# Measuring Intralesional Bedaquiline Exposures in Cavitary TB Using Noninvasive In Vivo PET Imaging

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $204,688

## Abstract

Current antibiotic dosing recommendations and breakpoints for drug susceptibility are based on plasma
concentrations and historic measures of efficacy, without specific information at the infection sites. Since
inappropriate antibiotic concentrations in target tissues can lead to treatment failure, selection of resistant
organisms, or toxicity, several studies and the U.S. Food and Drug Administration (FDA) support measuring
drug concentrations in infected tissues. However, current tools to detect tissue drug levels are invasive (require
tissue resection), which is difficult in humans and generally limited to a single time point even in animals.
 Our overarching hypothesis is that multiple, heterogeneous pathological states, e.g. cavitation, pneumonia,
and necrotic lesions in pulmonary tuberculosis (TB), occur simultaneously in the same patient. Moreover, these
lesions can also have distinct bacterial burdens and antibiotic exposures, which also change with disease
progression and antibiotic treatment. Cavitation is a key pathological feature of human TB and a well-
recognized risk factor for transmission of infection, relapse, and emergence of drug resistance after treatment.
While cavitary walls have high bacterial burden (107-109), they are poorly vascularized with thick fibrous
capsules. Therefore, while adequately high antibiotic levels are need to effectively kill bacteria in cavities, using
PET bioimaging in patients with pulmonary TB, we have demonstrated that rifampin exposure is paradoxically
the lowest in cavitary walls.
 Bedaquiline, a bromine-containing diarylquinoline, was recently approved for the treatment of multi-drug
resistant (MDR) tuberculosis (TB). However, bedaquiline distribution into infected tissues (e.g. granulomas and
cavitary lesions) has not been studied extensively whilst preliminary preclinical studies have reported variability
in the treatment response in mice with caseous necrotic granulomas. While highly effective in treating MDR-
TB, bedaquiline can also cause cardiac events (QT-interval prolongation) leading to safety warnings by
regulatory agencies. Therefore, there is a need for noninvasive methods to measure the biodistribution of
bedaquiline in infected tissues (e.g. cavities) and other target organs to inform appropriate dosing and develop
effective, antibiotic treatments with minimal toxicities. The overall goals of this project are to leverage our
expertise in animal models of TB and in vivo PET, a clinically translatable technology. We will develop efficient
radiolabeling methods for 76Br-bedaquiline. Using Mycobacterium tuberculosis infections as a model for
heterogeneous necrotic-lesions in multiple-compartments, quantitative 76Br-bedaquiline PET in live animals
and post-mortem high-resolution / sensitivity autoradiography (<10 µm resolution, sub-nanogram sensitivity)
will be utilized in animal models of cavitary TB to provide detailed biodistribution and temporal kinetics of
intralesional bedaquilin...

## Key facts

- **NIH application ID:** 10104440
- **Project number:** 5R21AI149760-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Sanjay K Jain
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2020-02-11 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104440

## Citation

> US National Institutes of Health, RePORTER application 10104440, Measuring Intralesional Bedaquiline Exposures in Cavitary TB Using Noninvasive In Vivo PET Imaging (5R21AI149760-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104440. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*