By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration has approved the combination of cefepime and enmetazobactam (FPE) for the treatment of complicated urinary tract infections (cUTIs). Cefepime is a fourth-generation cephalosporin with bactericidal action and enmetazobactam is a beta-lactamase inhibitor that protects cefepime from degradation from certain beta-lactamases (chromosomal-mediated [AmpC] and plasmid-meditated extended spectrum beta-lactamases). Cefepime-enmetazobactam was granted a priority review and a five-year marketing exclusivity as part of the Generating Antibiotic Incentive Now (GAIN) Act incentivizing development of new anti-infectives. FPE is distributed by Allecra Therapeutics SAS as Exblifep.
INDICATIONS
FPE is indicated for the treatment of patients 18 years of age and older with cUTIs including pyelonephritis caused by the following susceptible microorganism: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacaecomplex.1
DOSAGE
The recommended dose for FPE is 2 grams of cefepime and 0.5 grams of enmetazobactam given by intravenous (IV) infusion (over two hours) every eight hours for seven days and up to 14 days for patients with concurrent bacteremia.1 The dosing interval and infusion time are adjusted based on estimated glomerular filtration rate.
POTENTIAL ADVANTAGES
FPE has demonstrated superiority to piperacillin/tazobactam in terms of clinical and microbiological cure in patients with suspected gram-negative cUTI including pyelonephritis.2 It has shown excellent in vitro activity against different Enterobacterales strains.3
POTENTIAL DISADVANTAGES
Cefepime is associated with neurotoxicity with most cases reported in geriatric patients with renal impairment and given unadjusted doses.1 As with all antibacterials Clostridioides difficile-associated diarrhea may occur.1 Enmetazobactam shows less in vitro activity against OXA-48, K. pneumoniaecarbapenemase, and metallo-beta-lactamases producing microorganisms.3
COMMENTS
Cefepime is bactericidal by inhibition of cell wall synthesis by binding to penicillin-binding protein targets.1 The efficacy of FPE was evaluated in a randomized, double-blind, noninferiority trial.1,2 Participants with cUTI including pyelonephritis were randomized to FPE (n = 345) or piperacillin/tazobactam (n = 333) for seven days or up to 14 days (concurrent bacteremia).1,2 No switch from IV to oral antibacterial therapy was permitted. Overall, 51% had pyelonephritis and 49% had cUTI. The primary efficacy outcome was the proportion of study participants who achieved a composite outcome of clinical cure and microbiological eradication at test of cure visit (seven days after the end of treatment). Clinical cure was defined as complete resolution of the baseline signs and symptoms present at screening and microbiological cure is reduction of qualifying baseline pathogens to less than 103 colony-forming unit/mL in the urine. Seventy-nine percent of isolated pathogens were E. coli. Participants with microorganisms resistant to piperacillin/tazobactam were excluded from the analysis. Composite response was 79.1% for FPE vs. 58.9% for piperacillin/tazobactam. Microbiological response was 82.9% vs. 64.9% (83% vs. 59% for E. coli). FPE met the criterion for superiority compared with piperacillin/tazobactam in terms of clinical cure and microbiological eradication.2
CLINICAL IMPLICATIONS
Most UTIs are due to the colonization of the urogenital tract with rectal and perineal flora.4 Common organisms include E. coli, Enterococcus, Klebsiella, Pseudomonas, and other Enterococcusor Staphylococcusspecies. Of these, E. coliis the most common, followed by Klebsiella. The incidence of extended-spectrum beta-lactamases has increased over time.5 cUTI account for about 2% of hospital admissions.4 Antibacterial treatment recommendations by the Infectious Diseases Society of America (IDSA) are trimethoprim-sulfamethoxazole, ciprofloxacin, or levofloxacin. Alternatives are ertapenem, meropenem, imipenem-cilastatin, or an aminoglycoside as an alternative option. IDSA does not endorse the use of piperacillin/tazobactam. The IDSA rationale indicates minimum inhibitory concentration testing may be inaccurate and/or poorly reproducible when extended-spectrum beta lactamases are present, and the drug may not be effective with increased bacterial inoculum (e.g., abscesses).5 Although FPE is shown to be superior to piperacillin/tazobactam, the latter is not considered first-line therapy. Therefore, the role of FPE in therapy remains to be established. The cost for cefepime/enmetazobactam was not available at the time of this review.
REFERENCES
- Exblifep Prescribing Information. Allecra Therapeutics SAS. February 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216165s000lbl.pdf
- 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 2022;328:1304-1314.
- Vazquez-Ucha JC, Lasarte-Monterrubio C, Guijarro-Sanchez P, et al. Assessment of activity and resistance mechanisms to cefepime in combination with the novel β-lactamase inhibitors aidebactam, taniborbactam, and enmetazobactam against a multicenter collection of carbapenemase-producing enterobacterales. Antimicrob Agents Chemother 2022;66:e01676-21.
- National Library of Medicine. Complicated urinary tract infections. StatPearls [Internet]. Last update: Nov. 12, 2023. https://www.ncbi.nlm.nih.gov/books/NBK436013/
- Infectious Diseases Society of America. IDSA 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. https://www.idsociety.org/practice-guideline/amr-guidance/#Extended-Spectrum%CE%B2-Lactamase-ProducingEnterobacterales