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.

Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae

“…However, the composite endpoint of 30-day mortality or nephrotoxicity demonstrated a superior risk benefit profile for CAZ-AVI compared to colistin-containing regimens (p = 0.01). This is in line with recent reports showing that treatment-related nephrotoxicity was significantly higher in patients treated with colistin [38][39][40].…”

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

“…Serious drug‐related adverse events were reported in 16% of patients receiving IMI‐REL compared to 31% of patients treated with imipenem plus colistin in the phase III RESTORE‐IMI 1 trial . Additionally, among patients treated with IMI‐REL, treatment‐related development of nephrotoxicity was significantly less compared to best available therapy with imipenem plus colistin (10% vs 56%, p=0.02), as was development of elevated hepatic transaminase levels (0% vs 13%).…”

“…Of two phase III, multicenter, randomized, double-blind comparator trials evaluating IMI-REL, one, RESTORE-IMI 1, has been published. 84 The second trial, RESTORE-IMI 2 (ClinicalTrials.gov identifier NCT02493764) has data available, but has yet to be published. Results from these trials were not considered for the process of FDA approval.…”

“…RESTORE-IMI 1 compared IMI-REL to imipenem and colistin in the treatment of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP), cIAI, or cUTI caused by imipenem-nonsusceptible bacteria at 35 participating hospitals. 84 Adult patients requiring hospitalization and intravenous antibiotics were eligible for inclusion. At least one organism suspected of causing infection was required to have been an imipenem-nonsusceptible gram-negative pathogen.…”

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

“…While it is encouraging that clinical cure rates were similar between cefiderocol and BAT, this does not offset the mortality concerns. Cefiderocol is coming to market at a time when either RCT or real-world clinical data are available that strongly suggest the superiority of ceftazidime/ avibactam, meropenem/vaborbactam, imipenem/relebactam, ceftolozane/tazobactam, and plazomicin over this same comparator [48][49][50][51][52][53]. Therefore, the lack of an improvement in clinical cure combined with a signal for potentially increased mortality is suboptimal.…”