Aztreonam-Avibactam Combination Therapy
Primary Indication
Aztreonam-avibactam is specifically indicated for serious infections caused by metallo-β-lactamase (MBL)-producing Gram-negative bacteria, particularly those producing NDM, VIM, or IMP carbapenemases, where standard carbapenem therapy fails. 1
The combination works because avibactam protects aztreonam from degradation by extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, while aztreonam remains inherently stable against MBLs and provides the actual antibacterial activity. 1, 2 Ceftazidime-avibactam alone does not inhibit class B metallo-β-lactamases, which is why aztreonam must be added for MBL-producing organisms. 1
Approved Indications
Aztreonam-avibactam is approved by the European Medicines Agency (EMA) for the following infections caused by MBL-producing Gram-negative bacteria: 2, 3
- Complicated intra-abdominal infections (cIAI) - must be given with metronidazole for anaerobic coverage 4, 3
- Complicated urinary tract infections (cUTI) including pyelonephritis 4
- Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) 4, 5
- Bloodstream infections (BSI) 6
The Phase 3 REVISIT trial demonstrated clinical cure rates of 68.4% for aztreonam-avibactam versus 65.7% for meropenem across these indications, with particularly strong performance in cIAI (76.4% cure rate). 5 The ASSEMBLE trial specifically in MBL-producing infections showed a 42% clinical cure rate for aztreonam-avibactam versus 0% for best available therapy, though sample size was limited (n=15). 6
Standard Dosing
For adults with normal renal function (CrCl >50 mL/min):
- Aztreonam-avibactam: 2.5 g IV every 8 hours, infused over 2-3 hours 1
- Alternative formulation: Aztreonam 2 g IV every 6-8 hours PLUS ceftazidime-avibactam 2.5 g IV every 8 hours (when using separate agents) 4, 1
Duration of therapy: 1
- cIAI and cUTI: 5-14 days
- HAP/VAP: 7-14 days
- BSI: 7-14 days
Critical dosing consideration: Extended infusion of ceftazidime-avibactam over 3 hours (rather than 2 hours) was associated with higher 30-day survival in patients with KPC-producing organisms. 7 While this evidence is for KPC producers rather than MBL producers, the pharmacodynamic principle of maximizing time above MIC applies broadly.
Renal Dose Adjustments
Dose reduction is mandatory for renal impairment to prevent drug accumulation and neurotoxicity: 7, 1
- CrCl 30-50 mL/min: Reduce ceftazidime-avibactam dose per FDA labeling 1
- CrCl <30 mL/min: Further dose reduction required 1
- Hemodialysis: Administer ceftazidime-avibactam after dialysis, as approximately 55% of avibactam is removed during a 4-hour dialysis session 7, 1
Monitor closely for neurotoxicity (seizures, encephalopathy, confusion), particularly in patients with any degree of renal impairment, due to risk of beta-lactam accumulation. 7
Pediatric Dosing
No specific pediatric dosing information is provided in the available evidence. The Phase 3 trials (REVISIT and ASSEMBLE) enrolled only hospitalized adults. 5, 6 Pediatric use would require extrapolation from adult data and consultation with pediatric infectious disease specialists.
Contraindications
Absolute contraindications:
- Known hypersensitivity to aztreonam, avibactam, or any component of the formulation 2
Relative contraindications and cautions:
- Severe renal impairment without appropriate dose adjustment (risk of neurotoxicity) 7, 1
- History of seizure disorder (beta-lactams have pro-convulsive activity, though ceftazidime has lower risk than some other beta-lactams) 7
Alternative Therapies for MBL-Producing Organisms
When aztreonam-avibactam is unavailable or contraindicated, consider these alternatives for MBL-producing Gram-negative bacteria:
1. Ceftazidime-Avibactam Plus Aztreonam (Separate Agents)
This is the most evidence-based alternative. An observational study of 102 patients with MBL-producing CRE bacteremia showed this combination was associated with significantly lower 30-day mortality (HR 0.37,95% CI 0.13-0.74) compared to other therapies. 8 The isolates were mostly non-susceptible to aztreonam alone, but the combination restored activity.
- Ceftazidime-avibactam 2.5 g IV every 8 hours over 3 hours
- Aztreonam 2 g IV every 6-8 hours
2. Cefiderocol
Cefiderocol has activity against MBL-producing organisms through its siderophore mechanism. 8 However, the CREDIBLE trial showed similar cure rates between monotherapy and combination therapy, with no mortality data specifically for CRE. 8
3. Polymyxin-Based Combinations
Polymyxins (colistin or polymyxin B) remain options for MBL producers, though resistance is increasing and toxicity is significant. 8 The IDSA/ATS guidelines recommend polymyxins be reserved for settings with high prevalence of multidrug resistance and local expertise. 8
Dosing: 8
- Colistin: 5 mg/kg IV × 1 (loading dose), then 2.5 mg × (1.5 × CrCl + 30) IV every 12 hours
- Polymyxin B: 2.5-3.0 mg/kg/day divided in 2 daily IV doses
4. Aztreonam Plus Other Beta-Lactamase Inhibitor Combinations
In vitro data suggest aztreonam combined with vaborbactam or relebactam may have activity against MBL producers, but with lower efficiency than aztreonam-avibactam. 9 With high-dose aztreonam (2g × 4 daily), susceptibility rates for MBL-producing Enterobacterales were 78.9% for aztreonam-vaborbactam and 57.7% for aztreonam-relebactam, compared to 92.3% for aztreonam-avibactam. 9
Critical Clinical Pearls
1. Carbapenemase typing is essential: Aztreonam-avibactam is effective against MBLs (NDM, VIM, IMP) but NOT against serine carbapenemases alone (KPC, OXA-48). 4, 1 For KPC or OXA-48 producers, use ceftazidime-avibactam alone without aztreonam.
2. Mandatory metronidazole for cIAI: Aztreonam-avibactam lacks anaerobic coverage, so metronidazole must be added for intra-abdominal infections. 4, 3
3. Resistance emergence risk: Resistance to ceftazidime-avibactam has been reported in carbapenemase-producing K. pneumoniae, particularly with prior drug exposure and bla KPC-3 gene mutations. 4 For severe infections, some experts suggest combination therapy to prevent resistance development, though evidence is insufficient. 4
4. No standardized susceptibility testing: There are currently no standardized antimicrobial susceptibility testing methods or clinical interpretative breakpoints approved for the aztreonam-avibactam combination. 8 Testing must be performed for individual components.
5. Safety profile: Aztreonam-avibactam was generally well-tolerated in Phase 3 trials with no treatment-related serious adverse events in the aztreonam-avibactam group. 5, 6 The 28-day mortality rate was 8% for aztreonam-avibactam versus 33% for best available therapy in the ASSEMBLE trial. 6