Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

• Type of Material: Article
• Authors: Russell Kempker, Emory University; M. Tobias Heinrichs, University of Florida; Ketino Nikolaishvili, National Center for Tuberculosis and Lung Diseases; Irina Sabulua, National Center for Tuberculosis and Lung Diseases; Nino Bablishvili, National Center for Tuberculosis and Lung Diseases; Shota Gogishvili, National Center for Tuberculosis and Lung Diseases; Zaza Avaliani, National Center for Tuberculosis and Lung Diseases; Nestani Tukvadze, National Center for Tuberculosis and Lung Diseases; Brent Little, Emory University; Adam Bernheim, Emory University; Timothy Read, Emory University; Jeannette Guarner, Emory University; Hartmut Derendorf, University of Florida; Charles A. Peloquin, University of Florida; Henry Blumberg, Emory University; Sergo Vashakidze, National Center for Tuberculosis and Lung Diseases
• Language: English
• Date: 2017-06-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.00226-17
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• ISSN: 0066-4804
• Volume: 61
• Issue: 6
• Start Page: e00226-17
• End Page: e00226-17
• Grant/Funding Information: This work was supported in part by the National Institutes of Health Fogarty International Center (D43TW007124), the National Institute of Allergy and Infectious Diseases (K23AI103044, R21AI122001), the Atlanta Clinical and Translational Science Institute (UL1TR000454), and the Emory University Global Health Institute.
• Keywords: CHILDREN; Life Sciences & Biomedicine; Pharmacology & Pharmacy; PHARMACOKINETICS; MULTIDRUG; ADULTS; microdialysis; MYCOBACTERIUM-TUBERCULOSIS; PENETRATION; pharmacology; OUTCOMES; Science & Technology; tuberculosis; pyrazinamide; Microbiology; drug penetration; drug resistance; LESIONS
• Research Categories: Health Sciences, Pathology; Health Sciences, Radiology; Health Sciences, Epidemiology

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 using ex vivo lung 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 for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60μg/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.