Polymyxin Plus Aztreonam Synergy for Carbapenem-Resistant Enterobacteriaceae
Polymyxin plus aztreonam is NOT a recommended synergistic combination for treating carbapenem-resistant Enterobacteriaceae (CRE) infections. The preferred synergistic combination is ceftazidime-avibactam plus aztreonam, which demonstrates significantly superior mortality outcomes compared to polymyxin-based regimens 1.
Why This Combination Is Not Recommended
Lack of Evidence for Polymyxin-Aztreonam Synergy
- No guideline support exists for combining polymyxins with aztreonam specifically for CRE infections 1.
- The evidence consistently shows that polymyxin-based regimens should be used with companion drugs, but aztreonam is not identified as the preferred partner 1.
- When polymyxins are used in combination therapy, the guidelines note "no firm conclusions can be drawn on which companion drug should be preferred," but the focus is on carbapenems, tigecycline, or other agents—not aztreonam 1.
Superior Alternative: Ceftazidime-Avibactam Plus Aztreonam
For metallo-β-lactamase (MBL)-producing CRE (including NDM and VIM producers):
- Ceftazidime-avibactam plus aztreonam achieves 30-day mortality of 19.2% versus 44% with other active antimicrobials including polymyxin-based regimens (p=0.007) 1.
- This combination receives a STRONG recommendation with MODERATE certainty of evidence from Italian guidelines 1.
- The mechanism is rational: aztreonam is stable against MBLs, while ceftazidime-avibactam protects it from co-produced ESBLs and other β-lactamases 1, 2.
For KPC-producing CRE:
- Ceftazidime-avibactam plus aztreonam demonstrates 100% synergy in vitro against KPC-producers 3, 4.
- Clinical data shows this combination is superior to polymyxin-based therapy, with 66% lower day-14 mortality and 67% lower day-28 mortality 5.
Clinical Algorithm for CRE Treatment Selection
Step 1: Identify Carbapenemase Type
- MBL-producers (NDM, VIM): Use ceftazidime-avibactam plus aztreonam as first-line 1.
- KPC-producers: Use ceftazidime-avibactam or meropenem-vaborbactam monotherapy; consider adding aztreonam for high-level resistance 1, 3.
- OXA-48-producers: Use ceftazidime-avibactam monotherapy 1.
Step 2: When Polymyxins Must Be Used
If newer agents are unavailable or the organism is resistant to them:
- Combine polymyxins with high-dose extended-infusion meropenem (6g/day over 3 hours) when meropenem MIC ≤16 mg/L 1.
- Avoid polymyxins in renal insufficiency; consider tigecycline-based combinations instead 1, 6.
- Never use polymyxin monotherapy for serious CRE infections 1.
Step 3: Avoid Aztreonam Monotherapy
- Aztreonam alone will fail against CRE due to co-produced ESBLs and cephalosporinases, even when the organism produces MBLs 1, 7.
Critical Pitfalls to Avoid
Do not use polymyxin-based regimens when ceftazidime-avibactam plus aztreonam is available for MBL-producing CRE, as mortality data clearly favor the latter (19.2% vs 44%) 1.
Polymyxin nephrotoxicity is significantly higher than with ceftazidime-avibactam-based therapy (p=0.017), making it a less desirable option when alternatives exist 5.
The highest mortality rates in MBL-producing CRE infections occur with colistin-containing regimens, not with ceftazidime-avibactam plus aztreonam 1.
When Polymyxins Are Appropriate
Polymyxin-based combinations remain options when:
- Newer agents are unavailable or unaffordable 1.
- The organism is resistant to all newer β-lactam combinations 1.
- Treating carbapenem-resistant Acinetobacter baumannii (CRAB), where polymyxin-based therapy is equally preferable to tigecycline-based therapy 1, 6.
In these scenarios, combine polymyxins with carbapenems, tigecycline, or other active agents based on susceptibility testing—but not specifically with aztreonam as a synergistic strategy 1.