Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis

Abstract

The bactericidal activities of ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin were tested in three models of rifampin-tolerant Mycobacterium tuberculosis persisters. Model 1 was a 100-day-old, unshaken, anaerobically adapted culture in which serial dilutions of the quinolones were incubated for 5 days and CFU counts were then done In models 2 and 3, 100 mg of rifampin/liter was added to the 100-day culture for 5 or 7 days to produce tolerant organisms that did not grow on plates; the rifampin was then washed off, fresh medium was added to allow recovery of growth on plates, and the culture was incubated for 7 days before CFU counts. In model 2, the quinolones were added after rifampin had been washed off, whereas in model 3 the quinolones were added to the cultures containing rifampin. In models 1 and 2, ciprofloxacin had the least bactericidal activity, ofloxacin and levofloxacin had greater activities, and moxifloxacin and gatifloxacin had the greatest activities. In model 3, ofloxacin had no detectable activity whereas moxifloxacin killed about log(10) 0.279 CFU of the persisters per ml at concentrations attainable in lesions; isoniazid had virtually no activity. These findings predict that ofloxacin will not be found to have effective sterilizing activity in clinical studies now planned whereas moxifloxacin will be able to shorten treatment.

FIG. 1.

Diagrammatic representation of models of rifampin-tolerant M. tuberculosis. Abbreviations: RIF, rifampin; d, day; −ve, negative.

FIG. 2.

Viable counts after exposure of 100-day cultures of M. tuberculosis to various concentrations of quinolones (model 1).

FIG. 3.

Viable counts for 100-day cultures of M. tuberculosis subsequently exposed first to 100 μg of rifampin/ml and then to various concentrations of quinolones (model 2).

FIG. 4.

Viable counts for 100-day cultures of M. tuberculosis subsequently exposed to 100 μg of rifampin/ml together with various concentrations of ofloxacin, moxifloxacin, and isoniazid (model 3).