{Reference Type}: Journal Article
{Title}: In vitro activity of cefiderocol against European Enterobacterales, including isolates resistant to meropenem and recentβ-lactam/β-lactamase inhibitor combinations.
{Author}: Santerre Henriksen A;Arena F;Attwood M;Canton R;Gatermann S;Naas T;Morrissey I;Longshaw C; ;
{Journal}: Microbiol Spectr
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 21
{Factor}: 9.043
{DOI}: 10.1128/spectrum.04181-23
{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.
OBJECTIVE: 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.