Klebsiella pneumoniae Mutants Resistant to Ceftazidime-Avibactam Plus Aztreonam, Imipenem-Relebactam, Meropenem-Vaborbactam, and Cefepime-Taniborbactam

Abstract

We show that a previously described Klebsiella pneumoniae variant that is resistant to ceftazidime-avibactam plus meropenem-vaborbactam, has a ramR plus ompK36 mutation, and produces the V239G variant KPC-3 (V240G per the standard numbering system) exhibits resistance to ceftazidime-avibactam plus aztreonam and imipenem-relebactam but not cefepime-taniborbactam. The V239G variant does not generate collateral β-lactam susceptibility like many KPC-3 variants associated with ceftazidime-avibactam resistance. Additional mutation of ompK35 and production of the OXA-48-like carbapenemase OXA-232 were required to confer cefepime-taniborbactam resistance.

Keywords: KPC; carbapenemase.

FIG 1

Checkerboard assays for CAZ and AZT in the presence of AVI against K. pneumoniae KP21[ramR] ompK36 producing KPC-3 V239G. The image represents duplicate assays for an 8-by-8 array of wells in a 96-well plate. All wells contained cation-adjusted Mueller-Hinton broth (CA-MHB) containing avibactam (4 μg mL⁻¹). A serial dilution of aztreonam (AZT, x axis) and ceftazidime (CAZ, y axis) was created from 32 μg mL⁻¹ in each plate, as recorded. All wells were inoculated with a suspension of bacteria, made as per CLSI microtiter MIC guidelines (10), and the plate was incubated at 37°C for 20 h. Growth was recorded by measuring optical density at 600 nm (OD₆₀₀), and growth above background (broth) is recorded as a yellow block, while absence of growth is recorded as a white block. Growth represented by the red-edged block indicates resistance to both AZT and CAZ.