Next Article in Journal
Detection and Characterization of Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae from Hospital Effluents of Ouagadougou, Burkina Faso
Next Article in Special Issue
High Diversity but Monodominance of Multidrug-Resistant Bacteria in Immunocompromised Pediatric Patients with Acute Lymphoblastic Leukemia Developing GVHD Are Not Associated with Changes in Gut Mycobiome
Previous Article in Journal
A Narrative Review on the Role of Dalbavancin in the Treatment of Bone and Joint Infections
Previous Article in Special Issue
Predicting Extended-Spectrum Beta-Lactamase and Carbapenem Resistance in Enterobacteriaceae Bacteremia: A Diagnostic Model Systematic Review and Meta-Analysis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 12
Issue 10
10.3390/antibiotics12101493
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 Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria

by
Cécile Emeraud
1,2,
Sandrine Bernabeu
1,2 and
Laurent Dortet
1,2,*
1
Department of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique—Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France
2
INSERM UMR 1184, RESIST Unit, Faculty of Medicine, Paris-Saclay University, 94270 Le Kremlin-Bicêtre, France
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(10), 1493; https://doi.org/10.3390/antibiotics12101493
Submission received: 18 August 2023 / Revised: 26 September 2023 / Accepted: 28 September 2023 / Published: 29 September 2023
(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)
Browse Figure
Review Reports Versions Notes

Abstract

:
Background: Despite the availability of new options (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam and cefiderocol), it is still very difficult to treat infections caused by metallo-β-lactamase (MBLs)-producers resistant to aztreonam. The in vitro efficacy of aztreonam in association with avibactam, vaborbactam or relebactam was evaluated on a collection of MBL-producing Enterobacterales, MBL-producing P. aeruginosa and highly drug-resistant S. maltophilia. Methods: A total of fifty-two non-duplicate MBL-producing Enterobacterales, five MBL-producing P. aeruginosa and five multidrug-resistant S. maltophila isolates were used in this study. The minimum inhibitory concentrations (MICs) of aztreonam, meropenem-vaborbactam and imipenem-relebactam were determined by Etest® (bioMérieux, La Balme-les-Grottes) according to EUCAST recommendations. For aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam associations, the MICs were determined using Etest® on Mueller-Hinton (MH) agar supplemented with 8 mg/L of avibactam, 8 mg/L of vaborbactam and 4 mg/L of relebactam. The MICs were interpreted according to EUCAST guidelines. Results: The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a standard exposure of aztreonam (1g × 3, IV) were 84.6% (44/52), 55.8% and 34.6% for Enterobacterales and 0% for all combinations for P. aeruginosa and S. maltophila. The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a high exposure of aztreonam (2g × 4, IV) were 92.3%, 78.9% and 57.7% for Enterobacterales, 75%, 60% and 60% for P. aeruginosa and 100%, 100% and 40% for S. maltophila. Conclusions: As previously demonstrated for an aztreonam/ceftazidime-avibactam combination, aztreonam plus imipenem-relebactam and aztreonam plus meropenem-vaborbactam might be useful options, but with potentially lower efficiency, to treat infections caused by aztreonam-non-susceptible MBL-producing Gram-negative strains.

1. Introduction

The extensive dissemination of carbapenemase-producing Gram-negative bacteria poses a global threat to public health. It is crucial to implement new therapeutic strategies to treat infections caused by highly resistant pathogens. Carbapenemase belong to three of four classes of the Ambler classification: class A carbapenemases (mostly KPC types) [1], class B carbapenemases or metallo-β-lactamases (MBLs) (mostly NDM, VIM, or IMP types) [2], and class D carbapenemases (mostly OXA-48-like types in Enterobacterales) [3]. Recently, new therapeutic alternatives have been marked for the treatment of carbapenemase producers. These new drugs include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam and cefiderocol. Despite the availability of these new options, it is still very difficult to treat infections caused by MBL producers resistant to aztreonam. Indeed, these isolates are resistant to ceftazidime-avibactam, meropenem-vaborbactam and imipenem-relebactam through the MBL-hydrolyzing activity, which is not inhibited by the added β-lactamase inhibitor. Regarding cefiderocol, it might be active on MBLs, but NDM producers have cefiderocol’s MIC50 close to the clinical breakpoint of 2 mg/L, resulting in only 70% susceptibility [4]. Since current MBLs, such as VIM, NDM or IMP, are not able to hydrolyze aztreonam, resistance to this antimicrobial in MBL producers is due to the co-production of an ESBL or an AmpC. Accordingly, it has been demonstrated that the concomitant use of aztreonam plus ceftazidime-avibactam or amoxicillin-clavulanate or ceftolozane-tazobactam are accurate options to treat infections caused by MBL + ESBL or MBL + AmpC producers, with aztreonam plus ceftazidime-avibactam being the most powerful strategy [5]. Unfortunately, is has been recently shown that aztreonam-avibactam resistance emerged in NDM-producing E. coli through the association of modified penicillin-binding protein 3 (PBP3) and the production of CMY-42 cephalosporinase [6]. Thus, it is crucial to consider other therapeutic alternatives. In this study, we evaluated the susceptibility of aztreonam-resistant MBL-producing isolates to aztreonam in association with two other marketed β-lactamase inhibitors: vaborbactam and relebactam. Vaborbactam, a cyclic boronic β-lactamase inhibitor and relebactam, a diazabicyclooctane inhibitor, are very potent against KPC enzymes, but are also active on diverse class A (including ESBL) and class C β-lactamases (AmpC) [7]. As previously demonstrated for aztreonam-avibactam [5], aztreonam-vaborbactam and aztreonam-relebactam seemed to be effective on NDM-producing K. pneumoniae [8] and few multidrug-resistant S. maltophila [9]. Here, we assessed the susceptibility of aztreonam in combination with vaborbactam or relebactam or avibactam on a collection of MBL producers including Enterobacterales (including species other than K. pneumoniae), P. aeruginosa and S. maltophilia.

2. Results

A total of fifty-two non-duplicate MBL-producing Enterobacterales, five MBL-producing P. aeruginosa and five multidrug-resistant S. maltophila isolates were used in this study. These isolates have already been tested for aztreonam-avibactam in a previous study [5]. All strains were resistant to aztreonam due to the co-production of an ESBL and/or a cephalosporinase. The MBL-producing Enterobacterales included 30 NDM-producers with 11 isolates co-producing one OXA-48-like carbapenemase, fourteen VIM-producers, six IMP-producers, one GIM-1-producer and one TMB-1-producer. The MBL-producing P. aeruginosa were one VIM-2-, three IMP-1- and one IMP-2-producers. S. maltophila isolates were resistant to all β-lactams including ticarcillin-clavulanate, and to all other antimicrobials including fluoroquinolones and trimethoprim-sulfamethoxazole [5].
None of the strains included in the study were sensitive to aztreonam at standard exposure (the MICs range from 2 to >256 mg/L). Regarding the MIC distribution of each association, aztreonam-relebactam appeared to be more efficient than aztreonam-vaborbactam, but both are less efficient than aztreonam-avibactam (Figure 1).
The addition of avibactam, relebactam or vaborbactam decreases the MIC of aztreonam by at least four dilutions for 100%, 93.5% and 90.3% of the strains, respectively (Table 1). The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a standard exposure of aztreonam (meaning 1g × 3, IV according to EUCAST guidelines) (≤1 mg/L for Enterobacterales and ≤0.001 mg/L for S. maltophila and P. aeruginosa) were 84.6% (44/52), 55.8% (29/52) and 34.6% (18/52) for Enterobacterales and 0% for all combinations for P. aeruginosa and S. maltophila, respectively. The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a high exposure of aztreonam (meaning 2g × 4, IV according to EUCAST guidelines) (≤4 mg/L for Enterobacterales and ≤16 mg/L for S. maltophila and P. aeruginosa) were 92.3% (48/52), 78.9% (41/52) and 57.7% (30/52) for Enterobacterales, 75% (4/5), 60% (3/5) and 60% (3/5) for P. aeruginosa and 100% (5/5), 100% (5/5) and 40% (2/5) for S. maltophila isolates, respectively (Table 1). As previously observed for the aztreonam-avibactam combination [5], the MICs of aztreonam-relebactam and aztreonam-vaborbactam were higher for NDM-producing E. coli compared to NDM-producing K. pneumoniae.

3. Discussion

In conclusion, as previously demonstrated for the aztreonam/ceftazidime-avibactam combination [10,11,12,13,14,15,16,17,18], aztreonam plus imipenem-relebactam [19,20,21] and aztreonam plus meropenem-vaborbactam [21] might be useful options to treat infections caused by aztreonam-non-susceptible MBL-producing Gram-negative strains. Despite the fact that avibactam seems to be the most potent inhibitor in association with aztreonam, it should be noted that ceftazidime is strongly hydrolyzed by ESBL and MBL with MICs >256 mg/L resulting in a non-residual effect of this drug in the tripartite combination aztreonam-ceftazidime-avibactam. Contrarily, imipenem and meropenem are not hydrolyzed by ESBL or AmpC and might retain partial activity on MBL (sometimes the MICs range from 2 to 8 mg/L). Accordingly, the tripartite associations of aztreonam-imipenem-relebactam and aztreonam-meropenem-vaborbactam might benefit not only the activity of the inhibitor with aztreonam, but also partly the residual activity of the carbapenem. Notably, our collection of Gram-negative bacteria included only a few isolates of P. aeruginosa and S. maltophilia. Due to this limitation, the results of the susceptibility of these two species have to be confirmed in further studies.
According to the recent guidelines of the Infectious Diseases Society of America (IDSA) [22] and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [23], aztreonam-avibactam association produced by injecting aztreonam and ceftazidime-avibactam simultaneously [24] is considered the first-line treatment for infections caused by MBL producers. This is particularly the case for NDM producers that often display an increased MIC to cefiderocol [4,25,26,27], the other potential option for the treatment of infections caused by MBL producers [22,23].
In our collection, four NDM-producing E. coli displayed resistance to the aztreonam-avibactam association. In E. coli, the impact of the alteration of PBP3 has been recently described to be responsible for increased resistance to aztreonam-avibactam [11] and a cross-resistance to cefiderocol [28,29]. With the recent emergence of aztreonam-avibactam resistance among carbapenemase-producing Enterobacterales [11,29,30], these tripartite associations of aztreonam-imipenem-relebactam and aztreonam-meropenem-vaborbactam have to be taken into consideration as last-resort treatment options. Unfortunately, resistance to aztreonam-meropenem-vaborbactam has already been reported in a KPC variant producing K. pneumoniae [31]. Accordingly, the rapid development of additional options, such as new combinations with more potent inhibitors (e.g., zidebactam and taniborbactam) are mandatory [32,33,34]. However, as it was observed for aztreonam-avibactam, which is not already marketed, resistance to these very novel inhibitors already exists, as reported for cefepime-taniborbactam and NDM-9 producers [35,36].
In conclusion, aztreonam-vaborbactam and aztreonam-relebactam could be useful options for the treatment of infections caused by aztreonam-resistant MBL-producing isolates but with a potential lower efficiency compared to aztreonam-avibactam.

4. Materials and Methods

A total of 52 non-duplicate MBL-producing Enterobacterales, 5 MBL-producing P. aeruginosa and 5 multidrug-resistant S. maltophila isolates were used in this study. All strains were sequenced using the Illumina technique and the resistance genes were identified using Resfinder 4.1 (https://cge.food.dtu.dk/services/ResFinder/, 27 September 2023).
The MICs of aztreonam, meropenem-vaborbactam and imipenem-relebactam were determined by Etest® (bioMérieux, La Balme-les-Grottes) according to EUCAST recommendations. For aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam associations, MICs were determined using Etest® on MH agar supplemented with 8 mg/L of avibactam (provided by Pfizer, France), 8 mg/L of vaborbactam (CliniSciences, Nanterre, France) and 4 mg/L of relebactam (provided by MSD, Puteaux, France). The MICs of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam were interpreted in the same way as aztreonam alone, according to EUCAST guidelines as updated in 2022 (Table 2).
Since no recommendation exists regarding these molecules for S. maltophila, interpretation criteria of Pseudomonas spp. were used (Table 3). A control of the accuracy of β-lactam inhibitor-supplemented MH agar was performed. For this purpose, the MICs of 13 strains, obtained with the imipenem and meropenem Etest® (bioMérieux, France) on MH agar supplemented with 8 mg/L of vaborbactam and 4 mg/L of relebactam, were compared to the MICs obtained with the imipenem-relebactam and meropenem-vaborbactam Etest® (bioMérieux, France). The difference in MICs obtained between the two methods did not exceed two dilutions, validating the methodology used in this study (Table 3). However, due to the relatively low number of tested isolates, the full validity of this method might have to be confirmed in further studies.
Of note is the fact that the accuracy of determining the MIC of aztreonam-avibactam using MH agar supplemented with 8 mg/L of avibactam has already been demonstrated on this strain collection. In the previous study, this method was also demonstrated to give similar results with the Etest® strip superposition method [5]. E. coli ATCC 53126, K. pneumoniae ATCC 700,603 and two KPC-producing strains were used as quality controls.

Author Contributions

Conceptualization, L.D.; methodology, L.D. and C.E.; validation, L.D. and C.E.; formal analysis, L.D. and C.E.; investigation, S.B. and C.E.; resources, L.D.; data curation, C.E.; writing—original draft preparation, C.E.; writing—review and editing, L.D.; supervision, L.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Naas, T.; Dortet, L.; Iorga, B.I. Structural and Functional Aspects of Class A Carbapenemases. Curr. Drug Targets 2016, 17, 1006–1028. [Google Scholar] [CrossRef] [PubMed]
  2. Mojica, M.F.; Bonomo, R.A.; Fast, W. B1-Metallo-beta-Lactamases: Where Do We Stand? Curr. Drug Targets 2016, 17, 1029–1050. [Google Scholar] [CrossRef] [PubMed]
  3. Poirel, L.; Potron, A.; Nordmann, P. OXA-48-like carbapenemases: The phantom menace. J. Antimicrob. Chemother. 2012, 67, 1597–1606. [Google Scholar] [CrossRef] [PubMed]
  4. Bonnin, R.A.; Emeraud, C.; Jousset, A.B.; Naas, T.; Dortet, L. Comparison of disk diffusion, MIC test strip and broth microdilution methods for cefiderocol susceptibility testing on carbapenem-resistant enterobacterales. Clin. Microbiol. Infect. 2022, 28, 1156.e1–1156.e5. [Google Scholar] [CrossRef]
  5. Emeraud, C.; Escaut, L.; Boucly, A.; Fortineau, N.; Bonnin, R.A.; Naas, T.; Dortet, L. Aztreonam plus Clavulanate, Tazobactam, or Avibactam for Treatment of Infections Caused by Metallo-beta-Lactamase-Producing Gram-Negative Bacteria. Antimicrob. Agents Chemother. 2019, 63. [Google Scholar] [CrossRef] [PubMed]
  6. Sadek, M.; Juhas, M.; Poirel, L.; Nordmann, P. Genetic Features Leading to Reduced Susceptibility to Aztreonam-Avibactam among Metallo-beta-Lactamase-Producing Escherichia coli Isolates. Antimicrob. Agents Chemother. 2020, 64. [Google Scholar] [CrossRef]
  7. Zhanel, G.G.; Lawrence, C.K.; Adam, H.; Schweizer, F.; Zelenitsky, S.; Zhanel, M.; Lagace-Wiens, P.R.S.; Walkty, A.; Denisuik, A.; Golden, A.; et al. Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs 2018, 78, 65–98. [Google Scholar] [CrossRef]
  8. Maraki, S.; Mavromanolaki, V.E.; Moraitis, P.; Stafylaki, D.; Kasimati, A.; Magkafouraki, E.; Scoulica, E. Ceftazidime-avibactam, meropenen-vaborbactam, and imipenem-relebactam in combination with aztreonam against multidrug-resistant, metallo-beta-lactamase-producing Klebsiella pneumoniae. Eur. J. Clin. Microbiol. Infect. Dis. 2021, 40, 1755–1759. [Google Scholar] [CrossRef]
  9. Biagi, M.; Lamm, D.; Meyer, K.; Vialichka, A.; Jurkovic, M.; Patel, S.; Mendes, R.E.; Bulman, Z.P.; Wenzler, E. Activity of Aztreonam in Combination with Avibactam, Clavulanate, Relebactam, and Vaborbactam against Multidrug-Resistant Stenotrophomonas maltophilia. Antimicrob. Agents Chemother. 2020, 64. [Google Scholar] [CrossRef]
  10. Kang, Y.; Xie, L.; Yang, J.; Cui, J. Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa. Front. Cell Infect. Microbiol. 2023, 13, 1023948. [Google Scholar] [CrossRef]
  11. Livermore, D.M.; Mushtaq, S.; Vickers, A.; Woodford, N. Activity of aztreonam/avibactam against metallo-beta-lactamase-producing Enterobacterales from the UK: Impact of penicillin-binding protein-3 inserts and CMY-42 beta-lactamase in Escherichia coli. Int. J. Antimicrob. Agents 2023, 61, 106776. [Google Scholar] [CrossRef] [PubMed]
  12. Rossolini, G.M.; Stone, G.; Kantecki, M.; Arhin, F.F. In vitro activity of aztreonam/avibactam against isolates of Enterobacterales collected globally from ATLAS in 2019. J. Glob. Antimicrob. Resist. 2022, 30, 214–221. [Google Scholar] [CrossRef] [PubMed]
  13. Sader, H.S.; Castanheira, M.; Kimbrough, J.H.; Kantro, V.; Mendes, R.E. Aztreonam/avibactam activity against a large collection of carbapenem-resistant Enterobacterales (CRE) collected in hospitals from Europe, Asia and Latin America (2019–21). JAC Antimicrob. Resist. 2023, 5, dlad032. [Google Scholar] [CrossRef] [PubMed]
  14. Sonnevend, A.; Ghazawi, A.; Darwish, D.; Barathan, G.; Hashmey, R.; Ashraf, T.; Rizvi, T.A.; Pal, T. In vitro efficacy of ceftazidime-avibactam, aztreonam-avibactam and other rescue antibiotics against carbapenem-resistant Enterobacterales from the Arabian Peninsula. Int. J. Infect. Dis. 2020, 99, 253–259. [Google Scholar] [CrossRef]
  15. Wang, X.; Zhang, F.; Zhao, C.; Wang, Z.; Nichols, W.W.; Testa, R.; Li, H.; Chen, H.; He, W.; Wang, Q.; et al. In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob. Agents Chemother. 2014, 58, 1774–1778. [Google Scholar] [CrossRef]
  16. Wise, M.G.; Karlowsky, J.A.; Mohamed, N.; Kamat, S.; Sahm, D.F. In vitro activity of aztreonam-avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019–2021. Eur. J. Clin. Microbiol. Infect. Dis. 2023, 42, 1135–1143. [Google Scholar] [CrossRef]
  17. Zhang, B.; Zhu, Z.; Jia, W.; Qu, F.; Huang, B.; Shan, B.; Yu, H.; Tang, Y.; Chen, L.; Du, H. In vitro activity of aztreonam-avibactam against metallo-beta-lactamase-producing Enterobacteriaceae-A multicenter study in China. Int. J. Infect. Dis. 2020, 97, 11–18. [Google Scholar] [CrossRef]
  18. Zou, C.; Wei, J.; Shan, B.; Chen, X.; Wang, D.; Niu, S. In vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam Against Carbapenem-resistant Enterobacteriaceae Isolates Collected from Three Secondary Hospitals in Southwest China Between 2018 and 2019. Infect. Drug Resist. 2020, 13, 3563–3568. [Google Scholar] [CrossRef]
  19. Biagi, M.; Lee, M.; Wu, T.; Shajee, A.; Patel, S.; Deshpande, L.M.; Mendes, R.E.; Wenzler, E. Aztreonam in combination with imipenem-relebactam against clinical and isogenic strains of serine and metallo-beta-lactamase-producing enterobacterales. Diagn. Microbiol. Infect. Dis. 2022, 103, 115674. [Google Scholar] [CrossRef]
  20. O’Donnell, J.N.; Putra, V.; Belfiore, G.M.; Maring, B.L.; Young, K.; Lodise, T.P. In vitro activity of imipenem/relebactam plus aztreonam against metallo-beta-lactamase-producing, OprD-deficient Pseudomonas aeruginosa with varying levels of Pseudomonas-derived cephalosporinase production. Int. J. Antimicrob. Agents 2022, 59, 106595. [Google Scholar] [CrossRef]
  21. Vazquez-Ucha, J.C.; Alonso-Garcia, I.; Guijarro-Sanchez, P.; Lasarte-Monterrubio, C.; Alvarez-Fraga, L.; Cendon-Esteve, A.; Outeda, M.; Maceiras, R.; Pena-Escolano, A.; Martinez-Guitian, M.; et al. Activity of aztreonam in combination with novel beta-lactamase inhibitors against metallo-beta-lactamase-producing Enterobacterales from Spain. Int. J. Antimicrob. Agents 2023, 61, 106738. [Google Scholar] [CrossRef] [PubMed]
  22. Infectious Diseases Society of America. IDSA 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. 2023. Available online: https://www.idsociety.org/globalassets/idsa/practice-guidelines/amr-guidance/1.0/idsa-amr-guidance-v3.0.pdf (accessed on 31 December 2022).
  23. Paul, M.; Carrara, E.; Retamar, P.; Tangden, 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] [PubMed]
  24. Falcone, M.; Daikos, G.L.; Tiseo, G.; Bassoulis, D.; Giordano, C.; Galfo, V.; Leonildi, A.; Tagliaferri, E.; Barnini, S.; Sani, S.; et al. Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-beta-lactamase-Producing Enterobacterales. Clin. Infect. Dis. 2021, 72, 1871–1878. [Google Scholar] [CrossRef]
  25. Alzayer, M.; Alghoribi, M.F.; Alalwan, B.; Alreheli, A.; Aljohani, S.; Bosaeed, M.; Doumith, M. In vitro activity of cefiderocol against clinically important carbapenem non-susceptible Gram-negative bacteria from Saudi Arabia. J. Glob. Antimicrob. Resist. 2023, 32, 176–180. [Google Scholar] [CrossRef] [PubMed]
  26. Kohira, N.; Hackel, M.A.; Ishioka, Y.; Kuroiwa, M.; Sahm, D.F.; Sato, T.; Maki, H.; Yamano, Y. Reduced susceptibility mechanism to cefiderocol, a siderophore cephalosporin, among clinical isolates from a global surveillance programme (SIDERO-WT-2014). J. Glob. Antimicrob. Resist. 2020, 22, 738–741. [Google Scholar] [CrossRef]
  27. 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. [Google Scholar] [CrossRef]
  28. Poirel, L.; Ortiz de la Rosa, J.M.; Sakaoglu, Z.; Kusaksizoglu, A.; Sadek, M.; Nordmann, P. NDM-35-Producing ST167 Escherichia coli Highly Resistant to beta-Lactams Including Cefiderocol. Antimicrob. Agents Chemother. 2022, 66, e0031122. [Google Scholar] [CrossRef] [PubMed]
  29. Simner, P.J.; Bergman, Y.; Conzemius, R.; Jacobs, E.; Tekle, T.; Beisken, S.; Tamma, P.D. An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-beta-Lactam Resistance. Open Forum Infect. Dis. 2023, 10, ofad276. [Google Scholar] [CrossRef]
  30. Wu, S.; Ma, K.; Feng, Y.; Zong, Z. Resistance to aztreonam-avibactam due to a mutation of SHV-12 in Enterobacter. Ann. Clin. Microbiol. Antimicrob. 2023, 22, 49. [Google Scholar] [CrossRef]
  31. Satapoomin, N.; Dulyayangkul, P.; Avison, M.B. Klebsiella pneumoniae Mutants Resistant to Ceftazidime-Avibactam Plus Aztreonam, Imipenem-Relebactam, Meropenem-Vaborbactam, and Cefepime-Taniborbactam. Antimicrob. Agents Chemother. 2022, 66, e0217921. [Google Scholar] [CrossRef]
  32. Karvouniaris, M.; Almyroudi, M.P.; Abdul-Aziz, M.H.; Blot, S.; Paramythiotou, E.; Tsigou, E.; Koulenti, D. Novel Antimicrobial Agents for Gram-Negative Pathogens. Antibiotics 2023, 12, 761. [Google Scholar] [CrossRef] [PubMed]
  33. Le Terrier, C.; Nordmann, P.; Freret, C.; Seigneur, M.; Poirel, L. Impact of Acquired Broad Spectrum beta-Lactamases on Susceptibility to Novel Combinations Made of beta-Lactams (Aztreonam, Cefepime, Meropenem, and Imipenem) and Novel beta-Lactamase Inhibitors in Escherichia coli and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2023, 67, e0033923. [Google Scholar] [CrossRef] [PubMed]
  34. Le Terrier, C.; Nordmann, P.; Sadek, M.; Poirel, L. In vitro activity of cefepime/zidebactam and cefepime/taniborbactam against aztreonam/avibactam-resistant NDM-like-producing Escherichia coli clinical isolates. J. Antimicrob. Chemother. 2023, 78, 1191–1194. [Google Scholar] [CrossRef] [PubMed]
  35. Le Terrier, C.; Gruenig, V.; Fournier, C.; Nordmann, P.; Poirel, L. NDM-9 resistance to taniborbactam. Lancet Infect. Dis. 2023, 23, 401–402. [Google Scholar] [CrossRef] [PubMed]
  36. Le Terrier, C.; Nordmann, P.; Buchs, C.; Di, D.Y.W.; Rossolini, G.M.; Stephan, R.; Castanheira, M.; Poirel, L. Wide dissemination of Gram-negative bacteria producing the taniborbactam-resistant NDM-9 variant: A One Health concern. J. Antimicrob. Chemother. 2023, 78, 2382–2384. [Google Scholar] [CrossRef]
Antibiotics 12 01493 g001
Figure 1. MICs of aztreonam (A), aztreonam-avibactam (B), aztreonam-relebactam (C) and aztreonam-vaborbactam (D).
Figure 1. MICs of aztreonam (A), aztreonam-avibactam (B), aztreonam-relebactam (C) and aztreonam-vaborbactam (D).
Antibiotics 12 01493 g001
Table 1. MICs of aztreonam (ATM), aztreonam-avibactam (ATM + AVI), aztreonam-relebactam (ATM + REL) and aztreonam-vaborbactam (ATM + VAB).
Table 1. MICs of aztreonam (ATM), aztreonam-avibactam (ATM + AVI), aztreonam-relebactam (ATM + REL) and aztreonam-vaborbactam (ATM + VAB).
Speciesβ-LactamasesMICs (mg/L)
ATMATM + AVIAZM+ REL ATM + VAB
E. coli ATCC 53126 0.047ND0.0470.047
K. pneumoniae ATCC 700603 64ND0.52
E. coliKPC>256ND0.382
K. pneumoniaeKPC>256ND0.1250.25
E. coliNDM-1 + OXA-1 + OXA-10 + CMY-16 + TEM-1320.1250.1250.5
E. coliNDM-1 + CTX-M-15 + TEM-1>25611224
E. coliNDM-1 + OXA-1 + OXA-2 + CTX-M-15 + TEM-1>25621232
E. coliNDM-1 + CTX-M-15 + TEM-1>256632192
E. coliNDM-4 + CTX-M-15 + OXA-1>25661624
E. coliNDM-4 + CTX-M-15 + CMY-6>2566824
E. coliNDM-5 + TEM-1 + CTX-M-15>25682464
E. coliNDM-6 + CTX-M-15 + OXA-1>256138
E. coliNDM-7 + CTX-M-15>25641232
K. pneumoniaeNDM-1 + CTX-M-15 + SHV-11 + OXA-1>2560.12511.5
K. pneumoniaeNDM-1 + CTX-M-15 + CMY-4 + OXA-1>2560.75448
K. pneumoniaeNDM-1 + CTX-M-15 + OXA-1 + OXA-9 + TEM-1 + SHV-28 + SHV-11>2560.25412
K. pneumoniaeNDM-1 + OXA-1 + SHV-11>2560.0470.0940.094
K. pneumoniaeNDM-1 + OXA-1 + CTX-M-15 + TEM-1 + SHV-28 + OXA-9 + CMY-6>2560.0470.750.75
K. pneumoniaeNDM-1 + TEM-1 + CTX-M-15 + SHV-12 + OXA-9>2560.1251.51.5
K. pneumoniaeNDM-1 + TEM-1 + CTX-M-15 + SHV-12 + OXA-9>2560.1251.512
K. pneumoniaeNDM-1 + TEM-1 + CTX-M-15 + SHV-11 + OXA-1>2560.0640.750.75
P. stuartiiNDM-1 + OXA-1 + CMY-6 + TEM-180.0320.0160.032
Salmonella entericaNDM-1 + CTX-M-15 + TEM-1 + OXA-1 + OXA-9 + OXA-10>2560.1250.750.75
E. coliVIM-1 + CTX-M-3>2560.1251.512
E. coliVIM-4 + CTX-M15161.51.58
K. pneumoniaeVIM-1 + SHV-5>2560.25324
K. pneumoniaeVIM-1 + SHV-12>2560.12516
K. pneumoniaeVIM-1 + CTX-M-15>2560.190.1250.125
K. pneumoniaeVIM-1 + SHV-5160.1911
K. pneumoniaeVIM-1 + TEM-1 + SHV-5>2560.2516
K. pneumoniaeVIM-1 + SHV-5>2560.251232
K. pneumoniaeVIM-1 + SHV-5>2560.1251.58
K. pneumoniaeVIM-19 + CTX-M-3 + TEM-1 + SHV-160.0470.0320.094
E. cloacaeVIM-1 + SHV-702560.0940.52
E. cloacaeVIM-4 + CTX-M-15 + TEM-1 + SHV-316410.54
C. freundiiVIM-2 + TEM-1 + CTX-M-15160.2531.5
C. freundiiVIM-2 + TEM-1 + OXA-9 + OXA-10321.51.54
E. coliIMP-8 + SHV -121280.190.754
K. pneumoniaeIMP-1 + TEM-1530.0940.1250.38
K. pneumoniaeIMP-1 + TEM-15 + CTX-M-1520.0940.1250.38
K. pneumoniaeIMP-8 + SHV -12>2560.0940.1254
E. cloacaeIMP-8 + SHV-12120.0320.1250.38
S. marscecensIMP-1140.50.1250.38
E. cloacaeGIM-1 + CTX-M-15120.50.191
C. freundiiTMB-1 + overexpressed cephalosporinase640.1250.190.75
K. pneumoniaeNDM-1 + OXA-181 + SHV-11 + TEM-1 + CTX-M-15 + OXA-1 640.0940.50.5
K. pneumoniaeNDM-1 + OXA-181 + SHV-27 + CTX-M-15 + TEM-1 + OXA-1 1280.2511
K. pneumoniaeNDM-1 + OXA-181 + SHV-11 + CTX-M-15 + OXA-1 2560.1914
K. pneumoniaeNDM-1 + OXA-181 + SHV-11 + TEM-1 + CTX-M-15 + OXA-9 >2560.190.7516
K. pneumoniaeNDM-1 + OXA-181 + SHV-2 + CTX-M-15 + OXA-1 >2560.1250.751
C. freundiiNDM-1 + OXA-181 + OXA-1 + OXA-9 + OXA-10 + CTX-M-15 + TEM-1>2560.75432
E. coliNDM-1 + OXA-48 + CTX-M-15320.0940.51.5
E. coliNDM-1 + OXA-48 + CTX-M-15>2560.75616
K. pneumoniaeNDM-1 + OXA-232 + CTX-M-15640.0940.51.5
E. coliNDM-1 + OXA-232 + CTX-M-15>256161.5
E. coliNDM-5 + OXA-232 + CTX-M-15>2561632
Percentage of susceptible strains of Enterobacterales with standard exposure0%84.6%55.8%34.6%
Percentage of susceptible strains of Enterobacterales with high exposure8.1%92.3%78.9%57.7%
Percentage of resistant strains of Enterobacterales91.9%13.5%21.1%42.3%
S. maltophilia >2560.51.51.5
S. maltophilia >2562364
S. maltophilia >2560.514
S. maltophilia >2562348
S. maltophilia >2561132
P. aeruginosaVIM-2 + overexpressed Cephalosporinase3283224
P. aeruginosaIMP-2 + overexpressed Cephalosporinase61.522
P. aeruginosaIMP-1 + overexpressed Cephalosporinase243416
P. aeruginosaIMP-1 + overexpressed Cephalosporinase963212896
P. aeruginosaIMP-1 + overexpressed Cephalosporinase12386
Percentage of susceptible strains with standard exposure of aztreonam in the combination (total)0%66.1%45.2%29.0%
Percentage of susceptible strains with high exposure of aztreonam in the combination (total)4.8%87.1%79.1%56.4%
Percentage of resistant strains (total)95.2%12.9%21.0%43.6%
Percentage of strains with aztreonam MIC reduction ≥ 4-fold dilution 100%93.5%90.3%
Black: resistant; Grey: susceptible at high exposure; Blank: susceptible at standard dosage.
Table 2. EUCAST breakpoint of aztreonam for Enterobacterales and Pseudomonas aeruginosa (https://www.eucast.org/clinical_breakpoints, accessed on 27 September 2023).
Table 2. EUCAST breakpoint of aztreonam for Enterobacterales and Pseudomonas aeruginosa (https://www.eucast.org/clinical_breakpoints, accessed on 27 September 2023).
MICs (mg/L)
EnterobacteralesP. aeruginosa
Susceptible with standard exposure≤1≤0.001
Susceptible with high exposure≤4≤16
Resistant>4>16
Table 3. MICs of imipenem-relebactam (IMP + REL) and meropenem-vaborbactam (MEM + VAB) obtained using Etest® and supplemented Mueller–Hinton agar.
Table 3. MICs of imipenem-relebactam (IMP + REL) and meropenem-vaborbactam (MEM + VAB) obtained using Etest® and supplemented Mueller–Hinton agar.
MICs
IMP+ REL Etest®IMP+ REL Agar Method aMEM+VAB Etest®MEM+VAB Agar Method b
E. coliNDM-1 + OXA-1 + OXA-2 + CTX-M-15 + TEM-14868
E. coliNDM-4 + CTX-M-15 + OXA-116>3232>32
E. coliNDM-5 + TEM-1 + CTX-M-15>32>32>32>32
K. pneumoniaeNDM-1 + TEM-1 + CTX-M-15 + SHV-12 + OXA-92124
P. stuartiiNDM-1 + OXA-1 + CMY-6 + TEM-14822
E. coliVIM-4 + ESBL6431
K. pneumoniaeVIM-1 + SHV-5341.52
K. pneumoniaeVIM-19 + CTX-M-3 + TEM-1 + SHV-1120.751
K. pneumoniaeNDM-1 + OXA-181 + SHV-11 + CTX-M-15 + OXA-1 481212
E. coliNDM-1 + OXA-48 + ESBL2422
E. coliNDM-5 + OXA-232 + ESBL22168
S. maltophilia >32>32>32>32
P. aeruginosaIMP-1 + overexpressed Cephalosporinase>3216>32>32
a Mueller–Hinton agar supplemented with 4 mg/L of relebactam. b Mueller–Hinton agar supplemented with 8 mg/L of vaborbactam.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Emeraud, C.; Bernabeu, S.; Dortet, L. In Vitro Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria. Antibiotics 2023, 12, 1493. https://doi.org/10.3390/antibiotics12101493

AMA Style

Emeraud C, Bernabeu S, Dortet L. In Vitro Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria. Antibiotics. 2023; 12(10):1493. https://doi.org/10.3390/antibiotics12101493

Chicago/Turabian Style

Emeraud, Cécile, Sandrine Bernabeu, and Laurent Dortet. 2023. "In Vitro Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria" Antibiotics 12, no. 10: 1493. https://doi.org/10.3390/antibiotics12101493

APA Style

Emeraud, C., Bernabeu, S., & Dortet, L. (2023). In Vitro Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria. Antibiotics, 12(10), 1493. https://doi.org/10.3390/antibiotics12101493

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