Journal of Global Antimicrobial Resistance (Dec 2024)

Loss of OmpK35 and Glycine-aspartic acid Duplication in ompK36 Negatively Affect the in vitro Synergy of Meropenem in Combination with Piperacillin/tazobactam or Imipenem Against OXA-48-like Carbapenemase-producing Klebsiella pneumoniae

  • Abdullah Tarik Aslan,
  • Mervenur Demir,
  • Elif Seren Tanriverdi,
  • Budi Permana,
  • Rhys Izuagbe,
  • Kay A. Ramsay,
  • Brian Forde,
  • Baris Otlu,
  • David L. Paterson,
  • Patrick Harris,
  • Murat Akova,
  • Gulsen Hazirolan

Journal volume & issue
Vol. 39
p. 7

Abstract

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BACKGROUND-AIM: Although ceftazidime/avibactam is the agent of choice in OXA-48-producing Klebsiella pneumoniae infections, it is not readily available or prohibitively expensive in many countries. Since piperacillin/tazobactam plus meropenem combination was recently reported as highly synergistic against OXA-48-producing K. pneumoniae, we aimed to test in vitro synergy between piperacillin/tazobactam and meropenem against these isolates having a range of meropenem minimum inhibitory concentration (MIC) values. METHODS: Time-kill assays were performed in duplicate against 17 carbapenemase-producing K. pneumoniae isolates (OXA-48, n= 7; OXA-232, n= 6; NDM-1, n= 3; OXA-48 + NDM-1, n= 1) and 2 non-carbapenemase-producing K. pneumoniae isolates with a glycine-aspartic acid (GD) duplication in ompK36. Antibiotic concentrations simulated the clinically attainable concentrations in critically ill patients. RESULTS: The piperacillin/tazobactam plus meropenem and imipenem plus meropenem combinations were synergistic against 30.8% (4/13) and 46.2% (6/13) of OXA-48-like carbapenemase producers, respectively (P= 0.5). Among isolates with low meropenem MIC (1-2 mg/L), the synergy rate between piperacillin/tazobactam and meropenem was significantly higher than in those with meropenem MIC ≥16 mg/L (75% vs 11%; P= 0.05). Such a significant interaction was not observed between meropenem and imipenem (75% vs 33%, P= 0.26). The in vitro synergy in both combinations were negatively impacted by mutations in either or both ompK35 and ompK36 genes (piperacillin/tazobactam plus meropenem: 1/10 [10%] vs 3/3 [100%]; P= 0.014; imipenem plus meropenem: 3/10 [30%] vs 3/3 [100%] P= 0.070). CONCLUSIONS: The absence of OmpK35 and GD duplication in ompK36 hamper the synergy between piperacillin/tazobactam and meropenem against OXA-48-like carbapenemase-producing K. pneumoniae.

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