What is the recommended use and dosage of Aztreonam (Aztreonam) and Avibactam (Avibactam) for treating infections caused by Gram-negative bacteria?

Aztreonam-Avibactam for Multidrug-Resistant Gram-Negative Infections

Primary Indication and Mechanism

Aztreonam-avibactam is the preferred treatment for serious infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), demonstrating significantly lower 30-day mortality (19.2% vs 44%) compared to alternative therapies. 1, 2

The combination works synergistically because:

• Aztreonam is not hydrolyzed by metallo-β-lactamases but is susceptible to ESBLs and AmpC enzymes 2
• Avibactam inhibits the ESBLs and AmpC enzymes that would otherwise degrade aztreonam 2
• This dual mechanism provides coverage against MBL-producing organisms that resist most other antibiotics 1, 2

Standard Dosing Regimens

Aztreonam-Avibactam Fixed Combination

The approved regimen is aztreonam-avibactam 2.5g IV every 8 hours, administered as a 3-hour infusion, with a loading dose followed by regular maintenance doses. 3

Alternative: Separate Drug Administration

When using ceftazidime-avibactam plus aztreonam separately:

• Ceftazidime-avibactam: 2.5g IV every 8 hours (2-hour infusion) 4, 1
• Aztreonam: 2g IV every 8 hours 1, 5
• Critical caveat: IDSA-proposed regimens using separate drugs achieve inadequate avibactam exposures (joint PTA <85%) and should be avoided 3

Renal Dose Adjustments

For creatinine clearance 10-30 mL/min/1.73m²:

• Give standard loading dose (1-2g aztreonam), then halve the maintenance dose 5

For creatinine clearance <10 mL/min (including hemodialysis):

• Give standard initial dose, then one-fourth of usual dose at regular intervals 5
• Add one-eighth of initial dose after each hemodialysis session 5

Treatment Duration by Infection Type

Duration must be based on infection site and clinical response, not arbitrary fixed courses:

• Complicated urinary tract infections: 5-7 days 4, 1
• Bloodstream infections: 7-14 days 4, 1
• Hospital-acquired/ventilator-associated pneumonia: 10-14 days 4, 1
• Complicated intra-abdominal infections: 5-10 days 4
• Continue for at least 48 hours after patient becomes asymptomatic or bacterial eradication is documented 5

Clinical Decision Algorithm

Step 1: Identify Carbapenemase Type

Obtain carbapenemase genotyping or phenotypic testing immediately upon suspecting CRE infection. 2

Step 2: Select Regimen Based on Resistance Mechanism

For MBL-producing CRE (NDM, VIM, IMP):

• Use aztreonam-avibactam 2.5g IV q8h (3-hour infusion) 1, 2, 6
• Add metronidazole 500mg q6h for intra-abdominal infections 4

For KPC or OXA-48-producing CRE:

• Use ceftazidime-avibactam 2.5g IV q8h alone (monotherapy sufficient) 2, 7
• Nearly 100% of these strains are susceptible to ceftazidime-avibactam 2

For empiric therapy when carbapenemase type unknown:

• If local MBL prevalence is high: start aztreonam-avibactam 2
• If predominantly KPC/OXA-48: start ceftazidime-avibactam alone 2

Step 3: Monitor for Treatment Response

Clinical improvement should be evident within 48-72 hours of initiating appropriate therapy. 1

Critical Caveats and Pitfalls

Resistance Patterns to Avoid Misuse

Aztreonam-avibactam is NOT effective against:

• Acinetobacter species (intrinsic resistance due to OXA-type carbapenemases not inhibited by avibactam) 1
• Non-MBL resistance mechanisms in Pseudomonas aeruginosa 2
• Anaerobic bacteria (requires metronidazole addition for intra-abdominal infections) 4

Emerging Resistance During Therapy

Resistance to ceftazidime-avibactam in KPC-producing organisms has been reported during treatment, particularly with prior drug exposure. 1, 7

Pseudomonas Infections in Cystic Fibrosis

Aztreonam monotherapy has been ineffective in achieving bacteriologic cure in cystic fibrosis patients with P. aeruginosa, despite clinical improvement. 8, 9

Structural Urinary Tract Abnormalities

Patients with major underlying structural abnormalities of the urinary tract show early relapses of bacteriuria despite initial response. 9

Infection-Specific Considerations

Ventilator-Associated Pneumonia

For VAP caused by MBL-producing CRE, aztreonam-avibactam is the American Thoracic Society/IDSA preferred treatment, with superior outcomes compared to colistin-based regimens. 2

Complicated Intra-Abdominal Infections

Always add metronidazole 500mg IV q6h to aztreonam-avibactam for anaerobic coverage in intra-abdominal infections. 4

Bloodstream Infections

For critically unstable patients with CRE bacteremia, combination therapy with tigecycline plus polymyxin or meropenem is suggested until clinical stability is achieved. 4

Safety Profile

Aztreonam-avibactam is generally well-tolerated with no treatment-related serious adverse events reported in Phase 3 trials. 6