Ceftazidime-Avibactam Plus Aztreonam for MBL-Producing Infections
Recommended Dosing Regimen
Administer ceftazidime-avibactam 2.5g IV every 8 hours (infused over 2 hours) PLUS aztreonam 2g IV every 6 hours (8g/day total, infused over 2 hours) simultaneously for metallo-β-lactamase-producing Enterobacterales or Pseudomonas infections. 1, 2, 3
Key Dosing Principles
- Simultaneous administration is critical—staggered dosing (giving ceftazidime-avibactam first, then aztreonam) results in inferior bacterial killing and should be avoided 3
- Extended infusion duration (2 hours) is superior to 30-minute bolus infusions for both agents, maximizing time above MIC and enhancing bacterial eradication 3
- Aztreonam 8g/day (2g every 6 hours) demonstrates superior killing compared to 6g/day (2g every 8 hours), particularly for NDM-producing strains 3
- Continuous infusion of both agents is an alternative that achieved complete bacterial eradication in hollow-fiber models, though intermittent dosing is more practical in clinical settings 3
Treatment Duration
- Bloodstream infections: 10-14 days minimum 4
- Hospital-acquired/ventilator-associated pneumonia: 7-14 days depending on clinical response 2
- Complicated urinary tract infections: 7-10 days 4
- Intra-abdominal infections: 4-7 days after source control 4
Monitor for clinical deterioration within 48-72 hours and obtain repeat cultures—resistance emergence occurs in 3.8-10.4% of patients during treatment 1, 2
Renal Dose Adjustments
Ceftazidime-Avibactam Adjustments
| CrCl (mL/min) | Dose | Frequency |
|---|---|---|
| >50 | 2.5g | Every 8 hours |
| 31-50 | 1.25g | Every 8 hours |
| 16-30 | 0.94g | Every 12 hours |
| 6-15 | 0.94g | Every 24 hours |
| <6 or HD | 0.94g | Every 48 hours (after HD on dialysis days) |
Aztreonam Adjustments
| CrCl (mL/min) | Loading Dose | Maintenance Dose |
|---|---|---|
| >30 | 2g | 2g every 6-8 hours |
| 10-30 | 2g | 1g every 6-8 hours |
| <10 | 2g | 500mg every 6-8 hours |
Clinical Evidence Supporting This Regimen
The combination demonstrates 30-day mortality of 19.2% versus 44% with alternative regimens (including colistin-based therapy) for MBL-producing CRE bloodstream infections. 1, 2 This represents a strong recommendation with moderate certainty of evidence from both the Infectious Diseases Society of America and the Italian Society of Infection and Tropical Diseases 1
Mechanistic Rationale
- Aztreonam is uniquely stable against metallo-β-lactamases (NDM, VIM, IMP) because MBLs cannot hydrolyze monobactam antibiotics 1, 6
- Aztreonam CANNOT be used as monotherapy—MBL-producing organisms co-produce ESBLs and AmpC enzymes that rapidly inactivate aztreonam 1, 7
- Avibactam (from ceftazidime-avibactam) inhibits these co-produced serine β-lactamases, restoring aztreonam susceptibility in >99% of MBL-producing Enterobacterales 6
Critical Pitfalls to Avoid
- Never use aztreonam monotherapy for MBL infections—it will fail due to co-produced β-lactamases 1
- Confirm MBL production before using this combination—it is ineffective against non-MBL resistance mechanisms (KPC, OXA-48) where ceftazidime-avibactam monotherapy is preferred 2
- Do not add polymyxins or fosfomycin to this dual β-lactam regimen—the combination alone demonstrates superior outcomes 1
- Monitor for hepatotoxicity with high-dose aztreonam (8g/day), though this is dose-limiting primarily at doses >12g/day 5
Efficacy by Pathogen Type
Enterobacterales (Excellent Activity)
- 86% of MBL-producing Enterobacterales achieve susceptibility (MIC ≤4 mg/L) with this combination 7
- Clinical resolution in 80% of patients with MBL-producing Enterobacterales infections 4
Pseudomonas aeruginosa (Limited Activity)
- Only 6% of MBL-producing Pseudomonas achieve susceptibility with aztreonam-avibactam 4
- The combination is ineffective against non-MBL resistance mechanisms in Pseudomonas 2
- Consider cefiderocol as alternative for MBL-producing Pseudomonas (75% clinical cure rate in CREDIBLE-CR trial) 1