title: Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae.
abstract: Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine β-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 μg/ml). Overall, meropenem alone (MIC50 and MIC90, 16 and >64 μg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 μg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 μg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 μg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 μg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 μg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 μg/ml of the inhibitor (MIC50, ≤0.06 μg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 μg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-β-lactamases (MIC, 16 to >64 μg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 μg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 μg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA mariana.castanheira@jmilabs.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Rhomberg
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000378:metabolism; D000077731:Meropenem; D008826:Microbial Sensitivity Tests / Q000379:methods; D012694:Serine / Q000378:metabolism*; D013845:Thienamycins / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D012694:Serine; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem