Polymyxin Plus Aztreonam for CRE Infections
Polymyxin plus aztreonam is NOT the recommended combination for CRE infections—you should use ceftazidime-avibactam plus aztreonam instead, which demonstrates significantly superior mortality outcomes (19.2% vs 44% 30-day mortality) compared to polymyxin-based regimens. 1
Why This Combination Is Suboptimal
The question asks about polymyxin plus aztreonam, but this is not a guideline-recommended regimen for CRE. The evidence consistently supports different combinations:
For Metallo-β-Lactamase (MBL)-Producing CRE (NDM, VIM, IMP):
Use ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 6 hours as the preferred regimen. 2, 3, 4
- This combination achieved 19.2% 30-day mortality versus 44% with other active antimicrobials (including polymyxin-based therapies) in a propensity-score-adjusted study of 102 patients with MBL-producing CRE bacteremia. 1
- The hazard ratio for 30-day mortality was 0.37 (95% CI 0.13-0.74), representing a 63% reduction in mortality risk. 1
- Clinical failure rates and length of hospital stay were also significantly reduced with this combination. 1
For KPC-Producing or OXA-48-Producing CRE:
Use ceftazidime-avibactam monotherapy at 2.5g IV every 8 hours as a prolonged 3-hour infusion. 4
- Nearly 100% of KPC and OXA-48 producers are susceptible to ceftazidime-avibactam alone. 4
- Adding aztreonam provides no mortality benefit for non-MBL producers. 1
Why Polymyxin-Based Regimens Are Inferior
Multiple recent studies demonstrate that ceftazidime-avibactam-based therapy (with or without aztreonam) outperforms polymyxin-based combinations:
- Mortality advantage: Ceftazidime-avibactam-based therapy was 66% less likely to be associated with day 14 mortality (p=0.048) and 67% less likely to be associated with day 28 mortality (p=0.039) compared to polymyxin-based therapy. 5
- Reduced nephrotoxicity: Polymyxin-based regimens had significantly higher incidence of nephrotoxicity (p=0.017). 5
- Better clinical response: In a Cox multivariate regression analysis, ceftazidime-avibactam with or without aztreonam showed significantly better clinical response at day 14 (HR=0.78,95% CI 0.63-0.95, p=0.018) compared to polymyxins. 6
- Improved survival in high-prevalence NDM settings: In a South Indian cohort with high NDM prevalence, ceftazidime-avibactam plus aztreonam demonstrated 30-day mortality of 29.2% versus 56.9% with polymyxins (p=0.005), with hazard ratio of 2.02 for polymyxin use. 7
Mechanism Rationale
Aztreonam is uniquely stable against metallo-β-lactamases because MBLs cannot hydrolyze this monobactam antibiotic. 2, 3 However, aztreonam cannot be used as monotherapy because MBL-producing organisms co-produce other β-lactamases (ESBLs and cephalosporinases) that inactivate aztreonam. 3
Ceftazidime-avibactam protects aztreonam from these co-produced β-lactamases, restoring aztreonam susceptibility and creating synergistic activity in 90-100% of MBL-producing strains. 4, 8
Polymyxin does not provide this protective mechanism for aztreonam, making the combination mechanistically inferior. 8
Critical Implementation Points
- Determine carbapenemase type before treatment whenever possible through phenotypic or genotypic PCR testing for MBL genes. 4
- Administer ceftazidime-avibactam as prolonged 3-hour infusions, which are associated with improved 30-day survival. 4
- Do NOT add polymyxin or fosfomycin to the ceftazidime-avibactam plus aztreonam combination for MBL-producers, as the dual regimen alone demonstrates superior outcomes. 3, 4
- Monitor for resistance emergence: 3.8-10.4% of patients develop ceftazidime-avibactam resistance during treatment; obtain repeat cultures if clinical deterioration occurs within 48-72 hours. 3, 4
When Polymyxin-Based Therapy Might Be Considered
Polymyxin-based combination therapy may only be considered when:
- Ceftazidime-avibactam is unavailable or unaffordable
- The organism demonstrates in vitro resistance to ceftazidime-avibactam
- The patient has severe renal insufficiency requiring careful polymyxin dosing adjustment 1
Even in these scenarios, newer agents like cefiderocol or aztreonam-avibactam (when available) should be prioritized over polymyxin-based regimens given the superior safety and efficacy profiles. 9