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Ertapenem

Actions and Uses

    Ertapenem sodium (INVANZ) is a parenteral 1-ß methyl-carbapenem (molecular weight = 497.50) that is structurally related to beta-lactam antibiotics. It is indicated for the treatment of adult patients with the following infections caused by susceptible strains of the designated microorganisms:
    • Complicated Intra-abdominal Infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.
    • Complicated Skin and Skin Structure Infections due to Staphylococcus aureus (methicillin susceptible strains only), Streptococcus pyogenes, Escherichia coli, or Peptostreptococcus species.
    • Community Acquired Pneumonia due to Streptococcus pneumoniae (penicillin susceptible strains only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative strains only), or Moraxella catarrhalis.
    • Complicated Urinary Tract Infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae.
    • Acute Pelvic Infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia.
    Ertapenem has been shown to be active against most strains of the following microorganisms in vitro and in clinical infections.
    • Aerobic gram-positive microorganisms:
      • Staphylococcus aureus (methicillin susceptible strains only)
      • Streptococcus agalactiae
      • Streptococcus pneumoniae (penicillin susceptible strains only)
      • Streptococcus pyogenes
      • Note: Methicillin-resistant staphylococci and Enterococcus spp. are resistant to ertapenem.
    • Aerobic gram-negative microorganisms:
      • Escherichia coli
      • Haemophilus influenzae (Beta-lactamase negative strains only)
      • Klebsiella pneumoniae
      • Moraxella catarrhalis
    • Anaerobic microorganisms:
      • Bacteroides fragilis
      • Bacteroides distasonis
      • Bacteroides ovatus
      • Bacteroides thetaiotaomicron
      • Bacteroides uniformis
      • Clostridium clostridioforme
      • Eubacterium lentum
      • Peptostreptococcus species
      • Porphyromonas asaccharolytica
      • Prevotella bivia

 

Pharmacokinetics

  • Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding. Average plasma concentrations (mg/L) of ertapenem following a single 1 g dose (IV or IM) in healthy young adults are presented in Table 1.
  • There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.

    Table 1
    Average Plasma Concentrations (mg/L) of Ertapenem After Single Dose
    Dose/Route0.5 hr1 hr2 hr4 hr6 hr8 hr12 hr18 hr24 hr
      1 g IV*15511583483120931
      1 g IM3353675740271342
    *Infused at a constant rate over 30 minutes

  • Absorption via the intramuscular route
    Ertapenem, reconstituted with 1% lidocaine (in saline) is almost completely absorbed following IM administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (Cmax) are achieved in approximately 2.3 hours (Tmax).

  • Distribution
    • Ertapenem is highly bound to plasma proteins, primarily albumin.
    • The percent protein binding is dependent on the total erta;penem concentration (~ 95% at <100 mg/L and ~85% at 300 mg/L).
    • The apparent steady state volume of distribution of ertapenem in an average size adult is approximately 8.2 liters.
    • The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 2. The blister fluid to plasma ratio of AUC0-24 is 0.61.

      Table 2
      Concentrations of ertapenem (mg/L) in skin blister fluid
      at different intervals after a 1 gram dose
      0.5 hr1 hr2 hr4 hr8 hr12 hr24 hr
      712172424218

  • Metabolism
    • In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ringopened derivative formed by hydrolysis of the beta-lactam ring.
    • ln vitro studies in human liver microsomes indicate that ertapenem does not inhibit any of the following cytochrome p450 isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
    • In vitro studies suggest that ertapenem is neither a substrate nor a modulator of the P-glycoprotein-mediated transport

  • Elimination
    • Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour.
    • Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.

      Renal Insufficiency

      Following a single 1 g IV dose of ertapenem, the unbound ertapenem AUC increased proportionately to the degree of renal insufficiency

      CLcr
      mL/min/1.73 m2
      Increase in AUC of unbound drug
      60-901.5 fold
      31-592.3 fold
      5-304.4 fold
      <107.6 fold

    • Invanz® prescribing information states that "no dosage adjustment is necessary in patients with CLcr >31 mL/min/1.73 m2".
    • The effects of renal insufficiency on AUC of total drug were of smaller magnitude.

  • Hepatic Insufficiency
    • Ertapenem does not appear to undergo hepatic metabolism, and only 10% of a 1 g IV dose is recovered in the feces.
    • No dose adjustment is recommended in patients with hepatic insufficiency.

  • Geriatric Patients
    Due to age-relalated decline in renal function, drug exposure (AUC) increases markedly in elderly patients (>65 years of age) relative to young adults. However, no dosage adjustment is necessary based solely on age.

  • Pediatric Patients
    The pharmacokinetics of ertapenem in pediatric patients have not been established.

 

Contraindications and Warnings

  • WARNINGS: serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam therapy.
  • Ertapenem (INVANZ) is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.
  • Seizures and other CNS adverse experiences have been reported during treatment with INVANZ. Seizures occurred in 0.5% of patients treated with ertapenem (1 g qd). This adverse effect occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function.
  • Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ertapenem. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.
  • Lidocaine HCl is the diluent for intramuscular administration. Therefore, ertapenem administered IM is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type.
  • Prolonged use of ertapenem may result in overgrowth of non-susceptible organisms.
  • Caution should be taken when administering ertapenem IM to avoid inadvertent injection into a blood vessel.
  • Pregnancy Category B. There are, however, no adequate and well-controlled studies in pregnant women.
  • Ertapenem is excreted in human breast milk and therefore it should be administered to nursing mothers only when the expected benefit outweighs the risk.
  • Safety and effectiveness in pediatric patients have not been established. Therefore, use in patients under 18 years of age is not recommended.

 

Available As

    Ertapenem (INVANZ) is supplied as a sterile lyophilized powder in single dose vials each containing the equivalent of 1 gram of ertapenem (for IV infusion or for IM injection)(NDC 00006-3843-71 or 00006-3843-45).

 

Dose and Administration

  • The dose for adult patients with adequate renal function is 1 gram qday.
  • Dose must be adjusted for marked renal impairment as follows:

    CLcr
    mL/min/1.73 m2
    Dosage
    >301 g q24h
    <300.5 g q24h
    <10*0.5 g q24h
    *HD removes about 30% of dose. A supplementary dose of 150 mg is recommended if ertapenem is administered within 6 hours prior to hemodialysis.

  • Ertapenem may be administered by IV infusion for up to 14 days or IM injection for up to 7 days.
  • For IV administration:
    • Do not mix or co-infuse ertapenem with other drugs or with dextrose
    • The 1 gram vial is reconstituted with 10 mL of sterile water for injection or NS, immediately transfer contents into a 50-mL bag of normal saline, and mix. Ertapenem is incompatible with dextrose.
    • Infuse IV over 30 minutes
    • Infusion must be completed within 6 hours of reconstitution.
    • The diluted drug is stable for 6 hours at room temperature and for 24 hours in the refrigerator.
  • For IM administration:
    • Do not mix ertapenem with other drugs or with dextrose
    • Reconstitute the contents of a 1 g vial with 3.2 mL of 1.0% lidocaine HCl injection (without epinephrine). Shake vial thoroughly to form solution.
    • Immediately withdraw the contents of the vial and administer by deep intramuscular injection into a large muscle mass such as the gluteal muscles.
    • The reconstituted IM solution should be used within 1 hour after preparation.

 

Main Side Effects

    The most common drug-related adverse experiences in patients treated with ertapenem were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%), and vomiting (1.1%).

 

Drug Interactions

  • When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Probenecid increased the AUC by 25% and reduced the renal ertapenem clearance by 35%. The half-life increased from 4.0 to 4.8 hours. Because of the small effect on half-life, the coadministration with probenecid to extend the half-life of ertapenem is not recommended.
  • In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
  • In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following six cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.

 

References

  1. Invanz PI
  2. Odenholt I. Ertapenem: a new carbapenem. Expert Opin Investig Drugs. 2001;10(6):1157-66.

 

 

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