Clinical research on new antibacterial drugs should be more grounded in guiding practical applications

In an era where antimicrobial-resistant bacteria are increasingly prevalent and available antibiotics remain relatively scarce, the completion of the multinational, open-label, randomized controlled phase III REVISIT study for aztreonam-avibactam (a new β-lactamase inhibitor combination targeting resistant Gram-negative bacteria) is a significant milestone. The study demonstrated non-inferiority compared to meropenem (1). However, several issues warrant further exploration to optimize the clinical application of this antibiotic.

The REVISIT study population does not fully reflect clinical needs for aztreonam-avibactam

The primary advantage of aztreonam-avibactam lies in its efficacy against metallo-β-lactamase (MBL) producing Gram-negative bacteria. However, in the REVISIT study, only 80 of the 422 enrolled patients underwent carbapenemase testing, with 19 testing positive [9 serine-β-lactamases (SBLs) and 10 MBLs]. This limited representation raises questions about the antibiotic’s suitability as a first-line treatment in regions with varying resistance patterns. For instance, in Asia, the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) among Enterobacteriaceae is notably higher than in other regions, with significant differences in MBL carriage between Klebsiella pneumoniae and Escherichia coli (2).

To address this gap, head-to-head comparative studies between aztreonam-avibactam and ceftazidime-avibactam for Klebsiella pneumoniae carbapenemase (KPC)-producing strains are essential. Such studies would clarify whether aztreonam-avibactam offers superior efficacy or if ceftazidime-avibactam remains preferable due to cost advantages. Additionally, the REVISIT study predominantly included patients with complicated intra-abdominal infections (cIAI; 74% in both treatment groups), while hospital-acquired and ventilator-associated pneumonia (HAP/VAP) conditions with higher resistance rates and unmet therapeutic needs were underrepresented.

For cIAI, new tetracycline antibiotics may offer advantages over aztreonam-avibactam, such as broader anaerobic coverage and higher infection site concentrations (2,3). Conversely, HAP/VAP, where Klebsiella pneumoniae plays a more prominent role than Escherichia coli, demands more focused research. Furthermore, the study did not provide pathogen minimum inhibitory concentrations (MICs), which are critical for determining whether high-dose meropenem could suffice for some MBL-producing strains, avoiding unnecessary use of newer agents (4). Considering the ample safety and efficacy evidence for meropenem, we believe that more precise patient stratification is needed to identify the population that truly benefits from aztreonam-avibactam.

Recommendation: future studies should prioritize enrolling patients with confirmed MBL-producing infections and include more HAP/VAP cases to better define the antibiotic’s clinical niche.

Aztreonam-avibactam may not be clinically indispensable

The clinical necessity of aztreonam-avibactam is debatable, particularly in regions where both aztreonam and ceftazidime-avibactam are available. In vitro studies suggest that combining aztreonam with ceftazidime-avibactam may yield synergistic effects, outperforming aztreonam-avibactam alone (5). Moreover, pharmacokinetic/pharmacodynamic (PK/PD) studies highlight that avibactam underdosing can lead to KPC mutations, a resistance mechanism not addressed by aztreonam-avibactam (6,7).

Flexible dosing of aztreonam with ceftazidime-avibactam, guided by therapeutic drug monitoring (TDM), may offer superior outcomes compared to fixed-dose aztreonam-avibactam. Continuous infusion regimens for both drugs could further optimize efficacy in critically ill patients (8). While some argue that aztreonam-avibactam simplifies antibiotic management by reducing the defined daily dose (DDD), its complex administration protocol may offset these benefits.

Recommendation: comparative studies and real-world data are needed to evaluate whether aztreonam-avibactam provides tangible advantages over existing combination therapies.

Refining the clinical positioning of aztreonam-avibactam

Aztreonam-avibactam’s primary role should be reserved for infections caused by carbapenem-resistant organisms (CROs), particularly MBL-producing strains. The REVISIT study’s non-inferiority design does not support its use as a carbapenem substitute for empirical therapy. Misuse of such agents against sensitive pathogens could exacerbate resistance, as seen with ceftazidime-avibactam post-marketing.

Recommendation: clinical guidelines should emphasize aztreonam-avibactam’s use for confirmed CRO infections. Future trials must include more representative patient populations, particularly those with MBL-producing strains, to validate its role.

Addressing unmet questions: PK/PD, combination therapies, and long-term outcomes

The commentary rightly notes the need for deeper exploration of aztreonam-avibactam’s PK/PD properties and its potential in combination therapies. For instance, optimizing dosing regimens to prevent resistance and evaluating synergistic combinations with other antibiotics could enhance utility. Long-term studies are also critical to assess resistance development and patient outcomes over time.

Recommendation: future research should integrate PK/PD modeling, explore combination strategies, and monitor long-term efficacy and safety.

Integration into clinical practice

To facilitate aztreonam-avibactam’s adoption, practical considerations must be addressed. These include: (I) guideline development: clear recommendations for use in CRO infections; (II) diagnostic support: rapid diagnostics to identify MBL-producing strains; (III) stewardship programs: policies to prevent overuse and resistance.

Recommendation: multidisciplinary collaboration is needed to align clinical use with diagnostic and stewardship frameworks.

In summary, aztreonam-avibactam is a promising option for resistant Gram-negative infections, particularly those involving MBLs. However, its clinical value hinges on targeted use, robust comparative data, and optimized dosing strategies. Future research must address the gaps highlighted here to ensure this drug fulfills its potential without compromising long-term antibiotic sustainability.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2025-19/prf

Funding: This work was supported by the Project of the Key Laboratory of Multiple Organ Failure, Ministry of Education (Nos. 2023KF07, 2024KF03), the Key Laboratory of Intelligent Pharmacy and Individualized Treatment in Huzhou City (No. HZKF-20240101).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2025-19/coif). Y.Y. serves as the Editor-in-Chief of Journal of Emergency and Critical Care Medicine from September 2024 to August 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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