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