PMID- 32785589 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220521 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 73 IP - 11 DP - 2021 Dec 6 TI - 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). PG - e4539-e4548 LID - 10.1093/cid/ciaa803 [doi] AB - BACKGROUND: Imipenem combined with the beta-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. CI - (c) The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. FAU - Titov, Ivan AU - Titov I AD - Department of Anesthesiology and Intensive Care, Ivano-Frankivsk Regional Clinical Hospital, Ivano-Frankivsk, Ukraine. FAU - Wunderink, Richard G AU - Wunderink RG AD - Department of Medicine, Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. FAU - Roquilly, Antoine AU - Roquilly A AD - EA3826 Therapeutiques Anti-Infectieuses, Institut de Recherche en Sante 2 Nantes Biotech, Universite, de Nantes, Nantes, France. FAU - Rodriguez Gonzalez, Daniel AU - Rodriguez Gonzalez D AD - Department of Intensive Care, Hospital Civil de Guadalajara, Guadalajara, Mexico. FAU - David-Wang, Aileen AU - David-Wang A AD - Department of Medicine & Philippine General Hospital, Division of Pulmonary Medicine, University of the Philippines, Manila, Philippines. FAU - Boucher, Helen W AU - Boucher HW AD - Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA. FAU - Kaye, Keith S AU - Kaye KS AD - Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA. FAU - Losada, Maria C AU - Losada MC AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Du, Jiejun AU - Du J AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Tipping, Robert AU - Tipping R AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Rizk, Matthew L AU - Rizk ML AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Patel, Munjal AU - Patel M AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Brown, Michelle L AU - Brown ML AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Young, Katherine AU - Young K AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Kartsonis, Nicholas A AU - Kartsonis NA AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Butterton, Joan R AU - Butterton JR AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Paschke, Amanda AU - Paschke A AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. FAU - Chen, Luke F AU - Chen LF AD - Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA. LA - eng SI - ClinicalTrials.gov/NCT02493764 GR - U19 AI135964/AI/NIAID NIH HHS/United States GR - Merck Sharp and Dohme/ PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Anti-Bacterial Agents) RN - 0 (Azabicyclo Compounds) RN - 141A6AMN38 (Cilastatin) RN - 71OTZ9ZE0A (Imipenem) RN - SE10G96M8W (Tazobactam) RN - X00B0D5O0E (Piperacillin) RN - Y1MYA2UHFL (relebactam) SB - IM CIN - Clin Infect Dis. 2021 Dec 6;73(11):e4549-e4551. PMID: 32785576 MH - Adult MH - Aged MH - Anti-Bacterial Agents/adverse effects MH - Azabicyclo Compounds MH - *Cilastatin/adverse effects MH - Hospitals MH - Humans MH - *Imipenem/adverse effects MH - Piperacillin MH - Tazobactam MH - Ventilators, Mechanical PMC - PMC8662781 OTO - NOTNLM OT - Pseudomonas OT - KPC OT - carbapenem resistant OT - mechanical ventilation OT - nosocomial pneumonia EDAT- 2020/08/14 06:00 MHDA- 2022/03/15 06:00 PMCR- 2020/08/12 CRDT- 2020/08/14 06:00 PHST- 2019/12/23 00:00 [received] PHST- 2020/07/16 00:00 [accepted] PHST- 2020/08/14 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2020/08/14 06:00 [entrez] PHST- 2020/08/12 00:00 [pmc-release] AID - 5891450 [pii] AID - ciaa803 [pii] AID - 10.1093/cid/ciaa803 [doi] PST - ppublish SO - Clin Infect Dis. 2021 Dec 6;73(11):e4539-e4548. doi: 10.1093/cid/ciaa803.