By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a new antibacterial drug combination for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). This three-drug combination contains a new beta-lactamase inhibitor, relebactam, and an existing combination of imipenem/cilastatin. Relebactam is the third new beta-lactamase inhibitor after avibactam and vaborbactam. Imipenem/cilastatin and relebactam (IMI/REL) received the FDA’s qualified infectious disease product designation, given to products intended to treat serious or life-threatening infections, and was granted priority review. IML/REL is marketed as Recarbrio.

INDICATION

IMI/REL can be prescribed to treat cUTI, including pyelonephritis caused by these susceptible gram-negative microorganisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella aerogenes, and Pseudomonas aeruginosa.1 IMI/REL also can be prescribed to treat complicated intra-abdominal infections caused by these susceptible gram-negative microorganisms: Citrobacter freundii, E. coli, E. cloacae, Bacteroides species (fragilis, caccae, ovatus, thetaiotaomicron, stercoris, vulgatus, uniformis), Klebsiella oxytoca, K. aerogenes, K. pneumoniae, Fusobacterium nucleatum, P. aeruginosa, and Parabacteroides distasonis.

DOSAGE

The recommended dose is 1.25 g (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) given by intravenous infusion over 30 minutes every six hours.1 Dosage should be adjusted based on estimated creatinine clearance. Duration of treatment is four to 14 days based on severity and location of infection. IMI/REL is available as a single-dose vial containing imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg.

POTENTIAL ADVANTAGES

The inhibitions of mainly class A and class C beta-lactamases by relebactam results in a two- to 128-fold reduction in in vitro minimal inhibitory concentrations of various nonsusceptible imipenem gram-negative microorganisms, including Klebsiella pneumoniae carbapenemase (KPCs) and serine carbapenemase producers.2 Relebactam restored activity of imipenem/cilastatin in animal models of infection caused by imipenem-nonsusceptible, KPC-producing Enterobacteriaceae and P. aeruginosa (Pseudomonas-derived cephalosporinases).1

POTENTIAL DISADVANTAGES

Concomitant use of IMI/REL with ganciclovir, valproic acid, or divalproex is not recommended because of an increased risk for seizures.1 The safety and efficacy of IMI/REL in patients < 18 years of age have not been established.1 IML/REL is not active against class B beta-lactamases; it is minimally active against class D beta-lactamases.

COMMENTS

The approval of IMI/REL was supported by previous clinical data regarding the effects of imipenem/cilastatin on cIAI and cUTI.1,3,4 These Phase II studies showed that IMI/REL was noninferior to imipenem/cilastatin in terms of clinical or microbiological response.3,4 The contribution of relebactam mainly was based on in vitro and animal infection models. Clinical trials provided limited safety and efficacy data.1 The authors of a Phase III trial compared IMI/REL and colistimethate sodium against imipenem/cilastatin in the treatment of imipenem-resistant bacterial infections (n = 47).5 The trial included subjects with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumoniae (VABP), cIAI, and cUTI. The primary endpoint was the percent with favorable overall response (FOR) up to day 30 (up to nine days after completing study treatment). FOR was defined as: HABP/VABP survival through day 28; cIAI: all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional treatment (i.e., additional antibiotics, unplanned surgery, or procedures); cUTI: symptom resolution with no additional antibiotics or microbiological response. Percent with FOR was 71.4% for IMI/REL compared to 70.0% for IMI/colistimethate.

CLINICAL IMPLICATIONS

Generally, carbapenem resistance is due to the production of carbapenemases. Relebactam added to imipenem/cilastatin joins ceftazidime/avibactam as beta-lactamase-enhanced antibacterials indicated for cIAI and cUTI and meropenem/vaborbactam for cUTI. The three beta-lactamase inhibitors feature similar overlapping profiles against various beta-lactamase enzymes, particularly KPC-producing carbapenamases.2 However, there are nuances of activity against different mutations where one may be superior.6 In addition, the molecular partner is another factor, as imipenem is less likely to be subject to bacterial (e.g., Pseudomonas) efflux pumps (a resistance mechanism due to extrusion of the drug from the bacterial cell) than ceftazidime and meropenem.2,7

These antibacterials should be reserved only to treat infections that are caused by microorganisms that are proven or strongly suspected to be susceptible to these agents. The cost for IMI/REL was unavailable at the time of this review.

REFERENCES

  1. Merck & Co., Inc. Recarbrio Prescribing Information, July 2019. Available at: http://bit.ly/2U4x4bP. Accessed Aug. 26, 2019.
  2. Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam: Two novel carbapenem-beta-lactamase inhibitor combinations. Drugs 2018;78:65-98.
  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. 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.
  5. ClinicalTrials.gov. Efficacy and safety of imipenem+cilastatin/relebactam (MK-7655A) versus colistimethate sodium+imipenem+cilastatin in imipenem-resistant bacterial infection (MK-7655A-013) (RESTORE-IMI 1). Available at: http://bit.ly/2NApV1I. Accessed Aug. 26, 2019.
  6. 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: pii: e00642-17. doi: 10.1128/AAC.00642-17.
  7. Barnes MD, Bethel CR, Alsop J, et al. Inactivation of the pseudomonas-derived cephalosporinase-3 (PDC-3) by relebactam. Antimicrob Agents Chemother 2018;62. pii: e02406-17. doi: 10.1128/AAC.02406-17.