A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.
Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P = 0.035) and also significantly reduced uptake of [(18)F]-2-fluoro-2-deoxyglucose by positron emission tomography (P = 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P = 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Laura E
LE
Via
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Kathleen
K
England
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Danielle M
DM
Weiner
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Daniel
D
Schimel
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Matthew D
MD
Zimmerman
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Emmanuel
E
Dayao
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Ray Y
RY
Chen
Biostatistics Research Branch, NIAID, NIH, Bethesda, Maryland, USA.
Lori E
LE
Dodd
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Mike
M
Richardson
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Katherine K
KK
Robbins
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Ying
Y
Cai
Center for Infectious Disease Imaging, Radiology and Imaging Sciences, NIH, Bethesda, Maryland, USA.
Dima
D
Hammoud
Positron Emission Tomography Department, Division of Diagnostic Radiology, Clinical Center, NIH, Bethesda, Maryland, USA.
Peter
P
Herscovitch
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Véronique
V
Dartois
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
JoAnne L
JL
Flynn
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa cbarry@niaid.nih.gov.
Clifton E
CE
Barry
D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D019788:Fluorodeoxyglucose F18; D006099:Granuloma / Q000382:microbiology; D008297:Male; D009169:Mycobacterium tuberculosis; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012008:Recurrence; D014057:Tomography, X-Ray Computed; D014376:Tuberculosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000382:microbiology*
D000995:Antitubercular Agents; D004338:Drug Combinations; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18