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Clinical efficacy of RECARBRIO™ (imipenem, cilastatin, and relebactam)

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Supporting the case for RECARBRIOTM (imipenem, cilastatin, and relebactam)

A multinational, randomized, double-blind, active-controlled, noninferiority phase 3 trial in adult patients with HABP or VABP1

aMITT population is defined as all randomized participants who received at least 1 dose of trial treatment and did not have only Gram-positive cocci on Gram stain of the baseline lower respiratory tract specimen.

The mean age was 60 and 43% were 65 years of age or older. The mean APACHE II score was 15 and 47% of the population had an APACHE II score of ≥15. At randomization, 66% of patients were admitted to the ICU, 77% had been in the hospital for ≥5 days, and 48% had a creatinine clearance of <90 mL/min. Concurrent bacteremia was present at baseline in 5.8% of patients.

Day 28 all-cause mortality in MITT population

RECARBRIO achieved primary endpoint of noninferiority vs piperacillin/tazobactam in day 28 all-cause mortality1

RECARBRIO demonstrated a favorable response in certain high-risk subgroups1

  • Ventilated HABP and VABP patients
  • Patients with APACHE II scores ≥15

Additional clinical data2

In a noninferential trial vs colistin + imipenem…

Study description

  • A noninferential, prospective, randomized, double-blind trial of RECARBRIO (500 mg imipenem, 500 mg cilastatin, 250 mg relebactam) as compared to dose-optimized colistin (loading dose to achieve 300 mg colistin base activity, followed by maintenance doses up to 150 mg colistin base activity, every 12 hours) + 500 mg imipenem / 500 mg cilastatin every 6 hours in hospitalized adult patients.
  • Patients had bacterial infections that were imipenem nonsusceptible but susceptible to imipenem plus relebactam as well as to colistin
  • Primary analysis population: microbiological modified intent-to-treat, determined by meeting microbiological entry criteria, receiving ≥1 dose of study drug, and cultures collected within 1 week of enrollment confirming ≥1 qualifying Gram-negative pathogen from the primary infection site

Study limitations

This was a noninferential, descriptive, estimation trial without formal statistical testing for efficacy endpoints. The trial had several limitations, including the small sample size. Sample size was based on logistical feasibility and not statistical considerations. The trial was intended to generate limited clinical data in target population as part of a streamlined drug development program.

aOverall response

  • All-cause mortality through day 28 postrandomization in patients with HABP/VABP
  • Clinical response at day 28 postrandomization for patients with complicated intra-abdominal infection (cIAI)
  • The composite clinical and microbiological response 5-9 days after therapy for patients with complicated urinary tract infection (cUTI)

Secondary endpoints include

  • All-cause mortality: RECARBRIO 9.5% (n=2/21); colistin 30.0% (n=3/10)
  • Clinical response at day 28: RECARBRIO 71.4% (n=15/21); colistin 40.0% (n=4/10)
  • Treatment-emergent nephrotoxicity: RECARBRIO 10.3% (n=3/29); colistin 56.3% (n=9/16)

In patients with normal baseline renal function (serum creatinine <1.2 mg/dL), nephrotoxicity was defined as serum creatinine doubling (to >1.2 mg/dL) or ≥50% CLcr reduction. In patients with preexisting renal dysfunction (serum creatinine ≥1.2 mg/dL), nephrotoxicity was defined as serum creatinine increases ≥1 mg/dL, ≥20% CLcr reduction, or need for renal replacement therapy.

Adverse reactions in this noninferential study

The most frequently reported adverse events occurring in 2 or more patients treated with RECARBRIO were pyrexia, increased AST, increased ALT, nausea, and decreased CLcr.

The safety population comprised all randomized patients with ≥1 dose of study treatment according to the actual treatment received.

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References:

  1. Titov I et al. Clin Infect Dis. Published online August 12, 2020. doi.org/10.1093/cid/ciaa803 2. Motsch J et al. Clin Infect Dis. 2020;70(9):1799-1808.

APACHE II, Acute Physiology and Chronic Health Evaluation II; HABP, hospital-acquired bacterial pneumonia; ICU, intensive care unit; IV, intravenous; MITT, modified intent-to-treat; Q6H, every 6 hours; VABP, ventilator-associated bacterial pneumonia; vHABP, ventilated hospital-acquired bacterial pneumonia.

Indications and Usage

RECARBRIO™ (imipenem, cilastatin, and relebactam) is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens.

 

RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

 

RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and Pseudomonas aeruginosa.

 

Approval of the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Selected Safety Information

  • Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately.
  • Seizures and Other Central Nervous System (CNS) Adverse Reactions: CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (eg, brain lesions or history of seizures) and/or compromised renal function.
  • Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued.
  • Increased Seizure Potential Due to Interaction with Valproic Acid: Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems.
  • Clostridioides difficile–Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued.
  • Development of Drug-Resistant Bacteria: Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  • Adverse Reactions: The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%).
  • The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI patients treated with RECARBRIO were diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), phlebitis/infusion site reactions (2%), pyrexia (2%), and hypertension (2%).

 

Before prescribing RECARBRIO, please read the accompanying Prescribing information.

Indications and Usage

RECARBRIO™ (imipenem, cilastatin, and relebactam) is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens.

 

RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

 

RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and Pseudomonas aeruginosa.

 

Approval of the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

RECARBRIO™ (imipenem, cilastatin, and relebactam) is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

RECARBRIO™ (imipenem, cilastatin, and relebactam) is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex,

Selected Safety Information

  • Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately.
  • Seizures and Other Central Nervous System (CNS) Adverse Reactions: CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (eg, brain lesions or history of seizures) and/or compromised renal function.
  • Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued.
  • Increased Seizure Potential Due to Interaction with Valproic Acid: Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems.
  • Clostridioides difficile–Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued.
  • Development of Drug-Resistant Bacteria: Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  • Adverse Reactions: The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%).
  • The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI patients treated with RECARBRIO were diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), phlebitis/infusion site reactions (2%), pyrexia (2%), and hypertension (2%).

 

Before prescribing RECARBRIO, please read the accompanying Prescribing information.

Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO.

Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO.