Imipenem/Relebactam Resistance in Clinical Isolates of Extensively Drug Resistant Pseudomonas aeruginosa: Inhibitor-Resistant β-Lactamases and Their Increasing Importance

Antimicrob Agents Chemother. 2022 May 17;66(5):e0179021. doi: 10.1128/aac.01790-21. Epub 2022 Apr 18.


Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P. aeruginosa isolates, collected in the United States and Mexico, that demonstrated resistance to IMI/REL. Whole-genome sequencing (WGS) showed that both isolates contained acquired GES β-lactamases, intrinsic PDC and OXA β-lactamases, and disruptions in the genes encoding the OprD porin, thereby inhibiting uptake of carbapenems. In one isolate (ST17), the entire C terminus of OprD deviated from the expected amino acid sequence after amino acid G388. In the other (ST309), the entire oprD gene was interrupted by an ISPa1328 insertion element after amino acid D43, rendering this porin nonfunctional. The poor inhibition by REL of the GES β-lactamases (GES-2, -19, and -20; apparent Ki of 19 ± 2 μM, 23 ± 2 μM, and 21 ± 2 μM, respectively) within the isolates also contributed to the observed IMI/REL-resistant phenotype. Modeling of REL binding to the active site of GES-20 suggested that the acylated REL is positioned in an unstable conformation as a result of a constrained Ω-loop.

Keywords: GES β-lactamase; GES-19; GES-20; OXA β-lactamase; OprD deficient; Pseudomonas aeruginosa; imipenem; relebactam; relebactam resistance.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Azabicyclo Compounds / pharmacology
  • Azabicyclo Compounds / therapeutic use
  • Drug Combinations
  • Humans
  • Imipenem / pharmacology
  • Imipenem / therapeutic use
  • Microbial Sensitivity Tests
  • Porins / genetics
  • Pseudomonas Infections* / drug therapy
  • Pseudomonas aeruginosa* / genetics
  • Pseudomonas aeruginosa* / metabolism
  • United States
  • beta-Lactamases / metabolism


  • Amino Acids
  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • Porins
  • Imipenem
  • beta-Lactamases
  • relebactam