Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.
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Auteurs : Awewura Kwara [États-Unis] ; Anthony Enimil [Ghana] ; Fizza S. Gillani [États-Unis] ; Hongmei Yang [États-Unis] ; Anima M. Sarfo [Ghana] ; Albert Dompreh [Ghana] ; Antoinette Ortsin [Ghana] ; Lawrence Osei-Tutu [Ghana] ; Sandra Kwarteng Owusu [Ghana] ; Lubbe Wiesner [Afrique du Sud] ; Jennifer Norman [Afrique du Sud] ; Jaclynn Kurpewski [États-Unis] ; Charles A. Peloquin ; Daniel Ansong [Ghana] ; Sampson Antwi [Ghana]Source :
- Journal of the Pediatric Infectious Diseases Society [ 2048-7207 ] ; 2016.
Abstract
Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages.
DOI: 10.1093/jpids/piv035
PubMed: 26407268
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Charles A. Peloquin<affiliation><nlm:affiliation>College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville.</nlm:affiliation><wicri:noCountry code="subField">Gainesville</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.</title><author><name sortKey="Kwara, Awewura" sort="Kwara, Awewura" uniqKey="Kwara A" first="Awewura" last="Kwara">Awewura Kwara</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Rhode Island</region></placeName><wicri:cityArea>Department of Medicine, Warren Alpert Medical School of Brown University, Providence</wicri:cityArea></affiliation></author><author><name sortKey="Enimil, Anthony" sort="Enimil, Anthony" uniqKey="Enimil A" first="Anthony" last="Enimil">Anthony Enimil</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Gillani, Fizza S" sort="Gillani, Fizza S" uniqKey="Gillani F" first="Fizza S" last="Gillani">Fizza S. 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Peloquin</name><affiliation><nlm:affiliation>College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville.</nlm:affiliation><wicri:noCountry code="subField">Gainesville</wicri:noCountry></affiliation></author><author><name sortKey="Ansong, Daniel" sort="Ansong, Daniel" uniqKey="Ansong D" first="Daniel" last="Ansong">Daniel Ansong</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Antwi, Sampson" sort="Antwi, Sampson" uniqKey="Antwi S" first="Sampson" last="Antwi">Sampson Antwi</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26407268</idno><idno type="pmid">26407268</idno><idno type="doi">10.1093/jpids/piv035</idno><idno type="wicri:Area/PubMed/Corpus">000703</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000703</idno><idno type="wicri:Area/PubMed/Curation">000703</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000703</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.</title><author><name sortKey="Kwara, Awewura" sort="Kwara, Awewura" uniqKey="Kwara A" first="Awewura" last="Kwara">Awewura Kwara</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Rhode Island</region></placeName><wicri:cityArea>Department of Medicine, Warren Alpert Medical School of Brown University, Providence</wicri:cityArea></affiliation></author><author><name sortKey="Enimil, Anthony" sort="Enimil, Anthony" uniqKey="Enimil A" first="Anthony" last="Enimil">Anthony Enimil</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Gillani, Fizza S" sort="Gillani, Fizza S" uniqKey="Gillani F" first="Fizza S" last="Gillani">Fizza S. Gillani</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, The Miriam Hospital, Providence, Rhode Island.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Rhode Island</region></placeName><wicri:cityArea>Department of Medicine, The Miriam Hospital, Providence</wicri:cityArea></affiliation></author><author><name sortKey="Yang, Hongmei" sort="Yang, Hongmei" uniqKey="Yang H" first="Hongmei" last="Yang">Hongmei Yang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, New York.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry</wicri:cityArea></affiliation></author><author><name sortKey="Sarfo, Anima M" sort="Sarfo, Anima M" uniqKey="Sarfo A" first="Anima M" last="Sarfo">Anima M. Sarfo</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Dompreh, Albert" sort="Dompreh, Albert" uniqKey="Dompreh A" first="Albert" last="Dompreh">Albert Dompreh</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Ortsin, Antoinette" sort="Ortsin, Antoinette" uniqKey="Ortsin A" first="Antoinette" last="Ortsin">Antoinette Ortsin</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Osei Tutu, Lawrence" sort="Osei Tutu, Lawrence" uniqKey="Osei Tutu L" first="Lawrence" last="Osei-Tutu">Lawrence Osei-Tutu</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Kwarteng Owusu, Sandra" sort="Kwarteng Owusu, Sandra" uniqKey="Kwarteng Owusu S" first="Sandra" last="Kwarteng Owusu">Sandra Kwarteng Owusu</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Wiesner, Lubbe" sort="Wiesner, Lubbe" uniqKey="Wiesner L" first="Lubbe" last="Wiesner">Lubbe Wiesner</name><affiliation wicri:level="1"><nlm:affiliation>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.</nlm:affiliation><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town</wicri:regionArea></affiliation></author><author><name sortKey="Norman, Jennifer" sort="Norman, Jennifer" uniqKey="Norman J" first="Jennifer" last="Norman">Jennifer Norman</name><affiliation wicri:level="1"><nlm:affiliation>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.</nlm:affiliation><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town</wicri:regionArea></affiliation></author><author><name sortKey="Kurpewski, Jaclynn" sort="Kurpewski, Jaclynn" uniqKey="Kurpewski J" first="Jaclynn" last="Kurpewski">Jaclynn Kurpewski</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, The Miriam Hospital, Providence, Rhode Island.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Rhode Island</region></placeName><wicri:cityArea>Department of Medicine, The Miriam Hospital, Providence</wicri:cityArea></affiliation></author><author><name sortKey="Peloquin, Charles A" sort="Peloquin, Charles A" uniqKey="Peloquin C" first="Charles A" last="Peloquin">Charles A. Peloquin</name><affiliation><nlm:affiliation>College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville.</nlm:affiliation><wicri:noCountry code="subField">Gainesville</wicri:noCountry></affiliation></author><author><name sortKey="Ansong, Daniel" sort="Ansong, Daniel" uniqKey="Ansong D" first="Daniel" last="Ansong">Daniel Ansong</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Antwi, Sampson" sort="Antwi, Sampson" uniqKey="Antwi S" first="Sampson" last="Antwi">Sampson Antwi</name><affiliation wicri:level="1"><nlm:affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</nlm:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea></affiliation></author></analytic><series><title level="j">Journal of the Pediatric Infectious Diseases Society</title><idno type="eISSN">2048-7207</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">26407268</PMID><DateCreated><Year>2015</Year><Month>09</Month><Day>25</Day></DateCreated><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">2048-7207</ISSN><JournalIssue CitedMedium="Internet"><Volume>5</Volume><Issue>4</Issue><PubDate><Year>2016</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Journal of the Pediatric Infectious Diseases Society</Title><ISOAbbreviation>J Pediatric Infect Dis Soc</ISOAbbreviation></Journal><ArticleTitle>Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.</ArticleTitle><Pagination><MedlinePgn>356-365</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">Children with tuberculosis on first-line therapy for at least 4 weeks had blood samples collected at predose, 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods, and pharmacokinetic parameters were calculated using noncompartmental analysis. Factors associated with plasma peak concentration (Cmax) and the area under the time-concentration curve 0-8 hours (AUC0-8h) of each drug was examined using univariate and multivariate analysis.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Of the 62 children, 32 (51.6%) were male, 29 (46.8%) were younger than 5 years old, and 28 (45.2%) had human immunodeficiency virus (HIV) coinfection. Three patients had undetectable pyrazinamide and ethambutol concentrations. The median (interquartile range) AUC0-8h for isoniazid was 17.7 (10.2-23.4) µg·h mL(-1), rifampin was 26.0 (15.3-36.1) µg·h mL(-1), pyrazinamide was 144.6 (111.5-201.2) µg·h mL(-1), and ethambutol was 6.7 (3.8-10.4) µg·h mL(-1). Of the children who received recommended weight-band dosages, 44/51 (86.3%), 46/56 (82.1%), 27/56 (48.2%), and 21/51 (41.2%) achieved target Cmax for isoniazid, pyrazinamide, ethambutol, and rifampin, respectively. In multivariate analysis, age, sex, HIV coinfection status, and drug dosage in milligrams per kilogram were associated with the drugs' plasma drug Cmax or AUC0-8h.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">The revised dosages appeared to be adequate for isoniazid and pyrazinamide, but not for rifampin or ethambutol in this population. Higher dosages of rifampin and ethambutol than currently recommended may be required in most children.</AbstractText><CopyrightInformation>© The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kwara</LastName><ForeName>Awewura</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, The Miriam Hospital, Providence, Rhode Island.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Enimil</LastName><ForeName>Anthony</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gillani</LastName><ForeName>Fizza S</ForeName><Initials>FS</Initials><AffiliationInfo><Affiliation>Department of Medicine, The Miriam Hospital, Providence, Rhode Island.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Hongmei</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, New York.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sarfo</LastName><ForeName>Anima M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dompreh</LastName><ForeName>Albert</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ortsin</LastName><ForeName>Antoinette</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Osei-Tutu</LastName><ForeName>Lawrence</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kwarteng Owusu</LastName><ForeName>Sandra</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wiesner</LastName><ForeName>Lubbe</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Norman</LastName><ForeName>Jennifer</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kurpewski</LastName><ForeName>Jaclynn</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Medicine, The Miriam Hospital, Providence, Rhode Island.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peloquin</LastName><ForeName>Charles A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ansong</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Antwi</LastName><ForeName>Sampson</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>U01 AI068632</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 HD071779</GrantID><Acronym>HD</Acronym><Agency>NICHD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UM1 AI068632</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UM1 AI068634</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UM1 AI106701</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 AI042853</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UM1 AI068636</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>05</Month><Day>26</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Pediatric Infect Dis 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Version="1">19392636</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Am J Respir Crit Care Med. 1997 May;155(5):1717-22</RefSource><PMID Version="1">9154882</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Int J Tuberc Lung Dis. 2013 Dec;17(12):1518-23</RefSource><PMID Version="1">24200262</PMID></CommentsCorrections></CommentsCorrectionsList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">children</Keyword><Keyword MajorTopicYN="N">first-line antituberculosis drugs</Keyword><Keyword MajorTopicYN="N">pharmacokinetics</Keyword><Keyword MajorTopicYN="N">revised WHO dosage</Keyword><Keyword MajorTopicYN="N">tuberculosis</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>03</Month><Day>05</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>05</Month><Day>08</Day></PubMedPubDate><PubMedPubDate 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