New Combination Antibiotic Emerges to Tackle Escalating Gram-Negative Resistance Threat

This is the first episode in a short series on the REVISIT trial, which was a phase 3, randomized, multinational, open-label study that evaluated the efficacy and safety of aztreonam-avibactam compared to meropenem in hospitalized adults with serious Gram-negative bacterial infections, specifically complicated intra-abdominal infections (cIAI) and hospital-acquired/ventilator-associated pneumonia (HAP/VAP). Joshua Rosenberg, MD, leads the discussion around the study.

For more than two decades, gram-negative resistance has posed one of the most stubborn challenges in infectious diseases. Beginning in the late 1990s and early 2000s, clinicians began to see rising resistance among Enterobacterales—gut-dwelling organisms such as E. coli, Klebsiella, and Enterobacter species—as well as Pseudomonas and Acinetobacter. These organisms were increasingly able to withstand carbapenems, the strongest gram-negative antibiotics available at the time. As carbapenem resistance expanded, treatment options became progressively more limited, driving an urgent need for novel agents.

By the mid-2010s, new antibiotics such as ceftazidime–avibactam brought important advances by neutralizing common serine-based carbapenemases. However, a major gap remained: metallo-β-lactamases (MBLs), a class of enzymes used by certain bacteria to dismantle antibiotics using metal ions instead of the typical serine mechanism. These MBL-producing organisms spread globally and proved especially difficult to treat. While some agents offered partial activity, their effectiveness waned over time, and none provided reliable, comprehensive coverage. The field faced a persistent unmet need for an antibiotic capable of neutralizing both serine carbapenemases and MBLs across the Enterobacterales family.

This is where the investigational aztreonam–avibactam combination (formerly referenced as “MJH”) stands out. Aztreonam, a monobactam antibiotic with a unique chemical structure, is naturally stable against MBL-mediated hydrolysis—one of the few β-lactams that MBLs cannot easily break down. But real-world resistant bacteria rarely rely on a single mechanism. Strains with MBLs often carry multiple additional β-lactamases, including ESBLs and KPCs, which can rapidly inactivate aztreonam. Avibactam fills this gap by protecting aztreonam from these accompanying enzymes, preserving its ability to target MBL-producing pathogens.

The scientific rationale behind the combination was validated years before the formal clinical program began. As early as 2018, clinicians were co-administering aztreonam and ceftazidime–avibactam to rescue patients infected with highly resistant organisms. Pharmaceutical developers recognized the need for a streamlined, single-vial solution—one that avoids the challenges of running two separate infusions while ensuring consistent pharmacologic protection. Unlike other β-lactam/β-lactamase inhibitor pairs on the market, none include a β-lactam inherently stable to MBLs, nor a partner capable of shielding it from the many additional enzymes these organisms co-produce.

As a result, the aztreonam–avibactam combination is positioned to fill one of the most critical gaps in modern antimicrobial therapy. By targeting both major types of carbapenemases—serine-based and metallo-based—it represents one of the most comprehensive strategies developed to date against multidrug-resistant gram-negative infections.