Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate

J Antimicrob Chemother. 2017 Sep 1;72(9):2483-2488. doi: 10.1093/jac/dkx179.


Background: Avibactam is a novel broad-range β-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment.

Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I). Compared with WT CTX-M-14, expression of the CTX-M-14Δ170Δ264 isoform in Escherichia coli led to a >64- and 16-fold increase in ceftazidime and ceftazidime/avibactam MICs, respectively, functionally linking the observed SNPs and elevated MICs. The mutated CTX-M-14 isoform exhibited augmented ceftazidime hydrolytic activity, which was a reasonable cause for impaired susceptibility to avibactam inhibition. The P170S exchange in CTX-M-14 was found in association with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but was not sufficient for full resistance. Apparently, additional CTX-M-independent mechanisms contribute to ceftazidime/avibactam resistance in K. pneumoniae DT12.

Conclusions: This study on the molecular basis of ceftazidime/avibactam resistance in clinical K. pneumoniae emerging in vivo underscores the need for continuous monitoring of ceftazidime/avibactam susceptibility during therapy. Despite sustained inhibition of OXA-48, rapid development of CTX-M-14 isoforms exhibiting augmented ceftazidime hydrolytic activity may limit the usefulness of ceftazidime/avibactam monotherapies in infections caused by isolates carrying blaCTX-M-14 and blaOXA-48.

Publication types

  • Case Reports

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / pharmacology*
  • Azabicyclo Compounds / therapeutic use
  • Ceftazidime / administration & dosage
  • Ceftazidime / pharmacology*
  • Ceftazidime / therapeutic use
  • Drug Combinations
  • Drug Resistance, Multiple, Bacterial
  • Genome, Bacterial
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Klebsiella Infections / drug therapy
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / drug effects*
  • Klebsiella pneumoniae / genetics*
  • Klebsiella pneumoniae / isolation & purification
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • beta-Lactamase Inhibitors / pharmacology


  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • beta-Lactamase Inhibitors
  • avibactam
  • Ceftazidime