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Relebactam safe, effective against imipenem-resistant cUTIs
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BOSTON — Relebactam, an investigational beta-lactamase inhibitor, in combination with imipenem/cilastatin, was well-tolerated and noninferior to imipenem/cilastatin alone in patients with complicated urinary tract infections, according to recent phase 2 data.
At ASM Microbe 2016, Amanda Paschke, MD, MSCE, director of infectious disease clinical research at Merck, and colleagues reported that relebactam (Merck) is designed to restore imipenem activity against certain imipenem-resistant gram-negative bacteria, including Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae.
Amanda Paschke
According to separate findings also presented at the conference, the proportion of Enterobacteriaceae isolates with low minimum inhibitory concentrations, or MICs, for imipenem is decreasing while isolates with elevated-MICs are increasing. In 2001 and 2002, 77.4% of Enterobacteriaceae had low MIC values for imipenem, and 21.1% of isolates had elevated MIC values. In 2013 and 2014, the percentage of low MICs decreased to 68.8%, and elevated MICs increased to 27.8%. K. pneumoniae isolates were particularly affected by the imipenem MIC shift, with 95.8% of isolates having low MIC values in 2001 and 2002. That value dropped to 77.7% in 2013 and 2014 (P = .0002).
“The reason we need new drugs like imipenem-relebactam is because of the global epidemic of multidrug-resistant gram-negative bacteria and the continuing emergence of new threats of new mechanisms of resistance,” Paschke told Infectious Disease News. “Patients who have these infections are often complicated patients with multiple underlying medical conditions. In settings such as sepsis or septic shock, we only have days — or less than that — to treat them adequately and to select the right drug that will treat the pathogen they have. Imipenem-relebactam represents a new drug that can address these infections.”
For the phase 2, multicenter trial, 302 adults with complicated urinary tract infections (cUTIs; 51.7%) or acute pyelonephritis (48.3%) were randomly assigned to intravenously receive 250 mg of relebactam, 125 mg of relebactam, or placebo in addition to 500 mg of imipenem/cilastatin (IMI) every 6 hours for 4 to 14 days. The primary endpoint was the proportion of microbiologically evaluable patients with favorable responses after therapy discontinuation.
Of the 230 patients who were microbiologically evaluable after treatment discontinuation, 10.5% had imipenem-resistant gram-negative infections at baseline. Results were similar across the treatment groups, with favorable responses identified among 95.5% of patients who received 250 mg of relebactam plus IMI, 98.6% of patients who received 125 mg of relebactam plus IMI and 98.7% of patients who received IMI alone.
Safety profiles also were similar across the treatments groups, according to the researchers. The most common adverse events occurring up to 14 days after the last dose was administered included headache, diarrhea and nausea. The incidence of these adverse events ranged from 2% to 7.1%.
Moving forward, relebactam plus IMI is being further evaluated in two phase 3 trials. In one trial, the treatment is being compared with piperacillin/tazobactam in patients with hospital-acquired or ventilator-associated pneumonia; the other trial is comparing relebactam plus IMI with colistimethate sodium plus IMI in patients with imipenem-resistant infections, including hospital-acquired and ventilator-associated pneumonia, complicated intra-abdominal infections and cUTIs.
“New medicines are urgently needed to address the growing threat of antibiotic-resistant bacteria,” Paschke said in a press release. “We look forward to advancing our phase 3 clinical program evaluating relebactam in combination with imipenem for use in the treatment of several complicated gram-negative bacterial infections, and to continue to build on Merck's commitment to addressing infectious diseases.” – by Stephanie Viguers
References:
Lee MJ, et al. Imipenem MIC shift among carbapenem-susceptible Enterobacteriaceae: A single center metadata analysis between 2001 and 2014. Presented at: ASM Microbe; June 16-20, 2016; Boston.
Paschke A, et al. Phase 2 study of relebactam (REL) + imipenem/cilastatin (IMI) vs. IMI alone in subjects with complicated urinary tract infection (cUTI). Presented at: ASM Microbe; June 16-20, 2016; Boston.
Disclosure: Paschke is an employee of Merck.