{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:39:33Z","timestamp":1790181573422,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Tuberculosis meningitis (TBM) is the most lethal form of TB. It is difficult to treat in part due to poor or uncertain drug penetration into the central nervous system (CNS). To help fill this knowledge gap, we evaluated the cerebrospinal fluid (CSF) concentrations of fluoroquinolones and carbapenems in patients being treated for TBM.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Serial serum and CSF samples were collected from hospitalized patients being treated for TBM. CSF was collected from routine lumbar punctures between alternating timepoints of 2 and 6\u00a0h after drug administration to capture early and late CSF penetration. Rich serum sampling was collected after drug administration on day 28 for non-compartmental analysis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Among 22 patients treated for TBM (8 with confirmed disease), there was high use of fluoroquinolones (levofloxacin, 21; moxifloxacin, 10; ofloxacin, 6) and carbapenems (imipenem, 11; meropenem, 6). Median CSF total concentrations of levofloxacin at 2 and 6\u00a0h were 1.34\u00a0mg\/L and 3.36\u00a0mg\/L with adjusted CSF\/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6\u00a0h were 0.78\u00a0mg\/L and 1.02\u00a0mg\/L with adjusted CSF\/serum ratios of 0.44 and 0.62. Serum and CSF concentrations of moxifloxacin were not affected by rifampin use. Among the 76 CSF samples measured for carbapenem concentrations, 79% were undetectable or below the limit of detection.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.<\/jats:p>","DOI":"10.3389\/fphar.2022.1048653","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T06:14:12Z","timestamp":1670825652000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis"],"prefix":"10.3389","volume":"13","author":[{"given":"Nicole F.","family":"Maranchick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad H.","family":"Alshaer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison G. C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teona","family":"Avaliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Gujabidze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinatin","family":"Bakuradze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shorena","family":"Sabanadze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaza","family":"Avaliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maia","family":"Kipiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Peloquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell R.","family":"Kempker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1128\/AAC.33.10.1704","article-title":"Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites","volume":"33","author":"Akahane","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"B2","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1007\/s40265-014-0222-8","article-title":"Therapeutic drug monitoring in the treatment of tuberculosis: An update","volume":"74","author":"Alsultan","year":"2014","journal-title":"Drugs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/s0891-5520(05)70096-9","article-title":"Pharmacokinetics and pharmacodynamics of antibiotics in meningitis","volume":"13","author":"Andes","year":"1999","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B4","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1093\/jac\/dkq091","article-title":"Wild-type MIC distributions of four fluoroquinolones active against Mycobacterium tuberculosis in relation to current critical concentrations and available pharmacokinetic and pharmacodynamic data","volume":"65","author":"Angeby","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"B5","doi-asserted-by":"publisher","first-page":"321","DOI":"10.2174\/1871524911106040321","article-title":"Tuberculosis infections of the central nervous system","volume":"11","author":"Bartzatt","year":"2011","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2165\/00003495-200161010-00002","article-title":"The role of fluoroquinolones in tuberculosis today","volume":"61","author":"Berning","year":"2001","journal-title":"Drugs"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/j.idc.2009.06.003","article-title":"The newer fluoroquinolones","volume":"23","author":"Bolon","year":"2009","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B8","doi-asserted-by":"publisher","first-page":"312","DOI":"10.2165\/00003088-198207040-00003","article-title":"Clinical pharmacokinetics of cerebrospinal fluid","volume":"7","author":"Bonati","year":"1982","journal-title":"Clin. Pharmacokinet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3850","DOI":"10.1128\/AAC.48.10.3850-3857.2004","article-title":"[18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans","volume":"48","author":"Brunner","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1128\/AAC.39.12.2620","article-title":"Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis?","volume":"39","author":"Chambers","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e27900","DOI":"10.1371\/journal.pone.0027900","article-title":"Long-term mortality in patients with tuberculous meningitis: A Danish nationwide cohort study","volume":"6","author":"Christensen","year":"2011","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"S266","DOI":"10.1093\/clinids\/24.supplement_2.s266","article-title":"The pharmacology of meropenem, a new carbapenem antibiotic","volume":"24","author":"Craig","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s10928-013-9301-9","article-title":"Utility of CSF in translational neuroscience","volume":"40","author":"de Lange","year":"2013","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"B14","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/S2213-2600(17)30079-6","article-title":"The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis","author":"Dheda","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/jac\/33.4.685","article-title":"Structure-activity and structure-side-effect relationships for the quinolone antibacterials","volume":"33","author":"Domagala","year":"1994","journal-title":"J. Antimicrob. Chemother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.tube.2010.07.002","article-title":"Cerebrospinal fluid concentrations of antituberculosis agents in adults and children","volume":"90","author":"Donald","year":"2010","journal-title":"Tuberculosis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/s0378-4347(96)00498-7","article-title":"Determination of imipenem in plasma by high-performance liquid chromatography for pharmacokinetic studies in patients","volume":"692","author":"Garcia-Capdevila","year":"1997","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1802107","DOI":"10.1183\/13993003.02107-2018","article-title":"Levofloxacin pharmacokinetics, pharmacodynamics and outcome in multidrug-resistant tuberculosis patients","volume":"53","author":"Ghimire","year":"2019","journal-title":"Eur. Respir. J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"449","DOI":"10.3390\/antibiotics10040449","article-title":"Meropenem stability in human plasma at -20 \u00b0C: Detailed assessment of degradation","volume":"10","author":"Gijsen","year":"2021","journal-title":"Antibiot. (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/0378-4347(84)80069-9","article-title":"Determination of imipenem (N-formimidoyl thienamycin) in human plasma and urine by high-performance liquid chromatography, comparison with microbiological methodology and stability","volume":"310","author":"Gravallese","year":"1984","journal-title":"J. Chromatogr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1056\/NEJMoa1507062","article-title":"Intensified antituberculosis therapy in adults with tuberculous meningitis","volume":"374","author":"Heemskerk","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1128\/AAC.37.2.199","article-title":"Low neurotoxicity of LJC 10, 627, a novel 1 beta-methyl carbapenem antibiotic: Inhibition of gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats","volume":"37","author":"Hikida","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.1093\/jac\/dkab286","article-title":"Meropenem concentrations in brain tissue of neurointensive care patients exceed CSF levels","volume":"76","author":"Hosmann","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1126\/science.1167498","article-title":"Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis","volume":"323","author":"Hugonnet","year":"2009","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/S1474-4422(21)00435-X","article-title":"Tuberculous meningitis: Progress and remaining questions","volume":"21","author":"Huynh","year":"2022","journal-title":"Lancet. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.5588\/ijtld.16.0498","article-title":"Carbapenems against Mycobacterium tuberculosis: A review of the evidence","volume":"20","author":"Jaganath","year":"2016","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"B27","volume-title":"Levaquin [package insert]","year":"1996"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.tube.2016.01.004","article-title":"Safety and efficacy of additional levofloxacin in tuberculous meningitis: A randomized controlled pilot study","volume":"98","author":"Kalita","year":"2016","journal-title":"Tuberc. (Edinb)"},{"key":"B29","doi-asserted-by":"publisher","first-page":"6561","DOI":"10.1128\/AAC.01158-15","article-title":"Carbapenems and rifampin exhibit synergy against Mycobacterium tuberculosis and Mycobacterium abscessus","volume":"59","author":"Kaushik","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"682ciab992","DOI":"10.1093\/cid\/ciab992","article-title":"Cycloserine and linezolid for tuberculosis meningitis: Pharmacokinetic evidence of potential usefulness","volume":"29","author":"Kempker","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1345\/aph.10359","article-title":"Seizures associated with fluoroquinolones","volume":"35","author":"Kushner","year":"2001","journal-title":"Ann. Pharmacother."},{"key":"B32","doi-asserted-by":"publisher","first-page":"32","DOI":"10.2165\/00003088-199222010-00004","article-title":"Ofloxacin clinical pharmacokinetics","volume":"22","author":"Lamp","year":"1992","journal-title":"Clin. Pharmacokinet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.idc.2009.06.008","article-title":"Pharmacokinetics and pharmacodynamics of antibacterial agents","volume":"23","author":"Levison","year":"2009","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B34","doi-asserted-by":"publisher","first-page":"101924","DOI":"10.1016\/j.tube.2020.101924","article-title":"Preclinical models to optimize treatment of tuberculous meningitis - a systematic review","volume":"122","author":"Litjens","year":"2020","journal-title":"Tuberculosis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1345\/aph.1K347","article-title":"Safety concerns with fluoroquinolones","volume":"41","author":"Mehlhorn","year":"2007","journal-title":"Ann. Pharmacother."},{"key":"B36","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1128\/AAC.26.1.78","article-title":"Determination of imipenem and cilastatin in serum by high-pressure liquid chromatography","volume":"26","author":"Myers","year":"1984","journal-title":"Antimicrob. Agents Chemother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1128\/AAC.38.8.1849","article-title":"Kinetics of ofloxacin and its metabolites in cerebrospinal fluid after a single intravenous infusion of 400 milligrams of ofloxacin","volume":"38","author":"Nau","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1128\/CMR.00007-10","article-title":"Penetration of drugs through the blood-cerebrospinal fluid\/blood-brain barrier for treatment of central nervous system infections","volume":"23","author":"Nau","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1086\/521894","article-title":"Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis","volume":"45","author":"Nijland","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2165\/00002018-199615020-00001","article-title":"Neurotoxicity of carbapenem antibacterials","volume":"15","author":"Norrby","year":"1996","journal-title":"Drug Saf."},{"key":"B41","volume-title":"Ofloxacin [package insert]","year":"2008"},{"key":"B42","doi-asserted-by":"publisher","first-page":"S144","DOI":"10.1086\/428055","article-title":"Antimicrobial safety: Focus on fluoroquinolones","volume":"41","author":"Owens","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"B43","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1592\/phco.20.5.417.35062","article-title":"Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters","volume":"20","author":"Pickerill","year":"2000","journal-title":"Pharmacotherapy"},{"key":"B44","first-page":"979","article-title":"Effect of rifampicin & isoniazid on the steady state pharmacokinetics of moxifloxacin","volume":"136","author":"Ramachandran","year":"2012","journal-title":"Indian J. Med. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1055\/s-2000-9428","article-title":"Mycobacterium tuberculosis meningitis and other etiologies of the aseptic meningitis syndrome","volume":"20","author":"Roos","year":"2000","journal-title":"Semin. Neurol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.medmal.2020.01.001","article-title":"Comparative review of imipenem\/cilastatin versus meropenem","volume":"50","author":"Salmon-Rousseau","year":"2020","journal-title":"Med. Mal. Infect."},{"key":"B47","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1080\/17476348.2021.1927718","article-title":"Extrapulmonary tuberculosis","volume":"15","author":"Sharma","year":"2021","journal-title":"Expert Rev. Respir. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"632","DOI":"10.5588\/ijtld.21.0159","article-title":"Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens","volume":"25","author":"Smith","year":"2021","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"408","DOI":"10.7164\/antibiotics.48.408","article-title":"Structural features resulting in convulsive activity of carbapenem compounds: Effect of C-2 side chain","volume":"48","author":"Sunagawa","year":"1995","journal-title":"J. Antibiot."},{"key":"B50","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/s0891-5520(20)30289-0","article-title":"Use of antibacterial agents in infections of the central nervous system","volume":"3","author":"Thea","year":"1989","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B51","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/S1474-4422(13)70168-6","article-title":"Tuberculous meningitis: More questions, still too few answers","volume":"12","author":"Thwaites","year":"2013","journal-title":"Lancet. Neurol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"eaau0965","DOI":"10.1126\/scitranslmed.aau0965","article-title":"Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis","volume":"10","author":"Tucker","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"29","DOI":"10.2165\/00003495-199958002-00006","article-title":"Pharmacokinetics and pharmacodynamics of fluoroquinolones","volume":"58","author":"Turnidge","year":"1999","journal-title":"Drugs"},{"key":"B54","doi-asserted-by":"publisher","first-page":"E01489-18","DOI":"10.1128\/AAC.01489-18","article-title":"Evaluation of carbapenems for treatment of multi- and extensively drug-resistant Mycobacterium tuberculosis","volume":"63","author":"van Rijn","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2597","DOI":"10.1128\/AAC.01824-10","article-title":"Activity of carbapenems combined with clavulanate against murine tuberculosis","volume":"55","author":"Veziris","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1128\/AAC.46.8.2327-2332.2002","article-title":"Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units)","volume":"46","author":"Viaene","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1177\/106002809703101206","article-title":"Ofloxacin-induced seizure","volume":"31","author":"Walton","year":"1997","journal-title":"Ann. Pharmacother."},{"key":"B58","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nrneurol.2017.120","article-title":"Tuberculous meningitis","volume":"13","author":"Wilkinson","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1097\/00006454-199102000-00009","article-title":"Imipenem\/cilastatin treatment of bacterial meningitis in children","volume":"10","author":"Wong","year":"1991","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B60","volume-title":"Global tuberculosis report 2021","year":"2021"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.2165\/00003495-200767070-00006","article-title":"Comparative review of the carbapenems","volume":"67","author":"Zhanel","year":"2007","journal-title":"Drugs"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1048653\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T06:14:17Z","timestamp":1670825657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1048653\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":61,"alternative-id":["10.3389\/fphar.2022.1048653"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.1048653","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,12]]},"article-number":"1048653"}}