A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study)

BACKGROUND: Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1: 1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population. RESULTS: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48. 6% had ventilated HABP/VABP, 47. 5% APACHE II score ≥15, 24. 7% moderate/severe renal impairment, 42. 9% were ≥65 years old, and 66. 1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25. 6%) and Pseudomonas aeruginosa (18. 9%). Imipenem/cilastatin/relebactam was noninferior (P <. 001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15. 9% with imipenem/cilastatin/relebactam and 21. 3% with piperacillin/tazobactam (difference, -5. 3% 95% confidence interval CI, -11. 9% to 1. 2%), and favorable clinical response at early follow-up was 61. 0% and 55. 8%, respectively (difference, 5. 0% 95% CI, -3. 2% to 13. 2%). Serious adverse events (AEs) occurred in 26. 7% of imipenem/cilastatin/relebactam and 32. 0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5. 6% and 8. 2%, respectively; and drug-related AEs (none fatal) in 11. 7% and 9. 7%, respectively. CONCLUSIONS: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. CLINICAL TRIALS REGISTRATION: NCT02493764.