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

Abstract

Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening the therapy duration for is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an strategy to ultimately be tested in an hollow fiber infection model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) on strain H37Rv in log- and acid-phase growth and strain 18b in log- and nonreplicating-persister-phase growth in a plate system containing a 9-by-8 matrix of concentrations of both drugs alone and in combinations. A characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco universal response surface approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of nonoverlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing the emergence of resistance by to the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline

“…Specific pharmacokinetic (PK)/pharmacodynamic (PD) targets, especially the AUC divided by the MIC over 24 hours (AUC 0–24 /MIC), are being recognized as playing an important role in determining efficacy (231). This has been demonstrated most clearly in hollow fiber systems in vitro that isolate the activity of the drug against the organism (232, 233). Further evidence has been provided by animal models (mouse, rabbit, nonhuman primates) and through human clinical trials (234–237).…”

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

“…Since PA824 acts as a respiratory poison and inhibits cell wall synthesis and MXF targets DNA replication, it is reasonable to assume that they would have a lower potency against the metabolic phase with the lowest growth/turnover rates, such as the NRP phase in M. tuberculosis (19,20). This hierarchy of effects was previously observed in the same assay for bedaquiline (11), a drug that affects energy consumption and is therefore expected to present a greater impact on cells at a higher consumption state, such as log phase.…”

“…This study aimed to evaluate the combined effect of PA824 and MXF on bacterial killing of the main metabolic states of M. tuberculosis. The drug combination was evaluated using our recently developed screening strategy (11), which consists of evaluating a two-drug combination in a static in vitro 9-by 8-well checkerboard plate system where constant fractions and multiples of the MICs for both compounds were incubated with H37Rv in log phase and acid phase and streptomycin (STR)-starved M. tuberculosis 18b in NRP phase. Characterization of the interaction was performed by estimating the interaction parameter (␣) by use of the URSA model of Greco et al and culture data (12).…”

“…Therefore, given the promising activity of MXF and PA824 during early-phase trials for the treatment of both susceptible and resistant TB and the activity of PA824 toward NRP-phase bacteria, we decided to evaluate whether use of the combination of these drugs would be an even more promising strategy. We used our recently developed in vitro strategy (11) coupled to the Universal Response Surface Approach (URSA) model of Greco et al (12) to characterize the nature of the pharmacodynamic interaction between the two drugs. Combinations characterized as additive and synergistic will prompt further evaluation in the HFIM and animal studies.…”

Activity of Moxifloxacin against Mycobacterium tuberculosis in Acid Phase and Nonreplicative-Persister Phenotype Phase in a Hollow-Fiber Infection Model

“…As we mentioned previously (12), it might be beneficial to switch therapy completely after 4 to 6 weeks of the initial regimen. We have examined a follow-on regimen that is aimed primarily at NRP-phase organisms and acid-phase organisms but still possesses substantial log-phase activity (17); this combination is linezolid plus bedaquiline, with additive interaction. It remains to be proven that the resistance mechanisms are not overlapping.…”