What is the role of cefepime (Cefepime) and tazobactam (Tazobactam) combination in treating infections caused by resistant Gram-negative bacteria?

Cefepime-Enmetazobactam: A Novel Antibiotic Combination for Resistant Gram-Negative Infections

Cefepime-enmetazobactam is a superior treatment option for infections caused by ESBL-producing Enterobacterales, demonstrating significantly better clinical cure and microbiological eradication rates compared to piperacillin-tazobactam, with recent FDA and EMA approval for complicated urinary tract infections and hospital-acquired pneumonia. 1, 2

Composition and Mechanism of Action

• Composition: Fixed-dose combination of:

  • Cefepime (2g): A 4th generation cephalosporin with broad-spectrum activity
  • Enmetazobactam (0.5g): A novel penicillanic acid sulfone β-lactamase inhibitor structurally similar to tazobactam 3

• Mechanism of Action:

  • Cefepime: Binds to penicillin-binding proteins to inhibit bacterial cell wall synthesis
  • Enmetazobactam: Inhibits extended-spectrum β-lactamases (ESBLs), particularly CTX-M, TEM, and SHV types 3
  • The combination restores cefepime activity against ESBL-producing organisms that would otherwise hydrolyze cefepime 4

Antimicrobial Spectrum

• Highly effective against:

  • ESBL-producing Enterobacterales (including those resistant to piperacillin-tazobactam)
  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus mirabilis
  • Enterobacter cloacae complex
  • Pseudomonas aeruginosa 2

• Limited activity against:

  • Metallo-β-lactamases (MBLs) producing organisms
  • Anaerobic bacteria
  • Gram-positive bacteria

Clinical Evidence

• ALLIUM Phase 3 Trial (2022): Randomized, double-blind trial comparing cefepime-enmetazobactam vs. piperacillin-tazobactam in complicated UTIs and acute pyelonephritis 1
  • Results:
    • Clinical cure + microbiological eradication: 79.1% for cefepime-enmetazobactam vs. 58.9% for piperacillin-tazobactam
    • Between-group difference: 21.2% (95% CI, 14.3% to 27.9%)
    • Met criteria for both non-inferiority and superiority
  • Safety profile:
    • Treatment-emergent adverse events: 50.0% with cefepime-enmetazobactam vs. 44.0% with piperacillin-tazobactam
    • Most adverse events were mild to moderate (89.9% vs. 88.6%)
    • Discontinuation due to adverse events: 1.7% vs. 0.8%

Approved Indications

• United States (February 2024):

  • Complicated urinary tract infections (cUTI) including pyelonephritis 2

• European Union (March 2024):

  • Complicated urinary tract infections including pyelonephritis
  • Hospital-acquired pneumonia including ventilator-associated pneumonia
  • Bacteremia associated with these infections 2

Dosing and Administration

• Standard dosing: Cefepime 2g/enmetazobactam 0.5g IV every 8 hours 1
• Administration: 2-hour intravenous infusion
• Duration: Typically 7 days (up to 14 days for bacteremia) 1
• Renal dose adjustments 5:
  • CrCl 30-59 mL/min: 1g q8h
  • CrCl 15-29 mL/min: 500mg q8h
  • CrCl 8-14 mL/min or hemodialysis: 500mg q12h
  • Augmented renal clearance (CrCl 120-180 mL/min): Standard dose with prolonged 4-hour infusion

Pharmacokinetics-Pharmacodynamics

• PK-PD target for efficacy against ESBL-producing Enterobacterales 4:
  • Enmetazobactam: 44% fT > 2 μg/ml for 1-log10 bioburden reduction
  • Cefepime: 40-60% fT > MIC
• MIC coverage: Effective against isolates with cefepime-enmetazobactam MICs up to 16 mg/L 5

Clinical Positioning

1. Primary role: Carbapenem-sparing option for infections caused by ESBL-producing Enterobacterales 3

2. Advantages over other β-lactam/β-lactamase inhibitor combinations:

   • Superior to piperacillin-tazobactam for ESBL-producing organisms 1
   • Enhanced stability against AmpC cephalosporinases 3
   • Potential activity against organisms co-producing OXA-48-like enzymes with ESBLs 3

3. Potential applications in difficult-to-treat resistant infections:

   • While not specifically indicated for difficult-to-treat Pseudomonas aeruginosa (DTR-PA), it may be considered when other first-line options like ceftolozane-tazobactam or ceftazidime-avibactam are unavailable 6

Limitations and Considerations

• Not effective against metallo-β-lactamase (MBL) producing organisms; for these infections, aztreonam plus ceftazidime-avibactam is preferred 6, 7
• Limited data on efficacy for infections outside the approved indications
• Should not be routinely combined with other antibiotics for ESBL infections, as monotherapy is generally sufficient 6
• Not a replacement for carbapenems in all scenarios, particularly for carbapenem-resistant organisms other than those producing ESBLs and OXA-48-like enzymes

Conclusion

Cefepime-enmetazobactam represents an important addition to the antimicrobial armamentarium against ESBL-producing Enterobacterales, with demonstrated superiority over piperacillin-tazobactam. Its recent approval provides a valuable carbapenem-sparing option for treating resistant gram-negative infections, particularly in settings with high ESBL prevalence.