title: Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.
abstract: Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed usingex vivolung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n= 6 patients), mass-like (n= 3 patients), or consolidative (n= 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive forMycobacterium tuberculosisby culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R= -0.66,P= 0.04) and acid-fast bacilli (R= -0.75,P= 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA rkempke@emory.edu.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Kempker
authors.affiliation: University of Florida, College of Pharmacy, Gainesville, Florida, USA.
authors.forename: M Tobias
authors.initials: MT
authors.lastname: Heinrichs
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Ketino
authors.initials: K
authors.lastname: Nikolaishvili
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Irina
authors.initials: I
authors.lastname: Sabulua
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Nino
authors.initials: N
authors.lastname: Bablishvili
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Shota
authors.initials: S
authors.lastname: Gogishvili
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Zaza
authors.initials: Z
authors.lastname: Avaliani
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Nestani
authors.initials: N
authors.lastname: Tukvadze
authors.affiliation: Department of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Little
authors.affiliation: Department of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Bernheim
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Read
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Guarner
authors.affiliation: University of Florida, College of Pharmacy, Gainesville, Florida, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.affiliation: University of Florida, College of Pharmacy, Gainesville, Florida, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.|Departments of Epidemiology and Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Blumberg
authors.affiliation: National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
authors.forename: Sergo
authors.initials: S
authors.lastname: Vashakidze
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012293:Rifampin / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin
keywords: drug penetration; drug resistance; microdialysis; pharmacology; pyrazinamide; tuberculosis