#46; They were initially postulated for the L&#246;wenstein&#8211;Jensen medium&#44; and later equivalencies were established for Middlebrook 7H10 and 7H11 agar media&#44; as well as for automated liquid media culture systems&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In vitro</span> susceptibility testing in <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex must be performed on the first isolate obtained from a new patient&#44; in cases of suspected therapeutic failure and before the disease relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">7&#44;11&#8211;13</span></a> Also&#44; when the TB simultaneously affects more than one organ&#44; the tests must be done individually for each location&#44; without assuming that the results will always coincide&#46; All first-line drugs should be included &#40;isoniazid&#44; rifampicin&#44; pyrazinamide&#44; ethambutol and streptomycin&#41;&#44; since they provide information about the therapeutic scheme currently recommended for most patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">7&#44;11&#8211;14</span></a> Traditional second-line drugs &#40;amikacin&#44; capreomycin&#44; clofazimine&#44; cycloserine&#44; ethionamide&#44; kanamycin and PAS&#41; and new ones&#44; such as fluoroquinolones &#40;ciprofloxacin&#44; levofloxacin&#44; moxifloxacin&#41;&#44; linezolid&#44; and&#44; in certain cases&#44; rifabutin&#44; must be evaluated whenever&#58; &#40;a&#41; a strain is resistant to isoniazid&#44; rifampicin&#44; ethambutol or pyrazinamide&#59; &#40;b&#41; when mutations in genes that encode resistance to isoniazid and&#47;or rifampicin are detected using molecular techniques&#59; and &#40;c&#41; when clinical-epidemiological information is available that recommends doing so&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#8211;15</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Solid culture media-based methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">absolute concentrations</span> method&#44; described by Meissner&#44; is based on the comparison of the number of colonies in the presence of the drug to the number of colonies in the culture medium without the drug&#46; The results are affected by the size of the inoculum and by the precision in the definition of the critical concentration of each drug&#46; The <span class="elsevierStyleItalic">resistance ratio</span> method&#44; described by Mitchison&#44; compares the minimum inhibitory concentration &#40;MIC&#41; of a specific strain to that of a reference strain&#46; The results depend on the adequate standardisation of the drugs and the inoculum&#44; although the critical concentrations do not need to be defined&#46; The <span class="elsevierStyleItalic">multiple proportion</span> method&#44; described by Canetti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> in 1963&#44; shows the proportion of resistant bacilli present in a culture&#46; Micro-organism resistance is considered clinically significant when the resistant bacterial population exceeds 1&#37;&#46; This is the most precise method and the one that produces fewest false results&#44; which is why it is the most widely used worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">7&#44;11&#44;13&#44;16</span></a> The <span class="elsevierStyleItalic">epsilometer</span> &#40;E-test&#41; method is based on a gradient of antimicrobial diffusion combining the principles of disc diffusion and agar dilution in the study of <span class="elsevierStyleItalic">in vitro</span> susceptibility&#46; It is a quantitative technique to determine the MIC of antimicrobials&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Liquid culture media-based methods</span><p id="par0055" class="elsevierStylePara elsevierViewall">There are currently two nonradiometric systems for susceptibility testing&#58; BACTEC&#8482; MGIT&#8482; 960 &#40;Becton-Dickinson Diagnostics&#44; Sparks&#44; MD&#44; USA&#41; and VersaTREK<span class="elsevierStyleSup">&#174;</span> &#40;Thermo Scientific&#44; Westlake&#44; OH&#44; USA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">7&#44;11&#44;13&#44;18</span></a> Both use supplemented Middlebrook 7H9 medium&#44; and the growth is shown <span class="elsevierStyleItalic">via</span> detection of the consumption&#47;production of certain gases&#46; The initial and secondary critical concentrations that are analysed come predetermined by the manufacturer for first-line drugs&#46; Although the detection of MDR-TB does not usually pose any problems&#44; there are some inter-laboratory discrepancies with streptomycin&#44; ethambutol and pyrazinamide&#46; In the case of pyrazinamide&#44; since it is active in acidic media &#40;pH 5&#46;5&#41;&#44; the pH of the culture medium must match these conditions&#44; despite the fact that approximately 10&#37; of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> isolates do not grow well at this pH&#46; On the other hand&#44; it is also possible to analyse critical concentrations of other second-line drugs if the assessed substance is available&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Alternative susceptibility methods</span><p id="par0060" class="elsevierStylePara elsevierViewall">In <span class="elsevierStyleItalic">mycobacteriophage</span>-based techniques&#44; when adding the phages to a culture in the presence of an antibiotic&#44; the phages will only infect the viable mycobacteria&#44; which are the resistant ones&#46; These have been applied in isoniazid and rifampicin susceptibility tests&#44; but they present problems with susceptibility&#44; specificity and a high rate of contamination&#46; <span class="elsevierStyleItalic">Flow cytometry</span>&#44; using cell permeable nucleic acid stains&#44; shows viable mycobacteria &#40;the control mycobacteria and the drug-resistant ones&#41; with higher levels of fluorescence compared to the non-viable ones &#40;drug-susceptible&#41;&#46; One of the drawbacks is the high cost of the equipment&#46; <span class="elsevierStyleItalic">Broth microdilution</span> &#40;Mycotb Sensititre<span class="elsevierStyleSup">&#174;</span> Thermo Scientific&#41; allows for the MIC of multiple drugs to be determined&#46; The greatest difficulty lies in reading and interpreting the results&#44; since the growth of these bacteria is not homogeneous&#46; The <span class="elsevierStyleItalic">nitrate reductase test</span> is based on the capacity of the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex to reduce nitrates to nitrites&#46; Tubes of L&#246;wenstein&#8211;Jensen medium incorporating KNO<span class="elsevierStyleInf">3</span>&#44; with and without drugs&#44; are used for this purpose&#46; <span class="elsevierStyleItalic">Microscopic-observation drug-susceptibility</span> &#40;MODS&#41; is based on the early detection of the cord factor exhibited by the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex&#44; with the help of an inverted microscope&#46; <span class="elsevierStyleItalic">Resazurin microtiter assay</span> &#40;REMA&#41; is an indirect method based on the detection of colour changes in the culture medium due to oxidation &#40;blue&#41; and reduction &#40;pink&#41; of resazurin&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The WHO considers that nitrite reductase&#44; MODS and REMA are simple&#44; cheap techniques that can be used for rapid screening for resistance to isoniazid and rifampicin in countries with limited resources&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">11&#44;13&#44;19</span></a> Susceptibility and specificity data exceed 95&#37;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Antimicrobial susceptibility testing in nontuberculous mycobacteria</span><p id="par0070" class="elsevierStylePara elsevierViewall">Although more than 160 species of NTM have been reported&#44; susceptibility testing is only recommended in clinically-significant isolates for which a correlation has been shown between <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> results&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;13</span></a> Thus&#44; the Clinical and Laboratory Standards Institute &#40;CLSI&#41; establishes recommendations only for the group comprising <span class="elsevierStyleItalic">Mycobacterium avium</span> complex&#44; <span class="elsevierStyleItalic">M&#46; kansasii&#44; Mycobacterium marinum</span> and non-pigmented rapidly growing mycobacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Susceptibility testing in slow-growing nontuberculous mycobacteria</span><p id="par0075" class="elsevierStylePara elsevierViewall">In general&#44; the methodology of choice that CLSI recommends is microdilution in cation-adjusted Mueller Hinton &#40;CAMH&#41; broth&#44; supplemented with OADC or ADC&#46; However&#44; in some cases there are alternatives to this methodology&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Recommendations for <span class="elsevierStyleItalic">M&#46; avium</span> complex</span><p id="par0080" class="elsevierStylePara elsevierViewall">The treatment of <span class="elsevierStyleItalic">M&#46; avium</span> complex &#40;MAC&#41; is based on the use of clarithromycin as an essential or primary drug&#44; and ethambutol and rifampicin &#40;or rifabutin&#41; as adjunct therapies&#44; although there are data showing that other antibiotics &#40;amikacin&#44; linezolid and moxifloxacin&#41; could be useful in some cases&#46; Given that a clinical correlation has only been demonstrated with <span class="elsevierStyleItalic">in vitro</span> tests for macrolides&#44; the CLSI recommends that only these drugs be tested&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a> However&#44; when resistance to clarithromycin is present&#44; it is reasonable to test other drugs &#40;moxifloxacin&#44; linezolid and aminoglycosides&#41;&#46; Clarithromycin&#39;s activity is very sensitive to the culture medium and its pH&#44; therefore the MICs used generally as cut-off points correspond to a CAMH medium at a slightly basic pH of 7&#46;3&#8211;7&#46;4&#46; Another method that can be used is macrodilution using the BACTEC&#8482;&#44; MGIT&#8482; 960 and VersaTREK<span class="elsevierStyleSup">&#174;</span> systems&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;13</span></a> There is currently a commercial microdilution technique in microtitration plates &#40;Slomyco&#44; Sensititre<span class="elsevierStyleSup">&#174;</span>&#44; Thermo Scientific&#41;&#44; that allows for simple&#44; reproducible <span class="elsevierStyleItalic">in vitro</span> susceptibility testing with a standard incubation of 7 days&#46; Although it includes 13 antimicrobials with multiple concentrations&#44; it is important to maintain the previously stated interpretation criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Recommendations for <span class="elsevierStyleItalic">M&#46; kansasii</span></span><p id="par0085" class="elsevierStylePara elsevierViewall">Standard treatments for infections caused by this mycobacteria include rifampicin &#40;or rifabutin&#41;&#44; isoniazid&#44; and a third drug &#40;ethambutol or streptomycin&#41; for 18 months &#40;at least 12 months of negative cultures&#41;&#46; In cases of possible resistance&#44; susceptibility should be conducted <span class="elsevierStyleItalic">in vitro</span> for these and other potentially-active antimicrobials &#40;clarithromycin&#44; moxifloxacin or levofloxacin&#44; amikacin&#44; linezolid and rifabutin&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;7&#44;13</span></a> One aspect to highlight is that <span class="elsevierStyleItalic">M&#46; kansasii</span> naturally presents a somewhat decreased susceptibility to isoniazid in comparison with <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; although it has clinical activity&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The recommended method is microdilution&#44; although the proportion method in Middlebrook 7H10 agar and automated nonradiometric systems have been used&#46; As mentioned previously in MAC&#44; there is currently a commercial microdilution technique that&#44; although it includes multiple antimicrobials with diverse concentrations&#44; it is important to follow the current interpretation criteria &#40;CLSI&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recommendations for <span class="elsevierStyleItalic">M&#46; marinum</span></span><p id="par0095" class="elsevierStylePara elsevierViewall">Antimicrobial susceptibility testing is currently only recommended for this species when there is a clinical and microbiological failure&#44; using the broth microdilution method at 28&#8211;30<span class="elsevierStyleHsp" style=""></span>&#176;C for 7 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;7&#44;13</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Other slow-growing nontuberculous mycobacteria</span><p id="par0100" class="elsevierStylePara elsevierViewall">Generally&#44; it is recommended to perform <span class="elsevierStyleItalic">in vitro</span> susceptibility testing using broth microdilution with the same drugs and the same concentrations as for <span class="elsevierStyleItalic">M&#46; kansasii</span> for all species with good growth &#40;non-deficient&#41; and in those in which therapeutic failure and persistent positive cultures are detected&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Susceptibility testing in rapid-growing nontuberculous mycobacteria</span><p id="par0105" class="elsevierStylePara elsevierViewall">Treatment for these micro-organisms is usually conducted with drugs against which the remaining species are resistant or&#44; at least&#44; have a lesser susceptibility&#46; Due to all of this&#44; <span class="elsevierStyleItalic">in vitro</span> susceptibility tests have certain differentiating features from the rest of the mycobacteria&#46; The recommended technique is broth microdilution with an incubation of 3&#8211;4 days at 30<span class="elsevierStyleHsp" style=""></span>&#176;C &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3&#44;7&#44;13</span></a> Other methods present interpretation problems and should not be used&#46; We must keep in mind the possible presence of inducible <span class="elsevierStyleItalic">erm</span> methylases&#46; Therefore&#44; reincubating the plates for up to 14 days and assessing the increase of the macrolides&#8217; MIC is recommended to detect this phenomenon&#46; There is currently a commercial microdilution technique designed specifically for rapid-growing mycobacteria and aerobic actinomycetes &#40;Rapmyco&#44; Sensititre<span class="elsevierStyleSup">&#174;</span>&#44; Thermo Scientific&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Mycobacteria resistance mechanisms</span><p id="par0110" class="elsevierStylePara elsevierViewall">Antibacterial resistance is mainly due to chromosomal mutations in genes that encode their target or the activating enzymes&#46; They can be spontaneous or drug-induced after exposure to monotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3&#44;20&#44;21</span></a></p><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Isoniazid</span><p id="par0115" class="elsevierStylePara elsevierViewall">Resistance is associated above all with mutations in 2 genes &#40;68&#8211;90&#37;&#41;&#58; &#40;a&#41; the <span class="elsevierStyleItalic">katG</span> gene&#44; that is responsible for activating the drug&#59; the most common mutation affects codon 315 and is related to high-level resistance &#40;60&#8211;70&#37; of resistance&#41;&#44; and &#40;b&#41; the <span class="elsevierStyleItalic">inhA</span> gene&#44; which intervenes in the synthesis of the bacterial wall&#46; Mutations &#40;8&#8211;20&#37;&#41; cause low-level and cross-resistance with ethionamide&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#44;20&#44;21</span></a> NTM&#44; except for <span class="elsevierStyleItalic">M&#46; kansasii</span> and <span class="elsevierStyleItalic">M&#46; xenopi</span> are resistant due to incapacity of activation of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3&#44;13</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Rifampicin and other rifamycins</span><p id="par0130" class="elsevierStylePara elsevierViewall">Resistance to the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex is related to mutations in the <span class="elsevierStyleItalic">rpoB</span> gene &#40;&#62;95&#37;&#41;&#44; involved in protein synthesis&#46; Codons 526 and 531 are the most affected and confer high-level and cross-resistance with other rifamycins&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#44;20&#44;21</span></a> Mutations in some codons will maintain susceptibility to rifabutin&#46; Similar mutations in NTM have been described&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Aminoglycosides and capreomycin</span><p id="par0145" class="elsevierStylePara elsevierViewall">Resistance is based on ribosomal mutations involved in protein synthesis&#46; Resistance to streptomycin is associated with mutations &#40;50&#8211;60&#37;&#41; in the <span class="elsevierStyleItalic">rpsL</span> and <span class="elsevierStyleItalic">rrs</span> genes &#40;codons 530&#8211;912&#41;&#44; while resistance to amikacin&#44; kanamycin&#44; and capreomycin is associated with mutations in the <span class="elsevierStyleItalic">rrs</span> gene &#40;codons 1400&#8211;1500&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#44;20&#44;21</span></a> There is partial cross-resistance between them&#44; with isolated resistance to streptomycin that may be susceptible to the others&#46; The <span class="elsevierStyleItalic">tlyA</span> gene has been linked to resistance to capreomycin and the <span class="elsevierStyleItalic">eis</span> gene has been linked to resistance to kanamycin&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethambutol</span><p id="par0160" class="elsevierStylePara elsevierViewall">Resistance is related to mutations in the <span class="elsevierStyleItalic">embB</span> gene&#44; which is involved in bacterial wall synthesis&#46; The majority &#40;60&#8211;80&#37;&#41; have been described in codons 306 and 406&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#44;20&#44;21</span></a> Some species of NTM have natural resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Pyrazinamide</span><p id="par0175" class="elsevierStylePara elsevierViewall">Resistance is associated with mutations throughout the <span class="elsevierStyleItalic">pncA</span> gene &#40;72&#8211;97&#37;&#41; that regulates drug activation&#46; <span class="elsevierStyleItalic">Mycobacterium bovis</span> and its BGC variant&#44; as well as NTM&#44; have natural resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3&#44;13&#44;20&#44;21</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Fluoroquinolones</span><p id="par0190" class="elsevierStylePara elsevierViewall">The most frequent mechanism is mutations in the <span class="elsevierStyleItalic">gyrA</span> gene &#40;85&#37;&#41; and the <span class="elsevierStyleItalic">gyrB</span> gene &#40;10&#37;&#41;&#46; There is cross-resistance between fluoroquinolones&#44; but not full resistance&#44; depending on the affected codons&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3&#44;13&#44;20&#44;21</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Macrolides and ketolides</span><p id="par0205" class="elsevierStylePara elsevierViewall">Resistance is linked to mutations in the 23S ribosomal gene and&#44; above all&#44; to inducible methylases regulated by the <span class="elsevierStyleItalic">erm</span> gene&#46; These are observed in species such as <span class="elsevierStyleItalic">M&#46; fortuitum</span> and <span class="elsevierStyleItalic">M&#46; abscessus</span> subsp&#46; <span class="elsevierStyleItalic">abscessus</span> and subsp&#46; <span class="elsevierStyleItalic">bolletii&#46;</span><a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Beta-lactams</span><p id="par0220" class="elsevierStylePara elsevierViewall">Resistance is associated with a decrease in the permeability and affinity of the PBPs and&#44; mainly&#44; to beta-lactamases&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Tetracyclines and glycylglycines</span><p id="par0235" class="elsevierStylePara elsevierViewall">Resistance to tetracyclines is due to ribosomal protection proteins or efflux pumps&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#44;3</span></a> To date&#44; resistance to tigecycline has not been demonstrated&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Oxazolidinones</span><p id="par0250" class="elsevierStylePara elsevierViewall">The resistance of mycobacteria to linezolid is associated with mutations in the rRNA 23S gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#44;20</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Co-trimoxazole</span><p id="par0265" class="elsevierStylePara elsevierViewall">The resistance mechanism is not clear in mycobacteria&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Bedaquiline and delamanid</span><p id="par0280" class="elsevierStylePara elsevierViewall">The resistance to bedaquiline has been associated with a mutation in the <span class="elsevierStyleItalic">mmpR</span> gene and the resistance to delamanid has been associated with the <span class="elsevierStyleItalic">fbiA</span> and <span class="elsevierStyleItalic">fgd1</span> genes&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a></p></span></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Molecular detection of resistances</span><p id="par0290" class="elsevierStylePara elsevierViewall">The reference method for determining resistance to antituberculosis drugs is the conventional phenotypic susceptibility test&#44; although the results tend to take several weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">7&#44;11&#44;13</span></a> Molecular detection of resistance&#44; based on showing chromosomal mutations&#44; offers quick and useful results&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">21&#44;23</span></a> Commercial techniques are those which are most widely used due to their greater standardisation &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The most used are Xpert<span class="elsevierStyleSup">&#174;</span> MTB&#47;RIF Assay &#40;Cepheid&#44; Sunnyvale&#44; CA&#44; USA&#41; and GenoType<span class="elsevierStyleSup">&#174;</span> MTBDR<span class="elsevierStyleItalic">plus</span> &#40;Hain Lifescience&#44; Nehren&#44; Germany&#41;&#44; both approved by the WHO for the rapid diagnosis of MDR-TB&#46; Xpert<span class="elsevierStyleSup">&#174;</span> MTB&#47;RIF allows for diagnosis of the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex and the detection of mutations resistant to rifampicin in &#60;2<span class="elsevierStyleHsp" style=""></span>h&#44; with minimal manipulation&#44; limited to inserting the sample into a cartridge where the entire amplification and detection process is performed&#46; The system uses five fluorescent probes covering the natural sequence of the 81<span class="elsevierStyleHsp" style=""></span>pb region of the <span class="elsevierStyleItalic">rpoB</span> gene where more than 95&#37; of resistances to rifampicin occur&#46; For the diagnosis of pulmonary and extrapulmonary TB&#44; susceptibility is 95&#8211;98&#37; in samples with positive microscopy and 67&#8211;69&#37; with negative microscopy&#44; taking the culture as reference&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a> The specificity is 99&#37;&#46; In synthesis&#44; Xpert MTB&#47;RIF<span class="elsevierStyleSup">&#174;</span> provides 23&#37; more positive cases than microscopy&#46; Its greatest drawbacks are that it only detects resistance to rifampicin and its financial cost&#44; although for countries with limited resources&#44; the cost is 6&#8211;7 times lower &#40;less than &#8364;10&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a> The GenoType<span class="elsevierStyleSup">&#174;</span> MTBDR<span class="elsevierStyleItalic">plus</span> is based on amplification and reverse hybridisation on nitrocellulose strips that contain immobilised probes corresponding to natural sequences and sequences of the most frequent mutations in the <span class="elsevierStyleItalic">rpoB</span> &#40;rifampicin&#41; and <span class="elsevierStyleItalic">katG</span> and <span class="elsevierStyleItalic">inhA</span> &#40;isoniazid&#41; genes&#46; Currently&#44; it can be used based on cultures or clinical samples&#44; even with negative bacilloscopy&#46; Various meta-analyses establish a global susceptibility of 98&#37; for resistance to rifampicin and 84&#46;3&#37; for isoniazid&#44; with 98&#8211;99&#46;5&#37; specificity&#46; Samples with negative microscopy can have 5&#8211;12&#37; invalid results due to low susceptibility&#46; Results that are not interpretable due to the simultaneous absence of natural and mutated bands in the same <span class="elsevierStyleItalic">locus</span>&#44; due to mutations not contained in the kit have been reported&#46; Another possibility is a discrepant result with the sensitive genotype and resistant phenotype&#44; due to mechanisms other than those detected by the commercial product&#46; The resistant genotype and sensitive phenotype option would be caused by the coexistence of mixed or heteroresistant populations or low-level resistances&#44; that have been described in 4&#8211;13&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a> At least 50&#37; of patients with MDR-TB are resistant to other drugs&#46; Tests have also been marketed to detect mutations of resistance to second-line drugs&#46; The most well-known product is GenoType<span class="elsevierStyleSup">&#174;</span> MTBDR<span class="elsevierStyleItalic">sl</span> &#40;Hain Lifescience&#41;&#46; Two versions exist&#58; v1&#46;0 and v2&#46;0&#46; The first is directed at mutations of resistance to capreomycin and the aminoglycosides amikacin and kanamycin in the <span class="elsevierStyleItalic">rrs</span> gene &#40;codons 1401 and 1484&#41;&#44; as well as to fluoroquinolones in the <span class="elsevierStyleItalic">gyrA</span> gene &#40;codons 90&#44; 91 and 94&#41;&#44; and to ethambutol in the <span class="elsevierStyleItalic">embB</span> gene &#40;codon 306&#41;&#46; A recent analysis observed good susceptibility to fluoroquinolones &#40;83&#8211;85&#37;&#41;&#44; but lower susceptibility to aminoglycosides &#40;77&#37;&#41;&#44; attributable to kanamycin &#40;69&#46;9&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a> Version v2&#46;0 seeks to improve yield including the <span class="elsevierStyleItalic">gyrB</span> gene for fluoroquinolones and the <span class="elsevierStyleItalic">eis</span> gene for kanamycin&#44; suppressing the ethambutol of the kit&#46; It has recently been evaluated with a susceptibility of 96&#37; to kanamycin&#46; However&#44; a decrease in specificity for injectables &#40;91&#37;&#41; has also been observed&#44; due to the detection of mutations of still unknown significance in the <span class="elsevierStyleItalic">eis</span> gene in some susceptible strains&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> Aside from the above&#44; the following products are also being distributed to a certain extent&#58; INNO-Lipa<span class="elsevierStyleSup">&#174;</span> RifTB &#40;INNO Genetics&#44; Gent&#44; Belgium&#47;Fujirebio&#44; Tokyo&#44; Japan&#41;&#44; Anyplex II&#8482; MTB&#47;MDR&#47;XDR &#40;Seegene&#44; Seoul&#44; Korea&#41; and the TB Resistance<span class="elsevierStyleSup">&#174;</span> Assay &#40;AID&#59; Autoimmun Diagnostika&#44; Strassberg&#44; Germany&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">18&#44;21&#44;23</span></a> Although not discounting phenotypic susceptibility tests&#44; the main use of molecular resistance detection methods&#44; in our environment&#44; is to quickly confirm or rule out&#44; and to a greater or lesser extent&#44; based on the drugs&#44; resistance in cases of high suspicion&#46; Recently&#44; a method has been marketed &#40;GenoType<span class="elsevierStyleSup">&#174;</span> NTM-DR&#44; Hain Lifescience&#41; that&#44; in addition to identifying some NTM species&#44; allows detection of the <span class="elsevierStyleItalic">erm</span> gene in <span class="elsevierStyleItalic">M&#46; abscessus</span>&#44; and of the mutations in the <span class="elsevierStyleItalic">rrs</span> &#40;aminoglycosides&#41; and&#47;or <span class="elsevierStyleItalic">rrl</span> &#40;macrolides&#41; genes&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of interest</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors have declared that they have no conflicts of interest&#46;</p></span></span>"
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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" => "Antimicrobials"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Drugs used against the M&#46; tuberculosis complex"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Drugs used against nontuberculous mycobacteria"
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        6 => array:3 [
          "identificador" => "sec0025"
          "titulo" => "Drug susceptibility testing in M&#46; tuberculosis complex"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Solid culture media-based methods"
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              "identificador" => "sec0035"
              "titulo" => "Liquid culture media-based methods"
            ]
            2 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Alternative susceptibility methods"
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          ]
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        7 => array:3 [
          "identificador" => "sec0045"
          "titulo" => "Antimicrobial susceptibility testing in nontuberculous mycobacteria"
          "secciones" => array:2 [
            0 => array:3 [
              "identificador" => "sec0050"
              "titulo" => "Susceptibility testing in slow-growing nontuberculous mycobacteria"
              "secciones" => array:4 [
                0 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Recommendations for M&#46; avium complex"
                ]
                1 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Recommendations for M&#46; kansasii"
                ]
                2 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Recommendations for M&#46; marinum"
                ]
                3 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Other slow-growing nontuberculous mycobacteria"
                ]
              ]
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            1 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Susceptibility testing in rapid-growing nontuberculous mycobacteria"
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        8 => array:3 [
          "identificador" => "sec0080"
          "titulo" => "Mycobacteria resistance mechanisms"
          "secciones" => array:12 [
            0 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Isoniazid"
            ]
            1 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Rifampicin and other rifamycins"
            ]
            2 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Aminoglycosides and capreomycin"
            ]
            3 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Ethambutol"
            ]
            4 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Pyrazinamide"
            ]
            5 => array:2 [
              "identificador" => "sec0110"
              "titulo" => "Fluoroquinolones"
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            6 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Macrolides and ketolides"
            ]
            7 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Beta-lactams"
            ]
            8 => array:2 [
              "identificador" => "sec0125"
              "titulo" => "Tetracyclines and glycylglycines"
            ]
            9 => array:2 [
              "identificador" => "sec0130"
              "titulo" => "Oxazolidinones"
            ]
            10 => array:2 [
              "identificador" => "sec0135"
              "titulo" => "Co-trimoxazole"
            ]
            11 => array:2 [
              "identificador" => "sec0140"
              "titulo" => "Bedaquiline and delamanid"
            ]
          ]
        ]
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          "identificador" => "sec0145"
          "titulo" => "Molecular detection of resistances"
        ]
        10 => array:2 [
          "identificador" => "sec0150"
          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "tienePdf" => true
    "fechaRecibido" => "2016-04-06"
    "fechaAceptado" => "2016-04-07"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec912118"
          "palabras" => array:3 [
            0 => "Mycobacteria"
            1 => "Susceptibility testing"
            2 => "Resistance mechanisms"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec912117"
          "palabras" => array:3 [
            0 => "Micobacterias"
            1 => "Prueba de sensibilidad"
            2 => "Mecanismos de resistencia"
          ]
        ]
      ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mycobacteria are a large group of microorganisms&#44; multiple species of which are major causes of morbidity and mortality&#44; such as tuberculosis and leprosy&#46; At present&#44; the emergence and spread of multidrug-resistant strains of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> complex are one of the most serious health problems worldwide&#46; Furthermore&#44; in contrast to <span class="elsevierStyleItalic">M&#46; tuberculosis</span> and <span class="elsevierStyleItalic">Mycobacterium leprae</span>&#44; non-tuberculous mycobacteria &#40;NTM&#41; are more frequently isolated and&#44; in many cases&#44; treatment is based on drug susceptibility testing&#46; This article is a review of the different methods to determine the <span class="elsevierStyleItalic">in vitro</span> drug susceptibility of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex and the most relevant NTM isolates&#46; The molecular techniques currently used for rapid detection of resistance of clinical specimens are also analysed&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las micobacterias son un amplio grupo de microorganismos en el que m&#250;ltiples especies son causa de una importante morbimortalidad&#44; como la tuberculosis y la lepra&#46; La aparici&#243;n y diseminaci&#243;n de cepas del complejo <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> resistentes a diversos f&#225;rmacos constituye en la actualidad uno de los problemas sanitarios de mayor gravedad a nivel mundial&#46; Por otro lado&#44; las micobacterias diferentes de <span class="elsevierStyleItalic">M&#46; tuberculosis</span> y <span class="elsevierStyleItalic">Mycobacterium leprae</span>&#44; denominadas micobacterias no tuberculosas &#40;MNT&#41;&#44; son aislamientos cada vez m&#225;s frecuentes&#44; requiriendo en muchos casos un tratamiento que precisa una orientaci&#243;n sobre la sensibilidad de estos microorganismos a los antimicrobianos&#46; En el presente art&#237;culo se revisan los m&#233;todos para determinar la sensibilidad <span class="elsevierStyleItalic">in vitro</span> a los antimicobacterianos de los aislamientos del complejo <span class="elsevierStyleItalic">M&#46; tuberculosis</span> y las MNT m&#225;s relevantes&#46; Adem&#225;s&#44; tambi&#233;n se realiza un an&#225;lisis de las t&#233;cnicas moleculares de detecci&#243;n r&#225;pida de la resistencia a partir de las muestras cl&#237;nicas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Alcaide F&#44; Esteban J&#44; Gonz&#225;lez-Martin J&#44; Palacios J-J&#46; M&#233;todos de determinaci&#243;n de sensibilidad a los antimicrobianos en micobacterias&#46; Enferm Infecc Microbiol Clin&#46; 2017&#59;35&#58;527&#8211;533&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">MAC&#44; <span class="elsevierStyleItalic">M&#46; avium</span> complex&#59; MDR&#44; multidrug-resistant tuberculosis&#59; MK&#44; <span class="elsevierStyleItalic">M&#46; kansasii</span>&#59; NTM&#44; nontuberculous mycobacteria&#59; MTC&#44; <span class="elsevierStyleItalic">M&#46; tuberculosis</span> complex&#59; MX&#44; <span class="elsevierStyleItalic">M&#46; xenopi</span>&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action&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">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">Action spectrum&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">Population&#8211;action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Inhibition of the wall synthesis</td><td class="td" title="table-entry  " align="left" valign="top">Isoniazid &#40;isonicotinic acid hydrazide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC&#44; MK&#44; MX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericide &#40;active growth&#41;&#44; bacteriostatic &#40;latent&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethionamide&#44; prothionamide and thiacetazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC&#44; variable in NTM &#40;MK and <span class="elsevierStyleItalic">M&#46; marinum</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatics&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">MTC&#44; various slow-growing NTM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&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">MTC&#44; with the exception of <span class="elsevierStyleItalic">M&#46; bovis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericide &#40;active and latent growth&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cycloserine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC &#40;use restricted to MDR&#41;&#44; variable in NTM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&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">Use restricted to MDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Inhibition of protein synthesis</td><td class="td" title="table-entry  " align="left" valign="top">Rifamycins &#40;rifampicin&#44; rifabutin&#44; rifapentine&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC&#44; MK&#44; MX&#44; 50&#37; in MAC&#44; variable in the rest of species&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericides in active and latent growth&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">Aminoglycosides &#40;streptomycin&#44; amikacin&#44; tobramycin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC and most NTM &#40;especially amikacin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericides&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">MTC &#40;use in MDR&#41;&#46; Variable for NTM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericide&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">MTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericide in active growth&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">Macrolides &#40;clarithromycin&#44; azithromycin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very effective in MAC&#46; Active in NTM&#44; except for <span class="elsevierStyleItalic">M&#46; fortuitum</span> and <span class="elsevierStyleItalic">M&#46; abscessus</span>&#46; Of little use in MTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatics&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">Tetracyclines and tigecycline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Variable in NTM&#46; Tigecycline more effective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Inhibits folic acid synthesis</td><td class="td" title="table-entry  " align="left" valign="top">Dapsone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">M&#46; leprae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PAS &#40;para-aminosalicylic acid&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC &#40;use in MDR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&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">Co-trimoxazole&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Variable in NTM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&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">Inhibits DNA synthesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fluoroquinolones &#40;ofloxacin&#44; levofloxacin&#44; moxifloxacin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTC&#44; NTM &#40;MAC group 50&#37;&#44; rest variable&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericides in active growth&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">Interferes in Fe metabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " 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">MTC&#44; variable in NTM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bactericide&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">Inhibits ATP synthase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " 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">Use restricted to MDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bacteriostatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanism and action spectrum of antimycobacterials&#46;</p>"
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        "etiqueta" => "Table 2"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antimicrobial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC &#40;&#956;g&#47;ml&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Susceptible&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">Intermediate&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">Resistant&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"><span class="elsevierStyleItalic">Amikacin</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><td class="td" title="table-entry  " align="char" valign="top">&#8804;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Clarithromycin</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Microdilution &#40;pH 7&#46;3&#8211;7&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;32&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>Radiometric &#40;pH 7&#46;3&#8211;7&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#8211;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;32&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>Radiometric &#40;pH 6&#46;8&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Moxifloxacin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Linezolid</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The MIC for amikacin is not defined&#46; Due to assimilation into other species&#44; it may be considered resistant &#62;32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46;</p>"
            ]
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              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Cation-adjusted Mueller Hinton &#40;CAMH&#41; medium&#44; supplemented with OADC or ADC&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">12B radiometric medium&#46; Some authors consider the same MICs for the BACTEC MGIT 960 and VersaTREK media&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antimicrobial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC &#40;&#956;g&#47;ml&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Susceptible&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">Intermediate&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">Resistant&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">Amikacin<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;64&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">Cefoxitin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&#8211;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;128&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">Ciprofloxacin&#47;levofloxacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="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="char" valign="top">&#8804;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clarithromycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;8&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">Doxycycline&#47;minocycline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#8211;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;16&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">Imipenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;16&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">Co-trimoxazole<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;2&#47;38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;4&#47;76&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">Tobramycin<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8804;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;16&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="char" valign="top">&#8804;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8805;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1586949.png"
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            0 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">If the isolate is a strain of <span class="elsevierStyleItalic">M&#46; abscessus</span> and the MIC is &#8805;64<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; it must be repeated to confirm&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">MIC defined by an 80&#37; inhibition in growth control&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Only report in <span class="elsevierStyleItalic">M&#46; chelonae&#46;</span></p>"
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          ]
        ]
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Interpretation criteria for susceptibility testing of rapid-growing mycobacteria <span class="elsevierStyleItalic">via</span> broth microdilution&#46;</p>"
        ]
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        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at4"
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            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">AG&#44; aminoglycosides&#59; BD&#44; bedaquiline&#59; E&#44; ethambutol&#59; FQ&#44; fluoroquinolones&#59; H&#44; isoniazid&#59; LPA&#44; line probe assay&#59; N&#47;A&#44; not available&#59; PCR&#44; polymerase chain reaction&#59; PZ&#44; pyrazinamide&#59; R&#44; rifampicin&#59; RT-PCR&#44; real-time PCR&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Modified from <span class="elsevierStyleItalic">Tuberculosis Diagnostics Technology and Market Landscape</span>&#44; UNITAID WHO 2015&#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">Test&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">Brand&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">Method&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">Detection&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">Year&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">TB Resistance INH&#47;RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2013&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">TB Resistance FLQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2013&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">TB Resistance AMG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2013&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">BioFilmChip MDR TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autogenomics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; microarray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2011&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">Drug Resistance Detection Kit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CapitalBio Co&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; microarray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2009&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">Xpert MTB&#47;RIF assay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cepheid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2009&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">NTM&#47;MDR TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NIPRO Co&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">INH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NIPRO Co&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NIPRO Co&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PZ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">FLQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NIPRO Co&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">Anyplex II MTB&#47;MDR&#47;XDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Seegene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&#44; FQ&#44; AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">Anyplex MTB&#47;MDR&#47;XDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Seegene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">VereMTB Detection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Veredus Labs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; microarray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">MeltPro RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zeesan Biotech&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2014&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">MeltPro INH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zeesan Biotech&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2014&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">MeltPro FLQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zeesan Biotech&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2014&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">MeltPro AMG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zeesan Biotech&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2014&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">Genedrive Mycobact iD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Epistem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RT-PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2013&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">INNO-LiPA Rif&#46;TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">INNO Genetics&#47;Fujirebio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#47;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">GenoType MTBDR<span class="elsevierStyleItalic">plus</span> v2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hain Lifescience&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">GenoType MTBDR<span class="elsevierStyleItalic">sl</span> v1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hain Lifescience&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AG&#44; FQ&#44; E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2009&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">GenoType MTBDR<span class="elsevierStyleItalic">sl</span> v2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hain Lifescience&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; LPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AG&#44; FQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2013&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">iC2&#46;0-MYC assay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">iCubate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; microarray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&#44; E&#44; FQ&#44; AG&#44; BD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2012&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">HYDRA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insilixa Inc&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR&#44; microarray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">H&#44; R&#44; PZ&#44; E&#44; FQ&#44; AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information

ISSN: 2529993X
Original language: English

DOI:10.1016/j.eimce.2017.08.005

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2024 October	33	7	40
2024 September	64	15	79
2024 August	62	19	81
2024 July	71	23	94
2024 June	82	30	112
2024 May	82	17	99
2024 April	70	17	87
2024 March	74	20	94
2024 February	117	18	135
2024 January	100	9	109
2023 December	90	22	112
2023 November	118	24	142
2023 October	121	36	157
2023 September	86	15	101
2023 August	76	13	89
2023 July	88	26	114
2023 June	63	14	77
2023 May	91	13	104
2023 April	74	18	92
2023 March	60	21	81
2023 February	51	31	82
2023 January	97	55	152
2022 December	36	6	42
2022 November	68	22	90
2022 October	59	11	70
2022 September	39	15	54
2022 August	71	16	87
2022 July	37	10	47
2022 June	29	15	44
2022 May	37	18	55
2022 April	36	19	55
2022 March	83	16	99
2022 February	52	10	62
2022 January	98	19	117
2021 December	40	14	54
2021 November	46	16	62
2021 October	64	39	103
2021 September	50	19	69
2021 August	69	26	95
2021 July	39	29	68
2021 June	56	14	70
2021 May	63	19	82
2021 April	133	46	179
2021 March	317	49	366
2021 February	95	31	126
2021 January	69	23	92
2020 December	86	43	129
2020 November	76	36	112
2020 October	70	28	98
2020 September	58	24	82
2020 August	50	25	75
2020 July	50	25	75
2020 June	45	18	63
2020 May	41	15	56
2020 April	38	14	52
2020 March	52	18	70
2020 February	45	17	62
2020 January	46	16	62
2019 December	43	19	62
2019 November	32	23	55
2019 October	32	17	49
2019 September	34	18	52
2019 August	35	9	44
2019 July	31	22	53
2019 June	44	27	71
2019 May	70	42	112
2019 April	54	24	78
2019 March	14	11	25
2019 February	14	4	18
2019 January	11	7	18
2018 December	3	1	4
2018 November	8	2	10
2018 October	10	4	14
2018 September	24	1	25
2018 August	8	1	9
2018 July	8	0	8
2018 June	4	0	4
2018 May	8	1	9
2018 April	4	0	4
2018 January	5	1	6
2017 December	10	0	10
2017 November	24	1	25
2017 October	22	4	26

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