Gram-negative bacterial infection randomized controlled trials (RCTs) in the 21st century: characteristics and evolution.

Since 2000, several randomized controlled trials (RCTs) addressing treatment of infections due to Gram-negative bacilli (GNB) have been published. We reviewed RCTs targeting GNB infections published between 2000 and 2025, focusing on methodology, generalizability of results and impact on patient care. Included were phase 2-4 RCTs enrolling adults with complicated intrabdominal infections (cIAI), hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), complicated urinary tract infections (cUTI) and/or bloodstream infections (BSI). Sixty-eight studies were included. cIAIs and cUTIs were the most frequent infection syndromes studied [in 30 (44.1%) and 28 (41.2%) RCTs, respectively]. Forty-two (61.8%) studies used a double-blind design, and 30 (44.1%) entailed placebo administration. Non-inferiority was the most common pre-specified hypothesis tested (48 RCTs, 70.6%). Superiority was assessed in only four studies. Twenty-nine unique antibiotics were evaluated overall, with novel agents assessed in 43 studies (63.2%). Twelve RCTs targeted one or more specific pathogen, three of which (25.0%) addressed a single pathogen, Acinetobacter baumannii in two RCTs and Escherichia coli in one. All of the 12 studies focused on specific antimicrobial resistant pathogens: 3 (25.0%) on third-generation cephalosporin-resistant GNB and/or ESBL-producers and 9 (75.0%) on carbapenem-resistant pathogens. In summary, many high-quality RCTs of GNB infection treatment have been published in the 21st century. Results of many of these studies were influenced by methodological limitations and low rates of inclusion of multi-drug-resistant GNB, reducing generalizability to real-world clinical practice. Increased funding opportunities and regulatory modifications would facilitate conduct of real-world RCTs of GNB.