1954. Dynamic PET facilitated Modeling and Novel Antibiotic Regimens for Tuberculous Meningitis due to Multidrug-Resistant Strains

Abstract Background Tuberculous meningitis is the most serious form of tuberculosis (TB), affecting the young and immunocompromised. TB meningitis due to multidrug-resistant (MDR) strains is associated with high mortality (40-100%). Importantly, effective treatments for MDR TB meningitis are lacking, and the activity of the only approved MDR regimen for pulmonary TB (BPaL – bedaquiline, pretomanid, linezolid) is substantially inferior to the standard TB regimen in a mouse model of TB meningitis. Methods Dynamic positron emission tomography (PET) was performed using radioanalogs of antibiotics (18F-pretomanid, 18F-sutezolid, 18F-linezolid and 76Br-bedaquiline) active against MDR strains to measure multicompartmental exposures (area under the curve, AUC). Each radioanalog is chemically identical to the parent antibiotic and the radioisotope is retained within the major metabolite. PET facilitated pharmacokinetic modeling predicted tissue exposures which were used to design optimized regimens (Fig.1).Figure 1.Study design. Dynamic positron emission tomography (PET) was performed using radioanalogs of antibiotics (18F-pretomanid, 18F-sutezolid, 18F-linezolid and 76Br-bedaquiline) active against MDR strains to measure multicompartmental antibiotic exposures (area under the curve, AUC) in mouse models of TB. First-in-human 18F-pretomanid PET studies were performed in six subjects. PET signal was quantified by drawing volumes of interest (VOI) in brain, lung, and left ventricles (blood, converted to plasma) to measure antibiotic exposures [area under the concentration time curve (AUC)] represented as AUCtissue/plasma ratios. Pharmacokinetic analyses were performed to predict antibiotic exposures at human equipotent dosing in brain tissues, which were used to design optimized pretomanid-based regimens for TB meningitis. These optimized regimens were evaluated in the mouse model of TB meningitis. Approvals from the Johns Hopkins Biosafety, and Radiation Safety were also obtained for all studies. Results PET demonstrated discordant antibiotic exposure in lung and brain compartments in mouse studies. While all antibiotics achieved high lung exposures (AUClung/plasma ∼1), only 18F-pretomanid achieved high brain exposures (Fig. 2). First-in-human 18F-pretomanid PET studies (n = 6 subjects) also demonstrated high exposures in both lung and brain compartments (Fig. 3). Pharmacokinetic modeling confirmed equivalence between mouse and human PET studies and identified the h