Introduction

Ceftazidime-avibactam (CAZ-AVI) has been used as a frontline agent in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. However, its efficacy and safety on carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) remain unclear.

Aim

To assess the efficacy and safety of CAZ-AVI for the treatment of CRE BSIs

Methods

• A systematic review and meta-analysis
• Observational studies comparing the clinical outcome of CAZ-AVI with other regimens in CRE BSI were included if they reported data on mortality
• Eleven articles (3 prospective and 8 retrospective observational studies) included

  Patient Profile

• N=1,205 patients
• Site of bacteremia: Varied between studies; mainly urinary tract, respiratory tract, and intraabdominal structure or were catheter related
• Pathogens:
  • In 6 studies, all patients were infected with Klebsiella pneumoniae,
  • Multiple pathogens were identified in the other 5 studies, although K. pneumoniae was the major pathogen (79% to 88%).
  • Resistance Mechanism: KPC was the predominant mechanism of carbapenem resistance (70 - 100%) in 6 studies, OXA-48 in 2 studies and metallo-b-lactamases (MBLs) in 1 study
• Treatment:
  • Treatment group: CAZ-AVI was administered in 2% to 52% of patients (most common combination therapy with carbapenem and tigecycline)
  • Control group: Antimicrobial agents varied a lot and included mainly tigecycline and colistin-containing regimens (from 0% to 81.5% and 3% to 60%, respectively). The most common combination regimen was colistin and tigecycline

Study endpoints

Primary: All-cause 30-day mortality (including 28-day mortality)

Secondary: Clinical cure rate, Relapse Rate, and Nephrotoxicity

Results

All-cause 30-day mortality:

• Compared with the control group, CAZ-AVI group had a significantly lower 30-day mortality rate (RR = 0.55, 95%CI of 0.45 to 0.68, I² = 0%, P=0.00001)
• Compared to the treatment of colistin-containing regimens, the CAZ-AVI group showed a lower 30-day mortality rate (RR = 0.48, 95% CI of 0.33 to 0.69, I² = 36%, P=0.0001)
• Subgroup analysis of carbapenemase: Association of CAZ-AVI treatment with decreased mortality rate was observed both in patients infected with CRE producing KPC (RR = 0.59, I² = 0%, P=0.0001) and MBL (RR = 0.44, P = 0.01)

Clinical cure rate:

• Compared with the control group, CAZ-AVI group had a significantly higher clinical cure rate (RR = 1.85, 95% CI of 1.57 to 2.18, I² = 0%, P=0.00001)

  Relapse:

• Meta-analysis of 4 studies (n=455) showed a comparable relapse rate between both groups (RR = 0.69, I² = 54%, P = 0.41)

  Nephrotoxicity:

• Pooled results from 5 studies (n=380) indicated a lower nephrotoxicity rate in the CAZ-AVI group (RR = 0.41, I² = 2%, P = 0.02)

  Conclusion

• CAZ-AVI treatment was found to be effective and safe compared with other antibiotics, including colistin, in CRE BSI. It was associated with lower 30-day mortality, improved clinical cure and nephrotoxicity with comparable risk of relapse.
• CAZ-AVI treatment might be considered as drug of choice in selected patients; however, these results await validation by prospective randomised controlled trials.

Reference

Microbiol Spectr. 2022 Mar-Apr; 10(2): e02603-21