Next Article in Journal
Occurrence and Molecular Characterization of Multidrug-Resistant Vegetable-Borne Listeria monocytogenes Isolates
Next Article in Special Issue
Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence
Previous Article in Journal
Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors
Previous Article in Special Issue
Surveillance and Genomic Analysis of Third-Generation Cephalosporin-Resistant and Carbapenem-Resistant Klebsiella pneumoniae Complex in Germany
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 11
Issue 10
10.3390/antibiotics11101352
antibiotics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium

by
Saoussen Oueslati
1,2,3,
Pierre Bogaerts
4,
Laurent Dortet
1,2,3,
Sandrine Bernabeu
1,2,
Hend Ben Lakhal
5,
Christopher Longshaw
6,
Youri Glupczynski
4 and
Thierry Naas
1,2,3,*
1
Team ReSIST, LabEx LERMIT, INSERM U1184, School of Medicine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France
2
Bacteriology-Hygiene Unit, Assistance Publique/Hôpitaux de Paris, Bicêtre Hospital, 94270 Le Kremlin-Bicêtre, France
3
French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, 94270 Le Kremlin-Bicêtre, France
4
Laboratory of Clinical Microbiology, National Reference Center for Monitoring Antimicrobial Resistance in Gram-Negative Bacteria, CHU UCL Namur, 5530 Yvoir, Belgium
5
Centre Hospitalier d’Orsay, Service de Réanimation, 91400 Orsay, France
6
Medical Affairs Europe, Shionogi Europe, London WC2B 6UF, UK
*
Author to whom correspondence should be addressed.
Antibiotics 2022, 11(10), 1352; https://doi.org/10.3390/antibiotics11101352
Submission received: 12 August 2022 / Revised: 28 September 2022 / Accepted: 28 September 2022 / Published: 4 October 2022
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Jordi Vila—Outstanding Contributions in the Fields of Antimicrobial Resistance)
Versions Notes

Abstract

:
Infections with carbapenem-resistant (CR) Gram-negative (GN) pathogens have increased in many countries worldwide, leaving only few therapeutic options. Cefiderocol (CFDC) is approved in Europe for the treatment of aerobic GN infections in adults with limited treatment options. This study evaluated the in vitro activity of cefiderocol and comparators against multidrug-resistant (MDR) bacteria including meropenem-resistant (MR) or pandrug-resistant (PR) GN clinical isolates from France and Belgium. The minimum inhibitory concentrations (MICs) of CFDC were determined by broth microdilution, using iron-depleted cation-adjusted Mueller–Hinton broth, and were compared to those of 10 last-line antibiotics. The MICs were interpreted according to EUCAST and CLSI breakpoints, and in the absence of species-specific breakpoints, non-species-related pharmacokinetic/pharmacodynamic breakpoints were used. Among the 476 isolates tested, 322 were carbapenemase producers (CP), 58 non-CP-CRs, 52 intrinsically CR, 41 expanded-spectrum cephalosporin resistant and 5 were multi-susceptible. Susceptibility to CFDC was high using EUCAST breakpoints 81%, 99% and 84%, and was even higher using CLSI breakpoints to 93%, 100% and 88% for Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii, respectively. Susceptibility to cefiderocol using non-species-related breakpoints for Stenotrophomonas maltophilia, Achromobacter xylosoxydans and Burkholderia cepacia, was 100%, 100% and 92.3%, respectively. The susceptibility rates were lower with the NDM producers, with values of 48% and 30% using EUCAST breakpoints and 81% and 50% using CLSI breakpoints for Enterobacterales and Acinetobacter spp, respectively. CFDC demonstrated high in vitro susceptibility rates against a wide range of MDR GN pathogens, including MR and PR isolates.

1. Introduction

Among the antimicrobial agents that belong to the class of beta-lactams, carbapenems display the broadest spectrum of antimicrobial activities and are considered last-resort agents to treat infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales and multidrug-resistant (MDR) Gram-negative bacilli (GNB) [1,2,3,4]. However, their activity is challenged by the emergence and dissemination of carbapenem-resistant Enterobacterales (CRE) and non-fermenters such as Pseudomonas aeruginosa and Acinetobacter baumannii [5,6]. Antibiotic resistance among GNB poses a substantial global threat to patients and healthcare systems, often leading to an increased duration of hospital stays, higher medical costs and increased rates of mortality [1,2,3,4].
Carbapenem resistance may be the result of combined mechanisms of both outer-membrane permeability defects (e.g., porin defects) and non-carbapenemase β-lactamases (e.g., acquired or overexpressed chromosome-encoded cephalosporinase, and ESBLs) and carbapenemase production [7]. In France, there has been a steady increase in the spread of carbapenemase-producing Enterobacterales (CPE) in recent years [8,9]. The carbapenemases reported among CPE include KPC, NDM, VIM and OXA-48, and although KPC is prevalent in other European countries, OXA-48 remains the most common carbapenemase in France [8,9,10]. Furthermore, a 2018 report from the French National Reference Center (F-NRC) for CPEs showed a notable increase in isolates producing MBLs such as NDM and VIM, as well as the ongoing diversification of OXA-48-type carbapenemases, especially OXA-181 and OXA-244 variants [9,11,12]. These findings, along with the first isolation of IMP-producing Enterobacterales, highlight the evolving and challenging epidemiology of carbapenemases among Enterobacterales in France, and at a larger level in Europe [9,10].
Although the prevalence of infections caused by non-fermenting GN pathogens such as A. baumannii, P. aeruginosa and Stenotrophomonas maltophilia has remained relatively low in France and Belgium, rates of carbapenem resistance among these pathogens are considerably higher than those reported for Enterobacterales [11,13]. Among the 954 P. aeruginosa isolates submitted to the F-NRC of antibiotic resistances in 2018, 16.2% produced an ESBL (PER-1, SHV-2a, GES, VEB, OXA), 15.1% were carbapenemase producers (VIM, IMP, DIM, GES) and 2.8% of isolates produced both [11]. Similarly, among the 379 isolates of A. baumannii, 96.6% expressed at least one carbapenemase (primarily OXA-23, OXA-72 and NDM-1) together with an ESBL in 2.1% of the isolates [11]. The high levels of resistance among non-fermenters, particularly to carbapenems, reduce the arsenal of effective therapeutics, often making treatment more problematic [2,13,14].
Therapeutic options for carbapenem-resistant (CR) GNB infections in general are limited and many CR pathogens exhibit MDR phenotypes, including all β-lactams (e.g., cephalosporins and penicillins), and other common drug classes such as aminoglycosides and fluoroquinolones [13,14,15]. Furthermore, there has been a consistent rise in the annual number of extensively drug-resistant (XDR) CPEs identified in France since 2012 [8,9,11]. These emerging pathogens are resistant even to last-resort antibiotics such as colistin, or to newly released antibiotics, and are a source of great concern for the treatment of patients [16,17].
Cefiderocol (CFDC) is a novel siderophore cephalosporin developed for the treatment of infections caused by GNB, including those resistant to carbapenems [18]. CFDC is approved in the USA for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, hospital-acquired pneumonia and ventilator-acquired pneumonia caused by susceptible Gram-negative microorganisms, and has recently been approved in Europe for the treatment of infections caused by aerobic GNB in adults with limited or no alternative treatment options [18,19]. The structure of CFDC is based around a cephalosporin backbone with the addition of a catechol moiety at the three-position side chain [20,21]. The cephalosporin core enables CFDC to act like other cephalosporins, binding primarily to penicillin-binding proteins and killing bacterial cells by inhibiting peptidoglycan cell wall biosynthesis, and the catechol moiety chelates ferric (Fe-III) iron, mimicking natural siderophores, allowing CFDC to exploit the bacteria’s own active receptor-mediated iron transport system to cross the outer membrane [20,21]. The resulting increase in the periplasmic concentration circumvents non-specific resistance due to porin loss or efflux and enhances CFDC’s activity relative to carbapenems, other cephalosporins and β-lactam/β-lactamase inhibitor combinations [22]. CFDC is active against CR-GNB, including those with derepressed AmpC and/or ESBLs plus porin/efflux pump resistance mechanisms as well as those harboring carbapenemases from different Ambler classes, including KPC, VIM, IMP, NDM and OXA carbapenemases [22,23,24,25,26,27,28,29]. Activity has also been demonstrated against meropenem-resistant and MDR P. aeruginosa and A. baumannii [28,29,30].
Here, we report the antimicrobial activity of CFDC and comparators (aztreonam, amikacin, cefepime, ceftazidime, ceftazidime–avibactam, ceftolozane–tazobactam, ciprofloxacin, meropenem, colistin and tigecycline) against a panel of 476 mostly MDR GNB collected from hospitals in France and Belgium between 2012 and 2019, thus before any clinical use of CFDC (Table 1).

2. Results

2.1. Activity of Cefiderocol

The in vitro activity of CFDC and comparators was assessed in 476 Gram-negative isolates collected from two National Reference Centers (NRC) for AMR located in France and Belgium (Table 1). The 222 (46.6%) Enterobacterales isolates were from the French NRC for CREs and the remaining 254 (53.4%) bacteria came equally from the two NRCs. These isolates were MDR and of reduced susceptibility/resistant to carbapenems.
Susceptibility to CFDC was high for all the tested MDR GNB (Table 2). Susceptibility to CFDC using EUCAST breakpoints (<2 mg/L) was 81%, 99% and 84%, which rose with the investigational CLSI breakpoints (<4 mg/L) to 93%, 100% and 88% for Enterobacterales, P. aeruginosa and A. baumannii, respectively (Table 2) [31,32]. Susceptibility to CFDC using EUCAST non-species-related breakpoints for S. maltophilia, A. xylosoxydans and B. cepacia were 100%, 100% and 92.3%, respectively. The susceptibility rates were lower with NDM producers, with values of 48% and 30% using EUCAST breakpoints [31] and 81% and 50% using CLSI breakpoints [32,33] for Enterobacterales and A. baumannii, respectively.
The MIC50 and MIC90 values for CFDC and comparators are reported by pathogen in Table 3 and Table 4.
Among all Enterobacterales, the susceptibility rates to CFDC (81%) were comparable to those for colistin (84%) and tigecycline (73%); on the other hand, a higher proportion of Enterobacterales isolates were susceptible to CFDC than to ceftazidime/avibactam (63%) and ceftolozane/tazobactam (19%). Among the non-fermenting GNB, 84% of the A. baumannii isolates were susceptible to CFDC, which was higher than all other comparators apart from colistin (88%), and 99% of P. aeruginosa isolates were susceptible to CFDC, which was higher than all other comparators also including colistin (97%).

2.2. Cefiderocol Activity among Enterobacterales Isolates

The MIC50 of CFDC was at 1 mg/L, while those of other drugs were >64 mg/L for ceftazidime, 64 mg/L for ceftolozane–tazobactam, >32 mg/L for aztreonam, >16 mg/L for cefepime, 8 mg/L for meropenem and amikacin, >4 mg/L for ciprofloxacin, 4 mg/L for ceftazidime–avibactam, ≤0.25 mg/L for tigecycline and ≤0.5 mg/L for colistin.
The MIC90 for the Enterobacterales of CFDC was 4 mg/L (Table 3), while those of the comparator antibiotics were >64 mg/L for ceftolozane–tazobactam, meropenem, ceftazidime, ceftazidime–avibactam and amikacin; >32 mg/L for aztreonam; >16 mg/L for cefepime; >8 mg/L for colistin; >4 mg/L for ciprofloxacin; and 2 mg/L for tigecycline.
Among the 80 meropenem-susceptible isolates (MIC ≤ 2 mg/L), 10 (12.5%) were resistant to CFDC and 8 (10%) were resistant to ceftazidime–avibactam. Among the 44 meropenem intermediate isolates (considered susceptible with increased dosing regimen (MIC of 4 and 8 mg/L)), 6 (13.6%) were resistant to CFDC and 17 (38.6%) were resistant to ceftazidime–avibactam. Finally, with the 98 meropenem-resistant isolates (MIC > 8 mg/L), 27 (27.5%) were resistant to CFDC while 58 (59.2%) were resistant to ceftazidime–avibactam. Among the latter, 37 (64%) were still susceptible to CFDC. Among the 27 CFDC-resistant isolates, 18 were NDM producers.
Non-CP-producing Enterobacterales isolates with a reduced susceptibility to carbapenems had a susceptibility rate of 85% to CFDC, which was globally comparable to the susceptibility rates observed for ceftazidime–avibactam (90%), amikacin (81%) and colistin (79%).
A total of 92% of the KPC producers were susceptible to CFDC, with an MIC50/90 of 1/4 mg/L, results that are similar to those of ceftazidime/avibactam (94% susceptibility, and an MIC50/90 of 2/8). The only other competitive comparators were amikacin (76%), tigecycline (76%) (0.5/1) and colistin (62%) (0.5/>8). For all the other antibiotics, the MIC50/90 values were superior or equal to the upper limit of the concentration range used in the MIC testing.
OXA-48-like producing Enterobacterales were susceptible to a larger number of antibiotics compared with the KPC producers (Table 3). A total of 90% of the OXA-48-like producers were susceptible to CFDC, with low MIC50/90 values of 1 and 2 mg/L, respectively. Its direct competitors were ceftazidime–avibactam (96%; 1/8), meropenem (78% S+I; 4/32), amikacin (90%; ≤4/8), colistin (94%; ≤0.5/1) and tigecycline (75%; ≤0.5/2).
In total, 69% of the Enterobacterial isolates producing NDM, VIM or IMP carbapenemases (Table 3) were susceptible to CFDC with an MIC50/90 of 2/8 mg/L. The only comparator antibiotics with high susceptibility rates were colistin (91%; ≤0.5/1) and tigecycline (75%; ≤0.25/2).

2.3. Cefiderocol Activity against Meropenem-Resistant Non-Fermenters

Carbapenemase-producing P. aeruginosa were susceptible only to CFDC (0.25/1) and to colistin (1/2) (Table 3). The same resistance trend was observed for carbapenemase-producing A. baumannii strains (CFDC (1/8) and colistin (1/4)), except that the latter were also susceptible to tigecycline (1/2) (Table 3). The only unexpected result was the overall low activity of ceftolozane–tazobactam against those non-CP P. aeruginosa isolates (48.4% of susceptibility).
Among the 120 P. aeruginosa isolates tested, only one isolate exhibited an MIC value of CFDC of 4 mg/L, which is considered resistant by EUCAST, but still susceptible by CLSI. Noteworthy, in P. aeruginosa, CFDC was active against all MBL producers, while all comparators were below 20% except for colistin (97%). Thirteen A. baumannii (15.9%) had MICs > 2 mg/L, among which seven were NDM producers, three were ESBL producers (two PER and one VEB) and three were OXA-23 producers.

2.4. Cefiderocol Activity against Intrinsically Meropenem-Resistant Non-Fermenters

Among the intrinsically meropenem-resistant non-fermenters (S. maltophilia, A. xylosoxidans, Elizabethkingia spp.) or frequently meropenem-resistant non-fermenters (B. cepacia), 51 of the 52 isolates (98%) were susceptible to CFDC (Table 4).
Overall, a higher proportion of meropenem-resistant non-fermenters were susceptible to CFDC than to any of the other comparator antimicrobials tested (Table 4). Minocyclin for S. maltophilia (100% both), ceftazidime–avibactam for B. cepacia (92.3% vs. 69.2%) and colistin for A. xylosoxidans (100% vs. 33.3%) were the best comparators.

3. Discussion

In the French SIDERO-WT study, CFDC displayed excellent in vitro activity, but since only very few meropenem-resistant Enterobacterales were included, it was not possible to assess CFDC activity versus other antimicrobials as comparators for these isolates [29]. In the present evaluation of 476 GNB isolates, of which 472 were MDR, from France and Belgium (of which 66% were meropenem R (MIC > 8 mg/L)), CFDC demonstrated substantial in vitro activity. These isolates were from hospitals in France and Belgium and were mainly isolated in 2018 and 2019, thus before any clinical use of CFDC. Notably, CFDC demonstrated substantial activity against all isolates of P. aeruginosa, most A. baumannii and intrinsically meropenem-resistant GN non-fermenters such as S. maltophilia and A. xylosoxidans, where all other comparators demonstrated much lower susceptibility rates. Overall, more isolates were susceptible to CFDC than to a key subset of other currently available antimicrobial agents including the β-lactam/β-lactamase inhibitor combinations ceftazidime–avibactam and ceftolozane–tazobactam, and colistin, which is often considered a last resort molecule for MDR GNB infections.
Carbapenem resistance among GNB in France is steadily rising and poses a substantial threat to patients and healthcare systems, often leading to greater rates of mortality, morbidity and increased burden on hospitals [8,9,11]. In France and Belgium, OXA-48 remains the most common carbapenemase reported nationally among CPEs [8,9,11]. The OXA-48 variants, OXA-181 and the difficult-to-detect OXA-244 are increasingly isolated among CPEs, including ESBL producers. There is now increasing concern over the emergence of OXA-48-mediated resistance to new antibiotic regimens such as ceftazidime–avibactam [34]. Therefore, there is a continued need for new antibiotics and antibiotic regimens with activity against OXA-48-like producers, among others. Despite the dominance of OXA-48 in France and Belgium, over recent years there has been a notable shift in resistance mechanisms, with an increase in MBL producers such as NDM and VIM [8,9,11] and the first isolation of IMP-producing Enterobacterales. This shift to MBL-mediated resistance is of concern as new β-lactam/β-lactamase inhibitor combination therapies, including ceftazidime–avibactam, ceftolozane–tazobactam and meropenem–vaborbactam, are known to lack efficacy against MBLs. As such, these agents cannot be proposed for empirical treatment against infections that are suspected to involve MBL-producing GNB [35,36]. Previous reports from the SIDERO-WT study have shown potent in vitro activity of CFDC against carbapenemase-producing isolates including MBL producers [27,29]. In these studies, only a few MBL producers were included. Here, in our study, 54 MBLs, among which were 21 NDM producers, were studied. Only 50% of the NDM-producing Enterobacterales were susceptible, which was yet much higher than the comparators, except for colistin and tigecycline. In general, MICs for cefiderocol with Enterobacterales-producing MBLs are close to the breakpoints with 28% (n = 15) with an MIC = 1 mg/L, 20% (n = 11) with an MIC = 2 mg/L, and 20% (n = 11) with an MIC = 4 mg/L. A possible explanation for these higher MICs as compared to other carbapenemases [37] is likely due to the fact that MBLs and especially NDM have stronger hydrolytic activity against expanded-spectrum cephalosporins, including CFDC, as suggested by the addition the MBL inhibitor, dipicolinic acid, that reduced the MICs of CFDC against previously non-susceptible Enterobacterales isolates [38]. Based on resistance reports, the increased copy number of NDM may increase CFDC MIC values in the absence of CirA mutations, which is the iron transporter involved in CFDC uptake. However, when NDM overexpression is associated with mutations of the cirA gene, a loss of fitness was observed in these isolates. Of note, the combination of mutations in the iron transport genes and the expression of the NDM enzyme was found in CREs in China, way before CFDC was used in clinical practice [39]; thus, it has been suggested that resistance to CFDC may be the consequence of previous antibiotic treatments, to cancer therapies or to so far unknown mechanisms of selection [40,41,42].
Furthermore, in instances where resistance is not due to carbapenemase production, CFDC has demonstrated in vitro activity against isolates with AmpC, ESBLs, porin mutations and efflux pump upregulation.
Although the prevalence of infections caused by non-fermenting GNB currently remains relatively low in France, there is growing concern regarding the high propensity of these isolates to develop resistance, and the resulting depletion of available effective treatment options [13,43]. In this study, the CFDC activity exceeded that of all the tested comparators except colistin against meropenem-resistant isolates of S. maltophilia, P. aeruginosa and A. baumannii.
These findings are in line with previous reports in other countries, which demonstrated the potent in vitro activity of CFDC against MDR Enterobacterales, MDR A. baumannii, MDR P. aeruginosa and S. maltophilia [37,44]. Additionally, novel agents such as ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam have recently been approved against antibiotic-resistant GNB as they are effective against Enterobacterales-producing KPC but have limited or no efficacy against CR A. baumannii [35,43].
Overall, there are very few antimicrobial agents available to clinicians to treat patients infected with CR GNB, and the agents that are available are often associated with considerable toxicities and increasing resistance. Colistin is effective against a wide range of CR-GNB, and in this study, colistin was the only agent with comparable activity to CFDC against non-fermenters collected from patients with nosocomial pneumonia or bloodstream infections (BSI). However, the usage of colistin is associated with a potential risk of nephro- and neurotoxicity [45] and several species of Enterobacterales have demonstrated intrinsic colistin resistance. Additionally, in this study, fewer meropenem-resistant S. maltophilia isolates were susceptible to colistin than to CFDC. The in vivo results confirmed the excellent behavior of CFDC for the treatment of MDR GNB in bloodstream infections [46,47,48,49,50,51]. CFDC has also shown to be a promising new treatment option for patients with bone and joint infections due to CR A. baumannii and appears to be well tolerated for prolonged durations [49,50].

4. Materials and Methods

4.1. Bacteria

The tested isolates (Table 1) were from the French and Belgium National Reference Centers for antibiotic resistances among GNB and comprised (i) 222 isolates of Enterobacterales, selected to represent diverse carbapenemase producers and isolates with carbapenem resistance via combinations of porin loss with AmpC or ESBL activity; (ii) 120 isolates of P. aeruginosa, selected to represent producers of MBLs and GES carbapenemases, along with isolates that produced ESBLs and were carbapenem-resistant via porine OprD loss; (iii) 82 MDR isolates of A. baumannii expressing various carbapenemases, including NDM and/or various OXA carbapenemases; and (iv) 52 GNB naturally resistant to carbapenems: 25 S. maltophilia, 13 B. cepacia, 12 A. xylosoxidans and 2 Elizabethkingia sp.
These isolates were selected by both NRCs to represent the French and Belgium epidemiology of carbapenem-resistant GNB and challenging isolates expressing rare carbapenemases. As CFDC had not previously been tested, these isolates were chosen based on their carbapenem/expanded spectrum susceptibility profiles and their enzymatic content. Almost all the isolates tested were submitted for an investigation of MDR/XDR resistance phenotypes by hospital laboratories in France and Belgium between 2012 and 2019, thus before any clinical use of CFDC. Carbapenemases and ESBL enzymes were identified by PCR of their encoding genes or by whole-genome sequencing (WGS). Carbapenem resistance due to porin loss combined with ESBL or AmpC activity was inferred from previous susceptibility results and the absence of carbapenemase, as confirmed by PCR or WGS. Species identification was by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy.

4.2. Antimicrobial Susceptibility Testing

The MICs were determined using frozen 96-well broth microdilution panels with a pre-loaded antibiotic growth medium supplied by International Health Management Associates, Inc. (IHMA; Schaumburg, IL, USA). CFDC was tested in iron-depleted cation-adjusted Mueller–Hinton broth (ID-CAMHB), as recently approved by the CLSI ([32]; http://clsi.org/standards/micro/microbiology-files/, accessed on 1 September 2022), whereas the comparators were tested in cation-adjusted Mueller–Hinton broth (CAMHB). The strains were grown overnight on a non-selective agar media. Two to three colonies were resuspended in 3 mL sterile 0.85% NaCl in order to obtain a 0.5 McFarland suspension. One milliliter of this suspension was further diluted in 29 mL of sterile water, of which 10 μL were then added to each well, and the plates were subsequently incubated for 16–20 h at 35 °C, as recommended by the manufacturer and EUCAST guidelines [31]. Quality control testing was performed on each day of testing using E. coli ATCC 25922, K. pneumoniae ATCC 700603 and P. aeruginosa ATCC 27853 to ensure the stability of the panels and the validity of the test methods. The comparator antibiotics were for Enterobacterales, Pseudomonas spp., Acinetobacter spp., B. cepacia, A. xylosoxydans and Elizabethkingia spp. meropenem, ceftazidime, ceftazidime–avibactam (4 μg/mL), cefepime, ceftolozane–tazobactam (4 μg/mL), aztreonam, colistin, amikacin, ciprofloxacin and tigecycline, all sourced by IHMA. For S. maltophilia, cotrimoxazole, levofloxacin and minocycline were tested instead of cefepime, aztreonam and ciprofloxacin.
The MIC results of CFDC were interpreted using EUCAST breakpoint [31] values of S ≤ 2 mg/L and R >2   mg/L for Enterobacterales, P. aeruginosa, Acinetobacter spp and S. maltophilia, and for the other tested bacteria, non-species-related PK/PD values (≤2 mg/L ) were used; the Investigational CLSI MIC breakpoints for the same bacteria were used with values of S ≤ 4  mg/L and R ≥ 16  mg/L, which correspond to those when CFDC was in trial. The MICs of the comparator antibiotics were interpreted using EUCAST guidelines where available, the exceptions being ceftazidime and cefepime for Acinetobacter spp., for which only the CLSI breakpoints are available [32,33].

4.3. Ethics

Ethics approval was not required as all the bacterial isolates were from the French or Belgium NRC for antibiotic resistances and thus were anonymized and unrelated to the patients.

5. Conclusions

The increasing incidence and diversification of carbapenem resistance among GNB is of growing concern in France and in Belgium, as a shift toward more difficult-to-treat pathogens is putting pressure on the already limited available treatment options. CFDC demonstrates substantial and broad in vitro activity against a wide range of MDR pathogens, and even XDR GNB. The findings from this study are in line with those from previous reports and suggest that CFDC may offer an invaluable treatment option in the fight against antimicrobial-resistant GNB, particularly for carbapenem-resistant non-fermenters and MBL producers, especially Acinetobacter baumannii, for which there are currently few approved effective therapies. Colistin was the only other agent with similar activity as CFDC against meropenem-resistant GNB. It should be emphasized that CFDC displays much more favorable pharmacokinetic parameters (tissue diffusion and use in renal impairment) than colistin and tigecycline, which will be an important factor for choosing an adequate therapy for infections due to multidrug infections.
In addition to aztreonam, CFDC is the other beta-lactam with activity against MBL-producing CREs. Our results, along with other in vitro and surveillance studies, showed that CFDC MIC values are higher against NDM-producing isolates than VIM-producing isolates. Nevertheless, clinical studies demonstrated that NDM-producing CRE infections with CFDC MICs of 4 µg/mL, which corresponds to the CLSI susceptibility breakpoint, could be successfully treated [48]. The recent IDSA guidance and ESCMID guidelines provide recommendations on when and how to use the new antimicrobial agents, especially to prevent irrational use and the emergence of resistance [52,53]. Neither of them recommends a second agent to be used with the new antibiotics for the treatment of CRE infections. Even though resistance for each of the new agents has been described, great susceptibility rates are described globally, with some regional variations. Overall susceptibility rates are reduced for ceftazidime–avibactam, meropenem–vaborbactam and imipenem–relebactam in regions where MBLs are prevalent, and CFDC MICs are higher where NDM-producing CREs are more prevalent. This underlines the need for rapid diagnostic tests for resistance mechanisms that will improve the surveillance and diagnosis of CRE and, hence, the selection of the most appropriate antibiotic agent [54,55].

Author Contributions

Conceptualization, C.L. and T.N.; methodology, C.L.; validation, T.N., P.B., L.D. and Y.G.; formal analysis, S.O., S.B. and P.B.; investigation, S.O. and P.B.; resources, C.L.; data curation, T.N. and H.B.L.; writing—original draft preparation, T.N.; writing—review and editing, S.O., P.B., L.D., S.B., H.B.L., C.L., Y.G. and T.N.; supervision, P.B. and T.N.; project administration, T.N.; funding acquisition, T.N. and Y.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by Shionogi & Co., Ltd., Osaka, Japan, and by grants from the Ministère de l’Education Nationale et de la Recherche (Université Paris-Saclay) and Assistance Publique-Hôpitaux de Paris.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are grateful to the Pasteur International Bioresources Networking for providing the whole genome sequencing facilities (Paris, France).

Conflicts of Interest

T.N. reports non-financial support from Pfizer, personal fees and non-financial support from Shionogi, outside the submitted work. C.L. is a fulltime employee of Shionogi B.V., London, UK. All other authors have nothing to disclose. The funders had no role in the collection, analyses or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Papp-Wallace, K.M.; Endimiani, A.; Taracila, M.A.; Bonomo, R.A. Carbapenems: Past, present, and future. Antimicrob. Agents Chemother. 2011, 55, 4943–4960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef]
  3. Cassini, A.; Högberg, L.D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G.S.; Colomb-Cotinat, M.; Kretzschmar, M.E.; Devleesschauwer, B.; Cecchini, M.; et al. Burden of AMR Collaborative Group. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: A population-level modelling analysis. Lancet Infect. Dis. 2019, 19, 56–66. [Google Scholar] [CrossRef] [Green Version]
  4. Gupta, N.; Limbago, B.M.; Patel, J.B.; Kallen, A.J. Carbapenem-resistant Enterobacteriaceae: Epidemiology and prevention. Clin. Infect. Dis. 2011, 53, 60–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Buehrle, D.J.; Shields, R.K.; Clarke, L.G.; Potoski, B.A.; Clancy, C.J.; Hong Nguyen, M. Carbapenem-resistant Pseudomonas aeruginosa bacteremia: Risk factors for mortality and microbiologic treatment failure. Antimicrob. Agents Chemother. 2016, 61, e01243-16. [Google Scholar] [CrossRef] [Green Version]
  6. Higgins, P.G.; Dammhayn, C.; Hackel, M.; Seifert, H. Global spread of carbapenem-resistant Acinetobacter baumannii. J. Antimicrob. Chemother. 2009, 65, 233–238. [Google Scholar] [CrossRef] [Green Version]
  7. Nordmann, P.; Naas, T.; Poirel, L. Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg. Infect. Dis. 2011, 17, 1791–1798. [Google Scholar] [CrossRef]
  8. Colomb-Cotinat, M.; Soing-Altrach, S.; Leon, A.; Savitch, Y.; Poujol, I.; Naas, T.; Cattoir, V.; Berger-Carbonne, A.; Dortet, L.; CPIAS Network. Emerging extensively drug-resistant bacteria (eXDR) in France in 2018. Med. Mal. Infect. 2020, 50, 715–722. [Google Scholar] [CrossRef]
  9. Jousset, A.B.; Emeraud, C.; Bonnin, R.A.; Naas, T.; Dortet, L. Caractéristiques et Évolution des Souches d’Entérobactéries Productrices de Carbapénémases (EPC) Isolées en France, 2012–2020//Characteristics and Evolution of Carbapenemase-Producing Enterobacterales in France, 2012–2020. BEH 18–19|16 Novembre 2021. 2012, pp. 351–358. Available online: http://beh.santepubliquefrance.fr/beh/2021/18-19/2021_18-19_4.html (accessed on 1 September 2022).
  10. Brolund, A.; Lagerqvist, N.; Byfors, S.; Struelens, M.J.; Monnet, D.L.; Albiger, B.; Kohlenberg, A.; European Antimicrobial Resistance Genes Surveillance Network EURGen-Net Capacity Survey Group. Worsening epidemiological situation of carbapenemase-producing Enterobacteriaceae in Europe, assessment by national experts from 37 countries, July 2018. Euro Surveill. 2019, 24, 1900123. [Google Scholar] [CrossRef] [Green Version]
  11. Plésiat, P.; Bonnet, R.; Naas, T.; Dortet, L. Rapport d’Activite 2019–2020. Centre Nationale de Reference de la Resistance aux Antibiotiques. Available online: https://online.fliphtml5.com/kcktq/vxnt/?1623677121389#p=1 (accessed on 1 September 2022).
  12. Emeraud, C.; Girlich, D.; Bonnin, R.A.; Jousset, A.B.; Naas, T.; Dortet, L. Emergence and Polyclonal Dissemination of OXA-244-Producing Escherichia coli, France. Emerg. Infect. Dis. 2021, 27, 1206–1210. [Google Scholar] [CrossRef]
  13. Nordmann, P.; Poirel, L. Epidemiology and diagnostics of carbapenem resistance in Gram-negative bacteria. Clin. Infect. Dis. 2019, 69, S521–S528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Kerr, K.G.; Snelling, A.M. Pseudomonas aeruginosa: A formidable and ever-present adversary. J. Hosp. Infect. 2009, 73, 338–344. [Google Scholar] [CrossRef] [PubMed]
  15. Sheu, C.C.; Chang, Y.T.; Lin, S.Y.; Chen, Y.H.; Hsueh, P.R. Infections caused by carbapenem-resistant Enterobacteriaceae: An update on therapeutic options. Front. Microbiol. 2019, 10, 80. [Google Scholar] [CrossRef] [Green Version]
  16. Oueslati, S.; Iorga, B.I.; Tlili, L.; Exilie, C.; Zavala, A.; Dortet, L.; Jousset, A.B.; Bernabeu, S.; Bonnin, R.A.; Naas, T. Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity. J. Antimicrob. Chemother. 2019, 74, 2239–2246. [Google Scholar] [CrossRef] [PubMed]
  17. Jousset, A.B.; Oueslati, S.; Emeraud, C.; Bonnin, R.A.; Dortet, L.; Iorga, B.I.; Naas, T. KPC-39-Mediated Resistance to Ceftazidime-Avibactam in a Klebsiella pneumoniae ST307 Clinical Isolate. Antimicrob. Agents Chemother. 2021, 65, e0116021. [Google Scholar] [CrossRef]
  18. Shionogi & Co., Ltd. Fetroja (Cefiderocol) Prescribing Information. 2020. Available online: https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf (accessed on 1 September 2022).
  19. Shionogi & Co., Ltd. Fetcroja. Summary of Product Characteristics. 2020. Available online: https://www.ema.europa.eu/en/documents/product-information/fetcroja-epar-product-information_en.pdf (accessed on 1 September 2022).
  20. Ito, A.; Nishikawa, T.; Matsumoto, S.; Yoshizawa, H.; Sato, T.; Nakamura, R.; Tsuji, M.; Yamano, Y. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2016, 60, 7396–7401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Ito, A.; Kohira, N.; Bouchillon, S.K.; West, J.; Rittenhouse, S.; Sader, H.S.; Rhomberg, P.R.; Jones, R.N.; Yoshizawa, H.; Nakamura, R.; et al. In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria. J. Antimicrob. Chemother. 2016, 71, 670–677. [Google Scholar] [CrossRef] [Green Version]
  22. Ito, A.; Sato, T.; Ota, M.; Takemura, M.; Nishikawa, T.; Toba, S.; Kohira, N.; Miyagawa, S.; Ishibashi, N.; Matsumoto, S.; et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob. Agents Chemother. 2017, 62, e01454-17. [Google Scholar] [CrossRef] [Green Version]
  23. Ito, A.; Nishikawa, T.; Ota, M.; Ito-Horiyama, T.; Ishibashi, N.; Sato, T.; Tsuji, M.; Yamano, Y. Stability and low induction propensity of cefiderocol against chromosomal AmpC β-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae. J. Antimicrob. Chemother. 2018, 73, 3049–3052. [Google Scholar] [CrossRef] [Green Version]
  24. Longshaw, C.; Manissero, D.; Tsuji, M.; Echols, R.; Yamano, Y. In vitro activity of the siderophore cephalosporin, cefiderocol, against molecularly characterised, carbapenem-non-susceptible Gram-negative bacteria from Europe. JAC—Antimicrob. Resist. 2020, 2, dlaa060. [Google Scholar] [CrossRef]
  25. Kohira, N.; West, J.; Ito, A.; Ito-Horiyama, T.; Nakamura, R.; Sato, T.; Rittenhouse, S.; Tsuji, M.; Yamano, Y. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob. Agents Chemother. 2016, 60, 729–734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ito-Horiyama, T.; Ishii, Y.; Ito, A.; Sato, T.; Nakamura, R.; Fukuhara, N.; Tsuji, M.; Yamano, Y.; Yamaguchi, K.; Tateda, K. Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob. Agents Chemother. 2016, 60, 4384–4386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Hackel, M.A.; Tsuji, M.; Yamano, Y.; Echols, R.; Karlowsky, J.A.; Sahm, D.F. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 Study). Antimicrob. Agents Chemother. 2017, 61, e00093-17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Karlowsky, J.A.; Hackel, M.A.; Tsuji, M.; Yamano, Y.; Echols, R.; Sahm, D.F. In vitro activity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015–2016: SIDERO-WT-2015. Int. J. Antimicrob. Agents 2019, 53, 456–466. [Google Scholar] [CrossRef] [PubMed]
  29. Naas, T.; Lina, G.; Santerre-Henriksen, A.; Longshaw, C.; Jehl, F. In vitro activity of cefiderocol and comparators against isolates of Gram-negative pathogens from a range of infection sources: SIDERO-WT-2014-2018 studies in France. JAC Antimicrob. Resist. 2021, 3, dlab081. [Google Scholar] [CrossRef]
  30. Ballesté-Delpierre, C.; Ramírez, Á.; Muñoz, L.; Longshaw, C.; Roca, I.; Vila, J. Assessment of In Vitro Cefiderocol Susceptibility and Comparators against an Epidemiologically Diverse Collection of Acinetobacter baumannii Clinical Isolates. Antibiotics 2022, 11, 187. [Google Scholar] [CrossRef]
  31. EUCAST. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 10.0, 2020. 2020. Available online: http://www.eucast.org/clinical_breakpoints/ (accessed on 1 September 2022).
  32. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. In M07 Standard, 11th ed.; Clinical Laboratory Standards Institute: Wayne, PA, USA, 2018. [Google Scholar]
  33. Simner, P.J.; Patel, R. Cefiderocol antimicrobial susceptibility testing considerations: The Achilles’ heel of the Trojanhorse? J. Clin. Microbiol. 2021, 59, e00951-20. [Google Scholar] [CrossRef]
  34. Fröhlich, C.; Sørum, V.; Thomassen, A.M.; Johnsen, P.J.; Leiros, H.-K.S.; Samuelsen, Ø. OXA-48-mediated ceftazidime-avibactam resistance is associated with evolutionary trade-offs. mSphere 2019, 4, e00024-19. [Google Scholar] [CrossRef] [Green Version]
  35. Kazmierczak, K.M.; Biedenbach, D.J.; Hackel, M.; Rabine, S.; de Jonge, B.L.; Bouchillon, S.K.; Sahm, D.F.; Bradford, P.A. Global dissemination of blaKPC into bacterial species beyond Klebsiella pneumoniae and in vitro susceptibility to ceftazidime-avibactam and aztreonam-avibactam. Antimicrob. Agents Chemother. 2016, 60, 4490–4500. [Google Scholar] [CrossRef] [Green Version]
  36. De Jonge, B.L.; Karlowsky, J.A.; Kazmierczak, K.M.; Biedenbach, D.J.; Sahm, D.F.; Nichols, W.W. In vitro susceptibility to ceftazidime-avibactam of carbapenem-nonsusceptible Enterobacteriaceae isolates collected during the INFORM global surveillance study (2012 to 2014). Antimicrob. Agents Chemother. 2016, 60, 3163–3169. [Google Scholar] [CrossRef]
  37. Kazmierczak, K.M.; de Jonge, B.L.M.; Stone, G.G.; Sahm, D.F. Longitudinal analysis of ESBL and carbapenemase carriage among Enterobacterales and Pseudomonas aeruginosa isolates collected in Europe as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme, 2013–2017. J. Antimicrob. Chemother. 2020, 75, 1165–1173. [Google Scholar] [CrossRef]
  38. Mushtaq, S.; Sadouki, Z.; Vickers, A.; Livermore, D.M.; Woodford, N. In vitro activity of cefiderocol, a siderophore cephalosporin, against multidrug-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 2020, 64, e01582-20. [Google Scholar] [CrossRef]
  39. Lan, P.; Lu, Y.; Chen, Z.; Wu, X.; Hua, X.; Jiang, Y.; Zhou, J.; Yu, Y. Emergence of high-level cefiderocol resistance in carbapenem-resistant Klebsiella pneumoniae from bloodstream infections in patients with hematologic malignancies in China. Microbiol. Spectr. 2022, 10, e00084-22. [Google Scholar] [CrossRef] [PubMed]
  40. Hobson, C.A.; Cointe, A.; Jacquier, H.; Choudhury, A.; Magnan, M.; Courroux, C.; Tenaillon, O.; Bonacorsi, S.; Birgy, A. Cross-resistance to cefiderocol and ceftazidime-avibactam in KPC β-lactamase mutants and the inoculum effect. Clin. Microbiol. Infect. 2021, 27, 1172.e7–1172.e10. [Google Scholar] [CrossRef] [PubMed]
  41. Hobson, C.A.; Pierrat, G.; Tenaillon, O.; Bonacorsi, S.; Bercot, B.; Jaouen, E.; Jacquier, H.; Birgy, A. Klebsiella pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: An Evolutionary Overview. Antimicrob. Agents Chemother. 2022, 66, e00447-22. [Google Scholar] [CrossRef] [PubMed]
  42. Hobson, C.A.; Bonacorsi, S.; Hocquet, D.; Baruchel, A.; Fahd, M.; Storme, T.; Tang, R.; Doit, C.; Tenaillon, O.; Birgy, A. Impact of anticancer chemotherapy on the extension of beta-lactamase spectrum: An example with KPC-type carbapenemase activity towards ceftazidime-avibactam. Sci. Rep. 2020, 10, 589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Isler, B.; Doi, Y.; Bonomo, R.A.; Paterson, D.L. New treatment options against carbapenem-resistant Acinetobacter baumannii infections. Antimicrob. Agents Chemother. 2019, 63, e01110-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Dobias, J.; Dénervaud-Tendon, V.; Poirel, L.; Nordmann, P. Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens. Eur. J. Clin. Microbiol. Infect. Dis. 2017, 36, 2319–2327. [Google Scholar] [CrossRef] [Green Version]
  45. Ordooei, J.A.; Shokouhi, S.; Sahraei, Z. A review on colistin nephrotoxicity. Eur. J. Clin. Pharmacol. 2015, 71, 801–810. [Google Scholar] [CrossRef] [PubMed]
  46. Lodise, T.P.; Bassetti, M.; Ferrer, R.; Naas, T.; Niki, Y.; Paterson, D.L.; Zeitlinger, M.; Echols, R. All-cause mortality rates in adults with carbapenem-resistant Gram-negative bacterial infections: A comprehensive review of pathogen-focused, prospective, randomized, interventional clinical studies. Expert Rev. Anti Infect. Ther. 2022, 20, 707–719. [Google Scholar] [CrossRef]
  47. Paterson, D.L.; Kinoshita, M.; Baba, T.; Echols, R.; Portsmouth, S. Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies. Infect. Dis. Ther. 2022, 11, 853–870. [Google Scholar] [CrossRef] [PubMed]
  48. Timsit, J.F.; Paul, M.; Shields, R.K.; Echols, R.; Baba, T.; Yamano, Y.; Portsmouth, S. Cefiderocol for the Treatment of Infections Due To Metallo-Beta-Lactamase-Producing Pathogens in the CREDIBLE-CR And APEKS-NP Phase 3 Randomized Studies. Clin. Infect. Dis. 2022, ciac078. [Google Scholar] [CrossRef]
  49. Rose, L.; Lai, L.; Byrne, D. Successful prolonged treatment of a carbapenem-resistant Acinetobacter baumannii hip infection with cefiderocol: A case report. Pharmacotherapy 2022, 42, 268–271. [Google Scholar] [CrossRef] [PubMed]
  50. Falcone, M.; Tiseo, G.; Nicastro, M.; Leonildi, A.; Vecchione, A.; Casella, C.; Forfori, F.; Malacarne, P.; Guarracino, F.; Barnini, S.; et al. Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in intensive care unit patients. Clin. Infect. Dis. 2021, 72, 2021–2024. [Google Scholar] [CrossRef] [PubMed]
  51. Oliva, A.; Ceccarelli, G.; De Angelis, M.; Sacco, F.; Miele, M.C.; Mastroianni, C.M.; Venditti, M. Cefiderocol for compassionate use in the treatment of complicated infections caused by extensively and pan-resistant Acinetobacter baumannii. J. Glob. Antimicrob. Resist. 2020, 23, 292–296. [Google Scholar] [CrossRef]
  52. Paul, M.; Carrara, E.; Retamar, P.; Tängdén, T.; Bitterman, R.; Bonomo, R.A.; De Waele, J.; Daikos, G.L.; Akova, M.; Harbarth, S.; et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin. Microbiol. Infect. 2022, 28, 521–547. [Google Scholar] [CrossRef]
  53. Tamma, P.D.; Aitken, S.L.; Bonomo, R.A.; Mathers, A.J.; van Duin, D.; Clancy, C.J. Infectious Diseases Society of America 2022 guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin. Infect. Dis. 2022, ciac268. [Google Scholar] [CrossRef]
  54. Banerjee, R.; Humphries, R. Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae. Virulence 2017, 8, 427–439. [Google Scholar] [CrossRef] [Green Version]
  55. Bradley, N.; Lee, Y. Practical implications of new antibiotic agents for the treatment of carbapenem-resistant Enterobacteriaceae. Microbiol. Insights 2019, 12, 1178636119840367. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Panel of tested isolates.
Table 1. Panel of tested isolates.
ß-lactam Resistant MechanismCarbapenemase-ProducersImpermeabilityESC Resistant 1WTIR2Total
Genus/Species NDMVIM IMP GIMAIMSPMDIMSIMLMBTMBKPC GES IMI SME FRIOXA- 48 like OXA-372OXA-198OXA- 23 OXA- 24/40 hyper OXA- 51 OXA-58 OXA-143OXA-48/NDMOXA-48/VIMNDM/VIMNDM/KPCNDM/OXA-23ESBL + Dporin AMPC + Dporin ESBL/AmpC/DporinEffluxOprDAmpC/EffluxAmpC/Efflux/OprDHyper K1pAmpCCTX-MVEB BELPER SCO/RTG/CarbPMEESBL-OXA
E. coli1033 4 21 4 1 11 261 2 59
Klebsiella8107 121 21 7 12 213 1 12 88
Enterobacter 221 1514 13 1 183 1 1 1 45
Serratia 1 2 3 3 1 1 11
Citrobacter 2 1 1 21 22 1 12
Morganella 1 1
Providencia2 2
Salmonella enterica1 1
Proteus 1 1
Hafnia alvei 2 2
P. aeruginosa45292111 48 3 31212 521 11 113
P. putida 21 3
P. stutzeri 11 1 3
P. fluorescens 1 1
A. xylosoxydans 1 1112
A. baumannii923 1 8 199982 3 2 13 12 82
B. cepacia 1313
S. maltophilia 2525
E. miricola 11
E.meningoseptica 11
Total 3476273112111281843150131999821321131323431212249926315451476
1 ESC: Expanded-spectrum cephalosporin resistant; 2 IR = Intrinsic carbapenem-resistance
Table
Table 2. MIC distributions of cefiderocol by resistance mechanism and species group.
Table 2. MIC distributions of cefiderocol by resistance mechanism and species group.
MechanismTotal # of Isolates# of Isolates per MIC (mg/L)% Susceptible Isolates at Breakpoints of (mg/L)
≤0.030.060.1250.250.51248163264>64≤2 1≤4 2
Enterobacterales22265131831673927551238193
Non CPE67212101017158001108597
KPC24001051151100009296
other class A GES, IMI, SME, fri…900212201100007889
MBLs5411333151111131016989
NDM2100002447120014881
VIM1700010662011007688
IMP13113204020000085100
other MBLs (LMB, GIM, TMB)30000111000000100100
OXA-48513254111653200009096
Multi-Carbas1701000633010125976
P. aeruginosa12021022293017910000099100
Non-CP, ESBLs31017874310000097100
MBLS7728131918125000000100100
VIM561712141183000000100100
IMP110014510000000100100
NDM, GIM, DIM, SPM, AIM101101232000000100100
OXA-198, GES, KPC120122511000000100100
A. baumannii82171161516133310068488
ESBL, Non CP2600416570010028888
OXA-23, 40, 58, 14340177551021100019395
NDM-like1000000032200033050
VIM, IMP60000411000000100100
S. maltophilia2522210000000000100100
B. cepacia131001010001000092.392.3
A. xylosoxidans120014421000000100100
Elizabethkingia sp20010010000000100100
1 EUCAST susceptibility breakpoints 202; 2 CLSI susceptibility breakpoints 2022.
Table
Table 3. In vitro activity of cefiderocol and comparators against Enterobacterales, P. aeruginosa and A. baumannii with reduced susceptibility to carbapenems received at the French and Belgium NRC for antibiotic resistance in GN according to EUCAST guidelines.
Table 3. In vitro activity of cefiderocol and comparators against Enterobacterales, P. aeruginosa and A. baumannii with reduced susceptibility to carbapenems received at the French and Belgium NRC for antibiotic resistance in GN according to EUCAST guidelines.
SpeciesResistance Mechanism
(# of Isolates)		Antimicrobial AgentMIC (mg/L) S/I/R
RangeMIC50MIC90 S (%)I (%) 1R (%)
Enterobacterales
Total (222)Cefiderocol≤0.03–>6414 81/19
Ceftolozane–tazobactam≤0.03–>6464>64 19/81
Cefepime≤0.5–>16>16>16 141076
Ceftazidime0.12–>64>64>64 9883
Ceftazidime–avibactam0.06–>644>64 63/37
Aztreonam≤0.5–>32>32>32 14482
Meropenem0.06–>648>64 362044
Amikacin≤4–>64≤4>64 70/30
Ciprofloxacin≤0.25–>4>4>4 30565
Colistin≤0.5–>8≤0.5>8 84/16
Tigecycline≤0.25–>4≤0.252 73/27
Non-CPE (67)Cefiderocol0.12–6414 85/15
Ceftolozane–tazobactam0.12–>6416>64 30/70
Cefepime≤0.5–>1616>16 161668
Ceftazidime0.25–>64>64>64 7984
Ceftazidime–avibactam0.06–>64212 90/10
Aztreonam≤0.5–>32>32>32 10485
Meropenem0.06–>640.532 73621
Amikacin≤4–>64≤432 81919
Ciprofloxacin≤0.25–>41>4 34660
Colistin≤0.5–>8≤0.5>8 79/21
Tigecycline≤0.25–>40.52 69/31
Class A,
KPC producers (24)		Cefiderocol0.12–814 92/8
Ceftolozane–tazobactam0.25–>6432>64 29/71
Cefepime2–>1616>16 26965
Ceftazidime0.25–>6464>64 21376
Ceftazidime–avibactam0.12–>6428 94/6
Aztreonam2–>32>32>32 6985
Meropenem0.25–>6432>64 152065
Amikacin≤4–>64432 76/24
Ciprofloxacin≤0.25–>41>4 41653
Colistin≤0.5–>81>8 62/38
Tigecycline≤0.25–>40.51 76/24
Class A, other carbapenemase (IMI, NMC-A, SME, GES, FRI-1) producers (10)Cefiderocol0.12–80.54 78/22
Ceftolozane–tazobactam0.25–320.532 78/22
Cefepime≤0.5–>16≤0.516 781111
Ceftazidime0.25–>640.5>64 78022
Ceftazidime–avibactam0.25–40.58 100/0
Aztreonam1–>324>32 113356
Meropenem8–>6464>64 01189
Amikacin≤4–8≤48 100/0
Ciprofloxacin≤0.25–>4≤0.25>4 89011
Colistin1–>8>8>8 11/89
Tigecycline≤0.25–2≤0.252 67/33
Class B, MBLs total (54)Cefiderocol0.03–>6428 69/31
Ceftolozane–tazobactam64–>64>64>64 0/100
Cefepime2–>16>16>16 0298
Ceftazidime64–>64>64>64 00100
Ceftazidime–avibactam32–>64>64>64 0/100
Aztreonam≤0.5–>32>32>32 20080
Meropenem0.5–>6432>64 72469
Amikacin≤4–>6416>64 46/54
Ciprofloxacin0.25–>4>4>4 22672
Colistin≤0.5–>8≤0.51 91/9
Tigecycline≤0.25–>4≤0.252 70/30
Class B, NDM producers (21)Cefiderocol0.5–>64216 48/52
Ceftolozane–tazobactam>64>64>64 0/100
Cefepime16–>16>16>16 0/100
Ceftazidime>64>64>64 00100
Ceftazidime–avibactam>64>64>64 0/100
Aztreonam≤0.5–>32>32>32 14086
Meropenem16–>6432>64 00100
Amikacin≤4–>6416>64 33067
Ciprofloxacin2–>4>4>4 00100
Colistin≤0.5–>8≤0.51 48/52
Tigecycline≤0.25–4≤0.252 52/48
Class B, VIM producers (17)Cefiderocol0.25–>64216 76/24
Ceftolozane–tazobactam>64>64>64 0/100
Cefepime16–>16>16>16 00100
Ceftazidime>64>64>64 00100
Ceftazidime–avibactam32–>64>64>64 0/100
Aztreonam≤0.5–>32>32>32 18082
Meropenem1–>6432>64 62965
Amikacin≤4–>321632 24/76
Ciprofloxacin0.25–>4>4>4 24076
Colistin≤0.5–>8≤0.51 94/6
Tigecycline≤0.25–>40.51 76/24
Class B, IMP producers (13)Cefiderocol0.03–40.254 85/15
Ceftolozane–tazobactam64–>64>64>64 0/100
Cefepime2–>168>16 00100
Ceftazidime64–>64>64>64 00100
Ceftazidime–avibactam32–>64>64>64 0/100
Aztreonam≤0.5–>3216>32 38062
Meropenem1–64432 156223
Amikacin≤4–16≤416 85/15
Ciprofloxacin≤0.25–>4≤0.25>4 462331
Colistin≤0.5–>8≤0.51 92/8
Tigecycline≤0.25–>4≤0.251 92/8
Other class B producers (GIM, LMB, TMB) (3)Cefiderocol0.5–212 100/0
Ceftolozane–tazobactam64–>64>64>64 0/100
Cefepime2–888 33067
Ceftazidime>64>64>64 00100
Ceftazidime–avibactam32–>64>64>64 0/100
Aztreonam0.5–32>32>32 00100
Meropenem0.5–3232>64 33067
Amikacin444 100/0
Ciprofloxacin≤0.25–>4≤0.25>4 67033
Colistin≤0.5–>8≤0.51 100/0
Tigecycline≤0.25–>1≤0.251 67/33
Class D, OXA-48 producers (50) + OXA-372 (1)Cefiderocol≤0.03–812 90/10
Ceftolozane–tazobactam≤0.03–>648>64 37/73
Cefepime1–>1616>16 251461
Ceftazidime0.12–>64>64>64 152065
Ceftazidime–avibactam0.12–>6418 94/6
Aztreonam1–>32>32>32 24473
Meropenem0.06–>64432 453322
Amikacin≤4–>6448 90/10
Ciprofloxacin≤0.25–>4>4>4 35461
Colistin≤0.5–>812 94/6
Tigecycline≤0.25–>4≤0.252 75/25
Multiple Carbapenemase producers (17)Cefiderocol0.06–>642>64 76/24
Ceftolozane–tazobactam>64>64>64 0/100
Cefepime4–>64>64>64 0694
Ceftazidime32–>64>64>64 0 100
Ceftazidime–avibactam16–>64>64>64 0/100
Aztreonam2–>16>16>16 0 100
Meropenem≤4–>32>32>32 18 82
Amikacin≤0.5–1≤0.51 29/71
Ciprofloxacin≤4–>64>64>64 0 100
Colistin4–>8>4>4 94/6
Tigecycline≤0.25–4≤0.254 76/24
Acinetobacter spp.
Total (n = 82)Cefiderocol0.03–>6418 84/16
Ceftolozane–tazobactam1–>6464>64 13/87
Cefepime2–>16>16>16 0793
Ceftazidime8–>64>64>64 0298
Ceftazidime–avibactam8–>64>64>64 5/95
Aztreonam28–>32>32>32 0595
Meropenem2–>64>64>64 21187
Amikacin4–>6464>64 28/72
Ciprofloxacin0.5–>4>4>4 0991
Colistin0.5–814 88/12
Tigecycline0.25–>412 48/52
Non-CP (n = 26)Cefiderocol0.12–>6414 88/12
Ceftolozane–tazobactam2–>64>64>64 15/85
Cefepime2–>16>16>16 01288
Ceftazidime8–>64>64>64 0496
Ceftazidime–avibactam8–>64>64>64 4/96
Aztreonam2>32>32>32 00100
Meropenem2–>6432>64 82765
Amikacin≤4–>6464>64 23/77
Ciprofloxacin≤0.25–>4>4>4 01585
Colistin≤0.5–412 96/4
Tigecycline≤0.25–>412 46/54
Class D, OXA carbapenemase (n = 40)Cefiderocol0.03–>640.252 93/7
Ceftolozane–tazobactam2–>64>64>64 12/88
Cefepime8–>16>16>16 0595
Ceftazidime8–>64>64>64 0397
Ceftazidime–avibactam8–>6464>64 8/92
Aztreonam28–>32>32>32 0595
Meropenem8–>64>64>64 0595
Amikacin4–>6464>64 25/75
Ciprofloxacin4–>4>4>4 00100
Colistin<0.5–414 85/15
Tigecycline0.25–>412 42/57
Class B, NDM (n = 10)Cefiderocol2–>644>64 30/70
Ceftolozane–tazobactam>64>64>64 0/100
Cefepime>16>16>16 00100
Ceftazidime>64>64>64 0 100
Ceftazidime–avibactam>64>64>64 0/100
Aztreonam2>32>32>32 00100
Meropenem>6432>64 00100
Amikacin4–>644>64 50/50
Ciprofloxacin>4>4>4 00100
Colistin0.5–412 90/10
Tigecycline0.25–20.52 60/40
Class B, other MBLS (n = 6)Cefiderocol0.5–10.51 100/0
Ceftolozane–tazobactam1–>64>64>64 34/66
Cefepime8–>1616>16 01684
Ceftazidime32–>64>64>64 0 100
Ceftazidime–avibactam32–>64>64>64 0/100
Aztreonam216–>3232>32 03466
Meropenem16–>6464>64 00100
Amikacin≤4–>6464>64 34/66
Ciprofloxacin0.25–>40.25>4 05050
Colistin1–424 66/34
Tigecycline0.25–10.251 16/84
Pseudomonas spp.
Total (n = 120)Cefiderocol0.03–40.251 99/1
Ceftolozane–tazobactam0.5–>64>64>64 17/83
Cefepime2–>16>16>16 01585
Ceftazidime2–>6464>64 0595
Ceftazidime–avibactam2–>6432>64 22/78
Aztreonam2–>3232>32 01189
Meropenem1–>6464>64 31384
Amikacin4–>6432>64 34/66
Ciprofloxacin0.25–>4>4>4 01486
Colistin0.5–>812 97/3
Tigecycline31–>4>4>4 0/100
Non-CP-CR (n = 31)Cefiderocol0.06–40.252 97/3
Ceftolozane–tazobactam0.5–>644>64 52/48
Cefepime2–>16>16>16 02377
Ceftazidime2–>64>64>64 0694
Ceftazidime–avibactam2–>6416>64 48/52
Aztreonam8–>32>32>32 00100
Meropenem1–>6416>64 62965
Amikacin≤4–>6416>64 58/42
Ciprofloxacin≤0.25–>4>4>4 01684
Colistin≤0.5–>812 97/3
Tigecycline32–>4>4>4 0/100
OXA-198, GES, KPC (n = 12)Cefiderocol0.06–20.51 100/0
Ceftolozane–tazobactam4–>6416>64 25/75
Cefepime2–>16>16>16 01783
Ceftazidime4–>64>64>64 01783
Ceftazidime–avibactam2–>648>64 67/33
Aztreonam8–>32>32>32 00100
Meropenem16–>64>64>64 00100
Amikacin≤4–>6464>64 42/58
Ciprofloxacin≤0.25–>4>4>4 0892
Colistin≤0.5–212 100/0
Tigecycline32–>4>4>4 0/100
Class B, MBL (n = 77)Cefiderocol0.03–40.251 100/0
Ceftolozane–tazobactam0.5–>64>64>64 3/97
Cefepime2–>16>16>16 01288
Ceftazidime2–>6464>64 0397
Ceftazidime–avibactam2–>6464>64 5/95
Aztreonam2–>3216>32 01783
Meropenem1–>6464>64 1891
Amikacin≤4–>6432>64 23/77
Ciprofloxacin≤0.25–>4>4>4 01486
Colistin≤0.5–>812 97/3
Tigecycline31–>4>4>4 0/100
VIM (n = 56)Cefiderocol≤0.06–20.251 100/0
Ceftolozane–tazobactam2–>64>64>64 2/98
Cefepime8–>16>16>16 01388
Ceftazidime4–>6464>64 0298
Ceftazidime–avibactam4–>6464>64 5/95
Aztreonam2–>328>32 02080
Meropenem4–>6464>64 0793
Amikacin8–>6464>64 16/84
Ciprofloxacin≤0.25–>4>4>4 01684
Colistin≤0.5–412 98/2
Tigecycline31–>4>4>4 0/100
IMP (n = 11)Cefiderocol0.12–10.252 100/0
Ceftolozane–tazobactam64–>644>64 0/100
Cefepime>16>16>16 00100
Ceftazidime>64>64>64 00100
Ceftazidime–avibactam>6416>64 0/100
Aztreonam2–>32>32>32 01882
Meropenem8–>6416>64 0991
Amikacin≤4–>6416>64 36/64
Ciprofloxacin≤0.25–>4>4>4 0991
Colistin≤0.5–>412 91/9
Tigecycline31–>44>4 0/100
Other MBLs
(NDM, GIM, DIM, SPM, AIM) (n = 10)		Cefiderocol≤0.06–20.52 100/0
Ceftolozane–tazobactam0.5–>64>64>64 10/90
Cefepime2–>16>16>16 02080
Ceftazidime4–>64>64>64 01090
Ceftazidime–avibactam2–>64>64>64 10/90
Aztreonam8–>32>32>32 00100
Meropenem2–>6416>64 101080
Amikacin≤4–>6416>64 50/50
Ciprofloxacin≤0.25–>4>4>4 01090
Colistin≤0.5–212 100/0
Tigecycline32–>4>4>4 0/100
1 “I” refers to susceptible with high exposure according to EUCAST guidelines. 2 A. baumannii are intrinsically resistant to aztreonam. 3 P. aeruginosa are intrinsically resistant to tigecycline.
Table
Table 4. In vitro activity of cefiderocol and comparators against Gram-negative pathogens isolated from hospitals in France and Belgium according to EUCAST breakpoints.
Table 4. In vitro activity of cefiderocol and comparators against Gram-negative pathogens isolated from hospitals in France and Belgium according to EUCAST breakpoints.
Species# of IsolatesAntimicrobial AgentMIC (mg/L) S/I/R
RangeMIC50MIC90 S (%) I (%) R (%)
S. maltophilia(n = 25)Cefiderocol≤0.03–0.12≤0.030.06 100/0
Ceftolozane–tazobactam≤0.03–>6432>64 24/76
Ceftazidime0.5–>6464>64 01684
Ceftazidime–avibactam0.12–>6464>64 20/80
Meropenem2–>64>64>64 4096
SXT≤0.25–>160.5>16 0720
Amikacin≤4–>64>64>64 16/84
Levofloxacin≤1–8≤18 06040
Colistin≤0.5–>84>8 32/32
Minocycline≤2≤2≤2 10000
Tigecycline≤0.25–2≤0.251 76/24
B. cepacia(n = 13)Cefiderocol≤0.03–8≤0.030.5 92.3/7.7
Ceftolozane–tazobactam1–>644>64 61.5/38.5
Cefepime8–>16>16>16 015.484.6
Ceftazidime4–>648>64 061.538.5
Ceftazidime–avibactam4–64432 69.2/30.8
Aztreonam>32>32>32 00100
Meropenem16–643264 00100
Amikacin64–>64>64>64 0/100
Ciprofloxacin0.5–>41>4 07.792.3
Colistin 1>8>8>8 0/100
Tigecycline1–>44>4 0/100
A. xylosoxidans(n = 12)Cefiderocol0.25–20.51 100/0
Ceftolozane–tazobactam16–>64>64>64 0/100
Cefepime>16>16>16 00100
Ceftazidime16–>64>64>64 00100
Ceftazidime–avibactam8–6464>64 16.6/83.3
Aztreonam>32>32>32 00100
Meropenem0.5–323232 16.716.766.7
Amikacin64–>64>64>64 0/100
Ciprofloxacin2–>82>4 00100
Colistin0.5–>84>8 33.3/66.7
Tigecycline0.25–412 25075
Elizabethkingia sp.(n = 2)Cefiderocol0.12–1
Ceftolozane–tazobactam16–32
Cefepime8–32
Ceftazidime16–>64
Ceftazidime–avibactam>64
Aztreonam>32
Meropenem32
Amikacin4>64
Ciprofloxacin0.25–0.5
Colistin16
Tigecycline0.5–4
1B. cepacia isolates are naturally resistant to colistin.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Oueslati, S.; Bogaerts, P.; Dortet, L.; Bernabeu, S.; Ben Lakhal, H.; Longshaw, C.; Glupczynski, Y.; Naas, T. In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium. Antibiotics 2022, 11, 1352. https://doi.org/10.3390/antibiotics11101352

AMA Style

Oueslati S, Bogaerts P, Dortet L, Bernabeu S, Ben Lakhal H, Longshaw C, Glupczynski Y, Naas T. In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium. Antibiotics. 2022; 11(10):1352. https://doi.org/10.3390/antibiotics11101352

Chicago/Turabian Style

Oueslati, Saoussen, Pierre Bogaerts, Laurent Dortet, Sandrine Bernabeu, Hend Ben Lakhal, Christopher Longshaw, Youri Glupczynski, and Thierry Naas. 2022. "In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium" Antibiotics 11, no. 10: 1352. https://doi.org/10.3390/antibiotics11101352

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop