Assessment of Activity and Resistance Mechanisms to Cefepime in Combination with the Novel b-Lactamase Inhibitors Zidebactam, Taniborbactam, and Enmetazobactam against a Multicenter Collection of Carbapenemase-Producing Enterobacterales
2022
Carlos Vázquez-Ucha, Juan | Lasarte-Monterrubio, Cristina | Guijarro-Sánchez, Paula | Oviaño, Marina | Álvarez-Fraga, Laura | Alonso-García, Isaac | Arca-Suárez, Jorge | Bou, German | Beceiro, Alejandro | Instituto de Investigación Biomédica de A Coruña [La Corogne, Espagne] (INIBIC) ; A Coruña University Hospital [La Corogne, Espagne] | Laboratoire de Biotechnologie de l'Environnement [Narbonne] (LBE) ; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | This work was supported by the Fondo de Investigación Sanitaria (grant numbers PI17/01482 and PI20/01212 for A.B. and PI18/00501 for G.B. integrated in the Plan Nacional de I+D and funded by the Instituto de Salud Carlos III, ISCIII).CIBERINF (CIBER de Enfermedades Infecciosas). The research was also funded by the Spanish Network of Research in Infectious Diseases (REIPI), N° RD16/0016/0006, integrated in the National Plan for Scientific Research, Development and Technological Innovation 2013–2016 and funded by the ISCIII–General Subdirection of Assessment and Promotion of the Research–European Regional Development Fund (FEDER) “A way of making Europe.” The study was also funded by GAIN (Agencia Gallega de Innovacion, Conselleria de Economia, Emprego e Industria; IN607D2021/12, A.B. and IN607A 2016/22, G.B.).J.C.V.-U. was financially supported by the ISCIII project, FI18/00315. J.A.-S. was financially supported by the Rio Hortega program (ISCIII, CM19/00219) and C.L.-M. by GAIN (IN606A-2019/029). A.B. was financially supported by the Miguel Servet II program, CPII18/00024.
International audience
显示更多 [+] 显示较少 [-]英语. The global distribution of carbapenemases such as KPC, OXA-48, and metallo-β-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical β-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the most promising highlights for the treatment of multidrug-resistant bacteria. The activity of cefepime in combination with the novel BLIs zidebactam, taniborbactam, and enmetazobactam was studied in a collection of 400 carbapenemase-producing Enterobacterales (CPE). The genomes were fully sequenced and potential mechanisms of resistance to cefepime/BLI combinations were characterized. Cefepime resistance in the whole set of isolates was 79.5% (MIC50/90 64/≥128mg/L). The cefepime/zidebactam and cefepime/taniborbactam combinations showed the highest activity (MIC50/90 ≤0.5/1 and ≤0.5/2 mg/L, respectively). Cefepime/zidebactam displayed high activity, regardless of the carbapenemase or extended-spectrum β-lactamase (ESBL) considered (99% of isolates displayed MIC ≤2 mg/L). Cefepime/taniborbactam displayed excellent activity against OXA-48- and KPC-producing Enterobacterales and lower activity against MBL-producing isolates (four strains yielded MICs ≥16 mg/L: 2 NDM producers with an insertion in PBP3, one VIM-1 producer with nonfunctional OmpK35, and one IMP-8 producer). Cefepime/enmetazobactam displayed the lowest activity (MIC50/90 1/≥128 mg/L), with MICs ≥16 mg/L for 49 MBL producers, 40 OXA-48 producers (13 with amino acid changes in OmpK35/36, 4 in PBPs and 11 in RamR) and 25 KPC producers (most with an insertion in OmpK36). These results confirm the therapeutic potential of the new β-lactamase inhibitors, shedding light on the activity of cefepime and BLIs against CPE and resistance mechanisms. The cefepime/zidebactam and cefepime/taniborbactam combinations are particularly highlighted as promising alternatives to penicillin-based inhibitors for the treatment of CPE.
显示更多 [+] 显示较少 [-]