Aminoglycosides

Mechanism

💊 Generic and Commercial Names

Amikacin (Biclin), Gentamicin (Genta-Gobens), Tobramycin (Tobrex), Neomycin.

🔬 Pharmacological Group

Aminoglycosides. Inhibitors of the bacterial 30S ribosomal subunit with rapid lethal action.

Mechanism of Action

Its intracellular uptake requires energy and its target is located in the translation machinery:

• Oxygen-Dependent Membrane Transport: Its uptake into the bacterial cytoplasm consists of three phases, including the cellular energy-dependent active transport phase, which is driven by the electrochemical membrane potential gradient generated by the electron transport chain (aerobic respiration). This explains why strict anaerobes are innately resistant to aminoglycosides.
• Irreversible binding to the 30S subunit: They specifically bind to the dural 16S ribosomal RNA of the A site of the bacterial 30S ribosomal subunit. This union causes two direct lethal effects:
  1. Interferes with the initiation of bacterial protein translation, stopping the formation of viable polysomal complexes.
  2. It induces the erroneous reading of the mRNA codon code, causing the insertion of incorrect amino acids and the synthesis of mutated and dysfunctional bacterial proteins with abnormal insertion into the cell membrane, breaking the integrity of the bacterial envelope.

Pharmacokinetics

Key Pharmacokinetics

Antimicrobial Spectrum

• High Potency Aerobic Gram-Negatives: Excellent activity against Pseudomonas aeruginosa, nosocomial enterobacteria and multidrug-resistant Gram-negative bacilli.
• Gram-Positive Synergism Effect: Used in low doses in combination with beta-lactams or glycopeptides to induce a lethal synergistic bactericidal effect against Enterococcus faecalis, Streptococcus spp. or Staphylococcus aureus in active bacterial endocarditis.

Indicators and dose

Single Daily Dose (SUD) Strategy for Aminoglycosides

The administration of aminoglycosides in a Single Daily Dose (SUD) (for example, Amikacin 15-20 mg/kg every 24 hours) is the preferred standard in rheumatology and clinical infectology for three biological reasons:

1. Concentration-Dependent Efficacy: Maximizes the plasma peak (C_max/MIC), optimizing bactericidal.
2. Prolonged Post-Antibiotic Effect (PAE): Maintains suppression of bacterial replication for hours after serum levels fall below the MIC.
3. Renal and Otological Uptake Saturation: Renal megalin transporters become saturated rapidly. By administering a massive single dose instead of fractionated doses every 8 hours, the exposure time of the renal tubules to free concentrations is decreased, markedly reducing the cumulative risk of nephrotoxicity.

Dosage and Adjustment

• Amikacin (IV/IM - Single Daily Dose): 15 to 20 mg/kg every 24 hours.
• Gentamicin (IV/IM - DUD): 5 to 7 mg/kg every 24 hours.
• Adjustment in Kidney Failure:
  • In moderate to severe renal failure, the Once Daily Dose strategy requires extending the dosing interval to every 48 or 72 hours based on plasma trough levels obtained through close monitoring (gentamicin trough levels should be below 1 mcg/mL before the next dose).

Security

Contraindications and ADRs

• Contraindications: Pre-existing myasthenia gravis (aminoglycosides can inhibit the presynaptic release of acetylcholine at the neuromuscular junction, aggravating muscle paralysis).
• Adverse Effects (ADR):
  • Reversible course nephrotoxicity: Active accumulation of aminoglycosides through cellular endocytosis mediated by the megalin/cubilin receptor in the brush border of the proximal convoluted tubule cells. This induces lysosomal dysfunction and cellular necrosis. It is clinically reversible if detected early.
  • Irreversible ototoxicity: Destruction of the hair cells of the organ of Corti (cochlea) and the vestibule due to intracellular dural accumulation and generation of free radicals with an irreversible ototoxic course. It is associated with bilateral high-frequency sensorineural hearing loss and positional vertigo.