Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis.
Xie Yingda L,de Jager Veronique R,Chen Ray Y,Dodd Lori E,Paripati Praveen,Via Laura E,Follmann Dean,Wang Jing,Lumbard Keith,Lahouar Saher,Malherbe Stephanus T,Andrews Jenna,Yu Xiang,Goldfeder Lisa C,Cai Ying,Arora Kriti,Loxton Andre G,Vanker Naadira,Duvenhage Michael,Winter Jill,Song Taeksun,Walzl Gerhard,Diacon Andreas H,Barry Clifton E
Science translational medicine
Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[F]fluoro-d-glucose positron emission tomography and computerized tomography ([F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.
Ordonez Alvaro A,Wang Hechuan,Magombedze Gesham,Ruiz-Bedoya Camilo A,Srivastava Shashikant,Chen Allen,Tucker Elizabeth W,Urbanowski Michael E,Pieterse Lisa,Fabian Cardozo E,Lodge Martin A,Shah Maunank R,Holt Daniel P,Mathews William B,Dannals Robert F,Gobburu Jogarao V S,Peloquin Charles A,Rowe Steven P,Gumbo Tawanda,Ivaturi Vijay D,Jain Sanjay K
Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [C]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.