Timing of Aztreonam and Ceftazidime-Avibactam Combination Therapy
Yes, aztreonam and ceftazidime-avibactam should be administered simultaneously, not staggered, for optimal bacterial killing and resistance suppression. 1
Administration Timing
Simultaneous administration is superior to staggered dosing based on hollow-fiber infection model studies demonstrating that giving ceftazidime-avibactam followed by aztreonam resulted in inferior bacterial killing compared to concurrent administration. 1
Staggered administration (ceftazidime-avibactam first, then aztreonam) showed significantly reduced efficacy in pharmacodynamic models against NDM-producing Enterobacterales. 1
Optimal Dosing Strategy
The recommended regimen is ceftazidime-avibactam 2.5g every 8 hours plus aztreonam 2g every 6 hours (total 8g/day aztreonam), administered simultaneously. 1, 2
Extended infusion durations (2-hour infusions or continuous infusions) enhance bacterial killing compared to standard 30-minute infusions for both agents. 1
Continuous infusion of both agents resulted in maximal bacterial eradication and resistance suppression over 7 days in pharmacodynamic models. 1
Clinical Context
This combination is specifically indicated for severe infections caused by metallo-β-lactamase-producing carbapenem-resistant Enterobacterales (CRE), where it demonstrates significantly lower 30-day mortality (19.2% vs 44%) compared to alternative therapies. 3, 4, 5
The ESCMID guidelines suggest this combination therapy for patients with severe CRE infections carrying metallo-β-lactamases and/or resistant to newer antibiotic monotherapies (conditional recommendation, moderate evidence). 3
Mechanistic Rationale
Aztreonam is not hydrolyzed by metallo-β-lactamases but is susceptible to ESBLs and AmpC enzymes commonly co-produced by these organisms. 4, 6
Avibactam protects aztreonam from degradation by ESBLs, AmpC, and serine carbapenemases (KPC, OXA-48) that are frequently co-expressed with metallo-β-lactamases. 6, 7
Ceftazidime in the triple combination does not interfere with aztreonam-avibactam activity, with MICs remaining within one 2-fold dilution regardless of ceftazidime concentration. 7
Important Caveats
Higher aztreonam doses (8g/day vs 6g/day) provide more pronounced bacterial killing, though dose-limiting hepatotoxicity must be monitored. 1, 2
The carbapenemase type should be identified before treatment initiation whenever possible, as this combination is ineffective against non-MBL resistance mechanisms in Pseudomonas aeruginosa. 3, 8
This double β-lactam strategy requires further safety evaluation in clinical trials, particularly regarding potential hepatotoxicity and allergic reactions. 1