Effects of KPC variant and porin genotype on the in vitro activity of meropenem-vaborbactam against carbapenem-resistant Enterobacteriaceae [Mechanisms of Resistance]

Meropenem-vaborbactam is a new agent with potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We described the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory engineered E. coli harboring mutant bla_KPC 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 minimum inhibitory concentrations (MICs) were 1 and 0.03μg/mL, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MIC ≤4μg/mL). Against K. pneumoniae harboring mutant bla_KPC, the addition of vaborbactam lowered meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against KPC-producing K. pneumoniae with mutant (n=26) versus wild-type (n=54) ompK36 porin genes (0.25 vs 0.03μg/mL; P<0.0001). Against E. coli TOP10 with plasmid constructs containing wild-type bla_KPC or mutant bla_KPC, the addition of vaborbactam 8μg/mL lowered meropenem MICs 2 – 512-fold, resulting in meropenem-vaborbactam MICs 0.03 μg/mL. Rates of categorical agreement with broth microdilution for disk diffusion or gradient strips ranged between 90 and 95%. Essential agreement rates were higher for gradient strips manufactured by bioMérieux (82%) compared to Liofilchem (48%; P<0.0001). Taken together, our data highlight the potent in vitro 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 K. pneumoniae with ompK36 mutations displayed higher meropenem-vaborbactam MICs than isolates with wild-type ompK36. Susceptibility testing with bioMérieux gradient strips most closely aligned with broth microdilution methods.

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