Antimycobacterial agents differ with respect to their bacteriostatic versus bactericidal activities in relation to time of exposure, mycobacterial growth phase, and their use in combination

Abstract

A number of antimycobacterial agents were evaluated with respect to their bacteriostatic activity (growth inhibition) versus the bactericidal activity against a clinical isolate of Mycobacterium avium (Mycobacterium avium complex [MAC] strain 101) in relation to the time of exposure and the growth phase of the mycobacteria. In terms of growth inhibition the MAC in the active phase of growth was susceptible to clarithromycin, ethambutol, rifampin, amikacin, and the quinolones moxifloxacin, ciprofloxacin, and sparfloxacin. In terms of bactericidal activity in relation to the time of exposure these agents differed substantially with respect to the killing rate. An initial high killing capacity at low concentration was observed for amikacin, which in this respect was superior to the other agents. The bactericidal activity of clarithromycin and ethambutol was only seen at relatively high concentrations and increased with time. Killing by rifampin was concentration dependent as well as time dependent. The bactericidal activity of moxifloxacin was marginally dependent on the concentration or the time of exposure. The activity of clarithromycin in combination with ethambutol was not significantly enhanced compared to single-agent exposure. Only an additive effect was observed. The addition of rifampin or moxifloxacin as a third agent only marginally effected increased killing of MAC. However, by addition of amikacin the activity of the clarithromycin-ethambutol combination was significantly improved. The combination of amikacin and amoxicillin-clavulanic acid exhibited synergistic antimycobacterial activity. Towards MAC at low growth rates, only the quinolones exhibited a bactericidal effect.

FIG. 1.

Mycobacterium avium strain 101 in the early logarithmic phase of growth was exposed to clarithromycin at twofold increasing concentrations for 21 days at 37°C. After 1, 2, 3, 10 or 21 days of exposure quantitative cultures were performed.

FIG. 2.

Mycobacterium avium strain 101 in the early logarithmic phase of growth was exposed to ethambutol at twofold increasing concentrations for 21 days at 37°C. After 1, 2, 3, 10 or 21 days of exposure quantitative cultures were performed.

FIG. 3.

Mycobacterium avium strain 101 in the early logarithmic phase of growth was exposed to rifampin at twofold increasing concentrations for 21 days at 37°C. After 1, 2, 3, 10 or 21 days of exposure quantitative cultures were performed.

FIG. 4.

Mycobacterium avium strain 101 in the early logarithmic phase of growth was exposed to amikacin at twofold increasing concentrations for 21 days at 37°C. After 1, 2, 3, 10 or 21 days of exposure quantitative cultures were performed.

FIG. 5.

Mycobacterium avium strain 101 in the early logarithmic phase of growth was exposed to moxifloxacin at twofold increasing concentrations for 21 days at 37°C. After 1, 2, 3, 10 or 21 days of exposure quantitative cultures were performed.