All-cause mortality rates in adults with carbapenem-resistant Gram-negative bacterial infections: a comprehensive review of pathogen-focused, prospective, randomized, interventional clinical studies

Abstract

Carbapenem resistance; Gram-negative; Cefiderocol

Resistència als carbapenems; Gram-negatius; Cefiderocol

Resistencia a carbapenémicos; Gram-negativo; Cefiderocol

Introduction Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. Areas covered We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM). Expert opinion PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37–118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94–406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials.