Bactericidal action of gatifloxacin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis

Abstract

The bactericidal activity of gatifloxacin, alone and in combination with isoniazid and rifampin, was studied on both exponential- and stationary-phase cultures of Mycobacterium tuberculosis strain H37Rv. On log-phase cultures, the bactericidal activity of gatifloxacin at 4 microg/ml was rapid and was very similar to that of isoniazid. At concentrations of 0.25 and 4 microg/ml, gatifloxacin enhanced the activity of isoniazid. Killing of the stationary-phase culture was biphasic. During the first 2 days, gatifloxacin at 4 microg/ml slightly increased the limited bactericidal activities of isoniazid and rifampin. However, no further additional bactericidal activity was found during further incubation with isoniazid alone or when gatifloxacin was added to either isoniazid or rifampin. This suggested that the stationary-phase culture contained a mixture of occasionally dividing bacilli that were killed during the first 2 days and true static persisters in the residual population that mimicked those in human lesions. In view of the failure of gatifloxacin to add to the sterilizing activity of isoniazid or rifampin during days 2 to 6 of exposure in the stationary-phase culture, it is unlikely to be a sterilizing drug that can be used to shorten the duration of treatment appreciably when it is added to present treatment regimens.

FIG. 1.

Bactericidal activities of INH at 1 μg/ml, RIF at 1 μg/ml, OFX at 2 μg/ml, GAT1 at 0.25 μg/ml, and GAT2 at 4 μg/ml (G2) against exponential-phase (A), log-phase (B), and stationary-phase (C) cultures of M. tuberculosis. H, INH; R, RIF; G1, GAT1; G2, GAT2; and OF, OFX.

FIG. 2.

Bactericidal activities of INH alone and INH with RIF or GAT1 and GAT2 against log-phase (A) and stationary-phase (B) cultures of M. tuberculosis. See Fig. 1 for drug concentrations. H, INH; HG1, INH-GAT1; HG2, INH-GAT2; and HR, INH-RIF.

FIG. 3.

Bactericidal activities of RIF alone and RIF with INH or GAT1 and GAT2 against log-phase (A) and stationary-phase (B) cultures of M. tuberculosis. See Fig. 1 for drug concentrations. R, RIF; RG1, RIF-GAT1; RG2, RIF-GAT2; and HR, INH-RIF.

FIG. 4.

Bactericidal activities of INH, RIF, and INH-RIF with GAT1 and GAT2 against log-phase (A) and stationary-phase (B) cultures of M. tuberculosis. See Fig. 1 for drug concentrations. H, INH; R, RIF; HR, INH-RIF; HRG1, INH-RIF-GAT1; and HRG2, INH-RIF-GAT2.