Imipenem/cilastatin/relebactam

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Imipenem/cilastatin/relebactam
Combination of
Imipenem β-Lactam antibiotic
Cilastatin Dehydropeptidase inhibitor
Relebactam β-Lactamase inhibitor
Clinical data
Trade names Recarbrio
Other namesMK-7655A
AHFS/Drugs.com Monograph
MedlinePlus a619046
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
KEGG

Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio, [1] 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] [1]

Contents

The most common adverse reactions include nausea, diarrhea, headache, fever and increased liver enzymes. [3]

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). [8]

Antimicrobial activity

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. [9] Imipenem/cilastatin/relebactam maintains a limited activity against blaOXA-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. [10] [11] 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. [9] [12] [13]

Pharmacokinetic properties

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. [9]

Medical uses

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. [8] It is also indicated to treat HABP/VABP in adults 18 years of age and older. [8]

In the European Union it is indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. [1]

History

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] [8]

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. [1]

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. [8]

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. [8] Overall, 16% of participants who received imipenem/cilastatin/relebactam and 21% of participants who received piperacillin-tazobactam died through day 28 of the study. [8]

See also

Related Research Articles

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<span class="mw-page-title-main">Nitrofurantoin</span> Antibacterial drug

Nitrofurantoin is an antibacterial medication used to treat urinary tract infections, but it is not as effective for kidney infections. It is taken by mouth.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous β-lactam antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Imipenem/cilastatin</span> Combination antibiotic medication

Imipenem/cilastatin, sold under the brand name Primaxin among others, is an antibiotic useful for the treatment of a number of bacterial infections. It is made from a combination of imipenem and cilastatin. Specifically it is used for pneumonia, sepsis, endocarditis, joint infections, intra-abdominal infections, and urinary tract infections. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

<span class="mw-page-title-main">Imipenem</span> Carbapenem antibiotic

Imipenem is a synthetic β-lactam antibiotic belonging to the carbapenems chemical class. developed by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria, thus playing a key role in the treatment of infections not readily treated with other antibiotics. It is usually administered through intravenous injection.

<span class="mw-page-title-main">Cefoxitin</span> Chemical compound

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β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Ceftaroline fosamil</span> Chemical compound

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<span class="mw-page-title-main">Avibactam</span> Chemical compound

Avibactam is a non-β-lactam β-lactamase inhibitor developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA on February 25, 2015, for treating complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant Gram-negative bacterial pathogens.

<span class="mw-page-title-main">Eravacycline</span> Chemical compound

Eravacycline is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

<span class="mw-page-title-main">Ceftazidime/avibactam</span> Combination antibiotic medication

Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by injection into a vein.

<span class="mw-page-title-main">Vaborbactam</span> Chemical compound

Vaborbactam (INN) is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the β-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.

Meropenem/vaborbactam, sold under the brand name Vabomere among others, is a combination medication used to treat complicated urinary tract infections, complicated abdominal infections, and hospital-acquired pneumonia. It contains meropenem, a β-lactam antibiotic, and vaborbactam, a β-lactamase inhibitor. It is given by injection into a vein.

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<span class="mw-page-title-main">Relebactam</span> Chemical compound

Relebactam is a chemical compound used in combination with antibiotics to improve their efficacy. As a beta-lactamase inhibitor, it blocks the ability of bacteria to break down a beta-lactam antibiotic. In the United States, relebactam is approved for use in the combination imipenem/cilastatin/relebactam (Recarbrio).

<span class="mw-page-title-main">Sulbactam/durlobactam</span> Combination medication

Sulbactam/durlobactam, sold under the brand name Xacduro, is a co-packaged medication used for the treatment of bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex. It contains sulbactam, a beta-lactam antibacterial and beta-lactamase inhibitor; and durlobactam, a beta-lactamase inhibitor.

References

  1. 1 2 3 4 5 "Recarbrio EPAR". European Medicines Agency (EMA). 10 December 2019. Retrieved 1 March 2020.
  2. ↑ "Recarbrio Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  3. 1 2 3 4 5 6 7 8 9 "FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections". U.S. Food and Drug Administration (FDA) (Press release). 17 July 2019. Archived from the original on 20 November 2019. Retrieved 20 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. 1 2 3 4 5 6 "Drug Trial Snapshot: Recarbrio". U.S. Food and Drug Administration (FDA). 2 August 2019. Archived from the original on 20 November 2019. Retrieved 20 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. ↑ "Recarbrio (imipenem, cilastatin, and relebactam) FDA Approval History". Drugs.com. 21 July 2019. Retrieved 20 November 2019.
  6. ↑ "Drug Approval Package: Recarbrio". U.S. Food and Drug Administration (FDA). 22 July 2019. Retrieved 1 March 2020.
  7. ↑ "Recarbrio- imipenem anhydrous, cilastatin, and relebactam anhydrous injection, powder, for solution". DailyMed. 4 December 2019. Retrieved 1 March 2020.
  8. 1 2 3 4 5 6 7 "FDA Approves Antibiotic to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia". U.S. Food and Drug Administration. 4 June 2020. Retrieved 4 June 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. 1 2 3 Principe L, Lupia T, Andriani L, Campanile F, Carcione D, Corcione S, et al. (April 2022). "Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol-An All-Inclusive Guide for Clinicians". Pharmaceuticals. 15 (4): 463. doi: 10.3390/ph15040463 . PMC   9028825 . PMID   35455461.
  10. ↑ Lob SH, Hackel MA, Kazmierczak KM, Young K, Motyl MR, Karlowsky JA, Sahm DF (June 2017). "In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program)". Antimicrobial Agents and Chemotherapy. 61 (6): e02209–16. doi:10.1128/AAC.02209-16. PMC   5444184 . PMID   28320716.
  11. ↑ Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J (October 2019). "Molecular Basis of Class A β-Lactamase Inhibition by Relebactam". Antimicrobial Agents and Chemotherapy. 63 (10): e00564–19. doi:10.1128/AAC.00564-19. PMC   6761529 . PMID   31383664.
  12. ↑ "Health System Membership". Clinical & Laboratory Standards Institute. Retrieved 7 May 2023.
  13. ↑ "eucast: Clinical breakpoints and dosing of antibiotics". www.eucast.org. Retrieved 7 May 2023.
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