Novel Combination Antibiotic Shows Efficacy in Serious Bacterial Infections due to Gram-negative Bacteria

Results from Pfizer’s phase 3 REVISIT and ASSEMBLE trials for the novel combination antibiotic aztreonam-avibactam (ATM-AVI) demonstrated a therapeutic benefit and showed a favorable safety profile treating serious bacterial infections due to Gram-negative bacteria, including metallo-β-lactamase (MBL)-producing multidrug-resistant pathogens. The novel antibiotic combines aztreonam, a monobactam β-lactam, with avibactam, a broad-spectrum β-lactamase inhibitor.

Credit: Jairo - stock.adobe.com

The combination restores the activity of aztreonam against bacteria co-producing MBLs and other β-lactamases

“We believe these data demonstrate that ATM-AVI, if approved, could be an important treatment option for patients with life-threatening bacterial infections that are resistant to almost all currently available antibiotics,” James Rusnak, senior vice president and chief development officer, Internal Medicine, Anti-Infectives and Hospital, Pfizer, said in a press release. “We are committed to meeting this critical need and helping to address the global health threat of antimicrobial resistance.”

The REVISIT study investigated ATM-AVI ± metronidazole (MTZ) with meropenem (MER) ± colistin (COL) for the treatment of complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP).

Among patients with cIAI, the cure rate in the intention to treat (ITT) analysis set was 76.4% (95% confidence interval (CI) [70.3, 81.8]) in the ATM-AVI ± MTZ treatment cohort compared with 74.0% (95% CI [65.0, 81.7]) for the MER ± COL treatment cohort, with a treatment difference of 2.4% (95% CI [-12.4, 19.1]). Cure rates in the clinically evaluable (CE) analysis group were 85.1% (95% CI [79.2, 89.9]) for ATM-AVI ± MTZ compared with 79.5% (95% CI [69.9, 87.1]) for MER ± COL.

Among patients with HAP/VAP, the cure rate in the ITT analysis set was 45.9% (95% CI [34.9, 57.3]) for ATM-AVI ± MTZ compared with 41.7% (95% CI [26.7, 57.9]) for MER ± COL, with a treatment difference of 4.3% (95% CI [-25.6, 32.2]). The cure rate in the CE analysis set was 46.7% (95% CI [32.7, 61.1]) for ATM-AVI ± MTZ vs 54.5% (95% CI [34.3, 73.7]) for MER ± COL.

All-cause 28-day mortality rates for ATM-AVI ± MTZ were 4/208 (1.9%) compared with 3/104 (2.9%) for MER ± COL in cIAI, and 8/74 (10.8%) for ATM-AVI ± MTZ versus 7/36 (19.4%) for MER ± COL in HAP/VAP.

The novel combination therapy was well-tolerated, with incidence of treatment-emergent adverse events (AEs) similar with prior findings for aztreonam monotherapy. The incidence of serious AEs (SAEs) was similar among treatment cohorts, with 53 [19.3%] patients in the ATM-AVI ± MTZ group vs 25 [18.2%] patients in the MER ± COL group. There were no treatment-related SAEs reported among patients treated with ATM-AVI ± MTZ.

In the ASSEMBLE study, 5/12 (41.7%) patients in the ATM-AVI ± MTZ cohort with infections associated with confirmed MBL-producing Gram-negative bacteria were cured at TOC compared with 0/3 (0%) patients on best available therapy. The ATM-AVI cohort experienced AEs associated with treatment that mirrored those associated with aztreonam monotherapy. No patients administered ATM-AVI experienced a treatment-related SAE.

Pfizer said it is planning to provide the full findings from these studies at a future scientific publication, with regulatory filing planned in the second half of 2023 in the United States, European Union, United Kingdom, and China.

Reference

Phase 3 Studies of Pfizer’s Novel Antibiotic Combination Offer New Treatment Hope for Patients with Multidrug-Resistant Infections and Limited Treatment Options. Pfizer. News release. Accessed June 20, 2023. https://www.pfizer.com/news/press-release/press-release-detail/phase-3-studies-pfizers-novel-antibiotic-combination-offer