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

Hajihosseini, A., Myrick, J., Nole, J., Louie, A., Schmidt, S., & Drusano, G. L.

Antimicrobial agents and chemotherapy 63.1 (2019).

Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis (M. 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 towards killing of M. tuberculosis in Logarithmic growth phase (Log-phase), Acid-phase and Non-Replicating Persister phase (NRP-phase). Respective in vitro data generated for H37Rv and 18b strains, was evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco was used to characterize the nature of 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 in Acid-phase (α = 5.56e-8 with 95% CI = -0.278 to 0.278 and α = 0.408; 95% CI = 0.105 to 0.711), NRP-phase (α = 0.625 with 95% CI =-0.556 to 1.81 and α = 2.92 with 95% CI = 0.215 to 5.63), and Log-phase organisms (α = 1.57e-6 with 95% CI = -0.930 to 0.930 and α = 1.83e-6 with 95% CI= -0.929 and 0.929), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.

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

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