Aztreonam-Ceftazidime/Avibactam Administration Strategy for MBL-Producing Acute Pyelonephritis with Severe β-Lactam Allergy
For acute pyelonephritis caused by metallo-β-lactamase-producing organisms in patients with severe β-lactam allergy, administer aztreonam 2 grams IV every 8 hours PLUS ceftazidime-avibactam 2.5 grams IV every 8 hours for 10-14 days, with both agents adjusted for renal function. 1, 2
Rationale for This Specific Combination
Aztreonam is safe in β-lactam allergic patients because it is a monobactam with a unique structure that does not cross-react with penicillins or cephalosporins, making it the only β-lactam option for severe penicillin/cephalosporin allergy. 3, 4
Aztreonam alone will fail against MBL-producers because these organisms co-produce ESBLs (like CTX-M) and AmpC enzymes that hydrolyze aztreonam, necessitating the addition of avibactam to neutralize these co-produced enzymes. 1, 2
The synergistic mechanism works by avibactam (delivered via ceftazidime-avibactam) inhibiting the ESBLs and AmpC enzymes while aztreonam remains stable against the NDM or other metallo-β-lactamases. 2, 5
This combination reduced 30-day mortality from 44% to 19.2% (56% relative risk reduction) in bloodstream infections caused by NDM-producing organisms compared to other active antibiotics including colistin-based regimens. 1, 2
Standard Dosing Regimen
Aztreonam: 2 grams IV every 8 hours (infused over 20-60 minutes) 2, 4
Ceftazidime-avibactam: 2.5 grams IV every 8 hours (infused over 2 hours) 1, 2
Duration for acute pyelonephritis: 10-14 days total, with consideration for shorter duration (7-10 days) if clinical response is rapid and source control is adequate 2
Renal Dose Adjustments
For Aztreonam:
- CrCl >30 mL/min: 2 grams IV every 8 hours (no adjustment needed) 6
- CrCl 10-30 mL/min: 1 gram IV every 8 hours 6
- CrCl <10 mL/min: 500 mg IV every 8 hours 6
- Hemodialysis: 500 mg IV every 8 hours, with supplemental 500 mg dose after each dialysis session 6
For Ceftazidime-Avibactam:
- CrCl >50 mL/min: 2.5 grams IV every 8 hours (no adjustment needed) 6
- CrCl 31-50 mL/min: 1.25 grams IV every 8 hours 6
- CrCl 16-30 mL/min: 0.94 grams IV every 12 hours 6
- CrCl 6-15 mL/min: 0.94 grams IV every 24 hours 6
- Hemodialysis: 0.94 grams IV every 48 hours, administered after dialysis on dialysis days 6
Critical Implementation Considerations
Use CKD-EPI equation for eGFR calculation rather than Cockcroft-Gault, as this better predicts clearance for both drugs in critically ill patients. 6
Do not delay treatment waiting for carbapenemase typing—if MBL is suspected based on epidemiology (travel to Indian subcontinent, known local outbreaks) or rapid molecular testing, initiate this combination immediately. 1, 2
Infusion timing matters: Administer ceftazidime-avibactam as a 2-hour infusion to optimize time above MIC, which is the critical pharmacodynamic parameter for both drugs. 6
Monitor renal function every 48-72 hours in critically ill patients, as clearance can change rapidly and necessitate dose adjustments. 6
Common Pitfalls to Avoid
Never use aztreonam monotherapy for MBL infections—the co-produced β-lactamases will inactivate it and lead to treatment failure. 1, 2
Do not use ceftazidime-avibactam monotherapy for MBL-producers—avibactam has zero activity against metallo-β-lactamases and will fail. 2, 7
Avoid colistin-based regimens as first-line therapy—they are associated with significantly higher mortality rates compared to the aztreonam-ceftazidime/avibactam combination. 1, 2
Do not assume all MBL-producers will respond—approximately 18-25% of NDM-producing isolates demonstrate aztreonam MIC ≥4 μg/mL even when combined with avibactam, so obtain susceptibility testing when possible. 8, 4
Alternative Treatment Option
Cefiderocol may be considered as an alternative with 75% clinical cure rates in MBL-producing CRE infections, but this carries only a CONDITIONAL recommendation with LOW certainty of evidence. 1, 9
Cefiderocol concerns include higher MIC values against some MBL-producers, risk of treatment-emergent resistance, and unclear role of combination therapy. 2, 9
Cefiderocol is NOT safe in severe β-lactam allergy as it is a cephalosporin and would be contraindicated in this patient population. 9
Strength of Recommendation
STRONG recommendation with MODERATE certainty of evidence for aztreonam plus ceftazidime-avibactam as the preferred treatment for MBL-producing infections. 1, 2
This represents the highest quality evidence available, based on comparative observational studies showing significant mortality benefit and guideline endorsement from multiple international societies. 1