The role of imipenem, cilastatin , and relebactam

1. The role of imipenem, cilastatin, and relebactam Corina Montgomery, Pharm.D. PGY1 Resident Erie VA Medical Center

2. Disclosure • The presenter has no conflicts of interest • The views expressed in this presentation are those of the presenter and do not necessarily reflect the position or policy of the Department of Veterans Affairs of the United States government • This presentation is the result of work supported with resources and the use of facilities at the Erie VA Medical Center, Erie, PA

3. Objectives Pharmacist • Review background information about imipenem, cilastatin, and relebactam including mechanism of action, indications, and adverse effects • Discuss and analyze the current available literature to determine the appropriate use of imipenem, cilastatin, and relebactam Technician • Recognize the route of administration

4. Background • Antibacterial agent • FDA approved July 2019 • Received FDA Qualified Infectious Disease Product designation • Intravenous administration • Manufactured by Merck

5. Mechanism of Action

6. Indications • 18 years and older who have limited or no alternative treatment options • Complicated urinary tract infections, including pyelonephritis • Complicated intra-abdominal infections

7. Complicated urinary tract infections, including pyelonephritis • Gram-negative susceptible organisms • Enterobacter cloacae • Escherichia coli • Klebsiella aerogenes • Klebsiella pneumoniae • Pseudomonas aeruginosa https://www.cdc.gov/hai/organisms/pseudomonas.html

8. Complicated intra-abdominal infections • Gram-negative susceptible organisms • Bacteroides caccae, fragilis, ovatus, stercoris, thetaiotaomicron, uniformis, vulgatus • Citrobacter freundii • Enterobacter cloacae • Escherichia coli • Fusobacterium nucleatum • Klebsiella aerogenes, oxytoca, pneumoniae, • Parabacteroides distasonis • Pseudomonas aeruginosa

9. Dosing

10. Warnings & Adverse Reactions

11. Interactions • Ganciclovir • May increase the adverse/toxic effect of imipenem • Increase risk of seizures • Valproic acid or divalproex sodium • Case reports suggest decreased valproic acid concentrations • Increase risk of breakthrough seizures

12. ADVANTAGES OF relebactaM

13. RESTORE-IMI 1 Methods • Phase 3 double-blind randomized controlled trial • Compared imipenem/relebactam versus colistin+imipenem • Primary endpoint: favorable overall response • Defined by relevant endpoints for each infection

14. RESTORE-IMI 1 Inclusion criteria • ≥ 18 years of age • Infection types limited to HAP, VABP, cIAI, cUTI • Suspected causative pathogens • Identified as a Gram-negative bacterium • Has culture-confirmed imipenem resistance • Has culture-confirmed susceptibility to colistin • Must be physically incapable of reproduction or use at least two forms of contraception

15. RESTORE-IMI 1 Exclusion criteria • APACHE II score >30 at screening • Concurrent infection • Systemic colistin treatment for >24 hours within the 72 hours immediately prior to initiation of study therapy • HAP/VAP caused by an obstructive process • History of serious allergy, hypersensitivity to any of the study drug classes • Pregnant, expecting to conceive, or breastfeeding • Seizure disorder • Hemodialysis/peritoneal dialysis or CrCl <15 mL/min at screening

16. RESTORE-IMI 1 Results

17. Summary • Combination of previously approved agents, imipenem/cilastatin, and a new agent, relebactam • Imipenem, cilastatin, and relebactam should be reserved for those who do not have additional options to treat: • Complicated urinary tract infections, including pyelonephritis • Complicated intra-abdominal infections

18. Review Questions

19. Question #1 Which of the following is the mechanism of action of the relebactam component of the medication? • Inhibits cell wall synthesis • Limits renal metabolism of cilastatin • Protects imipenem from degradation

20. Question #2 What is the correct dose for a 51 year old patient with a CrCl of 45 mL/min? • 1.25 gram IV infusion over 30 minutes every 6 hours • 1 gram IV infusion over 30 minutes every 6 hours • 0.75 grams IV infusion over 30 minutes every 6 hours • 0.5 grams IV infusion over 60 minutes every 8 hours

21. References • Recarbrio [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019. • FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections [news release]. Silver Spring, MD; July 17, 2019: FDA website. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-complicated-urinary-tract-and-complicated-intra-abdominal-infections. Accessed October 5, 2019. • FDA Approves Merck’s RECARBRIO™ (imipenem, cilastatin, and relebactam) For the Treatment of Adults with Complicated Urinary Tract and Complicated Intra-Abdominal Bacterial Infections Where Limited or No Alternative Treatment Options Are Available [news release]. Kenilworth, NJ; July 17, 2019: Merck. https://www.mrknewsroom.com/news-release/prescription-medicine-news/fda-approves-mercks-recarbrio-imipenem-cilastatin-and-releba. Accessed October 5, 2019. • Johann Motsch, CláudiaMurta de Oliveira, Viktor Stus, IftiharKöksal, OlexiyLyulko, Helen W Boucher, Keith S Kaye, Thomas M File, Michelle L Brown, Ireen Khan, Jiejun Du, Hee-KoungJoeng, Robert W Tipping, Angela Aggrey, Katherine Young, Nicholas A Kartsonis, Joan R Butterton, Amanda Paschke, RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections, Clinical Infectious Diseases, , ciz530, https://doi.org/10.1093/cid/ciz530

22. The role of imipenem, cilastatin, and relebactam Corina Montgomery, Pharm.D. PGY1 Resident Erie VA Medical Center