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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: early experiences and challenges</title><author><name sortKey="Tadolini, Marina" sort="Tadolini, Marina" uniqKey="Tadolini M" first="Marina" last="Tadolini">Marina Tadolini</name><affiliation><nlm:aff id="af1">Unit of Infectious Diseases, Dept of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Garcia Prats, Anthony J" sort="Garcia Prats, Anthony J" uniqKey="Garcia Prats A" first="Anthony J." last="Garcia-Prats">Anthony J. Garcia-Prats</name><affiliation><nlm:aff id="af2">Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="D Ambrosio, Lia" sort="D Ambrosio, Lia" uniqKey="D Ambrosio L" first="Lia" last="D'Ambrosio">Lia D'Ambrosio</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af4">Public Health Consulting Group, Lugano, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Hewison, Catherine" sort="Hewison, Catherine" uniqKey="Hewison C" first="Catherine" last="Hewison">Catherine Hewison</name><affiliation><nlm:aff id="af5">Médecins Sans Frontières, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Centis, Rosella" sort="Centis, Rosella" uniqKey="Centis R" first="Rosella" last="Centis">Rosella Centis</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Schaaf, H Simon" sort="Schaaf, H Simon" uniqKey="Schaaf H" first="H. Simon" last="Schaaf">H. Simon Schaaf</name><affiliation><nlm:aff id="af2">Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Marais, Ben J" sort="Marais, Ben J" uniqKey="Marais B" first="Ben J." last="Marais">Ben J. Marais</name><affiliation><nlm:aff id="af6">Children's Hospital at Westmead and the Centre for Research Excellence in Tuberculosis, University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Ferreira, Hannetjie" sort="Ferreira, Hannetjie" uniqKey="Ferreira H" first="Hannetjie" last="Ferreira">Hannetjie Ferreira</name><affiliation><nlm:aff id="af7">MDR/XDR TB Unit, Tshepong Hospital Klerksdorp, Klerksdorp, South Africa</nlm:aff></affiliation></author><author><name sortKey="Caminero, Jose A" sort="Caminero, Jose A" uniqKey="Caminero J" first="Jose A." last="Caminero">Jose A. Caminero</name><affiliation><nlm:aff id="af8">MDR-TB Unit, Tuberculosis Division, International Union against Tuberculosis and Lung Disease (The Union), Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af9">Pneumology Dept, Hospital General de Gran Canaria “Dr Negrin”, Las Palmas de Gran Canaria, Spain</nlm:aff></affiliation></author><author><name sortKey="Jonckheere, Sylvie" sort="Jonckheere, Sylvie" uniqKey="Jonckheere S" first="Sylvie" last="Jonckheere">Sylvie Jonckheere</name><affiliation><nlm:aff id="af10">Médecins Sans Frontières, Mumbai, India</nlm:aff></affiliation></author><author><name sortKey="Sinha, Animesh" sort="Sinha, Animesh" uniqKey="Sinha A" first="Animesh" last="Sinha">Animesh Sinha</name><affiliation><nlm:aff id="af11">Médecins Sans Frontières, Moscow, Russian Federation</nlm:aff></affiliation></author><author><name sortKey="Herboczek, Krzysztof" sort="Herboczek, Krzysztof" uniqKey="Herboczek K" first="Krzysztof" last="Herboczek">Krzysztof Herboczek</name><affiliation><nlm:aff id="af12">Médecins Sans Frontières, London, UK</nlm:aff></affiliation></author><author><name sortKey="Khaidarkhanova, Zarema" sort="Khaidarkhanova, Zarema" uniqKey="Khaidarkhanova Z" first="Zarema" last="Khaidarkhanova">Zarema Khaidarkhanova</name><affiliation><nlm:aff id="af13">Republican TB Dispensary, Grozny, Chechen Republic, Russian Federation</nlm:aff></affiliation></author><author><name sortKey="Hayrapetyan, Armen" sort="Hayrapetyan, Armen" uniqKey="Hayrapetyan A" first="Armen" last="Hayrapetyan">Armen Hayrapetyan</name><affiliation><nlm:aff id="af14">Armenian National Tuberculosis Control Centre, Yerevan, Armenia</nlm:aff></affiliation></author><author><name sortKey="Khachatryan, Naira" sort="Khachatryan, Naira" uniqKey="Khachatryan N" first="Naira" last="Khachatryan">Naira Khachatryan</name><affiliation><nlm:aff id="af15">Médecins Sans Frontières, Yerevan, Armenia</nlm:aff></affiliation></author><author><name sortKey="Urtkmelidze, Ia" sort="Urtkmelidze, Ia" uniqKey="Urtkmelidze I" first="Ia" last="Urtkmelidze">Ia Urtkmelidze</name><affiliation><nlm:aff id="af16">National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia</nlm:aff></affiliation></author><author><name sortKey="Loreti, Carolina" sort="Loreti, Carolina" uniqKey="Loreti C" first="Carolina" last="Loreti">Carolina Loreti</name><affiliation><nlm:aff id="af17">Médecins Sans Frontières, Tbilisi, Georgia</nlm:aff></affiliation></author><author><name sortKey="Esposito, Susanna" sort="Esposito, Susanna" uniqKey="Esposito S" first="Susanna" last="Esposito">Susanna Esposito</name><affiliation><nlm:aff id="af18">Paediatric Highly Intensive Care Unit, Dept of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Matteelli, Alberto" sort="Matteelli, Alberto" uniqKey="Matteelli A" first="Alberto" last="Matteelli">Alberto Matteelli</name><affiliation><nlm:aff id="af19">University Dept of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy</nlm:aff></affiliation></author><author><name sortKey="Furin, Jennifer" sort="Furin, Jennifer" uniqKey="Furin J" first="Jennifer" last="Furin">Jennifer Furin</name><affiliation><nlm:aff id="af20">Harvard Medical School, Dept of Global Health and Social Medicine, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Varaine, Francis" sort="Varaine, Francis" uniqKey="Varaine F" first="Francis" last="Varaine">Francis Varaine</name><affiliation><nlm:aff id="af5">Médecins Sans Frontières, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Migliori, Giovanni Battista" sort="Migliori, Giovanni Battista" uniqKey="Migliori G" first="Giovanni Battista" last="Migliori">Giovanni Battista Migliori</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27338197</idno><idno type="pmc">5007219</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007219</idno><idno type="RBID">PMC:5007219</idno><idno type="doi">10.1183/13993003.00705-2016</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">001317</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001317</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: early experiences and challenges</title><author><name sortKey="Tadolini, Marina" sort="Tadolini, Marina" uniqKey="Tadolini M" first="Marina" last="Tadolini">Marina Tadolini</name><affiliation><nlm:aff id="af1">Unit of Infectious Diseases, Dept of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Garcia Prats, Anthony J" sort="Garcia Prats, Anthony J" uniqKey="Garcia Prats A" first="Anthony J." last="Garcia-Prats">Anthony J. Garcia-Prats</name><affiliation><nlm:aff id="af2">Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="D Ambrosio, Lia" sort="D Ambrosio, Lia" uniqKey="D Ambrosio L" first="Lia" last="D'Ambrosio">Lia D'Ambrosio</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af4">Public Health Consulting Group, Lugano, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Hewison, Catherine" sort="Hewison, Catherine" uniqKey="Hewison C" first="Catherine" last="Hewison">Catherine Hewison</name><affiliation><nlm:aff id="af5">Médecins Sans Frontières, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Centis, Rosella" sort="Centis, Rosella" uniqKey="Centis R" first="Rosella" last="Centis">Rosella Centis</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Schaaf, H Simon" sort="Schaaf, H Simon" uniqKey="Schaaf H" first="H. Simon" last="Schaaf">H. Simon Schaaf</name><affiliation><nlm:aff id="af2">Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</nlm:aff></affiliation><affiliation><nlm:aff id="af21">These authors contributed equally</nlm:aff></affiliation></author><author><name sortKey="Marais, Ben J" sort="Marais, Ben J" uniqKey="Marais B" first="Ben J." last="Marais">Ben J. Marais</name><affiliation><nlm:aff id="af6">Children's Hospital at Westmead and the Centre for Research Excellence in Tuberculosis, University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Ferreira, Hannetjie" sort="Ferreira, Hannetjie" uniqKey="Ferreira H" first="Hannetjie" last="Ferreira">Hannetjie Ferreira</name><affiliation><nlm:aff id="af7">MDR/XDR TB Unit, Tshepong Hospital Klerksdorp, Klerksdorp, South Africa</nlm:aff></affiliation></author><author><name sortKey="Caminero, Jose A" sort="Caminero, Jose A" uniqKey="Caminero J" first="Jose A." last="Caminero">Jose A. Caminero</name><affiliation><nlm:aff id="af8">MDR-TB Unit, Tuberculosis Division, International Union against Tuberculosis and Lung Disease (The Union), Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af9">Pneumology Dept, Hospital General de Gran Canaria “Dr Negrin”, Las Palmas de Gran Canaria, Spain</nlm:aff></affiliation></author><author><name sortKey="Jonckheere, Sylvie" sort="Jonckheere, Sylvie" uniqKey="Jonckheere S" first="Sylvie" last="Jonckheere">Sylvie Jonckheere</name><affiliation><nlm:aff id="af10">Médecins Sans Frontières, Mumbai, India</nlm:aff></affiliation></author><author><name sortKey="Sinha, Animesh" sort="Sinha, Animesh" uniqKey="Sinha A" first="Animesh" last="Sinha">Animesh Sinha</name><affiliation><nlm:aff id="af11">Médecins Sans Frontières, Moscow, Russian Federation</nlm:aff></affiliation></author><author><name sortKey="Herboczek, Krzysztof" sort="Herboczek, Krzysztof" uniqKey="Herboczek K" first="Krzysztof" last="Herboczek">Krzysztof Herboczek</name><affiliation><nlm:aff id="af12">Médecins Sans Frontières, London, UK</nlm:aff></affiliation></author><author><name sortKey="Khaidarkhanova, Zarema" sort="Khaidarkhanova, Zarema" uniqKey="Khaidarkhanova Z" first="Zarema" last="Khaidarkhanova">Zarema Khaidarkhanova</name><affiliation><nlm:aff id="af13">Republican TB Dispensary, Grozny, Chechen Republic, Russian Federation</nlm:aff></affiliation></author><author><name sortKey="Hayrapetyan, Armen" sort="Hayrapetyan, Armen" uniqKey="Hayrapetyan A" first="Armen" last="Hayrapetyan">Armen Hayrapetyan</name><affiliation><nlm:aff id="af14">Armenian National Tuberculosis Control Centre, Yerevan, Armenia</nlm:aff></affiliation></author><author><name sortKey="Khachatryan, Naira" sort="Khachatryan, Naira" uniqKey="Khachatryan N" first="Naira" last="Khachatryan">Naira Khachatryan</name><affiliation><nlm:aff id="af15">Médecins Sans Frontières, Yerevan, Armenia</nlm:aff></affiliation></author><author><name sortKey="Urtkmelidze, Ia" sort="Urtkmelidze, Ia" uniqKey="Urtkmelidze I" first="Ia" last="Urtkmelidze">Ia Urtkmelidze</name><affiliation><nlm:aff id="af16">National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia</nlm:aff></affiliation></author><author><name sortKey="Loreti, Carolina" sort="Loreti, Carolina" uniqKey="Loreti C" first="Carolina" last="Loreti">Carolina Loreti</name><affiliation><nlm:aff id="af17">Médecins Sans Frontières, Tbilisi, Georgia</nlm:aff></affiliation></author><author><name sortKey="Esposito, Susanna" sort="Esposito, Susanna" uniqKey="Esposito S" first="Susanna" last="Esposito">Susanna Esposito</name><affiliation><nlm:aff id="af18">Paediatric Highly Intensive Care Unit, Dept of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Matteelli, Alberto" sort="Matteelli, Alberto" uniqKey="Matteelli A" first="Alberto" last="Matteelli">Alberto Matteelli</name><affiliation><nlm:aff id="af19">University Dept of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy</nlm:aff></affiliation></author><author><name sortKey="Furin, Jennifer" sort="Furin, Jennifer" uniqKey="Furin J" first="Jennifer" last="Furin">Jennifer Furin</name><affiliation><nlm:aff id="af20">Harvard Medical School, Dept of Global Health and Social Medicine, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Varaine, Francis" sort="Varaine, Francis" uniqKey="Varaine F" first="Francis" last="Varaine">Francis Varaine</name><affiliation><nlm:aff id="af5">Médecins Sans Frontières, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Migliori, Giovanni Battista" sort="Migliori, Giovanni Battista" uniqKey="Migliori G" first="Giovanni Battista" last="Migliori">Giovanni Battista Migliori</name><affiliation><nlm:aff id="af3">Fondazione S. Maugeri, IRCCS, Tradate, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">The European Respiratory Journal</title><idno type="ISSN">0903-1936</idno><idno type="eISSN">1399-3003</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The World Health Organization (WHO) estimated that 480 000 new multidrug-resistant (MDR) tuberculosis (TB) cases occurred globally in 2014, with 190 000 deaths. Limited data are available on the burden of MDR-TB in children. A recent systematic review estimated that 32 000 children acquire MDR-TB annually; of these, very few are correctly diagnosed and provided with appropriate treatment [1].</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jenkins, He" uniqKey="Jenkins H">HE Jenkins</name></author><author><name sortKey="Tolman, Aw" uniqKey="Tolman A">AW Tolman</name></author><author><name sortKey="Yuen, Cm" uniqKey="Yuen C">CM Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Migliori, Gb" uniqKey="Migliori G">GB Migliori</name></author><author><name sortKey="Sotgiu, G" uniqKey="Sotgiu G">G Sotgiu</name></author><author><name sortKey="Gandhi, Nr" uniqKey="Gandhi N">NR Gandhi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Diel, R" uniqKey="Diel R">R Diel</name></author><author><name sortKey="Vandeputte, J" uniqKey="Vandeputte J">J Vandeputte</name></author><author><name sortKey="De Vries, G" uniqKey="De Vries G">G de Vries</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seddon, Ja" uniqKey="Seddon J">JA Seddon</name></author><author><name sortKey="Furin, Jj" uniqKey="Furin J">JJ Furin</name></author><author><name sortKey="Gale, M" uniqKey="Gale M">M Gale</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Bonnet, M" uniqKey="Bonnet M">M Bonnet</name></author><author><name sortKey="Bastard, M" uniqKey="Bastard M">M Bastard</name></author><author><name sortKey="Du Cros, P" uniqKey="Du Cros P">P du Cros</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pontali, E" uniqKey="Pontali E">E Pontali</name></author><author><name sortKey="Sotgiu, G" uniqKey="Sotgiu G">G Sotgiu</name></author><author><name sortKey="D Ambrosio, L" uniqKey="D Ambrosio L">L D'Ambrosio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Esposito, S" uniqKey="Esposito S">S Esposito</name></author><author><name sortKey="D Ambrosio, L" uniqKey="D Ambrosio L">L D'Ambrosio</name></author><author><name sortKey="Tadolini, M" uniqKey="Tadolini M">M Tadolini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tiberi, S" uniqKey="Tiberi S">S Tiberi</name></author><author><name sortKey="De Lorenzo, S" uniqKey="De Lorenzo S">S De Lorenzo</name></author><author><name sortKey="Centis, R" uniqKey="Centis R">R Centis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guglielmetti, L" uniqKey="Guglielmetti L">L Guglielmetti</name></author><author><name sortKey="Le Du, D" uniqKey="Le Du D">D Le Dû</name></author><author><name sortKey="Jachym, M" uniqKey="Jachym M">M Jachym</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lessem, E" uniqKey="Lessem E">E Lessem</name></author><author><name sortKey="Cox, H" uniqKey="Cox H">H Cox</name></author><author><name sortKey="Daniels, C" uniqKey="Daniels C">C Daniels</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Lachatre, M" uniqKey="Lachatre M">M Lachâtre</name></author><author><name sortKey="Rioux, C" uniqKey="Rioux C">C Rioux</name></author><author><name sortKey="Du, Dl" uniqKey="Du D">DL Dû</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tadolini, M" uniqKey="Tadolini M">M Tadolini</name></author><author><name sortKey="Lingtsang, Rd" uniqKey="Lingtsang R">RD Lingtsang</name></author><author><name sortKey="Tiberi, S" uniqKey="Tiberi S">S Tiberi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Matteelli, A" uniqKey="Matteelli A">A Matteelli</name></author><author><name sortKey="D Ambrosio, L" uniqKey="D Ambrosio L">L D'Ambrosio</name></author><author><name sortKey="Centis, R" uniqKey="Centis R">R Centis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nachman, S" uniqKey="Nachman S">S Nachman</name></author><author><name sortKey="Ahmed, A" uniqKey="Ahmed A">A Ahmed</name></author><author><name sortKey="Amanullah, F" uniqKey="Amanullah F">F Amanullah</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="letter"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Eur Respir J</journal-id><journal-id journal-id-type="iso-abbrev">Eur. Respir. J</journal-id><journal-id journal-id-type="publisher-id">ERJ</journal-id><journal-id journal-id-type="hwp">erj</journal-id><journal-title-group><journal-title>The European Respiratory Journal</journal-title></journal-title-group><issn pub-type="ppub">0903-1936</issn><issn pub-type="epub">1399-3003</issn><publisher><publisher-name>European Respiratory Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27338197</article-id><article-id pub-id-type="pmc">5007219</article-id><article-id pub-id-type="doi">10.1183/13993003.00705-2016</article-id><article-id pub-id-type="publisher-id">ERJ-00705-2016</article-id><article-categories><subj-group subj-group-type="heading"><subject>Agora</subject><subj-group><subject>Research Letters</subject></subj-group></subj-group><subj-group subj-group-type="hwp-journal-coll"><subject>4</subject></subj-group></article-categories><title-group><article-title>Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: early experiences and challenges</article-title><alt-title alt-title-type="short">Use of new drugs in children and adolescents with MDR/XDR-TB</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tadolini</surname><given-names>Marina</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Garcia-Prats</surname><given-names>Anthony J.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>D'Ambrosio</surname><given-names>Lia</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Hewison</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Centis</surname><given-names>Rosella</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Schaaf</surname><given-names>H. Simon</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Marais</surname><given-names>Ben J.</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ferreira</surname><given-names>Hannetjie</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Caminero</surname><given-names>Jose A.</given-names></name><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Jonckheere</surname><given-names>Sylvie</given-names></name><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Sinha</surname><given-names>Animesh</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Herboczek</surname><given-names>Krzysztof</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Khaidarkhanova</surname><given-names>Zarema</given-names></name><xref ref-type="aff" rid="af13">13</xref></contrib><contrib contrib-type="author"><name><surname>Hayrapetyan</surname><given-names>Armen</given-names></name><xref ref-type="aff" rid="af14">14</xref></contrib><contrib contrib-type="author"><name><surname>Khachatryan</surname><given-names>Naira</given-names></name><xref ref-type="aff" rid="af15">15</xref></contrib><contrib contrib-type="author"><name><surname>Urtkmelidze</surname><given-names>Ia</given-names></name><xref ref-type="aff" rid="af16">16</xref></contrib><contrib contrib-type="author"><name><surname>Loreti</surname><given-names>Carolina</given-names></name><xref ref-type="aff" rid="af17">17</xref></contrib><contrib contrib-type="author"><name><surname>Esposito</surname><given-names>Susanna</given-names></name><xref ref-type="aff" rid="af18">18</xref></contrib><contrib contrib-type="author"><name><surname>Matteelli</surname><given-names>Alberto</given-names></name><xref ref-type="aff" rid="af19">19</xref></contrib><contrib contrib-type="author"><name><surname>Furin</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="af20">20</xref></contrib><contrib contrib-type="author"><name><surname>Varaine</surname><given-names>Francis</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-2597-574X</contrib-id><name><surname>Migliori</surname><given-names>Giovanni Battista</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="corresp" rid="cor1"></xref></contrib></contrib-group><aff id="af1"><label>1</label>Unit of Infectious Diseases, Dept of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy</aff><aff id="af2"><label>2</label>Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</aff><aff id="af3"><label>3</label>Fondazione S. Maugeri, IRCCS, Tradate, Italy</aff><aff id="af4"><label>4</label>Public Health Consulting Group, Lugano, Switzerland</aff><aff id="af5"><label>5</label>Médecins Sans Frontières, Paris, France</aff><aff id="af6"><label>6</label>Children's Hospital at Westmead and the Centre for Research Excellence in Tuberculosis, University of Sydney, Sydney, Australia</aff><aff id="af7"><label>7</label>MDR/XDR TB Unit, Tshepong Hospital Klerksdorp, Klerksdorp, South Africa</aff><aff id="af8"><label>8</label>MDR-TB Unit, Tuberculosis Division, International Union against Tuberculosis and Lung Disease (The Union), Paris, France</aff><aff id="af9"><label>9</label>Pneumology Dept, Hospital General de Gran Canaria “Dr Negrin”, Las Palmas de Gran Canaria, Spain</aff><aff id="af10"><label>10</label>Médecins Sans Frontières, Mumbai, India</aff><aff id="af11"><label>11</label>Médecins Sans Frontières, Moscow, Russian Federation</aff><aff id="af12"><label>12</label>Médecins Sans Frontières, London, UK</aff><aff id="af13"><label>13</label>Republican TB Dispensary, Grozny, Chechen Republic, Russian Federation</aff><aff id="af14"><label>14</label>Armenian National Tuberculosis Control Centre, Yerevan, Armenia</aff><aff id="af15"><label>15</label>Médecins Sans Frontières, Yerevan, Armenia</aff><aff id="af16"><label>16</label>National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia</aff><aff id="af17"><label>17</label>Médecins Sans Frontières, Tbilisi, Georgia</aff><aff id="af18"><label>18</label>Paediatric Highly Intensive Care Unit, Dept of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy</aff><aff id="af19"><label>19</label>University Dept of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy</aff><aff id="af20"><label>20</label>Harvard Medical School, Dept of Global Health and Social Medicine, Boston, MA, USA</aff><aff id="af21"><label>21</label>These authors contributed equally</aff><author-notes><corresp id="cor1">Giovanni Battista Migliori, Fondazione S. Maugeri, Care and Research Institute, Via Roncaccio 16, 21049, Tradate, Italy. E-mail: <email>giovannibattista.migliori@fsm.it</email></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>6</month><year>2016</year></pub-date><pub-date pub-type="ppub"><month>9</month><year>2016</year></pub-date><volume>48</volume><issue>3</issue><fpage>938</fpage><lpage>943</lpage><history><date date-type="received"><day>07</day><month>4</month><year>2016</year></date><date date-type="accepted"><day>09</day><month>5</month><year>2016</year></date></history><permissions><copyright-statement>The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2016</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.</license-p></license></permissions><abstract abstract-type="extract"><p>The World Health Organization (WHO) estimated that 480 000 new multidrug-resistant (MDR) tuberculosis (TB) cases occurred globally in 2014, with 190 000 deaths. Limited data are available on the burden of MDR-TB in children. A recent systematic review estimated that 32 000 children acquire MDR-TB annually; of these, very few are correctly diagnosed and provided with appropriate treatment [1].</p></abstract><abstract abstract-type="short"><p><bold>First experience and challenges of compassionate use of new anti-TB drugs to treat MDR- and XDR-TB in children</bold><ext-link ext-link-type="uri" xlink:href="http://ow.ly/SWXF300a0UX">http://ow.ly/SWXF300a0UX</ext-link></p></abstract></article-meta></front><body><p>To the Editor:</p><p>The World Health Organization (WHO) estimated that 480 000 new multidrug-resistant (MDR) tuberculosis (TB) cases occurred globally in 2014, with 190 000 deaths. Limited data are available on the burden of MDR-TB in children. A recent systematic review estimated that 32 000 children acquire MDR-TB annually; of these, very few are correctly diagnosed and provided with appropriate treatment [<xref rid="C1" ref-type="bibr">1</xref>].</p><p>Treatment of drug-resistant TB is long, expensive and associated with frequent adverse events [<xref rid="C1" ref-type="bibr">1</xref>–<xref rid="C5" ref-type="bibr">5</xref>]. In children, treatment is further complicated by limited data on appropriate dosing and safety, and a lack of child-friendly formulations. New anti-TB drugs are urgently needed to improve treatment tolerability and outcome, particularly for MDR-TB cases with additional second-line drug resistance, for whom identifying at least four active drugs is difficult with the current armamentarium of drugs [<xref rid="C1" ref-type="bibr">1</xref>, <xref rid="C4" ref-type="bibr">4</xref>–<xref rid="C11" ref-type="bibr">11</xref>]. Two novel anti-TB drugs, delamanid [<xref rid="C6" ref-type="bibr">6</xref>, <xref rid="C8" ref-type="bibr">8</xref>, <xref rid="C12" ref-type="bibr">12</xref>] and bedaquiline [<xref rid="C6" ref-type="bibr">6</xref>, <xref rid="C7" ref-type="bibr">7</xref>, <xref rid="C9" ref-type="bibr">9</xref>, <xref rid="C10" ref-type="bibr">10</xref>, <xref rid="C12" ref-type="bibr">12</xref>], have received conditional approval for use in adults with MDR-TB. While the WHO interim guidance does not include a recommendation on their use in children due to lack of data, the Centers for Disease Control and Prevention guidelines state that bedaquiline use can be considered for children when treatment options are limited.</p><p>A number of paediatric clinical trials are ongoing or planned. The Otsuka 232 (phase 1, pharmacokinetics and safety to determine the appropriate dose for MDR-TB in children) and 233 (phase 2, 6-month safety, efficacy and pharmacokinetics trial in children with MDR-TB) trials of delamanid have begun recruitment. Preliminary pharmacokinetics and safety data in 6–17-year-old children from these trials have been presented, showing an excellent safety profile and leading to weight-based dosing recommendations for patients of 20–35 kg to receive half the adult dose (50 mg of delamanid twice daily) (presented in poster format (A-960) by J. Hafkin; Pharmacokinetics and safety of delamanid in paediatric MDR-TB patients, ages 6–17 years; San Diego, Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2015). A follow-up study to confirm the long-term safety, tolerability and pharmacokinetics of delamanid in these age groups and younger children (0–5 years) is ongoing and data are not yet available (presented in poster format (EP-115-04) by J. Hafkin; Long-term safety, tolerability and pharmacokinetics of delamanid in paediatric MDR-TB patients, ages 12–17 years; Cape Town, The 46th Union World Conference on Lung Health, 2015). Neither the Janssen C21 trial of bedaquiline (phase 2, pharmacokinetics, tolerability and anti-mycobacterial activity in children with MDR-TB) nor the US National Institutes of Health International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network planned trial of bedaquiline pharmacokinetics and safety in HIV-infected and uninfected children, have yet begun enrolling.</p><p>The Janssen bedaquiline compassionate use programme excluded all subjects aged <18 years, while delamanid is available to children from 12 years of age, and recently from 6 years, through the Otsuka compassionate use programme. Each request for delamanid compassionate use submitted to Otsuka is reviewed by an independent panel of experts, to assess the appropriateness and safety of delamanid use before the drug is provided. The aim of this report is to share the initial experience and challenges of compassionate use of delamanid in children and adolescents at a global level. The information reported here was collected through the two bodies providing independent advice on the rational use of new drugs: the TB Consilium (<ext-link ext-link-type="uri" xlink:href="www.tbconsilium.org">www.tbconsilium.org</ext-link>) [<xref rid="C8" ref-type="bibr">8</xref>] and the endTB committee (Médecins Sans Frontières (MSF), Partners in Health, and Interactive Research and Development; <ext-link ext-link-type="uri" xlink:href="www.endtb.org">www.endtb.org</ext-link>).</p><p>Between February 2014 and March 2016, Otsuka received 19 requests for delamanid compassionate use for paediatric patients aged <18 years. All requests were considered appropriate by both the external committees and Otsuka, and hence were enrolled in the delamanid compassionate use programme. Requests were received from Italy (n=1), South Africa (n=5), Georgia (MSF settings; n=4), India (n=5; four from MSF settings), Namibia (n=1), Swaziland, Russia and Armenia (MSF settings; one case each). Data from patients are summarised in <xref rid="TB1" ref-type="table">table 1</xref>.<table-wrap id="TB1" orientation="portrait" position="float"><label>TABLE 1</label><caption><p>Paediatric cases enrolled in Otsuka delamanid compassionate use programme, from February 2014 to March 2016</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"><bold>Patient</bold></td><td align="center" rowspan="1" colspan="1"><bold>Country of origin</bold></td><td align="center" rowspan="1" colspan="1"><bold>Age years</bold></td><td align="center" rowspan="1" colspan="1"><bold>Sex</bold></td><td align="center" rowspan="1" colspan="1"><bold>TB form</bold></td><td align="center" rowspan="1" colspan="1"><bold>Test results at time of delamanid request</bold></td><td align="center" rowspan="1" colspan="1"><bold>Resistance profile</bold></td><td align="center" rowspan="1" colspan="1"><bold>Expert panel consulted and indication for delamanid</bold></td><td align="center" rowspan="1" colspan="1"><bold>Drugs used prior to delamanid</bold></td><td align="center" rowspan="1" colspan="1"><bold>Started delamanid</bold></td><td align="center" rowspan="1" colspan="1"><bold>Treatment outcome or interim treatment response</bold></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1">Italy</td><td align="center" rowspan="1" colspan="1">13</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P and EP</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert+</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, Z, E, S, Rfb, Amk, Cm, Km, Lfx, Mfx, Ofx, Eto, Pto, HdH</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs, drug toxicity and limited options for treatment</td><td align="center" rowspan="1" colspan="1">H, Z, E, Amk, Mfx, Eto, PAS, Tzd, Amx/Clv, Clr, Cfz, Lzd, Mpm</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Cured</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1">South Africa</td><td align="center" rowspan="1" colspan="1">17</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+, Xpert+</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, Amk, Km, Ofx, Eto</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">H, Z, E, Cm, Km, Mfx, Eto, PAS, Tzd, Cfz, HdH</td><td align="center" rowspan="1" colspan="1">No<sup>#</sup></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1">South Africa</td><td align="center" rowspan="1" colspan="1">13</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+, Xpert+</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, Amk, Ofx</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">Z, E, Cm, Km, Mfx, Eto, PAS, Tzd, Amx/Clv, Clr, Cfz, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1">South Africa</td><td align="center" rowspan="1" colspan="1">13</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS−/C+ (MGIT), Xpert+</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, Amk, Ofx</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">E, Z, Cm, Mfx, Eto, PAS, Tzd, Cfz, HdH, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>5</bold></td><td align="center" rowspan="1" colspan="1">South Africa</td><td align="center" rowspan="1" colspan="1">8</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">Pre-XDR: H, R, Amk, Cm, Km, Eto</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">Z, Amk, Mfx, Eto, Tzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">First culture not yet available</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>6</bold></td><td align="center" rowspan="1" colspan="1">Namibia</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P and EP</td><td align="center" rowspan="1" colspan="1">SS−/C−, lymph C+ (MGIT)</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Amk, Cm, Km, Lfx, Mfx, Ofx, Eto, PAS, Cs, HdH</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">Z, Cm, Mfx, PAS, Cs, Amx/Clv, Clr, Cfz, HdH</td><td align="center" rowspan="1" colspan="1">No<sup>¶</sup></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>7</bold></td><td align="center" rowspan="1" colspan="1">South Africa</td><td align="center" rowspan="1" colspan="1">12</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS−/C+ (MGIT), Xpert indeterminate</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, S, Amk, Cm, Km, Ofx, Eto, Pto, HdH</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">H, R, Z, E, Eto, Tzd, Lfx</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>8</bold></td><td align="center" rowspan="1" colspan="1">India</td><td align="center" rowspan="1" colspan="1">12</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT)</td><td align="center" rowspan="1" colspan="1">XDR-TB: R, H, Z, E, S, Amk, Cm, Km, Mfx, Ofx, Eto, PAS, Cs, Lzd</td><td align="center" rowspan="1" colspan="1">TB Consilium: extensive resistance to SLDs and severe clinical presentation</td><td align="center" rowspan="1" colspan="1">E, Z, Cm, Mfx, PAS, Cs, Amx/Clv, Clr, Cfz, Lzd, Mpm</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">First culture not yet available</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>9</bold></td><td align="center" rowspan="1" colspan="1">India</td><td align="center" rowspan="1" colspan="1">17</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT)</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Amk, Cm, Km, Mfx, Ofx, Eto, PAS</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs</td><td align="center" rowspan="1" colspan="1">H, R, Z, E, S, Km, Mfx, Pto, PAS, Cs, Amx/Clv, Clr, Cfz, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>10</bold></td><td align="center" rowspan="1" colspan="1">India</td><td align="center" rowspan="1" colspan="1">15</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT)</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Amk, Km, Ofx, Eto, PAS, Cfz</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs</td><td align="center" rowspan="1" colspan="1">H, R, Z, E, Km, Mfx, Eto, PAS, Cfz, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>11</bold></td><td align="center" rowspan="1" colspan="1">India</td><td align="center" rowspan="1" colspan="1">16</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS−/C+ (MGIT)</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Amk, Cm, Km, Mfx, Ofx, Eto, PAS</td><td align="center" rowspan="1" colspan="1">endTB committee: failure of previous treatment and extensive resistance to SLDs</td><td align="center" rowspan="1" colspan="1">H, R, Z, E, Rfb, Cm, Km, Lfx, Mfx, Eto, PAS, Cs, Amx/Clv, Cfz, HdH, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>12</bold></td><td align="center" rowspan="1" colspan="1">India</td><td align="center" rowspan="1" colspan="1">13</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P and EP (lymph node)</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, Z, S, Amk, Cm, Km, Mfx, Ofx, Eto, PAS, Cs</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs</td><td align="center" rowspan="1" colspan="1">H, R, Z, E</td><td align="center" rowspan="1" colspan="1">No<sup>+</sup></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>13</bold></td><td align="center" rowspan="1" colspan="1">Georgia</td><td align="center" rowspan="1" colspan="1">16</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">MDR-TB: H, R, E, Z</td><td align="center" rowspan="1" colspan="1">endTB committee: no improvement with SLDs (still smear positive after 3 months of treatment)</td><td align="center" rowspan="1" colspan="1">E, Z, Cm, Mfx, Cs, PAS, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Georgia</td><td align="center" rowspan="1" colspan="1">17</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS−/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">Pre-XDR (FQ): H, R, E, S, Ofx</td><td align="center" rowspan="1" colspan="1">endTB committee: no improvement with SLDs (culture positive after 7 months of treatment, progression of infiltrates and cavities)</td><td align="center" rowspan="1" colspan="1">H, Z, E, Cm, Lfx, Mfx, Pto, PAS, Cs</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>15</bold></td><td align="center" rowspan="1" colspan="1">Georgia</td><td align="center" rowspan="1" colspan="1">15</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS−/C+ (MGIT), HAIN MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Km, Ofx</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs and severe clinical presentation (bilateral lesions)</td><td align="center" rowspan="1" colspan="1">H, R, Z, E, Cm, Lfx, Mfx, Pto, PAS, Cs, Cfz, Lzd</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>16</bold></td><td align="center" rowspan="1" colspan="1">Georgia</td><td align="center" rowspan="1" colspan="1">17</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">Pre-XDR (FQ): H, R, E, S, Ofx</td><td align="center" rowspan="1" colspan="1">endTB committee: no clinical or radiological improvement with SLDs</td><td align="center" rowspan="1" colspan="1">E, Z, Cm, Lfx, Mfx, Pto, PAS, Cs, Amx/Clv, Clr, Cfz</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Culture negative, good clinical response, delamanid completed</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>17</bold></td><td align="center" rowspan="1" colspan="1">Russia</td><td align="center" rowspan="1" colspan="1">16</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, S, Cm, Lfx</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs and severe clinical presentation (bilateral lesions)</td><td align="center" rowspan="1" colspan="1">Z, Cm, Lfx, Pto, PAS, Cs</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>18</bold></td><td align="center" rowspan="1" colspan="1">Armenia</td><td align="center" rowspan="1" colspan="1">16</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">Pre-XDR (FQ): H, R, Z, E, Amk, Cm, Pto</td><td align="center" rowspan="1" colspan="1">endTB committee: extensive resistance to SLDs and drug toxicity</td><td align="center" rowspan="1" colspan="1">Cm, Lfx, Pto, PAS, Cs, Amx/Clv, Cfz</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">Currently culture negative, good clinical response, delamanid ongoing</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>19</bold></td><td align="center" rowspan="1" colspan="1">Swaziland</td><td align="center" rowspan="1" colspan="1">15</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">P</td><td align="center" rowspan="1" colspan="1">SS+/C+ (MGIT), Xpert MTB+, R resistant</td><td align="center" rowspan="1" colspan="1">XDR-TB: H, R, E, S, Cm, Km, Mfx</td><td align="center" rowspan="1" colspan="1">endTB committee: failure of previous treatment and extensive resistance to SLDs</td><td align="center" rowspan="1" colspan="1">Z, Km, Lfx, Pto, PAS, Cs</td><td align="center" rowspan="1" colspan="1">Yes</td><td align="center" rowspan="1" colspan="1">First culture not yet available</td></tr></tbody></table><table-wrap-foot><fn><p>TB: tuberculosis; SS: sputum smear; C: culture; M: male; F: female; P: pulmonary; EP: extrapulmonary; MGIT: Mycobacteria Growth Indicator Tube (Becton, Dickinson and Company, Franklin Lakes, NJ, USA); Xpert: Xpert <italic>Mycobacterium tuberculosis</italic> (MTB)/rifampicin test (Cepheid, Sunnyvale, CA, USA); XDR: extensively drug-resistant; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin; Rfb: rifabutin; Amk: amikacin; Cm: capreomycin; Km: kanamycin; Lfx: levofloxacin; Mfx: moxifloxacin; Ofx: ofloxacin; Eto: ethionamide; Pto: prothionamide; HdH: high-dose isoniazid; SLDs: second-line drugs; PAS: para-aminosalicylic acid; Tzd: terizidone; Amx/Clv: amoxicillin plus clavulanate; Clr: clarithromycin; Cfz: clofazimine; Lzd: linezolid; Mpm: meropenem; Cs: cycloserine; MDR: multidrug-resistant; FQ: fluoroquinolones; HAIN: GenoType MTBDRplus (Hain Lifescience GmbH, Nehren, Germany). <sup>#</sup>: after inclusion in delamanid compassionate use programme, treating clinicians decided to withdraw the request for delamanid for this patient due to adverse effects and poor treatment adherence; <sup>¶</sup>: awaiting import permit from the relevant authorities; <sup>+</sup>: patient withdrawn from compassionate use programme for programmatic reasons.</p></fn></table-wrap-foot></table-wrap></p><p>The rationale for delamanid requests was mainly the limited treatment options due to extensive resistance pattern or poor response to second-line anti-TB treatment, although in one case it was for reinforcement of the treatment regimen in a patient with adverse events. The TB Consilium and endTB committee experts recommended the use of delamanid as the best treatment option in these patients.</p><p>All 19 paediatric cases enrolled in the delamanid compassionate use programme had bacteriologically confirmed pulmonary MDR- or extensively drug-resistant (XDR)-TB (two cases also had extrapulmonary TB). Drug susceptibility testing confirmed resistance to four to 15 anti-TB drugs. Only three patients (patients 5, 6 and 19 in table 1) were HIV positive.</p><p>Out of 19 enrolled patients, 16 (84%) have already started treatment with delamanid. The mean age at treatment initiation was 14.4 years (range 8–17 years). All cases received delamanid 100 mg twice daily (adult dosage), except one who received 50 mg twice daily due to a body weight of 22 kg. Of these, six patients have already completed 24 weeks of delamanid, while 10 are still receiving the delamanid.</p><p>All patients showed good tolerability to delamanid with no or mild adverse events, except one patient from India. This patient was receiving a combination of delamanid-capreomycin-ethionamide-cycloserine-clofazimine-imipenem-amoxicillin/clavulanate-pyrazinamide, and experienced severe vomiting, renal impairment and severe electrolyte disturbances (hypokalaemia and hypomagnesaemia) that led to QTcF (QT interval in the ECG corrected according to Fredericia formula) prolongation (>500 ms) requiring temporary delamanid discontinuation (albumin was normal). After management of vomiting and electrolyte imbalance correction, the patient was able to complete delamanid treatment without further QTcF prolongation.</p><p>As shown in table 1, the interim treatment response is good: 13 (81.2%) out of 16 were <italic>Mycobacterium tuberculosis</italic> culture-negative at the time of this report (three patients were recently started on delamanid, so the interim treatment responses are not yet available). Except for one patient who has successfully completed MDR-TB treatment, the remaining patients are continuing treatment and do not have final treatment outcomes yet.</p><p>The combination of delamanid and bedaquiline has been limited due to concerns regarding the QT prolongation effects of both drugs. However, there are initial experiences with their simultaneous use in adults (now also possible through compassionate use) [<xref rid="C13" ref-type="bibr">13</xref>, <xref rid="C14" ref-type="bibr">14</xref>]. This combination could be considered in children in the absence of effective alternative treatment options [<xref rid="C4" ref-type="bibr">4</xref>, <xref rid="C5" ref-type="bibr">5</xref>], under enhanced clinical monitoring [<xref rid="C12" ref-type="bibr">12</xref>–<xref rid="C15" ref-type="bibr">15</xref>].</p><p>Globally, there are very few children who have access to delamanid compared with the likely number who could benefit from it. Healthcare providers have described a number of challenges to the access of delamanid. The compassionate use mechanism, despite efforts to facilitate quick access, is a long, multistep and time-demanding process (request, permission for importation/use, informed consent, health staff training on the compassionate use protocol, reporting requirements and importation). This can result in substantial delays in treatment initiation, which could adversely affect treatment outcome. In our study, the median delay between process initiation and delamanid initiation was 73.5 days (range 14–153 days). The recent announcement that delamanid is accessible through the Global Drug Facility for USD 1700 per treatment is an important step forward in increasing international access, avoiding the need for a compassionate use mechanism. However, countries may still face other barriers, such as lack of appropriate tools (clinical guidelines, appropriate training and national implementation plans), pharmacovigilance reporting requirements (which, although essential, are a new challenge for providers and programmes), and, lastly, budgets to cover the costs of these drugs. All are required to ensure rational use of delamanid in adult and paediatric patients.</p><p>In addition, the lack of inclusion of children in bedaquiline trials to date is not acceptable and contributes to the current situation of very limited access to this drug among children.</p><p>Wider availability of both drugs for children, including those with clinical TB and contact with a known MDR/XDR-TB source case, is urgently needed, as is the proactive inclusion of children and adolescents in trials of novel TB drugs [<xref rid="C16" ref-type="bibr">16</xref>].</p><p>Case-by-case evaluation from independent bodies like the TB Consilium and endTB committee is a valuable support to clinicians and programmes in the use of the new drugs in children, particularly where the clinical cases are complex and in the absence of formal guidance for their paediatric use. The use of these services could contribute to an increase in the appropriate use of new drugs among children and adolescents in need.</p></body><back><fn-group><fn fn-type="other"><p>This article is one of a small annual allocation selected for open access publication at the discretion of the editor.</p></fn><fn fn-type="COI-statement"><p>Conflict of interest: None declared.</p></fn></fn-group><ack><title>Acknowledgements</title><p>The authors wish to thank Gunar Günther (Dept of Medicine, University of Namibia, School of Medicine, Windhoek, Namibia), Zarir F. Udwadia (Dept of Respiratory Medicine, P.D. Hinduja National Hospital and Medical Research Centre, Mumbai, India) and Charles Ssonko (Médecins Sans Frontières, Mbabane, Swaziland) for providing information on their cases. 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