In vitro activity of ceftazidime–avibactam, imipenem–cilastatin–relebactam, meropenem–vaborbactam, cefiderocol, and plazomicin against non-fermenting Gram-negative isolates obtained from Bulgarian inpatients

The present study aimed to evaluate the in vitro activity of ceftazidime-avibactam (CZA), imipenem-cilastatin-relebactam (IMR), meropenem-vaborbactam (MEV), cefiderocol (CFDC), and plazomicin (PLZ), against nosocomial carbapenem-resistant Pseudomonas aeruginosa (CRPA) (n = 40), carbapenem-resistant Acinetobacter baumannii (CRAB) (n = 56), and Stenotrophomonas maltophilia (n = 50) isolates from Bulgaria (2014-2023). Antimicrobial susceptibility testing, polymerase chain reaction screening for antimicrobial resistance (AMR) determinants, and whole-genome sequencing were performed. In CRPA, blaNDM-1 (20%), blaVIM-2 (5%), and blaVIM-4 (2.5%) metallo-β-lactamase (MBL)-encoding genes were detected. Both P. aeruginosa and S. maltophilia showed absolute susceptibility to CFDC, and 78.6% of the tested A. baumannii isolates were also susceptible. All CFDC-resistant (MIC values in the range of 4-64 mg L-1) CRAB isolates (12 out of 56) were positive for blaPER-1 (n = 12) and acquired class D carbapenemase genes, as follows: blaOXA-23-like (n = 7), blaOXA-24/40-like (n = 1), and blaOXA-23-like + blaOXA-24/40-like (n = 4). Only 22.5-25% of CRPA isolates revealed susceptibility to the combined β-lactam (BL)-β-lactamase inhibitor (BLI) antimicrobials. Equal PLZ MIC50 values were reported against P. aeruginosa and A. baumannii (8 mg L-1), but higher MIC90 values against CRAB (>256 vs. 16 mg L-1). MBL-producing CRPA demonstrated absolute resistance to all BL-BLI preparations, whereas non-MBL-producing isolates possessed significantly higher susceptibility (P < 0.05), ranging from 31% (for CZA and IMR) to 34.5% (MEV). In conclusion, the emergence of MBL-positive P. aeruginosa and the associated ineffectiveness of the novel BL-BLI combinations, as well as the relatively high proportion of CFDC-resistant A. baumannii isolates, are alarming. Therefore, continuous surveillance of AMR concerning newly approved antibiotics should be the mainstay of multifaceted global and national "One Health" strategies and infection control stewardship practices in hospital settings.