1. Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo
- Author
-
Michael Hogardt, Thomas A. Wichelhaus, Stephan Göttig, Anika Nolte, Denia Frank, Eleonora Mungo, and Silke Besier
- Subjects
Microbiology (medical) ,Imipenem ,Klebsiella pneumoniae ,Avibactam ,medicine.medical_treatment ,Ceftazidime ,Microbial Sensitivity Tests ,Moths ,beta-Lactamases ,Microbiology ,chemistry.chemical_compound ,Bacterial Proteins ,Drug Resistance, Multiple, Bacterial ,Sepsis ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,Beta-Lactamase Inhibitors ,Pharmacology ,Antiinfective agent ,biology ,business.industry ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,biology.organism_classification ,Ceftazidime/avibactam ,Anti-Bacterial Agents ,Klebsiella Infections ,Drug Combinations ,Kinetics ,Infectious Diseases ,Phenotype ,chemistry ,Larva ,Beta-lactamase ,Female ,business ,Azabicyclo Compounds ,medicine.drug - Abstract
ObjectivesThe 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.MethodsSequence 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.ResultsThe 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.ConclusionsCeftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection 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.
- Published
- 2019