Aztreonam-avibactam for carbapenem-resistant Gram-negative infections: Mechanisms, clinical efficacy, the challenge of resistance and susceptibility testing.

BACKGROUND

The escalating antimicrobial resistance crisis poses a significant threat to global health. Infections caused by carbapenem-resistant Gram-negative bacteria, particularly those producing metallo-β-lactamases (MBLs), present a formidable therapeutic challenge. Aztreonam-avibactam is a novel combination of a monobactam and a β-lactamase inhibitor that leverages aztreonam's stability against MBLs and avibactam's inhibition of co-produced serine β-lactamases, thereby demonstrating activity against all four Ambler classes.

DATA SOURCES: This review systematically collates current evidence concerning the synergistic mechanism, microbiological spectrum, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety profiles, resistance mechanisms, and antimicrobial susceptibility testing of aztreonam-avibactam.

RESULTS

Aztreonam-avibactam demonstrates potent in vitro activity against carbapenem-resistant Enterobacterales (CRE), including MBL-producing strains. Its efficacy and safety have been evaluated in Phase III trials for the treatment of complicated intra-abdominal infections (cIAIs), complicated urinary tract infections (cUTIs), and hospital-acquired pneumonia (HAP) in adults. However, clinical data specifically for microbiologically confirmed MBL-producing infections remain limited and exploratory because of very small subgroup sizes. PK/PD analyses indicate that the synergistic interaction ensures effective β-lactamase suppression. Aztreonam-avibactam resistance mechanisms, including penicillin-binding protein 3 (PBP3) modifications, β-lactamase variants, porin mutations, and efflux alterations, exhibit genus-specific variations. However, current susceptibility testing still faces limitations in clinical implementation.

CONCLUSIONS

Overall, aztreonam-avibactam offers a promising option for managing severe infections caused by carbapenem-resistant Gram-negative pathogens, supported by strong in vitro and PK/PD evidence. Future efforts should focus on expanding real-world evidence and optimizing dosing strategies to maximize its clinical utility.