Linezolid does not improve bactericidal activity of rifampin-containing first-line regimens in animal models of TB meningitis

Linezolid does not improve bactericidal activity of rifampin-containing first-line regimens in animal models of TB meningitis

Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB) and there is a critical need to optimize treatment. Linezolid is approved for multidrug resistant TB and has shown encouraging results in retrospective TB meningitis studies, with several clinical trials underwa...

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Bibliographic Details
Published in:International journal of antimicrobial agents Vol. 63; no. 1; p. 107048
Main Authors: Tucker, Elizabeth W, Ruiz-Bedoya, Camilo A, Mota, Filipa, Erice, Clara, Kim, John, de Jesus, Patricia, Jahdav, Ravindra, Bahr, Melissa, Flavahan, Kelly, Chen, Xueyi, Peloquin, Charles A, Freundlich, Joel S, Jain, Sanjay K
Format: Journal Article
Language:English
Published: Netherlands 01-01-2024
Subjects:
Animals
Antitubercular Agents - pharmacokinetics
Antitubercular Agents - therapeutic use
Linezolid - therapeutic use
Mammals
Mice
Models, Animal
Rabbits
Retrospective Studies
Rifampin - pharmacokinetics
Rifampin - therapeutic use
Tuberculosis, Meningeal - drug therapy
Tuberculosis, Multidrug-Resistant - drug therapy
Linezolid
Antimicrobial regimens
Positron emission tomography
Tuberculous meningitis
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Summary:Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB) and there is a critical need to optimize treatment. Linezolid is approved for multidrug resistant TB and has shown encouraging results in retrospective TB meningitis studies, with several clinical trials underway assessing its additive effects on high-dose (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin-containing regimens. However, the efficacy of adjunctive linezolid to rifampin-containing first-line TB meningitis regimens and the tissue pharmacokinetics (PK) in the central nervous system (CNS) are not known. We therefore conducted cross-species studies in two mammalian (rabbits and mice) models of TB meningitis to test the efficacy of linezolid when added to the first-line TB regimen and measure detailed tissue PK (multicompartmental positron emission tomography [PET] imaging and mass spectrometry). Addition of linezolid did not improve the bactericidal activity of the high-dose rifampin-containing regimen in either animal model. Moreover, the addition of linezolid to standard-dose rifampin in mice also did not improve its efficacy. Linezolid penetration (tissue/plasma) into the CNS was compartmentalized with lower than previously reported brain and cerebrospinal fluid (CSF) penetration, which decreased further two weeks after initiation of treatment. These results provide important data regarding the addition of linezolid for the treatment of TB meningitis.
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content type line 23
ISSN:0924-8579
1872-7913
DOI:10.1016/j.ijantimicag.2023.107048