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

Jean-Philippe LanoixThomas IoergerAimee OrmondFirat KayaJames SacchettiniVéronique DartoisEric Nuermberger
Published in: Antimicrobial agents and chemotherapy (2015)
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.
Keyphrases
  • high fat diet induced
  • drug resistant
  • mycobacterium tuberculosis
  • wild type
  • multidrug resistant
  • type diabetes
  • emergency department
  • cystic fibrosis
  • metabolic syndrome
  • hiv aids
  • pulmonary tuberculosis
  • hiv infected