What data supports imipenem-cilastatin/relebactam’s new indication for bacterial pneumonia?

Background

Imipenem-cilastatin/relebactam (brand name RecarbrioTM) is an antimicrobial agent containing a carbapenem antibiotic, renal dehydropeptidase inhibitor, and beta-lactamase inhibitor.1,2 This drug combination received initial Food and Drug Administration (FDA) approval in July of 2019; at the time, it was approved for the treatment of complicated urinary tract and complicated intra-abdominal infections in adults. As of June 4, 2020, imipenem-cilastatin/relebactam is now FDA-approved for an additional indication, treatment of hospital-acquired (HAP) and ventilator-associated bacterial pneumonia (VAP) in adults. Since this agent was approved fairly recently, relevant guidelines have not yet been updated to determine the place in therapy of imipenem-cilastatin/relebactam. Therefore, the purpose of this review is to describe this agent in more detail and summarize existing and upcoming literature that may help to inform its use for the treatment of bacterial pneumonia.

Spectrum of activity

Imipenem-cilastatin was the first FDA-approved carbapenem antibiotic, and received its initial approval in 1985.1 When administered independently, imipenem is broken down in the kidneys by dehydropeptidase enzymes; thus, it is formulated with cilastatin, a renal dehydropeptidase inhibitor, to ensure that it can maintain its activity after administration.3 As a class, the carbapenem antibiotics provide similar broad coverage over a number of gram-positive, gram-negative, and anaerobic organisms. When comparing the agents directly, imipenem is marginally more active against gram-positive organisms and slightly less active against gram-negative organisms compared to meropenem and doripenem; resistance profiles also can vary among agents.

Gram-negative bacterial resistance to carbapenems most frequently develops via drug efflux mechanisms, reduced expression of bacterial outer membrane porins leading to decreased permeability, or production of beta-lactamase enzymes that hydrolyze beta lactam antibiotics, including carbapenems.3,4 Resistance can occur due to one of these mechanisms, or a combination of multiple mechanisms. Of these mechanisms, production of beta-lactamases is arguably the most concerning, as these enzymes have the potential to inactivate most beta lactam antibiotics and can be transferred to other bacterial species.4 Class A carbapenemases are produced by several gram negative bacteria, most notably Klebsiella pneumoniae; K pneumoniae carbapenemases (KPCs) can hydrolyze all beta-lactam antibiotics and certain strains are also resistant to multiple drugs in different classes. Class B metallo-beta-lactamases are transmitted via plasmids. They have the ability to inactivate most beta lactams, and are found among pathogens such as K pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Finally, class D carbapenemases include oxacillinase enzymes and are commonly found in species of Acinetobacter. While Class D carbapenemases mainly inactivate penicillins, certain variants also have a limited ability to hydrolyze carbapenems.

Relebactam is a diazabicyclooctane beta-lactamase inhibitor with a similar structure to avibactam plus an additional piperidine ring.5 Both relebactam and avibactam work by covalently binding to the active site of class A, C, and D serine beta-lactamases. Relebactam binds with high affinity to these beta-lactamases and creates a stable acyl-enzyme complex. The prescribing information for imipenem-cilastatin/relebactam lists several gram-negative bacteria that it can be used to treat, including several pathogens that are often multi-drug resistant.2 For the treatment of HAP and VAP, these include: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, E coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxycoca, K pneumoniae, P aeruginosa, and Serratia marcescens.

Dosage and administration

Regardless of indication, imipenem-cilastatin/relebactam is dosed as an intravenous (IV) infusion given over 30 minutes every 6 hours for a total of 4 to 14 days.2 The dose should be adjusted in patients with renal impairnment. Dosing recommendations are provided in Table 1 below. The prescribing information provides further instructions for how to prepare reduced doses for patients with renal impairment, since the product is currently only available as a 1.25 gram vial for reconstitution.

Table 1. Imipenem-cilastatin/relebactam dosing recommendations. 2
Creatinine clearance mL/minRecommended dosage
≥ 901.25 grams (500 mg imipenem, 500 mg cilastatin, 250 mg relebactam)
60 to 891 gram (400 mg imipenem, 400 mg cilastatin, 200 mg relebactam)
30 to 590.75 grams (300 mg imipenem, 300 mg cilastatin, 150 mg relebactam)
15 to 29 or end-stage renal disease on hemodialysis a0.5 grams (200 mg imipenem, 200 mg cilastatin, 100 mg relebactam)
a When given to a patient on hemodialysis, administration should follow hemodialysis

Literature review

A search was conducted to find literature supporting the use of imipenem-cilastatin/relebactam for the treatment of bacterial HAP and VAP. Two phase 3, double-blind, multicenter, randomized controlled trials were identified, which are described below.

The RESTORE-IMI 1 trial compared use of imipenem-cilastatin/relebactam to colistin plus imipenem in 31 hospitalized adult patients with HAP/VAP (N=11), complicated intra-abdominal infections (N=4), or complicated urinary tract infections (N=16) that were caused by organisms resistant to imipenem.6 Eligible patients were randomized 2:1 to IV therapy with either imipenem-cilastatin/relebactam 500 mg/500 mg/250 mg every 6 hours plus placebo or colistimethate sodium (300 mg colistin base activity as a loading dose followed by doses up to 150 mg colistin base activity every 12 hours) plus imipenem 500 mg every 6 hours. All doses were given over 30 ± 5 minutes for a minimum of 5 and maximum of 21 days, and adjusted based on renal function. The trial was designed as an estimation trial; thus, efficacy endpoints were not assessed with formal statistical testing. The primary efficacy endpoint, overall response, varied based on infection type; for patients with HAP/VAP, overall response was based on 28-day all-cause mortality. The most common imipenem-resistant pathogens documented as the cause of infection among the study population were P aeruginosa (77.4%) and K pneumoniae (12.9%). A favorable overall response was observed among patients in the entire population treated with both imipenem-cilastatin/relebactam (71.4%) and those treated with colisin plus imipenem (70.0%; unadjusted treatment difference, 1.4%). Eight-seven and one-half percent (7 of 8 patients) with HAP/VAP treated with imipenem-cilastatin/relebactam achieved a favorable overall response compared to 66.7% (2 of 3 patients) of those treated with colistin imipenem. Secondary endpoints measured in the full population at day 28, including favorable clinical response and all-cause mortality, were numerically favorable in the imipenem-cilastatin/relebactam group (adjusted difference of 26.3% and -17.3%, respectively). Treatment-emergent nephrotoxicity was statistically assessed and found to be significantly reduced among patients treated with imipenem-cilastatin/relebactam compared to those treated with colistin plus imipenem (adjusted difference, -45.9%; 95% confidence interval [CI], -69.1% to -18.4%; p=0.002). Adverse events related to the study drug occurred in 16% of patients treated with imipenem-cilastatin/relebactam and 31% of patients treated with colistin plus imipenem; the most common adverse events reported were increased aspartate and alanine aminotransferases, pyrexia, and nausea. This study was limited by its small sample size, which did not allow for full statistical analysis.

The RESTORE-IMI 2 trial, published in August 2020, was a noninferiority trial comparing the use of IV imipenem-cilastatin/relebactam 500 mg/500 mg/250 mg to IV piperacillin/tazobactam 4 grams/500 mg among 537 hospitalized patients with nonventilated HAP or ventilated HAP or VAP.7 All patients received empiric treatment with IV linezolid 600 mg every 12 hours until baseline cultures of the lower respiratory tract confirmed that methicillin-resistant Staphylococcus aureus (MRSA) was not present. Patients without MRSA were then randomized 1:1 to one of the study groups. Treatment in both groups was administered as a 30-minute infusion given every 6 hours for a total of 7 to 14 days; doses were renally adjusted as needed. The primary endpoint for efficacy was all-cause mortality at 28 days. The main secondary endpoint measured was favorable clinical response at early follow-up (a visit that occurred 7 to 14 days after end of therapy and on day 28 after randomization). For the primary endpoint, noninferiority was met if the upper bound of the 2-sided 95% CI for the adjusted difference in treatment between imipenem-cilastatin/relebactam and piperacillin/tazobactam was -12.5%. The most commonly isolated pathogens at baseline included K pneumoniae (25.6%), P aeruginosa (18.9%), A calcoaceticus-baumannii complex (15.7%), E coli (15.5%), and methicillin-sensitive S aureus (10.4%). Imipenem-cilastatin/relebactam was found to be noninferior to piperacillin/tazobactam for both the primary endpoint (adjusted treatment difference, -5.3%; 95% CI, -11.9% to 1.2%; p<0.001) and the main secondary endpoint (adjusted treatment difference, 5%; 95% CI, -3.2% to 13.2%; p<0.001). Rates of adverse events related to the study drug were similar between groups, and most commonly included increased aspartate and alanine aminotransferase levels.

Ongoing clinical trials

A search of clinicaltrials.gov revealed 2 additional studies that are underway which will further define the role of imipenem-cilastatin/relebactam in the treatment of HAP and VAP.8 These include a study of imipenem-cilastatin/relebactam versus active control in pediatric patients with HAP/VAP or complicated urinary tract or intra-abdominal infections, and a study comparing imipenem-cilastatin/relebactam to piperacillin/tazobactam in adults with HAP or VAP. Details of these studies are provided in Table 2 below:

Table 2. Ongoing clinical trials assessing imipenem-cilastatin/relebactam for HAP and VAP 9,10
Trial identification numberPhasePatient populationTreatment groupsOutcomes assessedEstimated completion date
NCT039699012/3Pediatric (birth to <18 years) with confirmed or suspected HAP/VAP, cIAI, or cUTIImipenem-cilastatin/relebactam

Active control (phase 3)		Primary: adverse events

Key secondary: 28-day ACM; clinical response; microbiological response		November 1, 2022
NCT035833333Adults with diagnosed HAP or VAPImipenem-cilastatin/relebactam

Piperacillin/tazobactam		Primary : 28-day ACM

Key secondary: Clinical response; microbiological response; adverse events		April 1, 2021
Abbreviations: ACM=all-cause mortality; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; HAP=hospital-acquired pneumonia; VAP=ventilator-associated pneumonia

Conclusion

To date, 2 trials have been published which show that imipenem-cilastatin/relebactam is an effective treatment option for adult patients with HAP and VAP, including those with pathogens that are resistant to imipenem and other drugs. In a small phase 3 trial, imipenem-cilastatin/relebactam was shown to have similar efficacy and a better adverse effect profile compared to colistin plus imipenem. A larger phase 3 trial also showed that imipenem-cilastatin/relebactam was non-inferior to piperacillin/tazobactam for treatment of HAP/VAP when assessing all-cause mortality at 28 days and clinical response at early follow-up. Additional trials are currently underway to further define imipenem-cilastatin/relebactam’s role in the treatment of HAP and VAP, including one trial that will be conducted in pediatric patients. Overall, imipenem-cilastatin/relebactam offers a novel treatment option to further expand the treatment armamentarium for patients with multi-drug resistant infections.

References

  1. Drugs@FDA: FDA-approved drugs. U.S. Food and Drug Administration. Accessed August 19, 2020. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  2. Recarbrio. Package insert. Merck & Co., Inc.; 2020.
  3. Doi Y. Ertapenem, imipenem, meropenem, doripenem, and aztreonam. In: Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th ed. Elsevier, Inc; 2020.
  4. Elshamy AA, Aboshanab KM. A review on bacterial resistance to carbapenems: epidemiology, detection and treatment options. Future Sci OA. 2020;6(3):FSO438. doi:10.2144/fsoa-2019-0098
  5. Smith JR, Rybak JM, Claeys KC. Imipenem-cilastatin-relebactam: A novel β-lactam-β-lactamase inhibitor combination for the treatment of multidrug-resistant gram-negative infections. Pharmacotherapy. 2020;40(4):343-356. doi:10.1002/phar.2378
  6. 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. Clin Infect Dis. 2020;70(9):1799-1808. doi:10.1093/cid/ciz530
  7. Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. Published online August 12, 2020. doi:10.1093/cid/ciaa803
  8. ClinicalTrials.gov. U.S. National Library of Medicine. Accessed August 24, 2020. https://clinicaltrials.gov/
  9. Safety, tolerability, efficacy, and pharmacokinetics of imipenem/cilastatin/relebactam (MK-7655A) in pediatric participants with gram-negative bacterial infection (MK-7655A-021). Clinicaltrials.gov identifier: NCT03969901. Updated August 21, 2020. Accessed August 24, 2020. https://clinicaltrials.gov/ct2/show/NCT03969901?term=03969901&draw=2&rank=1
  10. Imipenem/cilastatin/relebactam (MK-7655A) versus piperacillin/tazobactam in participants with hospital-acquired or ventilator-associated bacterial pneumonia (MK-7655A-016). Clinicaltrials.gov identifier: NCT03583333. Updated August 7, 2020. Accessed August 24, 2020. https://clinicaltrials.gov/ct2/show/NCT03583333?term=03583333&draw=2&rank=1

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2020

The information presented is current as of August 17, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.