Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions

Abstract

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure(1). However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments(2). In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans(3). Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study(4) using dynamic [C-11]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [C-11]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development. Distinct patterns of exposure to a first-line tuberculosis drug in separate lung lesions within patients are revealed by PET-CT imaging. Use of the technique might help optimize the duration and dosing of antimicrobial drugs.