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)

Abstract

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.

Keywords: Pseudomonas; KPC; carbapenem resistant; mechanical ventilation; nosocomial pneumonia.

Figure 1.

Study analysis population flowchart. ^aReasons for exclusion from this analysis population are listed in Supplementary Table 1. Abbreviations: CE, clinically evaluable; IMI/REL, imipenem/cilastatin with relebactam; MITT, modified intent-to-treat; mMITT, microbiologic modified intent-to-treat; PIP/TAZ, piperacillin/tazobactam.

Figure 2.

Primary and key secondary efficacy endpoints in clinically relevant patient subgroups of the modified intent-to-treat (MITT) population: 28-day all-cause mortality (A) and favorable clinical response (B). (Note: Per-pathogen outcomes are shown for microbiologic modified intent-to-treat [mMITT] patients with all baseline lower respiratory tract [LRT] isolates susceptible to both study drugs.) ^aPost hoc analysis; all other subgroups were prospectively defined. ^bOutcomes in patients who received <24 hours of prior, systemic, gram-negative therapy (applicable to 20.5% of imipenem/cilastatin with relebactam [IMI/REL] and 25.5% of piperacillin/tazobactam [PIP/TAZ] patients) are not shown. ^cTwo patients in each treatment arm received >72 hours of concomitant, systemic, gram-negative therapy; outcomes in this very small subpopulation are not shown. ^dOutcomes are shown for the subpopulation of mMITT patients with only Enterobacterales (of any species) baseline LRT isolates and all baseline isolates susceptible to both IMI/REL and PIP/TAZ. ^eOutcomes are shown for the subpopulation of mMITT patients with ≥1 baseline LRT isolate of this pathogen and all baseline isolates susceptible to both IMI/REL and PIP/TAZ. ^fCIs were not calculated due to the low sample size (<5 patients in both arms) of this subpopulation. Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; CPIS, Clinical Pulmonary Infection Score; HABP, hospital-acquired bacterial pneumonia; IMI/REL, imipenem/cilastatin with relebactam; PIP/TAZ, piperacillin/tazobactam; VABP, ventilator-associated bacterial pneumonia.