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Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher\u2010dose rifampin and\/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK\/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)<jats:sub>0\u201324<\/jats:sub> = 92 mg*h\/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature\u2010derived. To attain target rifampin exposures, children require daily doses of at least 30 mg\/kg orally or 15 mg\/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19\u201333 mg\/kg. Our results provide data\u2010driven guidance to maximize pediatric TBM treatment while we await definitive trial results.<\/jats:p>","DOI":"10.1002\/cpt.202","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T09:00:04Z","timestamp":1439283604000},"page":"622-629","source":"Crossref","is-referenced-by-count":53,"title":["Pediatric tuberculous meningitis: Model\u2010based approach to determining optimal doses of the anti\u2010tuberculosis drugs rifampin and levofloxacin for children"],"prefix":"10.1111","volume":"98","author":[{"given":"RM","family":"Savic","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences University of California San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Ruslami","sequence":"additional","affiliation":[{"name":"Universitas Padjadjaran\/Hasan Sadikin Hospital Bandung Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JE","family":"Hibma","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences University of California San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Hesseling","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre Department of Paediatrics and Child Health Stellenbosch University Tygerberg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"National Institute for Research in Tuberculosis Chetpet Chennai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AR","family":"Ganiem","sequence":"additional","affiliation":[{"name":"Universitas Padjadjaran\/Hasan Sadikin Hospital Bandung Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"National Institute for Research in Tuberculosis Chetpet Chennai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"McIlleron","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Department of Medicine University of Cape Town Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Gupta","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Thakur","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"van Crevel","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Aarnoutse","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"KE","family":"Dooley","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,10,22]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.68.3.289"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008-1353"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/0028-3886.16407"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2002.tb00323.x"},{"key":"e_1_2_9_5_1","unstructured":"World Health Organization.Rapid advice: treatment of tuberculosis in children(WHO Library Cataloguing\u2010in\u2010Publication Data Geneva Switzerland 2010)."},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/148.3.650"},{"key":"e_1_2_9_7_1","unstructured":"Savic R.M.et al.PKPD analysis of rifapentine in patients during intensive phase treatment for tuberculosis from Tuberculosis Trial Consortium studies 29 and 29X. 6th International Workshop on Clinical Pharmacology of Tuberculosis Drugs Denver CO 9 September2013."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.11.0198"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(12)70264-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-3879(71)90017-1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00562440"},{"key":"e_1_2_9_12_1","first-page":"106","article-title":"Minimum daily efficient dose of ethambutol: general review [in French]","volume":"48","author":"Radenbach K.L.","year":"1973","journal-title":"Bull. 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