Clinical trials that could change the management of severe multidrug-resistant Gram-negative infections

This article reviews recent and ongoing randomized controlled trials (RCTs) investigating novel antibiotics and treatment strategies for severe Gram-negative infections, particularly those caused by multidrug-resistant (MDR) organisms. It discusses how these trials are reshaping clinical practice and outlines current limitations in their applicability to real-world scenarios.

Several novel β-lactams and β-lactam/β-lactamase inhibitor combinations have shown efficacy in RCTs targeting infections like complicated urinary tract infections, intra-abdominal infections, and hospital-acquired pneumonia. Additional considerations on the results of recent RCTs challenge the necessity of combination regimens, and a growing body of evidence from other RCTs support shorter treatment durations for selected Gram-negative infections, overall potentially reinforcing antimicrobial stewardship. However, limitations include small sample sizes in pathogen-specific subgroups, frequent exclusion of critically ill or immunocompromised patients, and a focus on sites and types of infections within narrow regulatory definitions.

Current RCTs have enriched clinical management of severe Gram-negative infections by validating new agents and supporting more personalized, safer, and shorter treatments. Nevertheless, gaps persist regarding their generalizability to high-risk populations and real-world infections. Complementary pathogen-focused trials, adaptive designs, and observational studies are needed to expand the evidence base, also for treatment duration in MDR infections, combination regimens, and resistance development. Integrating trial data with clinical judgment remains essential in bridging the gap between trial conditions and bedside care in line with the principles of precision medicine.