GL05

TB drugs face two major challenges in curing active disease and latent infection: (1) the site of disease which drugs need to reach is made of structurally different compartments, some of which are poorly served by the vascular system, and (2) intracellular and extracellular bacterial subpopulations that inhabit each of these niches are differentially susceptible to drug action. Our group develops methods to study the penetration and activity of TB drugs in lung lesions, with the objective of testing the hypothesis that a drug’s efficacy is a function of its concentration at the site of infection (pharmacokinetics [PK]), and its potency against the resident Mycobacterium tuberculosis (Mtb) populations (pharmacodynamics [PD]). In collaboration with PK-PD modeling experts, we use this knowledge to forecast ‘lesion coverage’ by drug combinations, to prioritize regimens with the best potential for sterilization and thus treatment shortening. While we have only scratched the surface of the question at hand, emerging data reveal correlations between lesion coverage and drug efficacy in animal models and TB patients. These tools can be applied to more rationally combine antibiotics that both reach and kill all bacterial subpopulations, and to guide the development of faster acting novel regimens, not only against TB but also against any persisting bacterial infection such as nontuberculous mycobacterial lung disease.