Mechanisms Responsible for Cross-Resistance and Dichotomous Resistance among the Quinolones

Resistance to the quinolones almost always arises from the accumulation of mutations in chromosomal genes responsible for the drug targets, permeability, or active efflux. This resistance can be depicted as a stepwise process in which each step, represented by separate mutations, diminishes susceptibility on average 4- to 8-fold. The precise path followed in this stepwise process differs with the quinolone that selects resistance as well as the organism involved. At each step, the influence of each mutation on susceptibility to other quinolones not used in the selection process varies greatly, and a pattern of either cross-resistance or dichotomous resistance may be seen. From an understanding of the stepwise process by which resistance to the quinolones evolves, it is possible to use an 8-fold rule to predict which compounds may provide effective therapy for a given infection and be least likely to select for resistance.