Research ArticleTuberculosis

Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis

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Science Translational Medicine  05 Dec 2018:
Vol. 10, Issue 470, eaau0965
DOI: 10.1126/scitranslmed.aau0965

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TB on the brain

Children and immunodeficient individuals are especially prone to tuberculosis infections in the brain, causing tuberculous meningitis. Tucker et al. used a rabbit model of tuberculous meningitis and PET imaging to better understand drug distribution. They found that despite sufficient drug concentration in the plasma, rifampin was not penetrating the TB lesions in the brain. These findings were reflected in the imaging of a human patient with tuberculous meningitis. Pharmacokinetic modeling revealed that dosing in pediatric patients would likely need to be adjusted to allow for sufficient rifampin penetration into affected brain areas.

Abstract

Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.

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