2841. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate (TZD) and Linezolid (LZD) for Treatment of Ventilated Gram-Positive (G+) Nosocomial Pneumonia

Abstract

Background. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are frequently caused by G+ cocci; TZD has potent in vitro activity against these pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The VITAL study compared the efficacy and safety of TZD vs. LZD for the treatment of ventilated patients with G+ HAP/VAP. Methods. Randomized, double-blind, double-dummy, global, phase 3 study in mechanically ventilated adult patients with presumed G+ HAP/VAP (clinicaltrials.gov NCT02019420). Patients were stratified by region, age, and trauma/nontrauma, then randomized 1:1 to intravenous (IV) TZD 200 mg once daily for 7 days or IV LZD 600 mg every 12 h for 10 d (patients with concurrent G+ bacteremia received 14 d of treatment). The primary efficacy endpoint was day 28 all-cause mortality (ACM) in the intent to treat (ITT) population (all randomized patients; noninferiority [NI] margin, 10%). Secondary endpoints included investigator-assessed clinical response at test of cure (TOC; NI margin, 12.5%). Results. In total, 726 patients were randomized (TZD n = 366; LZD n = 360). Baseline characteristics were well balanced between arms. TZD was noninferior to LZD for day 28 ACM in the ITT (table). Noninferiority was not demonstrated for TZD vs. LZD for investigator-assessed clinical success at TOC in the ITT. Stratification factors, analysis population, baseline clinical/laboratory signs of HAP/VAP, G+ only vs. mixed G+/gram-negative (G-) HAP/VAP, adjunctive G- therapy, MRSA vs. methicillin-susceptible S. aureus, and HAP vs. VAP were evaluated, and no single factor accounted for the observed imbalance in clinical response between treatment arms. Greater than 90% of patients experienced treatment-emergent adverse events (TEAEs). Anemia, hypokalemia, and diarrhea were the most frequently reported (TEAEs) in both arms. Types and incidence rates of TEAEs overall, and of drug-related TEAEs specifically, were comparable between TZD and LZD. Conclusion. TZD was noninferior to LZD for day 28 ACM in the treatment of ventilated G+ HAP/VAP. However, TZD was not noninferior to LZD based on the investigator-assessed clinical response at TOC. Both drugs were similarly well tolerated and TEAEs were well balanced between groups, with no new safety signals identified. (Table Presented).