National Institute of Allergy and Infectious Diseases 5R01AI153349-05

Measuring Intralesional Drug Exposures in Cavitary TB using Noninvasive In Vivo PET Imaging

This award funds a project at Johns Hopkins University to develop and apply noninvasive PET imaging techniques to measure antibiotic drug concentrations in cavitary tuberculosis lesions. The goal is to optimize TB treatment by understanding drug distribution and resistance, potentially shortening treatment duration and improving outcomes.

Description

Effective treatment of infections depends on achieving adequate antibiotic concentrations at infection sites, where the pathogen resides. However, with few exceptions, current antibiotic dosing recommendations are based on achievable plasma concentrations, without specific information on drug concentrations at the site of infection. Plasma drug levels do not correlate well with those at infection sites. Cavitary lesions, hallmark of human tuberculosis (TB), have limited drug penetration and are a risk factor for treatment failure, recurrence, and antibiotic resistance. Direct tissue measurements are invasive, only performed when clinically indicated, and provide data at a single time-point even in animal models. Multiple, pathologically distinct TB lesions coexist within the same host, making sampling bias a concern. Current antibiotic strategies aim for >85% efficacy at the population level but ignore heterogeneity within and between subjects. Shorter treatments could be effective for >70%, but tools to identify patients at risk for failure or needing longer treatments are needed. We developed novel noninvasive, multi-compartment in situ measurement tools for antibiotic concentration-time profiles. First-in-human PET/CT imaging in TB patients demonstrated spatially compartmentalized rifampin exposures, with low cavitary tissue levels. Repeat imaging showed independent temporal evolution of rifampin exposure in different lesions. Similar findings were confirmed in experimentally infected rabbits. Modeling identified that 35 mg/kg/day of rifampin is needed for a 4-month cure in cavitary disease. Optimized dosing could shorten treatments; suboptimal dosing contributes to failure and resistance, a top global health threat. Our goals are to leverage in vivo imaging, animal models, and hollow-fiber systems to: a) measure spatial and temporal distribution of TB drugs against resistant strains and optimize treatments; b) identify factors leading to failure or long-term cure; c) develop imaging biomarkers for early detection of treatment failure or need for extended therapy.

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