Acquisition of Rifampin Resistance in Pulmonary Tuberculosis

Abstract

Mycobacterium tuberculosis strains with spontaneous mutations conferring resistance to rifampin (RIF) are exceedingly rare, and fixed drug combinations typically prevent augmentation of resistance to single drugs. Fourteen newly diagnosed tuberculosis patients were treated with RIF alone for 14 days, and bacterial loads, including mutation frequencies, were determined. A statistical model estimated that 1% of the remaining viable mycobacteria could be RIF resistant after 30 days of monotherapy. This indicates that temporal and spatial windows of RIF monotherapy due to uneven drug distribution within lung lesions could contribute to the acquisition of resistance to RIF.

Keywords: resistance; rifampin; treatment; tuberculosis.

FIG 1

Modeled emergence of RIF resistance in M. tuberculosis on monotherapy. Statistical modeling estimating the time required for the emergence of RIF resistance in the M. tuberculosis population when TB patients are kept on RIF monotherapy beyond 2 weeks. Two weeks of RIF monotherapy induced a significant decrease of CFU (descending black line with dashed confidence interval) (P < 0.0001) and a significant increase of mutation frequency (ascending black line with dashed confidence interval) (P < 0.0001). The blue line is the estimated count of RIF-resistant CFU and the red line is the estimated 1% of total CFU. The model estimates that the proportion of 1% CFU, considered the breakpoint to define clinical resistance, can be reached after 30 days of RIF monotherapy (blue line crosses the red) and that, after around 40 days (blue line crosses the black), all remaining CFU will be resistant.