In vitro activity of cefiderocol against European Enterobacterales, including isolates resistant to meropenem and recentβ-lactam/β-lactamase inhibitor combinations

Abstract

Carbapenem-resistant Enterobacterales represent a major health threat and have few approved therapeutic options. Enterobacterales isolates were collected from hospitalized inpatients from 49 sites in six European countries (1 January-31 December 2020) and underwent susceptibility testing to cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L) and cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-‍resistant isolates by whole-genome sequencing, to identify resistance mechanisms. Overall, 1,909 isolates (including 970 Klebsiella spp., 382 Escherichia coli, and 244 Enterobacter spp.) were collected, commonly from bloodstream infections (43.6%). Cefiderocol susceptibility was higher than approved β-lactam/β-lactamase inhibitor combinations and largely comparable to cefepime-taniborbactam and aztreonam-avibactam against all Enterobacterales (98.1% vs 78.1%-‍97.4% and 98.7%-99.1%, respectively) and Enterobacterales resistant to meropenem (n = 148, including 125 Klebsiella spp.; 87.8% vs 0%-71.6% and 93.2%-98.6%, respectively), β-lactam/β-lactamase inhibitor combinations (66.7%-‍92.1% vs 0%-‍88.1% and 66.7%-97.9%, respectively), and to both meropenem and β-‌lactam/β-lactamase inhibitor combinations (61.9%-65.9% vs 0%-‍20.5% and 76.2%-97.7%, respectively). Susceptibilities to approved and developmental β-lactam/β-lactamase inhibitor combinations against cefiderocol-resistant Enterobacterales (n = 37) were 10.8%-‍56.8% and 78.4%-94.6%, respectively. Most meropenem-resistant Enterobacterales harbored Klebsiella pneumoniae carbapenemase (110/148) genes, although metallo-β-lactamase (35/148) and oxacillinase (OXA) carbapenemase (6/148) genes were less common; cefiderocol susceptibility was retained in β-lactamase producers, other than NDM, AmpC, and non-carbapenemase OXA producers. Most cefiderocol-resistant Enterobacterales had multiple resistance mechanisms, including ≥1 iron uptake-related mutation (37/37), carbapenemase gene (33/37), and ftsI mutation (24/37). The susceptibility to cefiderocol was higher than approved β-lac‌tam/β-lactamase inhibitor combinations against European Enterobacterales, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates.

Importance: This study collected a notably large number of Enterobacterales isolates from Europe, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates against which the in vitro activities of cefiderocol and developmental β-lactam/β-lactamase inhibitor combinations were directly compared for the first time. The MIC breakpoint for high-dose meropenem was used to define meropenem resistance, so isolates that would remain meropenem resistant with doses clinically available to patients were included in the data. Susceptibility to cefiderocol, as a single active compound, was high against Enterobacterales and was higher than or comparable to available β-lactam/β-lactamase inhibitor combinations. These results provide insights into the treatment options for infections due to Enterobacterales with resistant phenotypes. Early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow patients to receive the most appropriate treatment option(s) available in a timely manner. This is particularly important when options are more limited, such as against metallo-β-lactamase-producing Enterobacterales.

Keywords: Enterobacterales; Europe; Klebsiella pneumoniae; aztreonam-avibactam; cefepime-taniborbactam; cefiderocol; ceftazidime-avibactam; ceftolozane-tazobactam; imipenem-relebactam; meropenem; meropenem-vaborbactam; resistance.

Fig 1

Cumulative MIC distributions of cefiderocol, BLBLI combinations, and other relevant antibiotics against meropenem-resistant Enterobacterales isolates (n = 148). Imipenem-relebactam data exclude Morganellaceae, and colistin data exclude Morganellaceae and Serratia spp. Data on colistin activity are shown as dashed lines as colistin is not recommended for monotherapy and is not associated with a clinical monotherapy breakpoint (as per EUCAST v.14.0 guidance); ECOFF values were used to define the proportion of isolates that could be considered wild-type strains, i.e., those without phenotypically detectable acquired resistance mechanisms. Resistance to meropenem was defined using a breakpoint of MIC >8 mg/L, relating to high-dose, extended-infusion (2 g, 3-h infusion) meropenem (as per EUCAST v14.0 guidance). ^aN = 146 for imipenem-relebactam and colistin. ATM-AVI, aztreonam-avibactam; BLBLI, β‑lactam/β‑lactamase inhibitor; CST, colistin; C‑T, ceftolozane‑tazobactam; CZA, ceftazidime-avibactam; ECOFF, epidemiological cut-off; EUCAST, European Committee on Antimicrobial Susceptibility Testing; FDC, cefiderocol; FEP-TAN, cefepime-taniborbactam; I-R, imipenem-relebactam; and MVB, meropenem-vaborbactam.