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

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, MIC ≤ 0.25 mg/L, most MBC/MIC ratios = 1) and moderate activity against NDM-producing Enterobacterales (> 58% susceptibility, MIC ≤ 0.06 mg/L for E. coli, 8 mg/L for Klebsiella pneumoniae, and 64 mg/L for other carbapenem-resistant Enterobacterales, most MBC/MIC 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, MIC = 16 mg/L, MBC/MIC 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.