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Clin Infect Dis. 2019 Aug 10. pii: ciz530. doi: 10.1093/cid/ciz530. [Epub ahead of print]

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.

Author information

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.

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:

carbapenem resistant; KPC; cIAI; cUTI; nosocomial pneumonia

PMID:
31400759
DOI:
10.1093/cid/ciz530

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