Efficacy and safety of aztreonam-avibactam for the treatment of serious infections due to gram-negative bacteria, including metallo-beta-lactamase-producing pathogens: phase 3 REVISIT study
Presenter: Yehuda Carmeli, MD, Head of the Israeli National Center for Antibiotic Resistance, Israel Ministry of Health, Tel Aviv, Israel
BOSTON 14 OCTOBER 2023—Data from REVISIT, a phase 3 trial conducted among hospitalized adults, support potential use of aztreonam-avibactam to treat serious infections caused by susceptible multidrug-resistant gram-negative bacteria, according to Professor of Medicine Yehuda Carmeli, MD, Head of the Israeli National Center for Antibiotic Resistance, Israel Ministry of Health, Tel Aviv, Israel. Patients included in the study, Carmeli said in an ID Week 2023 oral presentation, had complicated intra-abdominal infection or hospital-acquired or ventilator-associated pneumonia due to gram-negative bacteria, including metallo-beta-lactamase-producing multidrug resistant pathogens, with limited or no treatment options.
Significant treatment challenges are posed by multidrug-resistant gram-negative bacteria, including metallo-beta-lactamase producers.1 While aztreonam has activity against metallo-beta-lactamase (class B)-producing pathogens, it can be inactivated by class A, C, or D beta-lactamases. Avibactam, when used in combination with aztreonam, restores aztreonam’s in vitro activity against these enzymes,2–5 Carmeli stated. The phase 2a REJUVENATE study, he added, demonstrated safety and a favorable benefit-risk profile for aztreonam-avibactam in patients with complicated intra-abdominal infections.6
REVISIT, a phase 3, prospective, randomized, multicenter, open-label, central assessor-blinded study, investigated the efficacy and safety of aztreonam-avibactam in 422 hospitalized adults, randomly assigning them in a 2:1 ratio to aztreonam-avibactam (with or without metronidazole in patients with complicated intra-abdominal infections only) (n = 282, mean age 55.2 years, 66.0% male) or to meropenem with or without colistin 5 to 14 days for patients with complicated intra-abdominal infections or 7 to 14 days for patients with hospital-acquired or ventilator-associated pneumonia (n = 140, mean age 54.0 years, 72.1% male). The primary efficacy endpoints were clinical cure at the test-of-cure visit and clinically evaluable analysis sets.
About 74% of patients in both groups had complicated intra-abdominal infections, and the rest had hospital-acquired or ventilator-associated pneumonia. In the latter group, 51.8% were undergoing mechanical ventilation at baseline (51.4% in the aztreonam-avibactam group, 52.8% in the meropenem group). Polymicrobial infection was found in 99 (36.5%) of the entire group (the rates were 39.5% in the aztreonam-avibactam group and 30.9% in the meropenem group). Metallo-beta-lactamase-positive pathogens were identified in the micro-intention-to-treat set among 10 (3.7%) of 271 patients.
Carmeli reported that for patients with complicated intra-abdominal infections, microbiological response rates at the test-of-cure visit were favorable for aztreonam-avibactam with or without metronidazole (cure rate 85.1%) and for meropenem with or without colistin (cure rate 79.5%), as they were for those with hospital-acquired or ventilator-associated pneumonia (46.7% vs 54.5% in the 2 treatment groups, respectively).
Twenty-eight day all-cause mortality rates among patients with complicated intra-abdominal infections were 1.9% (4 of 208 patients died) in the group receiving aztreonam-avibactam with or without metronidazole, vs 2.9% (3 of 104 died) in the group receiving meropenem with or without colistin. Among those with hospital-acquired or ventilator-associated pneumonia, mortality rates were 10.8% (8 of 74) vs 19.4% (7 of 36) with the 2 regimens, respectively. The higher mortality rates among patients with hospital-acquired or ventilator-associated pneumonia, Carmeli observed, were consistent with higher severity of illness.
Aztreonam-avibactam was generally well tolerated, treatment-related adverse events were generally balanced between treatment groups, and most events were mild or moderate. No treatment-related serious adverse events were reported.
Carmeli concluded that for treating complicated intra-abdominal infection and hospital-acquired or ventilator-associated pneumonia, aztreonam-avibactam with or without metronidazole was effective and similar to meropenem with or without colistin. “The REVISIT findings,” he said, “support potential use of aztreonam-avibactam for the treatment of serious infections caused by susceptible gram-negative bacteria.” Metallo-beta-lactamase-producing pathogens will be the focus of further analyses.
Disclosures. The REVISIT study (NCT03329092) was sponsored by Pfizer. Aztreonam-avibactam is jointly developed with AbbVie, also supported by the United States Biomedical Advanced Research and Development Authority and the European Innovative Medicines Initiative, under the COMBACTE-CARE consortium.
Dr. Carmeli has disclosed serving as an advisor and receiving grant support and honoraria from Pfizer, Qpex, Roche, and Merck.
References
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- Cornely OA, Cisneros JM, Torre-Cisneros J, et al. Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother 2020; 75(3):618–627. doi:10.1093/jac/dkz497