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Pharmacology

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

Russell R. Kempker, M. Tobias Heinrichs, Ketino Nikolaishvili, Irina Sabulua, Nino Bablishvili, Shota Gogishvili, Zaza Avaliani, Nestani Tukvadze, Brent Little, Adam Bernheim, Timothy D. Read, Jeannette Guarner, Hartmut Derendorf, Charles A. Peloquin, Henry M. Blumberg, Sergo Vashakidze
Russell R. Kempker
aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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M. Tobias Heinrichs
bUniversity of Florida, College of Pharmacy, Gainesville, Florida, USA
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Ketino Nikolaishvili
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Irina Sabulua
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Nino Bablishvili
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Shota Gogishvili
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Zaza Avaliani
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Nestani Tukvadze
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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Brent Little
dDepartment of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA
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Adam Bernheim
dDepartment of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA
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Timothy D. Read
aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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Jeannette Guarner
eDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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Hartmut Derendorf
bUniversity of Florida, College of Pharmacy, Gainesville, Florida, USA
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Charles A. Peloquin
bUniversity of Florida, College of Pharmacy, Gainesville, Florida, USA
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Henry M. Blumberg
aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
fDepartments of Epidemiology and Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
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Sergo Vashakidze
cNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia
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DOI: 10.1128/AAC.00226-17
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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 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.

FOOTNOTES

    • Received 1 February 2017.
    • Returned for modification 6 March 2017.
    • Accepted 23 March 2017.
    • Accepted manuscript posted online 3 April 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00226-17 .

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

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Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis
Russell R. Kempker, M. Tobias Heinrichs, Ketino Nikolaishvili, Irina Sabulua, Nino Bablishvili, Shota Gogishvili, Zaza Avaliani, Nestani Tukvadze, Brent Little, Adam Bernheim, Timothy D. Read, Jeannette Guarner, Hartmut Derendorf, Charles A. Peloquin, Henry M. Blumberg, Sergo Vashakidze
Antimicrobial Agents and Chemotherapy May 2017, 61 (6) e00226-17; DOI: 10.1128/AAC.00226-17

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Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis
Russell R. Kempker, M. Tobias Heinrichs, Ketino Nikolaishvili, Irina Sabulua, Nino Bablishvili, Shota Gogishvili, Zaza Avaliani, Nestani Tukvadze, Brent Little, Adam Bernheim, Timothy D. Read, Jeannette Guarner, Hartmut Derendorf, Charles A. Peloquin, Henry M. Blumberg, Sergo Vashakidze
Antimicrobial Agents and Chemotherapy May 2017, 61 (6) e00226-17; DOI: 10.1128/AAC.00226-17
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KEYWORDS

antitubercular agents
pyrazinamide
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
tuberculosis
drug resistance
drug penetration
pyrazinamide
microdialysis
pharmacology

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