Aztreonam-Avibactam vs. Meropenem for Serious Gram-Negative Bacterial Infections

SYNOPSIS: In this multinational, prospective, Phase III, randomized trial, aztreonam-avibactam was found to be a safe and effective option, when compared to meropenem with or without colistin, for treating complicated intra-abdominal infections, hospital-acquired pneumonia, and ventilator-acquired pneumonia caused by gram-negative bacteria.

SOURCE: Carmeli Y, Cisneros JM, Paul M, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by gram-negative bacteria (REVISIT): A descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis 2024;Oct 7:S1473-3099(24)00499-7. doi:10.1016/S1473-3099(24)00499-7. [Online ahead of print].

Carmeli and colleagues conducted the REVISIT trial, which was a multinational, prospective, Phase III, randomized clinical trial that assessed the efficacy and safety of aztreonam-avibactam as compared with meropenem for the treatment of patients hospitalized with a complicated intra-abdominal infection (cIAI), hospital-acquired pneumonia, or ventilator-acquired pneumonia (HAP-VAP) due to gram-negative bacteria.¹ Aztreonam is a monobactam antibiotic that has a broad spectrum of activity against gram-negative bacteria, but it does not have activity against gram-positive or anaerobic bacteria.

One of the distinctive features of aztreonam is its resistance to hydrolysis by class B metallo-β-lactamases (such as New Delhi metallo-β-lactamase [NDM]). However, it is susceptible to hydrolysis by most serine β-lactamases, which often are co-carried by gram-negative bacteria that harbor metallo-β-lactamases.² Avibactam is a non-β-lactam β-lactamase inhibitor that inhibits class A (e.g., extended-spectrum β-lactamases [ESBL]), class C (e.g., AmpC), and some of the class D β-lactamases (e.g., OXA-48), but it does not inhibit class B metallo-β-lactamases.³ Avibactam was first available in the United States for use as part of a fixed-dose combination with ceftazidime. For this reason, the pairing of aztreonam with ceftazidime-avibactam has been recommended for the treatment of infections caused by metallo-β-lactamase-producing Enterobacterales.²

The REVISIT trial was conducted at 81 centers in 20 countries and enrolled hospitalized patients aged 18 years or older with suspected or confirmed cIAI or confirmed HAP-VAP due to infection caused by gram-negative bacteria. Patients were excluded if their infections were known to be caused by gram-negative bacteria species that were not expected to be susceptible to either study drug (e.g., Acinetobacter baumanii) or by gram-positive bacteria alone. Patients who had received any systemic antibiotics for more than 24 hours within 48 hours of enrollment also were excluded, except for patients who were considered to have failed antibiotic treatment. Patients were randomized in a 2:1 ratio to receive either aztreonam-avibactam or meropenem. Metronidazole was added to aztreonam-avibactam for the cIAI group for anaerobic coverage but not for the HAP-VAP group.

The primary endpoint was the proportion of patients with evidence of clinical cure at the test-of-cure visit in the intention-to-treat (ITT) and in the clinically evaluable analysis sets.

A total of 318 participants in the ITT analysis set met criteria for inclusion in the clinically evaluable analysis set. The majority of patients had a primary diagnosis of cIAI (208 [74%] of 282 in the aztreonam-avibactam group and 104 [74%] of 140 in the meropenem group) and the remainder had a primary diagnosis of HAP-VAP (74 [26%] of 282 in the aztreonam-avibactam group and 36 [26%] of 140 in the meropenem group).

Demographic and baseline characteristics were similar between the groups. More patients with HAP-VAP had an Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 10 compared to those with cIAI (97 [88%] of 110 patients vs. 70 [22%] of 312 patients, respectively). Baseline pathogen profiles were similar between the groups. The most frequently identified pathogens in the overall microbiologic ITT analysis set were Enterobacterales (252 [93%] of 271 patients). Escherichia coli and Klebsiella pneumoniae were the most common pathogens identified in the cIAI and HAP-VAP groups, respectively. Polymicrobial infections were identified in 99 (37%) of 271 patients, and 15 (6%) of 271 patients had baseline bacteremia.

Pathogen resistance was determined by European Committee on Antimicrobial Susceptibility Testing minimum inhibitory concentration (MIC) criteria. Of the 308 gram-negative isolates tested, 97 (31%) were not susceptible to aztreonam (60 isolates from 55 [31%] of 177 patients in the aztreonam-avibactam group and 37 isolates from 36 [38%] of 94 patients in the meropenem group). Of the 80 gram-negative isolates tested for carbapenemases, 19 (24%) isolates from 19 patients were carbapenemase-positive (13 [7%] of 177 patients in the aztreonam-avibactam group, including seven with metallo-β-lactamase-positive isolates, and six [6%] of 94 patients in the meropenem group, of which three were metallo-β-lactamase-positive).

The mean duration of treatment was 8.5 days (standard deviation [SD], 3.5 days; range 1-15) in the aztreonam-avibactam group and 8.9 days (SD, 3.2 days; range 2-15) in the meropenem group.

In the ITT analysis set, the rates of adjudicated clinical cure at the test-of-cure visit were 68.4% (193 of 282 patients) in the aztreonam-avibactam group and 65.7% (92 of 140 patients) in the meropenem group, with a treatment difference of 2.7% (95 confidence interval [CI], -6.6 to 12.4). Clinical cure rates for patients with cIAI were 76.4% (159 of 208) and 74.0% (77 of 104) in the aztreonam-avibactam group and meropenem groups, respectively. For patients with HAP-VAP, clinical cure rates were 45.9% (34 of 74) in the aztreonam-avibactam group and 41.7% (15 of 36) in the meropenem group. Twenty-eight-day all-cause mortality rates were 4% (12 of 282) and 7% (10 of 140) in the aztreonam-avibactam group and meropenem groups, respectively. In the cIAI group, mortality rates were 2% (four of 208) and 3% (three of 104) in the aztreonam-avibactam group and meropenem groups, respectively. In the HAP-VAP group, mortality rates were 11% (eight of 74) and 19% (seven of 36) in the aztreonam-avibactam group and meropenem groups, respectively. Adverse event incidence was similar between the treatment groups and there were no treatment-related serious adverse events in the aztreonam-avibactam group. The safety profile of aztreonam-avibactam was found to be in line with that described for aztreonam alone.

Commentary

The growing threat of multidrug-resistant gram-negative bacteria requires an expansion of our antimicrobial armamentarium. This large randomized clinical trial performed by Carmeli and colleagues demonstrates that aztreonam-avibactam is an effective and well-tolerated treatment for serious infections caused by gram-negative bacteria, with clinical cure and microbiologic response rates similar to meropenem (with or without colistin). Although the REVISIT study was conducted intentionally in areas where metallo-β-lactamase-producing pathogens are prevalent, the number of patients in the study who were identified as having metallo-β-lactamase-positive pathogens was low, which limits the findings regarding clinical efficacy for these organisms.

The ASSEMBLE study is a Phase III, prospective, randomized, multicenter trial, that evaluated the efficacy and safety of aztreonam-avibactam compared with the best available therapy for the treatment of 15 patients hospitalized with infections confirmed to be due to metallo-β-lactamase-positive gram-negative organisms.⁴ Results from the ASSEMBLE study have not yet been published. The recruitment of larger patient populations with confirmed metallo-β-lactamase-positive infections likely will remain a challenge. However, there are in vitro data that have shown aztreonam-avibactam to have potent activity against metallo-β-lactamase-positive pathogens, including NDM variants and isolates co-carrying other carbapenemases.⁵

In summary, results from this Phase III, randomized clinical trial, in combination with in vitro data, indicate that aztreonam-avibactam is a safe and efficacious treatment option for serious infections caused by gram-negative bacteria and may serve an important need in the face of the global threat of antimicrobial resistance.

Jake Scott, MD, is Clinical Associate Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley.

References

1. Carmeli Y, Cisneros JM, Paul M, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by gram-negative bacteria (REVISIT): A descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis. 2024; Oct 7:S1473-3099(24)00499-7. doi:10.1016/S1473-3099(24)00499-7. [Online ahead of print].
2. Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024; Aug 7:ciae403. doi:10.1093/cid/ciae403. [Online ahead of print].
3. Yahav D, Giske CG, Grāmatniece A, et al. New β-lactam-β-lactamase inhibitor combinations. Clin Microbiol Rev. 2020;34:e00115-20.
4. Daikos GL, Cisneros JM, Carmeli Y, et al. Efficacy and safety of aztreonam–avibactam for the treatment of serious infections caused by metallo-β lactamase (MBL)-producing multidrug resistant gram-negative bacteria: Phase 3 ASSEMBLE trial. 34th European Society of Clinical Microbiology and Infectious Diseases (ECCMID); Barcelona, Spain: 2024.
5. Rossolini GM, Arhin FF, Kantecki M. In vitro activity of aztreonam-avibactam and comparators against metallo-β-lactamase-producing Enterobacterales from ATLAS Global Surveillance Program, 2016-2020. J Glob Antimicrob Resist. 2024;36:123-131.