In Vitro Activity of Aztreonam–Avibactam, Cefiderocol, and Conventional Antimicrobials Against Metallo-β-Lactamase-Producing Gram-Negative Urinary Isolates: A Systematic Review and Local Single-Center Retrospective Evaluation in a Tertiary Care Hospital (2016–2025) and Evaluation of Novel Agents (20

Abstract

Background: Metallo-β-lactamase (MBL)-producing Gram-negative bacteria represent one of the greatest therapeutic challenges in contemporary clinical microbiology because of their extensive antimicrobial resistance and the limited availability of effective treatment options. Aztreonam–avibactam and cefiderocol have emerged as promising therapeutic alternatives; however, comparative evidence from routine clinical practice remains limited. Methods: A systematic literature search was conducted in PubMed to identify studies published between 2015 and 2025 evaluating the in vitro activity of aztreonam–avibactam and cefiderocol against MBL-producing Gram-negative bacteria. A total of 22 fully accessible studies meeting the eligibility criteria were included and analyzed in the systematic review. In parallel, a retrospective cross-sectional study was performed including all urinary isolates producing MBL recovered at the Microbiology Laboratory of Virgen de las Nieves University Hospital (Granada, Spain) between January 2016 and December 2025. Antimicrobial susceptibility profiles for both novel agents and conventional antibiotics were analyzed. Results: Twenty-three studies met the inclusion criteria for the systematic review, of which 22 fully accessible articles were analyzed. In the systematic review, Enterobacterales accounted for 70.0% of the reported MBL isolates, with New Delhi metallo-β-lactamase (NDM) being the predominant enzyme globally (50.5%), followed by Verona integron-encoded metallo-β-lactamase (VIM) (39.4%). The crude aggregated in vitro susceptibility proportion across the literature was markedly higher for aztreonam–avibactam than for cefiderocol (93.1% vs. 58.1%). Conversely, in our local urinary cohort (n = 182), Enterobacterales were also the predominant pathogens (51.6%), but VIM was the most frequently detected carbapenemase (n = 107). In this local cohort, aztreonam–avibactam demonstrated 100% in vitro susceptibility against Enterobacterales (54/54) and exhibited a 77.8% wild-type (WT) phenotype against Pseudomonas spp. (35/45). Cefiderocol exhibited excellent activity against Pseudomonas spp. (86.2%, 50/58) but significantly lower susceptibility rates among Enterobacterales (39.6%, 21/53). Among conventional antimicrobials, in vitro susceptibility in Enterobacterales to gentamicin decreased significantly over time (from 62.5% to 32.8%; FDR-adjusted p = 0.029), whereas amikacin in vitro susceptibility significantly improved (from 60.0% to 88.1%; FDR-adjusted p = 0.048). Colistin maintained high susceptibility rates, ranging from 87.8% to 100% in Enterobacterales and 77.8% to 88.2% in Pseudomonas spp. Agents such as nitrofurantoin (restricted exclusively to Escherichia coli) and trimethoprim–sulfamethoxazole or fosfomycin were not evaluated for Pseudomonas spp., due to intrinsic resistance or absence of established EUCAST clinical breakpoints. Conclusions: Aztreonam–avibactam and cefiderocol exhibit promising but highly species-specific in vitro activity against MBL-producing Gram-negative bacteria. While colistin and amikacin remain active conventional in vitro alternatives, these laboratory findings represent potential microbiological potency rather than guaranteed clinical success. Prospective clinical trials and real-world outcome studies remain essential to evaluate the clinical efficacy, patient outcomes, and comparative in vivo effectiveness of these regimens in daily practice.