Interactions of linezolid and second-line anti-tuberculosis agents against multidrug-resistant Mycobacterium tuberculosis in vitro and in vivo

•The interactions of linezolid and other second-line anti-tuberculosis drugs in susceptible strains and multidrug-resistant clinical isolates in vitro were evaluated for the first time.•The results of the in vitro experiments were verified in a murine tuberculosis model.•A partial synergy effect was found between linezolid and capreomycin, and the combination was effective against Mycobacterium tuberculosis.•The results obtained in the in vitro experiments must be verified through in vivo experiments.

SummaryObjectivesThe objectives of this study were to evaluate the interactions between linezolid (LZD) and second-line anti-tuberculosis (TB) agents in susceptible and multidrug-resistant (MDR) TB in vitro, and to validate the in vitro results in a murine TB model.MethodsThe minimum inhibitory concentrations of LZD and seven second-line anti-TB drugs against H37Rv and three multidrug-resistant clinical isolates were determined by Alamar Blue assay, and the interaction patterns of LZD and the seven second-line anti-TB agents against the four isolates were studied using a dynamic checkerboard method. The activities of these combinations against Mycobacterium tuberculosis were evaluated in a murine model of TB.ResultsThe combination of LZD + capreomycin exhibited partial synergism for three of four isolates, LZD + para-aminosalicylic acid exhibited partial synergism for two of four isolates, and LZD + levofloxacin and LZD + amikacin exhibited partial synergism for one of four isolates; all other combinations showed indifference or an additive effect in vitro. The activities of six combinations and the standard regimen rifampicin + isoniazid + pyrazinamide were investigated in a murine model of TB (infection with H37Rv). Significant reductions in colony-forming units (CFU) were found in LZD + capreomycin and LZD + clofazimine groups when the CFU in the lungs on day 0 (the day of beginning treatment) was compared with the CFU in the lungs after 2 months of treatment.ConclusionsThese combinations of LZD and second-line anti-TB drugs were all active against MDR-TB with indifference or an additive effect, except LZD + capreomycin, which showed partial synergy.

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