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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions
Nature Medicine, Volume 26, No. 4, Year 2020
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Description
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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Authors & Co-Authors
Ordoñez, Alvaro Andres
United States, Baltimore
Johns Hopkins School of Medicine
Magombedze, Gesham
United States, Dallas
Baylor University Medical Center at Dallas
Srivastava, Shashikant
United States, Dallas
Baylor University Medical Center at Dallas
Tucker, Elizabeth Winans
United States, Baltimore
Johns Hopkins School of Medicine
Urbanowski, Michael E.
United States, Baltimore
Johns Hopkins School of Medicine
Lodge, Martin A.
United States, Baltimore
Johns Hopkins School of Medicine
Shah, Maunank S.
United States, Baltimore
Johns Hopkins School of Medicine
Peloquin, Charles Arthur
United States, Gainesville
University of Florida Health
Rowe, Steven P.
United States, Baltimore
Johns Hopkins School of Medicine
Gumbo, Tawanda
United States, Dallas
Baylor University Medical Center at Dallas
Jain, Sanjay K.
United States, Baltimore
Johns Hopkins School of Medicine
Statistics
Citations: 70
Authors: 11
Affiliations: 5
Identifiers
Doi:
10.1038/s41591-020-0770-2
ISSN:
10788956
Research Areas
Environmental
Genetics And Genomics
Infectious Diseases