In vitro
activity of cefiderocol against European Enterobacterales, including isolates resistant to meropenem and recentβ-lactam/β-lactamase inhibitor combinations
Authors: Santerre Henriksen Anne , Arena Fabio , Attwood Marie , Canton Rafael , Gatermann Sören , Naas Thierry , Morrissey Ian , Longshaw Christopher ,   ARTEMIS Study Investigators, Willinger Birgit , Leyssene David , Cattoen Christian , Alauzet Corentine , Boyer Pierre , Dubois Véronique , Jeannot Katy , Corvec Stephane , Pantel Alix , Guillard Thomas , Gontier Audrey Merens , Naas Thierry , Rohde Holger , Ziesing Stefan , Imirzalioglu Can , Hunfeld Klaus-Peter , Jung Jette , Gatermann Sören , Pletz Mathias , Bianco Gabriele , Giammanco Anna , Carcione Davide , Raponi Giammarco , Matinato Caterina , Domenico Enea Gino Di , Gaibani Paolo , Marchese Anna , Arena Fabio , Niccolai Claudia , Stefani Stefania , Pitart Cristina , Barrios Jose Luis , Cercenado Emilia , Bou German , Lopez Alicia Beteta , Canton Rafael , Hontangas Jose Lopez , Gracia-Ahufinger Irene , Oliver Antonio , Lopez-Cerero Lorena , Larrosa Nieves , Wareham David , Perry John , Casey Anna , Nahl Jasvir , Hughes Daniel , Coyne Michael , Lister Michelle , Attwood Marie 
Published: June 2024

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.