Aztreonam-avibactam and Cefiderocol Against Metallo-Β-lactamase-producing Enterobacterales and Other Carbapenem-Resistant Gram-negative Pathogens: Microbiological Activity and Clinical Evidence.

OBJECTIVES:Aztreonam-avibactam (ATM-AVI) and cefiderocol (CFDC) are two next-generation antibiotics that exhibit promising in vitro activity against metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE). However, differences in antibacterial spectra and resistance mechanisms among clinically important Gram-negative bacteria (GNB) between these two agents remain incompletely understood. METHODS:English-language publications indexed in PubMed (1990-2026), records retrieved from Google Scholar, and the 2018-2024 Antimicrobial Testing Leadership and Surveillance database were extensively reviewed to assess their potential clinical utility. RESULTS:ATM-AVI demonstrates broad activity against KPC-, MBL- and OXA-48/181-like-producing CRE. However, ATM-AVI non-susceptibility occurs in Escherichia coli and Providencia rettgeri isolates harboring blaCMY, penicillin-binding protein 3 (PBP3) modifications, and porin dysfunction or acrA efflux overexpression. In contrast, CFDC activity is primarily compromised by NDM production, reduced expression of iron transporters, and PBP3 alterations. Significant regional variation in CFDC susceptibility among MBL-producing CRE isolates collected in Asia and North America/Europe has been observed. Based on limited pooled real-world treatment experience, CFDC shows moderate efficacy (73%) for the treatment of infections caused by MBL-producing CRE. Both antibiotics also show potential in vitro activity against ceftazidime-avibactam-resistant, non-carbapenemase-producing CRE. Notably, CFDC exhibits excellent in vitro activity against contemporary CR-Pseudomonas aeruginosa, most CR-Acinetobacter baumannii harboring blaOXA-23/24/58 genes, Elizabethkingia anophelis, Stenotrophomonas maltophilia, Burkholderia cepacia and Burkholderia pseudomallei. Nevertheless, CFDC heteroresistance is most prevalent among CR-A. baumannii isolates. CONCLUSIONS:Continued assessment of clinical treatment experience with these two antibiotics against MBL-producing CRE and important non-fermenting GNB is warranted to accumulate further evidence regarding their therapeutic roles.