{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T07:49:16Z","timestamp":1776412156940,"version":"3.51.2"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21TW011035"],"award-info":[{"award-number":["R21TW011035"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tuberculous meningitis (TBM), a severe form of extrapulmonary tuberculosis, requires sustained therapeutic drug concentrations in the central nervous system (CNS). Linezolid is a promising treatment for TBM due to excellent CNS penetration and bactericidal activity against Mycobacterium tuberculosis. However, co-administration with rifampicin may alter linezolid pharmacokinetics (PK), potentially reducing efficacy due to drug\u2013drug interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We utilized data from the Adjunctive Linezolid for the Treatment of TubERculous Meningitis trial, a phase II study evaluating high-dose (35\u2005mg\/kg) versus standard-dose (10\u2005mg\/kg) rifampicin, with or without linezolid, in adults with TBM. Plasma sampling occurred on days 1 (dense) and 14 (sparse) with cerebrospinal fluid (CSF) sampling. Population PK modeling and simulation were employed to characterize linezolid disposition in plasma and CSF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eighteen participants contributed 73 plasma and 30 CSF samples to the analysis. Plasma concentrations were best described by a 1-compartment model with linear absorption and clearance, linked to a CSF compartment. High-dose rifampicin increased linezolid clearance by 34.2%, reducing systemic and CNS exposure. Simulations demonstrated that 1200\u2005mg once-daily dosing failed to maintain therapeutic plasma and CSF linezolid concentrations when co-administered with high-dose rifampicin. In contrast, 600\u2005mg twice-daily achieved adequate linezolid exposures even with higher rifampicin doses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>High-dose rifampicin significantly increases linezolid clearance, reducing plasma and CSF drug levels. However, twice-daily linezolid may mitigate this effect and maintain therapeutic concentrations. These findings underscore the importance of optimizing linezolid dosing when used with rifampicin in TBM and support evaluation in larger studies to guide treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ofid\/ofag154","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:36:02Z","timestamp":1774355762000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of High-Dose Rifampicin on Linezolid Pharmacokinetics in Tuberculous Meningitis"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6185-4380","authenticated-orcid":false,"given":"Dvijen","family":"Purohit","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , SanFrancisco, California ,","place":["USA"]},{"name":"UCSF Center for Tuberculosis, University of California , SanFrancisco, California ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"van Wijk","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , SanFrancisco, California ,","place":["USA"]},{"name":"UCSF Center for Tuberculosis, University of California , SanFrancisco, California ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paddy","family":"Kafeero","sequence":"additional","affiliation":[{"name":"Medical Research Council\/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit , Entebbe ,","place":["Uganda"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freddie","family":"Kibengo","sequence":"additional","affiliation":[{"name":"Medical Research Council\/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit , Entebbe ,","place":["Uganda"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-5009","authenticated-orcid":false,"given":"Veronique","family":"D'artois","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9440-9349","authenticated-orcid":false,"given":"Felicia C","family":"Chow","sequence":"additional","affiliation":[{"name":"UCSF Center for Tuberculosis, University of California , SanFrancisco, California ,","place":["USA"]},{"name":"Department of Neurology and Medicine (Infectious Diseases) and Weill Institute for Neurosciences, University of California , SanFrancisco, California ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rada M","family":"Savic","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California , SanFrancisco, California ,","place":["USA"]},{"name":"UCSF Center for Tuberculosis, University of California , SanFrancisco, California ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"2026041703020788100_ofag154-B1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research.","volume":"10","author":"Marais","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"2026041703020788100_ofag154-B2","first-page":"335","article-title":"Drug and 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