Plazomicin Sulfate

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 MIC 50 values were reported against P. aeruginosa  and A. baumannii (8 mg L −1 ), but higher MIC 90 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.

Treatment-emergent resistance is increasingly reported in carbapenem-resistant Enterobacterales during therapy with newly developed antibiotics. However, standardized definitions and studies evaluating the impact of treatment-emergent resistance on patient outcome are lacking.

To review current evidence on the epidemiology, risk factors, and clinical impact of resistance emerging during or after exposure to novel antibiotics against carbapenem-resistant Enterobacterales and to explore strategies to mitigate this phenomenon.

We searched PubMed/MEDLINE for studies published in the last 15 years, including clinical reports, observational studies, and in vitro studies focusing on ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, aztreonam-avibactam, eravacycline, and plazomicin.

Literature on resistance development during treatment with novel antibiotics is sparse and mainly represented by case reports or retrospective cohort studies. In most cases, data including antibiotic dosages, duration, or cross-resistance to other antibiotics are not reported. Treatment-emergent resistance is best described for ceftazidime-avibactam, with Klebsiella pneumoniae carbapenemase (KPC) variants carrying Ω-loop mutations (e.g. KPC-31) as the most common reported mechanism worldwide. Resistance during or after meropenem-vaborbactam or imipenem-relebactam therapy is uncommon and only reported in selected cases from Europe where the drugs have been used more broadly. Cefiderocol resistance is mainly reported from Europe and United States in New-Delhi metallo-β-lactamase (NDM)-producing Enterobacterales and commonly linked to iron transporter defects, penicillin-binding protein 3 (PBP3) substitutions, or increased bla_NDM copy number. For aztreonam-avibactam, resistance during or after treatment has been reported in selected strains of NDM-producing Escherichia coli isolates with PBP3 and CMY mutations from Singapore and United States.

Treatment-emergent resistance is a consequence of antibiotic exposure, but its impact is likely underestimated. Preventive strategies include optimization of pharmacokinetic/pharmacodynamic targets, therapeutic drug monitoring, timely and complete source control, and stewardship-driven rational use of novel agents.