Positron emission tomography reveals pretomanid CNS penetration and BPaL regimen efficacy for multidrug-resistant tuberculosis meningitis
Tuberculosis (TB) is still the leading cause of death from infectious diseases, and TB meningitis is particularly nasty – especially in its multidrug-resistant (MDR) form. Patients with MDR-TB meningitis are more likely to succumb to their illness compared with patients with drug-susceptible disease.
Pretomanid was granted FDA approval in 2019 for use against pulmonary MDR-TB; the antibiotic is also used in a combined regimen with bedaquiline and linezolid – BPaL – to treat TB meningitis; however, there is a lack of data on both the efficacy of the regimen and pretomanid’s ability to penetrate sites such as the central nervous system (CNS). Mass spec studies in healthy individuals have shown good penetration, but the technique is unable to provide detailed spatiotemporal concentration-time measures in infected tissues.
Furthermore, dosing recommendations of pretomanid are often based on plasma concentrations and fail to consider drug concentrations in infected tissues. But inappropriate antibiotic levels in target tissues can cause the selection of resistant organisms, organ failure, or toxicity – which ultimately leads to treatment failure.
Given the clear need for deeper insight into optimal regimens and dosing strategies for MDR-TB meningitis, researchers developed a molecular imaging methodology to assess whole-body penetration of pretomanid (1). “Pretomanid has three fluorine atoms and we developed methods to replace one of them with an isotope of fluorine, giving us 18F-pretomanid, which can then be imaged using positron emission tomography (PET),” says Sanjay Jain, senior author on the study. “Such radiochemistry uses specialized methodologies, but we were able to develop methods for use in both animals and humans.” Jain and colleagues also used a mouse model to test the BPaL regimen for TB meningitis.
In rabbit and mouse models of TB meningitis, pretomanid had excellent CNS penetration, but there were discordant antibiotic concentrations in the cerebrospinal fluid (CSF) and brain parenchyma, which are likely affected by drug properties. Jain says this is an important finding because “CSF studies are commonly used in many clinical trials, but CSF may not actually be an adequate surrogate of disease or drug levels in the brain tissues.”
In the mouse model of TB meningitis, bactericidal activity of the BPaL was substantially inferior to the standard TB regimen, even six weeks after treatment initiation. “This was a bit of a surprise. We believe it was due to the restricted penetration of bedaquiline and linezolid into the brain parenchyma,” notes Jain. They also found that, in the first in-human test of 18F-pretomanid PET in six healthy volunteers, the antibiotic had excellent penetration of the CNS, with higher levels in the brain parenchyma than in CSF.
How could the findings help in the fight against antibiotic resistance? “We believe our work will force investigators to think more carefully when developing treatments for CNS infections, as well as spur interest in developing new antibiotic regimens that would be effective against MDR-TB meningitis,” says Jain. He also thinks the findings could affect trends in research: “Animal models may gain new traction and receive more funding – not only for understanding TB meningitis but also developing new treatments. I also think people will now understand that CSF is not the adequate surrogate of disease or drug levels in brain tissues that we thought it was.”