Vázquez-Ucha, Juan CarlosMartínez Guitián, MartaManeiro Rey, MaríaConde-Pérez, KellyÁlvarez-Fraga, LauraTorrens Ribot, GabrielOliver, AntonioBuynak, JohnBonomo, RobertBou, GermánGonzález-Bello, ConcepciónPoza, MargaritaBeceiro Casas, Alejandro2026-02-122026-02-122019-09-23Vázquez-Ucha JC, Martínez-Guitián M, Maneiro M, Conde-Pérez K, Álvarez-Fraga L, Torrens G, Oliver A, Buynak JD, Bonomo RABou G, González-Bello C, Poza M, Beceiro A. 2019. Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother 63:10.1128/aac.01092-19. https://doi.org/10.1128/aac.01092-191098-65960066-4804https://hdl.handle.net/2183/47407[Abstract] The carbapenem-hydrolyzing class D β-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii. CHDLs are not effectively inactivated by clinically available β-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clinical isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, respectively, were used in the study. Pharmacokinetic (PK) parameters were determined. An experimental pneumonia model was used to evaluate the efficacy of the combined imipenem–LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. Intramuscular treatment with imipenem–LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, respectively, and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, respectively. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was observed in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.eng© American Society for MicrobiologyAcinetobacter baumanniiAnimal modelsAntimicrobial agentsBeta-lactamase inhibitorClass D carbapenemasesPreclinical drug studiesjournal articleopen access10.1128/aac.01092-19