Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio(Merck),[2] is a fixed-dose combination medication used as an antibiotic. In 2019, it was approved for use in the United States for the treatment of complicated urinary tract and complicated intra-abdominal infections.[3][4][5][6] It is administered via intravenous injection.[7][2]
The most common adverse reactions include nausea, diarrhea, headache, fever and increased liver enzymes.
The most common adverse reactions observed in people treated for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) include increased aspartate/alanine aminotransferases (increased liver enzymes), anemia, diarrhea, hypokalemia (low potassium), and hyponatremia (low sodium).
Imipenem/cilastatin/relebactam has improved activity against P. aeruginosa with decreased porins expression and/or overproducing β-lactamases of the category "AmpC", thanks to relebactam AmpC inhibition.[8] Imipenem/cilastatin/relebactam maintains a limited activity against bla OXA-48 -expressing carbapenem-resistant Enterobacterales, and has no activity against metallo-β-lactamase-producing isolates. Relebactam has no activity against OXA class D β-lactamases of A. baumannii.[9][10] For susceptibility testing purposes, the concentration of relebactam is fixed at 4 mg/L. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) provided a susceptibility clinical breakpoint of ≤2 mg/L for Enterobacterales, P. aeruginosa, and Acinetobacter spp., while The Clinical & Laboratory Standards Institute (CLSI) provided a susceptibility clinical breakpoint of ≤1 mg/L for Enterobacterales and ≤2 mg/L for P. aeruginosa.[8][11][12]
Imipenem/cilastatin/relabactam is an hydrophilic compound. The distribution of imipenem/relebactam is prevalent in the interstitial spaces. Protein binding is 20% for imipenem, 20% for cilastatin and 22% for relebactam; volume of distribution is 24.3 L for imipenem and cilastatin and 19 L for relebactam. The two drugs achieve relatively high concentrations in the respiratory system: the exposure in epithelial lining fluid, relative to that of unbound concentrations in plasma, is 55% for imipenem and 54% for relebactam. Both imipenem and relebactam have renal clearance and a half-life of approximately 1 h. Dose adjustment should be performed in renal impairment.[8]
In the United States imipenem/cilastatin/relebactam is indicated for the treatment of people with complicated urinary tract infections and complicated intra-abdominal infections who have limited or no alternative treatment options. It is also indicated to treat HABP/VABP in adults 18 years of age and older.
In the European Union it is indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.[2]
The application for imipenem/cilastatin/relebactam was granted Qualified Infectious Disease Product (QIDP), fast track, and priority review designations by the U.S. Food and Drug Administration (FDA).[3] The FDA granted the approval of Recarbrio to Merck & Co., Inc.[3]
The determination of efficacy of imipenem/cilastatin/relebactam was supported in part by the findings of the efficacy and safety of imipenem-cilastatin for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI).[3] The contribution of relebactam to imipenem/cilastatin/relebactam was assessed based on data from in vitro studies and animal models of infection.[3] The safety of imipenem/cilastatin/relebactam, administered via injection, was studied in two trials (Trial 1/NCT01505634, Trial 2/NCT01506271), one each for cUTI and cIAI.[3] The cUTI trial included 298 adult participants with 99 treated with the proposed dose of imipenem/cilastatin/relebactam.[3] The cIAI trial included 347 participants with 117 treated with the proposed dose of imipenem/cilastatin/relebactam.[3]
Trial 1 enrolled adult participants hospitalized with cUTI.[4] Trial 2 enrolled adult participants hospitalized with cIAI that required surgery or drainage.[4] In both trials, participants were assigned to either imipenem/cilastatin with varying doses of relebactam or imipenem/cilastatin with placebo intravenously, every 6 hours for 4 to 14 days.[4] Neither the participants nor the investigators knew which treatment was being given until after the trial was completed.[4] The trials were conducted in Europe, South America, the United States, Asia Pacific, Africa, and Mexico.[4]
It was approved for use in the European Union in February 2020.[2]
In June 2020, imipenem/cilastatin/relebactam was approved for the indication to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults 18 years of age and older.[13]
The safety and efficacy of imipenem/cilastatin/relebactam for the treatment of HABP/VABP were evaluated in a randomized, controlled clinical trial of 535 hospitalized adults with HABP/VABP due to Gram-negative bacteria (a type of bacteria) in which 266 participants were treated with imipenem/cilastatin/relebactam and 269 participants were treated with piperacillin-tazobactam, another antibacterial drug.[13] Overall, 16% of participants who received imipenem/cilastatin/relebactam and 21% of participants who received piperacillin-tazobactam died through day 28 of the study.[13]
