In Vivo Emergence of Resistance to Novel Cephalosporin-β-Lactamase Inhibitor Combinations through the Duplication of Amino Acid D149 from OXA-2 β-Lactamase (OXA-539) in Sequence Type 235 Pseudomonas aeruginosa

Antimicrob Agents Chemother. 2017 Aug 24;61(9):e01117-17. doi: 10.1128/AAC.01117-17. Print 2017 Sep.

Abstract

Resistance development to novel cephalosporin-β-lactamase inhibitor combinations during ceftazidime treatment of a surgical infection by Pseudomonas aeruginosa was investigated. Both initial (97C2) and final (98G1) isolates belonged to the high-risk clone sequence type (ST) 235 and were resistant to carbapenems (oprD), fluoroquinolones (GyrA-T83I, ParC-S87L), and aminoglycosides (aacA7/aacA8/aadA6). 98G1 also showed resistance to ceftazidime, ceftazidime-avibactam, and ceftolozane-tazobactam. Sequencing identified blaOXA-2 in 97C2, but 98G1 contained a 3-bp insertion leading to the duplication of the key residue D149 (designated OXA-539). Evaluation of PAO1 transformants producing cloned OXA-2 or OXA-539 confirmed that D149 duplication was the cause of resistance. Active surveillance of the emergence of resistance to these new valuable agents is warranted.

Keywords: Pseudomonas aeruginosa; ceftazidime-avibactam; ceftolozane-tazobactam; extended-spectrum OXA; multidrug resistance.

MeSH terms

  • Amino Acid Sequence / genetics*
  • Anti-Bacterial Agents / pharmacology
  • Azabicyclo Compounds / pharmacology*
  • Ceftazidime / pharmacology*
  • Ceftazidime / therapeutic use
  • Cephalosporins / pharmacology*
  • Cephalosporins / therapeutic use
  • DNA Gyrase / genetics
  • Drug Combinations
  • Drug Resistance, Multiple, Bacterial / genetics
  • Humans
  • Microbial Sensitivity Tests
  • Penicillanic Acid / analogs & derivatives*
  • Penicillanic Acid / pharmacology
  • Porins / genetics
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / isolation & purification
  • Tazobactam
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / genetics*

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Cephalosporins
  • Drug Combinations
  • Porins
  • avibactam, ceftazidime drug combination
  • beta-Lactamase Inhibitors
  • ceftolozane, tazobactam drug combination
  • OprD protein, Pseudomonas aeruginosa
  • Penicillanic Acid
  • Ceftazidime
  • beta-lactamase OXA-2
  • beta-Lactamases
  • DNA Gyrase
  • Tazobactam