title: PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.
abstract: Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. We show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in Mycobacterium tuberculosis-infected cynomolgus macaques with active TB. This effect coincided with a decline in 2-deoxy-2-[(18)F]-fluoro-d-glucose positron emission tomography (FDG PET) imaging avidity in the lungs of these animals and with reductions in pulmonary pathology measured by serial computed tomography (CT) scans over 2 months of monotherapy. In a parallel phase 2 clinical study of linezolid in patients infected with XDR-TB, we also collected PET/CT imaging data from subjects receiving linezolid that had been added to their failing treatment regimens. Quantitative comparisons of PET/CT imaging changes in these human subjects were similar in magnitude to those observed in macaques, demonstrating that the therapeutic effect of these oxazolidinones can be reproduced in this model of experimental chemotherapy. PET/CT imaging may be useful as an early quantitative measure of drug efficacy against TB in human patients.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Coleman
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Ray Y
authors.initials: RY
authors.lastname: Chen
authors.affiliation: International Tuberculosis Research Center, Changwon 631-710, Republic of Korea.
authors.forename: Myungsun
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA.
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Biostatistics Research Branch, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Lori E
authors.initials: LE
authors.lastname: Dodd
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maiello
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: International Tuberculosis Research Center, Changwon 631-710, Republic of Korea.
authors.forename: Youngran
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Marriner
authors.affiliation: Public Health Research Institute Center, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Scanga
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.affiliation: International Tuberculosis Research Center, Changwon 631-710, Republic of Korea. Department of Microbiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Sang Nae
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Institute of Infectious Disease and Molecular Medicine, and the Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch 7701, South Africa. cbarry@niaid.nih.gov joanne@pitt.edu.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. cbarry@niaid.nih.gov joanne@pitt.edu.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000081:Acetamides / Q000008:administration & dosage; D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D054908:Extensively Drug-Resistant Tuberculosis / Q000000981:diagnostic imaging / Q000188:drug therapy*; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000069349:Linezolid; D008198:Lymph Nodes / Q000473:pathology; D008251:Macaca; D064847:Multimodal Imaging; D023303:Oxazolidinones / Q000008:administration & dosage / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D013234:Stem Cells; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D019788:Fluorodeoxyglucose F18; C453362:posizolid; D000069349:Linezolid