RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

  • Clin Infect Dis. 2020 Apr 15;70(9):1799-1808. doi: 10.1093/cid/ciz530.
Johann Motsch  1 ,  Cláudia Murta de Oliveira  2 ,  Viktor Stus  3 ,  Iftihar Köksal  4 ,  Olexiy Lyulko  5 ,  Helen W Boucher  6 ,  Keith S Kaye  7 ,  Thomas M File  8 ,  Michelle L Brown  9 ,  Ireen Khan  9 ,  Jiejun Du  9 ,  Hee-Koung Joeng  9 ,  Robert W Tipping  9 ,  Angela Aggrey  9 ,  Katherine Young  9 ,  Nicholas A Kartsonis  9 ,  Joan R Butterton  9 ,  Amanda Paschke  9
Affiliations
  • 1. Universitätsklinikum Heidelberg, Germany.
  • 2. Santa Casa de Misericórdia, Belo Horizonte, Brazil.
  • 3. Dnipropetrovsk Medical Academy, Dnipro, Ukraine.
  • 4. Karadeniz Technical University School of Medicine, Trabzon, Turkey.
  • 5. Department of Urology, Zaporozhye State Medical University, Zaporozhye, Ukraine.
  • 6. Tufts Medical Center, Boston, Massachusetts.
  • 7. University of Michigan, Ann Arbor, Michigan.
  • 8. Summa Health, Akron, Ohio.
  • 9. Merck & Co., Inc., Kenilworth, New Jersey.
PMID: 31400759 DOI: 10.1093/cid/ciz530
Abstract

Background: The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections.

Methods: Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal Infection, or complicated urinary tract Infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5-21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each Infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment.

Results: Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), Other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, -27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, -46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively.

Conclusions: Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.

Clinical trials registration: NCT02452047.

Keywords
KPC; cIAI; cUTI; carbapenem resistant; nosocomial pneumonia.
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