FDA Approves Imipenem/Cilastatin + Relebactam

The US Food and Drug Administration has approved imipenem/cilastatin + relebactam (Recarbrio) for the treatment of complicated urinary tract infections and complicated intra-abdominal bacterial infections in adults who have limited or no alternative treatments available.

A new drug application (NDA) was accepted in February for the combination of relebactam, Merck’s investigational beta-lactamase inhibitor, with imipenem/cilastatin for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) caused by certain susceptible gram-negative bacteria.

Recarbrio is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of cUTI, including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa. It is also indicated for the treatment of cIAI caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis and Pseudomonas aeruginosa.

Imipenem is a penem antibacterial drug, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a beta-lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity. The FDA designated the combination of relebactam with imipenem/cilastatin for intravenous use as a Qualified Infectious Disease Product (QIDP) with Fast Track status for the treatment of cUTI, cIAI, and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP).

Merck indicates that the approval is based on limited clinical safety and efficacy data for the product.

In the phase 3 RESTORE-IMI 1 study, a multicenter, randomized, double-blind, comparator-controlled trial, imipenem/cilastatin + relebactam (IMI/REL) was evaluated versus colistin plus imipenem/cilastatin (COL+IMI) in patients with bacterial infections.

The study enrolled patients with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), cIAI, or cUTI. At enrollment, the participants were randomized 2:1 to receive IMI/REL or COL+IMI in a double-blind study. The therapy duration was to be 5-21 days for cUTI and cIAI and 7-21 days for HABP/VABP.

The primary endpoint of the study was favorable overall response in the microbiological modified intent-to-treat population (defined as patients with a qualifying baseline pathogen and having received at least 1 dose of study treatment). Secondary end points included favorable clinical response at Day 28, 28-day all-cause mortality, incidence of treatment emergent nephrotoxicity, and incidence of adverse events.

In the study, 31 of 47 participants met mMITT criteria. The study found that favorable overall response was comparable for the IMI/REL and COL+IMI treatment arms (71.4%, n = 15; 70.0%, n = 7, respectively). Favorable clinical response at Day 28 was found to be higher in the IMI/REL arm (71.4%; n = 15) compared with the COL+IMI group (40%; n=4). Additionally, 28-day all-cause mortality was lower in the IMI/REL arm (9.5%; n = 2) vs COL/IMI (30.0%; n = 3).

According to trial results, drug-related adverse events occurred in 16.1% patients in the IMI/REL arm compared to 31.3% of patients in the COL + IMI arm. Further, treatment-emergent nephrotoxicity was lower with IMI/REL compared to COL + IMI (10%; 3/29 patients vs 56%; 9/17 patients, respectively (p = 0.002).

“Recarbrio provides an important addition to our toolkit in the ongoing fight against infections caused by certain gram-negative pathogens,” said Keith Kaye, MD, professor of medicine and director of research for the division of infectious diseases, University of Michigan Heath System, a principal investigator in the clinical program, and Contagion® Editorial Advisory Board member. “Recarbrio offers an additional treatment option for patients with cIAI and cUTI who have limited and, in some cases, no alternative therapeutic options.”

Merck's press release also notes that the drug should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.