FIG 5.

Sequential acquisition of resistance and emergence of pre-XDR TB. (A) Pathways from RIF and FQ resistance, with and without additional PZA resistance. We demonstrate that, when PZA prevents the development of resistance to RIF and FQs, the primary pathway to developing pre-XDR TB goes through an intermediate step that includes resistance to both RIF and PZA (RIF/PZAr, arrow 4), rather than directly from RIF or FQ resistance (arrows 1 and 2). (B) Proportion of data-consistent simulations in which the projected pre-XDR TB prevalence in 2035 exceeds various acceptability thresholds, after blocking specific pathways of resistance acquisition. Blocking the progression from combined RIF and PZA resistance to RIF, FQ, and PZA resistance (corresponding to arrow 4 in panel A) greatly reduces the proportion of trajectories in which the prevalence exceeds the pre-XDR TB acceptability threshold in 2035, as shown in the rightmost bars. In contrast, blocking resistance amplification directly from strains that are RIF or FQ monoresistant results in a minimal change from the baseline scenario.