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 β-lactam/β-lactamase inhibitor combination with activity against type A and type C β-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 1.0 mg/liter (CAZ) and 4 mg/liter (AVI). We demonstrated that the time at ≥4.0 mg/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 8 mg/liter, AVI at up to 3 mg/liter allowed resistance emergence, whereas higher values did not. The threshold value was 3.72 mg/liter as a continuous infusion to counterselect resistance (AVI area under the concentration-time curve [AUC] of 89.3 mg · h/liter). The mechanism involved a 7-amino-acid deletion in the Ω-loop region of the Pseudomonas-derived cephalosporinase (PDC) β-lactamase. Further experiments in which CAZ and AVI were both administered intermittently with regimens above and below the AUC of 89.3 mg · 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 25 mg · 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.