#Therapeutic efficacy of LN-1-255 in combination with #imipenem in severe #infection caused by #carbapenem-resistant #Acinetobacter baumannii (Antimicrob Agents Chemother., abstract)

[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

DOI: 10.1128/AAC.01092-19

 

ABSTRACT

OBJETIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Imipenem; Acinetobacter baumannii; Animal models.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.