Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures.

Area of Science:

• Pharmacology
• Infectious Diseases
• Medical Imaging

Background:

• Tuberculosis (TB) meningitis, the most lethal form of TB, requires optimized antibiotic treatments for effective brain penetration.
• Current antibiotic regimens for tuberculous meningitis are adapted from pulmonary TB treatments, lacking specific optimization for CNS delivery.

Approach:

• First-in-human dynamic 18F-pretomanid positron emission tomography (PET) studies visualized antibiotic concentration-time exposures in brain and lung tissues.
• PET imaging with antibiotic radioanalogs in mice and rabbits, alongside mass spectrometry, confirmed tissue-specific partitioning of antibiotics active against multidrug-resistant (MDR) strains.
• PET-facilitated pharmacokinetic modeling determined optimal human dosing for achieving therapeutic brain exposures.

Key Points:

• Dynamic PET demonstrated preferential brain (AUCtissue/plasma 2.25) over lung (AUCtissue/plasma 0.97) partitioning of 18F-pretomanid.
• Optimized, pretomanid-based regimens showed excellent bactericidal activity in a mouse model of TB meningitis without increased brain injury.
• Discordant antibiotic activities in brain versus lung tissues correlated with compartmentalized tissue exposures, highlighting the importance of penetration.

Conclusions:

• This study provides a mechanistic understanding of compartmentalized antibiotic activity in TB meningitis.
• The findings support the development of optimized antimicrobial regimens for meningitis and other infections in specific body compartments.
• Dynamic PET imaging is a powerful tool for visualizing antibiotic pharmacokinetics and optimizing treatment strategies for complex infections.