Ertapenem

Introduction Overview

Generic Name

ertapenem

Brand Name

Invanz, INVanz ADD-Vantage

Dosage Form

injectable powder for injection (1 g)

Drug Class

Carbapenems

Pharmacokinetics

Absorption:
Ertapenem is administered parenterally, either intramuscularly or intravenously, since it is not absorbed orally due to its chemical structure and instability in the gastrointestinal tract. After intramuscular administration, ertapenem is rapidly absorbed with peak plasma concentrations typically achieved within 1 hour. The extent of absorption is nearly complete when given intramuscularly. Following intravenous administration, immediate plasma concentrations are observed. Ertapenem exhibits linear pharmacokinetics over a wide range of doses. Food intake does not affect its absorption or systemic exposure, though oral administration is not indicated.

Distribution:
Ertapenem is highly protein bound, approximately 85-95%, primarily to albumin, which influences its volume of distribution (approximately 8-12 liters). It distributes well into various tissues and body fluids, including skin, subcutaneous tissues, lung tissue, intra-abdominal tissues, pelvic tissues, and urine, aligning with its clinical use in treating infections in these sites. It penetrates inflamed meninges poorly; hence, its utility in central nervous system infections is limited. The high protein binding also results in a relatively low free (active) drug concentration in plasma, which is an important consideration in patients with hypoalbuminemia.

Metabolism:
Ertapenem is minimally metabolized in the body. The primary pathway involves hydrolysis of the β-lactam ring to inactive metabolites. There is no significant involvement of cytochrome P450 enzymes, reducing the risk of metabolic drug interactions. The drug remains largely unchanged in systemic circulation, which contributes to predictable pharmacokinetics and a relatively low potential for drug-drug metabolic interactions.

Elimination:
The elimination half-life of ertapenem is approximately 4 hours in individuals with normal renal function, allowing once-daily dosing. Ertapenem is primarily eliminated renally via glomerular filtration and tubular secretion. Approximately 80% of the administered dose is excreted unchanged in the urine within 24 hours. In patients with renal impairment, clearance is reduced and the half-life is prolonged, necessitating dosage adjustments. Minimal biliary excretion occurs. Ertapenem is not removed effectively by hemodialysis or peritoneal dialysis, but supplemental dosing may be required in these patients. The steady elimination profile supports its use in once-daily regimens for serious infections.

Dosage Forms

Available Dosage Forms:
- Injectable powder for injection reconstituted for intramuscular or intravenous use.
- Supplied as 1 g vial of powder for reconstitution.

Dosages for Adults and Adolescents:
- Standard dosing is 1 gram once daily administered by intravenous infusion over 30 minutes or intramuscular injection.
- Dosage adjusted based on infection severity, site, and renal function.
- Duration of therapy typically ranges from 5 to 14 days depending on infection.

Specific Patient Populations:
- Renal Impairment: Dose adjustment recommended for patients with creatinine clearance less than 30 mL/min; dosing interval may be extended or dose reduced.
- Pediatrics: Not recommended for children under 3 months of age due to insufficient safety and efficacy data.
- Geriatrics: No specific dosage adjustment necessary but renal function monitoring is advised.
- Pregnancy and Lactation: Use only if clearly needed; safety has not been established fully.

Storage and Preparation:
- Store unmixed powder at room temperature away from moisture and heat.
- After mixing for intramuscular injection, use within 1 hour.
- After mixing and dilution for intravenous use, can be stored up to 6 hours at room temperature or 24 hours refrigerated; must be used within 4 hours after refrigeration removal.

Mechanism Of Action

Ertapenem is a broad-spectrum carbapenem antibiotic that functions by inhibiting bacterial cell wall synthesis. It achieves this by binding to penicillin-binding proteins (PBPs) located on the bacterial cell membrane, which are essential enzymes in the final stages of peptidoglycan cross-linking necessary for bacterial cell wall rigidity and integrity. Disruption of this process results in a weakened cell wall leading to cell lysis and death, exhibiting bactericidal activity.

Its structure allows ertapenem to be highly resistant to the hydrolytic activity of most β-lactamases, including many extended-spectrum β-lactamases (ESBLs). This resistance enables ertapenem to maintain effectiveness against a broad range of gram-positive and gram-negative aerobic and anaerobic pathogens, including many strains resistant to other β-lactams.

Ertapenem has a high affinity especially for PBP 2 and PBP 3 in gram-negative bacteria and PBP 1a and PBP 1b in gram-positive organisms, disrupting cell wall synthesis across multiple bacterial species. Its spectrum includes common pathogens such as Escherichia coli, Klebsiella pneumoniae, Proteus species, and anaerobes like Bacteroides fragilis.

Compared to other carbapenems such as imipenem or meropenem, ertapenem has a longer half-life allowing once-daily dosing but has reduced activity against non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter species. Clinical studies have demonstrated its efficacy and safety in complicated intra-abdominal infections, skin and soft tissue infections, community-acquired pneumonia, pelvic infections, urinary tract infections, and surgical prophylaxis, aligning with its broad-spectrum mechanism.

Pharmacological Actions

Bactericidal activity through inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins.
High resistance to degradation by β-lactamase enzymes including many extended-spectrum β-lactamases.
Broad-spectrum activity against aerobic and anaerobic gram-positive and gram-negative bacteria.
Exhibits significant action against common pathogens causing intra-abdominal, pelvic, skin, and urinary tract infections.
Long plasma half-life (~4 hours) enabling convenient once-daily dosing regimen.
Poor penetration into cerebrospinal fluid limiting use for central nervous system infections.
Minimal metabolism, reducing potential for metabolic drug interactions.
High protein binding (85-95%) affecting free active drug concentration in plasma.
Renal excretion of unchanged drug making dose adjustments necessary in renal impairment.
Limited activity against non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter spp.
Demonstrates low incidence of resistance development compared to other β-lactams.
Active against anaerobic bacteria including Bacteroides species.
Reduces bacterial populations leading to resolution of infection signs and symptoms.

Therapeutic Or Clinical Uses

Treatment of complicated intra-abdominal infections including polymicrobial infections.
Management of complicated skin and skin structure infections caused by susceptible organisms.
Therapy of complicated urinary tract infections including pyelonephritis.
Treatment of community-acquired pneumonia caused by susceptible bacteria.
Treatment and prevention of pelvic infections, including postpartum and post-abortal infections.
Perioperative prophylaxis in colorectal surgery to reduce postoperative infections.
Empiric therapy for mixed aerobic and anaerobic infections in hospitalized patients.
Used in infections caused by extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae when sensitivity confirmed.
Alternative to other carbapenems in patients with specific drug allergies or resistance patterns.
Used in patients with complicated bacterial infections requiring broad-spectrum coverage.
Applied in prevention strategies for surgical site infections in high-risk surgeries.
Treatment of infections caused by susceptible strains of Escherichia coli, Klebsiella species, and Proteus species.

Side Or Adverse Effects

Nausea and vomiting occurring commonly with ertapenem administration.
Diarrhea, including potential development of Clostridioides difficile-associated diarrhea.
Headache reported as a frequent neurological side effect.
Injection site reactions such as pain, redness, and inflammation.
Hypersensitivity reactions including rash, urticaria, and anaphylaxis in susceptible individuals.
Seizures or convulsions, particularly in patients with predisposing CNS conditions or renal impairment.
Severe abdominal pain and watery or bloody diarrhea indicating possible pseudomembranous colitis.
Elevations in hepatic transaminases and liver function abnormalities occasionally observed.
Rare hematologic effects such as eosinophilia and thrombocytopenia.
Potential development of superinfection with resistant organisms or fungi during therapy.
Transient elevations in serum creatinine and blood urea nitrogen may occur.
Neurological impairments including dizziness and confusion have been rarely reported.
Potential allergic reactions can include swelling of face, lips, tongue, or throat requiring emergency treatment.
Local phlebitis or thrombophlebitis with intravenous administration.
Gastrointestinal disturbances such as abdominal cramps and flatulence.

Precautions

Assess for history of hypersensitivity to carbapenems, penicillins, cephalosporins due to potential cross-reactivity.
Use with caution in patients with seizure disorders or central nervous system diseases that may predispose to seizures.
Monitor renal function before and during therapy; dose adjustments needed for renal impairment.
Use cautiously in patients with electrolyte abnormalities such as hypokalemia or hypomagnesemia.
Consider risk of Clostridioides difficile-associated diarrhea in patients receiving prolonged therapy.
Avoid intramuscular injection in patients allergic to local anesthetics such as lidocaine.
Carefully evaluate for signs of superinfection or antibiotic-associated colitis during treatment.
Pregnancy and breastfeeding should be carefully considered; use only when benefits outweigh risks.
Do not use in neonates under 3 months of age due to lack of safety data.
Ensure correct reconstitution and storage conditions to maintain drug stability and efficacy.
Warn patients to report allergic symptoms promptly including hives, swelling, or difficulty breathing.
Inform patients not to discontinue treatment early even if symptoms improve to prevent resistance.
Avoid concurrent use of anti-diarrheal agents without physician consultation due to risk of worsening colitis.
Ensure proper disposal of needles and syringes to prevent needlestick injuries and contamination.
Check for potential interaction with valproic acid and probenecid which may affect drug levels.

Warnings

Risk of serious allergic reactions including anaphylaxis; emergency medical help required if symptoms appear.
Potential for seizures, especially in patients with pre-existing CNS conditions or renal impairment.
May cause severe and potentially fatal Clostridioides difficile-associated diarrhea sometimes weeks after therapy completion.
Not to be used in individuals with known hypersensitivity to carbapenems, penicillins, or cephalosporins.
Avoid injection into muscle if patient is allergic to local anesthetics like lidocaine.
Ensure proper dosing and administration to avoid subtherapeutic levels and bacterial resistance.
Adjust dose in renal dysfunction to prevent drug accumulation and toxicity.
Avoid sharing medication between individuals even with similar symptoms to prevent inappropriate use.
Avoid use in children under 3 months due to insufficient safety data.
Use only as directed by healthcare providers; unsupervised use increases risk of adverse outcomes.
Monitor for signs of superinfection or emergence of resistant organisms during and after therapy.
Handling precautions include safe disposal of injection materials to prevent accidental injuries.
Do not use to treat viral infections such as common cold or influenza.
Ertapenem-associated encephalopathy has been reported rarely; monitor neurological status.
Interrupt therapy if serious hypersensitivity or severe adverse reactions occur.

Contraindication

Known hypersensitivity to ertapenem or any component of the formulation.
Allergy to other carbapenems such as meropenem or imipenem.
Hypersensitivity to beta-lactam antibiotics including penicillins and cephalosporins.
Patients with a history of severe allergic reactions to any of the above antibiotics.
Use of intramuscular injection contraindicated in patients allergic to lidocaine or similar local anesthetics.
Not indicated for use in neonates younger than 3 months old due to safety concerns.
Patients with previous allergic reactions such as Stevens-Johnson Syndrome or toxic epidermal necrolysis to beta-lactams.
Use contraindicated if patient has a history of seizures related to carbapenem use.
Avoid use if known severe renal impairment not amenable to dose adjustment.
Contraindicated in patients with active severe gastrointestinal disease such as colitis.
Patients with hypersensitivity reactions to multiple classes of beta-lactams should avoid ertapenem.
Known intolerance or allergy to formulation additives or excipients.
Contraindicated if previous toxic reaction to ertapenem documented.
Avoid in patients with underlying brain tumors or CNS lesions predisposing to seizures unless benefits outweigh risks.

Drug Interactions

Probenecid decreases renal tubular secretion of ertapenem leading to increased plasma concentrations.
Valproic acid and divalproex sodium serum concentrations may be decreased by ertapenem, increasing risk of seizures.
Concurrent use with other neurotoxic drugs may enhance central nervous system adverse effects including seizures.
No significant metabolic drug interactions due to lack of cytochrome P450 involvement.
Potential interaction with anticoagulants; monitor coagulation parameters.
May interact with drugs altering renal function, affecting ertapenem clearance.
Concomitant use with aminoglycosides may increase nephrotoxic potential; monitoring needed.
Interaction with other β-lactams can interfere with antibacterial activity; avoid combined use if possible.
Antidiarrheal drugs may mask or worsen antibiotic-associated colitis when used concomitantly.
Drug concentrations may be influenced by renal replacement therapies requiring dose adjustment.
Interference with laboratory tests such as Coombs’ test has been reported rarely.
No significant interaction with oral contraceptives documented, but antibiotic use may reduce efficacy.
Interaction with immunosuppressants unknown but caution advised during combined therapy.
Herbal products and supplements interaction profile not well-established; monitor patient closely.
Monitor patients receiving multiple CNS-active agents for additive neurotoxicity.

Preparations Of The Drug

Ertapenem is supplied as a single-dose vial containing 1 gram of sterile powder.
The powder requires reconstitution with a suitable diluent recommended by manufacturer or pharmacist.
Diluent for intramuscular injection is typically sterile water or lidocaine (avoid if allergic to anesthetics).
For intravenous infusion, sterile normal saline, 5% dextrose in water, or lactated Ringer’s solution can be used for dilution.
After reconstitution, intramuscular preparations should be used promptly within 1 hour.
Reconstituted intravenous solutions can be stored at room temperature up to 6 hours or refrigerated up to 24 hours, but must be used within 4 hours after removal from refrigeration.
Packaging includes single-use vials to maintain sterility and prevent contamination.
Manufactured under strict sterile conditions to prevent microbial contamination.
Available commercially as Invanz and INVanz ADD-Vantage prefilled syringe system to facilitate administration.
Specific instructions for handling, reconstitution, and storage should be strictly followed to maintain drug stability.
Not designed for oral administration; only for parenteral use by injection.
Disposal instructions include placing used vials, needles, and syringes in puncture-resistant sharps containers.
Instructions advise against mixing with other drugs in the same syringe or infusion bag unless compatibility is established.
Shelf life and storage conditions noted on packaging to ensure drug potency and safety.
Patient instruction leaflets provide guidance for healthcare providers on appropriate preparation and administration.