What is Ceftazidime-Avibactam used for, especially in treating Klebsiella pneumoniae?

Ceftazidime-Avibactam for Klebsiella pneumoniae Infections

Ceftazidime-avibactam is strongly recommended for treating infections caused by carbapenem-resistant Klebsiella pneumoniae that produce serine carbapenemases (KPC and OXA-48), as it significantly reduces mortality and treatment failure compared to other antimicrobial options. 1

Mechanism of Action and Spectrum

Ceftazidime-avibactam combines:

• A third-generation cephalosporin (ceftazidime)
• A novel non-β-lactam β-lactamase inhibitor (avibactam)

The combination is effective against:

• Ambler class A (KPC) carbapenemases
• Class C (AmpC) β-lactamases
• Certain class D (OXA-48) carbapenemases 1

It is important to note that ceftazidime-avibactam is not active against metallo-β-lactamase (MBL) producers such as NDM, VIM, or IMP enzymes. 2

FDA-Approved Indications

Ceftazidime-avibactam (AVYCAZ) is FDA-approved for:

1. Complicated intra-abdominal infections (cIAI) in combination with metronidazole
2. Complicated urinary tract infections (cUTI), including pyelonephritis
3. Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) 3

Dosage and Administration

• Standard adult dose: 2.5 grams (2g ceftazidime + 0.5g avibactam) IV every 8 hours
• Infusion time: 2 hours
• Duration of treatment:
  • cIAI: 5-14 days
  • cUTI: 7-14 days
  • HABP/VABP: 7-14 days 3

Clinical Efficacy for Klebsiella pneumoniae

Evidence from observational studies shows that ceftazidime-avibactam treatment for carbapenem-resistant Enterobacteriaceae (CRE) infections may result in:

• 182 fewer deaths per 1000 patients (RR 0.55,95% CI 0.42-0.72)
• 307 fewer treatment failures per 1000 patients (RR 0.49,95% CI 0.34-0.70)
• 179 fewer pathogen eradication failures per 1000 patients
• 95 fewer cases of acute renal injury per 1000 patients compared to other antimicrobial therapies 1

For KPC-producing K. pneumoniae specifically, ceftazidime-avibactam has shown superior outcomes compared to colistin-based regimens, with a 64% probability of better outcomes (95% CI 57%-71%). 1

Special Considerations

Resistance Development

Resistance to ceftazidime-avibactam in KPC-producing K. pneumoniae has been reported:

• Can develop during treatment or without prior exposure
• Mechanisms include mutations in the KPC enzyme that disrupt avibactam binding
• Resistance rates of 3.7-8.1% have been observed in treated patients 1

Combination Therapy

For KPC-3 producing organisms, some experts recommend combination therapy with a carbapenem or colistin due to potential resistance development. 2

Metallo-β-lactamase Producers

For infections caused by metallo-β-lactamase-producing CRE:

• Ceftazidime-avibactam combined with aztreonam is suggested as a preferential choice
• This combination has shown lower 30-day mortality (19.2% vs 44%, p=0.007) and lower clinical treatment failure rates compared to other active antimicrobial agents 1

Algorithm for Treatment of K. pneumoniae Infections

1. Confirm susceptibility:

   • Determine carbapenemase type (KPC, OXA-48, NDM, etc.)
   • Test ceftazidime-avibactam susceptibility

2. Treatment decision:

   • For KPC or OXA-48-producing K. pneumoniae: Use ceftazidime-avibactam
   • For metallo-β-lactamase producers (NDM, VIM, IMP): Use ceftazidime-avibactam plus aztreonam
   • For susceptible strains without carbapenemases: Consider alternative options

3. Dosing:

   • 2.5 grams IV every 8 hours (infused over 2 hours)
   • Adjust dose for renal impairment

4. Monitor for:

   • Clinical response
   • Development of resistance
   • Adverse effects

Conclusion

Ceftazidime-avibactam represents a valuable treatment option for infections caused by carbapenem-resistant K. pneumoniae, particularly those producing KPC or OXA-48 carbapenemases. Its use should be guided by susceptibility testing and determination of the carbapenemase type to ensure appropriate application of this important antimicrobial agent.