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 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.

Keywords: drug penetration; drug resistance; microdialysis; pharmacology; pyrazinamide; tuberculosis.

FIG 1

Serum concentrations of pyrazinamide versus time after dosing in 10 adults with drug-resistant pulmonary tuberculosis.

FIG 2

(A) Correlation between peak serum pyrazinamide concentration and dosages; (B) correlation between serum free pyrazinamide concentration and lung tissue pyrazinamide concentration. *, Pearson correlation coefficient.

FIG 3

Representative transverse CT views from the seven patients with films available for review. Three main lesions types were identified, including cavitary lesions (a), mass lesions (b), and a consolidation from one patient (c).

FIG 4

Representative photomicrographs of hematoxylin and eosin-stained specimens for each of the nine patients with tissue pyrazinamide concentrations (listed) available. (a) Cases were classified as severe necrosis when, in addition to what is presented in the photomicrograph, confluent necrosis was present in multiple fields in multiple blocks (two or three blocks). (b) Cases were classified as moderate necrosis when necrosis was confluent with one field. (c) Cases were classified as having rare necrosis when necrosis was scattered within a field. Magnifications, ×4.