Combinatory activity of linezolid and levofloxacin with antituberculosis drugs in Mycobacterium tuberculosis

The increase of multidrug and extensively drug resistant Mycobacterium tuberculosis strains turns the search for new tuberculosis (TB) treatment options of paramount importance.

In this sense, the present study evaluates the in vitro activity of isoniazid (INH)/rifampicin (RIF)/levofloxacin (LVX) and INH/RIF/linezolid (LNZ) combinations in resistant M. tuberculosis.

The activities of the combinations were evaluated with M. tuberculosis H₃₇Rv, susceptible and 10 resistant clinical isolates by three-dimensional checkerboard. LVX and LNZ were used as the third drug at fixed ½ and ¼ minimum inhibitory concentration (MIC). INH and RIF were tested at concentrations ranging from 0.0009 μg/mL to 50 μg/mL and 0.0009 μg/mL to 800 μg/mL, respectively. The combinatorial effects were determined by the Fractional Inhibitory Concentration Index (FICI). FICI values ≤ 0.75, 0.75-4 and ≥4 were considered as synergism, indifferent and antagonism, respectively.

MIC ranged from 0.03 - 6.25 μg/mL for INH, 0.008-100 μg/mL for RIF, 0.12-0.25 μg/mL for LVX and 0.25-0.5 μg/mL for LNZ in the H₃₇Rv and all clinical isolates. INH/RIF/LVX and INH/RIF/LNZ synergisms were observed in 40 and 50% of the resistant M. tuberculosis clinical isolates and better observed for INH and RIF combined to LVX or LNZ at ¼ MIC.

The present study calls attention for the potential use of INH/RIF/LVX and INH/RIF/LNZ combinations in the treatment of resistant TB.