In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects

To assess the in vitro activity of cefiderocol (CFDC) against a collection of both ceftazidime-avibactam (CZA) susceptible and resistant KPC-producing Enterobacterales (KPC-EB) isolates. Secondly, to assess its synergistic activity in combination with different antibiotics.One hundred KPC-EB isolates were tested: 60 CZA susceptible and 40 CZA resistant. Among them, 17 pairs of CZA susceptible and resistant KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates were collected from 17 distinct patients before and after CZA treatment, respectively. CFDC susceptibility was evaluated by both broth microdilution (lyophilized panels; Sensititre; Thermo Fisher) and disk diffusion testing. Results were interpreted using EUCAST breakpoints. Synergistic activity of CFDC in combination with CZA, meropenem-vaborbactam, imipenem, and amikacin against six characterized KPC-Kp strains, before and after acquisition of CZA resistance, was evaluated using gradient diffusion strip crossing method.CFDC resistance rate was significantly higher in CZA resistant EB subset than in the susceptible one (p < 0.001): 82.5% vs 6.7%. MIC50 and MIC90 values were 0.25 and 2 mg/L, 8 and 64 mg/L in CZA-susceptible and CZA-resistant subset, respectively. KPC-Kp isolates harboring KPC-D179Y or KPC-Δ242-GT-243 variants showed CFDC MICs ranging from 4 to 64 mg/L. CFDC showed in vitro synergistic effect mostly with CZA, against both CZA susceptible and resistant isolates, resulting in a synergy rate of 66.7%.CZA resistance mechanisms in KPC-EB impair the in vitro activity of CFDC, often leading to co-resistance. CFDC in combination with the new β-lactamases inhibitors might represent a strategy to enhance its activity.