A study of the intrapulmonary pharmacology and immunology of tuberculosis therapy

Background: Shorter, more efficacious, treatments for pulmonary tuberculosis (TB) are required. Knowledge of the contributions of drug therapy and the immune system to TB cure will inform efforts to optimise treatment. This study investigates whether antibiotic exposure at the site of infection determines the rate of bacterial clearance and clinical treatment response; and whether impaired alveolar macrophage function in HIV-infection limits the ability of the immune system to eradicate TB. Methods: Malawian adults with microbiologically-confirmed pulmonary TB were recruited to a longitudinal cohort study. Participants received standard first-line therapy, and supplied serial sputum samples to assess TB bacillary elimination in the sputum. Two-month sputum culture status was recorded, and rates of failure or relapse to one-year post-treatment. Plasma and intrapulmonary samples were collected at 8 and 16 weeks into treatment, and drug concentrations measured. Population PK modelling generated estimates of drug exposure in plasma, epithelial lining fluid (ELF), and alveolar cells. Alveolar macrophage function was assessed using quantitative flow cytometry-based reporter bead assays, and ELF cytokine levels measured ... (continues)