Synergistic Activity of Cefiderocol in Combination with Avibactam, Sulbactam or Tazobactam against Carbapenem-Resistant Gram-Negative Bacteria

Abstract

We investigated the activity of cefiderocol/β-lactamase inhibitor combinations against clinical strains with different susceptibility profiles to cefiderocol to explore the potentiality of antibiotic combinations as a strategy to contain the major public health problem of multidrug-resistant (MDR) pathogens. Specifically, we evaluated the synergistic activity of cefiderocol with avibactam, sulbactam, or tazobactam on three of the most "Critical Priority" group of MDR bacteria (carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii). Clinical isolates were genomically characterized by Illumina iSeq 100. The synergy test was conducted with time-kill curve assays. Specifically, cefiderocol/avibactam, /sulbactam, or /tazobactam combinations were analyzed. Synergism was assigned if bacterial grow reduction reached 2 log₁₀ CFU/mL. We reported the high antimicrobial activity of the cefiderocol/sulbactam combination against carbapenem-resistant Enterobacterales, P. aeruginosa, and A. baumannii; of the cefiderocol/avibactam combination against carbapenem-resistant Enterobacterales; and of the cefiderocol/tazobactam combination against carbapenem-resistant Enterobacterales and P. aeruginosa. Our results demonstrate that all β-lactamase inhibitors (BLIs) tested are able to enhance cefiderocol antimicrobial activity, also against cefiderocol-resistant isolates. The cefiderocol/sulbactam combination emerges as the most promising combination, proving to highly enhance cefiderocol activity in all the analyzed carbapenem-resistant Gram-negative isolates, whereas the Cefiderocol/tazobactam combination resulted in being active only against carbapenem-resistant Enterobacterales and P. aeruginosa, and cefiderocol/avibactam was only active against carbapenem-resistant Enterobacterales.

Keywords: carbapenem-resistant Acinetobacter baumannii; carbapenem-resistant Enterobacteriales; carbapenem-resistant Pseudomonas aeruginosa; cefiderocol/avibactam; cefiderocol/sulbactam; cefiderocol/tazobactam.

Figure 1

TKC obtained for CRE, CFD-susceptible (A–C), and CFD-resistant (D–F); for CR-Pa, CFD-susceptible (G–I), and CFD-resistant (J–L); and for CR-Ab, CFD-susceptible (M–O), and CFD-resistant (P–R) with CFD in combination with avibactam (A,D,G,J,M,P), sulbactam (B,E,H,K,N,Q), and tazobactam (C,F,I,L,O,R).

Figure 2

The average (mean R) CFU/mL deviation from null response interaction model for tested cefiderocol (CFD)-β-lactamase inhibitor combinations at 24 h determined by time-kill curve analysis. Negative mean R values are indicative of average synergistic effects; positive values are indicative of average antagonistic effects.