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Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs.
Chen, Xueyi; Arun, Bhavatharini; Nino-Meza, Oscar J; Sarhan, Mona O; Singh, Medha; Jeon, Byeonghoon; Mane, Kishor; Shah, Maunank; Tucker, Elizabeth W; Carroll, Laurence S; Freundlich, Joel S; Peloquin, Charles A; Ivaturi, Vijay D; Jain, Sanjay K.
Afiliación
  • Chen X; Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Arun B; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Nino-Meza OJ; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Sarhan MO; Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD, USA.
  • Singh M; Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jeon B; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Mane K; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Shah M; Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Tucker EW; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Carroll LS; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Freundlich JS; Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Peloquin CA; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Ivaturi VD; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jain SK; Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun ; 15(1): 6657, 2024 Aug 14.
Article en En | MEDLINE | ID: mdl-39143055
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Pulmón / Mycobacterium tuberculosis / Antituberculosos Límite: Adult / Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Pulmón / Mycobacterium tuberculosis / Antituberculosos Límite: Adult / Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido