Journal Article

Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies

Holt, Daniel P., Mota, Filipa, Erice, Clara, De Jesus, Patricia, Kim, John, Lodge, Martin A., Peloquin, Charles A., Ruiz-Bedoya, Camilo A., Jain, Sanjay K., Dannals, Robert F., Bahr, Melissa, Ordonez, Alvaro A., Chen, Xueyi, Flavahan, Kelly, Brosnan, Mary Katherine, Tucker, Elizabeth W.

2022

Overview

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 18 F-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 18 F-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. Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/21 / 59/78 / 631/326/107 / 64/60 / 692/4017 / 692/617/375/1367 / 692/699/255/1856 / 82/58 / Animal models / Antibiotics / Antiinfectives and antibacterials / Bactericidal activity / Brain / Central nervous system / Cerebrospinal fluid / Drug resistance / Emission analysis / Emission measurements / Fluorine isotopes / Humanities and Social Sciences / Linezolid / Medical imaging / Meningitis / multidisciplinary / Multidrug resistance / Nervous system / Neuroimaging / Nitroimidazole / Parenchyma / Penetration / Penetration resistance / Pharmacokinetics / Positron emission / Positron emission tomography / Science / Science (multidisciplinary) / Tomography / Tuberculosis