Emergence of resistance to ceftazidime-avibactam in a pseudomonas aeruginosa isolate producing derepressed bla_PDC in a hollow-fiber infection model

Ceftazidime (CAZ)-avibactam (AVI) is a b-lactam/b-lactamase inhibitor combination with activity against type A and type C b-lactamases. Resistance emergence has been seen, with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic hollow-fiber infection model, delineating the linkage between drug exposure and both the rate of bacterial kill and resistance emergence by all mechanisms. The Pseudomonas aeruginosa isolate had MICs of 1.0mg/liter (CAZ) and 4mg/liter (AVI). We demonstrated that the time at$4.0mg/liter AVI was linked to the rate of bacterial kill. Linkage to resistance emergence/suppression was more complex. In one experiment in which CAZ and AVI administration was intermittent and continuous, respectively, and in which AVI was given in unitary steps from 1 to 8mg/liter, AVI at up to 3mg/liter allowed resistance emergence, whereas higher values did not. The threshold value was 3.72mg/liter as a continuous infusion to counterselect resistance (AVI area under the concentration-time curve [AUC] of 89.3mg · h/liter). The mechanism involved a 7-amino-acid deletion in the X-loop region of the Pseudomonas-derived cephalosporinase (PDC) b-lactamase. Further experiments in which CAZ and AVI were both administered intermittently with regimens above and below the AUC of 89.3mg · h/liter resulted in resistance in the lower-exposure groups. Deletion mutants were not identified. Finally, in an experiment in which paired exposures as both continuous and intermittent infusions were performed, the lower value of 25mg · h/liter by both profiles allowed selection of deletion mutants. Of the five instances in which these mutants were recovered, four had a continuous-infusion profile. Both continuous-infusion administration and low AVI AUC exposures have a role in selection of this mutation.