Abstract
We describe the in vivo emergence of resistance to ceftazidime/avibactam via modification of AmpC in a clinical Klebsiella aerogenes isolate during therapy with this combination. Paired ceftazidime/avibactam-susceptible/resistant isolates were obtained before and during ceftazidime/avibactam treatment. Whole genome sequencing revealed a differential mutation in AmpC (R148W) in the ceftazidime/avibactam-resistant isolate. Molecular cloning and structural studies confirmed the impact of this substitution, which affects the architecture of the H10 helix, on the evolved resistant phenotype.
Keywords:
AmpC; Klebsiella aerogenes; ceftazidime/avibactam; evolution; β-lactamase.
MeSH terms
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Anti-Bacterial Agents* / pharmacology
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Azabicyclo Compounds* / pharmacology
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Bacterial Proteins* / genetics
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Bacterial Proteins* / metabolism
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Ceftazidime* / pharmacology
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Drug Combinations*
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Drug Resistance, Multiple, Bacterial / genetics
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Enterobacter aerogenes* / drug effects
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Enterobacter aerogenes* / enzymology
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Enterobacter aerogenes* / genetics
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Humans
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Klebsiella Infections / drug therapy
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Klebsiella Infections / microbiology
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Microbial Sensitivity Tests*
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Mutation
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Whole Genome Sequencing
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beta-Lactamases* / genetics
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beta-Lactamases* / metabolism
Substances
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Ceftazidime
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Azabicyclo Compounds
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beta-Lactamases
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avibactam, ceftazidime drug combination
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AmpC beta-lactamases
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Drug Combinations
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Bacterial Proteins
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Anti-Bacterial Agents