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By Samaneh Pourali, PharmD, BCPS
Clinical Pharmacist, Stanford University School of Medicine
Dr. Pourali reports no financial relationships relevant to this field of study.
Imipenem-cilastatin-relebactam (IMI/REL) is a broad-spectrum antibiotic that combines three active ingredients: Imipenem (IMI) is a carbapenem antibiotic that inhibits bacterial cell wall synthesis through binding penicillin binding proteins, cilastatin sodium is a renal dehydropeptidase inhibitor that prevents inactivation if imipenem by renal enzymes, and relebactam is a class A/C beta-lactamase inhibitor preventing degradation of imipenem.
In July 2019, the Food and Drug Administration (FDA) approved IMI/REL for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis and complicated intra-abdominal infections (cIAI). In a Phase III, randomized, double-blind, controlled trial, investigators examined the efficacy and safety of IMI/REL compared to imipenem/cilastatin (IMI) plus colistin for the treatment of imipenem-nonsusceptible bacterial infections in 31 patients. The primary endpoint of overall favorable response was demonstrated in 71% of the IMI/REL group vs. 70% of the IMI plus colistin group (difference -7.3%; 90% confidence interval [CI], -27.5%, 21.4). Treatment emergent nephrotoxicity occurred in 10% of the IMI/REL group vs. 56% of the IMI plus colistin group (P = 0.002). An overview of Phase II and Phase III clinical trials evaluating the use of IMI/REL is summarized in Table 1.2-5
The FDA susceptibility breakpoint for IMI/REL against Enterobacteriaceae is ≤ 1/4 mcg/mL, with isolates with a minimum inhibitory concentration (MIC) of 2/4 mcg/mL considered intermediate, and ≥ /4 mcg/mL considered resistant. Clinical efficacy was shown for the following Enterobacteriaceae: Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Klebsiella oxytoca. The Pseudomonas aeruginosa breakpoint for IMI/REL is ≤ 2/4 mcg/mL, with isolates with a MIC of 4/4 mcg/mL considered intermediate and ≥ 8/4 mcg/mL considered resistant.
Additionally, the breakpoint for IMI/REL against anaerobic microorganisms is ≤ 4/4 mcg/mL, with isolates with a MIC of 8/4 mcg/mL considered intermediate and ≥ 16/4 mcg/mL considered resistant. Clinical efficacy was shown for the following anaerobes: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Fusobacterium nucleatum, and Parabacteroides distasonis. IMI/REL is not active against most isolates that contain metallo-beta-lactamases (MBLs) and some oxacillinases with carbapenemase activity.
IMI/REL is available as an intravenous formulation for administration. The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19 L, respectively. Plasma binding protein is 20%, 40%, and 22% for each of the components.
Imipenem is primarily metabolized by dehyropeptidases in the kidneys, while cilastatin and relebactam are minimally metabolized. All components are mainly excreted by the kidneys, and approximately 63% of imipenem, 77% of cilastatin, and 90% of relebactam were detected as unchanged drug in the urine.
The average half-life is one hour for imipenem and 1.2 hours for relebactam. The pharmacokinetic/pharmacodynamic parameter that best correlates with efficacy based on animal and in vitro models for imipenem is percent time of dosing interval that unbound plasma concentration of imipenem exceeds imipenem/relebactam MIC (% fT > MIC) against infecting organism. Relebactam’s pharmacokinetic/pharmacodynamic parameter is best demonstrated by the ratio of 24-hour unbound plasma relebactam AUC to IMI/REL MIC (fAUC 0 – 24 hr/MIC). (See Table 2.)
For patients with known hypersensitivity to imipenem, cilastatin, or relebactam, this antimicrobial is contraindicated. Seizures and other central nervous system (CNS) adverse reactions have been reported most commonly in patients with CNS disorders (brain lesions, history of seizures) and/or compromised renal function.
Common side effects (> 2%) include nausea, vomiting, diarrhea, phlebitis, pyrexia, headache, AST/ALT elevation, and hypertension. Rare adverse effects include agranulocytosis, increased eosinophils, hemolytic anemia, seizure, hepatic failure, and jaundice.
Clinically relevant drug-drug interactions include combination of IMI/REL with ganciclovir or valganciclovir and valproate. Increased risk of seizures has been observed with imipenem/cilastatin and ganciclovir or valganciclovir; thus, both antimicrobials should not be used unless the potential benefits outweigh the risks. Carbapenems have been shown to decrease valproic acid concentrations, which may increase the risk of breakthrough seizures; therefore, alternative antibiotics should be considered for patients whose seizures are well-controlled on valproic acid.
Imipenem-cilastatin-relebactam is a broad-spectrum antibiotic approved for the treatment of cUTI and cIAI in patients who have limited or no alternative treatment options. This antimicrobial combines imipenem/cilastatin with a new beta-lactamase inhibitor, relebactam. It provides enhanced activity against most strains of KPC-producing ESBLs and carbapenem-resistant Enterobacteriaceae (CRE), and restores susceptibility of imipenem against Pseudomonas spp. It appears to have a more favorable safety profile compared to colistin for the treatment of multidrug-resistant organisms.
Financial Disclosure: Peer Reviewer Patrick Joseph, MD, is a consultant for Genomic Health Reference Laboratory, Siemens Clinical Laboratory, and CareDx Clinical Laboratory. Infectious Disease Alert’s Editor Stan Deresinski, MD, FACP, FIDSA, Updates Author Carol A. Kemper, MD, FACP, Peer Reviewer Kiran Gajurel, MD, Executive Editor Shelly Morrow Mark, Editor Jason Schneider, and Editorial Group Manager Leslie Coplin report no financial relationships to this field of study.