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Dynamic Imaging in Patients with Tuberculosis Reveals Heterogeneous Drug Exposures in Pulmonary Lesions

2020.02.17.

Ordonez et al., Nature Medicine, 2020

Introduction

Small Animal Molecular imaging of infectious diseases in lung is becoming more and more important, especially at the time of COVID-19 outbreak. Dr. Sanjay K. Jain and his research group in Center for Infection and Inflammation Imaging Research (Ci3R, John Hopkins University) focuses on studying the pathogenesis of bacterial diseases, with a major focus on tuberculosis (TB). They have developed a pipeline of bacteria-specific PET-based imaging tracers. They also have developed imaging techniques to noninvasively determine antimicrobial penetration into infected lesions and understand lesions-specific host-responses. They translate their preclinical findings to the clinic and are testing some novel imaging tracers developed in their laboratory in human studies. For pre-clinical molecular imaging technique they are using Mediso nanoScan® PET/CT, so they are able to follow kinetic changes of a drug distribution in high temporal resolution, and can locate sites of pathogen and inflammation in high spatial resolution.

The main challenge working with M. tuberculosis, and working with SARS-CoV-2 even, is that it requires Biosafety Level 3 (BSL-3) environment. Dr. Jain and his co-workers have developed sealed biocontainment chambers for mouse and rabbit compliant with BSL-3 requirements in house. The high versatility and open design of nanoScan PET/CT allowed them to install their chamber on the Mediso system. Working in a BSL-2 environment with a BSL-3 compatible chamber makes researcher’s life easier. For these reasons Mediso in collaboration with Dr. Jain has developed a commercially available BSL-3 compatible chamber for the PET/CT MultiCell™ imaging system, (see details below).

Summary

In this recent publication Ordonez et al. provided estimates on rifampin dosing, a first-line TB drug, required to achieve faster cure in 4 months. Newly identified patients were enrolled in a first-in-human study using dynamic [11C]rifampin positron emission tomography (PET) and computed tomography (CT). The findings from human studies were supported with small animal imaging using Mediso nanoScan® PET/CT

An interesting finding was that [11C]rifampin exposures in human pulmonary TB lesions were low, were spatially compartmentalized and demonstrated between-patient and within-patient variability. [11C]rifampin (tissue-to-plasma) AUC ratios demonstrate limited [11C]rifampin exposure in lesions, with the lowest exposure noted in cavity walls, which paradoxically also have the highest bacterial burden. The pharmacokinetic studies conducted on a rabbit model also demonstrated limited and spatially compartmentalized [11C]rifampin exposures in TB lesions, with the lowest exposures in cavity walls.

The authors hypothesize that tissue necrosis and presumably the fibrotic extracellular matrix surrounding cavitary tissues limited the ability for passive diffusion and rifampin penetration into these lesions, thus minimizing the spread.

Commercially available BSL-3 compliant imaging chamber from Mediso

Mediso has developed in collaboration with Dr. Sanjay K. Jain a commercially available BSL-3 compliant imaging chamber for MultiCell™ imaging system.

The advance of using this chamber is that the PET/CT scanner doesn’t have to be in BSL-3 laboratory, so the animal imaging and the scanner maintenance become much easier. Moreover, the scanner in a such setup can be used for non BSL-3 required animal studies also.

As a workflow, the animals are anesthetized in a BSL-3 environment and placed into the imaging chamber and then sealed. The outer surface of the chamber is decontaminated before caring to BSL-2 environment.

The chamber can be attached by one-click to the scanner’s docking stage without any further tube connection. The anesthesia gas flows in and out through a 0.3 um pore filter. The heating air is circulating only in the chamber’s wall, so there is no transit between the heating air compartment and the chamber space. For kinetic studies the animal is cannulated in BSL-3 and the tubing is led out through a sealed opening (see Figure 1.)

This practical solution provides a tenable and flexible mechanism for routine imaging and for implementing the more severe constraints necessitated by BSL-3 imaging procedures in a simple and expeditious manner.

Figure 1. MultiCell™ BSL-3 compliant imaging chamber

Read the full article on Nature Medicine

 

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