[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Therapeutic efficacy of LN-1-255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii
Juan Carlos Vázquez-Ucha, Marta Martínez-Guitián, María Maneiro, Kelly Conde-Pérez, Laura Álvarez-Fraga, Gabriel Torrens, Antonio Oliver, John D. Buynak, Robert A. Bonomo,Germán Bou, Concepción González-Bello, Margarita Poza, Alejandro Beceiro
The Carbapenem-Hydrolyzing Class D β-Lactamases (CHDLs) are the main mechanism of carbapenem resistance in A. baumannii. CHDLs are not effectively inactivated by clinically available β-lactam-type inhibitors. We have previously described the in vitroefficacy 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 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 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 presence of LN-1-255. Intramuscular treatment with imipenem/LN-1-255 (30/50 mg/Kg) decreased the bacterial burden i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and the AB1 strains, respectively and ii) 2.5 and 4.5 log10 CFU/g lung 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 those treated with monoteraphy. No toxicity was observed in treated mice.
Imipenem treatment combined with LN-1-255 reduced significantly the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of the therapy of LN-1-255 and imipenem as new antibacterial treatment.
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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Imipenem; Acinetobacter baumannii; Animal models.