A Drug Monograph: Cefepime-Enmetazobactam

Öz

Cefepime-enmetazobactam is a novel antibacterial agent that combines cefepime, a fourth-generation cephalosporin, with enmetazobactam, a broad-spectrum β-lactamase inhibitor. This combination was developed to enhance efficacy against Gram-negative bacteria producing extended-spectrum β-lactamases (ESBLs). While cefepime exhibits strong gram-positive and gram-negative activity, its susceptibility to β-lactamase-producing pathogens is limited. Enmetazobactam significantly enhances cefepime's activity by inhibiting Ambler class A β-lactamases and certain class C β-lactamases. Clinical studies have demonstrated the effectiveness of cefepime-enmetazobactam in treating severe infections, including complicated urinary tract infections and intra-abdominal infections. According to FDA and EMA guidelines, this combination is considered a potential alternative for infections caused by carbapenem-resistant Enterobacterales. Additionally, it has demonstrated a superior efficacy profile compared to traditional β-lactam/β-lactamase inhibitor combinations. Cefepime-enmetazobactam is being evaluated as an alternative to carbapenems, offering a valuable option in the global fight against antibiotic resistance. This review discusses the pharmacodynamic and pharmacokinetic properties, clinical efficacy, resistance mechanisms, and current clinical trial data of cefepime-enmetazobactam in detail.

Anahtar Kelimeler

• Cefepime-enmetazobactam
• β-lactamase inhibitor
• antibiotic resistance
• extended-spectrum β-lactamases
• complicated urinary tract infections

Bir İlaç Monografı: Sefepim-Enmetazobaktam

Öz

Sefepim-enmetazobaktam, dördüncü nesil sefalosporin olan sefepim ile geniş spektrumlu bir β-laktamaz inhibitörü olan enmetazobaktam kombinasyonundan oluşan yeni bir antibakteriyel ajandır. Bu kombinasyon, özellikle genişletilmiş spektrumlu β-laktamaz (ESBL) üreten gram-negatif bakterilere karşı etkinliği artırmak amacıyla geliştirilmiştir. Sefepim, güçlü gram-pozitif ve gram-negatif aktivite gösteren bir sefalosporin olmasına rağmen, β-laktamaz üreten patojenlere karşı duyarlılığı sınırlıdır. Enmetazobaktam ise Ambler sınıf A β-laktamazları ve bazı sınıf C β-laktamazlarını inhibe ederek sefepimin etkinliğini önemli ölçüde artırmaktadır. Klinik çalışmalarda, sefepim-enmetazobaktamın özellikle komplike idrar yolu enfeksiyonları ve karın içi enfeksiyonlar dahil olmak üzere çeşitli ciddi enfeksiyonlarda etkinliği gösterilmiştir. FDA ve EMA tarafından belirlenen kriterlere göre, bu kombinasyonun karbapenem direncine sahip Enterobacterales suşları üzerinde etkili olabileceği belirtilmektedir. Ayrıca, geleneksel β-laktam/β-laktamaz inhibitör kombinasyonlarına kıyasla daha güçlü bir etkinlik profiline sahip olduğu gösterilmiştir. Sefepim-enmetazobaktam, karbapenemlere alternatif bir seçenek olarak değerlendirilmekte olup, antibiyotik direncinin küresel düzeyde yönetilmesine katkı sağlayabilecek önemli bir ajan olarak öne çıkmaktadır. Bu derlemede, sefepim-enmetazobaktamın farmakodinamik ve farmakokinetik özellikleri, klinik etkinliği, direnç mekanizmaları ve mevcut klinik çalışma verileri detaylı olarak ele alınacaktır.

Anahtar Kelimeler

• β-laktamaz inhibitörü
• Sefepim-enmetazobaktam
• antibiyotik direnci
• genişletilmiş spektrumlu β-laktamaz
• komplike idrar yolu enfeksiyonları

Kaynakça

1. 1. Vincent JL, Sakr Y, Singer M, et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA. 2020;323:1478-1487. doi:10.1001/jama.2020.2717
2. 2. Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia: a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285-295. doi:10.1016/S1473-309930747-8
3. 3. Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. 2021;73:e4539-e4548. doi:10.1093/cid/ciaa803
4. 4. Livermore DM. Defining new resistance mechanisms against antimicrobials. J Antimicrob Chemother. 2008;62 Suppl 1:i17-i20.
5. 5. Bush K, Bradford PA. β-Lactams and β-Lactamase Inhibitors: An Overview. Cold Spring Harb Perspect Med. 2016;6:a025247.
6. 6. Ramatla T, Mafokwane T, Lekota K, et al. “One Health” perspective on prevalence of co-existing extended-spectrum β-lactamase (esbl)- producing Escherichia coli and Klebsiella pneumoniae: a comprehensive systematic review and meta-analysis. Ann Clin Microbiol Antimicrob. 2023;22:88. doi:10.1186/s12941-023-00638-3
7. 7. Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320:984-994. doi:10.1001/jama.2018.12163
8. 8. Center for Disease Control and Prevention. Antimicrobial resistance threats in the United States, 2021–2022. Available from: https://www.cdc.gov/antimicrobial-resistance/data-research/threats/update-2022.html

9. 9. WHO. Bacterial priority pathogens list, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. Geneva: World Health Organization; 2024. Available from: https://www.who.int/publications/i/item/9789240093461
10. 10. McLaughlin M, Advincula MR, Malczynski M, et al. Correlations of antibiotic use and carbapenem resistance in Enterobacteriaceae. Antimicrob Agents Chemother. 2013;57:5131-5133. doi:10.1128/AAC.00607-13
11. 11. Fujimura S, Nakano Y, Sato T, et al. Relationship between the usage of carbapenem antibiotics and the incidence of imipenem-resistant Pseudomonas aeruginosa. J Infect Chemother. 2007;13:147-150. doi:10.1007/s10156-007-0507-x
12. 12. Meyer E, Schwab F, Schroeren-Boersch B, et al. Dramatic increase of third- generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resis- tance, 2001 to 2008. Crit Care. 2010;14:R113. doi:10.1186/cc9062
13. 13. Organization WH. WHO Publishes List of Bacteria for Which New Antibiotics Are Ur- gently Needed. Saudi Med J. 2017;38:444-445. Accessed March 7, 2023. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed
14. 14. Antibiotic resistance threats in the United States, 2019. Published online November 2019. doi:10.15620/CDC:82532 15. Bhowmick T, Cantón R, Pea F, Quevedo J. Cefepime-enmetazobactam: first approved cefepime-β-lactamase inhibitor combination for multi-drug resistant Enterobacterales. Future Microbiol. 2024;20.
15. 16. Darlow C, Hope W, Dubey V. Cefepime/Enmetazobactam: a microbiological, pharmacokinetic, pharmacodynamic and clinical evaluation. Expert Rev Anti Infect Ther. 2024;22:1479–1492.
16. 17. Rodríguez-Baño, J., Gutiérrez-Gutiérrez, B., Machuca, I., Pascual, Á., & Martínez-Martínez, L. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clinical Microbiology Reviews, 31.
17. 18. EXBLIFEP® for Injection, for Intravenous Use..
18. 19. Keam, S. J. Cefepime/Enmetazobactam: First Approval. Drugs of Today (Barcelona, Spain: 1998), 60, 403–408.
19. 20. Barradell, L. B., & Bryson, H. M. Cefepime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs, 47, 679–728.
20. 21. Morrissey I, Magnet S, Hawser S, et al. In Vitro Activity of Cefepime-Enmetazobactam Against Gram-Negative Isolates Collected from U.S. and European Hospitals During 2014–2015. Antimicrob Agents Chemother. 2019;63:e00514-19.
21. 22. Staten, A. R., & Baker, D. E. Cefepime/Enmetazobactam. Hospital Pharmacy, 59, 742–747.
22. 23. Johnson, A., McEntee, L., Farrington, N., Morgan, M., Nichols, W. W., & Dalhoff, A. Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-β-Lactamase Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy, 64.
23. 24. Bonnin, R. A., Doco-Lecompte, T., & Calvez, V. L. Cefepime/enmetazobactam: a promising new β-lactam/β-lactamase inhibitor combination. Journal of Antimicrobial Chemotherapy, 79, 32–39.
24. 25. Lanier, C., Melton, T. C., & Covert, K. L. Cefepime-Enmetazobactam: A Drug Review of a Novel Beta-Lactam/Beta-Lactamase Inhibitor. Infectious Diseases in Clinical Practice, 32, e1-e8.
25. 26. Herishanu, Y., Zlotnik, M., Mostoslavsky, M., Shapiro, M. S., & Treister, G. Cefuroxime‐induced encephalopathy. Annals of Neurology, 44, 840–841.
26. 27. Bresson, J., Paugam-Burtz, C., Josserand, J., et al. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. Clinical Toxicology, 46, 860–862.
27. 28. Bush, K., & Bradford, P. A. Interplay between β-lactamases and new β-lactam antibiotics. Nature Reviews Microbiology, 17, 295–306.
28. 29. Isler B, Harris PNA, Stewart AG, et al. An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy. 2024;79:682-691.
29. 30. Kaye KS, Belley A, Barth P, et al. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis. JAMA. 2022;327:1662-1672.
30. 31. Tamma, P. D., Aitken, S. L., Bonomo, R. A., et al. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales, Carbapenem-Resistant Enterobacterales, and Pseudomonas aeruginosa with Difficult-to-Treat Resistance. Clinical Infectious Diseases, 70, 1097–1109.