Journal Article

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

Rossi, Marianna, Cirillo, Daniela Maria, Di Marco, Federico, Muscatello, Antonio, Bielli, Alessandra, Matarazzo, Elisa, Bandera, Alessandra, Comelli, Agnese, Re, Noemi Lo, Palomba, Emanuele, Vismara, Chiara Silvia, Saluzzo, Francesca, Gori, Andrea

2025

Overview

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 603 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 Ninety-eight percent of KPC-Kp (591/603) 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 12 IMI/REL-resistant strains, which belonged to MLST STs 258 (3 isolates), 307 (8 isolates) and 512 (1 isolate), but no clonal relatedness was detected by the minimum spanning tree analysis, except for 2 strains isolated in the same hospital. Equal distribution of bla KPC−2 (6/12) and bla KPC−3 (6/12) was found, and in 11 isolates the presence of genetic variants associated with the production of beta-lactamases was also identified. KPC-Kp resistant to IMI/REL retained susceptibility to meropenem/vaborbactam (MVB, 12/12, 100%) and ceftazidime/avibactam (CZA, 11/12, 91.7%). Only one strain of 603 was resistant to either MVB and CZA but susceptible to IMI/REL with a MIC of 2 mg/L; 4/603 (0.7%) were resistant to CZA but susceptible to IMI/REL and MVB. 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 and produced carbapenemases, with KPC-2 and KPC-3 being equally distributed. MVB and CZA maintained good activity against IMI/REL resistant isolates.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Anti-Bacterial Agents - pharmacology / Antibiotics / Antimicrobial agents / Antimicrobial resistance / Azabicyclo Compounds - pharmacology / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / beta-Lactamases - genetics / beta-Lactamases - metabolism / Biochemistry / Biomedical and Life Sciences / Biomedicine / Brief Report / Carbapenem-resistant / Ceftazidime / Data collection / Dosage and administration / Drug Resistance / Drug resistance in microorganisms / Drug Resistance, Bacterial - genetics / Drug Resistance, Multiple, Bacterial - genetics / Drug therapy / Gene mutations / Gene sequencing / Genetic aspects / Genetic diversity / Genetic variance / Graph theory / Humans / Imipenem / Imipenem - pharmacology / Imipenem/relebactam / Infections / Infectious Diseases / Italy / Klebsiella / Klebsiella infections / Klebsiella Infections - drug therapy / Klebsiella Infections - microbiology / Klebsiella pneumoniae / Klebsiella pneumoniae - drug effects / Klebsiella pneumoniae - genetics / KPC / Medical Microbiology / Meropenem / Microbial Genetics and Genomics / Microbial Sensitivity Tests / Microbiological research / Minimum inhibitory concentration / Mutation / Parasitology / Physiological aspects / Porins - genetics / Retrospective Studies / Risk factors / Software / Testing / Whole Genome Sequencing