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Recarbrio: Combating Emerging Resistance

Monday, September 23, 2019  
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Written by: Jenni Thomas, Doctor of Pharmacy Candidate 2020, Duquesne University School of Pharmacy

Precepted by: Lauren Finoli, PharmD, BCPS, BCCCP, Allegheny General Hospital, Pittsburgh, PA

 

Background

Bacteria known as the “ESKAPE” pathogens (Enterococcus faeciumStaphylococcus aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosa, and Enterobacter species) are driving antibiotic resistance globally.1 The production of β-lactamases has long-been a common resistance mechanism, but one that is generally overcome via administration of a β-lactamase inhibitor alongside a β-lactam antibiotic. However, newly emerging β-lactamase-mediated mechanisms have led to resistance to agents typically used as last lines of defense, such as carbapenems.1 These multidrug-resistant (MDR) gram-negative organisms confer high mortality rates if not treated with effective antibiotics, thus necessitating the development of novel agents with activity against these emerging, resistant bacteria.

On July 17th, 2019, the United States Food and Drug Administration approved a new antibacterial agent for utilization in adults with complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). Recarbrio™ is combination of three antibiotics: imipenem, cilastatin, and relebactam. Imipenem is a broad-spectrum, beta-lactam antibiotic belonging to the carbapenem class. Cilastatin, which has no antibacterial activity, is an inhibitor of dehydropeptidase-I (DHP-I) which acts to prevent the breakdown of imipenem by renal DHP-I. Relebactam is a new class A/C beta-lactamase inhibitor which restores imipenem activity against more resistant gram-negative pathogens.1,2 Recarbrio™ is meant to be used only for patients with limited or no alternative treatment options for cUTI and cIAI to maintain its susceptibilities against MDR organisms.

Recarbrio Package Insert Information3

Recommended dosing of Recarbrio™ is 1.25 grams (containing imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) by intravenous (IV) infusion over 30 minutes every 6 hours in patients 18 years of age and older with creatinine clearance (CrCl) ≥ 90 mL/min. Renal dosing adjustments are shown in Table 1. Note that renal dosing adjustments include only an adjustment of the dose and dosing frequency remains every 6 hours regardless of degree of renal impairment. There is a paucity of evidence for dosing Recarbrio™ on continuous renal replacement therapy (CRRT), however; one may consider using the same CRRT dosing that is used for imipenem/cilastatin, since relebactam has similar protein binding as imipenem and cilastatin and 90% is excreted unchanged in the urine.3

Table 1.

Note: Recarbrio™ is not recommended in those with CrCl < 15 mL/min if dialysis is not started within 48 hours.

Recarbrio’s™ only contraindication per the package insert is patients with a history of severe hypersensitivity to any of the components. There are, however, a number of warnings and precautions. First, therapy should be discontinued immediately if a hypersensitivity reaction occurs, as these have been reported. Secondly, care should be used in monitoring for focal tremors, myoclonus, or seizures.  If any of these occur, patients should be evaluated to determine whether Recarbrio ™ was the cause, as seizures have been reported with the use of imipenem/cilastatin (a component of Recarbrio™). Lastly, Clostridium dificille- associated diarrhea has been reported and should be evaluated if it occurs.

Adverse reactions occurring in ≥ 2% of patients treated with Recarbrio™ were diarrhea, nausea, headache, vomiting, alanine aminotransferase elevation, aspartate aminotransferase elevation, phlebitis/infusion site reactions, pyrexia, and hypertension.

The published package insert recommends avoiding concomitant use with ganciclovir unless the potential benefits outweigh the risks. Generalized seizures have also been reported in patients who received ganciclovir concomitantly with imipenem/cilastatin. Valproic acid or divalproex sodium is also recommended to be avoided. Recarbrio™ may decrease valproic acid concentrations and therefore increase the risk of breakthrough seizures. Alternative antibacterial agents should be considered in these situations to treat patients whose seizures are controlled on valproic acid or divalproex sodium.

Relevant pharmacokinetic and pharmacodynamic parameters include that each component is primarily eliminated by the kidneys resulting in Recarbrio’s™ mean half-life being approximately one hour.  Relebactam is minimally metabolized, however, imipenem is primarily metabolized in the kidney by dehydropeptidase when given alone. The combination of imipenem with cilastatin ensures higher imipenem concentrations in the urine since cilastatin is a dehydropeptidase inhibitor and prevents the metabolism of imipenem in the kidney. Liver injury or hepatic impairment are not thought to have appreciable effects on patient exposure to imipenem, cilastatin, or relebactam.

Recarbrio™ has been shown to have activity against most isolates of the following bacteria:

Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection1

This was a prospective, multicenter, double-blind, randomized controlled trial conducted at 45 sites in 20 countries. A total of 351 subjects ≥ 18 years of age with cIAI were randomized 1:1:1 to receive 250 mg relebactam (REL), 125 mg REL, or placebo (each given IV concurrently with 500 mg imipenem-cilastatin [IMI]) every 6 hours for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of IV therapy (DCIV), defined by resolution of all or most presenting signs and symptoms of IAI infection without the need for further antibiotic therapy.

Rates of favorable clinical response at DCIV were similar across all three treatment groups, showing that REL at doses of 250 mg or 125 mg plus IMI was noninferior to IMI alone in the treatment of cIAI. Comparable clinical and microbiological responses rates were observed among the three groups. Rates of adverse events were similar across all groups, with the most common events (incidence >5%) being diarrhea, nausea, and vomiting. The biggest limitation of this study was the small number of resistant pathogens that were identified, which limited the assessment of the clinical utility of REL plus IMI in cIAI.

Table 2.

 

 

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 infections2

This was a prospective, multicenter, double-blind, randomized controlled trial conducted at 34 hospitals in 11 countries. A total of 302 subjects ≥ 18 years of age with cUTI were randomized 1:1:1 to receive 250 mg REL, 125 mg REL, or placebo, each given IV with 500 mg IMI every 6 hours for 4 to 14 days. Step down therapy to oral ciprofloxacin was optional. The primary endpoint was favorable microbiologic response rate (pathogen eradication) at DCIV in the ME population.

Results: For all 3 treatment groups, microbiological and clinical response rates exceeded 95% in ME patients. The similar microbiological response across treatment groups showed non-inferiority of REL at doses of 250 mg or 125 mg plus IMI compared to IMI alone in the treatment of cUTI. Clinically significant liver transaminase elevations were comparable between groups, and the most common adverse effects were nausea, headache, and diarrhea. Similar to the cIAI study, the biggest limitation was the small number of resistant pathogens that were identified.

Table 3.

Both trials had relatively non-restrictive inclusion criteria, leading to wider study populations that included a variety of pathogens, not simply MDR pathogens. The findings in these trials support Recarbrio™ as a non-inferior therapy when compared with imipenem-cilastatin alone for cIAI and cUTI, but do not have sufficient evidence to compare efficacy in solely MDR infections. However, in vitro studies have shown that relebactam restores imipenem susceptibility to many imipenem-resistant isolates.4,5

Conclusion

Recarbrio™ is a novel antibacterial agent composed of imipenem, cilastatin, and relebactam that has been newly approved for the treatment of cIAI and cUTI in adults. Recarbrio™ gives clinicians an option for patients infected with MDR gram-negative organisms that are carbapenem resistant. This agent has been well-tolerated in clinical trials, but due to the current lack of efficacy data, it should only be utilized with appropriate antimicrobial stewardship as an agent of last resort for patients with cIAI or cUTI with limited or no treatment options.

 

References:

  1. Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, 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.
  2. Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML. 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.
  3. Recarbrio [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019.
  4. Livermore DM, Warner M, Mushtaq S. 2013. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosaJ Antimicrob Chemother. 2013;68:2286–2290.
  5. Hirsch EB, Ledesma KR, Chang KT, Schwartz MS, Motyl MR, Tam VH. 2012. In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteriaAntimicrob Agents Chemother. 2012;56:3753–3757.

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