Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use; ATC code: J01BA01 Chloramphenicol is a broad-spectrum antibiotic. Usually bacteriostatic, chloramphenicol can be bactericidal at very high concentrations or against very sensitive microorganisms.
Chloramphenicol inhibits the protein synthesis of bacteria and to a lesser extent also that of eukaryotic cells. It acts by reversibly binding to the 50S subunit of the bacterial ribosome, thus inhibiting protein synthesis.
The generally sensitive microbial species (CMI 5 g / ml) are: Streptococci (groups A and B), Streptococcus pneumoniae (Pneumococcus), Neisseria gonorrhoeae (Gonococcus), Neisseria meningitis (Meningococcus); Bacillus subtilis, Corynebacterium, Listeria; Salmonella, Shigella, Brucella, Pasteurella, Haemophilus, Compybacter, Vibrio; Anaerobes (Bacterioides, Clostridium, Fusobacterium, Aeromonas); Rickettsial, Mycoplasma, Chlamydiae. The microbial species that are not always sensitive: Staphylococci, Enterococci, Colibacilli, Klebsiella, Proteus.
On the other hand, the following species are resistant (CMI 25 g / ml): Serratia, Acinetobacter, Pseudomonas.
The main mechanism of bacterial chemoresistance to chloramphenicol for gram-negative species consists in the enzymatic acetylation of the molecule, mediated by an R factor. This resistance has the characteristic of intra- and interspecies transferability. Resistance to chloramphenicol is also plasmid-mediated for gram-positive bacteria. A single plasmid can confer resistance to several antibiotics; for example, in case of salmonella, resistance extends to tetracyclines, streptomycin and sulfonamides. Cross-resistance to thiamphenicol may occur. Pseudomonas aeruginosa and some strains of Proteus and Klebsiella resist chloramphenicol with a non-enzymatic mechanism which includes an inducible blocking of permeability.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Chloramphenicol sodium succinate, administered parenterally, is hydrolysed in the liver, lungs and kidneys. The hydrolysis of chloramphenicol succinate is only partial, so that the blood concentration of chloramphenicol after parenteral administration is lower than that obtained after oral administration.


Distribution
Chloramphenicol spreads rapidly, however its distribution is not uniform. The highest concentrations are found in the liver and kidney; the lowest concentrations are found in the brain and cerebrospinal fluid. Chloramphenicol penetrates into the cerebrospinal fluid even in the absence of the meninx inflammatory state and reaches concentrations about half of those found in the blood. Measurable levels are also detected in pleural and ascitic fluids, saliva, milk, and aqueous and vitreous humors. Furthermore, chloramphenicol crosses the placental barrier.


The volume of distribution is 0.5-1 l/kg.
50%-80% of the dose is bound to plasma proteins.

Metabolism
Chloramphenicol is rapidly metabolised at hepatic level, mostly in derivates with glucuronic acid, microbiologically inactive, which are rapidly excreted by the kidney. It should be taken into consideration that in neonates the capacity for glucuronidation and renal elimination is very limited.


Elimination
Chloramphenicol is mainly excreted in the urine (90%) as a conjugate of glucuronic acid and, in a small amount, in unchanged form. Small amounts are excreted in bile (2-3%) and in faeces (1%).
The plasma half-life varies from 1.5 to 5 hours.
In patients with kidney impairment, the half-life varies from 3 to 7 hours.
In patients with reduced renal function, the half-life is generally prolonged, especially in patients with cirrhosis and jaundice.
The half-life of chloramphenicol reaches up to 28 hours in newborns with very few days of life.