Activity of imipenem/relebactam against KPC-producing Klebsiella pneumoniae and the role of Ompk36 mutation in determining resistance: an Italian retrospective analysis

Background: Antimicrobial resistance in Enterobacterales represents a substantial threat in modern clinical practice and the collection of data on the efficacy of new molecules is of paramount importance. Our study aimed to analyse the in vitro activity of imipenem/cilastatin/relebactam (IMI/REL) against KPC-producing Klebsiella pneumoniae (KPC-Kp) and investigate the genetic determinants of resistance to this agent.Methods: ''A total of 605 KPC-Kp strains, which were randomly collected during a multicentre study in northern Italy in the period 2016-2018, were analysed retrospectively. Antibiotic susceptibility testing was performed using a commercial broth microdilution. IMI-REL-resistant KPC-Kp strains were further analysed by whole genome sequencing to identify resistance determinants.Results: More than 97% of KPC-Kp (591/605, 97.7%) showed in vitro susceptibility to IMI/REL, with a minimum inhibitory concentration below the EUCAST cut-off. Different mutations in OmpK36 were found in all 14 IMI/REL-resistant strains. Interestingly, two of the analysed strains did not present any known variants associated with carbapenem resistance. Equal distribution of blaKPC-2 (6/12) and blaKPC-3 (6/12) was found, and in 11 isolates the presence of genetic variants associated with the production of beta-lactamases was also identified, namely blaSHV-28 or blaSHV-11, blaTEM-1, and blaOXA. No clonal dissemination was detected by the minimum spanning tree analysis. KPC-Kp resistant to IMI/REL retained susceptibility to meropenem/vaborbactam (MVB, 13/14, 92.9%) and ceftazidime/avibactam (CZA, 8/14, 57.1%). Only one strain was resistant to all the agent tested.Conclusions: IMI/REL showed good in vitro activity against the KPC-Kp strains analysed. All the IMI/REL-resistant strains displayed a mutation in porin OmpK36, whereas most produced carbapenemases, with KPC-2 and KPC-3 being equally distributed. MVB and CZA maintained good activity against IMI/REL resistant isolates