Resistance to Ceftazidime/Avibactam plus Meropenem/Vaborbactam When Both Are Used Together Is Achieved in Four Steps in Metallo-ß-Lactamase-Negative Klebsiella pneumoniae.

ABSTRACT

Serine ß-lactamases are dominant causes of ß-lactam resistance in Klebsiella pneumoniae isolates. Recently, this has driven clinical deployment of the ß-lactam-ß-lactamase inhibitor pairs ceftazidime/avibactam and meropenem/vaborbactam. We show that four steps, i.e., ompK36 and ramR mutation plus carriage of OXA-232 and KPC-3-D178Y variant ß-lactamases, confer ceftazidime/avibactam and meropenem/vaborbactam resistance when both pairs are used together. These findings have implications for decision making about sequential and combinatorial use of these ß-lactam-ß-lactamase inhibitor pairs to treat K. pneumoniae infections.