Mechanism of Action and Pharmacokinetics
Chemically, gentamicin is a polar hydrophilic compound consisting of amino sugars linked via glycosidic bonds to an aminocyclitol ring. In nature, it is produced by actinomycetes of the genus Micromonospora (hence the suffix "-mycin").
Its mechanism of action involves the inhibition of protein synthesis. Transport of the drug to its intracellular target (the 30S ribosomal subunit) occurs in two steps: passive diffusion through the bacterial cell wall and active transport across the cytoplasmic membrane.
Pharmacokinetics:
- The average volume of distribution ($V_d$) is approximately 15 L, which anatomically corresponds to the extracellular fluid volume (plasma plus interstitial fluid).
- Being a hydrophilic substance, gentamicin crosses capillary endothelium but does not penetrate cell membranes. Consequently, it does not enter host cells and is completely ineffective against intracellular infections.
- It does not cross the blood-brain barrier (BBB), making it ineffective for the treatment of bacterial meningitis.
- It is excreted unchanged by the kidneys. Renal impairment leads to drug cumulation (accumulation), sharply increasing the risk of toxicity.
Pharmacological Effects and Spectrum
Gentamicin is a potent antibiotic targeted at severe infections.
- It exhibits high efficacy against Gram-negative bacteria, most notably Pseudomonas aeruginosa.
- It is effective in tularemia.
- Important distinction from 1st-generation aminoglycosides: It has virtually no activity against Mycobacterium tuberculosis (unlike Streptomycin and Kanamycin).
Indications
Systemic Administration (Intramuscular, Intravenous): Indicated for severe infections caused by Gram-negative bacteria resistant to other antibiotics:
- Sepsis and infective endocarditis.
- Severe pneumonia.
- Complicated abdominal and urogenital infections.
- Brucellosis (used in combination with first-line drugs such as tetracyclines).
Topical Application:
- Surgery and Dermatology: Treatment of infected soft tissue wounds and burns (0.1% ointment topically).
- Ophthalmology: Bacterial eye infections such as blepharitis, keratitis, keratoconjunctivitis, and iridocyclitis (0.3% eye drops and 0.1% eye ointment).
Adverse Effects and Contraindications
Adverse effects of gentamicin can occur even at therapeutic doses and severely limit its clinical utility.
- The primary danger, typical of the entire aminoglycoside class, is ototoxicity (hearing loss).
- The risk of toxicity increases manifold in systemic excretory organ diseases (renal failure) due to reduced clearance and drug accumulation.
- Cardiovascular and pulmonary pathologies can cause hemodynamic alterations, which distort the drug's distribution profile within the body.
Drug Interactions
The cell walls of certain bacteria (e.g., enterococci) are poorly permeable to aminoglycosides during monotherapy. In such cases, a combination with $eta$-lactam antibiotics is used.
This is a classic example of synergism (potentiation):
- $eta$-lactams disrupt bacterial cell wall synthesis.
- Wall permeability increases.
- Transport of gentamicin into the cell to the ribosomes is facilitated.
Examples: For enterococcal infections, gentamicin is combined with benzylpenicillin, and for Klebsiella infections, with antipseudomonal penicillins.
Formulations and Prescribing
The drug is available in several systemic and topical formulations. Dosages for intramuscular and intravenous administration are calculated by body weight (0.0004 g/kg).
- Powder in vials of 0.08 g.
- 4% solution in 1–2 ml ampoules.
- 0.1% eye ointment, 10–15 g.
- 0.3% eye drops solution (1–2 drops into the conjunctival sac).
- 0.1% topical ointment.
Example prescription for injectable solution: Rp.: Sol. Gentamycini sulfatis 4% - 2 ml D.t.d. N. 10 in ampull. S. Intramuscularly, 2 ml twice daily.
Example prescription for eye drops: Rp.: Sol. Gentamycini sulfatis 0,3% - 5 ml D.S. 1–2 drops into the conjunctival sac 3 times a day.