{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:05:56Z","timestamp":1785319556078,"version":"3.55.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003747","name":"Victorian Government Department of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003747","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Bedaquiline, pretomanid, and linezolid (BPaL) is a 6-month regimen that has revolutionized treatment of multidrug-resistant (MDR) tuberculosis (TB). However, there is limited evidence of using BPaL to treat MDR tuberculous meningitis (TBM), a devastating illness that has high risk of mortality and permanent disability.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A patient with fluoroquinolone-resistant pre\u2013extensively drug-resistant (pre-XDR) TBM was cured with a 10-month regimen based on BPaL with clofazimine and cycloserine. Total concentrations of bedaquiline, pretomanid, and linezolid were measured in plasma and cerebrospinal fluid (CSF) via ultraperformance liquid chromatography. Unbound concentrations were estimated from plasma concentrations and CSF concentrations normalized to plasma protein concentrations using the Winter\u2013Tozer formula. AUC24 (24-hour area under the curve) was calculated using the trapezoidal method.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The CSF:plasma unbound AUC24 was 1.48 and 0.99 for pretomanid and linezolid, respectively. Pharmacokinetic\/pharmacodynamic targets were achieved for pretomanid with CSF concentration above the critical concentration of 0.5\u2005mg\/L throughout most of the dosing interval and linezolid AUC24\/minimum inhibitory concentration (MIC) of 171 for an MIC of 0.5\u2005mg\/L. However, CSF concentrations of pretomanid and linezolid may be below target for strains with MICs &gt;0.5\u2005mg\/L. Estimated unbound peak concentrations in CSF in week 21 were comparable to plasma (0.0034 mg\/L and 0.0032\u2005mg\/L, respectively), suggesting that therapeutic central nervous system concentrations of bedaquiline were achieved.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Fluoroquinolone-resistant pre-XDR TBM was cured with 10 months of treatment based on BPaL with clofazimine and cycloserine. BPaL achieved therapeutic concentrations in CSF for most TB strains. Further research is required into optimal treatment and dosing of drug-resistant TBM.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/ofid\/ofag445","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T11:38:20Z","timestamp":1784979500000},"source":"Crossref","is-referenced-by-count":0,"title":["Cerebrospinal Fluid Concentrations of Bedaquiline, Pretomanid, and Linezolid During Curative Treatment of Fluoroquinolone-Resistant Pre\u2013Extensively Drug-Resistant Tuberculous Meningitis"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5507-4204","authenticated-orcid":false,"given":"Adrian Robert","family":"Tramontana","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Western Health , Footscray, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Prince Charles Hospital , Chermside, Queensland ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-2843","authenticated-orcid":false,"given":"Maria","family":"Globan","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Reference Laboratory , Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"McWhinney","sequence":"additional","affiliation":[{"name":"Analytical Chemical Unit, Central Laboratory, Health Support Queensland, Pathology Queensland , Herston, Queensland ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-1310","authenticated-orcid":false,"given":"Aaron E","family":"Bloch","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Western Health , Footscray, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6214-5923","authenticated-orcid":false,"given":"Benjamin J","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Western Health , Footscray, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin T","family":"Denholm","sequence":"additional","affiliation":[{"name":"Victorian Tuberculosis Program, Melbourne Health The , Melbourne ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor James","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Western Health , Footscray, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2916-2818","authenticated-orcid":false,"given":"James S","family":"Molton","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Western Health , Footscray, Victoria ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"2026072905512902900_ofag445-B1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1164\/rccm.202410-2096ST","article-title":"Updates on the treatment of drug-susceptible and drug-resistant tuberculosis: an official ATS\/CDC\/ERS\/IDSA clinical practice guideline","volume":"211","author":"Saukkonen","year":"2025","journal-title":"Am J Respir Crit Care Med"},{"key":"2026072905512902900_ofag445-B2","volume-title":"WHO consolidated guidelines on tuberculosis. Module 4: treatment\u2014drug-resistant tuberculosis treatment, 2022 update","author":"World Health Organization (WHO)","year":"2022"},{"key":"2026072905512902900_ofag445-B3","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1093\/cid\/ciad312","article-title":"Implementation of bedaquiline, pretomanid, and linezolid in the United States: experience using a novel all-oral treatment regimen for treatment of rifampin-resistant or rifampin-intolerant tuberculosis disease","volume":"77","author":"Haley","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2026072905512902900_ofag445-B4","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1056\/NEJMoa2119430","article-title":"Bedaquiline\u2013pretomanid\u2013linezolid regimens for drug-resistant tuberculosis","volume":"387","author":"Conradie","year":"2022","journal-title":"N Engl J Med"},{"key":"2026072905512902900_ofag445-B5","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1056\/NEJMoa1901814","article-title":"Treatment of highly drug-resistant pulmonary tuberculosis","volume":"382","author":"Conradie","year":"2020","journal-title":"N Engl J Med"},{"key":"2026072905512902900_ofag445-B6","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1056\/NEJMoa2117166","article-title":"A 24-week, all-oral regimen for rifampin-resistant tuberculosis","volume":"387","author":"Nyang\u2019wa","year":"2022","journal-title":"N Engl J Med"},{"key":"2026072905512902900_ofag445-B7","doi-asserted-by":"crossref","DOI":"10.1136\/bcr-2021-245612","article-title":"Sterile tuberculous granuloma in a patient with XDR-TB treated with bedaquiline, pretomanid and linezolid","volume":"14","author":"Howell","year":"2021","journal-title":"BMJ Case Rep"},{"key":"2026072905512902900_ofag445-B8","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgph.0000069","article-title":"The global burden of tuberculous meningitis in adults: a modelling study","volume":"1","author":"Dodd","year":"2021","journal-title":"PLOS Glob Public Health"},{"key":"2026072905512902900_ofag445-B9","doi-asserted-by":"crossref","first-page":"ofaa257","DOI":"10.1093\/ofid\/ofaa257","article-title":"Treatment outcomes in adult tuberculous meningitis: a systematic review and meta-analysis","volume":"7","author":"Stadelman","year":"2020","journal-title":"Open Forum Infect Dis"},{"key":"2026072905512902900_ofag445-B10","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1056\/NEJMoa2502866","article-title":"Trial of high-dose oral rifampin in adults with tuberculous meningitis","volume":"393","author":"Meya","year":"2025","journal-title":"N Engl J Med"},{"key":"2026072905512902900_ofag445-B11","doi-asserted-by":"crossref","first-page":"e0270201","DOI":"10.1371\/journal.pone.0270201","article-title":"Long term outcomes of patients with tuberculous meningitis: the impact of drug resistance","volume":"17","author":"Evans","year":"2022","journal-title":"PLoS One"},{"key":"2026072905512902900_ofag445-B12","doi-asserted-by":"crossref","first-page":"3265","DOI":"10.1212\/WNL.0000000000203147","article-title":"Safety and tolerability of adjunctive linezolid with high or standard dose rifampin for the treatment of adults with HIV-associated tuberculous meningitis in Uganda: preliminary findings from the ALTER trial (S25.003)","volume":"100","author":"Kibengo","year":"2023","journal-title":"Neurology"},{"key":"2026072905512902900_ofag445-B13","doi-asserted-by":"crossref","first-page":"102351","DOI":"10.1016\/j.tube.2023.102351","article-title":"Escalate: linezolid as an add on treatment in the intensive phase of tubercular meningitis. A randomized controlled pilot trial","volume":"142","author":"Sahib","year":"2023","journal-title":"Tuberculosis"},{"key":"2026072905512902900_ofag445-B14","doi-asserted-by":"crossref","first-page":"6297","DOI":"10.1128\/AAC.02784-14","article-title":"Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-threatening tuberculous meningitis","volume":"58","author":"Sun","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2026072905512902900_ofag445-B15","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/cid\/civ921","article-title":"Pharmacokinetics of bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis","volume":"62","author":"Akkerman","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2026072905512902900_ofag445-B16","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1021\/acsinfecdis.9b00207","article-title":"Radiosynthesis and PET bioimaging of (76)Br-bedaquiline in a murine model of tuberculosis","volume":"5","author":"Ordonez","year":"2019","journal-title":"ACS Infect Dis"},{"key":"2026072905512902900_ofag445-B17","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1093\/jac\/dkac067","article-title":"Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB)","volume":"77","author":"Upton","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2026072905512902900_ofag445-B18","doi-asserted-by":"crossref","first-page":"7974","DOI":"10.1038\/s41467-022-35730-3","article-title":"Dynamic (18)F-pretomanid PET imaging in animal models of TB meningitis and human studies","volume":"13","author":"Mota","year":"2022","journal-title":"Nat Commun"},{"key":"2026072905512902900_ofag445-B19","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/cid\/ciad540","article-title":"Pre-extensively drug-resistant congenital tuberculosis in an extremely premature baby","volume":"78","author":"Boast","year":"2024","journal-title":"Clin Infect Dis"},{"key":"2026072905512902900_ofag445-B20","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1016\/j.xphs.2021.05.018","article-title":"Impact of changes in free concentrations and drug-protein binding on drug dosing regimens in special populations and disease states","volume":"110","author":"Celestin","year":"2021","journal-title":"J Pharm Sci"},{"key":"2026072905512902900_ofag445-B21","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1093\/jac\/dkae025","article-title":"Linezolid brain penetration in neurointensive care patients","volume":"79","author":"Hosmann","year":"2024","journal-title":"J Antimicrob Chemother"},{"key":"2026072905512902900_ofag445-B22","doi-asserted-by":"crossref","first-page":"1032674","DOI":"10.3389\/fphar.2022.1032674","article-title":"Population pharmacokinetics and dose evaluations of linezolid in the treatment of multidrug-resistant tuberculosis","volume":"13","author":"Zhang","year":"2023","journal-title":"Front Pharmacol"},{"key":"2026072905512902900_ofag445-B23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1128\/AAC.00849-10","article-title":"PA-824 exhibits time-dependent activity in a murine model of tuberculosis","volume":"55","author":"Ahmad","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2026072905512902900_ofag445-B24","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1128\/AAC.00414-07","article-title":"In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis complex isolated in Taiwan over 10 years","volume":"52","author":"Huang","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"2026072905512902900_ofag445-B25","volume-title":"WHO operational handbook on tuberculosis. Module 3: diagnosis\u2014rapid diagnostics for tuberculosis detection","author":"World Health Organization (WHO)","year":"2024","edition":"3rd ed"},{"key":"2026072905512902900_ofag445-B26","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1002\/bcp.70163","article-title":"Extrapolation of lung pharmacokinetics of bedaquiline across species using physiologically-based pharmacokinetic modelling","volume":"91","author":"Karakitsios","year":"2025","journal-title":"Br J Clin Pharmacol"},{"key":"2026072905512902900_ofag445-B27","author":"World Health Organization"},{"key":"2026072905512902900_ofag445-B28","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1186\/s12879-021-06705-4","article-title":"Decreased mortality seen in rifampicin\/multidrug-resistant tuberculous meningitis treated with linezolid in Shenzhen, China","volume":"21","author":"Fang","year":"2021","journal-title":"BMC Infect Dis"},{"key":"2026072905512902900_ofag445-B29","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1093\/cid\/ciab992","article-title":"Cycloserine and linezolid for tuberculosis meningitis: pharmacokinetic evidence of potential usefulness","volume":"75","author":"Kempker","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2026072905512902900_ofag445-B30","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1128\/AAC.39.1.253","article-title":"Cerebrospinal fluid penetration of amikacin in children with community-acquired bacterial meningitis","volume":"39","author":"Gaillard","year":"1995","journal-title":"Antimicrob Agents Chemother"},{"key":"2026072905512902900_ofag445-B31","doi-asserted-by":"crossref","first-page":"S308","DOI":"10.1093\/cid\/ciy624","article-title":"d-Cycloserine pharmacokinetics\/pharmacodynamics, susceptibility, and dosing implications in multidrug-resistant tuberculosis: a Faustian deal","volume":"67","author":"Deshpande","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2026072905512902900_ofag445-B32","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.2147\/IDR.S401281","article-title":"Pharmacokinetics of antituberculosis drugs in plasma and cerebrospinal fluid in a patient with pre-extensive drug resistant tuberculosis meningitis","volume":"16","author":"Liang","year":"2023","journal-title":"Infect Drug Resist"},{"key":"2026072905512902900_ofag445-B33","doi-asserted-by":"crossref","first-page":"e0093125","DOI":"10.1128\/aac.00931-25","article-title":"Cerebrospinal fluid penetration of cycloserine\/terizidone and clofazimine in patients with pulmonary TB","volume":"69","author":"Upton","year":"2025","journal-title":"Antimicrob Agents Chemother"},{"key":"2026072905512902900_ofag445-B34","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1093\/infdis\/jiad413","article-title":"Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis","volume":"229","author":"Abdelgawad","year":"2024","journal-title":"J Infect Dis"},{"key":"2026072905512902900_ofag445-B35","doi-asserted-by":"crossref","first-page":"11902","DOI":"10.1039\/C8RA00984H","article-title":"Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system.","volume":"8","author":"Pamreddy","year":"2018","journal-title":"RSC Adv"},{"key":"2026072905512902900_ofag445-B36","doi-asserted-by":"crossref","first-page":"1022090","DOI":"10.3389\/fphar.2023.1022090","article-title":"Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients","volume":"14","author":"Shao","year":"2023","journal-title":"Front Pharmacol"},{"key":"2026072905512902900_ofag445-B37","author":"World Health Organization"},{"key":"2026072905512902900_ofag445-B38","doi-asserted-by":"crossref","first-page":"5315","DOI":"10.1128\/AAC.01418-13","article-title":"Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug","volume":"58","author":"McLeay","year":"2014","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Open Forum Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/13\/7\/ofag445\/70334743\/ofag445.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/13\/7\/ofag445\/70334743\/ofag445.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T09:51:36Z","timestamp":1785318696000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ofid\/article\/doi\/10.1093\/ofid\/ofag445\/8746640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ofid\/ofag445","relation":{},"ISSN":["2328-8957"],"issn-type":[{"value":"2328-8957","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,7,1]]},"article-number":"ofag445"}}