In vitro activity of cefiderocol against a global collection of carbapenem-resistant Pseudomonas aeruginosa with a high level of carbapenemase diversity

Abstract

Objectives: To determine the in vitro activity of cefiderocol in a global collection of carbapenem-resistant Pseudomonas aeruginosa including >200 carbapenemase-producing isolates.

Methods: Isolates (n = 806) from the ERACE-PA Surveillance Program were assessed. Broth microdilution MICs were determined for cefiderocol (iron-depleted CAMHB) and comparators (CAMHB). Susceptibility was interpreted by CLSI and EUCAST breakpoints and reported as percent of isolates. The MIC distribution of cefiderocol in the entire cohort and by carbapenemase status was assessed.

Results: In the entire cohort, cefiderocol was the most active agent (CLSI 98% susceptible; EUCAST 95% susceptible; MIC50/90, 0.25/2 mg/L). Amikacin (urinary only breakpoint) was the second most active, with 70% of isolates testing as susceptible. The percentage of isolates susceptible to all other agents was low (<50%) including meropenem/vaborbactam, imipenem/relebactam, piperacillin/tazobactam and levofloxacin. Cefiderocol maintained significant activity against the most commonly encountered carbapenemases including VIM- (CLSI 97% susceptible; EUCAST 92% susceptible) and GES (CLSI 100% susceptible; EUCAST 97% susceptible)-harbouring isolates. The cefiderocol MIC distribution was similar regardless of carbapenemase status, with MIC50/90 values of 0.5/4 mg/L, 0.5/2 mg/L and 0.25/1 mg/L for MBL, serine carbapenemase and molecular carbapenemase-negative isolates, respectively.

Conclusions: Cefiderocol displayed potent in vitro activity in this global cohort of carbapenem-resistant P. aeruginosa including >200 carbapenemase-harbouring isolates. Cefiderocol was highly active against MBL-producing isolates, where treatment options are limited. These data can help guide empirical therapy guidelines based on local prevalence of carbapenemase-producing P. aeruginosa or in response to rapid molecular diagnostics.

Figure 1.

Proportion of isolates by cefiderocol MIC (mg/L). (a) Proportion of isolates by cefiderocol MIC for all included isolates (MIC₅₀, 0.25 mg/L; MIC₉₀, 2 mg/L; 98% susceptible per CLSI; 95% susceptible per EUCAST). (b) Proportion of isolates by cefiderocol MIC by molecular carbapenemase result (Carba-R NxG). MBL-positive: MIC₅₀, 0.5 mg/L; MIC₉₀, 4 mg/L; 97% susceptible per CLSI; 89% susceptible per EUCAST. Serine carbapenemase-positive: MIC₅₀, 0.5 mg/L; MIC₉₀, 2 mg/L; 100% susceptible per CLSI; 97% susceptible per EUCAST. Molecularly carbapenemase negative: MIC₅₀, 0.25 mg/L; MIC₉₀, 1 mg/L; 99% susceptible per CLSI; 96% susceptible per EUCAST.