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Ertapenem

Ertapenem: A Comprehensive Overview of Its Role in Antimicrobial Therapy

Introduction

Ertapenem, marketed under the brand name Invanz, is a broad-spectrum, parenteral carbapenem antibiotic used to treat various moderate to severe infections caused by susceptible bacteria. As a member of the β-lactam class, ertapenem plays a crucial role in managing infections, particularly those caused by multidrug-resistant organisms.

Mechanism of Action

Ertapenem exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), particularly PBP 2 and PBP 3, which are essential for the cross-linking of the peptidoglycan layer of the bacterial cell wall. This inhibition leads to cell lysis and death of the bacterium. Ertapenem is stable against most β-lactamases, including extended-spectrum β-lactamases (ESBLs), but not against carbapenemases.

Spectrum of Activity

Ertapenem has a broad spectrum of activity against many Gram-positive and Gram-negative aerobic and anaerobic bacteria. However, it lacks activity against certain non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter species.

Effective Against:

  • Gram-positive aerobes: Streptococcus species, methicillin-susceptible Staphylococcus aureus (MSSA)

  • Gram-negative aerobes: Escherichia coli, Klebsiella species, Proteus species

  • Anaerobes: Bacteroides fragilis, Clostridium species

Not Effective Against:

  • Pseudomonas aeruginosa

  • Acinetobacter baumannii

  • Enterococcus faecalis and Enterococcus faecium

Clinical Uses

Ertapenem is approved for the treatment of various infections, including:

  • Complicated intra-abdominal infections

  • Complicated skin and skin structure infections

  • Community-acquired pneumonia

  • Complicated urinary tract infections, including pyelonephritis

  • Acute pelvic infections

  • Prophylaxis of surgical site infections in colorectal surgery

Its once-daily dosing and broad-spectrum activity make it a convenient option for outpatient parenteral antimicrobial therapy (OPAT).

Pharmacokinetics

Ertapenem exhibits favorable pharmacokinetic properties:

  • Administration: Intravenous (IV) or intramuscular (IM)

  • Bioavailability: Approximately 99% after IM administration

  • Plasma protein binding: ~85-95%

  • Half-life: Approximately 4 hours

  • Excretion: Primarily via the kidneys

Due to its high protein binding and prolonged half-life, ertapenem allows for once-daily dosing, enhancing patient compliance.

Resistance Mechanisms

Resistance to ertapenem can occur through various mechanisms:

  1. Production of β-lactamases: Although ertapenem is stable against many β-lactamases, the production of certain enzymes, such as carbapenemases (e.g., KPC, NDM), can hydrolyze ertapenem, rendering it ineffective.

  2. Porin channel alterations: Changes or loss of outer membrane porins can reduce ertapenem uptake, especially in combination with β-lactamase production.

  3. Efflux pumps: Overexpression of efflux pumps can expel ertapenem from bacterial cells, decreasing its intracellular concentration.

  4. Mutations in regulatory genes: Mutations in genes like ramR can lead to increased expression of efflux pumps and decreased susceptibility to ertapenem.

Understanding these mechanisms is crucial for developing strategies to combat resistance and preserve the efficacy of ertapenem.

Adverse Effects

Ertapenem is generally well-tolerated, but some patients may experience side effects:

Common Side Effects:

  • Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain

  • Central nervous system: Headache, dizziness

  • Injection site reactions: Pain, redness, swelling

Serious Adverse Effects:

  • Allergic reactions: Rash, pruritus, anaphylaxis

  • Seizures: Particularly in patients with predisposing factors

  • Clostridioides difficile-associated diarrhea: Due to disruption of normal gut flora

Patients should be monitored for these adverse effects, and therapy should be adjusted accordingly.

Drug Interactions

Ertapenem may interact with other medications:

  • Probenecid: Inhibits renal excretion of ertapenem, increasing its plasma concentration.

  • Valproic acid: Co-administration may decrease valproic acid levels, increasing the risk of seizures.

Clinicians should review a patient's medication list to avoid potential interactions.

Dosage and Administration

Adults:

  • Standard dose: 1 gram once daily, administered IV or IM

Pediatric Patients (3 months to 17 years):

  • Dose: 15 mg/kg once daily (maximum 1 gram), administered IV

Dosage adjustments may be necessary for patients with renal impairment.

Use in Special Populations

Renal Impairment:

  • Moderate to severe impairment (CrCl <30 mL/min): Dose adjustment is recommended.

  • Hemodialysis patients: Ertapenem should be administered after dialysis sessions.

Hepatic Impairment:

  • No dosage adjustment is necessary.

Pregnancy and Lactation:

  • Pregnancy Category B: No adequate studies in pregnant women; use only if clearly needed.

  • Lactation: It is unknown whether ertapenem is excreted in human milk; caution is advised.

Conclusion

Ertapenem is a valuable antibiotic in the treatment of various infections caused by susceptible bacteria. Its once-daily dosing, broad-spectrum activity, and favorable pharmacokinetics make it a convenient option for both inpatient and outpatient settings. However, the emergence of resistance underscores the importance of antimicrobial stewardship and appropriate use. Ongoing research and surveillance are essential to preserve the efficacy of ertapenem and other critical antibiotics.