In-vitro evaluation of Cefiderocol and Ceftazidime/Avibactam against MDR and XDR gram-negative pathogens from clinical isolates, with whole genome sequencing-based analysis of Antimicrobial Resistance Genes in Cefiderocol-resistant Escherichia coli.

PURPOSE: The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacilli (GNB) poses a major therapeutic challenge. This study evaluated the in-vitro activity of cefiderocol and the synergistic potential of ceftazidime/avibactam with aztreonam against MDR and XDR isolates obtained in a tertiary care hospital from South India.

METHODS: A laboratory-based cross-sectional study was conducted with 152 non-duplicate MDR and XDR Gram-negative isolates. Antibiotic susceptibility testing was done by disc diffusion method on Mueller Hinton agar. Carbapenem-resistant isolates were tested for ceftazidime/avibactam-aztreonam synergy using modified E-test/disc diffusion method. Cefiderocol susceptibility was determined in accordance with CLSI 2025 guidelines. Whole genome sequencing (WGS) was performed for cefiderocol-resistant E.coli isolate.

RESULTS: Of the 152 isolates, 78 isolates were MDR (38 E.coli, 37 K.pneumoniae, 3 P.aeruginosa) and 74 were XDR (15 E.coli, 32 K.pneumoniae, 15 P.aeruginosa and 12 A.baumannii). Resistance to carbapenems and ceftazidime/avibactam was observed in 82.2% and 65.7% of isolates, respectively. Cefiderocol exhibited the highest in vitro activity, 99.3% of isolates remaining susceptible. Among 115 carbapenem-resistant isolates, all were resistant to aztreonam, while 74.8% showed ceftazidime/avibactam-aztreonam synergy. WGS result of an E.coli isolate showed multidrug-resistance including cefiderocol resistance due to mutations and insertion of 4 amino acids in FtsL protein.

CONCLUSIONS: Cefiderocol demonstrated excellent in-vitro activity against MDR and XDR GNB, while the ceftazidime/avibactam-aztreonam combination showed strong synergistic activity among Enterobacterales, highlighting their therapeutic potential. WGS of E.coli isolate confirmed the presence of the genetic determinant associated with cefiderocol resistance gene.