Imipenem-Cilastatin-Relebactam: Imipenem Is Rele Back Again

HISTORY AND RESISTANCE

β-Lactam antibiotics are the mainstays of treatment for many infectious diseases. Unsurprisingly, emerging resistance limits their use for some patient populations and infection types. There are multiple mechanisms of resistance demonstrated by gram-negative bacteria including the production of β-lactamases. β-Lactamases can be divided into the Ambler classification system and include class A enzymes (Klebsiella pneumoniae carbapenemase [KPCs], extended-spectrum β-lactamases [ESBLs]), class B metallo-β-lactamases (eg, New Delhi metallo-β-lactamase 1 enzyme, imipenamase), class C enzymes (AmpC), and class D enzymes (eg, oxacillin-hydrolysing).^1,2

In the late 1960s, β-lactamase inhibitors were developed to overcome resistance due to β-lactamase—producing enzymes. Developed in 1972, clavulanic acid was the first β-lactamase inhibitor available.³ When administered with a β-lactam antibiotic, β-lactamase inhibitors bind to β-lactamases, protecting and preventing inactivation of the antibiotic. Currently available β-lactamase inhibitors have slightly differing spectra of activity.⁴

Relebactam, formerly known as MK-7655, is a novel non— β-lactam, bicyclic diazabicyclooctane β-lactamase inhibitor. It is structurally similar to avibactam but has the addition of a piperidine ring. In vitro, it is a potent inhibitor of class A and C β-lactamases, including KPC enzymes.5 The addition of relebactam to imipenem-cilastatin improves activity against gram-negative organisms by significantly reducing the minimum inhibitory concentrations, including imipenem-resistant strains of Pseudomonas aeruginosa and Enterobacteriaceae.^1,5-7

Carbapenem-resistant Enterobacteriaceae is most commonly attributed to β-lactamase production including ESBLs and KPC-type carbapenemases. Relebactam inhibits ESBLs and KPC-type carbapenemases, therefore restoring imipenem activity.² P aeruginosa demonstrates resistance to imipenem via downregulation of porin protein synthesis in combination with AmpC overproduction. Relebactam inhibits AmpC production, therefore lowering the minimum inhibitory concentration and improving imipenem activity against P aeruginosa.² In contrast, meropenem-resistant P aeruginosa is a result of impermeability and overexpression of efflux pumps rather than β-lactamase production.⁶

Imipenem-cilastatin-relebactam (IMI-REL) was granted US Food and Drug Administration (FDA) approval on July 16, 2019, for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) in patients 18 years of age or older who have limited or no alternative treatment options available. The typical dose is a total of 1.25 grams, which consists of 500 mg of imipenem, 500 mg of cilastatin, and 250 mg of relebactam, administered via intravenous infusion over 30 minutes every 6 hours.⁸

CLINICAL STUDIES

IMI-REL has been studied in 2 active-controlled double-blind phase 2 clinical trials, 1 in patients with cUTIs and the other in patients with cIAIs.^9,10 Both trials met the FDA noninferiority end points. More clinically relevant data arise from 2 other studies: RESTORE-IMI 1 and RESTORE-IMI 2. RESTORE-IMI 1 compared IMI-REL with imipenem-cilastatin plus colistin (IMI+CST) in 47 adults with carbapenem-nonsusceptible cIAIs, cUTIs, hospital-acquired pneumonia, and ventilator-associated pneumonia.¹¹ This study demonstrated that IMI-REL was comparable to IMI+CST with similar efficacy outcomes. The favorable overall response rate was 71.4% and 70% in the modified microbiologic intent-to-treat IMI-REL and IMI+CST groups, respectively. Although not statistically significant, day 28 all-cause mortality was 20% lower in the IMI-REL group. Serious adverse events (AEs) occurred more frequently in the IMI+CST group, at 31.3% compared with the IMI-REL group at 9.7%. The results of RESTORE-IMI 1 support the conclusion that IMI-REL is an effective and well-tolerated option for the treatment of patients with carbapenem-nonsusceptible infections.

RESTORE-IMI 2 is a larger clinical trial that compares IMI-REL to piperacillin-tazobactam in patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in the intensive care unit. Data have not yet been published, but topline results demonstrate that IMI-REL met its primary and key secondary end points of noninferiority when compared with piperacillin-tazobactam in day 28 all-cause mortality and clinical response at early follow-up.¹²

PHARMACOKINETICS

Pharmacokinetic parameters were similar for single- and multiple-dose administration of imipenem-cilastatin-relebactam due to minimal accumulation. The mean area under the concentration time curve from 0 to 24 hours was 573.9 μM/hr and 427.3 μM/hr for imipenem and relebactam, respectively. The mean steady-state maximum concentration was 104.3 μM and 64.0 μM for imipenem and relebactam, respectively.⁹

The mean volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively. The area under the concentration-time curve from 0 to infinity in epithelial lining fluid relative to that in plasma for relebactam and imipenem is 54% and 55%, respectively.¹³ Protein binding of relebactam is 22% and is minimally metabolized. Relebactam has a half-life of 1.2 hours and greater than 90% of drug is excreted unchanged in urine. IMI-REL requires dose adjustments in patients with renal impairment.⁸

ADVERSE REACTIONS, WARNINGS, AND PRECAUTIONS

Imipenem-cilastatin-relebactam has similar warnings and precautions associated with other carbapenem antibiotics. Due to the inclusion of imipenem in this combination, adverse reactions may include seizures, states of confusion, and myoclonic activity. Concomitant use with valproic acid formulations can drastically decrease valproic acid concentrations, possibly leading to seizures. Generalized seizures have also been reported with concomitant use of ganciclovir. In the 2 clinical trials that led to FDA approval, the most commonly reported AEs included diarrhea, nausea, vomiting, headaches, elevated alanine aminotransferase levels, and elevated aspartate aminotransferase levels.^9,10 In the RESTORE-IMI 1 trial, reported drug-related AEs included decreased creatinine clearance, hyperglycemia, infusion site erythema, and pyrexia.¹¹

PLACE IN THERAPY

IMI-REL increases our armamentarium against multidrug-resistant gram-negative rods. In addition to restoring activity against many carbapenem-resistant Enterobacteriaceae, relebactam also improves activity of imipenem against many imipenem-resistant strains of P aeruginosa, (Table) whereas limited data suggest vaborbactam does not substantially do this for meropenem-resistant P aeruginosa.¹⁴ IMI-REL is currently indicated for the treatment of cIAIs and cUTIs and has clinical data for treating infections caused by resistant pathogens. Clinical data regarding its use in nosocomial pneumonia are pending.

Campanella is a PGY2 resident in infectious diseases pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at Thomas Jefferson University College of Pharmacy and a PGY1 residency at Penn State Health Milton S, Hershey Medical Center in Hershey, Pennsylvania. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, Pennsylvania. He is also the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple.

* indicates active members of the Society of Infectious Diseases Pharmacists.+ indicates active member of the Making a Difference in Infectious Diseases Research Network

References

1. Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF. In vitro activity of imipenem-relebactam against clinical isolates of gram-negative bacilli isolated in hospital laboratories in the United States as part of the SMART 2016 Program. Antimicrob Agents Chemother. 2018 Jun 26;62(7):e00169-18. doi: 10.1128/AAC.00169-18. Print 2018 Jul.
2. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201. doi: 10.1128/CMR.00037-09.
3. Geddes AM, Klugman KP, Rolinson GN. Introduction: historical perspective and development of amoxicillin/clavulanate. Int J Antimicrob Agents. 2007;30(suppl 2):S109-12. doi: 10.1016/j.ijantimicag.2007.07.015.
4. Toussaint KA, Gallagher JC. β-lactam/β-lactamase inhibitor combinations: from then to now [published online ahead of print October 31, 2014]. Ann Pharmacother. 2015;49(1):86-98. doi: 10.1177/1060028014556652.
5. Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against enterobacteriaceae and pseudomonas aeruginosa [published online ahead of print May 21, 2013]. J Antimicrob Chemother. 2013;68(10):2286-90. doi: 10.1093/jac/dkt178.
6. Hirsch EB, Ledesma KR, Chang KT, Schwartz MS, Motyl MR, Tam VH. In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant gram-negative bacteria [published online ahead of print April 23, 2012]. Antimicrob Agents Chemother. 2012;56(7):3753-7. doi: 10.1128/AAC.05927-11.
7. Haidar G, Clancy CJ, Chen L, et al. Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(9):e00642-17. pii: e00642-17. doi: 10.1128/AAC.00642-17. Print 2017 Sep.
8. Recarbrio (imipenem/cilastatin/relebactam) [package insert]. Whitehouse Station, NJ: Merck & Co; July 2019.
9. Sims M, Mariyanovski V, Mcleroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72(9):2616-2626. doi: 10.1093/jac/dkx139.
10. Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-43. doi: 10.1128/AAC.00633-16. Print 2016 Oct.
11. Motsch J, Murta de oliveira C, Stus V, et al. 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 [published online ahead of print]. Clin Infect Dis. 2019. pii: ciz530. doi: 10.1093/cid/ciz530.
12. Pivotal RESTORE-IMI 2 phase 3 study of Merck’s RECARBRIO (imipenem, cilastatin, and relebactam) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) met primary endpoint. Kenilworth, NJ. Merck. September 30, 2019. https://www.mrknewsroom.com/news-release/research-and-development-news/pivotal-restore-imi-2-phase-3-study-mercks-recarbrio-imip. Accessed November 25, 2019.
13. Rizk ML, Rhee EG, Jumes PA, et al. Intrapulmonary pharmacokinetics of relebactam, a novel β-lactamase inhibitor, dosed in combination with imipenem-cilastatin in healthy subjects. Antimicrob Agents Chemother. 2018;62(3). pii: e01411-17. doi: 10.1128/AAC.01411-17. Print 2018 Mar.
14. Lapuebla A, Abdallah M, Olafisoye O, et al. Activity of meropenem combined with RPX7009, a novel β-lactamase inhibitor, against gram-negative clinical isolates in New York City [published online ahead of print June 1, 2015]. Antimicrob Agents Chemother. 2015;59(8):4856-60. doi: 10.1128/AAC.00843-15.

>> Read more News and Breakthroughs articles:

December 2019: Teaching Old Dogs New Tricks: Make the Most of Twitter to Boost ID Education, Engagement, and Advocacy

October 2019: What's New From the CLSI Subcommittee on Antimicrobial Susceptibility Testing

August 2019: Doravirine: Researchers DRIVE for a Drug Ahead of Its Class