Am J Health Syst Pharm. 2021 Feb 13:zxab012. doi: 10.1093/ajhp/zxab012. Online ahead of print.
PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, efficacy, safety, and current regulatory status of a recently approved triple-drug therapy for complicated infections are reviewed.
SUMMARY: Imipenem/cilastatin/relebactam is a newly approved anti-infective combination of a well-established β-lactam and a new β-lactamase inhibitor for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options; the medication is also indicated for use in treating hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The medication is active in vitro against a wide range of pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenemase-resistant Enterobacterales such as Klebsiella pneumoniae carbapenemase. The addition of relebactam does not restore the activity of imipenem against metallo-β-lactamase (MBL)-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. Two phase 3 clinical trials of imipenem/cilastatin/relebactam were conducted. In the RESTORE-IMI 1 trial, the efficacy and safety of the triple-drug combination was found to be comparable to that of colistin/imipenem for treatment of infections caused by imipenem-nonsusceptible gram-negative bacteria in patients with HABP or VABP, cUTIs, and cIAIs, with a significantly lower incidence of nephrotoxicity reported with triple-drug therapy. The RESTORE-IMI 2 trial demonstrated the noninferiority of the triple-drug combination to piperacillin/tazobactam for the treatment of HABP and VABP. Commonly reported adverse events in clinical trials included anemia, elevated liver enzymes, electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, phlebitis and/or infusion-site reactions, and hypertension.
CONCLUSION: Imipenem/cilastatin/relebactam is a new β-lactam/β-lactamase inhibitor combination with activity against MDR gram-negative bacteria, including many CRE but not including MBL-producing Enterobacterales and carbapenem-resistant Acinetobacter isolates. It is approved for the treatment of cUTIs, cIAIs, HABP, and VABP.