Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay

Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis. However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF toward the killing of M. tuberculosis in logarithmic growth phase (log phase), acid phase, and nonreplicating- persister (NRP) phase. Respective in vitro data generated for the H37Rv and 18b strains were evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol Rev 47: 331- 385, 1995) was used to characterize the nature of the interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow- fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis organisms in acid phase (interaction parameter [alpha] = 5.56e-8 [95% confidence interval CI} = -0.278 to 0.278] and alpha = 0.408 [95% CI = 0.105 to 0.711], respectively), NRP phase (alpha = 0.625 [95% CI = -0.556 to 1.81] and alpha = 2.92 [95% CI = 0.215 to 5.63], respectively), and log phase (alpha = 1.57e-6 [95% CI = -0.930 to 0.930] and alpha = 1.83e-6 [95% CI = -0.929 and 0.929], respectively), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.