Carbapenems

Mechanism

💊 Generic and Commercial Names

Imipenem + Cilastatina (Tienam), Meropenem (Meronem), Ertapenem (Invanz).

🔬 Pharmacological Group

Beta-lactámicos. Carbapenémicos de espectro ultra-amplio y de espectro acotado de vida media larga (Ertapenem).

Mechanism of Action

Poseen una conformación trans del anillo de hidroxietilo que bloquea de forma estricta el acceso de las betalactamasas comunes:

• Unión de Máxima Afinidad a PBPs Críticas: Meropenem e Imipenem se unen con extraordinaria afinidad y rapidez a la PBP2 de Gram-negativos entéricos, induciendo la formación inmediata de esferoplastos inestables que experimentan lisis celular rápida sin requerir una fase de elongación intermedia.
• Papel de la Cilastatina con Imipenem: Imipenem es vulnerable a la inactivación metabólica hidrolítica mediada por la enzima deshidropeptidasa renal de tipo I (DHP-I), expresada en el borde en cepillo de los túbulos contorneados proximales. La Cilastatina es un inhibidor selectivo dural de la DHP-I, carente de actividad antimicrobiana, que se coadministra en proporción 1:1 con el imipenem para prevenir su degradación renal y bloquear la nefrotoxicidad local de los metabolitos hidrolíticos de desecho.
• El Perfil No-Pseudomonas de Ertapenem: Ertapenem posee un grupo ácido carboxílico polar en su anillo lateral que incrementa de forma masiva su unión a proteínas plasmáticas (prolongando su vida media), pero le impide atravesar las porinas de Pseudomonas aeruginosa y Acinetobacter baumannii, perdiendo toda actividad contra estos agentes nosocomiales.

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.