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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 |

REPOSITORIES: biostudies-literature

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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:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

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

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