Emergence of resistance to ceftazidime-avibactam in a derepressed blaPDC producing Pseudomonas aeruginosa isolate in a Hollow Fiber Infection Model.

Ceftazidime/Avibactam (CAZ/AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and 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 rate of bacterial kill and resistance emergence by all mechanisms. The P. aeruginosa isolate had an MIC of 1.0 mg/L (CAZ)/4 mg/L (AVI). We demonstrated that Time>4.0 mg/L AVI was linked to rate of bacterial kill. Linkage to resistance emergence/suppression was more complex. In one experiment where CAZ/AVI administration was intermittent/continuous and where AVI was given in unitary steps from 1-8 mg/L, AVI up to 3 mg/L allowed resistance emergence, whereas higher values did not. The threshold value was 3.72 mg/L as a continuous infusion to counterselect resistance (AUC of 89.3 mg*h/L AVI). The mechanism was by a 7 amino acid deletion in the Ω-loop region of the PDC β-lactamase. Further experiments, where CAZ/AVI were both administered intermittently with regimens above and below the AUC of 89.3 mg*hr/L resulted in resistance in the lower exposure groups. Deletion mutants were not identified. Finally, an experiment where paired exposures both as continuous and intermittent infusions were performed, the lower value of 25 mg*hr/L by both profiles allowed selection of deletion mutants. Of the five instances where these mutants were recovered, 4/5 were by the continuous infusion profile. Both continuous infusion administration and low avibactam AUC exposures have a role in selection of this mutation.