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

Area of Science:

• Infectious Diseases
• Clinical Trials
• Antimicrobial Resistance

Background:

• Numerous randomized controlled trials (RCTs) have addressed Gram-negative bacilli (GNB) infections since 2000.
• GNB infections pose a significant challenge due to rising antimicrobial resistance.

Purpose of the Study:

• To review RCTs on GNB infection treatment published between 2000 and 2025.
• To analyze the methodology, generalizability, and clinical impact of these RCTs.
• To identify trends in GNB infection research and highlight areas for improvement.

Main Methods:

• Systematic review of phase 2-4 RCTs involving adults with complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), complicated urinary tract infections (cUTI), and/or bloodstream infections (BSI).
• Data extraction focused on study design, patient population, infection types, antibiotic agents evaluated, and resistance patterns.
• Sixty-eight RCTs met the inclusion criteria.

Main Results:

• Complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) were the most studied syndromes.
• A majority of studies (61.8%) employed a double-blind design, and 44.1% included placebo administration.
• Non-inferiority was the primary hypothesis in 70.6% of trials, while superiority was assessed in only four studies.
• Twenty-nine antibiotics were evaluated, with novel agents in 63.2% of studies.
• Only 12 RCTs targeted specific pathogens, with a focus on carbapenem-resistant GNB (75.0% of pathogen-specific trials).
• Methodological limitations and low inclusion rates of multi-drug-resistant GNB were noted.

Conclusions:

• While many high-quality RCTs for GNB infections exist, methodological limitations and underrepresentation of resistant pathogens impact generalizability.
• Results from these trials may not fully reflect real-world clinical scenarios.
• Increased funding and regulatory adjustments are recommended to facilitate more clinically relevant RCTs for GNB infections.