Role of Aztreonam in NDM Treatment
Aztreonam combined with ceftazidime-avibactam is the preferred treatment for NDM-producing bacterial infections, demonstrating significantly lower 30-day mortality (19.2% vs 44%) compared to alternative regimens including colistin-based therapies. 1, 2, 3
Why This Combination Works
Aztreonam is uniquely stable against metallo-β-lactamases (including NDM) because MBLs cannot hydrolyze this monobactam antibiotic. 1, 3 However, aztreonam cannot be used as monotherapy because NDM-producing organisms co-produce other β-lactamases (ESBLs and cephalosporinases) that inactivate aztreonam. 1
The addition of ceftazidime-avibactam protects aztreonam from these co-produced enzymes, creating synergistic activity in 90% of MBL-producing strains. 2, 4
Dosing Regimen
- Ceftazidime-avibactam: 2.5 g IV every 8 hours as a prolonged 3-hour infusion 2
- Aztreonam: 2 g IV every 6 hours 2
- Duration: Minimum 4-6 weeks for bone infections; adjust based on infection site and clinical response 2
The prolonged 3-hour infusion of ceftazidime-avibactam is associated with improved 30-day survival compared to standard infusions. 2
Strength of Evidence
The Italian Society of Infection and Tropical Diseases (SIMIT) and multiple other Italian infectious disease societies provide a STRONG recommendation with MODERATE certainty of evidence for this combination in MBL-producing CRE infections. 1 This recommendation is based on observational data showing the mortality benefit and in vitro synergy studies demonstrating activity restoration in 86% of MBL-producing Enterobacterales. 1, 4
The Infectious Diseases Society of America similarly endorses this combination as preferred therapy for metallo-β-lactamase-producing carbapenem-resistant Enterobacterales. 2, 3, 5
Clinical Evidence
An observational study of bloodstream infections caused by MBL-producing CRE (predominantly NDM-producing Klebsiella pneumoniae) demonstrated that patients receiving ceftazidime-avibactam plus aztreonam had 30-day mortality of 19.2% versus 44% in those receiving other active antibiotics (P = 0.007). 1 Notably, the highest mortality rates occurred in patients receiving colistin-containing regimens. 1
Case reports confirm successful treatment of NDM-producing infections, including a case of Citrobacter sedlakii osteomyelitis and NDM-5-producing E. coli urinary tract infection. 4, 6
Alternative Option: Cefiderocol
Cefiderocol may be considered as an alternative with CONDITIONAL recommendation and LOW certainty of evidence. 1 In the CREDIBLE-CR trial subgroup with MBL-producing CRE, clinical cure was achieved in 75% (12/16) of patients treated with cefiderocol versus 29% (2/7) with best available therapy. 1 More recent pooled data showed 70.8% clinical cure rates and 12.5% 28-day mortality with cefiderocol. 1
However, concerns exist regarding high MIC values, risk of treatment-emergent resistance, and unclear role of combination therapy with cefiderocol. 1
Critical Pitfalls to Avoid
- Do NOT use aztreonam monotherapy for NDM infections—it will fail due to co-produced β-lactamases 1, 3
- Do NOT routinely add polymyxin or fosfomycin to the ceftazidime-avibactam plus aztreonam combination, as this dual regimen alone demonstrates superior outcomes compared to colistin-containing regimens 2
- Monitor for resistance emergence: 3.8-10.4% of patients develop ceftazidime-avibactam resistance during treatment of KPC-producing CRE; obtain repeat cultures if clinical deterioration occurs within 48-72 hours 2
- No standardized susceptibility testing exists for the ceftazidime-avibactam plus aztreonam combination, so clinical judgment and MIC testing of individual agents may be necessary 2
Alternative Combination (Cost Consideration)
Aztreonam plus amoxicillin-clavulanate restored susceptibility in 50% of MBL-producing Enterobacterales and was equally effective as aztreonam-ceftazidime-avibactam for Stenotrophomonas maltophilia (100% susceptibility). 4 This combination offers a markedly cheaper alternative when appropriate, though ceftazidime-avibactam plus aztreonam remains the most potent and broadly effective option. 4