Cefepime-Enmetazobactam: a novel β-Lactam/β-Lactamase inhibitor combination for complicated urinary tract infections

Arunkumar Ramaraj; Natarajan Thangam Nivasini; Vikram Balaji; Jerin James; Sathyanarayanan Varadarajan

doi:10.18203/2319-2003.ijbcp20251745

Authors

Arunkumar Ramaraj Department of Pharmacology, SRM Medical College Hospital & Research Centre, Kattankulathur, Tamil Nadu, India
Natarajan Thangam Nivasini Department of Pharmacology, SRM Medical College Hospital & Research Centre, Kattankulathur, Tamil Nadu, India
Vikram Balaji Department of Pharmacology, SRM Medical College Hospital & Research Centre, Kattankulathur, Tamil Nadu, India
Jerin James Department of Pharmacology, SRM Medical College Hospital & Research Centre, Kattankulathur, Tamil Nadu, India
Sathyanarayanan Varadarajan Department of Pharmacology, SRM Medical College Hospital & Research Centre, Kattankulathur, Tamil Nadu, India

DOI:

https://doi.org/10.18203/2319-2003.ijbcp20251745

Keywords:

Complicated urinary tract infections, Cefepime-Enmetazobactam, ESBL-producing pathogens, β-lactamase inhibitor, Antimicrobial resistance, Carbapenem-sparing therapy

Abstract

Complicated urinary tract infections (cUTIs) represent a significant global health challenge, particularly with the rising prevalence of extended-spectrum β-lactamase (ESBL)-producing pathogens. Cefepime-Enmetazobactam, approved in India in June 2024, represents a novel β-lactam/β-lactamase inhibitor combination specifically developed to address multidrug-resistant Gram-negative infections. This review examines the pharmacological properties, clinical efficacy, and therapeutic potential of Cefepime-Enmetazobactam in managing cUTIs. The Phase 3 ALLIUM trial demonstrated superior clinical cure and microbiological eradication rates compared to Piperacillin-Tazobactam, with particularly pronounced efficacy against ESBL-producing Enterobacterales (73.7% vs 51.5%). The combination exhibits a favourable safety profile with transaminase elevation, increased bilirubin, headache, and infusion site reactions being the most common adverse events. As a carbapenem-sparing option, Cefepime-Enmetazobactam addresses critical antimicrobial stewardship concerns while providing an effective treatment alternative for resistant pathogens. While demonstrating promising results, further research regarding long-term outcomes, resistance development, and cost-effectiveness is warranted to fully establish its role in contemporary antimicrobial therapy.

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References

McLellan LK, Hunstad DA. Urinary Tract Infection: Pathogenesis and Outlook. Trends Mol Med. 2016;22(11):946–57. DOI: https://doi.org/10.1016/j.molmed.2016.09.003

Barannik KS, Ishchenko OV, Duka RV, Molchanov RM, Stepanskyi DOS. Microbiological profile and antimicrobial susceptibility of bacteria associated with urinary tract infections in Ukrainian adults. Medical perspectives. 2024(2):105-11. DOI: https://doi.org/10.26641/2307-0404.2024.2.307596

Taneja N, Sharma M. ESBLs detection in clinical microbiology: why & how. Indian J Med Res. 2008;127(4):297–300.

Mohanty JR, Pradhan A, Jena S, Padhi BK, Das P, Soren D. Antibiotic resistance pattern of uropathogen among non-pregnant women: a hospital based cross sectional study from Odisha. J Pure Appl Microbiol. 2022;16(1):296-304. DOI: https://doi.org/10.22207/JPAM.16.1.18

Paul D, Anto N, Bhardwaj M, Prendiville A, Elangovan R, Bachmann TT, et al. Antimicrobial resistance in patients with suspected urinary tract infections in primary care in Assam, India. JAC-Antimicrob Resist. 2021;3(4):164. DOI: https://doi.org/10.1093/jacamr/dlab164

Patwardhan V, Kumar D, Goel V, Singh S. Changing prevalence and antibiotic drug resistance pattern of pathogens seen in community-acquired pediatric urinary tract infections at a tertiary care hospital of North India. J Lab Physicians. 2010;9(4):264–8. DOI: https://doi.org/10.4103/JLP.JLP_149_16

World Health Organization. Global antimicrobial resistance and use surveillance system (GLASS) report 2022. World Health Organization. 2022. Available at: https://www.who.int/publications. Accessed on 21 August 2024.

Bonkat G, Bartoletti R, Bruyere F, Cai T, Geerlings SE, Köves B, et al. EAU guidelines on urological infections. European Asso Urol. 2017;18:22-6.

Lutgring JD, Machado MJ, Benahmed FH, Conville P, Shawar RM, Patel J, et al. FDA-CDC Antimicrobial Resistance Isolate Bank: a publicly available resource to support research, development, and regulatory requirements. J Clin Microbiol. 2018;56(2):10-128. DOI: https://doi.org/10.1128/JCM.01415-17

Shaikh S, Fatima J, Shakil S, Rizvi SMohdD, Kamal MA. Risk factors for acquisition of extended spectrum beta lactamase producing Escherichia coli and Klebsiella pneumoniae in North-Indian hospitals. Saudi J Biol Sci. 2015;22(1):37–41. DOI: https://doi.org/10.1016/j.sjbs.2014.05.006

Bush K, Bradford PA. Epidemiology of β-Lactamase-Producing Pathogens. Clin Microbiol Rev. 2020;33(2):10. DOI: https://doi.org/10.1128/CMR.00047-19

Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nature Rev Microbiol. 2015;13(5):269-84. DOI: https://doi.org/10.1038/nrmicro3432

Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. The Lancet Infect Dis. 2007;7(5):338-48. DOI: https://doi.org/10.1016/S1473-3099(07)70109-3

Morrissey I, Magnet S, Hawser S, Shapiro S, Knechtle P. In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from US and European hospitals during 2014–2015. Antimicrob Agent Chemother. 2019;63(7):10-128. DOI: https://doi.org/10.1128/AAC.00514-19

Chen J, Shang X, Hu F, Lao X, Gao X, Zheng H, Yao W. β-Lactamase inhibitors: an update. Mini Rev Med Chemist. 2013;13(13):1846-61. DOI: https://doi.org/10.2174/13895575113139990074

Paul-Satyaseela M. Invention of Enmetazobactam: An Indian Triumph in Antimicrobial Drug Discovery. ACS Infect Dis. 2024;11(1):1-3. DOI: https://doi.org/10.1021/acsinfecdis.4c00982

Belley A, Morrissey I, Hawser S, Kothari N, Knechtle P. Third-generation cephalosporin resistance in clinical isolates of Enterobacterales collected between 2016-2018 from USA and Europe: genotypic analysis of β-lactamases and comparative in vitro activity of cefepime/enmetazobactam. J Glob Antimicrob Resist. 2021;25:93-101. DOI: https://doi.org/10.1016/j.jgar.2021.02.031

Wagenlehner FM, Gasink LB, McGovern PC, Moeck G, McLeroth P, Dorr M, et al. Cefepime–taniborbactam in complicated urinary tract infection. New England J Med. 2024;390(7):611-22. DOI: https://doi.org/10.1056/NEJMoa2304748

Kaye KS, Belley A, Barth P, Lahlou O, Knechtle P, Motta 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;328(13):1304–14. DOI: https://doi.org/10.1001/jama.2022.17034

Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, et al. Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9):1072–84. DOI: https://doi.org/10.1016/S1473-3099(23)00184-6

Topouzis S, Papapetropoulos A, Alexander SP, Cortese‐Krott M, Kendall DA, Martemyanov K, et al. Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review. British J Pharmacol. 2025;182(7):1416-45. DOI: https://doi.org/10.1111/bph.17458

Kaye KS, Belley A, Barth P, Lahlou O, Velicitat P. Treatment outcomes in secondary analysis populations of adult patients the allium phase 3 study comparing cefepime-enmetazobactam to piperacillin-tazobactam for complicated urinary tract infections (CUTI) or acute pyelonephritis (AP). Open Forum Infect Dis. 2021;8(1):421-5. DOI: https://doi.org/10.1093/ofid/ofab466.834

Bhowmick T, Canton R, Pea F, Quevedo J, Santerre Henriksen A, Timsit JF, et al. Cefepime-enmetazobactam: first approved cefepime-β-lactamase inhibitor combination for multi-drug resistant Enterobacterales. Future Microbiol. 2025;20(4):277-86. DOI: https://doi.org/10.1080/17460913.2025.2468112

Pitout JDD, DeVinney R. Escherichia coli ST131: a multidrug-resistant clone primed for global domination. Res. 2017;6:148. DOI: https://doi.org/10.12688/f1000research.10609.1

Livermore DM, Mushtaq S, Warner M, Vickers A, Woodford N. In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria. J Antimicrob Chemoth. 2017;72(5):1373-85. DOI: https://doi.org/10.1093/jac/dkw593

Darlow CA, Hope W, Dubey V. Cefepime/Enmetazobactam: a microbiological, pharmacokinetic, pharmacodynamic, and clinical evaluation. Exp Opin Drug Metabol Toxicol. 2025;21(2):115-23. DOI: https://doi.org/10.1080/17425255.2024.2427310

Maki DG. In complicated UTI or pyelonephritis, cefepime–enmetazobactam increased success vs. piperacillin–tazobactam at 14 d. Ann Int Med. 2023;176(2):21.

Belley A, Barth P, Kashyap S, Lahlou O, Motta P, Knechtle P, et al. Cefepime-enmetazobactam demonstrates superiority to piperacillin-tazobactam in a subgroup of patients with complicated urinary tract infections/acute pyelonephritis caused by extended spectrum β-lactamase-producing enterobacterales. Open Forum Infect Dis. 2020;7(1):845. DOI: https://doi.org/10.1093/ofid/ofaa515.1901

Maki DG. In complicated UTI or pyelonephritis, cefepime–enmetazobactam increased success vs. piperacillin–tazobactam at 14 d. Ann Int Med. 2023;176(2):21. DOI: https://doi.org/10.7326/J22-0114