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.

The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter, open-label, noncomparative phase 3 study

“…), but REL has no inhibitory activity against class B b-lactamases such as New Delhi metallo-blactamase (NDM) and imipenemase (IMP) [16,21e23]. The safety and efficacy of REL/IPM/CS was demonstrated in two phase 2 studies (PN003 for complicated urinary tract infections [cUTIs] [24] and PN004 for complicated intra-abdominal infections [cIAIs] [25]) and two phase 3 studies (PN013 for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia [HABP/VABP], cIAI, or cUTI caused by IPM-nonsusceptible gramnegative bacteria and PN014 for HABP/VABP) [26,27]. A limited number of Japanese patients participated in these global studies; therefore, this phase 3 study (PN017) was conducted to obtain additional safety and efficacy data among Japanese patients with cIAI or cUTI.…”

Clinical and Microbiologic Efficacy and Safety of Imipenem/Cilastatin/Relebactam in Complicated Infections: A Meta-analysis

“…Serious adverse events, including nephrotoxicity, occurred more frequently in the imipenem + colistin group than in the imipenem/relebactam group. RESTORE-IMI 2 trial was a phase 3 study where Imipenem/cilastatin/relebactam was appraised for the treatment of HABP and VABP compared with piperacillin-tazobactam (TZP) in ICU settings [ 38 ].…”

“…Adverse events in RESTORE-IMI 1 trial included were diminished creatinine clearance, fever, hyperglycemia, and injection site reaction [ 28 ]. Diarrhea and elevated liver enzymes were seen most frequently in RESTORE-IMI 2 trial [ 38 ]. Imipenem (in addition to other carbapenems) is known to decrease the seizure threshold.…”

Antibiotic advances: soil, sea and perverse disincentives

“…Of these, 48.6% were on ventilators, 47.5% showed APACHE II scores of at least 15, 24.7% exhibited moderate or severe renal impairment, 42.9% were aged 65 years or older and 66.1% were in intensive care units. At baseline, Klebsiella pneumoniae (25.6%) and P. aeruginosa (18.9%) were the most common pathogens 17 . At day 28, all‐cause mortality was 15.9% with imipenem, cilastatin plus relebactam and 21.3% with piperacillin plus tazobactam.…”

“…Neither difference was statistically different. Drug‐related adverse events (none of which was fatal) occurred in 11.7% and 9.7%, respectively, while 5.6% and 8.2% respectively discontinued following adverse events 17 …”