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

Filipa Mota, Camilo A. Ruiz-Bedoya, Elizabeth W. Tucker, Daniel P. Holt, Patricia Jesus, Martin A. Lodge, Clara Erice, Xueyi Chen, Melissa Bahr, Kelly Flavahan, John Kim, Mary Katherine Brosnan, Alvaro A. Ordonez, Charles A. Peloquin, Robert F. Dannals and Sanjay K. Jain ()
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Filipa Mota: Johns Hopkins University School of Medicine
Camilo A. Ruiz-Bedoya: Johns Hopkins University School of Medicine
Elizabeth W. Tucker: Johns Hopkins University School of Medicine
Daniel P. Holt: Johns Hopkins University School of Medicine
Patricia Jesus: Johns Hopkins University School of Medicine
Martin A. Lodge: Johns Hopkins University School of Medicine
Clara Erice: Johns Hopkins University School of Medicine
Xueyi Chen: Johns Hopkins University School of Medicine
Melissa Bahr: Johns Hopkins University School of Medicine
Kelly Flavahan: Johns Hopkins University School of Medicine
John Kim: Johns Hopkins University School of Medicine
Mary Katherine Brosnan: Johns Hopkins University School of Medicine
Alvaro A. Ordonez: Johns Hopkins University School of Medicine
Charles A. Peloquin: University of Florida College of Pharmacy
Robert F. Dannals: Johns Hopkins University School of Medicine
Sanjay K. Jain: Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35730-3

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