Emergence of #ceftazidime / #avibactam #resistance in #KPC-3-producing #Klebsiella pneumoniae in vivo (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

Stephan Göttig, Denia Frank, Eleonora Mungo, Anika Nolte, Michael Hogardt, Silke Besier,Thomas A Wichelhaus

Journal of Antimicrobial Chemotherapy, dkz330, https://doi.org/10.1093/jac/dkz330

Published: 31 July 2019

 

Abstract

Objectives

The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.

Methods

Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination.

Results

The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.

Conclusions

Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivoinfection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Ceftazidime; Avibactam; Imipenem; Klebsiella pneumoniae.

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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.