Carbapenems

Mechanism

💊 Generic and Commercial Names

Imipenem + cilastatin (Tienam), meropenem (Meronem), ertapenem (Invanz).

🔬 Pharmacological Group

Beta-lactams. Ultra-broad-spectrum carbapenems and a narrower-spectrum, long-half-life carbapenem (ertapenem).

Mechanism of Action

They have a trans conformation of the hydroxyethyl group that strictly blocks access by common beta-lactamases:

• Highest-Affinity Binding to Critical PBPs: Meropenem and Imipenem bind with extraordinary affinity and rapidity to the PBP2 of enteric Gram-negatives, inducing the immediate formation of unstable spheroplasts that undergo rapid cell lysis without requiring an intermediate elongation phase.
• Role of Cilastatin with Imipenem: Imipenem is susceptible to hydrolytic metabolic inactivation mediated by the enzyme renal dehydropeptidase type I (DHP-I), expressed in the brush border of the proximal convoluted tubules. Cilastatin is a selective inhibitor of DHP-I, lacking antimicrobial activity, which is co-administered in a 1:1 ratio with imipenem to prevent its renal degradation and block local nephrotoxicity of hydrolytic waste metabolites.
• The Non-Pseudomonal Profile of Ertapenem: Ertapenem has a polar carboxylic acid group in its lateral ring that massively increases its binding to plasma proteins (prolonging its half-life), but prevents it from crossing the porins of Pseudomonas aeruginosa and Acinetobacter baumannii, losing all activity against these nosocomial agents.

Pharmacokinetics

Key Pharmacokinetics

Antimicrobial Spectrum

• Imipenem / Meropenem: They cover almost all Gram-positive pathogens (except MRSA and resistant enterococci), Gram-negative including ESBL and AmpC producers, anaerobes of all types, and with robust coverage of Pseudomonas aeruginosa. Vulnerable only to metallo-beta-lactamases (Class B) and carbapenemases of the KPC or OXA-48 type.
• Ertapenem: Identical spectrum to that of meropenem for community Enterobacteriaceae and dural anaerobes, but with an absolute gap in coverage against the non-fermenting group (does not cover Pseudomonas spp. nor Acinetobacter spp.)..

Indicators and dose

Dosage and Adjustment

• Imipenem/Cilastatin: 500 mg to 1 g every 6 to 8 hours IV (maximum dose 4 g/day).
• Meropenem: 1 to 2 g every 8 hours by IV route (in nosocomial meningitis it is dosed strictly at 2 g every 8 hours).
• Ertapenem: 1 g every 24 hours IV or IM.
• Adjustment of Meropenem in Renal Failure:
  • Cl_cr 26-50 mL/min: Administer standard doses every 12 hours.
  • Cl_cr 10-25 mL/min: Administer 50% of the standard dose every 12 hours.
  • Cl_cr < 10 mL/min: Administer 50% of the standard dose every 24 hours.

Security

Contraindications and ADRs

• Contraindications: Proven severe allergy to carbapenems.
• Adverse Effects (ADR):
  • Cortical Seizures (Dose-dependent): Imipenem lowers the seizure threshold by competitively binding and blocking the dural gamma-aminobutyric acid (GABA_A) receptor in the CNS. This risk is significantly higher with Imipenem compared to Meropenem, favored by systemic accumulation in renal failure and a history of pre-existing brain lesions.
  • Transient myelotoxicity: Reversible neutropenia and isolated thrombocytopenia.

High Risk Interaction of Carbapenems with Valproic Acid

Coadministration of any carbapenem with valproic acid causes a sudden and irreversible drop in serum concentrations of the anticonvulsant in the first 24-48 hours (reductions of 60 to 90% of basal levels), which precipitates repeated epileptic seizures and status epilepticus. The mechanism combines the inhibition of hydrolysis of the valproate-glucuronide metabolite and the increase in biliary excretion of valproate. This interaction cannot be corrected by increasing the dose of valproate, so concomitant use is absolutely prohibited.