BACKGROUND: The ability of antituberculosis drugs to cross the blood-brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF). METHODS: We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration. RESULTS: A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration. CONCLUSIONS: Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.
BACKGROUND: The ability of antituberculosis drugs to cross the blood-brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF). METHODS: We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration. RESULTS: A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration. CONCLUSIONS: Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.
Authors: Onno W Akkerman; Omar F F Odish; Mathieu S Bolhuis; Wiel C M de Lange; Hubertus P H Kremer; Gert-Jan R Luijckx; Tjip S van der Werf; Jan-Willem Alffenaar Journal: Clin Infect Dis Date: 2015-11-03 Impact factor: 9.079
Authors: Elizabeth W Tucker; Lisa Pieterse; Matthew D Zimmerman; Zarir F Udwadia; Charles A Peloquin; Maria Tarcela Gler; Shashank Ganatra; Jeffrey A Tornheim; Prerna Chawla; Janice C Caoili; Brittaney Ritchie; Sanjay K Jain; Véronique Dartois; Kelly E Dooley Journal: Antimicrob Agents Chemother Date: 2019-09-23 Impact factor: 5.191
Authors: A Dorothee Heemskerk; Mai Thi Hoang Nguyen; Ha Thi Minh Dang; Chau Van Vinh Nguyen; Lan Huu Nguyen; Thu Dang Anh Do; Thuong Thuy Thuong Nguyen; Marcel Wolbers; Jeremy Day; Thao Thi Phuong Le; Bang Duc Nguyen; Maxine Caws; Guy E Thwaites Journal: Clin Infect Dis Date: 2017-07-01 Impact factor: 9.079
Authors: A G C Smith; M Gujabidze; T Avaliani; H M Blumberg; J M Collins; S Sabanadze; T Bakuradze; Z Avaliani; R R Kempker; M Kipiani Journal: Int J Tuberc Lung Dis Date: 2021-08-01 Impact factor: 3.427