Impact of genotype and KPC subtype on the activity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producing clinical isolates.

OBJECTIVES

The availability of new β-lactam/β-lactamase inhibitors ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam have redefined contemporary treatment of carbapenemase-producing (KPC-) infections. We aimed to characterize and contrast the activity of these agents against genetically diverse KPC- clinical isolates.

METHODS

We analysed genomes of 104 non-consecutive KPC- isolates and compared the antibiotic activity by KPC subtype and genotype. MICs were determined in triplicate by CLSI methods. Twenty representative isolates were selected for time-kill analyses against physiological steady-state and trough concentrations, as well as 4× MIC for each agent.

RESULTS

Fifty-eight percent and 42% of isolates harboured KPC-2 and KPC-3, respectively. mutations were more common among KPC-2- compared with KPC-3-producing (< 0.0001); mutations were classified as IS insertion, glycine-aspartic acid insertion at position 134 (GD duplication) and other mutations. Compared to isolates with WT , ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam MICs were elevated for isolates with IS by 2-, 4- and 16-fold, respectively (< 0.05 for each). Against isolates with GD duplication, imipenem/relebactam and meropenem/vaborbactam MICs were increased, but ceftazidime/avibactam MICs were not. In time-kill studies, ceftazidime/avibactam-mediated killing correlated with ceftazidime/avibactam MICs, and did not vary across genotypes. Imipenem/relebactam was not bactericidal against any isolate at trough concentrations. At steady-state imipenem/relebactam concentrations, regrowth occurred more commonly for isolates with IS mutations. Log-kills were lower in the presence of meropenem/vaborbactam for isolates with GD duplication compared with IS mutations.

CONCLUSIONS

Our investigation identified key genotypes that attenuate, to varying degrees, the activity for each of the new β-lactam/β-lactamase inhibitors. Additional studies are needed to translate the importance of these observations into clinical practice.