The challenge of administering anti-tuberculosis treatment in infants and pre-school children. pTBred Magistral Project

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Proyecto Magistral de pTBred" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1479 "Ancho" => 1555 "Tamanyo" => 91588 ] ] "descripcion" => array:1 [ "en" => "Number of patients with latent tuberculosis infection or active tuberculosis disease that received care at the surveyed institutions in 2014." ] ] ] "textoCompleto" => "Introduction and objectivesBetween 2003 and 2010, the Working Group on Tuberculosis and Infection by Other Mycobacteria of the Sociedad Española de Infectología Pediátrica (Spanish Society of Paediatric Infectology [SEIP]) published the consensus documents<a class="elsevierStyleCrossRefs" href="#bib0125">1–6</a> on the diagnosis and management of tuberculosis in children, collaborating with the Sociedad Española de Neumología Pediátrica (Spanish Society of Paediatric Pulmonology [SENP])<a class="elsevierStyleCrossRef" href="#bib0150">6</a> in the most recent one. These documents highlighted the lack of paediatric formulations prepared as solutions or suspensions for most antituberculosis agents, especially for those currently used as first-line treatment, which is one of the barriers to adherence.<a class="elsevierStyleCrossRefs" href="#bib0145">5,6</a> As of today, the challenge most frequently faced by paediatric specialists in respiratory or infectious diseases in their everyday practice still remains: how to administer antituberculosis agents to children that have yet to develop the ability to swallow solid dosage forms.In Spain, the only first-line antituberculosis agent that is commercially available as a liquid dosage form is rifampicin<a class="elsevierStyleCrossRef" href="#bib0155">7</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>). Under these circumstances, some paediatricians prescribe compounded preparations (CPs), while others prescribe tablets to be crushed and subsequently diluted in various fluids for their administration. There is no consensus on these practices, nor any pharmacokinetic studies to support them. There is also wide variability in the use of CPs, with variations in stability between different dosage forms and the excipients used in their formulation and in the conditions surrounding their preparation. The published literature on the stability of CPs is also scarce.<a class="elsevierStyleCrossRefs" href="#bib0160">8,9</a> There is also few data on the use of fixed dose combinations (FDCs) of antituberculosis drugs (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 2</a>), and furthermore their use is not approved in children aged less than 8 years.<a class="elsevierStyleCrossRef" href="#bib0170">10</a> In 2009, the World Health Organization established guidelines for the use of FDCs in children based on body weight, and warned that none of the existing combinations was ideal for use in children.<a class="elsevierStyleCrossRef" href="#bib0175">11</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The Red Española de Estudio de Tuberculosis Pediátrica (Spanish Network for the Study of Paediatric Tuberculosis [pTBred]) was created in 2013.<a class="elsevierStyleCrossRef" href="#bib0180">12</a> As of February 2015, the network comprises more than 120 researchers from 67 institutions and has gathered information on more than 200 children with tuberculosis in Spain.In light of the difficulty and lack of consensus that exists in the administration of antituberculosis agents to children, a group of researchers of the pTBred developed the Proyecto Magistral (Compounding Project, pTBred#3) in January and February 2015 with the main objective of assessing, in an initial phase, the suitability of developing specific dosage forms for children based on body weight of first-line oral antituberculosis drugs. The study also sought to determine the pattern of antituberculosis drug prescription in the member institutions of the pTBred, the availability of CPs in these centres, the regimens commonly prescribed for the management of latent tuberculosis infection (LTBI), the percentage of institutions that order directly observed therapy (DOT) and how adverse effects to first-line drugs are monitored.Materials and methodsWe conducted a cross-sectional, multicentre, descriptive, multidisciplinary nationwide study. The data for the study was collected by means of a survey to be completed on a voluntary basis, which was sent to the member institutions of the pTBred by electronic mail and created using Google Drive®. The survey was approved by the Scientific Committee of the pTBred and conducted between February 15, and March 1, 2015.The survey (<a class="elsevierStyleCrossRef" href="#sec0035">Appendix A</a>) included two parts. The first one was designed to determine the characteristics of the surveyed institutions, and the second comprised 21 questions arranged into three sections by subject: 7 questions on concepts related to the approach to the management of tuberculosis in children, 8 questions pertaining to the use of the most common antituberculosis agents, and lastly 6 questions on the availability of CPs in the different hospitals.The number of institutions that were members of the pTBred as of February 1, 2015 was 67. We estimated that we needed to receive responses from at least 51 institutions to achieve a large enough sample to be able to generalise the results to all the pTBred member institutions with a margin of error of less than 3%, a level of heterogeneity of 95% and a 95% confidence interval (CI). The sole inclusion criterion was to be a member of the pTBred, and we only accepted one response per institution.We performed a descriptive analysis of qualitative variables by calculating their relative frequencies using the statistical software SPSS v20.0. We did not include any patient data, as the survey only asked about aspects of clinical practice, and thus did not deem it necessary to submit the survey for evaluation by ethics committees. Only researchers that participated in the study had access to the data of the survey, which were collected solely for the purpose of statistical analysis.ResultsWe received 54 responses: 24 from institutions in the Autonomous Community of Madrid, 10 from Catalonia, 4 from Andalusia and 16 from other autonomous communities, all of which were represented except for Aragón, Murcia and Castilla-León. In 2014, most of the surveyed centres had served one to four children with LTBI and one to four children with active tuberculosis disease (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The most frequently used method to administer antituberculosis agents in children unable to swallow solid dosage forms was crushing compressed tablets, except in the case of rifampicin, which is available as a solution (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a>). The second most frequent method was the administration of drugs in CPs, although the preparation and availability was highly variable between members of the pTBred (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>). When it came to the use of FDCs, more than half of the institutions reported using them regularly, although the questionnaire did not specifically ask whether they were only used in older children and adolescents or also in children aged less than 8 years, and since this may lead to these results being biased, we decided not to include them in the discussion of the study.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Of the respondents that reported using crushed tablets, 58% dissolved them in water, 19% in juice and 4% in milk. Thirteen percent reported not having a preference in terms of the fluid used for dissolving them, and six percent reported never using crushed tablets. Of the 50 institutions that reported using crushed tablets, 76% did not recommend a specific type of pill splitter or crusher. Eighty-nine percent of respondents administered all the drugs under fasting conditions, while the rest recommended taking them with food in case the patient had poor tolerance.When it came to the question “Do you think that a compounded preparation or FDC with the following combination of antituberculosis agents: 150mg H, 200mg R, 350mg Z±200mg E (or else 75mg H, 100mg R, 175mg Z±100mg E) would be useful in the treatment of tuberculosis in children?” (we calculated these doses based on the recommendations of the SEIP<a class="elsevierStyleCrossRef" href="#bib0150">6</a> and the Committee on Medications of the AEP<a class="elsevierStyleCrossRef" href="#bib0185">13</a> [CM-AEP], which in turn are based on the recommendations of the WHO<a class="elsevierStyleCrossRef" href="#bib0190">14</a> and recent pharmacokinetics studies<a class="elsevierStyleCrossRefs" href="#bib0170">10,15</a>), 83% answered that this would be ideal, 4% that the currently available FDCs suffice, while 13% considered that the doses proposed for pyrazinamide and ethambutol are suboptimal or that it would be better to administer each drug separately.The regimens used for treating LTBI varied between institutions. Thus, 50% used a 9-month isoniazid regimen, 30% a 6-month isoniazid regimen, and 20% a 3-month isoniazid and rifampicin regimen. As for ethambutol, 69% of institutions used it routinely for the treatment of tuberculosis disease, except in cases in which the strain in the patient or the index case was known to be sensitive to isoniazid, rifampicin or pyrazinamide; 4% used it in all cases, regardless of what was known about the sensitivity of the strain; and the rest chose other answer options, for example using it exclusively for specific forms of disease such as tuberculous meningitis.As for DOT, 72% of respondents ordered it only if there seemed to be risk factors for poor adherence to treatment, 17% never ordered it, and 11% almost always ordered it, save for select patients in whom adherence to treatment was expected to be optimal. No institution reported always ordering DOT.We also found differences in the monitoring of adverse effects. When it came to monitoring liver function, 52% of institutions ordered liver enzyme tests prior to initiating treatment, but not after, unless the patient developed manifestations compatible with liver toxicity; 28% performed serial tests after initiating treatment; 7% did not order liver function tests before or after starting treatment; and seven institutions reported having approaches other than those proposed in the answers (before and after, weekly, monthly, etc.).Eye examinations were ordered by 33% of institutions for children aged less than 5 years treated with ethambutol, compared to 9% that never ordered them and 58% that only ordered them in specific cases, for instance, for patients taking doses of 25mg/kg/day or greater for treatment of tuberculous meningitis.DiscussionThe results of our survey show a lack of consensus in Spain when it comes to how to administer antituberculosis drugs to children, except for rifampicin, which is widely administered in the form of oral suspension. Most paediatricians prescribe tablets that need to be crushed and dissolved, while the rest prescribe CPs. More than 20% of the respondents reported that compounding was not available in their institution or not knowing whether it was available. It is difficult to make sense of the variability found in the administration of antituberculosis agents in Spain, and also hard to accept the lack of specific paediatric dosage forms for the administration of a treatment the success of which depends directly on patient adherence.The website of the Grupo Español de Farmacia Pediátrica (Spanish Group of Paediatric Pharmacy), which is part of the Sociedad Española de Farmacia Hospitalaria (Spanish Society of Hospital Pharmacy [SEFH]), offers instructions on how to compound various drugs in Spain.<a class="elsevierStyleCrossRef" href="#bib0200">16</a> For antituberculosis agents, the site only features directions for isoniazid 10mg/mL and pyrazinamide 100mg/mL. A CP of isoniazid at that concentration is not too useful in children, as it produces large volumes that are poorly received by these patients. At the time of this writing, this site did not describe the steps to compound any preparation of ethambutol, although many pharmacy departments already have information on how to prepare an oral suspension with this active ingredient. As far as we know, no clinical trials have been conducted recently to assess and guarantee the safety of the administration of these drugs as CPs, and the data available is from old trials.<a class="elsevierStyleCrossRef" href="#bib0205">17</a> However, as is the case of many other drugs in paediatric practice, their off-label use is authorised. Such use requires obtaining verbal consent from the parents or legal guardians, and while legal, it is not covered by the guarantees of drug regulatory agencies, and pharmaceutical companies would not be liable if complaints were to be filed.<a class="elsevierStyleCrossRef" href="#bib0210">18</a>Eighty-three percent of the surveyed institutions stated that it would be ideal to have fixed dose combinations specifically made for children with doses calculated based on the latest recommendations<a class="elsevierStyleCrossRefs" href="#bib0150">6,13,14</a> of the SEIP, CM-AEP and WHO. However, 13% declared that the proposed doses for pyrazinamide and ethambutol would be suboptimal, which is up for debate, as different dose ranges based on weight have been recommended, or believed that it was preferable to administer each drug separately, an opinion that is consistent with that of some experts in relation to the use of FDCs in adults.<a class="elsevierStyleCrossRef" href="#bib0215">19</a> Others believe that, all things considered, combination drugs are currently the best treatment option.<a class="elsevierStyleCrossRefs" href="#bib0220">20,21</a>When it came to the use of crushed tablets, there was also disagreement as to the type of fluid used to dissolve them. In fact, while 13% of the surveyed centres answered that it does not make any difference, both milk and the juice of some fruits can decrease the bioavailability of some drugs, so the recommendation of administering these medications with dairy or juices such as grapefruit juice should always be given after careful consideration.<a class="elsevierStyleCrossRef" href="#bib0230">22</a>The results of the survey also evinced that, despite the availability of consensus documents<a class="elsevierStyleCrossRefs" href="#bib0125">1–6</a> and that members of the pTBred<a class="elsevierStyleCrossRef" href="#bib0180">12</a> are expected to have a homogeneous approach, there is considerable variability between these institutions.For example, 30% of the surveyed centres use the 6-month isoniazid regimen to treat LTBI, when our guidelines recommend the 9-month regimen.<a class="elsevierStyleCrossRefs" href="#bib0145">5,6</a> When it comes to DOT, 16% of the responding institutions never order it, and nearly 75% only order it when there are risk factors for poor adherence to treatment. We must take into account the legal framework for the role of health professionals and the health authorities in ensuring adherence to treatment with the purpose of preventing the spread of tuberculosis in the community.<a class="elsevierStyleCrossRef" href="#bib0145">5</a>We also found inconsistencies in relation to patient safety and the monitoring of drug adverse effects. Different hospitals performed different numbers of liver function tests. The SEIP does not recommend routinely monitoring liver enzyme levels if patients have no risk factors for developing hepatitis.<a class="elsevierStyleCrossRefs" href="#bib0145">5,6</a> However, more than 90% of respondents reported performing at least one transaminase test, usually prior to initiating treatment. There also seems to be no agreement in relation to the performance of eye examinations when children are treated with ethambutol. We know that toxicity is low and reversible in most cases by discontinuing treatment, that it is dose-dependent, and that the prevalence of this adverse effect may be underestimated.<a class="elsevierStyleCrossRefs" href="#bib0235">23,24</a> In Spain, most providers perform some type of examination, but only for doses of 25mg/kg/day or higher.The main limitation of this study is that we only sent the survey to the member institutions of the pTBred, which obviously are not the only facilities in Spain that diagnose and treat tuberculosis in children.However, and despite this limitation, we consider that the results of the survey reflect a reality that must be reviewed, analysed and changed by paediatricians and pharmacists. There are enough clinical practice guidelines in Spain that recommend an appropriate and uniform approach to the management of tuberculosis in children, but they are useless if they are not applied or we cannot ensure adherence to treatment. We calculate the exact doses of antituberculosis agents by kilogram of body weight, but the drugs are administered with no knowledge of the final dose received by the children or their safety as it regards their pharmacokinetics. We also found significant differences in regards to the monitoring of potential side effects and the initiation of DOT.In conclusion, our survey showed that at present, and despite the available consensus documents, there is variability in the management of tuberculosis in children and the administration of antituberculosis agents in Spain. The Red Española de Estudio de la Tuberculosis Pediátrica has proposed the analysis of the differences found in this survey and the development of a pioneering and practical consensus document on the administration of antituberculosis drugs in children, with particular emphasis on infants and young children that may be unable to swallow solid dosage forms. This proposal of the pTBred has already secured the collaboration of the SEIP and the SENP, and will request the collaboration of the SEFH, the CM-AEP and the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency of Medicines and Medical Devices) for the joint development of this document. The goal is to create a consensus guideline for the compounding of suspensions of isoniazid, pyrazinamide and ethambutol, with an emphasis on concentrations of 100mg/mL. Along the same lines, we will study the possibility of developing paediatric dosage forms with fixed doses of two, three or four antituberculosis agents at the doses needed in the paediatric population, titrated based on kilogram of body weight. Last of all, we will review aspects in which the approach of providers across Spain are inconsistent, such as the management of LTBI, the need of DOT to ensure adherence to treatment, or the monitoring of the side effects of first-line antituberculosis agents.FundingStudy supported by the Comité de Medicamentos de la Asociación Española de Pediatría (Committee on Medicines of the Spanish Association of Pediatrics [CM-AEP]).The pTBred was awarded the 2013 Research Grant of the AEP. Specific funding was not awarded to this particular study.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres677628" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec683610" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres677629" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec683609" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction and objectives" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-03" "fechaAceptado" => "2015-07-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec683610" "palabras" => array:5 [ 0 => "Tuberculosis" 1 => "Children" 2 => "Anti-tuberculous drugs" 3 => "Community surveys" 4 => "Drug compounding" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec683609" "palabras" => array:5 [ 0 => "Tuberculosis" 1 => "Niños" 2 => "Fármacos antituberculosos" 3 => "Encuestas comunitarias" 4 => "Formulación magistral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionThere are no paediatric formulations of anti-tuberculous drugs in Spain, with the only exception being rifampicin. Some paediatricians often prescribe composite formulations (CF), while others prefer to give crushed tablets. Nevertheless, there is no consensus in this regard, or any pharmacokinetic studies validating these procedures. In this situation, the Spanish Network for the Study of Paediatric Tuberculosis (pTBred) has launched the Magistral Project, which aims at its first phase to analyse the desirability of developing child-friendly pharmaceutical formulations and other aspects regarding the anti-tuberculous drug prescription in children. Material and methodsA cross-sectional, multicentre, nationwide study was conducted, based on an online questionnaire sent to members of pTBred between February and March 2015. ResultsFifty-four responses from 67 consulted institutions were received. Most of the respondents reported prescribing crushed tablets. A significant number of those surveyed, although being fewer, prescribe CF, for which availability varies widely among institutions. Eighty-three percent replied that it would be essential to have fixed dose combinations of anti-tuberculous drugs, specifically adapted to paediatric doses and administered by CF or tablets. Among the surveyed institutions, differences were found in the management of latent tuberculosis infection, in the use of directly observed therapy, and in the monitoring of adverse events. ConclusionsOur survey reveals great diversity in anti-tuberculous drug prescription in children, due to the lack of suitable infant formulations, which could have an impact on treatment adherence and outcomes. pTBred intends to develop a pioneering and useful consensus document on the management of anti-tuberculous medication in children." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónEn España no existen presentaciones pediátricas de fármacos antituberculosos, salvo para rifampicina. Algunos pediatras prescriben fórmulas magistrales (FM), mientras que otros administran comprimidos triturados. No existe consenso al respecto, ni estudios de farmacocinética que avalen estos procedimientos. Ante esta situación, la Red Española de Estudio de la Tuberculosis Pediátrica (pTBred) desarrolla el Proyecto Magistral, con el objetivo de analizar, en su primera fase, la conveniencia de desarrollar formas farmacéuticas específicas para niños, así como estudiar otros aspectos relacionados con la administración de antituberculosos en niños. Material y métodosEstudio transversal, multicéntrico y de ámbito nacional, mediante encuesta on-line enviada por correo electrónico a los instituciones pertenecientes a pTBred entre febrero y marzo del 2015. ResultadosSe recibieron 54 respuestas de 67 instituciones consultadas. La mayoría de los centros trituran los comprimidos. Un porcentaje elevado, aunque menor, administra FM, cuya disponibilidad es variable entre las instituciones. El 83% responde que sería ideal disponer de combinaciones fijas de antituberculosos, adaptadas a las dosis pediátricas y administradas mediante FM o en un comprimido. Entre las instituciones encuestadas existen diferencias en el tratamiento de la infección tuberculosa latente, el uso de la terapia directamente observada y la monitorización de efectos adversos. ConclusionesNuestra encuesta revela gran heterogeneidad en la prescripción de antituberculosos en niños debido a la falta de formulaciones específicas para esta edad, que podría tener implicaciones en la adherencia al tratamiento y evolución. pTBred propone elaborar un pionero y útil documento de consenso sobre la administración de medicación antituberculosa en niños." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Piñeiro Pérez R, Santiago García B, Fernández-Llamazares CM, Baquero Artigao F, Noguera Julian A, Mellado Peña MJ, et al. El reto de la administración de antituberculosos en lactantes y preescolares. Proyecto Magistral de pTBred. An Pediatr (Barc). 2016;85:4–12." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Previous presentations: This is an original work that has not been previously presented in meetings, conferences or symposia." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:3 [ "apendice" => "Province: free text. Autonomous community: free text. Hospital: free text. Number of children with latent TB infection and active TB disease diagnosed in your centre in 2014 (does not include exposure to TB): None 1–5 children 5–10 children More than 10 children Select the combination drugs or FDCs that are widely used in your centre (multiple-choice, multiple answer question): Combinations of 150mg isoniazid+300mg rifampicin (Rifinah®) Combinations of 50mg isoniazid+120mg rifampicin+300mg pyrazinamide (Rifater®) Combinations of 75mg isoniazid+150mg rifampicin+400mg pyrazinamide+275mg ethambutol (Rimstar®) Other, note which: free text. Which is the regimen used most commonly in your hospital for the treatment of latent tuberculosis infection? Isoniazid for 9 months Isoniazid for 6 months Isoniazid+rifampicin for 3 months Rifampicin for 4 months Other. Which?: free text. Use of directly observed therapy or treatment monitoring in children: We always request it for all cases. We almost always request it, except in select cases in which it is believed that the family will adhere optimally to the treatment. We requested for approximately 50% of cases. We only request it when we consider that there are risk factors for poor adherence to treatment. We never request it. In regards to the use of ethambutol as the fourth antituberculosis drug (multiple choice, multiple answer): It is used in specific cases of tuberculosis disease (miliary, meningeal, etc.). It is used when the drug sensitivity of the strain of the index case is unknown. It is used routinely in immigrants from regions where the prevalence of isoniazid resistance is greater than 4%. It is used in all cases, regardless of the sensitivity of resistance of the index case strain. It is used routinely unless the strain (of the paediatric patient or the index patient) is known to be sensitive to H, R and Z. It is never used. Other: free text. In regards to eye checkups in children aged less than 5 years receiving ethambutol: We always order them, in all cases. We almost always order them, but not in all cases. We order them sometimes, approximately in half of the cases. We order them only occasionally, for example when doses of 25mg/kg/day are used for treatment of tuberculous meningitis. We never order them, as there is not enough evidence on the development of optical neuritis in children treated with ethambutol. In regards to liver enzyme tests: We never order them, unless the patient develops manifestations compatible with hepatic cytolysis. We always test before initiating treatment, but not after unless the patient develops manifestations compatible with hepatic cytolysis. We test before initiation of treatment and periodically thereon. Other: free text. Isoniazid Describe the form(s) in which you usually prescribe isoniazid to children unable to swallow pills (multiple choice, multiple answer): Compounded preparation of isoniazid 10mg/mL. Another compounded preparation of isoniazid. At which concentration?: free text. Isoniazid tablets (50, 150 or 300mg), crushed and mixed with water or juice. FDC tablets, crushed and mixed with water or juice. Describe the form in which you most frequently prescribe isoniazid to children unable to swallow pills (multiple choice, single answer):<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">–Compounded preparation of isoniazid 10mg/mL.</li><li class="elsevierStyleListItem" id="lsti0010">–Isoniazid compounded preparation (another). At which concentration?: free text.</li><li class="elsevierStyleListItem" id="lsti0015">–Isoniazid tablets (50, 150 or 300mg), crushed and mixed with water or juice.</li><li class="elsevierStyleListItem" id="lsti0020">–FDC tablets, crushed and mixed with water or juice.</li></ul> Rifampicin Describe the form(s) in which you usually prescribe rifampicin to children unable to swallow pills (multiple choice, multiple answer): Rifaldin® 20mg/mL suspension. Compounded formulation. At which concentration?: free text. Rifampicin 300mg capsules, opened and mixed with water or juice. Rifampicin 600mg tablets, crushed and mixed with water or juice. FDC tablets, crushed and mixed with water or juice. Describe the form in which you most frequently prescribe rifampicin to children unable to swallow pills (multiple choice, single answer):<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">–Rifaldin® 20mg/mL suspension.</li><li class="elsevierStyleListItem" id="lsti0030">–Compounded formulation. At which concentration?: free text.</li><li class="elsevierStyleListItem" id="lsti0035">–Rifampicin 300mg capsules, opened and mixed with water or juice.</li><li class="elsevierStyleListItem" id="lsti0040">–Rifampicin 600mg tablets, crushed and mixed with water or juice.</li><li class="elsevierStyleListItem" id="lsti0045">–FDC tablets, crushed and mixed with water or juice.</li></ul> Pyrazinamide Describe the form(s) in which you usually prescribe pyrazinamide to children unable to swallow pills (multiple choice, multiple answer): Compounded formulation of pyrazinamide 100mg/mL. Compounded formulation of pyrazinamide (other). At which concentration?: free text. Pyrazinamide 250mg tablets, crushed and mixed with water or juice. FDC tablets, crushed and mixed with water or juice. Describe the form in which you most frequently prescribe pyrazinamide to children unable to swallow pills (multiple choice, single answer):<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0050">–Compounded formulation of pyrazinamide 100mg/mL.</li><li class="elsevierStyleListItem" id="lsti0055">–Compounded formulation of pyrazinamide (other). At which concentration?: free text.</li><li class="elsevierStyleListItem" id="lsti0060">–Pyrazinamide 250mg tablets, crushed and mixed with water or juice.</li><li class="elsevierStyleListItem" id="lsti0065">–FDC tablets, crushed and mixed with water or juice.</li></ul> Ethambutol Describe the form(s) in which you usually prescribe ethambutol to children unable to swallow pills (multiple choice, multiple answer): Compounded formulation of ethambutol 50mg/mL. Compounded formulation of ethambutol (other). At which concentration?: free text. Coated tablets of ethambutol 400mg crushed and mixed with water or juice. FDC tablets crushed and mixed with water or juice. Describe the form in which you most frequently prescribe ethambutol to children unable to swallow pills (multiple choice, single answer):<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0070">–Compounded formulation of ethambutol 50mg/mL.</li><li class="elsevierStyleListItem" id="lsti0075">–Compounded formulation of ethambutol (other). At which concentration?: free text.</li><li class="elsevierStyleListItem" id="lsti0080">–Coated tablets of ethambutol 400mg crushed and mixed with water or juice.</li><li class="elsevierStyleListItem" id="lsti0085">–FDC tablets crushed and mixed with water or juice.</li></ul> Availability of compounded preparations in the hospital<elsevierMultimedia ident="tbl0005"></elsevierMultimedia> Availability of compounded preparations of isoniazid in your centre (multiple choice, multiple answer):<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0090">–Available at a concentration of 1mL=10mg.</li><li class="elsevierStyleListItem" id="lsti0095">–Available at a concentration of 1mL=100mg.</li><li class="elsevierStyleListItem" id="lsti0100">–We have compounded preparations at a different concentration. Which?: free text.</li><li class="elsevierStyleListItem" id="lsti0105">–No compounded preparation of isoniazid is available.</li><li class="elsevierStyleListItem" id="lsti0110">–We do not know.</li></ul>Availability of compounded preparations of pyrazinamide in your centre (multiple choice, multiple answer):<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0115">–Available at a concentration of 1mL10mg.</li><li class="elsevierStyleListItem" id="lsti0120">–Available at a concentration of 1mL=100mg.</li><li class="elsevierStyleListItem" id="lsti0125">–We have compounded preparations at a different concentration. Which?: free text.</li><li class="elsevierStyleListItem" id="lsti0130">–No compounded preparation of pyrazinamide is available.</li><li class="elsevierStyleListItem" id="lsti0135">–We do not know.</li></ul>Availability of compounded preparations of ethambutol in your centre (multiple choice, multiple answer):<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0140">–Available at a concentration of 1mL=50mg.</li><li class="elsevierStyleListItem" id="lsti0145">–Available at a concentration of 1mL=100mg.</li><li class="elsevierStyleListItem" id="lsti0150">–We have compounded preparations at a different concentration. Which?: free text.</li><li class="elsevierStyleListItem" id="lsti0155">–No compounded preparation of ethambutol is available.</li><li class="elsevierStyleListItem" id="lsti0160">–We do not know.</li></ul>Assuming you use crushed tablets, they are most frequently mixed with:<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0165">–Water.</li><li class="elsevierStyleListItem" id="lsti0170">–Milk.</li><li class="elsevierStyleListItem" id="lsti0175">–Juice.</li><li class="elsevierStyleListItem" id="lsti0180">–Other: free text.</li><li class="elsevierStyleListItem" id="lsti0185">–We do not crush tablets.</li><li class="elsevierStyleListItem" id="lsti0190">–We have no preference.</li></ul> Assuming you use crushed tablets, do you recommend a particular type of splitter/crusher?<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0195">–Yes.</li><li class="elsevierStyleListItem" id="lsti0200">–No.</li><li class="elsevierStyleListItem" id="lsti0205">–We do not crush tablets.</li></ul> In regards to the administration of medication under fasting conditions: All medications are administered under fasting conditions. Only rifampicin is administered under fasting conditions. Medications are not administered under fasting conditions, but with food. Not administered fasting or with food. Other: free text. Do you think that a compounded preparations or FDC with the following combination of antituberculosis agents: 150mg H, 200mg R, 350mg Z±200mg E (or else 75mg H, 100mg R, 175mg Z±100mg E) would be useful in the treatment of tuberculosis in children? Yes, it would be ideal. No, FDCs with those concentrations are already available. There are no FDCs with those concentrations, but the FDCs that are available suffice to adequately treat children." "etiqueta" => "Appendix A" "identificador" => "sec0035" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1479 "Ancho" => 1555 "Tamanyo" => 91588 ] ] "descripcion" => array:1 [ "en" => "Number of patients with latent tuberculosis infection or active tuberculosis disease that received care at the surveyed institutions in 2014." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Active ingredient \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">Commercial paediatric formulation \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">Compounded preparation \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">Isoniazid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unavailable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Isoniazid 10mg/mL Isoniazid 100mg/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rifaldin® oral suspension, 100mg/5mL \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">Pyrazinamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unavailable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pyrazinamide 50mg/mL Pyrazinamide 100mg/mL \t\t\t\t\t\t\n \t\t\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">Unavailable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ethambutol 50mg/mL Ethambutol 100mg/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1112123.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Antituberculosis agents available as oral solution or suspension in Spain." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "E, ethambutol; H, isoniazid; R, rifampicin; Z, pyrazinamide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Commercial formulation \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">Dosage forms and dosing (mg) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Combinations of de H+R</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifinah® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Compressed tablet 150 (H)/300 (R) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rimactazid® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Coated tablet 150 (H)/300 (R) and tablet 75 (H)/150 (R) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Combinations of H+R+Z</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifater® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Compressed tablet 50 (H)/120 (R)/300 (Z) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rimcure® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Compressed tablet 75 (H)/150 (R)/400 (Z) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Combinations of H+R+Z+E</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rimstar® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Compressed tablet 75 (H)/150 (R)/400 (Z)/275 (E) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1112121.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Fixed-dose combinations available in Spain. As of July 2015, the marketing authorisation for Rimactazid® and Rimcure® was suspended, based on data from the Centro de Información online de Medicamentos de la Agencia Española de Medicamentos y Productos Sanitarios (Online Medicines Information Centre of the Spanish Agency of Medicines and Medical Devices [CIMA-AEMPS])." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total (n=54) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of isoniazid 10mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (30%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of isoniazid 100mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid tablets (50, 150 or 300mg), crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 (46%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FDC tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (13%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total (n=54) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifaldin® suspension 20mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 (90%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin 300mg capsules, opened and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin 600mg tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (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">FDC tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (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">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></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">Total (n=54) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of pyrazinamide 50mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of pyrazinamide 100mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (43%) \t\t\t\t\t\t\n \t\t\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 250mg tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 (48%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FDC tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (7%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></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">Total (n=54) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of ethambutol 50mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (17%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Compounded preparation of ethambutol 100mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (26%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Coated tablets of ethambutol 400mg, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (37%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FDC tablets, crushed and mixed with water or juice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (9%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1112125.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Most frequent methods used to administer antituberculosis agents to children that are not able to swallow solid dosage forms. Multiple choice, single answer questions." ] ] 4 => array:8 [ "identificador" => "tbl0025" "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" => "Compounded preparations: multiple choice, single answer question." "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">Availability of compounded preparations in the hospital (n=54) \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">Isoniazid \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">Pyrazinamide \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">Ethambutol \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">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (9%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Never \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (17%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rarely \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sometimes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (11%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (15%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Almost always \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (17%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (19%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (13%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Always \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (42%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (40%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1112124.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Availability of compounded preparations in the hospital." ] ] 5 => array:5 [ "identificador" => "tbl0005" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" 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">Unknown \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">Never \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">Almost never \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">Sometimes \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">Nearly always \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">Always \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">Isoniazid \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="" valign="top"> \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="" valign="top"> \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="" 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">Rifampicin \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="" valign="top"> \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="" valign="top"> \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="" 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">Pyrazinamide \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="" valign="top"> \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="" valign="top"> \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="" 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">Ethambutol \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="" valign="top"> \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="" valign="top"> \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="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1112122.png" ] ] ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0125" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interpretación de la prueba de tuberculina en niños" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Grupo de trabajo de Tuberculosis de la Sociedad Española de Infectología Pediátrica" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2003" "volumen" => "59" "paginaInicial" => "582" "paginaFinal" => "585" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0130" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Documento de consenso sobre el tratamiento de la exposición a tuberculosis y de la infección tuberculosa latente en niños" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Grupo de trabajo de Tuberculosis de la Sociedad Española de Infectología Pediátrica" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2006" "volumen" => "64" "paginaInicial" => "59" "paginaFinal" => "65" "itemHostRev" => array:3 [ "pii" => "S0002939410000346" "estado" => "S300" "issn" => "00029394" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0135" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Documento de consenso sobre el tratamiento de la tuberculosis extrapulmonar y formas complicadas de tuberculosis pulmonar" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Grupo de trabajo de Tuberculosis de la Sociedad Española de Infectología Pediátrica" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2008" "volumen" => "69" "paginaInicial" => "271" "paginaFinal" => "278" "itemHostRev" => array:3 [ "pii" => "S0140673609606589" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0140" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Documento de consenso de la SEIP sobre la tuberculosis resistente a fármacos" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "en representación del Grupo de Trabajo de Tuberculosis de la SEIP" "etal" => false "autores" => array:3 [ 0 => "M.J. 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The challenge of administering anti-tuberculosis treatment in infants and pre-school children. pTBred Magistral Project

El reto de la administración de antituberculosos en lactantes y preescolares. Proyecto Magistral de pTBred

Roi Piñeiro Péreza,

Corresponding author

roipineiro@telefonica.net

Corresponding author.

, Begoña Santiago Garcíab, Cecilia M. Fernández-Llamazaresc, Fernando Baquero Artigaod, Antoni Noguera Juliane, María José Mellado Peñad, representación de pTBred (Red Española de Estudio de Tuberculosis Pediátrica)

a Servicio de Pediatría, Hospital General de Villalba, Madrid, Spain

b Servicio de Pediatría, Hospital General Universitario Gregorio Marañón, Madrid, Spain

c Servicio de Farmacia Hospitalaria, Hospital General Universitario Gregorio Marañón, Madrid, Spain

d Servicio de Pediatría, Hospital Universitario La Paz, Madrid, Spain

e Servicio de Pediatría, Hospital Sant Joan de Déu, Barcelona, Spain

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        "titulo" => "El reto de la administraci&#243;n de antituberculosos en lactantes y preescolares&#46; Proyecto Magistral de pTBred"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction and objectives</span><p id="par0005" class="elsevierStylePara elsevierViewall">Between 2003 and 2010&#44; the Working Group on Tuberculosis and Infection by Other Mycobacteria of the Sociedad Espa&#241;ola de Infectolog&#237;a Pedi&#225;trica &#40;Spanish Society of Paediatric Infectology &#91;SEIP&#93;&#41; published the consensus documents<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1&#8211;6</span></a> on the diagnosis and management of tuberculosis in children&#44; collaborating with the Sociedad Espa&#241;ola de Neumolog&#237;a Pedi&#225;trica &#40;Spanish Society of Paediatric Pulmonology &#91;SENP&#93;&#41;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> in the most recent one&#46; These documents highlighted the lack of paediatric formulations prepared as solutions or suspensions for most antituberculosis agents&#44; especially for those currently used as first-line treatment&#44; which is one of the barriers to adherence&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">5&#44;6</span></a> As of today&#44; the challenge most frequently faced by paediatric specialists in respiratory or infectious diseases in their everyday practice still remains&#58; <span class="elsevierStyleItalic">how to administer antituberculosis agents to children that have yet to develop the ability to swallow solid dosage forms</span>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain&#44; the only first-line antituberculosis agent that is commercially available as a liquid dosage form is rifampicin<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>&#41;&#46; Under these circumstances&#44; some paediatricians prescribe compounded preparations &#40;CPs&#41;&#44; while others prescribe tablets to be crushed and subsequently diluted in various fluids for their administration&#46; There is no consensus on these practices&#44; nor any pharmacokinetic studies to support them&#46; There is also wide variability in the use of CPs&#44; with variations in stability between different dosage forms and the excipients used in their formulation and in the conditions surrounding their preparation&#46; The published literature on the stability of CPs is also scarce&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">8&#44;9</span></a> There is also few data on the use of fixed dose combinations &#40;FDCs&#41; of antituberculosis drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 2</a>&#41;&#44; and furthermore their use is not approved in children aged less than 8 years&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">10</span></a> In 2009&#44; the World Health Organization established guidelines for the use of FDCs in children based on body weight&#44; and warned that none of the existing combinations was ideal for use in children&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The Red Espa&#241;ola de Estudio de Tuberculosis Pedi&#225;trica &#40;Spanish Network for the Study of Paediatric Tuberculosis &#91;pTBred&#93;&#41; was created in 2013&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> As of February 2015&#44; the network comprises more than 120 researchers from 67 institutions and has gathered information on more than 200 children with tuberculosis in Spain&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In light of the difficulty and lack of consensus that exists in the administration of antituberculosis agents to children&#44; a group of researchers of the pTBred developed the Proyecto Magistral &#40;Compounding Project&#44; pTBred&#35;3&#41; in January and February 2015 with the main objective of assessing&#44; in an initial phase&#44; the suitability of developing specific dosage forms for children based on body weight of first-line oral antituberculosis drugs&#46; The study also sought to determine the pattern of antituberculosis drug prescription in the member institutions of the pTBred&#44; the availability of CPs in these centres&#44; the regimens commonly prescribed for the management of latent tuberculosis infection &#40;LTBI&#41;&#44; the percentage of institutions that order directly observed therapy &#40;DOT&#41; and how adverse effects to first-line drugs are monitored&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a cross-sectional&#44; multicentre&#44; descriptive&#44; multidisciplinary nationwide study&#46; The data for the study was collected by means of a survey to be completed on a voluntary basis&#44; which was sent to the member institutions of the pTBred by electronic mail and created using Google Drive<span class="elsevierStyleSup">&#174;</span>&#46; The survey was approved by the Scientific Committee of the pTBred and conducted between February 15&#44; and March 1&#44; 2015&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The survey &#40;<a class="elsevierStyleCrossRef" href="#sec0035">Appendix A</a>&#41; included two parts&#46; The first one was designed to determine the characteristics of the surveyed institutions&#44; and the second comprised 21 questions arranged into three sections by subject&#58; 7 questions on concepts related to the approach to the management of tuberculosis in children&#44; 8 questions pertaining to the use of the most common antituberculosis agents&#44; and lastly 6 questions on the availability of CPs in the different hospitals&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The number of institutions that were members of the pTBred as of February 1&#44; 2015 was 67&#46; We estimated that we needed to receive responses from at least 51 institutions to achieve a large enough sample to be able to generalise the results to all the pTBred member institutions with a margin of error of less than 3&#37;&#44; a level of heterogeneity of 95&#37; and a 95&#37; confidence interval &#40;CI&#41;&#46; The sole inclusion criterion was to be a member of the pTBred&#44; and we only accepted one response per institution&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">We performed a descriptive analysis of qualitative variables by calculating their relative frequencies using the statistical software SPSS v20&#46;0&#46; We did not include any patient data&#44; as the survey only asked about aspects of clinical practice&#44; and thus did not deem it necessary to submit the survey for evaluation by ethics committees&#46; Only researchers that participated in the study had access to the data of the survey&#44; which were collected solely for the purpose of statistical analysis&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">We received 54 responses&#58; 24 from institutions in the Autonomous Community of Madrid&#44; 10 from Catalonia&#44; 4 from Andalusia and 16 from other autonomous communities&#44; all of which were represented except for Arag&#243;n&#44; Murcia and Castilla-Le&#243;n&#46; In 2014&#44; most of the surveyed centres had served one to four children with LTBI and one to four children with active tuberculosis disease &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The most frequently used method to administer antituberculosis agents in children unable to swallow solid dosage forms was crushing compressed tablets&#44; except in the case of rifampicin&#44; which is available as a solution &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a>&#41;&#46; The second most frequent method was the administration of drugs in CPs&#44; although the preparation and availability was highly variable between members of the pTBred &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 4</a>&#41;&#46; When it came to the use of FDCs&#44; more than half of the institutions reported using them regularly&#44; although the questionnaire did not specifically ask whether they were only used in older children and adolescents or also in children aged less than 8 years&#44; and since this may lead to these results being biased&#44; we decided not to include them in the discussion of the study&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Of the respondents that reported using crushed tablets&#44; 58&#37; dissolved them in water&#44; 19&#37; in juice and 4&#37; in milk&#46; Thirteen percent reported not having a preference in terms of the fluid used for dissolving them&#44; and six percent reported never using crushed tablets&#46; Of the 50 institutions that reported using crushed tablets&#44; 76&#37; did not recommend a specific type of pill splitter or crusher&#46; Eighty-nine percent of respondents administered all the drugs under fasting conditions&#44; while the rest recommended taking them with food in case the patient had poor tolerance&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">When it came to the question &#8220;Do you think that a compounded preparation or FDC with the following combination of antituberculosis agents&#58; 150<span class="elsevierStyleHsp" style=""></span>mg H&#44; 200<span class="elsevierStyleHsp" style=""></span>mg R&#44; 350<span class="elsevierStyleHsp" style=""></span>mg Z<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>mg E &#40;or else 75<span class="elsevierStyleHsp" style=""></span>mg H&#44; 100<span class="elsevierStyleHsp" style=""></span>mg R&#44; 175<span class="elsevierStyleHsp" style=""></span>mg Z<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg E&#41; would be useful in the treatment of tuberculosis in children&#63;&#8221; &#40;we calculated these doses based on the recommendations of the SEIP<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> and the Committee on Medications of the AEP<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a> &#91;CM-AEP&#93;&#44; which in turn are based on the recommendations of the WHO<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">14</span></a> and recent pharmacokinetics studies<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">10&#44;15</span></a>&#41;&#44; 83&#37; answered that this would be ideal&#44; 4&#37; that the currently available FDCs suffice&#44; while 13&#37; considered that the doses proposed for pyrazinamide and ethambutol are suboptimal or that it would be better to administer each drug separately&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The regimens used for treating LTBI varied between institutions&#46; Thus&#44; 50&#37; used a 9-month isoniazid regimen&#44; 30&#37; a 6-month isoniazid regimen&#44; and 20&#37; a 3-month isoniazid and rifampicin regimen&#46; As for ethambutol&#44; 69&#37; of institutions used it routinely for the treatment of tuberculosis disease&#44; except in cases in which the strain in the patient or the index case was known to be sensitive to isoniazid&#44; rifampicin or pyrazinamide&#59; 4&#37; used it in all cases&#44; regardless of what was known about the sensitivity of the strain&#59; and the rest chose other answer options&#44; for example using it exclusively for specific forms of disease such as tuberculous meningitis&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">As for DOT&#44; 72&#37; of respondents ordered it only if there seemed to be risk factors for poor adherence to treatment&#44; 17&#37; never ordered it&#44; and 11&#37; almost always ordered it&#44; save for select patients in whom adherence to treatment was expected to be optimal&#46; No institution reported always ordering DOT&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">We also found differences in the monitoring of adverse effects&#46; When it came to monitoring liver function&#44; 52&#37; of institutions ordered liver enzyme tests prior to initiating treatment&#44; but not after&#44; unless the patient developed manifestations compatible with liver toxicity&#59; 28&#37; performed serial tests after initiating treatment&#59; 7&#37; did not order liver function tests before or after starting treatment&#59; and seven institutions reported having approaches other than those proposed in the answers &#40;before and after&#44; weekly&#44; monthly&#44; etc&#46;&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Eye examinations were ordered by 33&#37; of institutions for children aged less than 5 years treated with ethambutol&#44; compared to 9&#37; that never ordered them and 58&#37; that only ordered them in specific cases&#44; for instance&#44; for patients taking doses of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day or greater for treatment of tuberculous meningitis&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">The results of our survey show a lack of consensus in Spain when it comes to how to administer antituberculosis drugs to children&#44; except for rifampicin&#44; which is widely administered in the form of oral suspension&#46; Most paediatricians prescribe tablets that need to be crushed and dissolved&#44; while the rest prescribe CPs&#46; More than 20&#37; of the respondents reported that compounding was not available in their institution or not knowing whether it was available&#46; It is difficult to make sense of the variability found in the administration of antituberculosis agents in Spain&#44; and also hard to accept the lack of specific paediatric dosage forms for the administration of a treatment the success of which depends directly on patient adherence&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The website of the Grupo Espa&#241;ol de Farmacia Pedi&#225;trica &#40;Spanish Group of Paediatric Pharmacy&#41;&#44; which is part of the Sociedad Espa&#241;ola de Farmacia Hospitalaria &#40;Spanish Society of Hospital Pharmacy &#91;SEFH&#93;&#41;&#44; offers instructions on how to compound various drugs in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> For antituberculosis agents&#44; the site only features directions for isoniazid 10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL and pyrazinamide 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46; A CP of isoniazid at that concentration is not too useful in children&#44; as it produces large volumes that are poorly received by these patients&#46; At the time of this writing&#44; this site did not describe the steps to compound any preparation of ethambutol&#44; although many pharmacy departments already have information on how to prepare an oral suspension with this active ingredient&#46; As far as we know&#44; no clinical trials have been conducted recently to assess and guarantee the safety of the administration of these drugs as CPs&#44; and the data available is from old trials&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a> However&#44; as is the case of many other drugs in paediatric practice&#44; their off-label use is authorised&#46; Such use requires obtaining verbal consent from the parents or legal guardians&#44; and while legal&#44; it is not covered by the guarantees of drug regulatory agencies&#44; and pharmaceutical companies would not be liable if complaints were to be filed&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">18</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Eighty-three percent of the surveyed institutions stated that it would be ideal to have fixed dose combinations specifically made for children with doses calculated based on the latest recommendations<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">6&#44;13&#44;14</span></a> of the SEIP&#44; CM-AEP and WHO&#46; However&#44; 13&#37; declared that the proposed doses for pyrazinamide and ethambutol would be suboptimal&#44; which is up for debate&#44; as different dose ranges based on weight have been recommended&#44; or believed that it was preferable to administer each drug separately&#44; an opinion that is consistent with that of some experts in relation to the use of FDCs in adults&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">19</span></a> Others believe that&#44; all things considered&#44; combination drugs are currently the best treatment option&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">When it came to the use of crushed tablets&#44; there was also disagreement as to the type of fluid used to dissolve them&#46; In fact&#44; while 13&#37; of the surveyed centres answered that it does not make any difference&#44; both milk and the juice of some fruits can decrease the bioavailability of some drugs&#44; so the recommendation of administering these medications with dairy or juices such as grapefruit juice should always be given after careful consideration&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">22</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The results of the survey also evinced that&#44; despite the availability of consensus documents<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1&#8211;6</span></a> and that members of the pTBred<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> are expected to have a homogeneous approach&#44; there is considerable variability between these institutions&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">For example&#44; 30&#37; of the surveyed centres use the 6-month isoniazid regimen to treat LTBI&#44; when our guidelines recommend the 9-month regimen&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">5&#44;6</span></a> When it comes to DOT&#44; 16&#37; of the responding institutions never order it&#44; and nearly 75&#37; only order it when there are risk factors for poor adherence to treatment&#46; We must take into account the legal framework for the role of health professionals and the health authorities in ensuring adherence to treatment with the purpose of preventing the spread of tuberculosis in the community&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">5</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">We also found inconsistencies in relation to patient safety and the monitoring of drug adverse effects&#46; Different hospitals performed different numbers of liver function tests&#46; The SEIP does not recommend routinely monitoring liver enzyme levels if patients have no risk factors for developing hepatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">5&#44;6</span></a> However&#44; more than 90&#37; of respondents reported performing at least one transaminase test&#44; usually prior to initiating treatment&#46; There also seems to be no agreement in relation to the performance of eye examinations when children are treated with ethambutol&#46; We know that toxicity is low and reversible in most cases by discontinuing treatment&#44; that it is dose-dependent&#44; and that the prevalence of this adverse effect may be underestimated&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">23&#44;24</span></a> In Spain&#44; most providers perform some type of examination&#44; but only for doses of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day or higher&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The main limitation of this study is that we only sent the survey to the member institutions of the pTBred&#44; which obviously are not the only facilities in Spain that diagnose and treat tuberculosis in children&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">However&#44; and despite this limitation&#44; we consider that the results of the survey reflect a reality that must be reviewed&#44; analysed and changed by paediatricians and pharmacists&#46; There are enough clinical practice guidelines in Spain that recommend an appropriate and uniform approach to the management of tuberculosis in children&#44; but they are useless if they are not applied or we cannot ensure adherence to treatment&#46; We calculate the exact doses of antituberculosis agents by kilogram of body weight&#44; but the drugs are administered with no knowledge of the final dose received by the children or their safety as it regards their pharmacokinetics&#46; We also found significant differences in regards to the monitoring of potential side effects and the initiation of DOT&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; our survey showed that at present&#44; and despite the available consensus documents&#44; there is variability in the management of tuberculosis in children and the administration of antituberculosis agents in Spain&#46; The Red Espa&#241;ola de Estudio de la Tuberculosis Pedi&#225;trica has proposed the analysis of the differences found in this survey and the development of a pioneering and practical consensus document on the administration of antituberculosis drugs in children&#44; with particular emphasis on infants and young children that may be unable to swallow solid dosage forms&#46; This proposal of the pTBred has already secured the collaboration of the SEIP and the SENP&#44; and will request the collaboration of the SEFH&#44; the CM-AEP and the Agencia Espa&#241;ola de Medicamentos y Productos Sanitarios &#40;Spanish Agency of Medicines and Medical Devices&#41; for the joint development of this document&#46; The goal is to create a consensus guideline for the compounding of suspensions of isoniazid&#44; pyrazinamide and ethambutol&#44; with an emphasis on concentrations of 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46; Along the same lines&#44; we will study the possibility of developing paediatric dosage forms with fixed doses of two&#44; three or four antituberculosis agents at the doses needed in the paediatric population&#44; titrated based on kilogram of body weight&#46; Last of all&#44; we will review aspects in which the approach of providers across Spain are inconsistent&#44; such as the management of LTBI&#44; the need of DOT to ensure adherence to treatment&#44; or the monitoring of the side effects of first-line antituberculosis agents&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">Study supported by the Comit&#233; de Medicamentos de la Asociaci&#243;n Espa&#241;ola de Pediatr&#237;a &#40;Committee on Medicines of the Spanish Association of Pediatrics &#91;<span class="elsevierStyleGrantSponsor" id="gs1">CM-AEP</span>&#93;&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The pTBred was awarded the 2013 Research Grant of the AEP&#46; Specific funding was not awarded to this particular study&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Introduction and objectives"
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          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Results"
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          "identificador" => "sec0020"
          "titulo" => "Discussion"
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          "identificador" => "sec0025"
          "titulo" => "Funding"
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          "identificador" => "sec0030"
          "titulo" => "Conflicts of interest"
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        10 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2015-07-03"
    "fechaAceptado" => "2015-07-21"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec683610"
          "palabras" => array:5 [
            0 => "Tuberculosis"
            1 => "Children"
            2 => "Anti-tuberculous drugs"
            3 => "Community surveys"
            4 => "Drug compounding"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec683609"
          "palabras" => array:5 [
            0 => "Tuberculosis"
            1 => "Ni&#241;os"
            2 => "F&#225;rmacos antituberculosos"
            3 => "Encuestas comunitarias"
            4 => "Formulaci&#243;n magistral"
          ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are no paediatric formulations of anti-tuberculous drugs in Spain&#44; with the only exception being rifampicin&#46; Some paediatricians often prescribe composite formulations &#40;CF&#41;&#44; while others prefer to give crushed tablets&#46; Nevertheless&#44; there is no consensus in this regard&#44; or any pharmacokinetic studies validating these procedures&#46; In this situation&#44; the Spanish Network for the Study of Paediatric Tuberculosis &#40;pTBred&#41; has launched the Magistral Project&#44; which aims at its first phase to analyse the desirability of developing child-friendly pharmaceutical formulations and other aspects regarding the anti-tuberculous drug prescription in children&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A cross-sectional&#44; multicentre&#44; nationwide study was conducted&#44; based on an online questionnaire sent to members of pTBred between February and March 2015&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Fifty-four responses from 67 consulted institutions were received&#46; Most of the respondents reported prescribing crushed tablets&#46; A significant number of those surveyed&#44; although being fewer&#44; prescribe CF&#44; for which availability varies widely among institutions&#46; Eighty-three percent replied that it would be essential to have fixed dose combinations of anti-tuberculous drugs&#44; specifically adapted to paediatric doses and administered by CF or tablets&#46; Among the surveyed institutions&#44; differences were found in the management of latent tuberculosis infection&#44; in the use of directly observed therapy&#44; and in the monitoring of adverse events&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our survey reveals great diversity in anti-tuberculous drug prescription in children&#44; due to the lack of suitable infant formulations&#44; which could have an impact on treatment adherence and outcomes&#46; pTBred intends to develop a pioneering and useful consensus document on the management of anti-tuberculous medication in children&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En Espa&#241;a no existen presentaciones pedi&#225;tricas de f&#225;rmacos antituberculosos&#44; salvo para rifampicina&#46; Algunos pediatras prescriben f&#243;rmulas magistrales &#40;FM&#41;&#44; mientras que otros administran comprimidos triturados&#46; No existe consenso al respecto&#44; ni estudios de farmacocin&#233;tica que avalen estos procedimientos&#46; Ante esta situaci&#243;n&#44; la Red Espa&#241;ola de Estudio de la Tuberculosis Pedi&#225;trica &#40;pTBred&#41; desarrolla el Proyecto Magistral&#44; con el objetivo de analizar&#44; en su primera fase&#44; la conveniencia de desarrollar formas farmac&#233;uticas espec&#237;ficas para ni&#241;os&#44; as&#237; como estudiar otros aspectos relacionados con la administraci&#243;n de antituberculosos en ni&#241;os&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio transversal&#44; multic&#233;ntrico y de &#225;mbito nacional&#44; mediante encuesta <span class="elsevierStyleItalic">on-line</span> enviada por correo electr&#243;nico a los instituciones pertenecientes a pTBred entre febrero y marzo del 2015&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se recibieron 54 respuestas de 67 instituciones consultadas&#46; La mayor&#237;a de los centros trituran los comprimidos&#46; Un porcentaje elevado&#44; aunque menor&#44; administra FM&#44; cuya disponibilidad es variable entre las instituciones&#46; El 83&#37; responde que ser&#237;a ideal disponer de combinaciones fijas de antituberculosos&#44; adaptadas a las dosis pedi&#225;tricas y administradas mediante FM o en un comprimido&#46; Entre las instituciones encuestadas existen diferencias en el tratamiento de la infecci&#243;n tuberculosa latente&#44; el uso de la terapia directamente observada y la monitorizaci&#243;n de efectos adversos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestra encuesta revela gran heterogeneidad en la prescripci&#243;n de antituberculosos en ni&#241;os debido a la falta de formulaciones espec&#237;ficas para esta edad&#44; que podr&#237;a tener implicaciones en la adherencia al tratamiento y evoluci&#243;n&#46; pTBred propone elaborar un pionero y &#250;til documento de consenso sobre la administraci&#243;n de medicaci&#243;n antituberculosa en ni&#241;os&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Pi&#241;eiro P&#233;rez R&#44; Santiago Garc&#237;a B&#44; Fern&#225;ndez-Llamazares CM&#44; Baquero Artigao F&#44; Noguera Julian A&#44; Mellado Pe&#241;a MJ&#44; et al&#46; El reto de la administraci&#243;n de antituberculosos en lactantes y preescolares&#46; Proyecto Magistral de pTBred&#46; An Pediatr &#40;Barc&#41;&#46; 2016&#59;85&#58;4&#8211;12&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Previous presentations&#58; This is an original work that has not been previously presented in meetings&#44; conferences or symposia&#46;</p>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:3 [
            "apendice" => "<p id="par0165" class="elsevierStylePara elsevierViewall">Province&#58; free text&#46;</p> <p id="par0170" class="elsevierStylePara elsevierViewall">Autonomous community&#58; free text&#46;</p> <p id="par0175" class="elsevierStylePara elsevierViewall">Hospital&#58; free text&#46;</p> <p id="par0180" class="elsevierStylePara elsevierViewall">Number of children with latent TB infection and active TB disease diagnosed in your centre in 2014 &#40;does not include exposure to TB&#41;&#58;</p> <p id="par0185" class="elsevierStylePara elsevierViewall">None</p> <p id="par0190" class="elsevierStylePara elsevierViewall">1&#8211;5 children</p> <p id="par0195" class="elsevierStylePara elsevierViewall">5&#8211;10 children</p> <p id="par0200" class="elsevierStylePara elsevierViewall">More than 10 children</p> <p id="par0205" class="elsevierStylePara elsevierViewall">Select the combination drugs or FDCs that are widely used in your centre &#40;multiple-choice&#44; multiple answer question&#41;&#58;</p> <p id="par0210" class="elsevierStylePara elsevierViewall">Combinations of 150<span class="elsevierStyleHsp" style=""></span>mg isoniazid<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>mg rifampicin &#40;Rifinah<span class="elsevierStyleSup">&#174;</span>&#41;</p> <p id="par0215" class="elsevierStylePara elsevierViewall">Combinations of 50<span class="elsevierStyleHsp" style=""></span>mg isoniazid<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>120<span class="elsevierStyleHsp" style=""></span>mg rifampicin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>mg pyrazinamide &#40;Rifater<span class="elsevierStyleSup">&#174;</span>&#41;</p> <p id="par0220" class="elsevierStylePara elsevierViewall">Combinations of 75<span class="elsevierStyleHsp" style=""></span>mg isoniazid<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>mg rifampicin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>400<span class="elsevierStyleHsp" style=""></span>mg pyrazinamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>275<span class="elsevierStyleHsp" style=""></span>mg ethambutol &#40;Rimstar<span class="elsevierStyleSup">&#174;</span>&#41;</p> <p id="par0225" class="elsevierStylePara elsevierViewall">Other&#44; note which&#58; free text&#46;</p> <p id="par0230" class="elsevierStylePara elsevierViewall">Which is the regimen used most commonly in your hospital for the treatment of latent tuberculosis infection&#63;</p> <p id="par0235" class="elsevierStylePara elsevierViewall">Isoniazid for 9 months</p> <p id="par0240" class="elsevierStylePara elsevierViewall">Isoniazid for 6 months</p> <p id="par0245" class="elsevierStylePara elsevierViewall">Isoniazid<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rifampicin for 3 months</p> <p id="par0250" class="elsevierStylePara elsevierViewall">Rifampicin for 4 months</p> <p id="par0255" class="elsevierStylePara elsevierViewall">Other&#46; Which&#63;&#58; free text&#46;</p> <p id="par0260" class="elsevierStylePara elsevierViewall">Use of directly observed therapy or treatment monitoring in children&#58;</p> <p id="par0265" class="elsevierStylePara elsevierViewall">We always request it for all cases&#46;</p> <p id="par0270" class="elsevierStylePara elsevierViewall">We almost always request it&#44; except in select cases in which it is believed that the family will adhere optimally to the treatment&#46;</p> <p id="par0275" class="elsevierStylePara elsevierViewall">We requested for approximately 50&#37; of cases&#46;</p> <p id="par0280" class="elsevierStylePara elsevierViewall">We only request it when we consider that there are risk factors for poor adherence to treatment&#46;</p> <p id="par0285" class="elsevierStylePara elsevierViewall">We never request it&#46;</p> <p id="par0290" class="elsevierStylePara elsevierViewall">In regards to the use of ethambutol as the fourth antituberculosis drug &#40;multiple choice&#44; multiple answer&#41;&#58;</p> <p id="par0295" class="elsevierStylePara elsevierViewall">It is used in specific cases of tuberculosis disease &#40;miliary&#44; meningeal&#44; etc&#46;&#41;&#46;</p> <p id="par0300" class="elsevierStylePara elsevierViewall">It is used when the drug sensitivity of the strain of the index case is unknown&#46;</p> <p id="par0305" class="elsevierStylePara elsevierViewall">It is used routinely in immigrants from regions where the prevalence of isoniazid resistance is greater than 4&#37;&#46;</p> <p id="par0310" class="elsevierStylePara elsevierViewall">It is used in all cases&#44; regardless of the sensitivity of resistance of the index case strain&#46;</p> <p id="par0315" class="elsevierStylePara elsevierViewall">It is used routinely unless the strain &#40;of the paediatric patient or the index patient&#41; is known to be sensitive to H&#44; R and Z&#46;</p> <p id="par0320" class="elsevierStylePara elsevierViewall">It is never used&#46;</p> <p id="par0325" class="elsevierStylePara elsevierViewall">Other&#58; free text&#46;</p> <p id="par0330" class="elsevierStylePara elsevierViewall">In regards to eye checkups in children aged less than 5 years receiving ethambutol&#58;</p> <p id="par0335" class="elsevierStylePara elsevierViewall">We always order them&#44; in all cases&#46;</p> <p id="par0340" class="elsevierStylePara elsevierViewall">We almost always order them&#44; but not in all cases&#46;</p> <p id="par0345" class="elsevierStylePara elsevierViewall">We order them sometimes&#44; approximately in half of the cases&#46;</p> <p id="par0350" class="elsevierStylePara elsevierViewall">We order them only occasionally&#44; for example when doses of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day are used for treatment of tuberculous meningitis&#46;</p> <p id="par0355" class="elsevierStylePara elsevierViewall">We never order them&#44; as there is not enough evidence on the development of optical neuritis in children treated with ethambutol&#46;</p> <p id="par0360" class="elsevierStylePara elsevierViewall">In regards to liver enzyme tests&#58;</p> <p id="par0365" class="elsevierStylePara elsevierViewall">We never order them&#44; unless the patient develops manifestations compatible with hepatic cytolysis&#46;</p> <p id="par0370" class="elsevierStylePara elsevierViewall">We always test before initiating treatment&#44; but not after unless the patient develops manifestations compatible with hepatic cytolysis&#46;</p> <p id="par0375" class="elsevierStylePara elsevierViewall">We test before initiation of treatment and periodically thereon&#46;</p> <p id="par0380" class="elsevierStylePara elsevierViewall">Other&#58; free text&#46;</p> <p id="par0385" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Isoniazid</span></p> <p id="par0390" class="elsevierStylePara elsevierViewall">Describe the form&#40;s&#41; in which you usually prescribe isoniazid to children unable to swallow pills &#40;multiple choice&#44; multiple answer&#41;&#58;</p> <p id="par0395" class="elsevierStylePara elsevierViewall">Compounded preparation of isoniazid 10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p> <p id="par0400" class="elsevierStylePara elsevierViewall">Another compounded preparation of isoniazid&#46; At which concentration&#63;&#58; free text&#46;</p> <p id="par0405" class="elsevierStylePara elsevierViewall">Isoniazid tablets &#40;50&#44; 150 or 300<span class="elsevierStyleHsp" style=""></span>mg&#41;&#44; crushed and mixed with water or juice&#46;</p> <p id="par0410" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p> <p id="par0415" class="elsevierStylePara elsevierViewall">Describe the form in which you most frequently prescribe isoniazid to children unable to swallow pills &#40;multiple choice&#44; single answer&#41;&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8211;</span><p id="par0420" class="elsevierStylePara elsevierViewall">Compounded preparation of isoniazid 10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8211;</span><p id="par0425" class="elsevierStylePara elsevierViewall">Isoniazid compounded preparation &#40;another&#41;&#46; At which concentration&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8211;</span><p id="par0430" class="elsevierStylePara elsevierViewall">Isoniazid tablets &#40;50&#44; 150 or 300<span class="elsevierStyleHsp" style=""></span>mg&#41;&#44; crushed and mixed with water or juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8211;</span><p id="par0435" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p></li></ul></p> <p id="par0440" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Rifampicin</span></p> <p id="par0445" class="elsevierStylePara elsevierViewall">Describe the form&#40;s&#41; in which you usually prescribe rifampicin to children unable to swallow pills &#40;multiple choice&#44; multiple answer&#41;&#58;</p> <p id="par0450" class="elsevierStylePara elsevierViewall">Rifaldin<span class="elsevierStyleSup">&#174;</span> 20<span class="elsevierStyleHsp" style=""></span>mg&#47;mL suspension&#46;</p> <p id="par0455" class="elsevierStylePara elsevierViewall">Compounded formulation&#46; At which concentration&#63;&#58; free text&#46;</p> <p id="par0460" class="elsevierStylePara elsevierViewall">Rifampicin 300<span class="elsevierStyleHsp" style=""></span>mg capsules&#44; opened and mixed with water or juice&#46;</p> <p id="par0465" class="elsevierStylePara elsevierViewall">Rifampicin 600<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&#46;</p> <p id="par0470" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p> <p id="par0475" class="elsevierStylePara elsevierViewall">Describe the form in which you most frequently prescribe rifampicin to children unable to swallow pills &#40;multiple choice&#44; single answer&#41;&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8211;</span><p id="par0480" class="elsevierStylePara elsevierViewall">Rifaldin<span class="elsevierStyleSup">&#174;</span> 20<span class="elsevierStyleHsp" style=""></span>mg&#47;mL suspension&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8211;</span><p id="par0485" class="elsevierStylePara elsevierViewall">Compounded formulation&#46; At which concentration&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8211;</span><p id="par0490" class="elsevierStylePara elsevierViewall">Rifampicin 300<span class="elsevierStyleHsp" style=""></span>mg capsules&#44; opened and mixed with water or juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8211;</span><p id="par0495" class="elsevierStylePara elsevierViewall">Rifampicin 600<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8211;</span><p id="par0500" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p></li></ul></p> <p id="par0505" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Pyrazinamide</span></p> <p id="par0510" class="elsevierStylePara elsevierViewall">Describe the form&#40;s&#41; in which you usually prescribe pyrazinamide to children unable to swallow pills &#40;multiple choice&#44; multiple answer&#41;&#58;</p> <p id="par0515" class="elsevierStylePara elsevierViewall">Compounded formulation of pyrazinamide 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p> <p id="par0520" class="elsevierStylePara elsevierViewall">Compounded formulation of pyrazinamide &#40;other&#41;&#46; At which concentration&#63;&#58; free text&#46;</p> <p id="par0525" class="elsevierStylePara elsevierViewall">Pyrazinamide 250<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&#46;</p> <p id="par0530" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p> <p id="par0535" class="elsevierStylePara elsevierViewall">Describe the form in which you most frequently prescribe pyrazinamide to children unable to swallow pills &#40;multiple choice&#44; single answer&#41;&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8211;</span><p id="par0540" class="elsevierStylePara elsevierViewall">Compounded formulation of pyrazinamide 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8211;</span><p id="par0545" class="elsevierStylePara elsevierViewall">Compounded formulation of pyrazinamide &#40;other&#41;&#46; At which concentration&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8211;</span><p id="par0550" class="elsevierStylePara elsevierViewall">Pyrazinamide 250<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8211;</span><p id="par0555" class="elsevierStylePara elsevierViewall">FDC tablets&#44; crushed and mixed with water or juice&#46;</p></li></ul></p> <p id="par0560" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Ethambutol</span></p> <p id="par0565" class="elsevierStylePara elsevierViewall">Describe the form&#40;s&#41; in which you usually prescribe ethambutol to children unable to swallow pills &#40;multiple choice&#44; multiple answer&#41;&#58;</p> <p id="par0570" class="elsevierStylePara elsevierViewall">Compounded formulation of ethambutol 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p> <p id="par0575" class="elsevierStylePara elsevierViewall">Compounded formulation of ethambutol &#40;other&#41;&#46; At which concentration&#63;&#58; free text&#46;</p> <p id="par0580" class="elsevierStylePara elsevierViewall">Coated tablets of ethambutol 400<span class="elsevierStyleHsp" style=""></span>mg crushed and mixed with water or juice&#46;</p> <p id="par0585" class="elsevierStylePara elsevierViewall">FDC tablets crushed and mixed with water or juice&#46;</p> <p id="par0590" class="elsevierStylePara elsevierViewall">Describe the form in which you most frequently prescribe ethambutol to children unable to swallow pills &#40;multiple choice&#44; single answer&#41;&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8211;</span><p id="par0595" class="elsevierStylePara elsevierViewall">Compounded formulation of ethambutol 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8211;</span><p id="par0600" class="elsevierStylePara elsevierViewall">Compounded formulation of ethambutol &#40;other&#41;&#46; At which concentration&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8211;</span><p id="par0605" class="elsevierStylePara elsevierViewall">Coated tablets of ethambutol 400<span class="elsevierStyleHsp" style=""></span>mg crushed and mixed with water or juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8211;</span><p id="par0610" class="elsevierStylePara elsevierViewall">FDC tablets crushed and mixed with water or juice&#46;</p></li></ul></p> <p id="par0615" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Availability of compounded preparations in the hospital</span><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></p> <p id="par0620" class="elsevierStylePara elsevierViewall">Availability of compounded preparations of isoniazid in your centre &#40;multiple choice&#44; multiple answer&#41;&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8211;</span><p id="par0625" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8211;</span><p id="par0630" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8211;</span><p id="par0635" class="elsevierStylePara elsevierViewall">We have compounded preparations at a different concentration&#46; Which&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8211;</span><p id="par0640" class="elsevierStylePara elsevierViewall">No compounded preparation of isoniazid is available&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8211;</span><p id="par0645" class="elsevierStylePara elsevierViewall">We do not know&#46;</p></li></ul>Availability of compounded preparations of pyrazinamide in your centre &#40;multiple choice&#44; multiple answer&#41;&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8211;</span><p id="par0650" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8211;</span><p id="par0655" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8211;</span><p id="par0660" class="elsevierStylePara elsevierViewall">We have compounded preparations at a different concentration&#46; Which&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8211;</span><p id="par0665" class="elsevierStylePara elsevierViewall">No compounded preparation of pyrazinamide is available&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8211;</span><p id="par0670" class="elsevierStylePara elsevierViewall">We do not know&#46;</p></li></ul>Availability of compounded preparations of ethambutol in your centre &#40;multiple choice&#44; multiple answer&#41;&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8211;</span><p id="par0675" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8211;</span><p id="par0680" class="elsevierStylePara elsevierViewall">Available at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#8211;</span><p id="par0685" class="elsevierStylePara elsevierViewall">We have compounded preparations at a different concentration&#46; Which&#63;&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#8211;</span><p id="par0690" class="elsevierStylePara elsevierViewall">No compounded preparation of ethambutol is available&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#8211;</span><p id="par0695" class="elsevierStylePara elsevierViewall">We do not know&#46;</p></li></ul>Assuming you use crushed tablets&#44; they are most frequently mixed with&#58;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">&#8211;</span><p id="par0700" class="elsevierStylePara elsevierViewall">Water&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">&#8211;</span><p id="par0705" class="elsevierStylePara elsevierViewall">Milk&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">&#8211;</span><p id="par0710" class="elsevierStylePara elsevierViewall">Juice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">&#8211;</span><p id="par0715" class="elsevierStylePara elsevierViewall">Other&#58; free text&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">&#8211;</span><p id="par0720" class="elsevierStylePara elsevierViewall">We do not crush tablets&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">&#8211;</span><p id="par0725" class="elsevierStylePara elsevierViewall">We have no preference&#46;</p></li></ul></p> <p id="par0730" class="elsevierStylePara elsevierViewall">Assuming you use crushed tablets&#44; do you recommend a particular type of splitter&#47;crusher&#63;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">&#8211;</span><p id="par0735" class="elsevierStylePara elsevierViewall">Yes&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">&#8211;</span><p id="par0740" class="elsevierStylePara elsevierViewall">No&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">&#8211;</span><p id="par0745" class="elsevierStylePara elsevierViewall">We do not crush tablets&#46;</p></li></ul></p> <p id="par0750" class="elsevierStylePara elsevierViewall">In regards to the administration of medication under fasting conditions&#58;</p> <p id="par0755" class="elsevierStylePara elsevierViewall">All medications are administered under fasting conditions&#46;</p> <p id="par0760" class="elsevierStylePara elsevierViewall">Only rifampicin is administered under fasting conditions&#46;</p> <p id="par0765" class="elsevierStylePara elsevierViewall">Medications are not administered under fasting conditions&#44; but with food&#46;</p> <p id="par0770" class="elsevierStylePara elsevierViewall">Not administered fasting or with food&#46;</p> <p id="par0775" class="elsevierStylePara elsevierViewall">Other&#58; free text&#46;</p> <p id="par0780" class="elsevierStylePara elsevierViewall">Do you think that a compounded preparations or FDC with the following combination of antituberculosis agents&#58; 150<span class="elsevierStyleHsp" style=""></span>mg H&#44; 200<span class="elsevierStyleHsp" style=""></span>mg R&#44; 350<span class="elsevierStyleHsp" style=""></span>mg Z<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>mg E &#40;or else 75<span class="elsevierStyleHsp" style=""></span>mg H&#44; 100<span class="elsevierStyleHsp" style=""></span>mg R&#44; 175<span class="elsevierStyleHsp" style=""></span>mg Z<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg E&#41; would be useful in the treatment of tuberculosis in children&#63;</p> <p id="par0785" class="elsevierStylePara elsevierViewall">Yes&#44; it would be ideal&#46;</p> <p id="par0790" class="elsevierStylePara elsevierViewall">No&#44; FDCs with those concentrations are already available&#46;</p> <p id="par0795" class="elsevierStylePara elsevierViewall">There are no FDCs with those concentrations&#44; but the FDCs that are available suffice to adequately treat children&#46;</p>"
            "etiqueta" => "Appendix A"
            "identificador" => "sec0035"
          ]
        ]
      ]
    ]
    "multimedia" => array:6 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Number of patients with latent tuberculosis infection or active tuberculosis disease that received care at the surveyed institutions in 2014&#46;</p>"
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      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at1"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Active ingredient&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">Commercial paediatric formulation&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">Compounded preparation&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">Isoniazid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unavailable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Isoniazid 10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL<br>Isoniazid 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&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">Rifampicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rifaldin<span class="elsevierStyleSup">&#174;</span> oral suspension&#44; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;5<span class="elsevierStyleHsp" style=""></span>mL&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">Pyrazinamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unavailable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pyrazinamide 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL<br>Pyrazinamide 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&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">Unavailable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ethambutol 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL<br>Ethambutol 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1112123.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Antituberculosis agents available as oral solution or suspension in Spain&#46;</p>"
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at2"
            "detalle" => "Table "
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">E&#44; ethambutol&#59; H&#44; isoniazid&#59; R&#44; rifampicin&#59; Z&#44; pyrazinamide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Commercial formulation&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">Dosage forms and dosing &#40;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Combinations of de H</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">R</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>Rifinah<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Compressed tablet 150 &#40;H&#41;&#47;300 &#40;R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rimactazid<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Coated tablet 150 &#40;H&#41;&#47;300 &#40;R&#41; and tablet 75 &#40;H&#41;&#47;150 &#40;R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Combinations of H</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Z</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>Rifater<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Compressed tablet 50 &#40;H&#41;&#47;120 &#40;R&#41;&#47;300 &#40;Z&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rimcure<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Compressed tablet 75 &#40;H&#41;&#47;150 &#40;R&#41;&#47;400 &#40;Z&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Combinations of H</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Z</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">E</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>Rimstar<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Compressed tablet 75 &#40;H&#41;&#47;150 &#40;R&#41;&#47;400 &#40;Z&#41;&#47;275 &#40;E&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Fixed-dose combinations available in Spain&#46; As of July 2015&#44; the marketing authorisation for Rimactazid<span class="elsevierStyleSup">&#174;</span> and Rimcure<span class="elsevierStyleSup">&#174;</span> was suspended&#44; based on data from the Centro de Informaci&#243;n online de Medicamentos de la Agencia Espa&#241;ola de Medicamentos y Productos Sanitarios &#40;Online Medicines Information Centre of the Spanish Agency of Medicines and Medical Devices &#91;CIMA-AEMPS&#93;&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><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">Isoniazid</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of isoniazid 10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;30&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of isoniazid 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Isoniazid tablets &#40;50&#44; 150 or 300<span class="elsevierStyleHsp" style=""></span>mg&#41;&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25 &#40;46&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FDC tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;13&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Rifampicin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rifaldin<span class="elsevierStyleSup">&#174;</span> suspension 20<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49 &#40;90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rifampicin 300<span class="elsevierStyleHsp" style=""></span>mg capsules&#44; opened and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rifampicin 600<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FDC tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Pyrazinamide</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of pyrazinamide 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of pyrazinamide 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23 &#40;43&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pyrazinamide 250<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;48&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FDC tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Ethambutol</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of ethambutol 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;17&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Compounded preparation of ethambutol 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;26&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Coated tablets of ethambutol 400<span class="elsevierStyleHsp" style=""></span>mg&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20 &#40;37&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FDC tablets&#44; crushed and mixed with water or juice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Availability of compounded preparations in the hospital &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&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">Isoniazid&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">Pyrazinamide&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">Ethambutol&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">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#37;&#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">Never&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;17&#37;&#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">Rarely&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;6&#37;&#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">Sometimes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;15&#37;&#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">Almost always&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;17&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;19&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;13&#37;&#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">Always&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23 &#40;42&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22 &#40;40&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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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="" 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">Unknown&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">Never&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">Almost never&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">Sometimes&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">Nearly always&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">Always&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">Isoniazid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></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="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 23412879
Original language: English

DOI:10.1016/j.anpede.2015.07.038

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Year/Month	Html	Pdf	Total

2024 November	8	8	16
2024 October	59	50	109
2024 September	64	26	90
2024 August	60	43	103
2024 July	91	24	115
2024 June	75	35	110
2024 May	75	33	108
2024 April	71	43	114
2024 March	54	31	85
2024 February	63	27	90
2024 January	75	23	98
2023 December	127	33	160
2023 November	108	34	142
2023 October	74	28	102
2023 September	67	25	92
2023 August	74	15	89
2023 July	102	35	137
2023 June	57	26	83
2023 May	78	33	111
2023 April	40	30	70
2023 March	85	33	118
2023 February	67	10	77
2023 January	79	37	116
2022 December	68	35	103
2022 November	90	35	125
2022 October	68	37	105
2022 September	63	42	105
2022 August	112	44	156
2022 July	91	34	125
2022 June	91	42	133
2022 May	79	40	119
2022 April	83	27	110
2022 March	117	41	158
2022 February	75	41	116
2022 January	83	46	129
2021 December	86	43	129
2021 November	137	43	180
2021 October	185	81	266
2021 September	63	41	104
2021 August	87	45	132
2021 July	72	23	95
2021 June	103	47	150
2021 May	100	47	147
2021 April	217	98	315
2021 March	110	31	141
2021 February	70	21	91
2021 January	103	23	126
2020 December	90	29	119
2020 November	84	26	110
2020 October	76	26	102
2020 September	95	31	126
2020 August	88	20	108
2020 July	88	14	102
2020 June	87	19	106
2020 May	107	29	136
2020 April	62	18	80
2020 March	97	29	126
2020 February	109	21	130
2020 January	93	24	117
2019 December	89	24	113
2019 November	61	11	72
2019 October	88	19	107
2019 September	126	16	142
2019 August	97	20	117
2019 July	69	29	98
2019 June	86	29	115
2019 May	133	22	155
2019 April	95	22	117
2019 March	51	18	69
2019 February	48	13	61
2019 January	68	16	84
2018 December	73	30	103
2018 November	118	32	150
2018 October	169	44	213
2018 September	96	22	118
2018 August	1	0	1
2018 June	3	0	3
2018 May	5	0	5
2018 April	25	0	25
2018 March	19	0	19
2018 February	11	0	11
2018 January	19	0	19
2017 December	16	0	16
2017 November	17	0	17
2017 October	11	0	11
2017 September	9	0	9
2017 August	20	0	20
2017 July	25	0	25
2017 June	32	8	40
2017 May	41	9	50
2017 April	16	4	20
2017 March	11	1	12
2017 February	10	4	14
2017 January	15	3	18
2016 December	32	27	59
2016 November	36	24	60
2016 October	45	17	62
2016 September	47	4	51
2016 August	55	6	61
2016 July	46	14	60

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