Is there synergy between ceftazidime (a cephalosporin antibiotic), avibactam (a beta-lactamase inhibitor), and aztreonam (a monobactam antibiotic) for treating multi-drug resistant gram-negative bacterial infections?

Ceftazidime-Avibactam Plus Aztreonam Synergy

Yes, the combination of ceftazidime-avibactam plus aztreonam demonstrates clinically significant synergy specifically against metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), with a strong recommendation for use based on significantly reduced 30-day mortality (19.2% vs 44%, P=0.007) compared to alternative therapies. 1

Mechanism of Synergy

The synergistic activity occurs through complementary mechanisms:

• Aztreonam is not hydrolyzed by metallo-β-lactamases but remains susceptible to ESBLs and AmpC β-lactamases that are commonly co-produced by MBL-producing organisms 2, 3
• Avibactam inhibits the ESBLs and AmpC enzymes that would otherwise degrade aztreonam, thereby restoring aztreonam's activity against the organism 2, 4
• This dual mechanism provides coverage against organisms producing both MBLs (NDM, VIM) and serine β-lactamases simultaneously 1

Clinical Evidence and Mortality Benefit

The strongest clinical evidence comes from a prospective observational study of 102 patients with MBL-producing CRE bacteremia (82 NDM-producing, 20 VIM-producing strains):

• 30-day mortality: 19.2% with ceftazidime-avibactam-aztreonam vs 44% with other active therapies (HR 0.37,95% CI 0.13-0.74) 1
• Lower clinical failure rates and reduced length of hospital stay 1
• Colistin-containing regimens showed the highest mortality rates in comparison groups 1
• This provides moderate-certainty evidence for the combination 1

Guideline Recommendations by Pathogen Type

For MBL-Producing CRE (NDM, VIM):

• Strong recommendation for ceftazidime-avibactam 2.5g IV q8h (infused over 2 hours) PLUS aztreonam 1, 2
• This is the preferred treatment according to Italian and European guidelines 1, 2
• The combination is specifically indicated when MBL production is confirmed or suspected 2

For KPC or OXA-48-Producing CRE:

• Ceftazidime-avibactam monotherapy is preferred as nearly 100% of these strains are susceptible to ceftazidime-avibactam alone 2
• The addition of aztreonam provides no additional benefit for non-MBL producers 1

For Pseudomonas aeruginosa:

• In vitro synergy demonstrated against MBL-producing P. aeruginosa (IMP, VIM producers), with synergy and restored bactericidal activity in 80% (4/5) of isolates tested 5
• Clinical data more limited than for Enterobacterales, with 16/19 VIM-producing isolates showing synergistic activity 6
• Important caveat: P. aeruginosa with non-β-lactamase resistance mechanisms may remain resistant despite combination therapy 7

In Vitro Synergy Data

Multiple studies confirm synergistic activity:

• 86% of MBL-producing Enterobacterales had aztreonam susceptibility fully restored when combined with ceftazidime-avibactam 4
• Time-kill assays demonstrate ≥2.15-log10 CFU/ml decrease, meeting criteria for synergy 8
• 4-fold decrease in MICs observed for majority of K. pneumoniae strains with combination therapy 8

Practical Implementation Algorithm

Step 1: Identify or suspect MBL production

• Obtain carbapenemase genotyping or phenotypic testing immediately 2
• If local epidemiology shows high MBL prevalence, initiate empiric combination therapy 2

Step 2: Dosing regimen

• Ceftazidime-avibactam 2.5g IV q8h infused over 2-3 hours (prolonged infusion associated with improved survival) 1, 2
• Aztreonam standard dosing (typically 2g IV q8h)
• Ensure appropriate renal dose adjustment 1

Step 3: De-escalation based on results

• If KPC or OXA-48 confirmed: switch to ceftazidime-avibactam monotherapy 2
• If MBL confirmed: continue combination therapy 1

Critical Caveats and Limitations

No standardized susceptibility testing methods exist for this combination:

• Disk elution, strip stacking, and strip crossing methods show 100% sensitivity and specificity in research settings 7
• No FDA-approved clinical interpretive breakpoints available 1
• Testing should be performed if available to confirm activity 7

Resistance development concerns:

• Combination therapy does not reduce emergence of ceftazidime-avibactam resistance compared to monotherapy (10.4% and 3.8% resistance development in two cohorts) 1
• This differs from in vitro predictions and should not be used as rationale for combination in non-MBL producers 1

Limited evidence for combination therapy in KPC producers:

• Mortality not different between monotherapy and combination for KPC-producing K. pneumoniae (26.1% vs 25.0%, P=0.79) 1
• Combination may have benefit in ventilator-associated pneumonia specifically 1

Alternative for MBL Producers

Cefiderocol represents a conditional alternative with lower quality evidence:

• Clinical cure 75% (12/16) in MBL-producing CRE subgroup from CREDIBLE-CR trial 1, 2
• Concerns include high MIC values, treatment-emergent resistance risk, and unclear role of combination therapy 1
• Should be considered second-line to ceftazidime-avibactam-aztreonam combination 1, 2