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. 2020 Mar 1;75(3):559-565.
doi: 10.1093/jac/dkz468.

In vitro selection of aztreonam/avibactam resistance in dual-carbapenemase-producing Klebsiella pneumoniae

Siqiang Niu  1 , Jie Wei  2 , Chunhong Zou  3 , Kalyan D Chavda  4 , Jingnan Lv  5 , Haifang Zhang  5 , Hong Du  5 , Yi-Wei Tang  6 , Johann D D Pitout  7 , Robert A Bonomo  8   9   10 , Barry N Kreiswirth  4 , Liang Chen  4
Affiliations

In vitro selection of aztreonam/avibactam resistance in dual-carbapenemase-producing Klebsiella pneumoniae

Siqiang Niu et al. J Antimicrob Chemother. .

Abstract

Objectives: To examine the in vitro selection of aztreonam/avibactam resistance among MBL-producing Klebsiella pneumoniae and to understand the mechanism of increased resistance.

Methods: The MICs of aztreonam were determined with and without avibactam (4 mg/L) using a broth microdilution method. Single-step and multi-step mutant selection was conducted on five MBL-producing K. pneumoniae strains, including two dual carbapenemase producers. Genomic sequencing and gene cloning were performed to investigate the mechanism of increased resistance.

Results: We examined the MICs for 68 MBL-producing K. pneumoniae isolates, including 13 dual carbapenemase producers. Compared with aztreonam alone, the addition of avibactam (4 mg/L) reduced the MICs for all isolates by >128-fold, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively. One NDM-1-, OXA-48-, CTX-M-15- and CMY-16-positive ST101 K. pneumoniae strain was selected to be resistant to aztreonam/avibactam, with a >16-fold increase in MIC (>128 mg/L). WGS revealed that the resistant mutants lost the blaNDM-1 gene, but acquired amino acid substitutions in CMY-16 (Tyr150Ser and Asn346His). Construction of blaCMY-16 mutants confirmed that the substitutions (Tyr150Ser and Asn346His) were primarily responsible for the decreased susceptibility to aztreonam/avibactam. In addition, transfer of blaCMY-16 mutant (Tyr150Ser and Asn346His) plasmid constructs into certain clinical carbapenemase-producing isolates demonstrated >64-fold increased MICs of aztreonam/avibactam and aztreonam/avibactam/ceftazidime.

Conclusions: Aztreonam in combination with avibactam showed potent in vitro activity against MBL-producing K. pneumoniae. However, our study suggested the likelihood of aztreonam/avibactam resistance among MBL- and AmpC-co-producing strains and clinical practice should beware of the possibility of the emerging resistance.

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Figures

Figure 1.
Figure 1.
(a) Plasmid structure comparison between blaNDM-1-harbouring pKp202_1 and the selected mutants. (b) The blaNDM-1 deletion in Kp202 selected mutants. Coloured arrows indicate ORFs, with purple, orange, green, red and blue arrows representing replication genes, mobile elements, plasmid transfer genes, the antimicrobial and heavy metal resistance gene, and plasmid backbone genes, respectively. Blue shading denotes regions of shared homology among different elements.
See this image and copyright information in PMC

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