Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs

Xueyi Chen, Bhavatharini Arun, Oscar J. Nino-Meza, Mona O. Sarhan, Medha Singh, Byeonghoon Jeon, Kishor Mane, Maunank Shah, Elizabeth W. Tucker, Laurence S. Carroll, Joel S. Freundlich, Charles A. Peloquin, Vijay D. Ivaturi and Sanjay K. Jain ()
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Xueyi Chen: Johns Hopkins University School of Medicine
Bhavatharini Arun: University of Maryland School of Pharmacy
Oscar J. Nino-Meza: Johns Hopkins University School of Medicine
Mona O. Sarhan: Johns Hopkins University School of Medicine
Medha Singh: Johns Hopkins University School of Medicine
Byeonghoon Jeon: Johns Hopkins University School of Medicine
Kishor Mane: Rutgers New Jersey Medical School
Maunank Shah: Johns Hopkins University School of Medicine
Elizabeth W. Tucker: Johns Hopkins University School of Medicine
Laurence S. Carroll: Johns Hopkins University School of Medicine
Joel S. Freundlich: Rutgers New Jersey Medical School
Charles A. Peloquin: Pharmacotherapy and Translational Research, University of Florida College of Pharmacy
Vijay D. Ivaturi: University of Maryland School of Pharmacy
Sanjay K. Jain: Johns Hopkins University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.

Date: 2024
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DOI: 10.1038/s41467-024-50989-4

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