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Aztreonam and Avibactam Receive FDA Approval for Treatment of Adults With Complicated Intra-Abdominal Infections
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Key Takeaways
- Aztreonam and avibactam, combined with metronidazole, target complicated intra-abdominal infections in adults with limited treatment options.
- The combination addresses antimicrobial resistance in Gram-negative bacteria, including Escherichia coli and Klebsiella species.
The decision offers patients with antimicrobial resistance, who have limited or no treatment options, a new alternative.
Aztreonam and avibactam (Emblaveo; AbbVie) were approved by the FDA as the first and only fixed-dose intravenous monobactam/β-lactamase inhibitor combination antibiotic in combination with metronidazole (Metrogel; Galderma Labs) for patients ages 18 and older with limited or no alternative options for the treatment of complicated intra-abdominal infections (cIAI), including those caused by the susceptible Gram-negative microorganisms Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae complex, Citrobacter freundii complex, and Serratia marcescens.
Antimicrobial molecules | Image Credit: © Oleksandr - stock.adobe.com
Antimicrobial resistance (AMR) is an urgent, significant global public health threat estimated to cause over 39 million deaths by 2050 and claim the lives of approximately 11.4 million individuals in 2021 alone. Gram-negative microorganisms, which cause infections such as pneumonia and sepsis, are among the most challenging for health care professionals to treat due to high AMR, rendering most, if not all, available medications ineffective. This underscores the critical need for a therapeutic option to prevent worsening infection or death.1
Aztreonam and avibactam is a combination therapy designed to treat cIAI caused by Gram-negative bacteria. Aztreonam is a monobactam β-lactam antibiotic that is effective against Gram-negative bacteria, including those that produce metallo-β-lactamases (MBLs). MBLs are a class of enzymes that give resistance to most β-lactam antibiotics. However, aztreonam's clinical usefulness has been limited because it is susceptible to degradation by other β-lactamases that are often co-produced with MBLs.1
To overcome this challenge, it is combined with avibactam, a broad-spectrum β-lactamase inhibitor to protect aztreonam from being broken down by serine β-lactamases, restoring its effectiveness against multidrug-resistant bacteria.1
The safety and efficacy of aztreonam and avibactam were observed in this randomized, active-controlled, central assessor-blinded, multicenter trial phase 3 REVISIT trial (NCT03329092) evaluating the agent plus metronidazole versus meropenem (Merrem; Pfizer) and colistin (polymyxin E; Xellia Pharmaceuticals ApS) in patients with cIAI or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HAP-VAP).1-3
The 422 patients were randomized by infection type in a 2:1 ratio to receive either aztreonam-avibactam (with metronidazole for complicated intra-abdominal infection; n = 282) or meropenem with or without colistin for 5 to 14 days for complicated intra-abdominal infection or 7 to 14 days for HAP–VAP (n = 140). Of the total population, 64% had at least 1 Gram-negative pathogen, of which the most frequent at baseline were Enterobacterales (252 [93%] of 271). In 80 bacterial isolates that were tested for carbapenemase production, 24% of patients were found to be carbapenemase-positive, indicating the presence of either serine β-lactamase, metallo-β-lactamase, or both.1,3
The primary end point of the study was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population, with secondary endpoints including 28-day mortality in the ITT population and safety in patients in the ITT population who received the study drug.3
The data showed that 68.4% of patients in the aztreonam-avibactam treatment group achieved clinical cure at the test-of-cure visit compared with 65.7% of patients in the meropenem group. This resulted in a treatment difference of 2.7% (95% CI, 6.6-12.4). For patients diagnosed with cIAI, the adjudicated clinical cure rate was 76.4% for the aztreonam-avibactam group, compared with 74.0% for the meropenem group. In patients with HAP-VAP, the clinical cure rates were lower in both the aztreonam-avibactam group (45.9%) and the meropenem group (41.7%).3
The 28-day all-cause mortality rate was 4% for aztreonam-avibactam and 7% for meropenem. Among patients with cIAI, mortality was 2% and 3% in the aztreonam-avibactam and meropenem groups, respectively. For patients with HAP-VAP, mortality was notably higher, at 11% in the aztreonam-avibactam group and 19% in the meropenem group.3
The safety profile of aztreonam–avibactam was generally well tolerated and aligned with the known safety profile of aztreonam monotherapy, suggesting that the combination therapy does not introduce unexpected safety concerns.3
"The continued evolution of antimicrobial resistance among Gram-negative bacteria has left some patients with little to no treatment options, resulting in extended hospital stays, additional morbidity, and death," James A. McKinnell, MD, infectious disease specialist, Milefchik-Rand Medical Group, Torrance Memorial Medical Center in Torrance, California, said in a press release. "The approval of [aztreonam and avibactam] provides physicians a much-needed therapeutic option to help address some of the most difficult antimicrobial-resistant pathogens and provides doctors an opportunity to treat patients with these challenging infections."1
