Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy
Juan C Vázquez-UchaAlejandro Beceiro

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 in...Continue Reading

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Citations

Dec 10, 2020·International Journal of Molecular Sciences·Juan C Vázquez-UchaAlejandro Beceiro
Oct 31, 2019·Journal of Medicinal Chemistry·Concepción González-BelloEsther Colchón
Mar 21, 2020·Journal of Medicinal Chemistry·Diana RodríguezConcepción González-Bello

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