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

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.

Figure 1.

Prescreening for gram-negative isolates nonsusceptible to imipenem but susceptible to both imipenem/relebactam and colistin. ^aFrom specimen types of interest, including blood, urinary, intraabdominal, or lower respiratory sources. If information on infection-site specimen source was not available, all gram-negative bacteria were to be tested. Abbreviations: GNB, gram-negative bacteria; MIC, minimum inhibitory concentration; SOP, standard operating procedure.

Figure 2.

Assessment schedule. ^aPatients in these treatment groups had bacterial infections that were imipenem-nonsusceptible but susceptible to imipenem plus relebactam as well as to colistin. ^b≤24 hours prior to randomization. ^c≤24 hours after the last dose of IV study therapy. Minimum duration of IV therapy was 5 full days for complicated intraabdominal infections and complicated urinary tract infections and 7 full days for hospital-acquired pneumonia/ventilator-associated pneumonia. Maximum duration could not exceed 21 days without study sponsor approval. ^d5 to 9 days (up to an additional 2 days) following the end of therapy. ^e28 days (up to an additional 3 days) following randomization. ^fIf the day 28 visit occurred prior to 14 days after the end of therapy, an additional safety follow-up visit was required. Abbreviations: AE, adverse event; day 28, day 28 postrandomization; EFU, early follow-up; EOT, end of therapy; IMI, imipenem/cilastatin; IMI/REL, imipenem/cilastatin plus relebactam; IV, intravenous; OTX, on therapy.

Figure 3.

Study analysis populations flow chart. ^aLocal diagnostic laboratories at each investigative site were asked to prescreen all incoming gram-negative isolates obtained from infection sites of interest against the sponsor-provided screening panels for resistance to IMI and susceptibility to IMI/REL and colistin. Investigators were notified of all isolates that met microbiologic eligibility criteria. Investigators then reviewed the patient’s general information to determine whether to proceed with actual screening, that is, based on protocol-specified procedures. Many patients with eligible isolates did not enter the formal screening process if, for example, the investigator was able to readily determine that a patient did not meet a major entry criterion. Screening was performed after obtaining patient consent. Abbreviations: IMI, imipenem/cilastatin; IMI/REL, imipenem/cilastatin plus relebactam; IV, intravenous.