Study Insights on Aztreonam and Avibactam for Complicated Intra-Abdominal Infections
Todd Riccobene, PhD, senior scientific director, Anti-Infectives and Infectious Diseases, US Medical Affairs + Health Impact at AbbVie provides more information on the newly approved antibiotic combination for these infections.
Todd Riccobene, PhD
Image credit: Abbvie
Earlier this month, the FDA approved aztreonam and avibactam (Emblaveo) as the first and only fixed-dose, intravenous, monobactam/β-lactamase inhibitor combination antibiotic. Abbvie and Pfizer developed the antibiotic together, and it was approved in combination with metronidazole, for patients 18 years and older who have limited or no alternative options for the treatment of complicated intra-abdominal infections (cIAI). The combination therapy can be used for Gram-negative pathogens including: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae complex, Citrobacter freundii complex, and Serratia marcescens.
To learn more about aztreonam and avibactam, Contagion spoke with Todd Riccobene, PhD, senior scientific director, Anti-Infectives and Infectious Diseases, US Medical Affairs + Health Impact at AbbVie.
Contagion: Can you talk about the clinical treatment challenges associated with complicated intra-abdominal infections?
Riccobene: cIAI is an infection that extends beyond its origin into the abdominal cavity and is associated with an abscess or peritonitis. It is among the most common infections in critically ill patients, accounting for close to 20% of ICU infections, and often involves antibiotic resistant Gram-negative bacteria. Gram-negative bacterial infections are among the most challenging for healthcare professionals to control due to high antimicrobial resistance (AMR).
Patients with antibiotic-resistant infections are critically ill with limited or no treatment options, and the testing required to determine the ideal selection of antibiotics to kill the infection is often slow or not done at all, depending on the hospital's capabilities. Patient outcomes suffer as resistant pathogens are frequently missed by the initial antibiotic choice.
Contagion: Can you provide an overview of this combination therapy and its mechanism of action?
Riccobene: Emblaveo is a medication that combines two components: aztreonam, a monobactam β-lactam antibiotic, and avibactam, a non-β-lactam, β-lactamase inhibitor. Like other β-lactam antibiotics, aztreonam inhibits penicillin binding proteins (PBPs), specifically PBP3, resulting in bacterial cell lysis and death. Aztreonam has a unique monocyclic β-lactam nucleus that makes it structurally different from other β-lactam antibiotics and resistant to degradation by Metallo-β-lactamases (MBLs; Ambler Class B), an increasing source of antibiotic resistance among multi-drug resistant (MDR) bacteria worldwide. However, aztreonam remains susceptible to hydrolysis by many serine β-lactamases of Ambler Class A, C, or D, which are frequently co-produced with MBLs, limiting the activity of aztreonam by itself.
Avibactam was the first approved (in combination with ceftazidime) diazabicyclooctane β-lactamase inhibitor. It acts by forming a reversible covalent adduct with β-lactamase enzymes that is stable to hydrolysis. Avibactam inhibits Ambler Class A, C, and some Class D beta-lactamases, including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase (KPC), AmpC enzymes, and OXA-48 carbapenemases. Although avibactam itself possesses no intrinsic antibacterial activity at clinically relevant concentrations, it has been shown to restore the activity of aztreonam against pathogens that produce Class A, C, and D β-lactamases along with Class B MBLs. The combination of aztreonam and avibactam thus has activity against Gram-negative bacteria that produce all 4 classes of β-lactamases.
Contagion: Can you offer some insights on the phase 3 REVISIT study and its results?
Riccobene: The Phase 3 REVISIT clinical trial was a randomized, active-controlled, central assessor-blinded, multicenter trial evaluating EMBLAVEO ± metronidazole versus the combination of meropenem ± colistin in patients with cIAI or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (not an approved indication for EMBLAVEO in the US).
The study enrolled 422 patients across 81 locations globally. The primary endpoint was clinical cure at the test-of-cure (TOC) visit (days 25-31) in the intent-to-treat (ITT) population. Secondary endpoints included clinical cure at TOC by infection type in the ITT population, 28-day mortality in the ITT population, clinical cure and a favorable per-patient microbiological response at TOC in the microbiological-ITT (micro-ITT), and safety in patients in the ITT population who received the study drug. The REVISIT trial included 312 hospitalized patients with cIAI that were randomized 2:1 to receive treatment with EMBLAVEO with metronidazole or meropenem ± colistin for five to 14 days of therapy.
Although the study was conducted largely in areas where carbapenem-resistant Enterobacterales, including MBL-producers, were prevalent, the number of patients enrolled with confirmed MBL-producing pathogens was low, highlighting the challenges of recruiting these patients into registrational clinical trials.
The clinical data from the REVSIT study provide further support for the use of aztreonam and avibactam as a potential therapeutic option for cIAI caused by Gram-negative bacteria and are particularly promising given the complexities of managing severe infections in these hospitalized patients.
Contagion: The therapy is expected to be available in the US in the third quarter of this year. What needs to be done in order for it to be available?
Riccobene: Gram-negative bacteria are a significant public health concern in the U.S., and new therapeutics are needed to support critically ill patients. AbbVie is working tirelessly to ensure access to this important medicine for the infectious disease community by Q3 of this year.
To find more information on the results of the trial, interested readers can go here.
