In vitro activity of plazomicin against β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE)

Background: Carbapenem-resistant Enterobacteriaceae (CRE) represent an urgent threat because few drugs are available to treat infections caused by these pathogens. Plazomicin is a novel aminoglycoside that recently completed a Phase 3 clinical trial for treatment of infections caused by CRE. Methods: A set of 110 characterized unique CRE patient isolates from central Indiana healthcare centres was tested by microbroth dilution for susceptibility to plazomicin, and to reference aminoglycosides and carbapenems. WGS was conducted to analyse the isolate with an elevated plazomicin MIC. Results: The isolates, 107 of which produced KPC carbapenemases, were 97.3% and 100% non-susceptible to meropenem and imipenem, respectively, with variable rates of non-susceptibility to amikacin (76.4%), gentamicin (18.2%), kanamycin (91.8%) and tobramycin (96.4%). MIC50/MIC90 values for plazomicin were the lowest of all the drugs tested: 0.5/0.5 mg/L for 96 KPC-producing Klebsiella pneumoniae isolates and 0.5/1 mg/L for all 110 carbapenemase-producing isolates. Higher MIC50/MIC90 values were observed for the other antibiotics tested: amikacin (32/32 mg/L), gentamicin (1/16 mg/L), kanamycin (>64/>64 mg/L), tobramycin (32/64 mg/L), imipenem (8/32 mg/L) and meropenem (>= 16/>= 16 mg/L). Only one isolate, an NDM-1-producing K. pneumoniae strain that carried the armA 16S rRNA methyltransferase gene, was resistant to plazomicin, with an MIC of 256 mg/L; this strain was cross-resistant to all the other antibiotics tested. Conclusions: Plazomicin demonstrated the most potent overall in vitro inhibitory activity of all the aminoglycosides and carbapenems in the study, and has the potential to be an effective agent for the treatment of infections caused by CRE.