Palomba Emanuele, Comelli Agnese, Saluzzo Francesca, Di Marco Federico, Matarazzo Elisa, Re Noemi Lo, Bielli Alessandra, Vismara Chiara Silvia, Muscatello Antonio, Rossi Marianna, Cirillo Daniela Maria, Bandera Alessandra, Gori Andrea
Department of Infectious Diseases, Luigi Sacco Hospital, Via G.B. Grassi 74, 20157, Milan, Italy.
Centre for Multidisciplinary Research in Health Science (MACH), University of Milano, Milan, Italy.
Ann Clin Microbiol Antimicrob. 2025 Apr 13;24(1):23. doi: 10.1186/s12941-025-00792-w.
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.
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.
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 (6/12) and bla (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.
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.
肠杆菌科细菌的耐药性是现代临床实践中的重大威胁，收集有关新分子疗效的数据至关重要。我们的研究旨在分析亚胺培南/西司他丁/雷利巴坦（IMI/REL）对产KPC的肺炎克雷伯菌（KPC-Kp）的体外活性，并研究对该药物耐药的遗传决定因素。
回顾性分析了2016年至2018年期间在意大利北部多中心研究中随机收集的603株KPC-Kp菌株。使用商业肉汤微量稀释法进行药敏试验。对耐IMI-REL的KPC-Kp菌株进行全基因组测序，以确定耐药决定因素。
98%的KPC-Kp（591/603）对IMI/REL表现出体外敏感性，最低抑菌浓度低于欧盟CAST标准。在所有12株耐IMI/REL的菌株中均发现了OmpK36的不同突变，这些菌株属于多位点序列分型（MLST）ST258（3株）、ST307（8株）和ST512（1株），但最小生成树分析未检测到克隆相关性，同一医院分离的2株除外。blaKPC-2和blaKPC-3分布均等（6/12），在11株分离株中还鉴定出与β-内酰胺酶产生相关的基因变体。耐IMI/REL的KPC-Kp对美罗培南/瓦博巴坦（MVB，12/12，100%）和头孢他啶/阿维巴坦（CZA，11/12，91.7%）仍敏感。603株中只有1株对MVB或CZA耐药，但对IMI/REL敏感，MIC为2mg/L；4/603（0.7%）对CZA耐药，但对IMI/REL和MVB敏感。
IMI/REL对所分析的KPC-Kp菌株显示出良好的体外活性。所有耐IMI/REL的菌株在孔蛋白OmpK36上均有突变，并产生碳青霉烯酶，KPC-2和KPC-3分布均等。MVB和CZA对耐IMI/REL的分离株仍保持良好活性。
