{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T22:03:11Z","timestamp":1789596191969,"version":"build-2803163510"},"reference-count":33,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001713","name":"European and Developing Countries Clinical Trials Partnership","doi-asserted-by":"publisher","award":["TRIA2015-1102-PanACEA"],"award-info":[{"award-number":["TRIA2015-1102-PanACEA"]}],"id":[{"id":"10.13039\/501100001713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006209","name":"Radboudumc","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,12,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Tuberculous meningitis (TBM) treatment outcomes are poor, partly due to suboptimal drug penetration into the cerebrospinal fluid (CSF). Little is known about the CSF pharmacokinetics of many TB drugs, both established and new. This study investigated the CSF penetration of cycloserine (administered as terizidone) and clofazimine, two core second-line drugs for drug-resistant tuberculosis (TB). We recruited participants with pulmonary drug-resistant TB, but without TBM, receiving terizidone and\/or clofazimine for at least 2 weeks and collected serial plasma samples and a single CSF sample. Drug concentrations were quantified with validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were determined using noncompartmental analysis, and population pharmacokinetic modeling was used to estimate the partition coefficient and equilibration half-life. Data were available from 27 participants, with a median age of 36 (range 20\u201360) and a weight of 52 kg (30\u201373 kg), who contributed 216 plasma and 27 CSF samples. The plasma pharmacokinetics of both drugs was in line with previous reports. Terizidone, measured as cycloserine, achieved CSF exposure of 69% relative to plasma, with plasma and CSF concentrations equilibrating with a half-life of 4.7 hours. Clofazimine CSF penetration was 0.13% of plasma exposure, with an equilibration half-life of 55.4 hours. Cycloserine and clofazimine concentrations in CSF approximated their estimated unbound (active) concentration in plasma, thus suggesting good penetration of the unbound drug into the CSF, supporting their potential use in TBM regimens. This study demonstrates a feasible and reproducible method for effective assessment of CSF drug penetration for CNS infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00931-25","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T17:13:49Z","timestamp":1761066829000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Cerebrospinal fluid penetration of cycloserine\/terizidone and clofazimine in patients with pulmonary TB"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-3320","authenticated-orcid":true,"given":"Caryn M.","family":"Upton","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wg1m734","id-type":"ROR","asserted-by":"publisher"}],"name":"Radboud University Medical Center, Radboud Institute for Medical Innovation","place":["Nijmegen, the Netherlands"]},{"name":"TASK","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0310-6949","authenticated-orcid":true,"given":"Jose M.","family":"Calderin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas H.","family":"Diacon","sequence":"additional","affiliation":[{"name":"TASK","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Boeree","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wg1m734","id-type":"ROR","asserted-by":"publisher"}],"name":"Radboud University Medical Center, Radboud Institute for Medical Innovation","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":true,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":true,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-4976","authenticated-orcid":true,"given":"Tracy","family":"Kellermann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bk57929","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University","place":["Stellenbosch, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"McCulloch","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bk57929","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University","place":["Stellenbosch, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Aarnoutse","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wg1m734","id-type":"ROR","asserted-by":"publisher"}],"name":"Radboud University Medical Center, Radboud Institute for Medical Innovation","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-022-11052-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-019-0966-8"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020077"},{"key":"e_1_3_4_5_2","unstructured":"Geneva: World Health Organization. 2022. 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Technical report on critical concentrations for drug susceptibility testing of medicines used in the treatment of drug-resistant tuberculosis. 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