Preclinical models to optimize treatment of tuberculous meningitis – A systematic review

Litjens, Carlijn H C; Aarnoutse, Rob E.; Brake, Lindsey H.M. te

doi:10.1016/j.tube.2020.101924

Cited by 6 publications

(4 citation statements)

References 99 publications

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“…Neuro-TB also continues to be an important health concern in those with HIV, especially in children [ 85 ]. Models of neurological infection with mycobacteria have been developed in guinea pig, rabbits, and standard mouse inbred strains [ 86 ]. These models have application to understanding several different aspects of mycobacterial infection and drug penetration.…”

Section: Humanized Mice As Models Of Neurological Diseasementioning

confidence: 99%

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

et al. 2021

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Humanized mice have become an important workhorse model for HIV research. Advances that enabled development of a human immune system in immune deficient mouse strains have aided new basic research in HIV pathogenesis and immune dysfunction. The small animal features facilitate development of clinical interventions that are difficult to study in clinical cohorts, and avoid the high cost and regulatory burdens of using non-human primates. The model also overcomes the host restriction of HIV for human immune cells which limits discovery and translational research related to important co-infections of people living with HIV. In this review we emphasize recent advances in modeling bacterial and viral co-infections in the setting of HIV in humanized mice, especially neurological disease, and Mycobacterium tuberculosis and HIV co-infections. Applications of current and future co-infection models to address important clinical and research questions are further discussed.

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Section: Humanized Mice As Models Of Neurological Diseasementioning

confidence: 99%

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

et al. 2021

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“…Several animal models have been developed to test antibiotic treatments and alternative therapies for TBM ( 24 , 25 ). A mouse model of TBM was developed to study drug distribution in the CNS and reports the efficacy of high-dose rifampin, supporting clinical data.…”

Section: Introductionmentioning

confidence: 99%

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease

Lanni,

Antilus Sainte,

Hansen,

et al. 2023

Antimicrob Agents Chemother

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Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.

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“…This is especially a concern following resolution of meningeal inflammation ( Thwaites et al, 2013 ; Roos, 2000 ). Second-line medications including fluoroquinolones appear to have improved penetration across the blood brain barrier, making them appealing antibiotics for the treatment of TBM ( Litjens et al, 2020 ). Fluoroquinolones, such as levofloxacin and moxifloxacin, may be implemented into both short term and long-term regimens ( Ghimire et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis

et al. 2022

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Background: 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.Methods: 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 h 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.Results: 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 h were 1.34 mg/L and 3.36 mg/L with adjusted CSF/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6 h were 0.78 mg/L and 1.02 mg/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.Conclusion: Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.

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Preclinical models to optimize treatment of tuberculous meningitis – A systematic review

Cited by 6 publications

References 99 publications

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease

Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis

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