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Prospective, Randomized, Double-Blind, Phase 2 Dose-Ranging Study Comparing Efficacy and Safety of imipenem/cilastatin Plus Relebactam With imipenem/cilastatin Alone in Patients With Complicated Urinary Tract Infections

Prospective, Randomized, Double-Blind, Phase 2 Dose-Ranging Study Comparing Efficacy and Safety of imipenem/cilastatin Plus Relebactam With imipenem/cilastatin Alone in Patients With Complicated Urinary Tract Infections

Matthew Sims, Valeri Mariyanovski, Patrick McLeroth, Wayne Akers, Yu-Chieh Lee, Michelle L Brown, Jiejun Du, Alison Pedley, Nicholas A Kartsonis, Amanda Paschke

J Antimicrob Chemother. 2017 Sep 1;72(9):2616-2626.

PMID: 28575389

Abstract:

Objectives:
The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens.
Methods:
To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%.
Results:
At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache.
Conclusions:
Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP74431235-A	Imipenem		74431-23-5	Price

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