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 ϭ 6 patients), mass-like (n ϭ 3 patients), or consolidative (n ϭ 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of Յ5.5. 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 g/ml. The median lung tissue free pyrazinamide concentration was 20.96 g/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 ϭ Ϫ0.66, P ϭ 0.04) and acid-fast bacilli (R ϭ Ϫ0.75, P ϭ 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.

Impact of immunopathology on the antituberculous activity of pyrazinamide

“…These discrepancies were attributed to the relatively high pH of C3HeB/FeJ mouse caseum ( Lanoix et al, 2015a ). The range of caseum pH measured in this study (6.1–8.0) is in line with the human caseum pH range of 5.5–8.0 ( Koller and Leuthardt, 1934 ; Dahl, 1950 ; Weiss et al, 1954 ; Kempker et al, 2017 ). Thus, in rabbits and TB patients, different lesions present pH conditions that are more or less favorable to PZA’s activity, which may contribute to the observed interlesion variability in treatment response.…”

“…Because PZA is largely recognized as a “sterilizing” drug ( Mitchison, 1985 , 2004b ; Chigutsa et al, 2015 ) and necrotic lesions are most recalcitrant to therapy, it follows that PZA should be efficacious against bacterial populations that inhabit necrotic niches. However, direct demonstration of PZA’s activity against these populations is lacking, and several recent findings indirectly support or contradict this hypothesis ( Ahmad et al, 2011 ; Irwin et al, 2015 ; Lanoix et al, 2015a ; Prideaux et al, 2015 ; Kempker et al, 2017 ; Sarathy et al, 2018 ). Interestingly, we previously observed that PZA contributes very little if anything in reducing bacterial burden in C3HeB/FeJ mouse necrotic lesions ( Lanoix et al, 2015a ; Irwin et al, 2016 ).…”

Extreme Drug Tolerance of Mycobacterium tuberculosis in Caseum

“…This may generate a “halo” of low pH in the direct vicinity of the bacterial cell, creating microenvironmental conditions favorable to the cidality of pyrazinamide and its active metabolite, pyrazinoic acid ( 47 , 48 ). In a very recent study, pH values of 5 to 5.5 were measured in 8 of 10 cavity caseum samples obtained from resected human lung tissue ( 49 ), in contrast with the pH of C3HeB/FeJ mouse ( 43 ) and rabbit caseum. It is thus possible that our assay underestimated the activity of pyrazinamide against M. tuberculosis present in the caseum of human lesions, although its preferred target population may be intracellular in the acidified phagolysosome of activated macrophages ( 43 ).…”

Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis

“…The traditional dogma is that penicillin microbial kill stops in stationary-phase bacteria and is best with rapidly multiplying bacteria; thus, penicillin should not be effective against NRP or SDB ( 35 ). Moreover, penicillin is labile at low pH, and some extracellular SDB in lung cavities are at low pH ( 36 – 38 ). We compared the effect of penicillin (at a T MIC of 100%) plus avibactam versus the standard three-drug regimen of isoniazid, rifampin, and pyrazinamide in the HFS-TB NRP model based on the streptomycin-dependent auxotroph M. tuberculosis SS18b in acidified (pH = 5.8) Middlebrook broth ( 23 , 39 ).…”