What is the efficacy of combining polymyxin (Polymyxin B) and aztreonam for treating New Delhi metallo-beta-lactamase (NDM) producing bacterial infections?

Polymyxin and Aztreonam Synergy in NDM Infections

Direct Recommendation

Adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM-producing infections improves bacterial killing and reduces lung inflammation in preclinical models, but current clinical guidelines strongly recommend aztreonam plus ceftazidime-avibactam WITHOUT polymyxin as the preferred regimen, based on superior mortality outcomes compared to polymyxin-containing regimens. 1, 2

Guideline-Based Treatment Approach

First-Line Therapy (Without Polymyxin)

• The Italian Society of Infection and Tropical Diseases (SIMIT) provides a STRONG recommendation with MODERATE certainty of evidence for aztreonam combined with ceftazidime-avibactam as the preferred treatment for MBL-producing CRE infections, including NDM. 1, 2

• This combination demonstrates 30-day mortality of 19.2% versus 44% in patients receiving alternative active antibiotics (including colistin-based regimens). 1, 2

• Importantly, the highest mortality rates were observed in patients who received colistin-containing regimens, making polymyxin-based therapy inferior to the aztreonam-ceftazidime/avibactam combination. 1

Mechanistic Rationale for the Standard Combination

• Aztreonam is uniquely stable against metallo-β-lactamases (NDM, VIM, IMP) because MBLs cannot hydrolyze this monobactam antibiotic. 2, 3

• However, aztreonam cannot be used as monotherapy because NDM-producing organisms co-produce other β-lactamases (ESBLs and AmpC cephalosporinases) that inactivate aztreonam. 1, 2

• Ceftazidime-avibactam provides avibactam, which inhibits these co-produced serine β-lactamases, thereby protecting aztreonam and allowing it to exert its anti-MBL activity. 1

Evidence for Adding Polymyxin B (Triple Therapy)

Preclinical Data Supporting Synergy

• A 2022 mechanistic study using hollow fiber infection models and neutropenic rabbit pneumonia models demonstrated that adding polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing and led to eradication of NDM-1 and CTX-M-coproducing K. pneumoniae. 4

• The triple combination (aztreonam + ceftazidime-avibactam + polymyxin B) produced statistically significant decreases in lung weights (P < 0.05), indicating decreased inflammatory processes compared to the dual combination alone. 4

• This triple therapy also suppressed resistance amplification and limited virulence changes in preclinical models. 4

Clinical Reality vs. Preclinical Promise

• Despite promising preclinical data, clinical guidelines do NOT recommend adding polymyxin to the aztreonam-ceftazidime/avibactam combination because observational clinical data show that polymyxin-containing regimens have the highest mortality rates. 1

• A 2024 retrospective cohort study from South India comparing ceftazidime-avibactam +/- aztreonam versus polymyxins showed 30-day mortality of 29.2% versus 56.9% respectively (P = 0.005), with hazard ratio for mortality with polymyxin use of 2.02 (95% CI: 1.03-3.9). 5

Clinical Outcomes with Standard Dual Therapy

• A 2024 Polish single-center study of 23 patients with KP-NDM infections treated with aztreonam plus ceftazidime-avibactam achieved microbiological eradication in 100% of cases, with 17.4% mortality (primarily in patients with underlying neoplastic disease or COVID-19). 6

• A systematic review of 94 patients treated with aztreonam + avibactam (given as ceftazidime/avibactam) showed clinical resolution in 80% of patients, with 19% mortality in bloodstream infections. 7

Critical Pitfalls to Avoid

• Never use aztreonam monotherapy for NDM infections—it will fail due to co-produced β-lactamases that hydrolyze aztreonam. 2, 3

• Do not default to polymyxin-based therapy when aztreonam plus ceftazidime-avibactam is available, as polymyxin regimens are associated with significantly higher mortality. 1, 5

• Confirm MBL production (NDM, VIM, IMP) before using this combination, as it is ineffective against non-MBL resistance mechanisms. 3, 8

• Monitor for ceftazidime-avibactam resistance development during treatment (occurs in 3.8-10.4% of cases); obtain repeat cultures if clinical deterioration occurs within 48-72 hours. 2, 8

Dosing Specifications

• Ceftazidime-avibactam: 2.5 g IV every 8 hours in patients with normal renal function. 6

• Aztreonam: 2 g IV every 8 hours in patients with normal renal function. 6

• Adjust both agents for reduced renal function. 6

When to Consider Alternatives

• Cefiderocol may be considered as an alternative with CONDITIONAL recommendation and LOW certainty of evidence, achieving clinical cure in 75% (12/16) of patients with MBL-producing CRE in the CREDIBLE-CR trial subgroup. 1, 2

• However, cefiderocol has concerns regarding high MIC values, risk of treatment-emergent resistance, and unclear role of combination therapy that require further investigation. 1