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Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

ABSTRACT: Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure¹. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments². In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans³. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study⁴ using dynamic [¹¹C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [¹¹C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.

SUBMITTER: Ordonez AA

PROVIDER: S-EPMC7160048 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

Ordonez Alvaro A AA Wang Hechuan H Magombedze Gesham G Ruiz-Bedoya Camilo A CA Srivastava Shashikant S Chen Allen A Tucker Elizabeth W EW Urbanowski Michael E ME Pieterse Lisa L Fabian Cardozo E E Lodge Martin A MA Shah Maunank R MR Holt Daniel P DP Mathews William B WB Dannals Robert F RF Gobburu Jogarao V S JVS Peloquin Charles A CA Rowe Steven P SP Gumbo Tawanda T Ivaturi Vijay D VD Jain Sanjay K SK

Nature medicine 20200217 4

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure<sup>1</sup>. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments<sup>2</sup>. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans< ...[more]

PMID: 32066976

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Project description:Understanding how the bacteriomes in tuberculous lesions can be influenced by the susceptibility of Mycobacterium tuberculosis (MTB) can provide valuable information for preventing and treating drug resistant tuberculosis (DR-TB). High-throughput 16S rRNA sequencing was employed to analyze the bacteriome in pulmonary TB lesions from 14 patients with DR-TB and 47 patients with drug sensitive tuberculosis (DS-TB), along with 18 normal lung tissues (NT) from 18 lung cancer patients serving as the bacterial baseline. The phylogenetic investigation of communities by reconstruction of unobserved states2 (PICRUSt2) algorithm was utilized to predict bacterial metabolic functions. The major phyla of pulmonary bacteriomes included Proteobacteria, Actinobacteria, Bacteroidetes, Firmicutes and Fusobacteria. Alpha diversity indices, including ACE, Chao1, Shannon and OTU observed, all demonstrated different bacterial communities of DS-TB samples from that of NT samples; while only Shannon indicated difference between DR-TB and NT samples. The analysis of similarity (ANOSIM) showed significantly different bacterial communities within TB lesions compared to NT samples (R = 0.418, p = 0.001). However, difference was not observed between DR-TB and DS-TB samples (ANOSIM, R = 0.069, p = 0.173). The bacterial profiles within each DR-TB individual appeared unique, with no obvious clusters corresponding to drug-resistant phenotypes. Nevertheless, indicator genera identified in DR-TB and DS-TB lesions demonstrated distinctive micro-ecological environments. Most COG functions were enriched in TB lesions, and the most significant one was [J] translation, ribosomal structure and biogenesis. The distinct enrichment patterns of bacterial enzymes in DR-TB and DS-TB lesions suggest that pulmonary bacterial activities can be modulated by the susceptibility of MTB bacilli. This study provides fresh perspectives and strategies for the precise diagnosis and assessment of drug resistance tuberculosis.

Project description:BACKGROUND:Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been shown to be a promising technique for assessing lung lesions. However, DCE-MRI often suffers from motion artifacts and insufficient imaging speed. Therefore, highly accelerated free-breathing DCE-MRI is of clinical interest for lung exams. PURPOSE:To test the performance of rapid free-breathing DCE-MRI for simultaneous qualitative and quantitative assessment of pulmonary lesions using Golden-angle RAdial Sparse Parallel (GRASP) imaging. STUDY TYPE:Prospective. POPULATION:Twenty-six patients (17 males, mean age = 55.1 ± 14.4) with known pulmonary lesions. FIELD STRENGTH/SEQUENCE:3T MR scanner; a prototype fat-saturated, T1 -weighted stack-of-stars golden-angle radial sequence for data acquisition and a Cartesian breath-hold volumetric-interpolated examination (BH-VIBE) sequence for comparison. ASSESSMENT:After a dual-mode GRASP reconstruction, one with 3-second temporal resolution (3s-GRASP) and the other with 15-second temporal resolution (15s-GRASP), all GRASP and BH-VIBE images were pooled together for blind assessment by two experienced radiologists, who independently scored the overall image quality, lesion delineation, overall artifact level, and diagnostic confidence of each case. Perfusion analysis was performed for the 3s-GRASP images using a Tofts model to generate the volume transfer coefficient (Ktrans ) and interstitial volume (Ve ). STATISTICAL TESTS:Nonparametric paired two-tailed Wilcoxon signed-rank test; Cohen's kappa; unpaired Student's t-test. RESULTS:15s-GRASP achieved comparable image quality with conventional BH-VIBE (P > 0.05), except for the higher overall artifact level in the precontrast phase (P = 0.018). The Ktrans and Ve in inflammation were higher than those in malignant lesions (Ktrans : 0.78 ± 0.52 min-1 vs. 0.37 ± 0.22 min-1 , P = 0.020; Ve : 0.36 ± 0.16 vs. 0.26 ± 0.1, P = 0.177). Also, the Ktrans and Ve in malignant lesions were also higher than those in benign lesions (Ktrans : 0.37 ± 0.22 min-1 vs. 0.04 ± 0.04 min-1 , P = 0.001; Ve : 0.26 ± 0.12 vs. 0.10 ± 0.00, P = 0.063). DATA CONCLUSION:This feasibility study demonstrated the performance of high spatiotemporal resolution free-breathing DCE-MRI of the lung using GRASP for qualitative and quantitative assessment of pulmonary lesions. LEVEL OF EVIDENCE:2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:459-468.

Project description:BackgroundTuberculosis (TB) is one of the leading causes of death worldwide. Radiology has an important role in the diagnosis of both drug-sensitive (DS) and rifampicin-resistant (RR) pulmonary TB (PTB). This study aimed to compare the chest x-ray (CXR) patterns of microbiologically confirmed DS and RR PTB cases stratified by HIV serostatus in Uganda.MethodsWe conducted a hospital-based retrospective study at the Mulago National Referral Hospital (MNRH) TB wards. All participants had a microbiologically confirmed diagnosis of PTB. CXR findings extracted included infiltrates, consolidation, cavity, fibrosis, bronchiectasis, atelectasis, and other non-lung parenchymal findings. All films were examined by two independent radiologists blinded to the clinical diagnosis.ResultsWe analyzed CXR findings of 165 participants: 139 DS- and 26 RR-TB cases. The majority (n = 118, 71.7%) of the participants were seronegative for HIV. Overall, 5/165 (3%) participants had normal CXR. There was no statistically significant difference in the proportion of participants with consolidations (74.8% versus 88.5%; p = 0.203), bronchopneumonic opacities (56.1% versus 42.3%, p = 0.207) and cavities (38.1% versus 46.2%, p = 0.514), across drug susceptibility status (DS versus RR TB). Among HIV-infected participants, consolidations were predominantly in the middle lung zone in the DS TB group and in the lower lung zone in the RR TB group (42.5% versus 12.8%, p = 0.66). HIV-infected participants with RR TB had statistically significantly larger cavity sizes compared to their HIV uninfected counterparts with RR TB (7.7 ± 6.8 cm versus 4.2 ± 1.3 cm, p = 0.004).ConclusionsWe observed that a vast majority of participants had similar CXR changes, irrespective of drug susceptibility status. However, HIV-infected RR PTB had larger cavities.The diagnostic utility of cavity sizes for the differentiation of HIV-infected and non-infected RR TB could be investigated further.

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Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

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Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

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