What are the indications for Cefepime with a beta-lactamase inhibitor?

Cefepime-Enmetazobactam Indications

Cefepime-enmetazobactam is primarily indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by susceptible Gram-negative bacteria, particularly ESBL-producing Enterobacterales. 1

Approved Indications

Cefepime-enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination with specific regulatory approvals:

• US FDA approval: Treatment of complicated urinary tract infections (cUTI) 1
• European Medicines Agency and UK Healthcare Products Regulatory Agency approvals:
  • Complicated urinary tract infections (cUTI)
  • Hospital-acquired pneumonia including ventilator-associated pneumonia
  • Bacteremia in adults 1

Mechanism of Action and Antimicrobial Coverage

Cefepime-enmetazobactam combines two active components:

• Cefepime: A 4th generation cephalosporin with broad-spectrum bactericidal activity and enhanced stability against chromosomal and plasmid-mediated AmpC cephalosporinases and OXA-48 like carbapenemases 1
• Enmetazobactam: A novel penicillanic acid sulfone β-lactamase inhibitor (structurally similar to tazobactam) that inhibits:
  • CTX-M type ESBLs
  • TEM and SHV ESBLs
  • Other class A β-lactamases 1

Clinical Evidence Supporting Use

The strongest evidence supporting cefepime-enmetazobactam comes from a phase 3 randomized clinical trial that demonstrated:

• Superior efficacy compared to piperacillin-tazobactam for cUTI/pyelonephritis
• 79.1% overall treatment success with cefepime-enmetazobactam versus 58.9% with piperacillin-tazobactam
• Significant between-group difference of 21.2% (95% CI, 14.3% to 27.9%) 2

Positioning in Treatment Algorithms

Based on current guidelines for antimicrobial therapy:

For Complicated UTIs:

• Cefepime-enmetazobactam represents a carbapenem-sparing option for ESBL-producing Enterobacterales 1
• May be positioned similarly to other advanced cephalosporins with β-lactamase inhibitors for complicated UTIs 3

For Intra-abdominal Infections:

• While not specifically FDA-approved for this indication, cefepime (with metronidazole) is listed in guidelines as an option for complicated intra-abdominal infections 3
• The addition of enmetazobactam would potentially enhance activity against ESBL-producing organisms 3

Advantages Over Other Agents

1. Carbapenem-sparing option: Helps preserve carbapenems for more resistant infections 1
2. Superior efficacy to piperacillin-tazobactam in cUTI/pyelonephritis 2
3. Activity against multiple resistance mechanisms:
   • ESBL-producing Enterobacterales
   • Potential activity against pathogens co-producing OXA-48 like enzymes with ESBLs 1

Limitations and Considerations

• Safety profile shows treatment-emergent adverse events in 50% of patients, though most were mild to moderate in severity 2
• 1.7% discontinuation rate due to adverse events 2
• Should be used with caution in settings with high incidence of ESBL-producing Enterobacterales to avoid selection pressure 3

Dosing

Standard dosing for cefepime-enmetazobactam is 2g/0.5g administered intravenously 2.

Comparison to Other β-Lactam/β-Lactamase Inhibitor Combinations

Cefepime-enmetazobactam is one of several new cephalosporin/β-lactamase inhibitor combinations:

• Cefepime-enmetazobactam: Primarily targets ESBL-producing organisms 1, 4
• Cefepime-taniborbactam: Has broader activity against KPC and OXA-48 producers 4, 5, 6
• Ceftolozane-tazobactam and ceftazidime-avibactam: Mentioned in guidelines for intra-abdominal infections involving resistant pathogens 3

Conclusion

Cefepime-enmetazobactam fills an important niche in the treatment of infections caused by ESBL-producing Enterobacterales, particularly for complicated UTIs. Its superior efficacy compared to piperacillin-tazobactam positions it as a valuable carbapenem-sparing option for appropriate patients.