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Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies
Filipa Mota1,2,3, Camilo A Ruiz-Bedoya1,2,3, Elizabeth W Tucker1,2,4
1Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Abstract:
Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis.
Insights
Pretomanid effectively penetrates the central nervous system (CNS) for treating drug-resistant tuberculosis meningitis. However, the full BPaL regimen shows limited efficacy due to poor penetration of other drugs into the brain.
Area of Science:
- Pharmacology
- Infectious Diseases
- Neuroscience
Background:
- Pretomanid, bedaquiline, and linezolid (BPaL) treat multidrug-resistant tuberculosis (MDR-TB).
- Efficacy of BPaL for TB meningitis and CNS penetration are poorly understood.
- MDR-TB meningitis has high mortality and limited treatment options.
Purpose of the Study:
- To assess CNS penetration of pretomanid using novel 18F-pretomanid synthesis and PET imaging.
- To evaluate the efficacy of the BPaL regimen in a TB meningitis mouse model.
- To determine pretomanid CNS penetration in healthy human volunteers.
Main Methods:
- Developed 18F-pretomanid for PET imaging.
- Conducted cross-species PET imaging in mouse and rabbit TB meningitis models.
- Assessed BPaL regimen efficacy in a mouse TB meningitis model.
- Performed first-in-human 18F-pretomanid PET scans in healthy volunteers.
Main Results:
- 18F-pretomanid demonstrated excellent CNS penetration in mouse and rabbit models.
- Cerebrospinal fluid (CSF) pretomanid levels did not correlate with brain parenchyma concentrations.
- BPaL regimen showed inferior bactericidal activity in the mouse model compared to standard TB treatment, likely due to poor bedaquiline and linezolid CNS penetration.
- Human PET scans confirmed excellent pretomanid CNS penetration, with higher brain parenchyma than CSF levels.
Conclusions:
- Pretomanid exhibits strong CNS penetration, suggesting potential for TB meningitis treatment.
- Limited efficacy of the BPaL regimen in TB meningitis may stem from insufficient penetration of bedaquiline and linezolid into the brain.
- Further research is needed to develop effective CNS-penetrant antibiotic regimens for MDR-TB meningitis.
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