In vitro
activity of cefiderocol against European
Pseudomonas aeruginosa
and
Acinetobacter
spp., including isolates resistant to meropenem and recent β-lactam/β-lactamase inhibitor combinations
Authors: Santerre Henriksen Anne , Jeannot Katy , Oliver Antonio , Perry John D. , Pletz Mathias W. , Stefani Stefania , Morrissey Ian , Longshaw Christopher ,   ARTEMIS Study Investigators, Willinger Birgit , Leyssene David , Cattoen Christian , Alauzet Corentine , Boyer Pierre , Dubois Véronique , Jeannot Katy , Corvec Stephane , Lavigne Jean-Philippe , 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: April 2024

ABSTRACT

Carbapenem-resistant
Pseudomonas aeruginosa
and
Acinetobacter
spp. represent major threats and have few approved therapeutic options. Non-‍fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950
P
.
aeruginosa
; 501
Acinetobacter
spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than ‍β‍-‍l‍a‍c‍t‍a‍m‍/‍β‍-‍l‍a‍c‍t‍a‍mase‍ inhibitor combinations against
P. aeruginosa
(98.9% vs 83.3%–91.4%), and
P. ‍aeruginosa
resistant to meropenem (
n
= 139; 97.8% vs 12.2%–59.7%), β-lactam/β-lactamase inhibitor combinations (93.6%–98.1% vs 10.7%–71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%–‍‍45.0%) or ‍ceftolozane-tazobactam (98.4% vs 8.1%–54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against
Acinetobacter
spp. (92.4% and 97.0%) and meropenem-resistant
Acineto‍bacter
‍spp. (
n
= 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- (
n
‍= 15; 13.3%) and cefiderocol- (
n
= 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant
P. aeruginosa
and
Acinetobacter
spp., the most common β-‍‍lactamase genes were metallo-β-lactamases [30/139;
bla
VIM-2
(15/139)] and oxacillinases [215/227;
bla
OXA-23
(194/227)], respectively. Acquired β-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant
P. aeruginosa
and
Acinetobacter
spp., and
pirA
-like or
piuA
mutations in 10/10 and 37/38, respectively.
Conclusion:
cefiderocol susceptibility was high against
P. aeruginosa
and
Acinetobacter
spp., including meropenem-resistant isolates and those resistant to recent β-lactam/β-lactamase inhibitor combinations common in first-line treatment of European non-fermenters.

IMPORTANCE

This was the first study in which the
in vitro
activity of cefiderocol and non-licensed β-lactam/β-lactamase inhibitor combinations were directly compared against
Pseudomonas aeruginosa
and
Acinetobacter
spp., including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and β-lactam/β-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant
P. aeruginosa
and
Acinetobacter
spp. and indicate how early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.