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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.

Author information

Tucker EW1,2,3,4, Guglieri-Lopez B5, Ordonez AA1,2,6, Ritchie B1,2,3, Klunk MH1,2,6, Sharma R1,2,6, Chang YS1,2,6, Sanchez-Bautista J1,2,6, Frey S1,7, Lodge MA7, Rowe SP7, Holt DP7, Gobburu JVS5, Peloquin CA8, Mathews WB7, Dannals RF7, Pardo CA9, Kannan S3, Ivaturi VD10, Jain SK11,2,6,7.
1
Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Division of Pediatric Critical Care, Johns Hopkins All Children's Hospital, St. Petersburg, FL 33701, USA.
5
Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
6
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
7
Division of Nuclear Medicine and Molecular Imaging, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
8
Infectious Disease Pharmacokinetics Laboratory, Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.
9
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
10
Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. vivaturi@rx.umaryland.edu sjain5@jhmi.edu.
11
Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. vivaturi@rx.umaryland.edu sjain5@jhmi.edu.