A New Therapeutic Option Against Metallo-β-Lactamase-Producing Gram-Negative Bacteria: Aztreonam-Avibactam

Öz

Aztreonam-avibactam (ATM-AVI) is a newly developed intravenous antibacterial agent targeting metallo-β-lactamase (MBL)-producing Gram-negative bacteria. It consists of a combination of aztreonam, a monobactam, and avibactam, a broad-spectrum β-lactamase inhibitor. This combination is specifically designed to enhance efficacy against multidrug-resistant Enterobacterales and other Gram-negative pathogens that co-produce MBLs and serine β-lactamases. While aztreonam retains stability against MBL enzymes, it can be inactivated by serine β-lactamases. Avibactam restores the activity of aztreonam by inhibiting Ambler class A, C, and certain class D β-lactamases. Clinical studies have demonstrated the efficacy and safety of the ATM-AVI combination in the treatment of complicated intraabdominal infections, hospital-acquired pneumonia, and infections with limited treatment options. The Phase III REVISIT and ASSEMBLE trials have reported promising outcomes, with high clinical success rates and low mortality. Approved by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), ATM-AVI is considered an alternative therapeutic option against carbapenem-resistant isolates. This review presents a comprehensive evaluation of the pharmacokinetic and pharmacodynamic properties, mechanism of action, susceptibility testing, clinical trials’ data, and potential applications of ATM-AVI.

Anahtar Kelimeler

• Aztreonam
• avibaktam
• metallo-β-laktamaz
• komplike intraabdominal enfeksiyon
• antibiyotik direnci
• Enterobacterales

Metallo-β-Laktamaz Üreten Gram-Negatif Bakterilere Karşı Yeni Bir Tedavi Seçeneği: Aztreonam-Avibaktam

Öz

Aztreonam-avibaktam (ATM-AVI), metallo-β-laktamaz (MBL) üreten Gram-negatif bakterilere karşı geliştirilmiş, intravenöz uygulanan yeni bir antibakteriyel ajan olup, monobaktam sınıfından aztreonam ile geniş spektrumlu bir β-laktamaz inhibitörü olan avibaktamın kombinasyonundan oluşmaktadır. Bu kombinasyon, özellikle MBL ve eş zamanlı olarak serin β-laktamazlar üreten çok ilaca dirençli Enterobacterales ve diğer Gram-negatif patojenlere karşı etkinliği artırmak amacıyla tasarlanmıştır. Aztreonam, MBL enzimlerine karşı stabilitesini korumasına rağmen, serin β-laktamazlar tarafından inaktive edilebilmektedir. Avibaktam ise Ambler sınıfı A, C ve bazı D β-laktamazları inhibe ederek aztreonamın bu enzimlere karşı etkinliğini yeniden kazandırmaktadır. Klinik çalışmalarda, ATM-AVI kombinasyonunun komplike intraabdominal enfeksiyonlar, hastane kaynaklı pnömoni ve sınırlı tedavi seçeneği bulunan enfeksiyonlarda etkili ve güvenli olduğu gösterilmiştir. Faz III REVISIT ve ASSEMBLE çalışmaları, bu ajanın yüksek klinik başarı oranları ve düşük mortalite ile umut vadeden sonuçlar sunduğunu ortaya koymuştur. Avrupa İlaç Ajansı (EMA) ve ABD Gıda ve İlaç Dairesi (FDA) tarafından onaylanmış olan ATM-AVI, karbapenemlere dirençli izolatlara karşı alternatif bir tedavi seçeneği olarak değerlendirilmektedir. Bu derlemede, ATM-AVI’nin farmakokinetik ve farmakodinamik özellikleri, etki mekanizması, duyarlılık testleri, klinik çalışmaların verileri ve potansiyel kullanımı ele alınmıştır.

Anahtar Kelimeler

• Aztreonam
• avibaktam
• metallo-β-laktamaz
• komplike intraabdominal enfeksiyon
• antibiyotik direnci
• Enterobacterales

Kaynakça

1. 1. Naghavi M, Vollset SE, Ikuta KS, et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. The Lancet. 2024;404(10459):1199-1226.
2. 2. WHO. Antimicrobial resistance. November 2023. Available from: https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance.
3. 3. Mojica MF, Rossi MA, Vila AJ, et al. The urgent need for metallo-β-lactamase inhibitors: an unattended global threat. Lancet Infect Dis. 2022;22(1):e28-e34.
4. 4. Sati H, Carrara E, Savoldi A, et al. The WHO Bacterial Priority Pathogens List 2024: a prioritisation study to guide research, development, and public health strategies against antimicrobial resistance. Lancet Infect Dis. 2025.
5. 5. Mojica MF, Bonomo RA, Fast W. B1-Metallo-β-Lactamases: Where Do We Stand? Curr Drug Targets. 2016;17(9):1029-1050.
6. 6. Palzkill T. Metallo-β-lactamase structure and function. Ann N Y Acad Sci. 2013;1277:91-104.
7. 7. Nordmann P, Poirel L. The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect. 2014;20(9):821-830.
8. 8. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence. 2017;8(4):460-469.

9. 9. Grabein B, Arhin FF, Daikos GL, et al. Navigating the Current Treatment Landscape of Metallo-β-Lactamase-Producing Gram-Negative Infections: What are the Limitations? Infect Dis Ther. 2024;13(11):2423-2447.
10. 10. Süzük Yıldız S, Şimşek H, Bakkaloğlu Z, et al. The Epidemiology of Carbapenemases in Escherichia coli and Klebsiella pneumoniae Isolated in 2019 in Turkey. Mikrobiyol Bul. 2021;55(1):1-16. doi:10.5578/mb.20124.
11. 11. Sangiorgio G, Calvo M, Stefani S. Aztreonam and avibactam combination therapy for metallo-β-lactamase-producing gram-negative bacteria: A Narrative Review. Clin Microbiol Infect. 2025;31(6):971-978.
12. 12. Falcone M, Giordano C, Leonildi A, et al. Clinical Features and Outcomes of Infections Caused by Metallo-β-Lactamase-Producing Enterobacterales: A 3-Year Prospective Study From an Endemic Area. Clin Infect Dis. 2024;78(5):1111-1119.
13. 13. FDA. Antimicrobial Resistance. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/antimicrobial-resistance.
14. 14. WHO. Antibacterial agents in clinical and preclinical development: an overview and analysis. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO. 2023.
15. 15. Westley-Horton E, Koestner JA. Aztreonam: A Review of the First Monobactam. The American Journal of the Medical Sciences. 1991;302(1):46-49.
16. 16. Lin L-Y, Debabov D, Chang W, et al. Antimicrobial Activity of Ceftazidime-Avibactam and Comparators against Pathogens Harboring OXA-48 and AmpC Alone or in Combination with Other β-Lactamases Collected from Phase 3 Clinical Trials and an International Surveillance Program. Antimicrobial Agents and Chemotherapy. 2022;66(3):e01985-01921.
17. 17. Piérard D, Hermsen ED, Kantecki M, et al. Antimicrobial Activities of Aztreonam-Avibactam and Comparator Agents against Enterobacterales Analyzed by ICU and Non-ICU Wards, Infection Sources, and Geographic Regions: ATLAS Program 2016-2020. Antibiotics (Basel). 2023;12(11).
18. 18. EMA. New antibiotic to fight infections caused by multidrug-resistant bacteria, 2024. Available from: https://www.ema.europa.eu/en/news/new-antibiotic-fight-infections-caused-multidrug-resistant-bacteria.
19. 19. Pfizer. European Commission approves Pfizer’s EMBLAVEO® for patients with multidrug-resistant infections and limited treatment options, 2024. Available from: https://www.pfizer.com/news/press-release/press-release-detail/european-commission-approves-pfizers-emblaveor-patients.
20. 20. EMBLAVEO, Package Insert. Available from: https://www.rxabbvie.com/pdf/emblaveo_pi.pdf.
21. 21. Sadek M, Juhas M, Poirel L, et al. Genetic Features Leading to Reduced Susceptibility to Aztreonam-Avibactam among Metallo-β-Lactamase-Producing Escherichia coli Isolates. Antimicrob Agents Chemother. 2020;64(12).
22. 22. Livermore DM, Mushtaq S, Vickers A, et al. Activity of aztreonam/avibactam against metallo-β-lactamase-producing Enterobacterales from the UK: Impact of penicillin-binding protein-3 inserts and CMY-42 β-lactamase in Escherichia coli. International Journal of Antimicrobial Agents. 2023;61(5):106776.
23. 23. Niu S, Wei J, Zou C, et al. In vitro selection of aztreonam/avibactam resistance in dual-carbapenemase-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2020;75(3):559-565.
24. 24. Nordmann P, Yao Y, Falgenhauer L, et al. Recent Emergence of Aztreonam-Avibactam Resistance in NDM and OXA-48 Carbapenemase-Producing Escherichia coli in Germany. Antimicrobial Agents and Chemotherapy. 2021;65(11):10.1128/aac.01090-01021.
25. 25. Mauri C, Maraolo AE, Di Bella S, et al. The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases. Antibiotics (Basel). 2021;10(8).
26. 26. EUCAST. Aztreonam-avibactam: Rationale for EUCAST Clinical Breakpoints, 2024. Available from: https://www.eucast.org/publications-and-documents/rd.
27. 27. TMC. Available from: https://www.tmc-online.org/index.php.
28. 28. EUCAST. The European Committee on Antimicrobial Susceptibility Testing. Clinical Breakpoints, Version 15.0. 2025.
29. 29. Cornely OA, Cisneros JM, Torre-Cisneros J, et al. Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother. 2020;75(3):618-627.
30. 30. Carmeli Y, Cisneros JM, Paul M, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial. The Lancet Infectious Diseases. 2025;25(2):218-230.
31. 31. Daikos GL CJ, Carmeli Y. Efficacy and safety of aztreonam–avibactam for the treatment of serious infections caused by metallo-β-lactamase (MBL) producing multidrug resistant Gram-negative bacteria: phase 3 ASSEMBLE trial. 34th European Society of Clinical Microbiology and Infectious Diseases (ECCMID); Barcelona, Spain, 2024.
32. 32. Vijayakumar M, Selvam V, Renuka MK, et al. The Comparative Efficacy of Ceftazidime-Avibactam with or without Aztreonam vs Polymyxins for Carbapenem-resistant Enterobacteriaceae Infections: A Prospective Observational Cohort Study. Indian J Crit Care Med. 2023;27(12):923-929.