AZTREONAM/AVIBACTAM (EMBLAVEO) FOR SERIOUS GRAM-NEGATIVE INFECTIONS: A CLINICAL REVIEW OF MECHANISM, PHARMACOKINETICS, CLINICAL TRIAL EVIDENCE, AND STEWARDSHIP CONSIDERATIONS

Background: Metallo-β-lactamase (MBL)-producing gram-negative bacteria hydrolyze nearly all conventional β-lactam antibiotics, including carbapenems, and remain outside the inhibitory spectrum of currently available β-lactamase inhibitors, creating a major therapeutic gap. Aztreonam/avibactam (Emblaveo) combines aztreonam, a monobactam intrinsically stable to MBL hydrolysis, with avibactam, a non-β-lactam inhibitor of co-produced serine β-lactamases, to restore antibacterial activity against this resistance phenotype. Objective: To review the mechanism of action, pharmacokinetics, pivotal clinical trial evidence, safety profile, dosing considerations, and antimicrobial stewardship role of aztreonam/avibactam. Methods: A narrative clinical review was conducted using PubMed/MEDLINE, The Lancet Infectious Diseases, JAC-Antimicrobial Resistance, Clinical Infectious Diseases, current FDA approval documentation and prescribing information, and conference proceedings, focusing on the pivotal REVISIT and ASSEMBLE phase 3 trials, the REJUVENATE pharmacokinetic study, and the dose-selection literature supporting current dosing recommendations. Results: The FDA approved aztreonam/avibactam (a fixed 3:1 aztreonam:avibactam ratio, supplied as 1.5 g aztreonam/0.5 g avibactam per vial) on February 7, 2025, in combination with metronidazole, for adults with complicated intra-abdominal infection (cIAI) who have limited or no alternative treatment options, based on prior aztreonam efficacy/safety data and phase 3 REVISIT trial results. REVISIT (422 patients randomized 2:1 to aztreonam/avibactam ± metronidazole versus meropenem ± colistin) found comparable clinical cure at test-of-cure in the cIAI population (76.4%, 95% CI 70.3–81.8%, versus 74.0%, 95% CI 65.0–81.7%) and comparable 28-day all-cause mortality across the trial overall (4% [12/282] versus 7% [10/140]); mortality in the hospital-acquired/ventilator-associated pneumonia (HAP/VAP) subgroup was numerically lower with aztreonam/avibactam (11% [8/74]) than meropenem ± colistin (19% [7/36]), though HAP/VAP is not an FDA-approved indication. In the dedicated MBL-focused phase 3 ASSEMBLE trial (15 patients with confirmed MBL-producing pathogens, predominantly NDM-1/NDM-5/VIM-2/L1 subtypes), clinical cure at test-of-cure was 42% (5/12) with aztreonam/avibactam versus 0% (0/3) with best available therapy, and 28-day mortality was 8% (1/12) versus 33% (1/3), though the small sample size precludes definitive statistical inference. No treatment-related serious adverse events occurred with aztreonam/avibactam in either trial; the most common adverse reactions in REVISIT were hepatic transaminase elevation, anemia, diarrhea, hypokalemia, and pyrexia. Dosing requires adjustment across renal function strata, reflecting the substantially renal elimination of both components. Conclusion: Aztreonam/avibactam represents a mechanistically distinct and clinically validated option for difficult-to-treat gram-negative infections, particularly those involving MBL-producing organisms for which few alternatives exist, though its currently approved indication is limited to cIAI with limited/no alternative options, and appropriate use requires accurate microbiological diagnosis, renal-function-based dosing, and antimicrobial stewardship oversight.