In Vitro Activity of Cefiderocol Against Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa

Abstract

The objective of this study was to assess the susceptibility of cefiderocol against multidrug-resistant carbapenemase-producing and nonproducing bacteria. The panel comprised 182 isolates of the order Enterobacterales, and 40 strains of Pseudomonas aeruginosa. Antimicrobial susceptibility testing has been performed using broth microdilution method according to the European Committee on Antimicrobial Susceptibility Testing recommendations. Mass spectrometry matrix-assisted laser desorption/ionization-time of flight mass spectrometry and carbapenemase-producing test were used to verify the presence of carbapenemases in clinical isolates. The genetic expression of single carbapenemases (bla_KPC, bla_OXA-48, bla_NDM, bla_VIM, bla_IMP, bla_GES) was determined by real-time polymerase chain reaction. Cefiderocol exhibited a good activity against the majority of strains tested in this study. Altogether, growth of 81.9% (n = 149) strains of the order Enterobacterales and 77.5% (n = 31) of P. aeruginosa isolates were inhibited at minimal inhibitory concentration (MIC) ≤2 mg/L. Values MIC₅₀/MIC₉₀ were 0.5/8 mg/L for enterobacteria, and 1/8 mg/L for P. aeruginosa. One isolate (Klebsiella pneumoniae) harboring two carbapenemases (bla_OXA-48, bla_NDM) had cefiderocol MIC 0.5 mg/L. In enterobacteria resistant to cefiderocol, bla_NDM carbapenemase prevailed (43.3%, n = 29), followed by bla_OXA-48 (31.3%, n = 21) and bla_KPC (4.5%, n = 3). bla_IMP (n = 8) and bla_VIM (n = 1) metallo-β-lactamases dominated in cefiderocol-resistant P. aeruginosa (n = 9) isolates. Very good susceptibility (100%) to this drug showed bla_GES-positive strains of P. aeruginosa (n = 8) and isolates resistant to meropenem without confirmed carbapenemase gene (n = 10). In this study, cefiderocol demonstrated potent activity against important nosocomial pathogens, therefore, therapeutic options of this drug against multidrug-resistant bacteria should be considered.

Keywords: Enterobacterales; Pseudomonas aeruginosa; carbapenemase; cefiderocol.

FIG. 1.

Distribution of 182 strains of Enterobacterales according to the MICs (mg/L) of cefiderocol. Ten species of the order Enterobacterales were included in the study: Citrobacter braakii (n = 1), Citrobacter freundii (n = 8), Enterobacter cloacae complex (n = 16), Escherichia coli (n = 33), Klebsiella oxytoca (n = 1), Klebsiella pneumoniae (n = 115), Moraganella morganii (n = 1), Proteus mirabilis (n = 3), Providencia stuartii (n = 1), Serratia marcescens (n = 3). Axis x represents MICs ranges of cefiderocol from ≤0.125 to ≥8 of strains examined in this study, y axis depicts the percentage of isolates belonging to a corresponding MIC. MIC, minimum inhibitory concentration.

FIG. 2.

Antibiotic profiles of cefiderocol-resistant strains (n = 33) belonging to the order Enterobacterales. Broth microdilution method was used to examine the susceptibility of isolates to single antibiotic (EUCAST methodology). R, resistance to the tested antibiotic; I, susceptible, with increased exposure; S, susceptibility to the tested antibiotic. *Isolates intrinsically resistant to ampicillin and ampicillin-sulbactam were excluded from the table (n = 28): Citrobacter freundii (n = 1), Enterobacter cloacae complex (n = 1), Klebsiella pneumoniae (n = 26). AMI, amikacin; AMP, ampicillin; AMS, ampicillin-sulbactam; CAA, ceftazidime-avibactam; CIP, ciprofloxacin; COL, colistin; COT, trimethoprim-sulfamethoxazole; CPM, cefepime; CTT, ceftolozane-tazobactam; CTX, cefotaxime; CTZ, ceftazidime; CXT, cefoxitin; EUCAST, European Committee on Antimicrobial Susceptibility Testing; GEN, gentamicin; MER, meropenem; PPT, piperacillin-tazobactam; TOB, tobramycin; TRI, trimethoprim.

FIG. 3.

Distribution of 40 isolates of Pseudomonas aeruginosa according to the MICs (mg/L) of cefiderocol. Axis x represents MICs ranges of cefiderocol from ≤0.125 to ≥8 of strains examined in this study, y axis depicts the percentage of isolates belonging to a corresponding MIC.

FIG. 4.

Antibiotic profiles of cefiderocol-resistant (n = 9) Pseudomonas aeruginosa isolates. Antibiotic susceptibility of isolates was measured with broth microdilution method (EUCAST methodology). R, resistance to the tested antibiotic; S, susceptibility to the tested antibiotic. LEV, levofloxacin; MER, meropenem; PPT, piperacillin-tazobactam; TOB, tobramycin.