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Author Notes:

Address correspondence to Russell R. Kempker, rkempke@emory.edu

No author has a commercial or other association that might pose a conflict of interest.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Microbiology
  • Pharmacology & Pharmacy
  • tuberculosis
  • drug resistance
  • drug penetration
  • pyrazinamide
  • microdialysis
  • pharmacology
  • MYCOBACTERIUM-TUBERCULOSIS
  • MULTIDRUG
  • OUTCOMES
  • PHARMACOKINETICS
  • PENETRATION
  • CHILDREN
  • LESIONS
  • ADULTS

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

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Journal Title:

Antimicrobial Agents and Chemotherapy

Volume:

Volume 61, Number 6

Publisher:

, Pages e00226-17-e00226-17

Type of Work:

Article | Final Publisher PDF

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.

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© 2017 American Society for Microbiology. All Rights Reserved.

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