LB4. Efficacy and Safety of Cefiderocol vs. High-Dose Meropenem in Patients with Nosocomial Pneumonia—Results of a Phase 3, Randomized, Multicenter, Double-Blind, Non-Inferiority Study

Abstract

BackgroundCefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. In this study, Day 14 all-cause mortality (ACM) rates were compared between CFDC and meropenem (MEM) in patients with nosocomial Gram-negative pneumonia.MethodsThe study (NCT03032380) was a Phase 3, international, double-blind, randomized, non-inferiority study in hospitalized patients with ventilator-associated, hospital-acquired, or healthcare-associated pneumonia caused by suspected Gram-negative bacteria. Patients were treated with CFDC (2 g, q8h) or MEM (2 g, q8h), both infused for 3 hours, for 7–14 days. Adjunctive linezolid (600 mg, q12h, ≥5 days) was given in both arms to cover Gram-positive bacteria. The primary endpoint was non-inferiority of CFDC to MEM for Day 14 ACM rate in the modified intent-to-treat population (mITT; non-inferiority margin: –12.5%). Key secondary endpoints were clinical and microbiological outcomes at test of cure (TOC), and Day 28 mortality. Safety was investigated up to 28 days after the end of treatment.ResultsIn the ITT population, 148 patients were randomized to CFDC and 150 to MEM: 59.7% were ventilated, 32.6% had failure of prior therapy, the median APACHE II score was 15, and 6.0% had concomitant Gram-negative bacteremia at baseline. In the mITT population, non-inferiority of CFDC to MEM for Day 14 ACM was demonstrated; CFDC: 12.4% (18 out of 145 patients) vs. MEM: 11.6% (17 out of 146 patients); treatment difference: 0.8; 95% confidence interval: –6.6; 8.2. Comparable Day 28 ACM (CFDC: 21.0% vs. MEM: 20.5%), clinical cure (CFDC: 64.8% vs. MEM: 66.7%), and microbiological eradication (CFDC: 47.6% vs. MEM: 48.0%) rates were demonstrated in the mITT population at TOC. Clinical cure rates for major target pathogens at TOC were similar between CFDC and MEM arms (figure). The rates of treatment-emergent adverse events (TEAEs), drug-related TEAEs, serious AEs, discontinuation due to TEAEs, and deaths were similar between treatment arms (table).ConclusionThis study demonstrated the non-inferiority of CFDC to high-dose MEM for the pre-specified endpoint of Day 14 ACM. No unexpected safety signals were observed in the study. DisclosuresRichard G. Wunderink, MD, Merck (Consultant, Grant/Research Support), Shionogi Inc. (Consultant), Yuko Matsunaga, MD, Shionogi Inc. (Employee), Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee), Roger Echols, MD, Shionogi Inc. (Consultant), Anju Menon, PhD, Shionogi Inc. (Employee), Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee).