And Relebactam
And Relebactam Uses, Dosage, Side Effects, Food Interaction and all others data.
Cilastatin is an inhibitor of renal dehydropeptidase, an enzyme responsible for both the metabolism of thienamycin beta-lactam antibiotics as well as conversion of leukotriene D4 to leukotriene E4. Since the antibiotic, imipenem, is one such antibiotic that is hydrolyzed by dehydropeptidase, cilastatin is used in combination with imipenem to prevent its metabolism. The first combination product containing both drugs was approved by the FDA in November of 1985 under the trade name Primaxin, marketed by Merck & Co. A newer triple-drug product was approved in July 2019 under the trade name Recarbrio which also contains relebactam.
Cilastatin is a chemical compound which inhibits the human enzyme dehydropeptidase. Renal Dehydropeptidase degrades the antibiotic imipenem. Cilastatin is therefore combined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect. However, cilastatin in and of itself does not have any antibacterial activity. The increased renal excretion of unchanged imipenem appears to prevent proximal tubular necrosis associated with high doses of imipenem.
Imipenem is a semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to many beta-lactamases. Similar compounds include meropenem, known for having greater activity against Gram negative bacteria, and the newer ertapenem which exhibits a longer half-life due to increased binding to plasma proteins. Imipenem is commonly used in combination with cilastatin and is now available in a triple-drug product with cilastatin and relebactam which was recently approved by the FDA. Imipenem was first approved by the FDA in November 1985 as the combination product Primaxin marketed by Merck & Co.
Imipenem is a beta-lactam antibiotic belongings to the subgroup of carbapenems. Imipenem is active against aerobic and anaerobic Gram positive as well as Gram negative bacteria including Pseudomonas aeruginosa and the Enterococcus. It exerts a bactericidal effects by disrupting cell wall synthesis.
Relebactam is a diazabicyclooctane beta-lactamase inhibitor, similar in structure to avibactam. It includes a piperidine ring which reduces export from bacterial cells by producing a positive charge. It is currently available in a combination product which includes imipenem and cilastatin to treat complicated urinary tract infections (UTIs), pyelonephritis, and complicated intra-abdominal infections in adults. It is considered to be a last-line treatment option and gained FDA approval as part of the combination product RecarbrioⓇ in July 2019.
Relebactam prevents the hydrolysis of imipenem, allowing it to exert its bactericidal effect.
| Trade Name | And Relebactam |
| Generic | Imipenem + cilastatin + relebactam |
| Weight | 1.25g, |
| Type | Intravenous Powder For Injection, Intravenous |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Cilastatin is a renal dehydropeptidase inhibitor used to prevent degradation of imipenem. Both medications are used together to treat a variety of infections.
Cilastatin is indicated, in combination with imipenem with or without relebactam, for the treatment of bacterial infections including respiratory, skin, bone, gynecologic, urinary tract, and intra-abdominal as well as septicemia and endocarditis.
Imipenem is a carbapenem antibiotic normally administered with cilastatin to treat a variety of infections.
Imipenem is indicated, in combination with cilastatin with or without relebactam, for the treatment of bacterial infections including respiratory, skin, bone, gynecologic, urinary tract, and intra-abdominal as well as septicemia and endocarditis.
Relebactam is a beta-lactamase inhibitor used to prevent hydrolysis of beta-lactam antibiotics, leading to increased effectiveness.
Relebactam is indicated in combination with imipenem and cilastatin for the treatment of complicated urinary tract infections (including pyelonephritis), and complicated intra-abdominal infections caused by susceptible organisms in adults.
And Relebactam is also used to associated treatment for these conditions: Bloodstream Infections, Bone and Joint Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Endocarditis caused by staphylococcus aureus, Gynaecological infection, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Neutropenic Fever, Pyelonephritis, Skin and Subcutaneous Tissue Bacterial Infections, Surgical Site Infections, Uncomplicated Urinary Tract Infections, Hepatic abscessBloodstream Infections, Bone and Joint Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Infection, Complicated Urinary Tract Infection, Endocarditis caused by staphylococcus aureus, Gynaecological infection, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Pyelonephritis, Skin and Subcutaneous Tissue Bacterial Infections, Uncomplicated Urinary Tract InfectionsComplicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Pyelonephritis
How And Relebactam works
Cilastatin is a renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism of imipenem.
Imipenem acts as an antimicrobial through the inhibition of cell wall synthesis of various gram-positive and gram-negative bacteria. This inhibition of cell wall synthesis in gram-negative bateria is attained by binding to penicillin-binding proteins (PBPs). In E. coli and selected strains of P. aeruginosa, imipenem has shown to have the highest affinity to PBP-2, PBP-1a, and PBP-1b. This inhibition of PBPs prevents the bacterial cell from adding to the peptidoglycan polymer which forms the bacterial cell wall eventually leading to cell death.
Relebactam is a beta-lactamase inhibitor known to inhibit many types of beta-lactamases including Ambler class A and Ambler class C enzymes, helping to prevent imipenem from degrading in the body. Similar to the structurally-related avibactam, first, relebactam binds non-covalently to a beta-lactamase binding site, then, it covalently acylates the serine residue in the active site of the enzyme. In contrast to some other beta-lactamase inhibitors, once relebactam de-acylates from the active site, it can reform it's 5 membered ring and is capable of rebinding to target enzymes.
Toxicity
In case of overdose with the combination product, including relebactam and imipenem, it is recommended to provide supportive care. Imipenem, cilastatin, and relebactam may be removed via hemodialysis.
In case of overdose with the combination product, including relebactam and cilastatin, it is recommended to provide supportive care. Imipenem, cilastatin, and relebactam may be removed via hemodialysis.
If overdose with the combination product which includes relebactam, imipenem and cilastatin occurs, the drug should be stopped immediately and the patient should be provided with supportive care. Relebactam, imipenem, and cilastatin may be removed via hemodialysis; however, the use of hemodialysis to manage cases of overdose has not been studied.
Volume of Distribution
Cilastatin has a volume of distribution of 14.6-20.1L.
The reported volume of distribution for imipenem ranges from 0.23-0.31 L/kg.
Relebactam has a volume of distribution of approximately 19 L with both single and steady state dosing.
Elimination Route
Imipenem is not effectively absorbed from the gastrointestinal tract and therefore must be administered parenterally. The bioavailability of the IM injection is 89%.
Currently, relebactam is only available as an intravenous product; therefore, there is no relevant absorption data in the literature.
Half Life
The half-life of cilastatin is approximately 1h.
When given via IV injection imipenem has a half-life of 1 h. The apparent half-life of the IM injection ranges from 1.3-5.1 h, likely due to slower absorption form the injection site.
Relebactam has a half-life of 1.2 hours as per official FDA labeling. Values reported in pharmacokinetic studies vary from 1.35-1.8 hours.
Clearance
Cilastatin has a total clearance of 0.2 L/h/kg and a renal clearance of 0.10-0.16 L/h/kg.
The total clearance of imipenem is 0.2 L/h/kg. When used alone, the renal clearance is 0.05 L/h/kg. In combination with cilastatin the renal clearance of imipenem is 0.15 L/h/kg, likely due to the increased concentration of the parent drug.
Relebactam has a reported total clearance of approximately 130-150 mL/min (8 L/h). About 30% of the total drug clearance can be attributed to active tubular secretion.
Elimination Route
Cilastatin is reported by official FDA labeling to be 70% excreted in the urine, however published literature has reported values as high as 98%.
Approximately 70% of imipenem is excreted in the urine as the parent drug.
Approximately 90-100% of relebactam is renally eliminated.
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