By Samaneh Pourali, PharmD, BCPS

Clinical Pharmacist, Stanford University School of Medicine

Dr. Pourali reports no financial relationships relevant to this field of study.

Imipenem-cilastatin-relebactam (IMI/REL) is a broad-spectrum antibiotic that combines three active ingredients: Imipenem (IMI) is a carbapenem antibiotic that inhibits bacterial cell wall synthesis through binding penicillin binding proteins, cilastatin sodium is a renal dehydropeptidase inhibitor that prevents inactivation if imipenem by renal enzymes, and relebactam is a class A/C beta-lactamase inhibitor preventing degradation of imipenem.

In July 2019, the Food and Drug Administration (FDA) approved IMI/REL for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis and complicated intra-abdominal infections (cIAI). In a Phase III, randomized, double-blind, controlled trial, investigators examined the efficacy and safety of IMI/REL compared to imipenem/cilastatin (IMI) plus colistin for the treatment of imipenem-nonsusceptible bacterial infections in 31 patients. The primary endpoint of overall favorable response was demonstrated in 71% of the IMI/REL group vs. 70% of the IMI plus colistin group (difference -7.3%; 90% confidence interval [CI], -27.5%, 21.4). Treatment emergent nephrotoxicity occurred in 10% of the IMI/REL group vs. 56% of the IMI plus colistin group (P = 0.002). An overview of Phase II and Phase III clinical trials evaluating the use of IMI/REL is summarized in Table 1.2-5

Table 1: Overview of Phase II and Phase III Trials Evaluating IMI/REL2-5

Clinical Trial

Design

Study Intervention

Infection

Primary Outcomes

Sims et al2

Phase II, randomized double-blind, dose-ranging

IMI-REL vs. IMI 500 mg every 6 hours

cUTI

Favorable microbiological response at EOT: 95.5%/98.6% IMI/REL vs. 98.7% IMI

Lucasti et al3

Phase II, randomized double-blind, dose-ranging

IMI-REL vs. IMI 500 mg every 6 hours

cIAI

Favorable microbiological response at EOT: 96.3%/98.8% IMI/REL vs. 95.2% IMI

RESTORE-IMI-14

Phase III, randomized double-blind, non-inferiority

IMI-REL 500 mg every 6 hours vs. IMI 500 mg every 6 hours + colistin (300 mg load, 150 mg every 12 hours)

HAP, VAP, cIAI, cUTI

Favorable overall response: 71.4% IMI/REL vs. 70% IMI + colistin

RESTORE IMI-25

Phase III, randomized double-blind, comparator-controlled

IMI-REL 500 mg every 6 hours vs. piperacillin/tazobactam 4.5 g every 6 hours

HAP/VAP

Results to be published

28-day survival

IMI-REL = imipenem, cilastatin, relebactam; IMI = imipenem, cilastatin; cUTI = complicated urinary tract infection;

cIAI = complicated intra-abdominal infection; HAP = hospital-acquired pneumonia; VAP = ventilator-associated pneumonia; EOT = end of therapy

MICROBIOLOGY1

The FDA susceptibility breakpoint for IMI/REL against Enterobacteriaceae is ≤ 1/4 mcg/mL, with isolates with a minimum inhibitory concentration (MIC) of 2/4 mcg/mL considered intermediate, and ≥ /4 mcg/mL considered resistant. Clinical efficacy was shown for the following Enterobacteriaceae: Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Klebsiella oxytoca. The Pseudomonas aeruginosa breakpoint for IMI/REL is ≤ 2/4 mcg/mL, with isolates with a MIC of 4/4 mcg/mL considered intermediate and ≥ 8/4 mcg/mL considered resistant.

Additionally, the breakpoint for IMI/REL against anaerobic microorganisms is ≤ 4/4 mcg/mL, with isolates with a MIC of 8/4 mcg/mL considered intermediate and ≥ 16/4 mcg/mL considered resistant. Clinical efficacy was shown for the following anaerobes: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Fusobacterium nucleatum, and Parabacteroides distasonis. IMI/REL is not active against most isolates that contain metallo-beta-lactamases (MBLs) and some oxacillinases with carbapenemase activity.

PHARMACOKINETICS/PHARMACODYNAMICS1

IMI/REL is available as an intravenous formulation for administration. The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19 L, respectively. Plasma binding protein is 20%, 40%, and 22% for each of the components.

Imipenem is primarily metabolized by dehyropeptidases in the kidneys, while cilastatin and relebactam are minimally metabolized. All components are mainly excreted by the kidneys, and approximately 63% of imipenem, 77% of cilastatin, and 90% of relebactam were detected as unchanged drug in the urine.

The average half-life is one hour for imipenem and 1.2 hours for relebactam. The pharmacokinetic/pharmacodynamic parameter that best correlates with efficacy based on animal and in vitro models for imipenem is percent time of dosing interval that unbound plasma concentration of imipenem exceeds imipenem/relebactam MIC (% fT > MIC) against infecting organism. Relebactam’s pharmacokinetic/pharmacodynamic parameter is best demonstrated by the ratio of 24-hour unbound plasma relebactam AUC to IMI/REL MIC (fAUC 0 – 24 hr/MIC). (See Table 2.)

Table 2: IMI/REL Dosage and Adjustments for Renal Impairment1

Estimated CrCl (mL/min)*

Recommended Dose +

Dosing Interval

> 90

1.25 g (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg)

Every 6 hours

60-89

1 g (imipenem 400 mg, cilastatin 400 mg, relebactam 200 mg)

Every 6 hours

30-59

0.75 g (imipenem 300 mg, cilastatin 300 mg, relebactam 150 mg)

Every 6 hours

15-29

0.5 g (imipenem 200 mg, cilastatin 200 mg, relebactam 100 mg)

Every 6 hours

< 15

Avoid unless IHD instituted within 48 hours

-

ESRD on hemodialysisc

0.5 g (imipenem 200 mg, cilastatin 200 mg, relebactam 100 mg)

Every 6 hours

Peritoneal dialysis

Not recommended (inadequate data)

-

CrCl = creatinine clearance; ESRD = end-stage renal disease; IHD = intermittent hemodialysis

* Cockroft-Gault formula

+ Administer intravenously over 30 minutes

c Administration should be timed after hemodialysis and at intervals following IHD

ADVERSE EFFECTS/WARNINGS1

For patients with known hypersensitivity to imipenem, cilastatin, or relebactam, this antimicrobial is contraindicated. Seizures and other central nervous system (CNS) adverse reactions have been reported most commonly in patients with CNS disorders (brain lesions, history of seizures) and/or compromised renal function.

Common side effects (> 2%) include nausea, vomiting, diarrhea, phlebitis, pyrexia, headache, AST/ALT elevation, and hypertension. Rare adverse effects include agranulocytosis, increased eosinophils, hemolytic anemia, seizure, hepatic failure, and jaundice.

Clinically relevant drug-drug interactions include combination of IMI/REL with ganciclovir or valganciclovir and valproate. Increased risk of seizures has been observed with imipenem/cilastatin and ganciclovir or valganciclovir; thus, both antimicrobials should not be used unless the potential benefits outweigh the risks. Carbapenems have been shown to decrease valproic acid concentrations, which may increase the risk of breakthrough seizures; therefore, alternative antibiotics should be considered for patients whose seizures are well-controlled on valproic acid.

CONCLUSION

Imipenem-cilastatin-relebactam is a broad-spectrum antibiotic approved for the treatment of cUTI and cIAI in patients who have limited or no alternative treatment options. This antimicrobial combines imipenem/cilastatin with a new beta-lactamase inhibitor, relebactam. It provides enhanced activity against most strains of KPC-producing ESBLs and carbapenem-resistant Enterobacteriaceae (CRE), and restores susceptibility of imipenem against Pseudomonas spp. It appears to have a more favorable safety profile compared to colistin for the treatment of multidrug-resistant organisms.

REFERENCES

  1. Recarbrio (imipenem/cilastatin/relebactam) prescribing information. Merck & Co Inc.; July 2019.
  2. 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;72:2616-2626.
  3. 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;60:6234-6243.
  4. 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 2019. doi: 10.1093/cid/ciz530. [Epub ahead of print].
  5. Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014) (RESTORE-IMI 2). https://clinicaltrials.gov/ct2/show/NCT02493764.
  6. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103-e120.
  7. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infections in adults and children: Guidelines by the Surgical Infection Society and Infectious Diseases Society of America. Clin Infect Dis 2010;50:133-164.
  8. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61-e111.