Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum. Academic Article uri icon

abstract

  • Pyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. We recently reported selective inactivity of PZA in a subset of C3HeB/FeJ mice with large caseous lung lesions. In the present study, we evaluated whether such inactivity was explained by poor penetration of PZA into such lesions or selection of drug-resistant mutants. Despite demonstrating similar dose-proportional PZA exposures in plasma, epithelial lining fluid, and lung lesions, no dose response was observed in a subset of C3HeB/FeJ mice with the highest CFU burden. Although PZA-resistant mutants eventually replaced the susceptible bacilli in BALB/c mice and in C3HeB/FeJ mice with low total CFU burdens, they never exceeded 1% of the total population in nonresponding C3HeB/FeJ mice. The selective inactivity of PZA in large caseous lesions of C3HeB/FeJ mice is best explained by the neutral pH of liquefying caseum.

published proceedings

  • Antimicrob Agents Chemother

altmetric score

  • 10

author list (cited authors)

  • Lanoix, J., Ioerger, T., Ormond, A., Kaya, F., Sacchettini, J., Dartois, V., & Nuermberger, E.

citation count

  • 59

complete list of authors

  • Lanoix, Jean-Philippe||Ioerger, Thomas||Ormond, Aimee||Kaya, Firat||Sacchettini, James||Dartois, Véronique||Nuermberger, Eric

publication date

  • February 2016