Effects of KPC Variant and Porin Genotype on the Activity of Meropenem-Vaborbactam against Carbapenem-Resistant .

Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant (CRE) infections. We describe the activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered isolates harboring mutant genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam MICs were 1 and 0.03 µg/ml, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MICs ≤ 4 µg/ml). Against isolates harboring mutant , the addition of vaborbactam lowered the meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against carbapenemase (KPC)-producing isolates with mutant porin genes ( = 26) than against those with wild-type porin genes ( = 54) (0.25 versus 0.03 µg/ml;  < 0.0001). Against TOP10 isolates with plasmid constructs containing wild-type or mutant , the addition of vaborbactam at 8 µg/ml lowered the meropenem MICs 2- to 512-fold, resulting in meropenem-vaborbactam MICs of 0.03 µg/ml. The rates of categorical agreement with broth microdilution for disk diffusion or gradient strips ranged from 90 to 95%. Essential agreement rates were higher for research-use-only (RUO) gradient strips manufactured by bioMérieux (82%) than for those manufactured by Liofilchem (48%) (0.0001). Taken together, our data highlight the potent activity of meropenem-vaborbactam against CRE, including isolates resistant to ceftazidime-avibactam. Vaborbactam inhibited both wild-type and variant KPC enzymes. On the other hand, KPC-producing isolates with mutations displayed higher meropenem-vaborbactam MICs than isolates with wild-type The results of susceptibility testing with RUO bioMérieux gradient strips most closely aligned with those of broth microdilution methods.