Pharmacotherapeutic group: Antibacterials for systemic use, gentamicin.
ATCvet code: QJ01GB03
Pharmacodynamic properties
Gentamicin sulphate exerts concentration-dependent bacterial killing characteristics. Their rate of killing increases as the gentamicin concentration increases above the minimum concentration (MIC) for a given Gram-negative pathogen, with optimal maximum serum concentration (Cmax) to MIC ratio of 8-10.
Gentamicin sulphate is bactericidal in action by irreversibly binding to 30S ribosomal subunits, and acts through two different mechanisms. In one mechanism, gentamicin can interfere with the correct amino acid polymerisation and elongation. This mechanism takes place at high concentrations. Another mechanism predominates at low concentrations in which amino acid codons are misread by tRNA and proof-reading is impaired. This leads to incorrect amino acid sequencing and nonsense proteins. The substance is highly polar, hydrophilic and transport appears to be an active process closely linked to electron transport, oxidative phosphorylation and the respiratory quinones in the cell membrane. Gentamicin is primarily distributed within extracellular fluids. Gentamicin does not distribute to the cerebrospinal fluid.
Gentamicin is best considered as a narrow-spectrum Gram-negative bactericidal antimicrobial (e.g. E. Coli, Proteus, Pseudomonas). Gentamicin does not have effects on anaerobe bacteria and mycoplasmas. Gentamicin does not penetrate intracellularly, or into abscesses. Gentamicin is deactivated in the presence of inflammatory debris, low oxygen environments and low pH. Gentamicin is eliminated unchanged by the kidney via glomerular filtration, including 85-95% of the dose.
There are several mechanisms by which various strains of bacteria have developed resistance against aminoglycosides like gentamicin. Enzymatic modification is the most common type of aminoglycoside resistance. Over 50 different enzymes have been identified. Enzymatic modification results in high level resistance. The genes encoding for aminoglycoside modifying enzymes are usually found on plasmids and transposons.
There are three types of aminoglycoside modifying enzymes:
1. N-Acetyltransferases (AAC) - catalyses acetyl CoA-dependent acetylation of an amino group
2. O-Adenyltransferases (ANT) - catalyses ATP-dependent adenylation of hydroxyl group
3. O-Phosphotransferases (APH) - catalyses ATP-dependent phosphorylation of a hydroxyl group
Two other mechanisms of resistance include ribosomal mutations of the binding site of aminoglycosides, the 30S subunit and the bacteria decreasing the permeability of aminoglycosides.
Pharmacokinetic properties
Gentamicin sulphate is poorly absorbed from the gastrointestinal tract thus the product must be administered parenterally for systemic action. It appears in the synovial and peritoneal fluids but effective levels are not reached in CSF, bronchial secretions, ocular fluids or milk. Elimination is mainly by glomerular filtration and it rapidly appears in the urine.
Gentamicin is a highly polar drug with poor tissue penetration; it distributes mainly into extracellular fluids.