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Purpose <p>Carbapenem-resistant organisms pose a significant public health threat due to high mortality and limited treatment options. This study aimed to evaluate the in vitro antimicrobial activity of the novel β-lactamase inhibitor FL058 combined with meropenem against carbapenem-resistant Enterobacterales and <i>Pseudomonas aeruginosa</i> clinical isolates.</p> Methods <p>The MICs of 85 clinical isolates, including KPC- or NDM-producing Enterobacterales and carbapenem-resistant/susceptible <i>P. aeruginosa</i>, were determined using broth microdilution. Additionally, bactericidal activity, effects of culture conditions, post-antibiotic effect, and post-β-lactamase inhibitory effect of meropenem-FL058 were evaluated. Ceftazidime-avibactam served as comparator.</p> Results <p>Meropenem-FL058 showed potent activity against KPC-producing Enterobacterales (100% susceptibility, MIC<sub>90</sub> ≤ 0.25&#xa0;mg/L, most MBC<sub>90</sub>/MIC<sub>90</sub> ratios = 1) and moderate activity against NDM-producing Enterobacterales (&gt; 58% susceptibility, MIC<sub>90</sub> ≤ 0.06&#xa0;mg/L for <i>E. coli</i>, 8&#xa0;mg/L for <i>Klebsiella pneumoniae</i>, and 64&#xa0;mg/L for other carbapenem-resistant Enterobacterales, most MBC<sub>90</sub>/MIC<sub>90</sub> ratios = 2). Of note, NDM-producing <i>E. coli</i> achieved a susceptibility of 91.7%. Meropenem-FL058 showed susceptibility rates of 73.9% for NDM-1 and 62.5% for NDM-5-producing strains. Activity against carbapenem-resistant <i>P. aeruginosa</i> was limited (18.2% susceptibility, MIC<sub>90</sub> = 16&#xa0;mg/L, MBC<sub>90</sub>/MIC<sub>90</sub> ratio = 8). Inoculum density and culture medium pH significantly affected the antimicrobial activity, while serum and metal ions had minimal effects. No significant post-antibiotic effect or post-β-lactamase inhibitory effect was observed.</p> Conclusion <p>Meropenem-FL058 showed promising in vitro activity against KPC-producing Enterobacterales and some NDM-1/5-producing strains. However, its limited efficacy against certain NDM-producers and carbapenem-resistant <i>P. aeruginosa</i> highlights the variability in activity across different resistance mechanisms, suggesting the potential need for combination strategies in clinical settings.</p>

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In vitro activity of the novel β-lactamase inhibitor FL058 combined with meropenem against KPC- or NDM-producing enterobacterales and Pseudomonas aeruginosa

  • 期刊论文

  • 发表日期：

    2025年8月12日

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  • Feng Yang,
  • Yang Yang,
  • Shi Wu,
  • Chengkang Tang,
  • Dandan Yin,
  • Yan Guo,
  • Demei Zhu,
  • Fupin Hu

摘要

Purpose

Carbapenem-resistant organisms pose a significant public health threat due to high mortality and limited treatment options. This study aimed to evaluate the in vitro antimicrobial activity of the novel β-lactamase inhibitor FL058 combined with meropenem against carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa clinical isolates.

Methods

The MICs of 85 clinical isolates, including KPC- or NDM-producing Enterobacterales and carbapenem-resistant/susceptible P. aeruginosa, were determined using broth microdilution. Additionally, bactericidal activity, effects of culture conditions, post-antibiotic effect, and post-β-lactamase inhibitory effect of meropenem-FL058 were evaluated. Ceftazidime-avibactam served as comparator.

Results

Meropenem-FL058 showed potent activity against KPC-producing Enterobacterales (100% susceptibility, MIC90 ≤ 0.25 mg/L, most MBC90/MIC90 ratios = 1) and moderate activity against NDM-producing Enterobacterales (> 58% susceptibility, MIC90 ≤ 0.06 mg/L for E. coli, 8 mg/L for Klebsiella pneumoniae, and 64 mg/L for other carbapenem-resistant Enterobacterales, most MBC90/MIC90 ratios = 2). Of note, NDM-producing E. coli achieved a susceptibility of 91.7%. Meropenem-FL058 showed susceptibility rates of 73.9% for NDM-1 and 62.5% for NDM-5-producing strains. Activity against carbapenem-resistant P. aeruginosa was limited (18.2% susceptibility, MIC90 = 16 mg/L, MBC90/MIC90 ratio = 8). Inoculum density and culture medium pH significantly affected the antimicrobial activity, while serum and metal ions had minimal effects. No significant post-antibiotic effect or post-β-lactamase inhibitory effect was observed.

Conclusion

Meropenem-FL058 showed promising in vitro activity against KPC-producing Enterobacterales and some NDM-1/5-producing strains. However, its limited efficacy against certain NDM-producers and carbapenem-resistant P. aeruginosa highlights the variability in activity across different resistance mechanisms, suggesting the potential need for combination strategies in clinical settings.