Role of Cefepime Enmetazobactam in Complicated UTI

Key Messages:

• Treatment of complicated urinary tract infections (cUTIs) has become increasingly complex due to the rising incidences of antimicrobial resistance.
• Cefepime/enmetazobactam is a novel β-lactamase inhibitor combination with a well-known fourth-generation cephalosporin, cefepime.
• Cefepime/enmetazobactam may be the first-line therapy for the treatment of suspected gram-negative infections in cUTI including pyelonephritis, and hospital-acquired pneumonia, including ventilator associated pneumonia, and the treatment of patients with bacteraemia occurring in association with or suspected to be associated with any of these infections.
• Cefepime/enmetazobactam is superior to piperacillin/tazobactam in reducing cUTI signs and symptoms in patients with ESBL-producing pathogens at baseline (difference, 30.2% [95% CI, 13.4% to 45.1%]).
• The Central Drugs Standard Control Organization (CDSCO, an Indian regulatory authority), the European Medicines Agency (EMA) and UK Medicines and Healthcare Products (UKMHRA) have approved the combination of cefepime/enmetazobactam in 2024 for the following indications- cUTI, acute pyelonephritis, ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP), as well as bacteremia when it is suspected or associated with cUTI and HAP in patients who are 18 years of age or older. In 2024, the combination was also approved by the United States Food and Drug Administration (USFDA) for the treatment of acute pyelonephritis and cUTI (1,2,3).

Combining beta (β)-lactams with novel β-lactamase inhibitors can improve therapeutic benefit against extended-spectrum β-lactam–resistant pathogens. Cefepime/enmetazobactam combination could be a potential empirical therapy for these resistant gram-negative infections. (4)

Cefepime/Enmetazobactam - Pharmacological Edge:

Cefepime/enmetazobactam is a combination of cefepime, a well-known fourth-generation cephalosporin, and enmetazobactam, a novel β-lactamase inhibitor. The structure of enmetazobactam, formerly known as AAI101, is similar to that of tazobactam, but a significant structural variation results in a net neutral (zwitterionic) charge that promotes bacterial cell penetration. Enmetazobactam was found to have restored the activity of cefepime against Enterobacterales that produce class A serine β-lactamases in an in vitro study. Preclinical studies demonstrated that cefepime and enmetazobactam have comparable pharmacokinetic profiles, including similar half-lives and high urinary excretion 5,6. Against the ESBL-producing E.coli and Klebsiella pneumonia, MIC90 values for cefepime/enmetazobactam are 0.12 µg/ml and 1 µg/ml, whereas it is >64 µg/ml for Cefepime alone. (7)

A Phase 3, Randomized, Double-Blind, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of Cefepime-AAI101 Compared to Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, in Adults (ALLIUM) - Cefepime/Enmetazobactam Over Piperacillin/tazobactam in the Treatment of Complicated UTI Patients. (8)

Kaye et al. carried out a randomized, double-blind, noninferiority trial to assess whether cefepime/enmetazobactam was non-inferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with cUTI or acute pyelonephritis. Throughout 90 sites in Europe, North and Central America, South America, and South Africa, 1041 patients were recruited in the trial. They were randomly assigned to receive either piperacillin, 4 g/tazobactam, 0.5 g (n = 521) or 2 g/enmetazobactam, 0.5 g (n = 520), via 2-hour infusion every 8 hours for 7 days (or up to 14 days in patients who had a positive blood culture at baseline). The primary outcome was to determine the percentage of patients in the primary analysis set who, by day 14, had reduced the qualifying baseline pathogen to less than 103 CFU/mL in urine (microbiological eradication) and completely resolved the baseline signs and symptoms that were present at screening (clinical cure). (8)

Cefepime/enmetazobactam was noninferior to piperacillin/tazobactam in achieving the primary composite outcome (79.1% versus 58.9% patients; difference, 21.2%). It also met the criterion for superiority as compared with piperacillin/tazobactam. Cefepime/enmetazobactam therapy achieved significant microbiological eradication versus piperacillin/tazobactam at day 14 (82.9% vs 64.9%; treatment difference, 19.0%) and day 21; however, the clinical cure rate was similar between the two groups. The composite outcome was significantly higher with cefepime/enmetazobactam vs. piperacillin/tazobactam at day 14 in patients with an extended-spectrum β-lactamase–producing baseline pathogen (73.7% vs. 51.5%; treatment difference, 30.2%), in patients not excluded from the study (78.6% vs. 58.7%, treatment difference, 20.7%) and among patients who received at least 1 dose of drug (59.1% vs. 43.4%; treatment difference, 15.6%). Microbiological recurrence was lower with cefepime/enmetazobactam than piperacillin/tazobactam at day 14 (11.3% vs. 29.4%) in the primary analysis set. Among patients in the primary analysis set but excluding those with a piperacillin/tazobactam minimum inhibitory concentration >16 μg/mL &/or an Enterobacterales pathogen with an extended-spectrum β-lactamase genotype, cefepime/enmetazobactam was significantly better than piperacillin/tazobactam (80.9% vs 60.7%; difference, 20.2%). (8)

Cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication.Microbiological recurrence was lower in patients receiving cefepime/enmetazobactam compared with piperacillin/tazobactam.Cefepime/enmetazobactam may be an appropriate empirical therapy for suspected gram-negative complicated UTI. (8)

Reference:

1. Keam SJ. Cefepime/Enmetazobactam: First Approval. Drugs. 2024 Jun;84(6):737-744. doi: 10.1007/s40265-024-02035-2. Epub 2024 May 18. PMID: 38761353.

2. DCGI Approval for antibiotic drug combination of cefepime and enmetazobactam. Retrieved oon 15th July 2024 from https://www.expresspharma.in/orchid-pharma-receives-dcgi-approval-for-its-antibiotic-drug-combination-of-cefepime-and-enmetazobactam-nce/

3. FDA. Access Data.Exblifep (cefepime and enmetazobactam). 2024. Retrieved on 9th July 2024 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216165s000lbl.pdf

4. Wagenlehner FM, Naber KG. Current challenges in the treatment of complicated urinary tract infections and prostatitis. Clin Microbiol Infect. 2006 May;12 Suppl 3:67-80. doi: 10.1111/j.1469-0691.2006.01398.x. PMID: 16669930.

5. Morrissey I, Magnet S, Hawser S, Shapiro S, Knechtle P. In Vitro Activity of Cefepime-Enmetazobactam against Gram-Negative Isolates Collected from U.S. and European Hospitals during 2014-2015. Antimicrob Agents Chemother. 2019 Jun 24;63(7):e00514-19. doi: 10.1128/AAC.00514-19. PMID: 30988152; PMCID: PMC6591593.

6. Papp-Wallace KM, Bethel CR, Caillon J, Barnes MD, Potel G, Bajaksouzian S, Rutter JD, Reghal A, Shapiro S, Taracila MA, Jacobs MR, Bonomo RA, Jacqueline C. Beyond Piperacillin-Tazobactam: Cefepime and AAI101 as a Potent β-Lactam-β-Lactamase Inhibitor Combination. Antimicrob Agents Chemother. 2019 Apr 25;63(5):e00105-19. doi: 10.1128/AAC.00105-19. PMID: 30858223; PMCID: PMC6496078.

7. A.Belley, I. Morrissey, S. Hawser et al. The Novel β-lactamase Inhibitor Enmetazobactam is More Potent than Tazobactam against ESBL-producing Enterobacteriaceae. 2019. Presented at the ASM-ESCMID Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance.

8. 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: a randomized clinical trial.  JAMA. Published October 4, 2022. doi:10.1001/jama.2022.17034